The "Ad Circulorum" Fallacy and Comparative Advantage Debating or: Why Don't Debate Cases Make Sense to Outside Listeners?

ERIC Educational Resources Information Center

Richardson, Larry S.

Circular reasoning is often employed in comparative advantage debate cases when only a plan and advantages are articulated without adequate reference to the resolution which inspired the proposal. The advancing of such subtopical analyses as debate cases is deleterious to the long-range interests of educational debate because the practice…

Using the Disease State Fingerprint Tool for Differential Diagnosis of Frontotemporal Dementia and Alzheimer's Disease

PubMed Central

Muñoz-Ruiz, Miguel Ángel; Hall, Anette; Mattila, Jussi; Koikkalainen, Juha; Herukka, Sanna-Kaisa; Husso, Minna; Hänninen, Tuomo; Vanninen, Ritva; Liu, Yawu; Hallikainen, Merja; Lötjönen, Jyrki; Remes, Anne M.; Alafuzoff, Irina; Soininen, Hilkka; Hartikainen, Päivi

2016-01-01

Background Disease State Index (DSI) and its visualization, Disease State Fingerprint (DSF), form a computer-assisted clinical decision making tool that combines patient data and compares them with cases with known outcomes. Aims To investigate the ability of the DSI to diagnose frontotemporal dementia (FTD) and Alzheimer's disease (AD). Methods The study cohort consisted of 38 patients with FTD, 57 with AD and 22 controls. Autopsy verification of FTD with TDP-43 positive pathology was available for 14 and AD pathology for 12 cases. We utilized data from neuropsychological tests, volumetric magnetic resonance imaging, single-photon emission tomography, cerebrospinal fluid biomarkers and the APOE genotype. The DSI classification results were calculated with a combination of leave-one-out cross-validation and bootstrapping. A DSF visualization of a FTD patient is presented as an example. Results The DSI distinguishes controls from FTD (area under the receiver-operator curve, AUC = 0.99) and AD (AUC = 1.00) very well and achieves a good differential diagnosis between AD and FTD (AUC = 0.89). In subsamples of autopsy-confirmed cases (AUC = 0.97) and clinically diagnosed cases (AUC = 0.94), differential diagnosis of AD and FTD performs very well. Conclusions DSI is a promising computer-assisted biomarker approach for aiding in the diagnostic process of dementing diseases. Here, DSI separates controls from dementia and differentiates between AD and FTD. PMID:27703465

Association of the apolipoprotein E {epsilon}4 allele with clinical subtypes of autopsy-confirmed Alzheimer`s Disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zubenko, G.S.; Stiffler, S.; Kopp, U.

1994-09-15

Consistent with previous reports, we observed a significant association of the APOE {epsilon}4 allele with Alzheimer`s Disease (AD) in a series of 91 autopsy-confirmed cases. The {epsilon}4 allele frequency was higher in cases with a family history of AD-like dementia (0.54 {+-} 0.07), although the {epsilon}4 allele frequency in the AD cases with a negative family history (0.38 {+-} 0.05) remained significantly greater than that for the non-AD control group (0.13 {+-} 0.03). A similar increase in {epsilon}4 allele frequency (0.54 {+-} 0.07) was observed in the AD cases with amyloid angiopathy, compared to those who did not have amyloidmore » angiopathy (0.35 {+-} 0.04). Contrary to previous reports, no effect of the dosage of the {epsilon}4 allele was found on the age of onset of dementia among the AD cases and, contrary to reports suggesting an association of {epsilon}4 and atherosclerosis, the {epsilon}4 allele frequency was similar in cases with or without concurrent brain infarcts. Modest but consistent correlations were observed between the dosage of {epsilon}4 alleles and the cortical density of senile plaques, but not neurofibrillary tangles. The last finding suggests that the pathogenic events mediated by the {epsilon}4 allele may be more directly involved in the formation of senile plaques, the identifying lesions in AD, than neurofibrillary tangles. A robust association of both the presence of an {epsilon}4 allele and a family history of AD-like dementia with concurrent amyloid angiopathy occurred within our sample of AD cases. This association arose from an interaction of the {epsilon}4 allele with a separate familial factor for which a family history of dementia served as a surrogate. These results suggest that amyloid angiopathy may be a common or central feature of a form of familial AD that is associated with the transmission of the APOE {epsilon}4 allele. 22 refs., 2 figs., 5 tabs.« less

Cost-effectiveness of liraglutide versus lixisenatide as add-on therapies to basal insulin in type 2 diabetes

PubMed Central

2018-01-01

Background We assessed the cost-effectiveness of the glucagon-like peptide 1 receptor agonists liraglutide 1.8 mg and lixisenatide 20 μg (both added to basal insulin) in patients with type 2 diabetes (T2D) in Sweden. Methods The Swedish Institute for Health Economics cohort model for T2D was used to compare liraglutide and lixisenatide (both added to basal insulin), with a societal perspective and with comparative treatment effects derived by indirect treatment comparison (ITC). Drug prices were 2016 values, and all other costs 2015 values. The cost-effectiveness of IDegLira (fixed-ratio combination of insulin degludec and liraglutide) versus lixisenatide plus basal insulin was also assessed, under different sets of assumptions. Results From the ITC, decreases in HbA1c were –1.32% and –0.43% with liraglutide and lixisenatide, respectively; decreases in BMI were –1.29 and –0.65 kg/m2, respectively. An estimated 2348 cases of retinopathy, 265 of neuropathy and 991 of nephropathy would be avoided with liraglutide compared with lixisenatide in a cohort of 10,000 patients aged over 40 years. In the base-case analysis, total direct costs were higher with liraglutide than lixisenatide, but costs associated with complications were lower. The cost/quality-adjusted life-year (QALY) for liraglutide added to basal insulin was SEK30,802. Base-case findings were robust in sensitivity analyses, except when glycated haemoglobin (HbA1c) differences for liraglutide added to basal insulin were abolished, suggesting these benefits were driving the cost/QALY. With liraglutide 1.2 mg instead of liraglutide 1.8 mg (adjusted for efficacy and cost), liraglutide added to basal insulin was dominant over lixisenatide 20μg.IDegLira was dominant versus lixisenatide plus basal insulin when a defined daily dose was used in the model. Conclusions The costs/QALY for liraglutide, 1.8 or 1.2 mg, added to basal insulin, and for IDegLira (all compared with lixisenatide 20 μg added to basal insulin) were below the threshold considered low by Swedish authorities. In some scenarios, liraglutide and IDegLira were cost-saving. PMID:29408938

Cost-effectiveness of liraglutide versus lixisenatide as add-on therapies to basal insulin in type 2 diabetes.

PubMed

Ericsson, Åsa; Glah, Divina; Lorenzi, Maria; Jansen, Jeroen P; Fridhammar, Adam

2018-01-01

We assessed the cost-effectiveness of the glucagon-like peptide 1 receptor agonists liraglutide 1.8 mg and lixisenatide 20 μg (both added to basal insulin) in patients with type 2 diabetes (T2D) in Sweden. The Swedish Institute for Health Economics cohort model for T2D was used to compare liraglutide and lixisenatide (both added to basal insulin), with a societal perspective and with comparative treatment effects derived by indirect treatment comparison (ITC). Drug prices were 2016 values, and all other costs 2015 values. The cost-effectiveness of IDegLira (fixed-ratio combination of insulin degludec and liraglutide) versus lixisenatide plus basal insulin was also assessed, under different sets of assumptions. From the ITC, decreases in HbA1c were -1.32% and -0.43% with liraglutide and lixisenatide, respectively; decreases in BMI were -1.29 and -0.65 kg/m2, respectively. An estimated 2348 cases of retinopathy, 265 of neuropathy and 991 of nephropathy would be avoided with liraglutide compared with lixisenatide in a cohort of 10,000 patients aged over 40 years. In the base-case analysis, total direct costs were higher with liraglutide than lixisenatide, but costs associated with complications were lower. The cost/quality-adjusted life-year (QALY) for liraglutide added to basal insulin was SEK30,802. Base-case findings were robust in sensitivity analyses, except when glycated haemoglobin (HbA1c) differences for liraglutide added to basal insulin were abolished, suggesting these benefits were driving the cost/QALY. With liraglutide 1.2 mg instead of liraglutide 1.8 mg (adjusted for efficacy and cost), liraglutide added to basal insulin was dominant over lixisenatide 20μg.IDegLira was dominant versus lixisenatide plus basal insulin when a defined daily dose was used in the model. The costs/QALY for liraglutide, 1.8 or 1.2 mg, added to basal insulin, and for IDegLira (all compared with lixisenatide 20 μg added to basal insulin) were below the threshold considered low by Swedish authorities. In some scenarios, liraglutide and IDegLira were cost-saving.

Metaphor Comprehension in Alzheimer's Disease: Novelty Matters

ERIC Educational Resources Information Center

Amanzio, Martina; Geminiani, Giuliano; Leotta, Daniela; Cappa, Stefano

2008-01-01

The comprehension of non-literal language was investigated in 20 probable Alzheimer's disease (pAD) patients by comparing their performance to that of 20 matched control subjects. pAD patients were unimpaired in the comprehension of conventional metaphors and idioms. However, their performance was significantly lower in the case of…

Added Diagnostic Value of Cerebrospinal Fluid Biomarkers for Differential Dementia Diagnosis in an Autopsy-Confirmed Cohort.

PubMed

Niemantsverdriet, Ellis; Feyen, Bart F E; Le Bastard, Nathalie; Martin, Jean-Jacques; Goeman, Johan; De Deyn, Peter Paul; Bjerke, Maria; Engelborghs, Sebastiaan

2018-01-01

Differential dementia diagnosis remains a challenge due to overlap of clinical profiles, which often results in diagnostic doubt. Determine the added diagnostic value of cerebrospinal fluid (CSF) biomarkers for differential dementia diagnosis as compared to autopsy-confirmed diagnosis. Seventy-one dementia patients with autopsy-confirmed diagnoses were included in this study. All neuropathological diagnoses were established according to standard neuropathological criteria and consisted of Alzheimer's disease (AD) or other dementias (NONAD). CSF levels of Aβ1 - 42, T-tau, and P-tau181 were determined and interpreted based on the IWG-2 and NIA-AA criteria, separately. A panel of three neurologists experienced with dementia made clinical consensus dementia diagnoses. Clinical and CSF biomarker diagnoses were compared to the autopsy-confirmed diagnoses. Forty-two patients (59%) had autopsy-confirmed AD, whereas 29 patients (41%) had autopsy-confirmed NONAD. Of the 24 patients with an ambiguous clinical dementia diagnosis, a correct diagnosis would have been established in 67% of the cases applying CSF biomarkers in the context of the IWG-2 or the NIA-AA criteria respectively. AD CSF biomarkers have an added diagnostic value in differential dementia diagnosis and can help establishing a correct dementia diagnosis in case of ambiguous clinical dementia diagnoses.

Interaction between Cytomegalovirus and Herpes Simplex Virus Type 1 Associated with the Risk of Alzheimer's Disease Development.

PubMed

Lövheim, Hugo; Olsson, Jan; Weidung, Bodil; Johansson, Anders; Eriksson, Sture; Hallmans, Göran; Elgh, Fredrik

2018-01-01

Several environmental factors, including infectious agents, have been suggested to cause Alzheimer's disease (AD). Cytomegalovirus (CMV) has been associated with AD in several recent studies. To investigate whether carriage of CMV, alone or in combination with Herpes simplex virus (HSV), increased the risk of developing AD. Plasma samples from 360 AD cases (75.3% women, mean age 61.2 years), taken an average of 9.6 years before AD diagnosis, and 360 age-, sex-, cohort-, and sampling date matched dementia-free controls were analyzed to detect anti-CMV (immunoglobulin [Ig] G and IgM), group-specific anti-HSV (IgG and IgM), and specific anti-HSV1 and HSV2 IgG antibodies by enzyme-linked immunosorbent assays. AD cases and dementia-free controls were compared using conditional logistic regression analyses. The presence of anti-CMV IgG antibodies did not increase the risk of AD (odds ratio [OR], 0.857; p = 0.497). Among AD cases, an association between CMV and HSV1 carriage was detected (OR 7.145, p < 0.001); in a conditional logistic regression model, the interaction between CMV and HSV1 was associated with AD development (OR 5.662; p = 0.007). The present findings do not support a direct relationship between CMV infection and the development of AD; however, an interaction between CMV and HSV1 was found to be associated significantly with AD development. These findings suggest that CMV infection facilitates the development of HSV1-associated AD, possibly via its effects on the immune system.

Rarity of the Alzheimer Disease–Protective APP A673T Variant in the United States

PubMed Central

Wang, Li-San; Naj, Adam C.; Graham, Robert R.; Crane, Paul K.; Kunkle, Brian W.; Cruchaga, Carlos; Gonzalez Murcia, Josue D.; Cannon-Albright, Lisa; Baldwin, Clinton T.; Zetterberg, Henrik; Blennow, Kaj; Kukull, Walter A.; Faber, Kelley M.; Schupf, Nicole; Norton, Maria C.; Tschanz, JoAnn T.; Munger, Ronald G.; Corcoran, Christopher D.; Rogaeva, Ekaterina; Lin, Chiao-Feng; Dombroski, Beth A.; Cantwell, Laura B.; Partch, Amanda; Valladares, Otto; Hakonarson, Hakon; St George-Hyslop, Peter; Green, Robert C.; Goate, Alison M.; Foroud, Tatiana M.; Carney, Regina M.; Larson, Eric B.; Behrens, Timothy W.; Kauwe, John S. K.; Haines, Jonathan L.; Farrer, Lindsay A.; Pericak-Vance, Margaret A.; Mayeux, Richard; Schellenberg, Gerard D.

2015-01-01

IMPORTANCE Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States. OBJECTIVE To determine the frequency of the APP A673T variant in a large group of elderly cognitively normal controls and AD cases from the United States and in 2 case-control cohorts from Sweden. DESIGN, SETTING, AND PARTICIPANTS Case-control association analysis of variant APP A673T in US and Swedish white individuals comparing AD cases with cognitively intact elderly controls. Participants were ascertained at multiple university-associated medical centers and clinics across the United States and Sweden by study-specific sampling methods. They were from case-control studies, community-based prospective cohort studies, and studies that ascertained multiplex families from multiple sources. MAIN OUTCOMES AND MEASURES Genotypes for the APP A673T variant were determined using the Infinium HumanExome V1 Beadchip (Illumina, Inc) and by TaqMan genotyping (Life Technologies). RESULTS The A673T variant genotypes were evaluated in 8943 US AD cases, 10 480 US cognitively normal controls, 862 Swedish AD cases, and 707 Swedish cognitively normal controls. We identified 3 US individuals heterozygous for A673T, including 1 AD case (age at onset, 89 years) and 2 controls (age at last examination, 82 and 77 years). The remaining US samples were homozygous for the alanine (A673) allele. In the Swedish samples, 3 controls were heterozygous for A673T and all AD cases were homozygous for the A673 allele. We also genotyped a US family previously reported to harbor the A673T variant and found a mother-daughter pair, both cognitively normal at ages 72 and 84 years, respectively, who were both heterozygous for A673T; however, all individuals with AD in the family were homozygous for A673. CONCLUSIONS AND RELEVANCE The A673T variant is extremely rare in US cohorts and does not play a substantial role in risk for AD in this population. This variant may be primarily restricted to Icelandic and Scandinavian populations. PMID:25531812

Implementing an advance care planning program in German nursing homes: results of an inter-regionally controlled intervention trial.

PubMed

In der Schmitten, Jürgen; Lex, Katharina; Mellert, Christine; Rothärmel, Sonja; Wegscheider, Karl; Marckmann, Georg

2014-01-24

Advance Care Planning (ACP) is a systematic approach to ensure that effective advance directives (ADs) are developed and respected. We studied the effects of implementing a regional ACP program in Germany. In a prospective, inter-regionally controlled trial focusing on nursing homes (n/hs), we compared the number, relevance and validity of new ADs completed in the intervention region versus the control region. Intervention n/h residents and their families were offered professional facilitation including standardized documentation. Data from 136 residents of three intervention n/hs were compared with data from 439 residents of 10 control n/hs over a study period of 16.5 months. In the intervention region, 49 (36.0%) participating residents completed a new AD over the period of the study, compared to 18 (4.1%) in the control region; these ADs included 30 ADs by proxy in the intervention region versus 10 in the control region. Proxies were designated in 94.7% versus 50.0% of cases, the AD was signed by a physician in 93.9% versus 16.7%, and an emergency order was included in 98.0% versus 44.4%. Resuscitation status was addressed in 95.9% versus 38.9% of cases (p<0.01 for all of the differences mentioned above). In the intervention region, new ADs were preceded by an average of 2.5 facilitated conversations (range, 2–5) with a mean total duration of 100 minutes (range, 60–240 minutes). The implementation of an ACP program in German nursing homes led, much more frequently than previously reported, to the creation of advance directives with potential relevance to medical decision-making. Future research should assess the effect of such programs on clinical and structural outcomes.

Elevated serum pesticide levels and risk for Alzheimer disease.

PubMed

Richardson, Jason R; Roy, Ananya; Shalat, Stuart L; von Stein, Richard T; Hossain, Muhammad M; Buckley, Brian; Gearing, Marla; Levey, Allan I; German, Dwight C

2014-03-01

The causes of late-onset Alzheimer disease (AD) are not yet understood but likely include a combination of genetic, environmental, and lifestyle factors. Limited epidemiological studies suggest that occupational pesticide exposures are associated with AD. Previously, we reported that serum levels of dichlorodiphenyldichloroethylene (DDE), the metabolite of the pesticide dichlorodiphenyltrichloroethane (DDT), were elevated in a small number of patients with AD (n=20). To evaluate the association between serum levels of DDE and AD and whether the apolipoprotein E (APOE) genotype modifies the association. A case-control study consisting of existing samples from patients with AD and control participants from the Emory University Alzheimer's Disease Research Center and the University of Texas Southwestern Medical School's Alzheimer's Disease Center. Serum levels of DDE were measured in 79 control and 86 AD cases. Serum DDE levels, AD diagnosis, severity of AD measured by the Mini-Mental State Examination score, and interaction with APOE4 status. Levels of DDE were 3.8-fold higher in the serum of those with AD (mean [SEM], 2.64 [0.35] ng/mg cholesterol) when compared with control participants (mean [SEM], 0.69 [0.1] ng/mg cholesterol; P < .001). The highest tertile of DDE levels was associated with an odds ratio of 4.18 for increased risk for AD (95% CI, 2.54-5.82; P < .001) and lower Mini-Mental State Examination scores (-1.605; range, -3.095 to -0.114; P < .0001). The Mini-Mental State Examination scores in the highest tertile of DDE were -1.753 points lower in the subpopulation carrying an APOE ε4 allele compared with those carrying an APOE ε3 allele (P interaction = .04). Serum levels of DDE were highly correlated with brain levels of DDE (ρ = 0.95). Exposure of human neuroblastoma cells to DDT or DDE increased levels of amyloid precursor protein. Elevated serum DDE levels are associated with an increased risk for AD and carriers of an APOE4 ε4 allele may be more susceptible to the effects of DDE. Both DDT and DDE increase amyloid precursor protein levels, providing mechanistic plausibility for the association of DDE exposure with AD. Identifying people who have elevated levels of DDE and carry an APOE ε4 allele may lead to early identification of some cases of AD.

Candidate genes for alcohol dependence: A genetic association study from India.

PubMed

Malhotra, Savita; Basu, Debasish; Khullar, Madhu; Ghosh, Abhishek; Chugh, Neera

2016-11-01

Search for candidate genes for alcohol dependence (AD) has been inconsistent and inconclusive. Moreover, most of the research has been confined to a few specific ethnic groups. Hence, the aim of our study was to explore specific candidate genes for AD in north Indian male population. In this clinic-based genetic association study, 210 males with AD and 200 controls matched for age, gender and ethnicity were recruited from the clinic and the general population, respectively. Cases were diagnosed with Semi-structured Assessment for Genetics of Alcoholism-II (SSAGA-II). Single-nucleotide polymorphism genotyping was done by real-time quantitative-polymerase chain reaction (PCR) using Taq Man assay (ABI 7500) fast real-time PCR system. Both at the genotypic level and at allelic frequency, Met158 variant of catechol-O-methyl transferase (COMT) showed significant increase in cases as compared to controls. The frequency of heterozygous genotype (A/G) of gamma-aminobutyric acid receptor A1 (GABRA1) was significantly lower in cases as compared to controls. Likewise, for GABRA2, the frequency of homozygous recessive genotype (G/G) was significantly higher in the control group. With respect to the 5-hydroxytryptamine (5HT) transporter long promoter region (5HTTLPR), cholinergic receptor muscarinic (CHRM2) and alcohol dehydrogenase 1B (ADH1B) genes, there was no significant difference between the cases and the controls. Aldehyde dehydrogenase (ALDH2) gene was found to be monomorphic in our study population. Our study findings showed COMT polymorphism conferring risk and GABRA polymorphism as a protective genotype for Indian male with AD. Genes for alcohol metabolism, serotonin transporter and cholinergic receptor gene polymorphism were perhaps not contributory to AD for Indian population.

Seizures during antidepressant treatment in psychiatric inpatients--results from the transnational pharmacovigilance project "Arzneimittelsicherheit in der Psychiatrie" (AMSP) 1993-2008.

PubMed

Köster, M; Grohmann, R; Engel, R R; Nitsche, M A; Rüther, E; Degner, D

2013-11-01

There is little clinical data available about seizure rates in psychiatric inpatients, and there are no studies with reference data to the frequencies of antidepressant (AD) use for this important clinical population. This study investigates seizure rates during AD treatment in psychiatric inpatient settings, drawn from the transnational pharmacovigilance programme Arzneimittelsicherheit in der Psychiatrie (AMSP) in relation to the known frequencies of ADs used in the participating clinics. Comparisons are made to former publications and their limitations. Seventy-seven cases were identified with grand mal seizures (GMS) during AD treatment between 1993 and 2008, with a total number of 142,090 inpatients under surveillance treated with ADs in the participating hospitals. The calculated overall rate of reported seizures of patients during AD treatment in this collective is 0.05 % for ADs imputed alone or in combination with other psychotropic drug groups and 0.02 % when only ADs were given and held responsible for GMS. The patients receiving tri- or tetracyclic ADs (TCAs) had a 2-fold risk to develop a seizure as compared to the overall average rate in this sample. In 11 cases, there was only one AD imputed--the majority of these cases (9/11) were TCA. Monotherapy with selective serotonin reuptake inhibitors (SSRI) or dual serotonin and noradrenaline reuptake inhibitors (SNRI) were never imputed alone in this sample. The results of the study favour the assumption that SSRIs, noradrenergic and specific serotonergic antidepressants (NaSSA) and dual SNRI might be more appropriate than TCAs for the treatment of psychiatric patients with an enhanced seizure risk.

Neuropathological findings processed by artificial neural networks (ANNs) can perfectly distinguish Alzheimer's patients from controls in the Nun Study

PubMed Central

Grossi, Enzo; Buscema, Massimo P; Snowdon, David; Antuono, Piero

2007-01-01

Background Many reports have described that there are fewer differences in AD brain neuropathologic lesions between AD patients and control subjects aged 80 years and older, as compared with the considerable differences between younger persons with AD and controls. In fact some investigators have suggested that since neurofibrillary tangles (NFT) can be identified in the brains of non-demented elderly subjects they should be considered as a consequence of the aging process. At present, there are no universally accepted neuropathological criteria which can mathematically differentiate AD from healthy brain in the oldest old. The aim of this study is to discover the hidden and non-linear associations among AD pathognomonic brain lesions and the clinical diagnosis of AD in participants in the Nun Study through Artificial Neural Networks (ANNs) analysis Methods The analyses were based on 26 clinically- and pathologically-confirmed AD cases and 36 controls who had normal cognitive function. The inputs used for the analyses were just NFT and neuritic plaques counts in neocortex and hippocampus, for which, despite substantial differences in mean lesions counts between AD cases and controls, there was a substantial overlap in the range of lesion counts. Results By taking into account the above four neuropathological features, the overall predictive capability of ANNs in sorting out AD cases from normal controls reached 100%. The corresponding accuracy obtained with Linear Discriminant Analysis was 92.30%. These results were consistently obtained in ten independent experiments. The same experiments were carried out with ANNs on a subgroup of 13 non severe AD patients and on the same 36 controls. The results obtained in terms of prediction accuracy with ANNs were exactly the same. Input relevance analysis confirmed the relative dominance of NFT in neocortex in discriminating between AD patients and controls and indicated the lesser importance played by NP in the hippocampus. Conclusion The results of this study suggest that: a) cortical NFT represent the key variable in AD neuropathology; b) the neuropathologic profile of AD subjects is complex, however, c) ANNs can analyze neuropathologic features and differentiate AD cases from controls. PMID:17584929

Neuropathological findings processed by artificial neural networks (ANNs) can perfectly distinguish Alzheimer's patients from controls in the Nun Study.

PubMed

Grossi, Enzo; Buscema, Massimo P; Snowdon, David; Antuono, Piero

2007-06-21

Many reports have described that there are fewer differences in AD brain neuropathologic lesions between AD patients and control subjects aged 80 years and older, as compared with the considerable differences between younger persons with AD and controls. In fact some investigators have suggested that since neurofibrillary tangles (NFT) can be identified in the brains of non-demented elderly subjects they should be considered as a consequence of the aging process. At present, there are no universally accepted neuropathological criteria which can mathematically differentiate AD from healthy brain in the oldest old. The aim of this study is to discover the hidden and non-linear associations among AD pathognomonic brain lesions and the clinical diagnosis of AD in participants in the Nun Study through Artificial Neural Networks (ANNs) analysis The analyses were based on 26 clinically- and pathologically-confirmed AD cases and 36 controls who had normal cognitive function. The inputs used for the analyses were just NFT and neuritic plaques counts in neocortex and hippocampus, for which, despite substantial differences in mean lesions counts between AD cases and controls, there was a substantial overlap in the range of lesion counts. By taking into account the above four neuropathological features, the overall predictive capability of ANNs in sorting out AD cases from normal controls reached 100%. The corresponding accuracy obtained with Linear Discriminant Analysis was 92.30%. These results were consistently obtained in ten independent experiments. The same experiments were carried out with ANNs on a subgroup of 13 non severe AD patients and on the same 36 controls. The results obtained in terms of prediction accuracy with ANNs were exactly the same. Input relevance analysis confirmed the relative dominance of NFT in neocortex in discriminating between AD patients and controls and indicated the lesser importance played by NP in the hippocampus. The results of this study suggest that: a) cortical NFT represent the key variable in AD neuropathology; b) the neuropathologic profile of AD subjects is complex, however, c) ANNs can analyze neuropathologic features and differentiate AD cases from controls.

Energy modulated electron therapy using a few leaf electron collimator in combination with IMRT and 3D-CRT: Monte Carlo-based planning and dosimetric evaluation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Al-Yahya, Khalid; Schwartz, Matthew; Shenouda, George

2005-09-15

Energy modulated electron therapy (EMET) based on Monte Carlo dose calculation is a promising technique that enhances the treatment planning and delivery of superficially located tumors. This study investigated the application of EMET using a novel few-leaf electron collimator (FLEC) in head and neck and breast sites in comparison with three-dimensional conventional radiation therapy (3D-CRT) and intensity modulated radiation therapy (IMRT) techniques. Treatment planning was performed for two parotid cases and one breast case. Four plans were compared for each case: 3D-CRT, IMRT, 3D-CRT in conjunction with EMET (EMET-CRT), and IMRT in conjunction with EMET (EMET-IMRT), all of which weremore » performed and calculated with Monte Carlo techniques. For all patients, dose volume histograms (DVHs) were obtained for all organs of interest and the DVHs were used as a means of comparing the plans. Homogeneity and conformity of dose distributions were calculated, as well as a sparing index that compares the effect of the low isodose lines. In addition, the whole-body dose equivalent (WBDE) was estimated for each plan. Adding EMET delivered with the FLEC to 3D-CRT improves sparing of normal tissues. For the two head and neck cases, the mean dose to the contralateral parotid and brain stem was reduced relative to IMRT by 43% and 84%, and by 57% and 71%, respectively. Improved normal tissue sparing was quantified as an increase in sparing index of 47% and 30% for the head and neck and the breast cases, respectively. Adding EMET to either 3D-CRT or IMRT results in preservation of target conformity and dose homogeneity. When adding EMET to the treatment plan, the WBDE was reduced by between 6% and 19% for 3D-CRT and by between 21% and 33% for IMRT, while WBDE for EMET-CRT was reduced by up to 72% when compared with IMRT. FLEC offers a practical means of delivering modulated electron therapy. Although adding EMET delivered using the FLEC results in perturbation of target conformity when compared to IMRT, it significantly improves normal tissue sparing while offering enhanced target conformity to the 3D-CRT planning. The addition of EMET systematically leads to a reduction in WBDE especially when compared with IMRT.« less

Role of familial factors in late-onset Alzheimer disease as a function of age.

PubMed

Wu, Z; Kinslow, C; Pettigrew, K D; Rapoport, S I; Schapiro, M B

1998-09-01

Whereas early-onset Alzheimer disease (AD; usually onset at age < 50 years) has been defined with genetic mutation on chromosomes 1, 14, and 21, the degree of familial contribution to late-onset AD is unclear. Further, it is uncertain if subgroups of late-onset AD exist. To examine the influence of familial factors as a function of age in late-onset AD we investigated lifetime risks and age-specific hazard rates of AD-like illness among late-onset AD probands' and controls' first-degree relatives, using questionnaires and medical records. As part of a longitudinal study on aging and AD, we studied 78 AD probands with age of onset > or =50 years (28 "definite" and 50 "probable" AD according to NINCDS/ADRDA criteria) and 101 healthy old controls seen since 1981. Both probands and controls were screened rigorously with medical tests and brain imaging and seen regularly until autopsy. Multiple informants and medical records were used for first-degree relatives. Among first-degree relatives, 49 secondary cases of AD-like illness were found for the AD probands' relatives (391 relatives 40 years old or older) compared with 20 cases among controls' relatives (456 relatives 40 years old or older). Relatives of AD probands had a significantly increased lifetime risk of AD-like illness of 52.8+/-11.4% by age 94 years compared with a lifetime risk in relatives of controls of 22.1+/-5.8% by age 90 years. Age-specific hazard rates in relatives of AD probands increased until the 75-79-year age interval and then decreased; in contrast the age-specific hazard rates increased in relatives of controls after the 80-84-year age interval. To determine if a dividing line exist among late-onset AD, several cutoff ages were used in our study to compare cumulative risk curves of AD-like illness between relatives of late-onset probands and relatives of late-late-onset probands. Differences in the pattern of cumulative incidence of AD in relatives showed that 67-71 years is the range for a dividing line between late- and late-late-onset AD. Age-specific hazard rates of AD in relatives supported a difference between late- and late-late-onset. Whereas these rates increased until the 75-79-year age interval and then decreased in late-onset AD, the rates began increasing after the 65-69-year age interval and through the oldest age interval in both late-late-onset AD and control groups. Our results support the concept that familial factors exist in late-onset AD and that different familial factors may exist in late-onset AD subgroups.

Angiotensin Converting Enzyme Inhibitors and Alzheimer Disease in the Presence of the Apolipoprotein E4 Allele

PubMed Central

Qiu, Wendy Wei Qiao; Lai, Angela; Mon, Timothy; Mwamburi, Mkaya; Taylor, Warren; Rosenzweig, James; Kowall, Neil; Stern, Robert; Zhu, Haihao; Steffens, David C.

2013-01-01

Objective The effect of angiotensin converting enzyme (ACE) inhibitors on Alzheimer disease (AD) remains unclear, with conflicting results reported. We studied the interaction of the Apolipoprotein E (ApoE) genotype and ACE inhibitors on AD. Methods This was a cross-sectional study of homebound elderly with an AD diagnosis and documentation of medications taken. ApoE genotype was determined. Results A total of 355 subjects with status on ApoE alleles and cognitive diagnoses were studied. The average age (mean ± SD) of this population was 73.3 ± 8.3 years old, and 73% were female. Cross-sectionally, there was no difference in the number of AD cases between ApoE4 carriers and ApoE4 non-carriers or between ACE inhibitor users and non-users in the homebound elderly. ApoE4 carriers treated with ACE inhibitors, however, had more diagnoses of AD compared with those who did not have the treatment (28% versus 6%, p = 0.01) or ApoE4 non-carriers treated with an ACE inhibitor (28% versus 10%, p = 0.03). ACE inhibitor use was associated with AD diagnosis only in the presence of an E4 allele. Using multivariate logistic regression analysis, we found that in diagnosed AD cases there was a significant interaction between ApoE4 and ACE inhibitor use (odds ratio: 20.85; 95% confidence interval: 3.08–140.95; p = 0.002) after adjusting for age, sex, ethnicity, and education. Conclusion The effects of ACE inhibitors on AD may be different depending on ApoE genotype. A prospective study is needed to determine whether ACE inhibitor use accelerates or poorly delays AD development in ApoE4 carriers compared with ApoE4 non-carriers. PMID:23567418

Micro RNA as a potential blood-based epigenetic biomarker for Alzheimer's disease.

PubMed

Fransquet, Peter D; Ryan, Joanne

2018-06-06

As the prevalence of Alzheimer's disease (AD) increases, the search for a definitive, easy to access diagnostic biomarker has become increasingly important. Micro RNA (miRNA), involved in the epigenetic regulation of protein synthesis, is a biological mark which varies in association with a number of disease states, possibly including AD. Here we comprehensively review methods and findings from 26 studies comparing the measurement of miRNA in blood between AD cases and controls. Thirteen of these studies used receiver operator characteristic (ROC) analysis to determine the diagnostic accuracy of identified miRNA to predict AD, and three studies did this with a machine learning approach. Of 8098 individually measured miRNAs, 23 that were differentially expressed between AD cases and controls were found to be significant in two or more studies. Only six of these were consistent in their direction of expression between studies (miR-107, miR-125b, miR-146a, miR-181c, miR-29b, and miR-342), and they were all shown to be down regulated in individuals with AD compared to controls. Of these directionally concordant miRNAs, the strongest evidence was for miR-107 which has also been shown in previous studies to be involved in the dysregulation of proteins involved in aspects of AD pathology, as well as being consistently downregulated in studies of AD brains. We conclude that imperative to the discovery of reliable and replicable miRNA biomarkers of AD, standardised methods of measurements, appropriate statistical analysis, utilization of large datasets with machine learning approaches, and comprehensive reporting of findings is urgently needed. Copyright © 2017. Published by Elsevier Inc.

Angiotensin converting enzyme inhibitors and Alzheimer disease in the presence of the apolipoprotein E4 allele.

PubMed

Qiu, Wendy Wei Qiao; Lai, Angela; Mon, Timothy; Mwamburi, Mkaya; Taylor, Warren; Rosenzweig, James; Kowall, Neil; Stern, Robert; Zhu, Haihao; Steffens, David C

2014-02-01

The effect of angiotensin converting enzyme (ACE) inhibitors on Alzheimer disease (AD) remains unclear, with conflicting results reported. We studied the interaction of the Apolipoprotein E (ApoE) genotype and ACE inhibitors on AD. This was a cross-sectional study of homebound elderly with an AD diagnosis and documentation of medications taken. ApoE genotype was determined. A total of 355 subjects with status on ApoE alleles and cognitive diagnoses were studied. The average age (mean ± SD) of this population was 73.3 ± 8.3 years old, and 73% were female. Cross-sectionally, there was no difference in the number of AD cases between ApoE4 carriers and ApoE4 non-carriers or between ACE inhibitor users and non-users in the homebound elderly. ApoE4 carriers treated with ACE inhibitors, however, had more diagnoses of AD compared with those who did not have the treatment (28% versus 6%, p = 0.01) or ApoE4 non-carriers treated with an ACE inhibitor (28% versus 10%, p = 0.03). ACE inhibitor use was associated with AD diagnosis only in the presence of an E4 allele. Using multivariate logistic regression analysis, we found that in diagnosed AD cases there was a significant interaction between ApoE4 and ACE inhibitor use (odds ratio: 20.85; 95% confidence interval: 3.08-140.95; p = 0.002) after adjusting for age, sex, ethnicity, and education. The effects of ACE inhibitors on AD may be different depending on ApoE genotype. A prospective study is needed to determine whether ACE inhibitor use accelerates or poorly delays AD development in ApoE4 carriers compared with ApoE4 non-carriers. Copyright © 2014. Published by Elsevier Inc.

Adding Salt to Meals as a Risk Factor of Type 2 Diabetes Mellitus: A Case-Control Study.

PubMed

Radzeviciene, Lina; Ostrauskas, Rytas

2017-01-13

Type 2 diabetes mellitus (T2DM) is thought to arise from the complex interplay between genetic and environmental factors. It is important to identify modifiable risk factors that may help to reduce the risk of diabetes. Data on salt intake and the risk of type 2 diabetes are limited. The aim of this study was to assess the relationship between adding salt to prepared meals and the risk of type 2 diabetes. In a case-control study, we included 234 cases, all of whom were patients aged 35-86 years with a newly confirmed diagnosis of T2DM, and 468 controls that were free of the disease. Cases and controls (ratio 1:2) were matched by gender and age (±5 years). A questionnaire was used to collect information on possible risk factors for diabetes. Adding salt to prepared meals was assessed according to: Never, when there was not enough, or almost every time without tasting. The odds ratios (OR), and 95% confidence intervals (CI) for type 2 diabetes was calculated using a conditional logistic regression. The cases had a higher body mass index and a significantly lower education level compared to the controls. Variables such as waist circumference, body mass index, eating speed, smoking, family history of diabetes, arterial hypertension, plasma triglycerides, educational level, occupational status, morning exercise, marital status, daily urine sodium excretion, and daily energy intake were retained in the models as confounders. After adjusting for possible confounders, an approximately two-fold increased risk of type 2 diabetes was determined in subjects who add salt to prepared meals when "it is not enough" or "almost every time without tasting" (1.82; 95% CI 1.19-2.78; p = 0.006) compared with never adding salt. Presented data suggest the possible relationship between additional adding of salt to prepared meals and an increased risk of type 2 diabetes.

Lack of association between alpha2-macroglobulin polymorphisms and Alzheimer's disease.

PubMed

Wang, X; Luedecking, E K; Minster, R L; Ganguli, M; DeKosky, S T; Kamboh, M I

2001-02-01

This study was undertaken to investigate the role of two alpha2-macroglobulin (A2M) polymorphisms, an intronic 5-bp deletion and Ile1000Val, in the development of Alzheimer's disease (AD) and to evaluate the interaction between the apolipoprotein E (APOE) and A2M polymorphisms. The A2M polymorphisms were screened by using polymerase-chain-reaction-based assays in 555 white late-onset AD cases and 446 controls. The gentoype distributions of the 5-bp deletion and Ile1000Val polymorphisms were comparable between cases and controls (P = 0.158 and P = 0.148, respectively). Likewise, there was no significant difference in allele frequencies of each polymorphism among cases and controls (P = 0.361 and P = 0.062, respectively). The stratification of data by APOE*4 status also did not yield any significant association. In conclusion, we observed no association between either the intronic deletion polymorphism or the Ile1000Val polymorphism of A2M and AD in our case-control cohort.

A comparative study of the dentate gyrus in hippocampal sclerosis in epilepsy and dementia.

PubMed

Bandopadhyay, R; Liu, J Y W; Sisodiya, S M; Thom, M

2014-02-01

Hippocampal sclerosis (HS) is long-recognized in association with epilepsy (HSE ) and more recently in the context of cognitive decline or dementia in the elderly (HSD ), in some cases as a component of neurodegenerative diseases, including Alzheimer's disease (AD) and fronto-temporal lobe dementia (FTLD). There is an increased risk of seizures in AD and spontaneous epileptiform discharges in the dentate gyrus of transgenic AD models; epilepsy can be associated with an age-accelerated increase in AD-type pathology and cognitive decline. The convergence between these disease processes could be related to hippocampal pathology. HSE typically shows re-organization of both excitatory and inhibitory neuronal networks in the dentate gyrus, and is considered to be relevant to hippocampal excitability. We sought to compare the pathology of HSE and HSD , focusing on re-organization in the dentate gyrus. In nine post mortem cases with HSE and bilateral damage, 18 HSD and 11 controls we carried out immunostaining for mossy fibres (dynorphin), and interneuronal networks (NPY, calbindin and calretinin) on sections from the mid-hippocampal body. Fibre sprouting (FS) or loss of expression in the dentate gyrus was semi-quantitatively graded from grade 0 (normal) to grade 3 (marked alteration). Significantly more re-organization was seen with all four markers in the HSE than HSD group (P < 0.01). Mild alterations were noted in HSD group with dynorphin (FS in 3 cases), calretinin (FS in 6 cases), NPY (FS in 11 cases) and calbindin (loss in 10 cases). In eight HSD cases, alteration was seen with more than one antibody but in no cases were the highest grades seen. We also noted NPY and, to a lesser extent, calretinin labelling of Hirano bodies in CA1 of AD cases and some older controls, but not in HSE . Reorganization of excitatory and inhibitory networks in the dentate gyrus is more typical of HSE . Subtle alterations in HSD may be a result of increased hippocampal excitability, including unrecognized seizure activity. An unexpected finding was the identification of NPY-positive Hirano bodies in HSD but not HSE , which may be a consequence of the relative vulnerabilities of interneurons in these conditions. © 2013 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.

A comparative study of the dentate gyrus in hippocampal sclerosis in epilepsy and dementia

PubMed Central

Bandopadhyay, R; Liu, J Y W; Sisodiya, S M; Thom, M

2014-01-01

Aims: Hippocampal sclerosis (HS) is long-recognized in association with epilepsy (HSE) and more recently in the context of cognitive decline or dementia in the elderly (HSD), in some cases as a component of neurodegenerative diseases, including Alzheimer's disease (AD) and fronto-temporal lobe dementia (FTLD). There is an increased risk of seizures in AD and spontaneous epileptiform discharges in the dentate gyrus of transgenic AD models; epilepsy can be associated with an age-accelerated increase in AD-type pathology and cognitive decline. The convergence between these disease processes could be related to hippocampal pathology. HSE typically shows re-organization of both excitatory and inhibitory neuronal networks in the dentate gyrus, and is considered to be relevant to hippocampal excitability. We sought to compare the pathology of HSE and HSD, focusing on re-organization in the dentate gyrus. Methods: In nine post mortem cases with HSE and bilateral damage, 18 HSD and 11 controls we carried out immunostaining for mossy fibres (dynorphin), and interneuronal networks (NPY, calbindin and calretinin) on sections from the mid-hippocampal body. Fibre sprouting (FS) or loss of expression in the dentate gyrus was semi-quantitatively graded from grade 0 (normal) to grade 3 (marked alteration). Results: Significantly more re-organization was seen with all four markers in the HSE than HSD group (P < 0.01). Mild alterations were noted in HSD group with dynorphin (FS in 3 cases), calretinin (FS in 6 cases), NPY (FS in 11 cases) and calbindin (loss in 10 cases). In eight HSD cases, alteration was seen with more than one antibody but in no cases were the highest grades seen. We also noted NPY and, to a lesser extent, calretinin labelling of Hirano bodies in CA1 of AD cases and some older controls, but not in HSE. Conclusion: Reorganization of excitatory and inhibitory networks in the dentate gyrus is more typical of HSE. Subtle alterations in HSD may be a result of increased hippocampal excitability, including unrecognized seizure activity. An unexpected finding was the identification of NPY-positive Hirano bodies in HSD but not HSE, which may be a consequence of the relative vulnerabilities of interneurons in these conditions. PMID:24028428

The rare TREM2 R47H variant exerts only a modest effect on Alzheimer disease risk.

PubMed

Hooli, Basavaraj V; Parrado, Antonio R; Mullin, Kristina; Yip, Wai-Ki; Liu, Tian; Roehr, Johannes T; Qiao, Dandi; Jessen, Frank; Peters, Oliver; Becker, Tim; Ramirez, Alfredo; Lange, Christoph; Bertram, Lars; Tanzi, Rudolph E

2014-10-07

Recently, 2 independent studies reported that a rare missense variant, rs75932628 (R47H), in exon 2 of the gene encoding the "triggering receptor expressed on myeloid cells 2" (TREM2) significantly increases the risk of Alzheimer disease (AD) with an effect size comparable to that of the APOE ε4 allele. In this study, we attempted to replicate the association between rs75932628 and AD risk by directly genotyping rs75932628 in 2 independent Caucasian family cohorts consisting of 927 families (with 1,777 affected and 1,235 unaffected) and in 2 Caucasian case-control cohorts composed of 1,314 cases and 1,609 controls. In addition, we imputed genotypes in 3 independent Caucasian case-control cohorts containing 1,906 cases and 1,503 controls. Meta-analysis of the 2 family-based and the 5 case-control cohorts yielded a p value of 0.0029, while the overall summary estimate (using case-control data only) resulted in an odds ratio of 1.67 (95% confidence interval 0.95-2.92) for the association between the TREM2 R47H and increased AD risk. While our results serve to confirm the association between R47H and risk of AD, the observed effect on risk was substantially smaller than that previously reported. © 2014 American Academy of Neurology.

The rare TREM2 R47H variant exerts only a modest effect on Alzheimer disease risk

PubMed Central

Hooli, Basavaraj V.; Parrado, Antonio R.; Mullin, Kristina; Yip, Wai-Ki; Liu, Tian; Roehr, Johannes T.; Qiao, Dandi; Jessen, Frank; Peters, Oliver; Becker, Tim; Ramirez, Alfredo; Lange, Christoph; Bertram, Lars

2014-01-01

Objectives: Recently, 2 independent studies reported that a rare missense variant, rs75932628 (R47H), in exon 2 of the gene encoding the “triggering receptor expressed on myeloid cells 2” (TREM2) significantly increases the risk of Alzheimer disease (AD) with an effect size comparable to that of the APOE ε4 allele. Methods: In this study, we attempted to replicate the association between rs75932628 and AD risk by directly genotyping rs75932628 in 2 independent Caucasian family cohorts consisting of 927 families (with 1,777 affected and 1,235 unaffected) and in 2 Caucasian case-control cohorts composed of 1,314 cases and 1,609 controls. In addition, we imputed genotypes in 3 independent Caucasian case-control cohorts containing 1,906 cases and 1,503 controls. Results: Meta-analysis of the 2 family-based and the 5 case-control cohorts yielded a p value of 0.0029, while the overall summary estimate (using case-control data only) resulted in an odds ratio of 1.67 (95% confidence interval 0.95–2.92) for the association between the TREM2 R47H and increased AD risk. Conclusions: While our results serve to confirm the association between R47H and risk of AD, the observed effect on risk was substantially smaller than that previously reported. PMID:25186855

No association of toll-like receptor 2 polymorphisms with Alzheimer's disease in Han Chinese.

PubMed

Yu, Jin-Tai; Sun, Yan-Ping; Ou, Jiang-Rong; Cui, Wei-Zhen; Zhang, Wei; Tan, Lan

2011-10-01

Toll-like receptor 2 (TLR2) represents a reasonable functional and positional candidate gene for Alzheimer's disease (AD) as it is located under the linkage region of AD on chromosome 4q, and is functionally involved in the microglia-mediated inflammatory response and amyloid β (Aβ) clearance. In the current study, 7 single nucleotide polymorphisms (SNPs) that span the TLR2 were selected and their associations with late-onset AD (LOAD) risk were assessed in a case-control sample comprising 785 individuals in a Han Chinese population. No significant differences in the frequency of TLR2 alleles, genotypes, and haplotypes in the AD cases were detected compared with the controls. TLR2 gene might not play a major role in the genetic predisposition to late-onset Alzheimer's disease in this population. Copyright © 2011 Elsevier Inc. All rights reserved.

Interactions Among Polymorphisms of Susceptibility Loci for Alzheimer’s Disease or Depressive Disorder

PubMed Central

Kitzlerová, Eva; Lelková, Petra; Jirák, Roman; Zvěřová, Martina; Hroudová, Jana; Manukyan, Ada; Martásek, Pavel; Raboch, Jiří

2018-01-01

Background Several genetic susceptibility loci for major depressive disorder (MDD) or Alzheimer’s disease (AD) have been described. Interactions among polymorphisms are thought to explain the differences between low- and high-risk groups. We tested for the contribution of interactions between multiple functional polymorphisms in the risk of MDD or AD. Material/Methods A genetic association case-control study was performed in 68 MDD cases, 84 AD cases (35 of them with comorbid depression), and 90 controls. The contribution of 7 polymorphisms from 5 genes (APOE, HSPA1A, SLC6A4, HTR2A, and BDNF) related to risk of MDD or AD development was analyzed. Results Significant associations were found between MDD and interactions among polymorphisms in HSPA1A, SLC6A4, and BDNF or HSPA1A, BDNF, and APOE genes. For polymorphisms in the APOE gene in AD, significant differences were confirmed on the distributions of alleles and genotype rates compared to the control or MDD. Increased probability of comorbid depression was found in patients with AD who do not carry the ɛ4 allele of APOE. Conclusions Assessment of the interactions among polymorphisms of susceptibility loci in both MDD and AD confirmed a synergistic effect of genetic factors influencing inflammatory, serotonergic, and neurotrophic pathways at these heterogenous complex diseases. The effect of interactions was greater in MDD than in AD. A presence of the ɛ4 allele was confirmed as a genetic susceptibility factor in AD. Our findings indicate a role of APOE genotype in onset of comorbid depression in a subgroup of patients with AD who are not carriers of the APOE ɛ4 allele. PMID:29703883

Screening of Early and Late Onset Alzheimer's Disease Genetic Risk Factors in a Cohort of Dementia Patients from Liguria, Italy.

PubMed

Ferrari, Raffaele; Ferrara, Michela; Alinani, Anwar; Sutton, Roger Brian; Famà, Francesco; Picco, Agnese; Rodriguez, Guido; Nobili, Flavio; Momeni, Parastoo

2015-01-01

Cohorts from a defined geographical area enable ad hoc genotype-phenotype correlation studies providing novel and unique insight into disease. We analysed genetic risk factors associated with early and late onset Alzheimer's disease (EOAD and LOAD) in a population from Liguria (northern Italy), as part of an ongoing longitudinal study. We screened 37 AD, 8 mild cognitive impairment (MCI), 3 AD and CVD (cerebrovascular disease), 3 MCI and CVD, 8 frontotemporal dementia (FTD) and 2 progressive supranuclear palsy (PSP) patients, and 28 normal controls (NCs).We sequenced PSEN1, PSEN2 and APP (EOAD risk factors), as well as MAPT, GRN and TARDBP for all cases and NCs, and analysed the APOE, CLU, CR1 and PICALM genotypes as well as the MAPT and ACE haplotypes (LOAD risk factors) for the AD (n = 37) and AD + MCI (n = 45) cases and NCs (n = 28).We identified variants in PSEN1, PSEN2 and TARDBP across a range of phenotypes (AD, AD and CVD, FTD and PSP), suggesting that screening of all known candidate genes of Alzheimer's and non-Alzheimer's forms of dementias in all dementia cases might be warranted. The analysis of the LOAD risk factors revealed no association with AD or AD + MCI status after Bonferroni correction. Lack of association with APOE is supported by previous studies in the Italian population. Our data also evidenced: 1) a potentially protective haplotype at the PSEN2 locus; 2) a nominal association with the GWAS-risk allele A for rs3818361 in CR1 and; 3) a threefold prevalence of AD in the female population compared to men.Our results will need to be further assessed and confirmed in larger cohorts from this area. 

A systematic review and meta-analysis of the circulatory, erythrocellular and CSF selenium levels in Alzheimer's disease: A metal meta-analysis (AMMA study-I).

PubMed

Reddy, Varikasuvu Seshadri; Bukke, Suman; Dutt, Naveen; Rana, Puneet; Pandey, Arun Kumar

2017-07-01

Available studies in the literature on the selenium levels in Alzheimer's disease (AD) are inconsistent with some studies reporting its decrease in the circulation, while others reported an increase or no change as compared to controls. The objective of this study was to perform a meta-analysis of circulatory (plasma/serum and blood), erythrocyte and cerebrospinal fluid (CSF) selenium levels in AD compared controls. We also performed a meta-analysis of the correlation coefficients (r) to demonstrate the associations between selenium and glutathione peroxidase (GPx) in AD patients. All major databases were searched for eligible studies. We included 12 case-control/observational studies reporting selenium concentrations in AD and controls. Pooled-overall effect size as standardized mean difference (SMD) and pooled r-values were generated using Review Manager 5.3 and MedCalc 15.8 software. Random-effects meta-analysis indicated a decrease in circulatory (SMD=-0.44), erythrocellular (SMD=-0.52) and CSF (SMD=-0.14) selenium levels in AD patients compared to controls. Stratified meta-analysis demonstrated that the selenium levels were decreased in both the subgroups with (SMD=-0.55) and without (SMD=-0.37) age matching between AD and controls. Our results also demonstrated a direct association between decreased selenium levels and GPx in AD. This meta-analysis suggests that circulatory selenium concentration is significantly lower in AD patients compared to controls and this decrease in selenium is directly correlated with an important antioxidant enzyme, the GPx, in AD. Copyright © 2017 Elsevier GmbH. All rights reserved.

Elevated Serum Pesticide Levels and Risk for Alzheimer Disease

PubMed Central

Richardson, Jason R.; Roy, Ananya; Shalat, Stuart L.; von Stein, Richard T.; Hossain, Muhammad M.; Buckley, Brian; Gearing, Marla; Levey, Allan I.; German, Dwight C.

2014-01-01

IMPORTANCE The causes of late-onset Alzheimer disease (AD) are not yet understood but likely include a combination of genetic, environmental, and lifestyle factors. Limited epidemiological studies suggest that occupational pesticide exposures are associated with AD. Previously, we reported that serum levels of dichlorodiphenyldichloroethylene (DDE), the metabolite of the pesticide dichlorodiphenyltrichloroethane (DDT), were elevated in a small number of patients with AD (n=20). OBJECTIVE To evaluate the association between serum levels of DDE and AD and whether the apolipoprotein E (APOE) genotype modifies the association. DESIGN, SETTING, AND PARTICIPANTS A case-control study consisting of existing samples from patients with AD and control participants from the Emory University Alzheimer’s Disease Research Center and the University of Texas Southwestern Medical School’s Alzheimer’s Disease Center. Serum levels of DDE were measured in 79 control and 86 AD cases. MAIN OUTCOMES AND MEASURES Serum DDE levels, AD diagnosis, severity of AD measured by the Mini-Mental State Examination score, and interaction with APOE4 status. RESULTS Levels of DDE were 3.8-fold higher in the serum of those with AD (mean [SEM], 2.64 [0.35] ng/mg cholesterol) when compared with control participants (mean [SEM], 0.69 [0.1] ng/mg cholesterol; P < .001). The highest tertile of DDE levels was associated with an odds ratio of 4.18 for increased risk for AD (95% CI, 2.54–5.82; P < .001) and lower Mini-Mental State Examination scores (−1.605; range, −3.095 to −0.114; P < .0001). The Mini-Mental State Examination scores in the highest tertile of DDE were −1.753 points lower in the subpopulation carrying an APOE ε4 allele compared with those carrying an APOE ε3 allele (P interaction = .04). Serum levels of DDE were highly correlated with brain levels of DDE (ρ = 0.95). Exposure of human neuroblastoma cells to DDT or DDE increased levels of amyloid precursor protein. CONCLUSIONS AND RELEVANCE Elevated serum DDE levels are associated with an increased risk for AD and carriers of an APOE4 ε4 allele may be more susceptible to the effects of DDE. Both DDT and DDE increase amyloid precursor protein levels, providing mechanistic plausibility for the association of DDE exposure with AD. Identifying people who have elevated levels of DDE and carry an APOE ε4 allele may lead to early identification of some cases of AD. PMID:24473795

Support for an hypothesis linking Alzheimer`s disease and Down syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Geller, L.N.; Benjamin, M.B.; Dressler, D.

1994-09-01

A connection between Alzheimer`s disease (AD) and Down syndrome (trisomy 21) is indicated by the fact that Down syndrome individuals develop AD neuropathology by the third or fourth decade of life. One explanation for the connection between AD and Down syndrome would be that the overexpression of a gene or genes on chromosome 21 results in Alzheimer`s disease, the most likely candidate being the amyloid precursor protein (APP) gene. However, mutations in the APP gene have been found to be associated with only a very small percentage of familial AD cases. An alternative cause of some Alzheimer`s disease cases maymore » be sporadic trisomy of chromosome 21, resulting from mutations or toxins that cause chromosome nondisjunction. Several predictions can be made based on this hypothesis. One prediction is that there should be more trisomy 21 in cells from AD individuals than from unaffected controls. Using quantitative fluorescence in situ hybridization to compare the number of trisomy chromosome 21 cells in cultured fibroblasts from AD and unaffected individuals, we have shown that there are a significantly larger number of trisomy 21 cells from AD individuals. Another prediction is that a defect in the mitotic spindle apparatus could be the underlying cause of the aneuploidy. Cultured lymphoblasts from AD and unaffected individuals were briefly exposed to the microtubule-disrupting agent colchicine. As assayed by the subsequent appearance of metaphase chromosomes showing centromere separation, cells from AD patients were significantly more sensitive to colchicine treatment compared to cells from unaffected individuals, supporting the prediction of an altered spindle apparatus. Finally, we would predict that both types of patients should share some physical symptoms. We have also found that AD, like Down`s patients, are hypersensitive to the effect of the cholinergic antagonist, tropicamide, on pupil dilation, which may serve as a diagnostic test for Alzheimer`s disease.« less

Altered expression levels of the protein phosphatase 2A ABalphaC enzyme are associated with Alzheimer disease pathology.

PubMed

Sontag, Estelle; Luangpirom, Ampa; Hladik, Christa; Mudrak, Ingrid; Ogris, Egon; Speciale, Samuel; White, Charles L

2004-04-01

The formation of amyloid-containing senile plaques and tau-rich neurofibrillary tangles are central events in Alzheimer disease (AD) pathogenesis. Significantly, ABalphaC, a major protein phosphatase 2A (PP2A) holoenzyme, specifically binds to and dephosphorylates tau. Deregulation of PP2A results in tau hyperphosphorylation in vivo. Here, we compared the expression levels and distribution of PP2A subunits in various brain regions from autopsy cases of AD and aged controls with or without histological evidence of age-related neurofibrillary degeneration. Immunoblotting analyses revealed that there was a significant reduction in the total amounts of ABalphaC in AD frontal and temporal cortices that matched the decrease in PP2A activity measured in the same brain homogenates. Immunohistochemical studies showed that neuronal ABalphaC expression levels were significantly and selectively decreased in AD-affected regions and in tangle-bearing neurons, but not in AD cerebellum and in non-AD dementias. Reduced neuronal ABalphaC immunoreactivity closely correlated with tangle load, but not plaque burden, suggesting that ABalphaC dysfunction contributes to AD tau pathology. Glial cells within senile plaques were also positive for ABalphaC. Increased glial PP2A immunoreactivity was observed in both AD and non-AD cases and may play a role in the brain's response to general inflammatory processes and amyloidogenesis.

Molecular genetics of Alzheimer disease.

PubMed

St George-Hyslop, P H

1999-01-01

Epidemiological and individual case studies indicate that genetic factors play a significant role in the genesis of Alzheimer Disease (AD). To date, molecular genetic studies in families multiply affected with AD have identified three genes (Presenilin 1-PS1, Presenilin 2-PS2, and beta-amyloid precursor protein--betaAPP) associated with highly penetrant early onset AD, and one gene (Apolipoprotein E) associated with late onset AD. A fifth potential AD susceptibility locus has been mapped to a broad region of chromosome 12, but the responsible gene defect has not yet been identified. Case-control studies comparing the frequency of alleles in numerous other candidate genes have identified a number of additional potential AD genes. However, methodological difficulties and conflicting results in follow-up studies, make it unclear whether allelic variations in these genes are truly pathogenic. Nevertheless, analysis of the biochemical effects of mutations in PS1, PS2, betaAPP at least, suggest a common biochemical effect-namely disturbances in the processing of betaAPP protein. In addition to utility in defining potential therapeutic targets, in some circumstances these genes can also potentially be used as adjunctives in clinical presymptomatic, symptomatic or pharmacogenomic diagnosis.

Correlated patterns of neuropsychological and behavioral symptoms in frontal variant of Alzheimer disease and behavioral variant frontotemporal dementia: a comparative case study.

PubMed

Li, Pan; Zhou, Yu-Ying; Lu, Da; Wang, Yan; Zhang, Hui-Hong

2016-05-01

Although the neuropathologic changes and diagnostic criteria for the neurodegenerative disorder Alzheimer's disease (AD) are well-established, the clinical symptoms vary largely. Symptomatically, frontal variant of AD (fv-AD) presents very similarly to behavioral variant frontotemporal dementia (bvFTD), which creates major challenges for differential diagnosis. Here, we report two patients who present with progressive cognitive impairment, early and prominent behavioral features, and significant frontotemporal lobe atrophy on magnetic resonance imaging, consistent with an initial diagnosis of probable bvFTD. However, multimodal functional neuroimaging revealed neuropathological data consistent with a diagnosis of probable AD for one patient (pathology distributed in the frontal lobes) and a diagnosis of probable bvFTD for the other patient (hypometabolism in the bilateral frontal lobes). In addition, the fv-AD patient presented with greater executive impairment and milder behavioral symptoms relative to the bvFTD patient. These cases highlight that recognition of these atypical syndromes using detailed neuropsychological tests, biomarkers, and multimodal neuroimaging will lead to greater accuracy in diagnosis and patient management.

Tocopherols and tocotrienols plasma levels are associated with cognitive impairment.

PubMed

Mangialasche, Francesca; Xu, Weili; Kivipelto, Miia; Costanzi, Emanuela; Ercolani, Sara; Pigliautile, Martina; Cecchetti, Roberta; Baglioni, Mauro; Simmons, Andrew; Soininen, Hilkka; Tsolaki, Magda; Kloszewska, Iwona; Vellas, Bruno; Lovestone, Simon; Mecocci, Patrizia

2012-10-01

Vitamin E includes 8 natural compounds (4 tocopherols, 4 tocotrienols) with potential neuroprotective activity. α-Tocopherol has mainly been investigated in relation to cognitive impairment. We examined the relation of all plasma vitamin E forms and markers of vitamin E damage (α-tocopherylquinone, 5-nitro-γ-tocopherol) to mild cognitive impairment (MCI) and Alzheimer's disease (AD). Within the AddNeuroMed-Project, plasma tocopherols, tocotrienols, α-tocopherylquinone, and 5-nitro-γ-tocopherol were assessed in 168 AD cases, 166 MCI, and 187 cognitively normal (CN) people. Compared with cognitively normal subjects, AD and MCI had lower levels of total tocopherols, total tocotrienols, and total vitamin E. In multivariable-polytomous-logistic regression analysis, both MCI and AD cases had 85% lower odds to be in the highest tertile of total tocopherols and total vitamin E, and they were, respectively, 92% and 94% less likely to be in the highest tertile of total tocotrienols than the lowest tertile. Further, both disorders were associated with increased vitamin E damage. Low plasma tocopherols and tocotrienols levels are associated with increased odds of MCI and AD. Copyright © 2012 Elsevier Inc. All rights reserved.

A CT-rich haplotype in intron 4 of SNCA confers risk for Lewy body pathology in Alzheimer’s disease and affects SNCA expression

PubMed Central

Lutz, Michael W.; Saul, Robert; Linnertz, Colton; Glenn, Omolara-Chinue; Roses, Allen D.; Chiba-Falek, Ornit

2015-01-01

INTRODUCTION We recently showed that tagging-SNPs across the SNCA locus were significantly associated with increased risk for LB pathology in AD cases. However, the actual genetic variant(s) that underlie the observed associations remain elusive. METHODS We used a bioinformatics algorithm to catalogue Structural-Variants in a region of SNCA-intron4, followed by phased-sequencing. We performed a genetic-association analysis in autopsy series of LBV/AD cases compared with AD-only controls. We investigated the biological functions by expression analysis using temporal-cortex samples. RESULTS We identified four distinct haplotypes within a highly-polymorphic-low-complexity CT-rich region. We showed that a specific haplotype conferred risk to develop LBV/AD. We demonstrated that the CT-rich site acts as an enhancer element, where the risk haplotype was significantly associated with elevated levels of SNCA-mRNA. DISCUSSION We have discovered a novel haplotype in a CT-rich region in SNCA that contributes to LB pathology in AD patients, possibly via cis-regulation of the gene expression. PMID:26079410

Prevalence of Mathematical and Visuospatial Learning Disabilities in Patients With Posterior Cortical Atrophy.

PubMed

Miller, Zachary A; Rosenberg, Lynne; Santos-Santos, Miguel A; Stephens, Melanie; Allen, Isabel E; Hubbard, H Isabel; Cantwell, Averill; Mandelli, Maria Luisa; Grinberg, Lea T; Seeley, William W; Miller, Bruce L; Rabinovici, Gil D; Gorno-Tempini, Maria Luisa

2018-06-01

Increased prevalence of language-based learning disabilities (LDs) has been previously reported in patients with primary progressive aphasia (PPA). This study hypothesized that patients with focal neurodegenerative syndromes outside the language network, such as posterior cortical atrophy (PCA), would have a higher rate of nonlanguage LDs, congruent with their mainly visuospatial presentation. To investigate the prevalence and type of LD (language and/or mathematical and visuospatial) in a large cohort of patients with PCA compared with patients with logopenic variant PPA (lvPPA) and amnestic Alzheimer disease (AD). This case-control study reviewed 279 medical records from a university-based clinic and research center for patients with neurodegenerative diseases for LD history, including patients with PCA (n = 95), patients with lvPPA (n = 84), and a matched cohort with amnestic AD (n = 100). No records were excluded. The study compared cognitive and neuroimaging features of patients with PCA with and without LDs. A review of the records of patients presenting from March 1, 1999, to August 31, 2014, revealed 95 PCA cases and 84 lvPPA cases. Then 100 patients with amnestic AD from this same period were chosen for comparison, matching against the groups for age, sex, and disease severity. Data analysis was performed from September 8, 2013, to November 6, 2017. Prevalence of total LD history and prevalence of language and mathematical or visuospatial LD history across all cohorts. A total of 179 atypical AD cases (95 with PCA and 84 with lvPPA) and 100 disease control cases (amnestic AD) were included in the study. The groups were not statistically different for mean (SD) age at first visit (PCA, 61.9 [7.0] years; lvPPA, 65.1 [8.7] years; amnestic AD, 64.0 [12.6] years; P = .08), mean (SD) age at first symptom (PCA, 57.5 [7.0] years; lvPPA, 61.1 [9.0] years; amnestic AD, 59.6 [13.7] years; P = .06), or sex (PCA, 66.3% female; lvPPA, 56.0% female; amnestic AD, 57.0% female; P = .30) but differed on non-right-hand preference (PCA, 18.3%; lvPPA, 20.2%; amnestic AD, 7.7%; P = .04), race/ethnicity (PCA, 88.3% white; lvPPA, 99.0% white; amnestic AD, 80.0% white; P < .001), and mean (SD) educational level (PCA, 15.7 [3.2] years; lvPPA, 16.2 [3.3] years; amnestic AD, 14.8 [3.5] years; P = .02). A total of 18 of the 95 patients with PCA (18.9%) reported a history of LD, which is greater than the 3 of 100 patients (3.0%) in the amnestic AD cohort (P < .001) and the 10.0% expected rate in the general population (P = .007). In the PCA cohort, 13 of 95 patients (13.7%) had a nonlanguage mathematical and/or visuospatial LD; this rate was greater than that in the amnestic AD (1 of 100 [1.0%]; P < .001) and lvPPA (2 of 84 [2.4%]; P = .006) cohorts and greater than the 6.0% expected general population rate of mathematical LD (P = .003). Compared with the patients with PCA without LDs, the group with LDs had greater preservation of global cognition and a more right-lateralized pattern of atrophy. Nonlanguage mathematical and visuospatial LDs were associated with focal, visuospatial predominant neurodegenerative clinical syndromes. This finding supports the hypothesis that neurodevelopmental differences in specific brain networks are associated with phenotypic manifestation of later-life neurodegenerative disease.

Association of Glucocerebrosidase Mutations With Dementia With Lewy Bodies

PubMed Central

Clark, Lorraine N.; Kartsaklis, Lykourgos A.; Wolf Gilbert, Rebecca; Dorado, Beatriz; Ross, Barbara M.; Kisselev, Sergey; Verbitsky, Miguel; Mejia-Santana, Helen; Cote, Lucien J.; Andrews, Howard; Vonsattel, Jean-Paul; Fahn, Stanley; Mayeux, Richard; Honig, Lawrence S.; Marder, Karen

2009-01-01

Background Mutations in the glucocerebrosidase (GBA) gene are associated with Lewy body (LB) disorders. Objective To determine the relationship of GBA mutations and APOE4 genotype to LB and Alzheimer disease (AD) pathological findings. Design Case-control study. Setting Academic research. Participants The 187 subjects included patients with primary neuropathological diagnoses of LB disorders with or without AD changes (95 cases), randomly selected patients with AD (without significant LB pathological findings; 60 cases), and controls with neither LB nor AD pathological findings (32 cases). Main Outcome Measures GBA mutation status, APOE4 genotype, LB pathological findings (assessed according to the third report of the Dementia With Lewy Body Consortium), and Alzheimer plaque and tangle pathological findings (rated by criteria of Braak and Braak, the Consortium to Establish a Registry for Alzheimer Disease, and the National Institute on Aging–Reagan Institute). Results GBA mutations were found in 18% (34 of 187) of all subjects, including 28% (27 of 95) of those with primary LB pathological findings compared with 10% (6 of 60) of those with AD pathological findings and 3% (1 of 32) of those without AD or LB pathological findings (P=.001). GBA mutation status was significantly associated with the presence of cortical LBs (odds ratio, 6.48; 95% confidence interval, 2.45–17.16; P<.001), after adjusting for sex, age at death, and presence of APOE4. GBA mutation carriers were significantly less likely to meet AD pathological diagnostic (National Institute on Aging–Reagan Institute intermediate or high likelihood) criteria (odds ratio, 0.35; 95% confidence interval, 0.15–0.79; P=.01) after adjustment for sex, age at death, and APOE4. Conclusion GBA mutations may be associated with pathologically “purer” LB disorders, characterized by more extensive (cortical) LB, and less severe AD pathological findings and may be a useful marker for LB disorders. PMID:19433657

Altered distribution of the gangliosides GM1 and GM2 in Alzheimer's disease.

PubMed

Pernber, Z; Blennow, K; Bogdanovic, N; Månsson, J-E; Blomqvist, M

2012-01-01

Alzheimer's disease (AD) is a neurodegenerative disorder where β-amyloid tends to aggregate and form plaques. Lipid raft-associated ganglioside GM1 has been suggested to facilitate β-amyloid aggregation; furthermore, GM1 and GM2 are increased in lipid rafts isolated from cerebral cortex of AD cases. The distribution of GM1 and GM2 was studied by immunohistochemistry in the frontal and temporal cortex of AD cases. Frontotemporal dementia (FTD) was included as a contrast group. The distribution of GM1 and GM2 changes during the process of AD (n = 5) and FTD (n = 3) compared to controls (n = 5). Altered location of the GM1-positive small circular structures seems to be associated with myelin degradation. In the grey matter, the staining of GM1-positive plasma membranes might reflect neuronal loss in the AD/FTD tissue. The GM1-positive compact bundles were only visible in cells located in the AD frontal grey matter, possibly reflecting raft formation of GM1 and thus a pathological connection. Furthermore, our results suggest GM2 to be enriched within vesicles of pyramidal neurons of the AD/FTD brain. Our study supports the biochemical finding of ganglioside accumulation in cellular membranes of AD patients and shows a redistribution of these molecules. Copyright © 2012 S. Karger AG, Basel.

A quantitative comparison of plaque types in Alzheimer's disease and senile dementia of the Lewy body type.

PubMed

McKenzie, J E; Edwards, R J; Gentleman, S M; Ince, P G; Perry, R H; Royston, M C; Roberts, G W

1996-01-01

In a previous study we reported no difference in the overall beta-amyloid protein (beta AP) load between Alzheimer's disease (AD) and senile dementia of the Lewy body type (SDLT). However, it is possible that differences in the morphology of beta AP plaque types exist, analogous to the differences in cytoskeletal pathology found in these two disorders. We have carried out a quantitative image analysis of plaque subtypes in the temporal lobe of AD (n = 8), SDLT (n = 9) and control (n = 11) cases. Measurements of beta AP load and plaque density were consistently higher in AD and SDLT than in controls. When AD and SDLT cases were compared no differences were seen in either the density or relative proportions of classic and diffuse plaques. Based on these results we suggest that the variation in the clinical course of these diseases reflects differences in the cytoskeletal pathology, whereas the final stages of profound dementia common to both disorders is associated with the deposition of beta AP.

Candidate SNP Markers of Familial and Sporadic Alzheimer's Diseases Are Predicted by a Significant Change in the Affinity of TATA-Binding Protein for Human Gene Promoters

PubMed Central

Ponomarenko, Petr; Chadaeva, Irina; Rasskazov, Dmitry A.; Sharypova, Ekaterina; Kashina, Elena V.; Drachkova, Irina; Zhechev, Dmitry; Ponomarenko, Mikhail P.; Savinkova, Ludmila K.; Kolchanov, Nikolay

2017-01-01

While year after year, conditions, quality, and duration of human lives have been improving due to the progress in science, technology, education, and medicine, only eight diseases have been increasing in prevalence and shortening human lives because of premature deaths according to the retrospective official review on the state of US health, 1990-2010. These diseases are kidney cancer, chronic kidney diseases, liver cancer, diabetes, drug addiction, poisoning cases, consequences of falls, and Alzheimer's disease (AD) as one of the leading pathologies. There are familial AD of hereditary nature (~4% of cases) and sporadic AD of unclear etiology (remaining ~96% of cases; i.e., non-familial AD). Therefore, sporadic AD is no longer a purely medical problem, but rather a social challenge when someone asks oneself: “What can I do in my own adulthood to reduce the risk of sporadic AD at my old age to save the years of my lifespan from the destruction caused by it?” Here, we combine two computational approaches for regulatory SNPs: Web service SNP_TATA_Comparator for sequence analysis and a PubMed-based keyword search for articles on the biochemical markers of diseases. Our purpose was to try to find answers to the question: “What can be done in adulthood to reduce the risk of sporadic AD in old age to prevent the lifespan reduction caused by it?” As a result, we found 89 candidate SNP markers of familial and sporadic AD (e.g., rs562962093 is associated with sporadic AD in the elderly as a complication of stroke in adulthood, where natural marine diets can reduce risks of both diseases in case of the minor allele of this SNP). In addition, rs768454929, and rs761695685 correlate with sporadic AD as a comorbidity of short stature, where maximizing stature in childhood and adolescence as an integral indicator of health can minimize (or even eliminate) the risk of sporadic AD in the elderly. After validation by clinical protocols, these candidate SNP markers may become interesting to the general population [may help to choose a lifestyle (in childhood, adolescence, and adulthood) that can reduce the risks of sporadic AD, its comorbidities, and complications in the elderly]. PMID:28775688

Clinical criteria for the diagnosis of Alzheimer disease: still good after all these years.

PubMed

Ranginwala, Najeeb A; Hynan, Linda S; Weiner, Myron F; White, Charles L

2008-05-01

To examine the impact of newer neuropathological techniques on the power of National Institute of Neurological and Communicative Disorders and Stroke-AD and Related Disorders Association criteria for Alzheimer disease (AD) to detect AD at later postmortem study. We examined clinical and postmortem diagnoses of persons evaluated postmortem with thioflavin-S staining for plaques and tangles and immunohistochemical staining techniques for alpha synuclein, uhiquitin, and tau protein. Alzheimer Disease Center. Clinically evaluated persons for whom tissue diagnosis was available. Of 313 evaluees, 166 met criteria for probable AD. An additional 59 subjects had clinical diagnoses that included AD, e.g., possible AD, Lewy body variant of AD, AD and Parkinsonism, and mixed AD and vascular dementia. Of the 166 probable AD cases, 147 of 166 (88.6%) met pathologic criteria for AD. When all five AD groups were combined, 194 of 225 subjects (86.2%) met pathologic criteria for AD. There were five cases diagnosed pathologically as tangle-only dementia, which was considered a variant of AD. A pathologic diagnosis of Lewy body variant of AD was made in 56 (17.9%) of cases, including 44 of 313 (14.1%) cases diagnosed as probable or possible AD. Pure dementia with Lewy bodies was seen in 13 (4.2%). There were 9 (2.9%) cases of mixed AD and vascular dementia, and 37 (11.4%) cases of frontotemporal dementia. McKhann et al. criteria for probable and possible AD are valid for AD but do not exclude additional Lewy body pathology.

Diagnostic performance of the atopy patch test with inhalant allergens.

PubMed

Fuiano, N; Diddi, G; Delvecchio, M; Incorvaia, C

2015-01-01

This study evaluated the diagnostic performance of the atopy patch test (APT) compared with skin prick testing (SPT) and in vitro IgE measurement in a large group of patients with atopic dermatitis (AD) with or without respiratory symptoms (RS). The study included 521 patients (292 males, 229 females; age, 0.5-18 years; median age, 6 years) with AD and RS with different clinical presentations: current AD, 47 patients (Group A); current AD and RS, 72 patients (Group B), past AD and RS, 69 patients (Group C); and RS only, 280 patients (Group D). Fifty-three healthy individuals served as controls. All participants underwent the APT, SPT, and CAP/RAST with the most common inhalant allergens. The presence of a control group allowed calculation of specificity and positive and negative predictive values. A significant difference was found for a positive APT versus both SPT and CAP/RAST (P < .0001) but not for SPT versus CAP/RAST. The differences for APT were significant in all group comparisons except group B vs C and group C vs D. In the control group, the APT was positive in 2% of cases (specificity of 96.2%), SPT was positive in 6% of cases (specificity of 88.4%), and CAP/RAST was positive in 4% of cases (specificity of 92.5%). In young patients sensitized to inhalant allergens with AD in addition to RS, the APT has a superior diagnostic performance to SPT and in vitro IgE measurement.

Added value of cardiac computed tomography for evaluation of mechanical aortic valve: Emphasis on evaluation of pannus with surgical findings as standard reference.

PubMed

Suh, Young Joo; Lee, Sak; Im, Dong Jin; Chang, Suyon; Hong, Yoo Jin; Lee, Hye-Jeong; Hur, Jin; Choi, Byoung Wook; Chang, Byung-Chul; Shim, Chi Young; Hong, Geu-Ru; Kim, Young Jin

2016-07-01

The added value of cardiac computed tomography (CT) with transesophageal echocardiography (TEE) for evaluating mechanical aortic valve (AV) dysfunction has not yet been investigated. The purposes of this study were to investigate the added value of cardiac CT for evaluation of mechanical AVs and diagnoses of pannus compared to TEE, with surgical findings of redo-aortic valve replacement (AVR) used as a standard reference. 25 patients who underwent redo-AVR due to mechanical AV dysfunction and cardiac CT before redo-AVR were included. The presence of pannus, encroachment ratio by pannus, and limitation of motion (LOM) were evaluated on CT. The diagnostic performance of pannus detection was compared using TEE, CT, and CT+TEE, with surgical findings as a standard reference. The added value of CT for diagnosing the cause of mechanical AV dysfunction was assessed compared to TTE+TEE. In two patients, CT analysis was not feasible due to severe metallic artifacts. On CT, pannus and LOM were found in 100% (23/23) and 60.9% (14/23). TEE identified pannus in 48.0% of patients (12/25). CT, TEE, and CT+TEE correctly identified pannus with sensitivity of 92.0%, 48.0%, and 92.0%, respectively (P=0.002 for CT vs. TEE). In 11 of 13 cases (84.6%) with inconclusive or negative TEE results for pannus, CT detected the pannus. Among 13 inconclusive cases of TTE+TEE for the cause of mechanical AV dysfunction, CT suggested 6 prosthetic valve obstruction (PVO) by pannus, 4 low-flow low-gradient PVO, and one LOM without significant PVO. Cardiac CT showed added diagnostic value with TEE in the detection of pannus as the cause of mechanical AV dysfunction. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Implications of comorbidity on costs for patients with Alzheimer disease.

PubMed

Kuo, Tzu-Chun; Zhao, Yang; Weir, Sharada; Kramer, Marilyn Schlein; Ash, Arlene S

2008-08-01

No prior studies have used a comprehensive clinical classification system to examine the effect of differences in overall illness burden and the presence of other diseases on costs for patients with Alzheimer disease (AD) when compared with demographically matched nondemented controls. Of a total of 627,775 enrollees who were eligible for medical and pharmacy benefits for 2003 and 2004 in the MarketScan Medicare Supplemental and Coordination of Benefits Database, we found 25,109 AD patients. For each case, 3 demographically matched nondemented controls were selected using propensity scores. Applying the diagnostic cost groups (DCGs) model to all enrollees, 2003 diagnoses were used to estimate prospective relative risk scores (RRSs) that predict 2004 costs from all illness other than AD. RRSs were then used to control for illness burden to estimate AD's independent effect on costs. Compared with the control group, the AD cohort has more comorbid conditions (8.1 vs. 6.5) and higher illness burden (1.23 vs. 1.04). Individuals with AD are more likely to have mental health conditions, neurologic conditions, cognitive disorders, cerebrovascular disease, diabetes with acute complications, and injuries. Annual costs for AD patients are $3567 (34%) higher than for controls. Excess costs attributable to AD, after controlling for non-AD illness burden, are estimated at $2307 per year with outpatient pharmacy being the key driver ($1711 in excess costs). AD patients are sicker and more expensive than demographically matched controls. Even after adjusting for differences in illness burden, costs remain higher for AD patients.

Mitochondrial dysfunction: the missing link between aging and sporadic Alzheimer's disease.

PubMed

Grimm, Amandine; Friedland, Kristina; Eckert, Anne

2016-04-01

Alzheimer's disease (AD) is a progressive neurodegenerative disease that represents the most common form of dementia among the elderly. Despite the fact that AD was studied for decades, the underlying mechanisms that trigger this neuropathology remain unresolved. Since the onset of cognitive deficits occurs generally within the 6th decade of life, except in rare familial case, advancing age is the greatest known risk factor for AD. To unravel the pathogenesis of the disease, numerous studies use cellular and animal models based on genetic mutations found in rare early onset familial AD (FAD) cases that represent less than 1 % of AD patients. However, the underlying process that leads to FAD appears to be distinct from that which results in late-onset AD. As a genetic disorder, FAD clearly is a consequence of malfunctioning/mutated genes, while late-onset AD is more likely due to a gradual accumulation of age-related malfunction. Normal aging and AD are both marked by defects in brain metabolism and increased oxidative stress, albeit to varying degrees. Mitochondria are involved in these two phenomena by controlling cellular bioenergetics and redox homeostasis. In the present review, we compare the common features observed in both brain aging and AD, placing mitochondrial in the center of pathological events that separate normal and pathological aging. We emphasize a bioenergetic model for AD including the inverse Warburg hypothesis which postulates that AD is a consequence of mitochondrial deregulation leading to metabolic reprogramming as an initial attempt to maintain neuronal integrity. After the failure of this compensatory mechanism, bioenergetic deficits may lead to neuronal death and dementia. Thus, mitochondrial dysfunction may represent the missing link between aging and sporadic AD, and represent attractive targets against neurodegeneration.

Using the genome aggregation database, computational pathogenicity prediction tools, and patch clamp heterologous expression studies to demote previously published long QT syndrome type 1 mutations from pathogenic to benign.

PubMed

Clemens, Daniel J; Lentino, Anne R; Kapplinger, Jamie D; Ye, Dan; Zhou, Wei; Tester, David J; Ackerman, Michael J

2018-04-01

Mutations in the KCNQ1-encoded Kv7.1 potassium channel cause long QT syndrome (LQTS) type 1 (LQT1). It has been suggested that ∼10%-20% of rare LQTS case-derived variants in the literature may have been published erroneously as LQT1-causative mutations and may be "false positives." The purpose of this study was to determine which previously published KCNQ1 case variants are likely false positives. A list of all published, case-derived KCNQ1 missense variants (MVs) was compiled. The occurrence of each MV within the Genome Aggregation Database (gnomAD) was assessed. Eight in silico tools were used to predict each variant's pathogenicity. Case-derived variants that were either (1) too frequently found in gnomAD or (2) absent in gnomAD but predicted to be pathogenic by ≤2 tools were considered potential false positives. Three of these variants were characterized functionally using whole-cell patch clamp technique. Overall, there were 244 KCNQ1 case-derived MVs. Of these, 29 (12%) were seen in ≥10 individuals in gnomAD and are demotable. However, 157 of 244 MVs (64%) were absent in gnomAD. Of these, 7 (4%) were predicted to be pathogenic by ≤2 tools, 3 of which we characterized functionally. There was no significant difference in current density between heterozygous KCNQ1-F127L, -P477L, or -L619M variant-containing channels compared to KCNQ1-WT. This study offers preliminary evidence for the demotion of 32 (13%) previously published LQT1 MVs. Of these, 29 were demoted because of their frequent sighting in gnomAD. Additionally, in silico analysis and in vitro functional studies have facilitated the demotion of 3 ultra-rare MVs (F127L, P477L, L619M). Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Neuropathology of Autosomal Dominant Alzheimer Disease in the National Alzheimer Coordinating Center Database.

PubMed

Ringman, John M; Monsell, Sarah; Ng, Denise W; Zhou, Yan; Nguyen, Andy; Coppola, Giovanni; Van Berlo, Victoria; Mendez, Mario F; Tung, Spencer; Weintraub, Sandra; Mesulam, Marek-Marsel; Bigio, Eileen H; Gitelman, Darren R; Fisher-Hubbard, Amanda O; Albin, Roger L; Vinters, Harry V

2016-03-01

Alzheimer disease (AD) represents a genetically heterogeneous entity. To elucidate neuropathologic features of autosomal dominant AD ([ADAD] due to PSEN1, APP, or PSEN2 mutations), we compared hallmark AD pathologic findings in 60 cases of ADAD and 120 cases of sporadic AD matched for sex, race, ethnicity, and disease duration. Greater degrees of neuritic plaque and neurofibrillary tangle formation and cerebral amyloid angiopathy (CAA) were found in ADAD (p values < 0.01). Moderate to severe CAA was more prevalent in ADAD (63.3% vs. 39.2%, p = 0.003), and persons with PSEN1 mutations beyond codon 200 had higher average Braak scores and severity and prevalence of CAA than those with mutations before codon 200. Lewy body pathology was less extensive in ADAD but was present in 27.1% of cases. We also describe a novel pathogenic PSEN1 mutation (P267A). The finding of more severe neurofibrillary pathology and CAA in ADAD, particularly in carriers of PSEN1 mutations beyond codon 200, warrants consideration when designing trials to treat or prevent ADAD. The finding of Lewy body pathology in a substantial minority of ADAD cases supports the assertion that development of Lewy bodies may be in part driven by abnormal β-amyloid protein precursor processing. © 2016 American Association of Neuropathologists, Inc. All rights reserved.

The occult aftermath of boxing.

PubMed Central

Roberts, G W; Allsop, D; Bruton, C

1990-01-01

The repeated head trauma experienced by boxers can lead to the development of dementia pugilistica (DP)--punch drunk syndrome. The neuropathology of DP in a classic report by Corsellis et al describes the presence of numerous neurofibrillary tangles in the absence of plaques, in contrast to the profusion of tangles and plaques seen in Alzheimer's disease (AD). The DP cases used in that report were re-investigated with immunocytochemical methods and an antibody raised to the beta-protein present in AD plaques. We found that all DP cases with substantial tangle formation showed evidence of extensive beta-protein immunoreactive deposits (plaques). These diffuse "plaques" were not visible with Congo-red or standard silver stains. The degree of beta-protein deposition was comparable to that seen in AD. Our data indicate that the present neuropathological description of DP (tangles but no plaques) should be altered to acknowledge the presence of substantial beta-protein deposition (plaques). The molecular markers present in the plaques and tangles of DP are the same as those in AD. Similarities in clinical symptoms, distribution of pathology and neurochemical deficits also exist. Epidemiological studies have shown that head injury is a risk factor in AD. It is probable that DP and AD share common pathogenic mechanisms leading to tangle and plaque formation. Images PMID:2191084

Blood type gene locus has no influence on ACE association with Alzheimer's disease.

PubMed

Braae, Anne; Medway, Christopher; Carrasquillo, Minerva; Younkin, Steven; Kehoe, Patrick G; Morgan, Kevin

2015-04-01

The ABO blood group locus was recently found to contribute independently and via interactions with angiotensin-converting enzyme (ACE) gene variation to plasma levels of ACE. Variation in ACE has previously been not only implicated as individually conferring susceptibility for Alzheimer's disease (AD) but also proposed to confer risk via interactions with other as yet unknown genes. More recently, larger studies have not supported ACE as a risk factor for AD, whereas the role of ACE pathway in AD has come under increased levels of scrutiny with respect to various aspects of AD pathology and possible therapies. We explored the potential combined involvement of ABO and ACE variations in the genetic susceptibility of 2067 AD cases compared with 1376 nondemented elderly. Including the effects of ABO haplotype did not provide any evidence for the genetic association of ACE with AD. Copyright © 2015 Elsevier Inc. All rights reserved.

Should we systematically test patients with clinically isolated syndrome for auto-antibodies?

PubMed

Negrotto, Laura; Tur, Carmen; Tintoré, Mar; Arrambide, Georgina; Sastre-Garriga, Jaume; Río, Jordi; Comabella, Manuel; Nos, Carlos; Galán, Ingrid; Vidal-Jordana, Angela; Simon, Eva; Castilló, Joaquín; Palavra, Filipe; Mitjana, Raquel; Auger, Cristina; Rovira, Àlex; Montalban, Xavier

2015-12-01

Several autoimmune diseases (ADs) can mimic multiple sclerosis (MS). For this reason, testing for auto-antibodies (auto-Abs) is often included in the diagnostic work-up of patients with a clinically isolated syndrome (CIS). The purpose was to study how useful it was to systematically determine antinuclear-antibodies, anti-SSA and anti-SSB in a non-selected cohort of CIS patients, regarding the identification of other ADs that could represent an alternative diagnosis. From a prospective CIS cohort, we selected 772 patients in which auto-Ab levels were tested within the first year from CIS. Baseline characteristics of auto-Ab positive and negative patients were compared. A retrospective revision of clinical records was then performed in the auto-Ab positive patients to identify those who developed ADs during follow-up. One or more auto-Ab were present in 29.4% of patients. Only 1.8% of patients developed other ADs during a mean follow-up of 6.6 years. In none of these cases the concurrent AD was considered the cause of the CIS. In all cases the diagnosis of the AD resulted from the development of signs and/or symptoms suggestive of each disease. Antinuclear-antibodies, anti-SSA and anti-SSB should not be routinely determined in CIS patients but only in those presenting symptoms suggestive of other ADs. © The Author(s), 2015.

Advance directives in nursing homes: prevalence, validity, significance, and nursing staff adherence.

PubMed

Sommer, Sarah; Marckmann, Georg; Pentzek, Michael; Wegscheider, Karl; Abholz, Heinz-Harald; in der Schmitten, Jürgen

2012-09-01

The German Advance Directives Act of 2009 confirms that advance directives (ADs) are binding. Little is known, however, about their prevalence in nursing homes, their quality, and whether they are honored. In 2007, we carried out a cross-sectional survey in all 11 nursing homes of a German city in the state of North Rhine-Westphalia (total nursing home population, 1089 residents). The ADs were formally analyzed and assessed by 3 raters with respect to 5 clinical decision-making scenarios. The specifications of the ADs were compared with what the nurses reported that they would do in each scenario. 11% of the nursing home residents had a personal AD, and a further 1.4% an AD by proxy. 52% of the 119 ADs that we analyzed contained no documentation of the patient's decision-making capacity and/or voluntariness, and only 3% contained documentation of a medical consultation. Most ADs failed to state what should be done in case the patient acutely became incapable of consenting to treatment (inter-rater agreement [IRA] >83%). For the case of permanent decisional incapacity, many ADs contained ambiguous information (IRA<43%). 23 directives stated that the patient should not have cardiopulmonary resuscitation in case an arrest occurred in the patient's current clinical condition, but the nurses reported a corresponding do-not-resuscitate agreement for only 9 of these 23 patients. In 2007, ADs were rare in these German nursing homes, and most of the existing ones were invalid, of little meaning, and/or disregarded by the nursing staff. There is little reason to believe that the Advance Directives Act of 2009 will bring about any major change in this miserable status quo. Advance care planning, a system-oriented concept still uncommon in Germany, could give new impulses to promote a cultural change in this respect.

Reformatted images improve the detection rate of acute traumatic subdural hematomas on brain CT compared with axial images alone.

PubMed

Amrhein, Timothy J; Mostertz, William; Matheus, Maria Gisele; Maass-Bolles, Genevieve; Sharma, Komal; Collins, Heather R; Kranz, Peter G

2017-02-01

Subdural hematomas (SDHs) comprise a significant percentage of missed intracranial hemorrhage on axial brain CT. SDH detection rates could be improved with the addition of reformatted images. Though performed at some centers, the potential additional diagnostic sensitivity of reformatted images has not yet been investigated. The purpose of our study is to determine if the addition of coronal and sagittal reformatted images to an axial brain CT increases the sensitivity and specificity for detection of acute traumatic SDH. We retrospectively reviewed consecutive brain CTs acquired for acute trauma that contained new SDHs. An equivalent number of normal brain CTs served as control. Paired sets of images were created for each case: (1) axial images only ("axial only") and (2) axial, coronal, sagittal images ("reformat added"). Three readers interpreted both the axial only and companion reformat added for each case, separated by 1 month. Reading times and SDH detection rates were compared. One hundred SDH and 100 negative examinations were collected. Sensitivity and specificity for the axial-only scans were 75.7 and 94.3 %, respectively, compared with 88.3 and 98.3 % for reformat added. There was a 24.3 % false negative (missed SDH) rate with axial-only scans versus 11.7 % with reformat added (p = <0.001). Median reader interpretation times were longer with the addition of reformatted images (125 versus 89 s), but this difference was not significant (p = 0.23). The addition of coronal and sagittal images in trauma brain CT resulted in improved sensitivity and specificity as well as a reduction in SDH false negatives by greater than 50 %. Reformatted images substantially reduce the number of missed SDHs compared with axial images alone.

Adenovirus 36 seropositivity is strongly associated with race and gender, but not obesity, among US military personnel.

PubMed

Broderick, M P; Hansen, C J; Irvine, M; Metzgar, D; Campbell, K; Baker, C; Russell, K L

2010-02-01

Although several studies have shown a positive association between evidence of anti-adenovirus 36 (Ad-36) antibodies (Ad-36 exposure) and (1) obesity and (2) serum cholesterol in animals, there is limited research demonstrating this association in humans. There is also limited research on transmission, presentation and demographics of Ad-36 infection. (1) Body mass (body mass index (BMI)), (2) fasting serum cholesterol and triglyceride levels and (3) demographic characteristics were compared between Ad-36 seropositive and seronegative groups. The majority of subjects were matched as cases versus controls on a number of demographic variables. A total of 150 obese and 150 lean active-duty military personnel were studied. Subjects completed a questionnaire regarding demographic and behavioral characteristics. Subject serum samples were tested by serum neutralization assay for the presence of anti-Ad-36 antibodies. In all, 34% of obese and 39% of lean subjects had Ad-36 exposure, an insignificant difference. Serum cholesterol and triglyceride levels were significantly higher among the obese subjects than among the lean, but there were no associations between serum cholesterol and triglyceride levels and Ad-36 exposure. Positive associations were found between Ad-36 exposure and age, race and gender. The study stands in contrast to previous work that has shown a positive relationship between Ad-36 exposure and (1) obesity, and (2) levels of serum cholesterol and triglycerides. In this study there was no association in either case. Unanticipated relationships between Ad-36 exposure and age, race and gender were found, and this is the first time that such a link between Ad-36 exposure and demographics has been found.

Microglia show altered morphology and reduced arborization in human brain during aging and Alzheimer's disease.

PubMed

Davies, Danielle S; Ma, Jolande; Jegathees, Thuvarahan; Goldsbury, Claire

2017-11-01

Changes in microglia function are involved in Alzheimer's disease (AD) for which ageing is the major risk factor. We evaluated microglial cell process morphologies and their gray matter coverage (arborized area) during ageing and in the presence and absence of AD pathology in autopsied human neocortex. Microglial cell processes were reduced in length, showed less branching and reduced arborized area with aging (case range 52-98 years). This occurred during normal ageing and without microglia dystrophy or changes in cell density. There was a larger reduction in process length and arborized area in AD compared to aged-matched control microglia. In AD cases, on average, 49%-64% of microglia had discontinuous and/or punctate Iba1 labeled processes instead of continuous Iba1 distribution. Up to 16% of aged-matched control microglia displayed discontinuous or punctate features. There was no change in the density of microglial cell bodies in gray matter during ageing or AD. This demonstrates that human microglia show progressive cell process retraction without cell loss during ageing. Additional changes in microglia occur with AD including Iba1 protein puncta and discontinuity. We suggest that reduced microglial arborized area may be an aging-related correlate of AD in humans. These variations in microglial cells during ageing and in AD could reflect changes in neural-glial interactions which are emerging as key to mechanisms involved in ageing and neurodegenerative disease. © 2016 International Society of Neuropathology.

Gender-specific association of ATP-binding cassette transporter 1 (ABCA1) polymorphisms with the risk of late-onset Alzheimer's disease.

PubMed

Sundar, Purnima Desai; Feingold, Eleanor; Minster, Ryan L; DeKosky, Steven T; Kamboh, M Ilyas

2007-06-01

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder caused by a complex interaction of genetic and environmental factors. Increasing evidence highlights a potential role for cholesterol in the pathophysiology of AD. The ABCA1 gene, located in close vicinity to the 9q linkage peaks identified by genome-wide AD linkage studies, plays an important role in cellular cholesterol efflux, and is likely a good candidate gene. However, results from published genetic association studies between ABCA1 and AD are ambiguous. In the present study, we examined the role of two ABCA1 polymorphisms, R219K (rs2230806) and G-17C (rs2740483) in modifying the risk of late-onset AD (LOAD) in a large American white cohort of 992 AD cases and 699 controls. We observed significant gender x R219K interaction (p=0.00008). Female carriers of the 219K allele showed a 1.75-fold increased risk of developing AD compared to non-219K carrier females (95% CI 1.34-2.29; p=0.00004). The overall two-site haplotype distribution was also significant between female AD cases and controls (p=0.017). The risk associated with the R219K polymorphism was independent of the recently reported significant association in the ubiquilin (UBQLN1) gene in this region on chromosome 9q. Our data suggest a gender-specific and APOE and UBQLN1 independent association between the ABCA1/R219K polymorphism and LOAD.

Detecting navigational deficits in cognitive aging and Alzheimer disease using virtual reality.

PubMed

Cushman, Laura A; Stein, Karen; Duffy, Charles J

2008-09-16

Older adults get lost, in many cases because of recognized or incipient Alzheimer disease (AD). In either case, getting lost can be a threat to individual and public safety, as well as to personal autonomy and quality of life. Here we compare our previously described real-world navigation test with a virtual reality (VR) version simulating the same navigational environment. Quantifying real-world navigational performance is difficult and time-consuming. VR testing is a promising alternative, but it has not been compared with closely corresponding real-world testing in aging and AD. We have studied navigation using both real-world and virtual environments in the same subjects: young normal controls (YNCs, n = 35), older normal controls (ONCs, n = 26), patients with mild cognitive impairment (MCI, n = 12), and patients with early AD (EAD, n = 14). We found close correlations between real-world and virtual navigational deficits that increased across groups from YNC to ONC, to MCI, and to EAD. Analyses of subtest performance showed similar profiles of impairment in real-world and virtual testing in all four subject groups. The ONC, MCI, and EAD subjects all showed greatest difficulty in self-orientation and scene localization tests. MCI and EAD patients also showed impaired verbal recall about both test environments. Virtual environment testing provides a valid assessment of navigational skills. Aging and Alzheimer disease (AD) share the same patterns of difficulty in associating visual scenes and locations, which is complicated in AD by the accompanying loss of verbally mediated navigational capacities. We conclude that virtual navigation testing reveals deficits in aging and AD that are associated with potentially grave risks to our patients and the community.

Picture agnosia as a characteristic of posterior cortical atrophy.

PubMed

Sugimoto, Azusa; Midorikawa, Akira; Koyama, Shinichi; Futamura, Akinori; Hieda, Sotaro; Kawamura, Mitsuru

2012-01-01

Posterior cortical atrophy (PCA) is a degenerative disease characterized by progressive visual agnosia with posterior cerebral atrophy. We examine the role of the picture naming test and make a number of suggestions with regard to diagnosing PCA as atypical dementia. We investigated 3 cases of early-stage PCA with 7 control cases of Alzheimer disease (AD). The patients and controls underwent a naming test with real objects and colored photographs of familiar objects. We then compared rates of correct answers. Patients with early-stage PCA showed significant inability to recognize photographs compared to real objects (F = 196.284, p = 0.0000) as measured by analysis of variants. This difficulty was also significant to AD controls (F = 58.717, p = 0.0000). Picture agnosia is a characteristic symptom of early-stage PCA, and the picture naming test is useful for the diagnosis of PCA as atypical dementia at an early stage. Copyright © 2012 S. Karger AG, Basel.

Identification and medical utilization of incident cases of alcohol dependence: A population-based case-control study.

PubMed

Pan, Chun-Hung; Li, Min-Shan; Yang, Tien-Wey; Huang, Ming-Chyi; Su, Sheng-Shiang; Hung, Yen-Ni; Chen, Chiao-Chicy; Kuo, Chian-Jue

2018-05-05

Patients with alcohol dependence (AD) often seek help from medical professionals due to alcohol-related diseases, but the overall distribution of medical specialties identifying new AD cases is unclear. We investigated how such cases were identified and how medical resources were utilized before the identification of AD in a nationwide cohort. We enrolled a population-based cohort (N = 1,000,000) using the National Health Insurance Research Database of Taiwan; 8181 cases with incident AD were retrieved between January 1, 2000, and December 31, 2010. For this nested case-control study, four controls were matched for age and sex with each case based on risk-set sampling. We measured various dimensions of medical utilization before AD was diagnosed, including department visited, physical comorbidity, and medication used. Conditional logistic regression was used for estimating the variables associated with AD. Patients living in less urbanized areas who were unemployed were more likely to develop AD. The highest proportions (34.2%) of AD cases were identified in the internal medicine department, followed by the emergency (22.3%) and psychiatry (18.7%) departments. AD patients had a higher risk of comorbid chronic hepatic disease (adjusted RR = 2.72, p < 0.001) before identification of AD than controls. AD patients also had greater numbers of hospital admissions than controls, including non-psychiatric and psychiatric hospitalizations. Outpatient visit numbers were similar for AD patients and controls. The findings indicate that clinicians providing care in diverse medical settings should be prepared to screen for unhealthy alcohol use and to mitigate its detrimental effects. Copyright © 2018 Elsevier B.V. All rights reserved.

When Cognitive Decline and Depression Coexist in the Elderly: CSF Biomarkers Analysis Can Differentiate Alzheimer's Disease from Late-Life Depression.

PubMed

Liguori, Claudio; Pierantozzi, Mariangela; Chiaravalloti, Agostino; Sancesario, Giulia M; Mercuri, Nicola B; Franchini, Flaminia; Schillaci, Orazio; Sancesario, Giuseppe

2018-01-01

Late-life depression (LLD) and Alzheimer's Disease (AD) are the two most frequent neuropsychiatric disorders affecting elderly. LLD and AD may clinically present with depressive and cognitive symptoms. Therefore, when cognitive decline is coupled with depression in the elderly, the differential diagnosis between LLD and AD could be challenging. The aim of the present study was to evaluate in a population of elderly patients affected by depression and dementia the usefulness of CSF AD biomarkers (tau proteins and β-amyloid 42 -Aβ 42 ) and 2-[18F]fluoro-2-deoxy-d-glucose positron emission tomography (18FFDG-PET) in early differentiating LLD from AD. Two hundred and fifty-six depressed and demented patients, after performing CSF AD biomarkers and 18FFDG-PET, were distributed in two groups on the basis of the current diagnostic guidelines for AD ( n = 201) and LLD ( n = 55). Patients were then observed for 2 years to verify the early diagnosis. After the 2 year follow-up we compared AD and LLD patients' CSF and 18FFDG-PET data obtained at baseline to a group of age- and sex-matched controls. We found CSF Aβ 42 levels significantly higher in LLD compared to AD patients. Remarkably, CSF Aβ 42 levels of LLD patients (range between 550 and 1204 pg/mL) did not overlap with those of AD patients (range between 82 and 528 pg/mL). Moreover, we documented no differences in CSF AD biomarkers (Aβ 42 and tau proteins) when comparing LLD patients to controls. In addition, AD patients showed the significant reduction of 18FFDG-PET uptake in temporo-parietal regions compared to both controls and LLD. Conversely, LLD and control groups did not differ at 18FFDG-PET analysis, although LLD patients showed heterogeneous patterns of glucose hypometabolism involving cortical and subcortical brain areas. It is noteworthy that at the end of the clinical follow-up, patients owing to AD group showed the expected significant decline of cognitive performances, whereas patients assigned to LLD group improved cognition as depressive symptoms recovered. Hence, in case of co-existence of cognitive impairment and depression in the elderly, we propose CSF AD biomarkers analysis to early differentiate LLD from AD and properly target the patient's therapeutic strategy and clinical follow-up.

Magnetic Resonance Imaging and Anatomical Correlation of Human Temporal Lobe Landmarks, in 3D Euclidean Space: A Study of Control and Alzheimer's Disease Subjects.

PubMed

Delgado-González, José-Carlos; Florensa-Vila, José; Mansilla-Legorburo, Francisco; Insausti, Ricardo; Artacho-Pérula, Emilio

2017-01-01

The medial temporal lobe (MTL), and in particular the hippocampal formation, is essential in the processing and consolidation of declarative memory. The 3D environment of the anatomical structures contained in the MTL is an important issue. Our aim was to explore the spatial relationship of the anatomical structures of the MTL and changes in aging and/or Alzheimer's disease (AD). MTL anatomical landmarks are identified and registered to create a 3D network. The brain network is quantitatively described as a plane, rostrocaudally-oriented, and presenting Euclidean/real distances. Correspondence between 1.5T RM, 3T RM, and histological sections were assessed to determine the most important recognizable changes in AD, based on statistical significance. In both 1.5T and 3T RM images and histology, inter-rater reliability was high. Sex and hemisphere had no influence on network pattern. Minor changes were found in relation to aging. Distances from the temporal pole to the dentate gyrus showed the most significant differences when comparing control and AD groups. The best discriminative distance between control and AD cases was found in the temporal pole/dentate gyrus rostrocaudal length in histological sections. Moreover, more distances between landmarks were required to obtain 100% discrimination between control (divided into <65 years or >65 years) and AD cases. Changes in the distance between MTL anatomical landmarks can successfully be detected by using measurements of 3D network patterns in control and AD cases.

Glutamate and GABA-metabolizing enzymes in post-mortem cerebellum in Alzheimer's disease: phosphate-activated glutaminase and glutamic acid decarboxylase.

PubMed

Burbaeva, G Sh; Boksha, I S; Tereshkina, E B; Savushkina, O K; Prokhorova, T A; Vorobyeva, E A

2014-10-01

Enzymes of glutamate and GABA metabolism in postmortem cerebellum from patients with Alzheimer's disease (AD) have not been comprehensively studied. The present work reports results of original comparative study on levels of phosphate-activated glutaminase (PAG) and glutamic acid decarboxylase isoenzymes (GAD65/67) in autopsied cerebellum samples from AD patients and matched controls (13 cases in each group) as well as summarizes published evidence for altered levels of PAG and GAD65/67 in AD brain. Altered (decreased) levels of these enzymes and changes in links between amounts of these enzymes and other glutamate-metabolizing enzymes (such as glutamate dehydrogenase and glutamine synthetase-like protein) in AD cerebella suggest significantly impaired glutamate and GABA metabolism in this brain region, which was previously regarded as not substantially involved in AD pathogenesis.

Conventional metrizamide myelography (MM) and computed tomographic metrizamide myelography (CTMM) in scoliosis: a comparative study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pettersson, H.; Harwood-Nash, D.C.; Fitz, C.R.

1982-01-01

A retrospective examination was performed to assess the accuracy of metrizamide myelography (MM) and computed tomographic metrizamide myelography (CTMM) in scoliosis. Of 81 consecutive scoliotic children studied by myelography, 30 had only MM while the remaining 51 had CTMM immediately afterward. CTMM added esential diagnostic information in 13 cases of dysraphism and 4 cases, both methods gave the same imformation. The outhors conclude that in patients with severe scoliosis, dysraphism, and scoliosis with localized neurological disturbances, CTMM should always be added to MM or be the only examination; while in idiopathic scoliosis with vague neurological disturbances a survey of themore » entire spine is essential, preferably with MM.« less

Neuropathology of dementia with Lewy bodies in advanced age: a comparison with Alzheimer disease.

PubMed

Ubhi, Kiren; Peng, Kevin; Lessig, Stephanie; Estrella, Jennilyn; Adame, Anthony; Galasko, Douglas; Salmon, David P; Hansen, Lawrence A; Kawas, Claudia H; Masliah, Eliezer

2010-11-26

Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder of the aging population characterized by α-synuclein accumulation in cortical and subcortical regions. Although neuropathology in advanced age has been investigated in dementias such as Alzheimer Disease (AD), severity of the neuropathology in the oldest old with DLB remains uncharacterized. For this purpose we compared characteristics of DLB cases divided into three age groups 70-79, 80-89 and ≥ 90 years (oldest old). Neuropathological indicators and levels of synaptophysin were assessed and correlated with clinical measurements of cognition and dementia severity. These studies showed that frequency and severity of DLB was lower in 80-89 and ≥ 90 year cases compared to 70-79 year old group but cognitive impairment did not vary with age. The extent of AD neuropathology correlated with dementia severity only in the 70-79 year group, while synaptophysin immunoreactivity more strongly associated with dementia severity in the older age group in both DLB and AD. Taken together these results suggest that the oldest old with DLB might represent a distinct group. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Smoking, death, and Alzheimer disease: a case of competing risks.

PubMed

Chang, Chung-Chou H; Zhao, Yongyun; Lee, Ching-Wen; Ganguli, Mary

2012-01-01

If smoking is a risk factor for Alzheimer disease (AD) but a smoker dies of another cause before developing or manifesting AD, smoking-related mortality may mask the relationship between smoking and AD. This phenomenon, referred to as competing risk, complicates efforts to model the effect of smoking on AD. Typical survival regression models assume that censorship from analysis is unrelated to an individual's probability for developing AD (ie, censoring is noninformative). However, if individuals who die before developing AD are younger than those who survive long enough to develop AD, and if they include a higher percentage of smokers than nonsmokers, the incidence of AD will appear to be higher in older individuals and in nonsmokers. Further, age-specific mortality rates are higher in smokers because they die earlier than nonsmokers. Therefore, if we fail to take into account the competing risk of death when we estimate the effect of smoking on AD, we bias the results and are in fact only comparing the incidence of AD in nonsmokers with that in the healthiest smokers. In this study, we demonstrate that the effect of smoking on AD differs in models that are and are not adjusted for competing risks.

Detecting navigational deficits in cognitive aging and Alzheimer disease using virtual reality

PubMed Central

Cushman, Laura A.; Stein, Karen; Duffy, Charles J.

2008-01-01

Background: Older adults get lost, in many cases because of recognized or incipient Alzheimer disease (AD). In either case, getting lost can be a threat to individual and public safety, as well as to personal autonomy and quality of life. Here we compare our previously described real-world navigation test with a virtual reality (VR) version simulating the same navigational environment. Methods: Quantifying real-world navigational performance is difficult and time-consuming. VR testing is a promising alternative, but it has not been compared with closely corresponding real-world testing in aging and AD. We have studied navigation using both real-world and virtual environments in the same subjects: young normal controls (YNCs, n = 35), older normal controls (ONCs, n = 26), patients with mild cognitive impairment (MCI, n = 12), and patients with early AD (EAD, n = 14). Results: We found close correlations between real-world and virtual navigational deficits that increased across groups from YNC to ONC, to MCI, and to EAD. Analyses of subtest performance showed similar profiles of impairment in real-world and virtual testing in all four subject groups. The ONC, MCI, and EAD subjects all showed greatest difficulty in self-orientation and scene localization tests. MCI and EAD patients also showed impaired verbal recall about both test environments. Conclusions: Virtual environment testing provides a valid assessment of navigational skills. Aging and Alzheimer disease (AD) share the same patterns of difficulty in associating visual scenes and locations, which is complicated in AD by the accompanying loss of verbally mediated navigational capacities. We conclude that virtual navigation testing reveals deficits in aging and AD that are associated with potentially grave risks to our patients and the community. GLOSSARY AD = Alzheimer disease; EAD = early Alzheimer disease; MCI = mild cognitive impairment; MMSE = Mini-Mental State Examination; ONC = older normal control; std. wt. = standardized weight; THSD = Tukey honestly significant difference; VR = virtual reality; YNC = young normal control. PMID:18794491

An Estimate of Attributable Cases of Alzheimer Disease and Vascular Dementia due to Modifiable Risk Factors: The Impact of Primary Prevention in Europe and in Italy.

PubMed

Mayer, Flavia; Di Pucchio, Alessandra; Lacorte, Eleonora; Bacigalupo, Ilaria; Marzolini, Fabrizio; Ferrante, Gianluigi; Minardi, Valentina; Masocco, Maria; Canevelli, Marco; Di Fiandra, Teresa; Vanacore, Nicola

2018-01-01

Up to 53.7% of all cases of dementia are assumed to be due to Alzheimer disease (AD), while 15.8% are considered to be due to vascular dementia (VaD). In Europe, about 3 million cases of AD could be due to 7 potentially modifiable risk factors: diabetes, midlife hypertension and/or obesity, physical inactivity, depression, smoking, and low educational level. To estimate the number of VaD cases in Europe and the number of AD and VaD cases in Italy attributable to these 7 potentially modifiable risk factors. Assuming the nonindependence of the 7 risk factors, the adjusted combined population attributable risk (PAR) was estimated for AD and VaD. In Europe, adjusted combined PAR was 31.4% for AD and 37.8% for VaD. The total number of attributable cases was 3,033,000 for AD and 873,000 for VaD. In Italy, assuming a 20% reduction of the prevalence of each risk factor, adjusted combined PAR decreased from 45.2 to 38.9% for AD and from 53.1 to 46.6% for VaD, implying a 6.4 and 6.5% reduction in the prevalence of AD and VaD, respectively. A relevant reduction of AD and VaD cases in Europe and Italy could be obtained through primary prevention.

Case-based synthesis in automatic advertising creation system

NASA Astrophysics Data System (ADS)

Zhuang, Yueting; Pan, Yunhe

1995-08-01

Advertising (ads) is an important design area. Though many interactive ad-design softwares have come into commercial use, none of them ever support the intelligent work -- automatic ad creation. The potential for this is enormous. This paper gives a description of our current work in research of an automatic advertising creation system (AACS). After careful analysis of the mental behavior of a human ad designer, we conclude that case-based approach is appropriate to its intelligent modeling. A model for AACS is given in the paper. A case in ads is described as two parts: the creation process and the configuration of the ads picture, with detailed data structures given in the paper. Along with the case representation, we put forward an algorithm. Some issues such as similarity measure computing, and case adaptation have also been discussed.

A Comparative Analysis of Strategic Approaches for Information Technology (IT) Management for Commander Naval Surface Forces

DTIC Science & Technology

2010-03-01

29 d. Coca Cola Case Study .............................................................31 3. Outsourcing...Electric, Coca - Cola , Hershey Foods, International Business Machines Corporation (IBM), and BP/Amoco (Lousek, 2000). c. Disadvantages of ERP ERP...look at all aspects of the organization to determine if the value added is worth the cost of implementing an ERP system. d. Coca Cola Case Study

MR imaging of the hippocampus in normal pressure hydrocephalus: correlations with cortical Alzheimer's disease confirmed by pathologic analysis.

PubMed

Savolainen, S; Laakso, M P; Paljärvi, L; Alafuzoff, I; Hurskainen, H; Partanen, K; Soininen, H; Vapalahti, M

2000-02-01

MR studies have shown hippocampal atrophy to be a sensitive diagnostic feature of Alzheimer's disease (AD). In this study, we measured the hippocampal volumes of patients with a clinical diagnosis of normal pressure hydrocephalus (NPH), a potentially reversible cause of dementia when shunted. Further, we examined the relationship between the hippocampal volumes and cortical AD pathologic findings, intracranial pressure, and clinical outcomes in cases of NPH. We measured hippocampal volumes from 37 patients with a clinical diagnosis of NPH (27 control volunteers and 24 patients with AD). The patients with NPH underwent biopsy, and their clinical outcomes were followed for a year. Compared with those for control volunteers, the findings for patients with NPH included a minor left-side decrease in the hippocampal volumes (P < .05). Compared with those for patients with AD, the findings for patients with NPH included significantly larger hippocampi on both sides. Although not statistically significant, trends toward larger volumes were observed in patients with NPH who had elevated intracranial pressure, who benefited from shunting, and who did not display cortical AD pathologic findings. Measurements of hippocampal volumes among patients with a clinical diagnosis of NPH have clear clinical implications, providing diagnostic discrimination from AD and possibly prediction of clinical outcome after shunting.

Alzheimer's disease - a neurospirochetosis. Analysis of the evidence following Koch's and Hill's criteria.

PubMed

Miklossy, Judith

2011-08-04

It is established that chronic spirochetal infection can cause slowly progressive dementia, brain atrophy and amyloid deposition in late neurosyphilis. Recently it has been suggested that various types of spirochetes, in an analogous way to Treponema pallidum, could cause dementia and may be involved in the pathogenesis of Alzheimer's disease (AD). Here, we review all data available in the literature on the detection of spirochetes in AD and critically analyze the association and causal relationship between spirochetes and AD following established criteria of Koch and Hill. The results show a statistically significant association between spirochetes and AD (P = 1.5 × 10-17, OR = 20, 95% CI = 8-60, N = 247). When neutral techniques recognizing all types of spirochetes were used, or the highly prevalent periodontal pathogen Treponemas were analyzed, spirochetes were observed in the brain in more than 90% of AD cases. Borrelia burgdorferi was detected in the brain in 25.3% of AD cases analyzed and was 13 times more frequent in AD compared to controls. Periodontal pathogen Treponemas (T. pectinovorum, T. amylovorum, T. lecithinolyticum, T. maltophilum, T. medium, T. socranskii) and Borrelia burgdorferi were detected using species specific PCR and antibodies. Importantly, co-infection with several spirochetes occurs in AD. The pathological and biological hallmarks of AD were reproduced in vitro by exposure of mammalian cells to spirochetes. The analysis of reviewed data following Koch's and Hill's postulates shows a probable causal relationship between neurospirochetosis and AD. Persisting inflammation and amyloid deposition initiated and sustained by chronic spirochetal infection form together with the various hypotheses suggested to play a role in the pathogenesis of AD a comprehensive entity. As suggested by Hill, once the probability of a causal relationship is established prompt action is needed. Support and attention should be given to this field of AD research. Spirochetal infection occurs years or decades before the manifestation of dementia. As adequate antibiotic and anti-inflammatory therapies are available, as in syphilis, one might prevent and eradicate dementia.

Association studies in late onset sporadic Alzheimer`s disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goate, A.M.; Lendon, C.; Talbot, C.

1994-09-01

Alzheimer`s disease (AD) is characterized by an adult onset progressive dementia and the presence of numerous plaques and tangles within the brain at autopsy. The senile plaques are composed of a proteinaceous core surrounded by dystrophic neurites. The major protein component of the core is {beta}-amyloid but antibodies to many other proteins bind to senile plaques, e.g., antibodies to apolioprotein E (ApoE) and to {alpha}1-antichymotrypsin (AACT). Genetic studies have implicated mutations within the {beta}-amyloid precursor protein gene as the cause of AD in a small number of early onset AD families. More recently, assocition studies in late onset AD havemore » demonstrated a positive association between ApoE-{epsilon}4 and AD. We report evidence for a negative association between ApoE-{epsilon}2 and AD in a large sample of sporadic late onset AD cases and matched controls supporting the role of ApoE in the etiology of AD. Ninety-three patients with sporadic AD (average age = 75 years, s.d. 8 yrs.) and 67 normal controls from the same ethnic background (age = 77 yrs., s.d. 10 yrs.) were recruited through the patient registry of the Washington University Alzheimer`s Disease Research Center. We found a statistically significant increase in ApoE-{epsilon}4 allele frequency in patients compared with controls ({chi}{sup 2}=7.75, 1 d.f., one tailed p=0.0027) and a significant decrease in {epsilon}2 allele frequency (Fisher`s exact test, one tailed p=0.0048), whereas the decreased frequency of {epsilon}3 in the patient groups was not statistically significant. Allele {epsilon}2 conferred a strong protective effect in our sample, with the odds ratio for AD for subjects possessing this allele being 0.08 (85% confidence interval 0.01-0.69). Similar studies using a polymorphism within the AACT gene showed no association with alleles at this locus in the entire AD sample or in AD cases homozygous for ApoE-{epsilon}3.« less

Impact of Muscarinic M3 Receptor Antagonism on the Risk of Type 2 Diabetes in Antidepressant-Treated Patients: A Case-Controlled Study.

PubMed

Tran, Yen-Hao; Schuiling-Veninga, Catharina C M; Bergman, Jorieke E H; Groen, Henk; Wilffert, Bob

2017-06-01

M 3 muscarinic receptor antagonism has been associated with glucose intolerance and disturbance of insulin secretion. Our objective was to examine the risk of type 2 diabetes mellitus (T2DM) in patients using antidepressants with and without M 3 muscarinic receptor antagonism (AD_antaM 3 and AD_nonantaM 3 , respectively). We designed a case-control study using a pharmacy prescription database. We selected a cohort of patients who initiated antidepressant use between the ages of 20 and 40 years and who did not receive any anti-diabetic prescriptions at baseline. Cases were defined as those who developed T2DM [i.e., receiving oral anti-diabetic medication, Anatomical Therapeutic Chemical (ATC) code A10B] during the follow-up period (1994-2014), and ten random controls were picked for each case from the cohort of patients who did not develop T2DM. A total of 530 cases with incident T2DM and 5300 controls were included. Compared with no use of antidepressants during the previous 2 years, recent (within the last 6 months) exposure to AD_antaM 3 was associated with a moderately increased risk of T2DM: adjusted odds ratio 1.55 (95% confidence interval 1.18-2.02). In the stratified analyses, this association was dose dependent (>365 defined daily doses) and significant for patients who were in the younger age group (<45 years at the end of follow-up), were female and had no co-morbidity. On the other hand, recent exposure to AD_nonantaM 3 was not associated with a risk for T2DM in any of our analyses. Our results suggest that exposure to AD_antaM 3 was associated with the development of T2DM among antidepressant users.

Modeling screening, prevention, and delaying of Alzheimer's disease: an early-stage decision analytic model

PubMed Central

2010-01-01

Background Alzheimer's Disease (AD) affects a growing proportion of the population each year. Novel therapies on the horizon may slow the progress of AD symptoms and avoid cases altogether. Initiating treatment for the underlying pathology of AD would ideally be based on biomarker screening tools identifying pre-symptomatic individuals. Early-stage modeling provides estimates of potential outcomes and informs policy development. Methods A time-to-event (TTE) simulation provided estimates of screening asymptomatic patients in the general population age ≥55 and treatment impact on the number of patients reaching AD. Patients were followed from AD screen until all-cause death. Baseline sensitivity and specificity were 0.87 and 0.78, with treatment on positive screen. Treatment slowed progression by 50%. Events were scheduled using literature-based age-dependent incidences of AD and death. Results The base case results indicated increased AD free years (AD-FYs) through delays in onset and a reduction of 20 AD cases per 1000 screened individuals. Patients completely avoiding AD accounted for 61% of the incremental AD-FYs gained. Total years of treatment per 1000 screened patients was 2,611. The number-needed-to-screen was 51 and the number-needed-to-treat was 12 to avoid one case of AD. One-way sensitivity analysis indicated that duration of screening sensitivity and rescreen interval impact AD-FYs the most. A two-way sensitivity analysis found that for a test with an extended duration of sensitivity (15 years) the number of AD cases avoided was 6,000-7,000 cases for a test with higher sensitivity and specificity (0.90,0.90). Conclusions This study yielded valuable parameter range estimates at an early stage in the study of screening for AD. Analysis identified duration of screening sensitivity as a key variable that may be unavailable from clinical trials. PMID:20433705

Modeling screening, prevention, and delaying of Alzheimer's disease: an early-stage decision analytic model.

PubMed

Furiak, Nicolas M; Klein, Robert W; Kahle-Wrobleski, Kristin; Siemers, Eric R; Sarpong, Eric; Klein, Timothy M

2010-04-30

Alzheimer's Disease (AD) affects a growing proportion of the population each year. Novel therapies on the horizon may slow the progress of AD symptoms and avoid cases altogether. Initiating treatment for the underlying pathology of AD would ideally be based on biomarker screening tools identifying pre-symptomatic individuals. Early-stage modeling provides estimates of potential outcomes and informs policy development. A time-to-event (TTE) simulation provided estimates of screening asymptomatic patients in the general population age > or =55 and treatment impact on the number of patients reaching AD. Patients were followed from AD screen until all-cause death. Baseline sensitivity and specificity were 0.87 and 0.78, with treatment on positive screen. Treatment slowed progression by 50%. Events were scheduled using literature-based age-dependent incidences of AD and death. The base case results indicated increased AD free years (AD-FYs) through delays in onset and a reduction of 20 AD cases per 1000 screened individuals. Patients completely avoiding AD accounted for 61% of the incremental AD-FYs gained. Total years of treatment per 1000 screened patients was 2,611. The number-needed-to-screen was 51 and the number-needed-to-treat was 12 to avoid one case of AD. One-way sensitivity analysis indicated that duration of screening sensitivity and rescreen interval impact AD-FYs the most. A two-way sensitivity analysis found that for a test with an extended duration of sensitivity (15 years) the number of AD cases avoided was 6,000-7,000 cases for a test with higher sensitivity and specificity (0.90,0.90). This study yielded valuable parameter range estimates at an early stage in the study of screening for AD. Analysis identified duration of screening sensitivity as a key variable that may be unavailable from clinical trials.

Differential diagnosis of degenerative dementias using basic neuropsychological tests: multivariable logistic regression analysis of 301 patients.

PubMed

Jiménez-Huete, Adolfo; Riva, Elena; Toledano, Rafael; Campo, Pablo; Esteban, Jesús; Barrio, Antonio Del; Franch, Oriol

2014-12-01

The validity of neuropsychological tests for the differential diagnosis of degenerative dementias may depend on the clinical context. We constructed a series of logistic models taking into account this factor. We retrospectively analyzed the demographic and neuropsychological data of 301 patients with probable Alzheimer's disease (AD), frontotemporal degeneration (FTLD), or dementia with Lewy bodies (DLB). Nine models were constructed taking into account the diagnostic question (eg, AD vs DLB) and subpopulation (incident vs prevalent). The AD versus DLB model for all patients, including memory recovery and phonological fluency, was highly accurate (area under the curve = 0.919, sensitivity = 90%, and specificity = 80%). The results were comparable in incident and prevalent cases. The FTLD versus AD and DLB versus FTLD models were both inaccurate. The models constructed from basic neuropsychological variables allowed an accurate differential diagnosis of AD versus DLB but not of FTLD versus AD or DLB. © The Author(s) 2014.

Leading with Data: Evidence from the National Center on Scaling up Effective Schools

ERIC Educational Resources Information Center

Cohen-Vogel, Lora; Harrison, Christopher

2013-01-01

Through comparative case study, we seek to understand the ways in which actors in high schools use and think about performance data. In particular, we compare data use in higher and lower value-added schools. Data use is conceptualized here as having access to a host of available performance data on students, using them to guide instructional…

Experiment evaluates ocean models and data assimiliation in the Gulf Stream

NASA Astrophysics Data System (ADS)

Willems, Robert C.; Glenn, S. M.; Crowley, M. F.; Malanotte-Rizzoli, P.; Young, R. E.; Ezer, T.; Mellor, G. L.; Arango, H. G.; Robinson, A. R.; Lai, C.-C. A.

Using data sets of known quality as the basis for comparison, a recent experiment explored the Gulf Stream Region at 27°-47°N and 80°-50°W to assess the nowcast/forecast capability of specific ocean models and the impact of data assimilation. Scientists from five universities and the Naval Research Laboratory/Stennis Space Center participated in the Data Assimilation and Model Evaluation Experiment (DAMEÉ-GSR).DAMEÉ-GSR was based on case studies, each successively more complex, and was divided into three phases using case studies (data) from 1987 and 1988. Phase I evaluated models' forecast capability using common initial conditions and comparing model forecast fields with observational data at forecast time over a 2-week period. Phase II added data assimilation and assessed its impact on forecast capability, using the same case studies as in phase I, and phase III added a 2-month case study overlapping some periods in Phases I and II.

Global warming potential of material fractions occurring in source-separated organic household waste treated by anaerobic digestion or incineration under different framework conditions.

PubMed

Naroznova, Irina; Møller, Jacob; Scheutz, Charlotte

2016-12-01

This study compared the environmental profiles of anaerobic digestion (AD) and incineration, in relation to global warming potential (GWP), for treating individual material fractions that may occur in source-separated organic household waste (SSOHW). Different framework conditions representative for the European Union member countries were considered. For AD, biogas utilisation with a biogas engine was considered and two potential situations investigated - biogas combustion with (1) combined heat and power production (CHP) and (2) electricity production only. For incineration, four technology options currently available in Europe were covered: (1) an average incinerator with CHP production, (2) an average incinerator with mainly electricity production, (3) an average incinerator with mainly heat production and (4) a state-of-the art incinerator with CHP working at high energy recovery efficiencies. The study was performed using a life cycle assessment in its consequential approach. Furthermore, the role of waste-sorting guidelines (defined by the material fractions allowed for SSOHW) in relation to GWP of treating overall SSOHW with AD was investigated. A case-study of treating 1tonne of SSOHW under framework conditions in Denmark was conducted. Under the given assumptions, vegetable food waste was the only material fraction which was always better for AD compared to incineration. For animal food waste, kitchen tissue, vegetation waste and dirty paper, AD utilisation was better unless it was compared to a highly efficient incinerator. Material fractions such as moulded fibres and dirty cardboard were attractive for AD, albeit only when AD with CHP and incineration with mainly heat production were compared. Animal straw, in contrast, was always better to incinerate. Considering the total amounts of individual material fractions in waste generated within households in Denmark, food waste (both animal and vegetable derived) and kitchen tissue are the main material fractions allowing GWP mitigation with AD when it is compared to incineration. The inclusion of other material fractions in SSOHW sorting guidelines may be considered of less importance. Copyright © 2016 Elsevier Ltd. All rights reserved.

Specific serum and CSF microRNA profiles distinguish sporadic behavioural variant of frontotemporal dementia compared with Alzheimer patients and cognitively healthy controls

PubMed Central

Oberhauser, Felix; Kornhuber, Johannes; Wiltfang, Jens; Fassbender, Klaus; Schroeter, Matthias L.; Volk, Alexander E.; Diehl-Schmid, Janine; Prudlo, Johannes; Danek, Adrian; Landwehrmeyer, Bernhard; Lauer, Martin; Otto, Markus; Jahn, Holger

2018-01-01

Information on circulating miRNAs in frontotemporal lobar degeneration is very limited and conflicting results have complicated an interpretation in Alzheimer’s disease thus far. In the present study we I) collected samples from multiple clinical centers across Germany, II) defined 3 homogenous patient groups with high sample sizes (bvFTD n = 48, AD n = 48 and cognitively healthy controls n = 44), III) compared expression levels in both CSF and serum samples and IV) detected a limited set of miRNAs by using a MIQE compliant protocol based on SYBR-green miRCURY assays that have proven reliable to generate reproducible results. We included several quality controls that identified and reduced technical variation to increase the reliability of our data. We showed that the expression levels of circulating miRNAs measured in CSF did not correlate with levels in serum. Using cluster analysis we found expression pattern in serum that, in part, reflects the genomic organization and affiliation to a specific miRNA family and that were specifically altered in bvFTD, AD, and control groups. Applying factor analysis we identified a 3-factor model characterized by a miRNA signature that explained 80% of the variance classifying healthy controls with 97%, bvFTD with 77% and AD with 72% accuracy. MANOVA confirmed signals like miR-320a and miR-26b-5p at BH corrected significance that contributed most to discriminate bvFTD cases with 96% sensitivity and 90% specificity and AD cases with 89% sensitivity and specificity compared to healthy controls, respectively. Correlation analysis revealed that miRNAs from the 3-factor model also correlated with levels of protein biomarker amyloid-beta1-42 and phosphorylated neurofilament heavy chain, indicating their potential role in the monitoring of progressive neuronal degeneration. Our data show that miRNAs can be reproducibly measured in serum and CSF without pre-amplification and that serum includes higher expressed signals that demonstrate an overall better ability to classify bvFTD, AD and healthy controls compared to signals detected in CSF. PMID:29746584

Operative vaginal delivery in case of persistent occiput posterior position after manual rotation failure: a 6-month follow-up on pelvic floor function.

PubMed

Guerby, Paul; Parant, Olivier; Chantalat, Elodie; Vayssiere, Christophe; Vidal, Fabien

2018-07-01

To compare the short- and long-term perineal consequences (at 6 months postpartum) and short-term neonatal consequences of instrumental rotation (IR) to those induced by assisted delivery (AD) in the occiput posterior (OP) position, in case of manual rotation failure. A prospective observational cohort study; tertiary referral hospital including all women presenting with persistent OP position who delivered vaginally after manual rotation failure with attempted IR or AD in OP position from September 2015 to October 2016. Maternal and neonatal outcomes of all attempted IR deliveries were compared with OP operative vaginal deliveries. Main outcomes measured were pelvic floor function at 6 months postpartum including Wexner score for anal incontinence and ICIQ-FLUTS for urinary symptoms. Perineal morbidity comprised severe perineal tears, corresponding to third and fourth degree lacerations. Fetal morbidity parameters comprised low neonatal Apgar scores, acidaemia, major and minor fetal injuries and neonatal intensive care unit admissions. Among 5265 women, 495 presented with persistent OP positions (9.4%) and 111 delivered after manual rotation failure followed by AD delivery: 58 in the IR group and 53 in the AD in OP group. The incidence of anal sphincter injuries was significantly reduced after IR attempt (1.7% vs. 24.5%; p < 0.001) without increasing neonatal morbidity. At 6 months postpartum, AD in OP position was associated with higher rate of anal incontinence (30% vs. 5.5%, p = 0.001) and with more urinary symptoms, dyspareunia and perineal pain. OP operative deliveries are associated with significant perineal morbidity and pelvic floor dysfunction at 6 months postpartum.

Lipoperoxidation is selectively involved in progressive supranuclear palsy.

PubMed

Odetti, P; Garibaldi, S; Norese, R; Angelini, G; Marinelli, L; Valentini, S; Menini, S; Traverso, N; Zaccheo, D; Siedlak, S; Perry, G; Smith, M A; Tabaton, M

2000-05-01

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by extensive neurofibrillary tangle (NFT) formation and neuronal loss in selective neuronal populations. Currently, no clues to the biological events underlying the pathological process have emerged. In Alzheimer disease (AD), which shares with PSP the occurrence of NFTs, advanced glycation end products (AGEs) as well as oxidation adducts have been found to be increased in association with neurofibrillary pathology. The presence and the amount of lipid and protein oxidation markers, as well as of pyrraline and pentosidine. 2 major AGEs, was assessed by biochemical, immunochemical, and immunocytochemical analysis in midbrain tissue from 5 PSP cases, 6 sporadic AD cases, and 6 age-matched control cases. The levels of 4-hydroxynonenal (HNE) and thiobarbituric acid reactive substances (TBARS), 2 major products of lipid peroxidation, were significantly increased by 1.6-fold (p < 0.04) and 3.9-fold (p < 0.01), respectively, in PSP compared with control tissues, whereas in AD only TBARS were significantly increased. In PSP tissue the intensity of neuronal HNE immunoreactivity was proportional to the extent of abnormal aggregated tau protein. The amount of protein oxidation products and AGEs was instead similar in PSP and control tissues. In AD, a higher but not significant level of pyrraline and pentosidine was measured, whereas the level of carbonyl groups was doubled. These findings indicate that in PSP, unlike in AD, lipid peroxidation is selectively associated with NFT formation. The intraneuronal accumulation of toxic aldehydes may contribute to hamper tau degradation, leading to its aggregation in the PSP specific abnormal filaments.

Exploring avenues for best use of cytotechnologists in non-gynaecological cytology: Double screening or independent sign-out.

PubMed

Fischer, G; Haddad, M; Cormier, K

2018-02-01

Cytotechnologist (CT) screening workload has been decreasing due to the falling number of Papanicolaou tests. This continuing trend has prompted exploration of ways to best employ the CT skillset. One potential way of more effective use is by having two CTs double screen non-gynaecological (NGC) cases to assess whether this improves screening quality and concordance with pathologists. Another is evaluating the CT's performance on low-complexity negative NGC cases for a potential independent CT sign-out without pathologist review. In total, 1119 NGC cases were reviewed; 577 screened by two CTs and 542 screened by one CT. All cases were signed out by a pathologist and all CT interpretations were compared to the pathologist final diagnoses. The disagreements were classified based on degree of discrepancy. The extra workload by adding the second screener was assessed. The agreement rate between the CT's screening interpretation and pathologist's interpretation did not improve by adding a second CT compared to a single screener (91.5% vs 92.9%, respectively). CT to pathologist concordance was very high on low complexity NGC cases (voided urine, fluid, sputum) whether screened and interpreted as negative by one CT (97.3%) or two CTs (99.3%). Double screening of NGC cases by two cytotechnologists prior to pathologist sign-out does not improve screening quality and is not cost-effective. The high concordance between the CTs and pathologists in this limited group of low complexity negative cases suggests that such cases could be signed out independently by cytotechnologists. © 2017 John Wiley & Sons Ltd.

Protein levels of ADAM10, BACE1, and PSEN1 in platelets and leukocytes of Alzheimer's disease patients.

PubMed

Bram, Jessyka Maria de França; Talib, Leda Leme; Joaquim, Helena Passarelli Giroud; Sarno, Tamires Alves; Gattaz, Wagner Farid; Forlenza, Orestes Vicente

2018-05-29

The clinical diagnosis of Alzheimer's disease (AD) is a probabilistic formulation that may lack accuracy particularly at early stages of the dementing process. Abnormalities in amyloid-beta precursor protein (APP) metabolism and in the level of APP secretases have been demonstrated in platelets, and to a lesser extent in leukocytes, of AD patients, with conflicting results. The aim of the present study was to compare the protein level of the APP secretases A-disintegrin and metalloprotease 10 (ADAM10), Beta-site APP-cleaving enzyme 1 (BACE1), and presenilin-1 (PSEN1) in platelets and leukocytes from 20 non-medicated older adults with AD and 20 healthy elders, and to determine the potential use of these biomarkers to discriminate cases of AD from controls. The protein levels of all APP secretases were significantly higher in platelets compared to leukocytes. We found statistically a significant decrease in ADAM10 (52.5%, p < 0.0001) and PSEN1 (32%, p = 0.02) in platelets from AD patients compared to controls, but not in leukocytes. Combining all three secretases to generate receiver-operating characteristic (ROC) curves, we found a good discriminatory effect (AD vs. controls) when using platelets (the area under the curve-AUC-0.90, sensitivity 88.9%, specificity 66.7%, p = 0.003), but not in leukocytes (AUC 0.65, sensitivity 77.8%, specificity 50.0%, p = 0.2). Our findings indicate that platelets represent a better biological matrix than leukocytes to address the peripheral level of APP secretases. In addition, combining the protein level of ADAM10, BACE1, and PSEN1 in platelets, yielded a good accuracy to discriminate AD from controls.

Usefulness of 3-dimensional stereotactic surface projection FDG PET images for the diagnosis of dementia

PubMed Central

Kim, Jahae; Cho, Sang-Geon; Song, Minchul; Kang, Sae-Ryung; Kwon, Seong Young; Choi, Kang-Ho; Choi, Seong-Min; Kim, Byeong-Chae; Song, Ho-Chun

2016-01-01

Abstract To compare diagnostic performance and confidence of a standard visual reading and combined 3-dimensional stereotactic surface projection (3D-SSP) results to discriminate between Alzheimer disease (AD)/mild cognitive impairment (MCI), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). [18F]fluorodeoxyglucose (FDG) PET brain images were obtained from 120 patients (64 AD/MCI, 38 DLB, and 18 FTD) who were clinically confirmed over 2 years follow-up. Three nuclear medicine physicians performed the diagnosis and rated diagnostic confidence twice; once by standard visual methods, and once by adding of 3D-SSP. Diagnostic performance and confidence were compared between the 2 methods. 3D-SSP showed higher sensitivity, specificity, accuracy, positive, and negative predictive values to discriminate different types of dementia compared with the visual method alone, except for AD/MCI specificity and FTD sensitivity. Correction of misdiagnosis after adding 3D-SSP images was greatest for AD/MCI (56%), followed by DLB (13%) and FTD (11%). Diagnostic confidence also increased in DLB (visual: 3.2; 3D-SSP: 4.1; P < 0.001), followed by AD/MCI (visual: 3.1; 3D-SSP: 3.8; P = 0.002) and FTD (visual: 3.5; 3D-SSP: 4.2; P = 0.022). Overall, 154/360 (43%) cases had a corrected misdiagnosis or improved diagnostic confidence for the correct diagnosis. The addition of 3D-SSP images to visual analysis helped to discriminate different types of dementia in FDG PET scans, by correcting misdiagnoses and enhancing diagnostic confidence in the correct diagnosis. Improvement of diagnostic accuracy and confidence by 3D-SSP images might help to determine the cause of dementia and appropriate treatment. PMID:27930593

HHEX_23 AA Genotype Exacerbates Effect of Diabetes on Dementia and Alzheimer Disease: A Population-Based Longitudinal Study

PubMed Central

Xu, Wei-Li; Pedersen, Nancy L.; Keller, Lina; Kalpouzos, Grégoria; Wang, Hui-Xin; Graff, Caroline; Winblad, Bengt; Bäckman, Lars; Fratiglioni, Laura

2015-01-01

Background Research has suggested that variations within the IDE/HHEX gene region may underlie the association of type 2 diabetes with Alzheimer disease (AD). We sought to explore whether IDE genes play a role in the association of diabetes with dementia, AD, and structural brain changes using data from two community-based cohorts of older adults and a subsample with structural MRI. Methods and Findings The first cohort, which included dementia-free adults aged ≥75 y (n = 970) at baseline, was followed for 9 y to detect incident dementia (n = 358) and AD (n = 271) cases. The second cohort (for replication), which included 2,060 dementia-free participants aged ≥60 y at baseline, was followed for 6 y to identify incident dementia (n = 166) and AD (n = 121) cases. A subsample (n = 338) of dementia-free participants from the second cohort underwent MRI. HHEX_23 and IDE_9 were genotyped, and diabetes (here including type 2 diabetes and prediabetes) was assessed. In the first cohort, diabetes led to an adjusted hazard ratio (HR) of 1.73 (95% CI 1.19–2.32) and 1.66 (95% CI 1.06–2.40) for dementia and AD, respectively, among all participants. Compared to people carrying the GG genotype without diabetes, AA genotype carriers with diabetes had an adjusted HR of 5.54 (95% CI 2.40–7.18) and 4.81 (95% CI 1.88–8.50) for dementia and AD, respectively. There was a significant interaction between HHEX_23-AA and diabetes on dementia (HR 4.79, 95% CI 1.63–8.90, p = 0.013) and AD (HR 3.55, 95% CI 1.45–9.91, p = 0.025) compared to the GG genotype without diabetes. In the second cohort, the HRs were 1.68 (95% CI 1.04–2.99) and 1.64 (1.02–2.33) for the diabetes–AD and dementia–AD associations, respectively, and 4.06 (95% CI 1.06–7.58, p = 0.039) and 3.29 (95% CI 1.02–8.33, p = 0.044) for the interactions, respectively. MRI data showed that HHEX_23-AA carriers with diabetes had significant structural brain changes compared to HHEX_23-GG carriers without diabetes. No joint effects of IDE_9 and diabetes on dementia were shown. As a limitation, the sample sizes were small for certain subgroups. Conclusions A variant in the HHEX_23 gene interacts with diabetes to be associated with a substantially increased risk of dementia and AD, and with structural brain changes among dementia-free elderly people. PMID:26173052

The position of the anal dimple in newborns and infants with anorectal malformations and its correlation with the normal anal position.

PubMed

Patel, Jigar N; Kumar, Amit; Yadav, Partap Singh; Chadha, Rajiv; Datta, Vikram; Roy Choudhury, Subhasis

2017-11-16

The anal position index (API) defines the normal anal position as the ratio of fourchette-anal distance to fourchette-coccyx distance for females and the scrotum-anal distance to scrotum-coccyx distance for males. In this study, measurement of the API in newborns and infants with anorectal malformations (ARM), using the center of the midline anal dimple (AD) to represent the center of the proposed neoanus, was performed to assess whether or not the AD was located in a significantly abnormal position as correlated with the normal anal position. The cases comprised 65 consecutive newborn and infants with ARM, divided into 2 age-based groups (Group A: 1st day to 1month; Group B: 1-12months), without sacral or significant perineal abnormalities. Controls included an equal number of age and gender matched patients admitted for other conditions. The characteristics of the AD ('well developed' or 'moderately developed') as well as those of the midline perineal raphé in males and the perineal groove in females were also recorded. Combining both age groups, the mean API±SD was 0.41±0.012 in male cases and 0.53±0.07 in male controls (p value 0.003). The corresponding values for female cases and controls were 0.31±0.09 and 0.36±0.07 respectively (p = 0.040). In male newborns, the API in cases was significantly lower than the API in controls (p<0.001). Combining both males and female newborns, the differences between the API in cases and controls was also statistically significant (p<0.001). In older boys as well as in girls from both age groups, apart from cases of persistent cloaca, the API was lower in cases than in controls, especially in boys, although the difference was not statistically significant. On comparing the API in individual male ARM with that in male controls, cases of rectobulbar urethral fistula (RBUF) and rectovesical fistula had a statistically significant lower API (p<0.001). In the 4 cases of persistent cloaca, the mean API (0.40±0.1) was higher than the mean API in female controls and the AD was well developed with a well-delineated, narrow perineal groove. The majority (53/65; 81.53%) of patients had a 'well developed' AD. Twelve patients (18.47%) had a 'moderately developed' AD including 10 females and 2 males. There were 15 patients with a depressed AD (anal fossette); of these 12 (80%) were females. All boys had a well delineated perineal raphé in contrast to 10 girls (29.4% of total female ARM) who had a poorly delineated midline perineal groove. During definitive surgery for ARM, if the AD is taken as the site of the proposed neoanus, the neoanal position is likely to be anterior to the normal anal position in both males and females and especially so in males. Overall, girls with ARM appear to be more likely to have a relatively poorly developed and/ or depressed AD and a poorly delineated perineal groove. Clinical Research. Level III. Copyright © 2017 Elsevier Inc. All rights reserved.

Ascertainment bias in dementias: a secondary to tertiary centre analysis in Central Italy and conceptual review.

PubMed

Bonanni, L; Bontempo, G; Borrelli, I; Bifolchetti, S; Buongarzone, M P; Carlesi, N; Carolei, A; Ciccocioppo, F; Colangelo, U; Colonna, G; Desiderio, M; Ferretti, S; Fiorelli, L; D'Alessio, O; D'Amico, A; D'Amico, M C; De Lucia, R; Del Re, L; Di Blasio, F; Di Giacomo, R; Di Iorio, A; Di Santo, E; Di Giuseppe, M; Felice, N; Litterio, P; Gabriele, A; Mancino, E; Manzoli, L; Maruotti, V; Mearelli, S; Molino, G; Monaco, D; Nuccetelli, F; Onofrj, M; Perfetti, B; Sacchet, C; Sensi, F; Sensi, S; Sucapane, P; Taylor, J P; Thomas, A; Viola, P; Viola, S; Zito, M; Zhuzhuni, H

2013-06-01

Ascertainment bias (AB) indicates a bias of an evaluation centre in estimating the prevalence/incidence of a disease due to the specific expertise of the centre. The aim of our study was to evaluate classification of different types of dementia in new cases appearing in secondary and tertiary centres, in order to evidence possible occurrence of AB in the various (secondary to tertiary) dementia centres. To assess the mechanism of AB, the rates of new cases of the different forms of dementia reported by different centres were compared. The centres involved in the study were 11 hospital-based centres including a tertiary centre, located in the University Department of Clinical Neurology. The tertiary centre is endowed with state-of-the-art diagnostic facilities and its scientific production is prominently focused on dementia with Lewy bodies (DLB) thus suggesting the possible occurrence of a bias. Four main categories of dementia were identified: Alzheimer's disease (AD), DLB, fronto-temporal dementia (FTD), vascular dementia (VaD), with other forms in a category apart. The classification rate of new cases of dementia in the tertiary centre was compared with rates reported by secondary centres and rates of recoding were calculated during a follow-up of 2 years. The study classified 2,042 newly diagnosed cases of dementia in a population of 1,370,000 inhabitants of which 315,000 were older than 65. AD was categorized in 48-52 % of cases, DLB in 25-28 %, FTD in 2-4 % and VaD in 17-28 %. During the 2-year follow-up the diagnosis was re-classified in 40 patients (3 %). The rate of recoding was 5 % in the tertiary centre, 2-8 % in referrals from secondary to tertiary centre, 2-10 % in recodings performed in secondary centres and addressed to tertiary centre. Recoding or percentages of new cases of AD or DLB were not different in the comparison between secondary or between secondary and tertiary centres. FTD and VaD were instead significantly recoded. The results of the study suggest that in a homogeneous area, AB is not interfering with diagnosis of AD or DLB.

Evidence of Recessive Alzheimer Disease Loci in a Caribbean Hispanic Data Set

PubMed Central

Ghani, Mahdi; Sato, Christine; Lee, Joseph H.; Reitz, Christiane; Moreno, Danielle; Mayeux, Richard; St George-Hyslop, Peter; Rogaeva, Ekaterina

2014-01-01

IMPORTANCE The search for novel Alzheimer disease (AD) genes or pathologic mutations within known AD loci is ongoing. The development of array technologies has helped to identify rare recessive mutations among long runs of homozygosity (ROHs), in which both parental alleles are identical. Caribbean Hispanics are known to have an elevated risk for AD and tend to have large families with evidence of inbreeding. OBJECTIVE To test the hypothesis that the late-onset AD in a Caribbean Hispanic population might be explained in part by the homozygosity of unknown loci that could harbor recessive AD risk haplotypes or pathologic mutations. DESIGN We used genome-wide array data to identify ROHs (>1 megabase) and conducted global burden and locus-specific ROH analyses. SETTING A whole-genome case-control ROH study. PARTICIPANTS A Caribbean Hispanic data set of 547 unrelated cases (48.8% with familial AD) and 542 controls collected from a population known to have a 3-fold higher risk of AD vs non-Hispanics in the same community. Based on a Structure program analysis, our data set consisted of African Hispanic (207 cases and 192 controls) and European Hispanic (329 cases and 326 controls) participants. EXPOSURE Alzheimer disease risk genes. MAIN OUTCOMES AND MEASURES We calculated the total and mean lengths of the ROHs per sample. Global burden measurements among autosomal chromosomes were investigated in cases vs controls. Pools of overlapping ROH segments (consensus regions) were identified, and the case to control ratio was calculated for each consensus region. We formulated the tested hypothesis before data collection. RESULTS In total, we identified 17 137 autosomal regions with ROHs. The mean length of the ROH per person was significantly greater in cases vs controls (P = .0039), and this association was stronger with familial AD (P = .0005). Among the European Hispanics, a consensus region at the EXOC4 locus was significantly associated with AD even after correction for multiple testing (empirical P value 1 [EMP1], .0001; EMP2, .002; 21 AD cases vs 2 controls). Among the African Hispanic subset, the most significant but nominal association was observed for CTNNA3, a well-known AD gene candidate (EMP1, .002; 10 AD cases vs 0 controls). CONCLUSIONS AND RELEVANCE Our results show that ROHs could significantly contribute to the etiology of AD. Future studies would require the analysis of larger, relatively inbred data sets that might reveal novel recessive AD genes. The next step is to conduct sequencing of top significant loci in a subset of samples with overlapping ROHs. PMID:23978990

The metabolic syndrome, diabetes, and Alzheimer's disease.

PubMed

García-Lara, Juan Miguel Antonio; Aguilar-Navarro, Sara; Gutiérrez-Robledo, Luis Miguel; Avila-Funes, José Alberto

2010-01-01

The metabolic syndrome (MS) is a cluster of metabolic abnormalities that has been controversially associated with Alzheimer's disease (AD), so the purpose of this report was to investigate the association between these two chronic diseases a sample of older persons. Case-control study of 90 consecutive outpatients with AD and 180 non-demented controls from a dementia clinic at a tertiary care hospital in Mexico City. Probable or possible AD was diagnosed according to the guidelines of the Consortium to Establish a Registry for Alzheimer's Disease, whereas control participants where those classified as normal by the same instrument. MS was defined according to the World Health Organization criteria. Patients were matched 1:2 by age, sex, and years of education. Conditional regression analysis was used to test the association between MS and AD. Compared to controls, MS was more frequent among AD patients (72.2% vs. 23.3%; P < 0.01). While all components of MS were more frequent among cases than control patients, only diabetes was statistically significant, whereas hypertriglyceridemia and low HDL cholesterol were marginally associated. Conditional regression analysis showed that among AD participants, the probability of having MS was about sevenfold higher than for their non-demented counterparts (OR 6.72, 95% CI 3.72-12.13; P < 0.01). The MS is a clinical entity that encompasses a diverse range of chronic diseases, which could be a better risk indicator than any individual MS component for adverse health outcomes, like AD. Our findings underscore the harmful role of MS in the health status of the elderly.

Differentiating cognitive impairment due to corticobasal degeneration and Alzheimer disease.

PubMed

Day, Gregory S; Lim, Tae Sung; Hassenstab, Jason; Goate, Alison M; Grant, Elizabeth A; Roe, Catherine M; Cairns, Nigel J; Morris, John C

2017-03-28

To identify clinical features that reliably differentiate individuals with cognitive impairment due to corticobasal degeneration (CBD) and Alzheimer disease (AD). Clinical features were compared between individuals with autopsy-proven CBD (n = 17) and AD (n = 16). All individuals presented with prominent cognitive complaints and were evaluated annually with semistructured interviews, detailed neurologic examinations, and neuropsychological testing. Substantial overlap was observed between individuals with dementia due to CBD and AD concerning presenting complaints, median (range) duration of symptoms before assessment (CBD = 3.0 [0-5.0] years, AD = 2.5 [0-8.0] years; p = 0.96), and median (range) baseline dementia severity (Clinical Dementia Rating Sum of Boxes: CBD = 3.5 [0-12.0], AD = 4.25 [0.5-9.0], p = 0.49). Subsequent emergence of asymmetric motor/sensory signs, hyperreflexia, gait abnormalities, parkinsonism, falls, urinary incontinence, and extraocular movement abnormalities identified individuals with CBD, with ≥3 discriminating features detected in 80% of individuals within 3.1 years (95% confidence interval 2.9-3.3) of the initial assessment. Individuals with CBD exhibited accelerated worsening of illness severity and declines in episodic memory, executive functioning, and letter fluency. Semiquantitative pathologic assessment revealed prominent tau pathology within the frontal and parietal lobes of CBD cases. Comorbid AD neuropathologic change was present in 59% (10 of 17) of CBD cases but did not associate with the clinical phenotype, rate of dementia progression, or dementia duration. CBD may mimic AD dementia early in its disease course. Interval screening for discriminating clinical features may improve antemortem diagnosis in individuals with CBD and prominent cognitive symptoms. © 2017 American Academy of Neurology.

Pathological reorganization of NMDA receptors subunits and postsynaptic protein PSD-95 distribution in Alzheimer's disease.

PubMed

Leuba, Genevieve; Vernay, Andre; Kraftsik, Rudolf; Tardif, Eric; Riederer, Beat Michel; Savioz, Armand

2014-01-01

In Alzheimer's disease (AD), synaptic alterations play a major role and are often correlated with cognitive changes. In order to better understand synaptic modifications, we compared alterations in NMDA receptors and postsynaptic protein PSD-95 expression in the entorhinal cortex (EC) and frontal cortex (FC; area 9) of AD and control brains. We combined immunohistochemical and image analysis methods to quantify on consecutive sections the distribution of PSD-95 and NMDA receptors GluN1, GluN2A and GluN2B in EC and FC from 25 AD and control cases. The density of stained receptors was analyzed using multivariate statistical methods to assess the effect of neurodegeneration. In both regions, the number of neuronal profiles immunostained for GluN1 receptors subunit and PSD-95 protein was significantly increased in AD compared to controls (3-6 fold), while the number of neuronal profiles stained for GluN2A and GluN2B receptors subunits was on the contrary decreased (3-4 fold). The increase in marked neuronal profiles was more prominent in a cortical band corresponding to layers 3 to 5 with large pyramidal cells. Neurons positive for GluN1 or PSD-95 staining were often found in the same localization on consecutive sections and they were also reactive for the anti-tau antibody AD2, indicating a neurodegenerative process. Differences in the density of immunoreactive puncta representing neuropile were not statistically significant. Altogether these data indicate that GluN1 and PSD-95 accumulate in the neuronal perikarya, but this is not the case for GluN2A and GluN2B, while the neuropile compartment is less subject to modifications. Thus, important variations in the pattern of distribution of the NMDA receptors subunits and PSD-95 represent a marker in AD and by impairing the neuronal network, contribute to functional deterioration.

Assessment of the Genetic Architecture of Alzheimer's Disease Risk in Rate of Memory Decline.

PubMed

Del-Aguila, Jorge L; Fernández, Maria Victoria; Schindler, Suzanne; Ibanez, Laura; Deming, Yuetiva; Ma, Shengmei; Saef, Ben; Black, Kathleen; Budde, John; Norton, Joanne; Chasse, Rachel; Harari, Oscar; Goate, Alison; Xiong, Chengjie; Morris, John C; Cruchaga, Carlos

2018-01-01

Many genetic studies for Alzheimer's disease (AD) have been focused on the identification of common genetic variants associated with AD risk and not on other aspects of the disease, such as age at onset or rate of dementia progression. There are multiple approaches to untangling the genetic architecture of these phenotypes. We hypothesized that the genetic architecture of rate of progression is different than the risk for developing AD dementia. To test this hypothesis, we used longitudinal clinical data from ADNI and the Knight-ADRC at Washington University, and we calculated PRS (polygenic risk score) based on the IGAP study to compare the genetic architecture of AD risk and dementia progression. Dementia progression was measured by the change of Clinical Dementia Rating Sum of Boxes (CDR)-SB per year. Out of the 21 loci for AD risk, no association with the rate of dementia progression was found. The PRS rate was significantly associated with the rate of dementia progression (β= 0.146, p = 0.03). In the case of rare variants, TREM2 (β= 0.309, p = 0.02) was also associated with the rate of dementia progression. TREM2 variant carriers showed a 23% faster rate of dementia compared with non-variant carriers. In conclusion, our results indicate that the recently identified common and rare variants for AD susceptibility have a limited impact on the rate of dementia progression in AD patients.

Impact of cerebro-spinal fluid biomarkers of Alzheimer's disease in clinical practice: a multicentric study.

PubMed

Mouton-Liger, François; Wallon, David; Troussière, Anne-Cécile; Yatimi, Rachida; Dumurgier, Julien; Magnin, Eloi; de la Sayette, Vincent; Duron, Emannuelle; Philippi, Nathalie; Beaufils, Emilie; Gabelle, Audrey; Croisile, Bernard; Robert, Philippe; Pasquier, Florence; Hannequin, Didier; Hugon, Jacques; Paquet, Claire

2014-01-01

CSF biomarkers of Alzheimer's disease are well validated in clinical research; however, their pragmatic utility in daily practice is still unappreciated. These biomarkers are used in routine practice according to Health Authority Recommendations. In 604 consecutive patients explored for cognitive disorders, questionnaires were prospectively proposed and filled. Before and after CSF biomarker results, clinicians provided a diagnosis and an estimate of their diagnostic confidence. Analysis has compared the frequency of diagnosis before and after CSF biomarker results using the net reclassification improvement (NRI) method. We have evaluated external validity comparing with data of French Bank National of AD (BNA). A total of 561 patients [Alzheimer's disease (AD), n = 253; non-AD, n = 308] were included (mean age, 68.6 years; women, 52 %). Clinically suspected diagnosis and CSF results were concordant in 65.2 % of cases. When clinical hypothesis and biological results were discordant, a reclassification occurred in favour of CSF biomarkers results in 76.9 %. The NRI was 39.5 %. In addition, the results show a statistically significant improvement in clinician confidence for their diagnosis. In comparison with BNA data, patients were younger and more frequently diagnosed with AD. Clinicians tend to heavily rely on the CSF AD biomarkers results and are more confident in their diagnoses using CSF AD biomarkers. Thus, these biomarkers appear as a key tool in clinical practice.

Differences in MYB expression and gene abnormalities further confirm that salivary cribriform basal cell tumors and adenoid cystic carcinoma are two distinct tumor entities.

PubMed

Tian, Zhen; Li, Lei; Zhang, Chun-Ye; Gu, Ting; Li, Jiang

2016-10-01

In practices, some cases of salivary basal cell tumors that consist mainly of cribriform growth pattern are difficult to differentiate from adenoid cystic carcinoma (AdCC). Identification of reliable molecular biomarkers for the differential diagnosis between them is required. Twenty-two cases of cribriform salivary basal cell tumors (at least 10% cribriform pattern present in each tumor) comprising 18 cases of basal cell adenoma (BCA) and four cases of basal cell adenocarcinoma (BcAC) were collected between 1985 and 2008. Twenty cases of cribriform AdCC were retrieved from our archives. MYB protein expression and gene abnormalities were detected in all cases by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) analyses, respectively. Neither MYB protein nor split genes were detected in any of the cases of cribriform basal cell tumors, while 55% (11/20) of cases of cribriform AdCC had MYB protein expression. High MYB expression was detected in 81.8% (9/11) cases, while low expression was found in the remaining cases. FISH analysis indicated that nine AdCC tumors with high MYB protein expression were split gene-positive, while MYB gene splitting was not detected in the 11 cases with low or absent MYB protein expression. The molecular changes in AdCC differ from those associated with cribriform basal cell tumors, which further confirms that cribriform basal cell tumors and AdCC are two distinct tumor entities. Simultaneous detection of MYB protein expression and the associated molecular changes could be beneficial in differentiating salivary cribriform basal cell tumors from AdCC. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Meta-analysis of expression and function of neprilysin in Alzheimer's disease.

PubMed

Zhang, Huifeng; Liu, Dan; Wang, Yixing; Huang, Huanhuan; Zhao, Yujia; Zhou, Hui

2017-09-14

Neprilysin (NEP) is one of the most important Aβ-degrading enzymes, and its expression and activity in Alzheimer's brain have been widely reported, but the results remain debatable. Thus, the meta-analysis was performed to elucidate the role of NEP in Alzheimer's disease (AD). The relevant case-control or cohort studies were retrieved according to our inclusion/exclusion criteria. Six studies with 123 controls and 141 AD cases, seven studies with 102 controls and 90 AD cases, and four studies with 93 controls and 132 AD cases were included in meta-analysis of NEP's protein, mRNA, and enzyme activity respectively. We conducted Meta regression to detect the sources of heterogeneity and further performed cumulative meta-analysis or subgroup analysis. Our meta-analysis revealed a significantly lower level of NEP mRNA (SMD=-0.44, 95%CI: -0.87, -0.00, p=0.049) in AD cases than in non-AD cases, and such pattern was not altered over time in the cumulative meta-analysis. However, the decrease of NEP protein (SMD=-0.18, 95%CI: -0.62, 0.25) and enzyme activity (SMD=-0.35, 95%CI: -1.03, 0.32) in AD cases did not pass the significance check, while the cumulative meta-analysis by average age showed the pooled effect became insignificant as adding the studies with younger subjects, which indicates that the protein expression and enzyme activity of NEP in the cortex are affected by age. Therefore, the present meta-analysis suggests the need of further investigation of roles of NEP in AD pathogenesis and treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

How much do persons with Alzheimer's disease cost Medicare?

PubMed

Taylor, D H; Sloan, F A

2000-06-01

Medicare claims are increasingly being used to identify persons with chronic diseases such as Alzheimer's disease (AD) for the purpose of determining the cost to Medicare of caring for such persons. Past work has been limited by the use of only 1 or 2 years of claims data to identify cases, leading to worries that this might lead to an undercount of prevalent cases and bias cost findings. To analyze the average total cost to the Medicare program in 1994 of persons with a claims-based diagnosis of AD, using a 12-year period of claims history to identify prevalent cases, and to investigate the effect on cost of time since diagnosis. A cross-sectional design with a 12-year retrospective period to identify persons with AD. Medical care practices, hospitals, and other providers of services to Medicare beneficiaries in the US in 1994. Respondents to the screener (n = 10,858) and community (5429) and institutional (n = 1341) questionnaire of the 1994 National Long Term Care Survey, with and without a claims-based diagnosis of AD. Average total cost to Medicare in 1994, measured as the actual amount Medicare paid for inpatient, outpatient, home health, skilled nursing facility, hospice, and Part B services, including payments to physicians, and other items such as durable medical equipment. We also measured disability in a variety of ways, including cognition, activity limitations, and residence in a nursing home. The average total cost to Medicare of persons with a claims-based diagnosis of AD was $6021 versus $2310 (P < .001) for persons without a diagnosis. When adjusting for patient characteristics, the ratio of cost between persons with AD and those without was reduced to about 1.6 to 1. Time since diagnosis was an important predictor of average total cost in 1994, with each additional year since diagnosis resulting in a $248 (P = .04) decrease in total cost (about 10% of the total sample mean cost of $2426). There was mixed evidence that persons with a diagnosis of AD incurred less cost than otherwise similarly disabled Medicare beneficiaries. Time since diagnosis with AD is an important predictor of cost and one that should be explicitly included in any rate-setting formula. Expanding the period used to identify cases resulted in an increase in the unadjusted ratio of cost of a Medicare beneficiary with AD relative to one without primarily because our control group costs are lower compared with those of past work.

Neuropathology of Nondemented Aging: Presumptive Evidence for Preclinical Alzheimer Disease

PubMed Central

Price, Joseph L.; McKeel, Daniel W.; Buckles, Virginia D.; Roe, Catherine M.; Xiong, Chengjie; Grundman, Michael; Hansen, Lawrence A.; Petersen, Ronald C.; Parisi, Joseph E.; Dickson, Dennis W.; Smith, Charles D.; Davis, Daron G.; Schmitt, Frederick A.; Markesbery, William R.; Kaye, Jeffrey; Kurlan, Roger; Hulette, Christine; Kurland, Brenda F.; Higdon, Roger; Kukull, Walter; Morris, John C.

2009-01-01

Objective To determine the frequency and possible cognitive effect of histological Alzheimer’s disease (AD) in autopsied older nondemented individuals. Design Senile plaques (SPs) and neurofibrillary tangles (NFTs) were assessed quantitatively in 97 cases from 7 Alzheimer’s Disease Centers (ADCs). Neuropathological diagnoses of AD (npAD) were also made with four sets of criteria. Adjusted linear mixed models tested differences between participants with and without npAD on the quantitative neuropathology measures and psychometric test scores prior to death. Spearman rank-order correlations between AD lesions and psychometric scores at last assessment were calculated for cases with pathology in particular regions. Setting Washington University Alzheimer’s Disease Research Center. Participants Ninety-seven nondemented participants who were age 60 years or older at death (mean = 84 years). Results About 40% of nondemented individuals met at least some level of criteria for npAD; when strict criteria were used, about 20% of cases had npAD. Substantial overlap of Braak neurofibrillary stages occurred between npAD and no-npAD cases. Although there was no measurable cognitive impairment prior to death for either the no-npAD or npAD groups, cognitive function in nondemented aging appears to be degraded by the presence of NFTs and SPs. Conclusions Neuropathological processes related to AD in persons without dementia appear to be associated with subtle cognitive dysfunction and may represent a preclinical stage of the illness. By age 80–85 years, many nondemented older adults have substantial AD pathology. PMID:19376612

Neuroinflammation is increased in the parietal cortex of atypical Alzheimer's disease.

PubMed

Boon, Baayla D C; Hoozemans, Jeroen J M; Lopuhaä, Boaz; Eigenhuis, Kristel N; Scheltens, Philip; Kamphorst, Wouter; Rozemuller, Annemieke J M; Bouwman, Femke H

2018-05-29

While most patients with Alzheimer's disease (AD) present with memory complaints, 30% of patients with early disease onset present with non-amnestic symptoms. This atypical presentation is thought to be caused by a different spreading of neurofibrillary tangles (NFT) than originally proposed by Braak and Braak. Recent studies suggest a prominent role for neuroinflammation in the spreading of tau pathology. We aimed to explore whether an atypical spreading of pathology in AD is associated with an atypical distribution of neuroinflammation. Typical and atypical AD cases were selected based on both NFT distribution and amnestic or non-amnestic clinical presentation. Immunohistochemistry was performed on the temporal pole and superior parietal lobe of 10 typical and 9 atypical AD cases. The presence of amyloid-beta (N-terminal; IC16), pTau (AT8), reactive astrocytes (GFAP), microglia (Iba1, CD68, and HLA-DP/DQ/DR), and complement factors (C1q, C3d, C4b, and C5b-9) was quantified by image analysis. Differences in lobar distribution patterns of immunoreactivity were statistically assessed using a linear mixed model. We found a temporal dominant distribution for amyloid-beta, GFAP, and Iba1 in both typical and atypical AD. Distribution of pTau, CD68, HLA-DP/DQ/DR, C3d, and C4b differed between AD variants. Typical AD cases showed a temporal dominant distribution of these markers, whereas atypical AD cases showed a parietal dominant distribution. Interestingly, when quantifying for the number of amyloid-beta plaques instead of stained surface area, atypical AD cases differed in distribution pattern from typical AD cases. Remarkably, plaque morphology and localization of neuroinflammation within the plaques was different between the two phenotypes. Our data show a different localization of neuroinflammatory markers and amyloid-beta plaques between AD phenotypes. In addition, these markers reflect the atypical distribution of tau pathology in atypical AD, suggesting that neuroinflammation might be a crucial link between amyloid-beta deposits, tau pathology, and clinical symptoms.

An acoustic comparison of two women's infant- and adult-directed speech

NASA Astrophysics Data System (ADS)

Andruski, Jean; Katz-Gershon, Shiri

2003-04-01

In addition to having prosodic characteristics that are attractive to infant listeners, infant-directed (ID) speech shares certain characteristics of adult-directed (AD) clear speech, such as increased acoustic distance between vowels, that might be expected to make ID speech easier for adults to perceive in noise than AD conversational speech. However, perceptual tests of two women's ID productions by Andruski and Bessega [J. Acoust. Soc. Am. 112, 2355] showed that is not always the case. In a word identification task that compared ID speech with AD clear and conversational speech, one speaker's ID productions were less well-identified than AD clear speech, but better identified than AD conversational speech. For the second woman, ID speech was the least accurately identified of the three speech registers. For both speakers, hard words (infrequent words with many lexical neighbors) were also at an increased disadvantage relative to easy words (frequent words with few lexical neighbors) in speech registers that were less accurately perceived. This study will compare several acoustic properties of these women's productions, including pitch and formant-frequency characteristics. Results of the acoustic analyses will be examined with the original perceptual results to suggest reasons for differences in listener's accuracy in identifying these two women's ID speech in noise.

QCD Condensates and Holographic Wilson Loops for Asymptotically AdS Spaces

DOE Office of Scientific and Technical Information (OSTI.GOV)

Quevedo, R. Carcasses; Goity, Jose L.; Trinchero, Roberto C.

2014-02-01

The minimization of the Nambu-Goto (NG) action for a surface whose contour defines a circular Wilson loop of radius a placed at a finite value of the coordinate orthogonal to the border is considered. This is done for asymptotically AdS spaces. The condensates of dimension n = 2, 4, 6, 8, and 10 are calculated in terms of the coefficients in the expansion in powers of the radius a of the on-shell subtracted NG action for small a->0. The subtraction employed is such that it presents no conflict with conformal invariance in the AdS case and need not introduce anmore » additional infrared scale for the case of confining geometries. It is shown that the UV value of the gluon condensates is universal in the sense that it only depends on the first coefficients of the difference with the AdS case.« less

Frontotemporal dementia: evidence for impairment of ascending serotoninergic but not noradrenergic innervation. Immunocytochemical and quantitative study using a graph method.

PubMed

Yang, Y; Schmitt, H P

2001-03-01

A graph method was employed to analyze the spatial neuronal patterns of nuclear grays of the pontine tegmentum with ascending aminergic projections to the forebrain in 12 cases of frontotemporal dementia (FTD). The nuclear grays examined were the nucleus centralis superior (NCS), a part of the nucleus raphae dorsalis (NRD), and the locus coeruleus (LC). The results were compared with 30 cases of Alzheimer's disease (AD) and 35 non-demented controls. In addition to the graph evaluations, neuronal cytoplasmic inclusion bodies were stained by silver impregnation and ubiquitin (Ub) and tau immunohistochemistry. The FTD cases showed a significant, 40%, decline in number of neurons in the NCS and NRD, while the LC was spared. The magnitude of neuronal loss matched that of AD where, by contrast, the LC was also severely changed. Amyloid deposition and Alzheimer neurofibrillary tangles occurred in the aminergic nuclei almost exclusively in AD and, to a minor extent, in some aged controls. No cytoplasmic inclusion bodies were found in the aminergic nuclei of the FTD cases. However, 6 cases had Ub-positive but tau-negative neuronal inclusions in the hippocampal dentate fascia and in layer 2 of the prefrontal isocortex, and 3 showed clinical and histological signs of motor neuron disease. Our results suggest that the serotoninergic raphe nuclei with ascending projections to the forebrain, but not the LC, become directly or indirectly involved in frontotemporal dementia both with and without motor neuron disease.

Recognition and treatment of Alzheimer's disease: a case-based review.

PubMed

Marseille, Dana M; Silverman, Daniel H S

2006-01-01

Early recognition and treatment initiation are pivotal in managing Alzheimer's disease (AD). Once a diagnosis of AD is made, a treatment plan is developed and should include treatment initiation with cholinesterase inhibitors (ChEIs) to improve cognition, management of comorbid conditions, and treat behavioral symptoms. Caregiver compliance is integral to AD treatment success. The purpose of this report is to present two real case studies of "suspected" AD or related dementia and stress the significance of early and accurate diagnosis in disease management. In case 1, a caregiver reports gradual but progressive loss of memory, and the patient himself complains of memory impairment. Neuroimaging analysis confirms "typical " AD. In case 2, initiation of ChEI therapy is followed by substantial clinical improvement in the face of a complex medical picture, and neuroimaging revealing more neurodegenerative changes than could be accounted for by "pure" AD.

A case-cohort study of recurrent salivary adenoid cystic carcinoma after iodine 125 brachytherapy and resection treatment.

PubMed

Li, Bin-bin; Xie, Xiao-Yan; Jia, Sheng-Nan

2015-02-01

Recurrent adenoid cystic carcinoma (rAdCC) can be challenging to be treated with brachytherapy, although brachytherapy is safe and effective in treating head and neck cancers. Patients of adenoid cystic carcinoma (AdCC), who underwent resection and iodine 125 ((125)I) radioactive seed implantation, were recruited for this study. Clinical data, surgical details of resection and seed implantation, histologic characteristics, and prognosis were studied. There were 16 rAdCC cases among 140 cases of AdCC treated with brachytherapy and resection. The mean follow-up duration for the recurrent cases was 61 months. The 3-year local control rate of rAdCC was 51.6%, and the overall disease-specific survival rate was 49.4%. Eight patients showed distant metastasis (50%, 8/16). The histologic grades of 10 rAdCCs were upgraded (62.5%, 10/16).Two cases displayed sarcomatous transformation after brachytherapy (1.4%, 2/140). Although the overall local control rate and survival rate were relatively favorable, some rAdCCs with an aggressive phenotype appeared to respond poorly to (125)I seed implantation. Preventive adjuvant chemotherapy should be prescribed for these rAdCCs. Copyright © 2014 Elsevier Inc. All rights reserved.

Simple and efficient LCAO basis sets for the diffuse states in carbon nanostructures.

PubMed

Papior, Nick R; Calogero, Gaetano; Brandbyge, Mads

2018-06-27

We present a simple way to describe the lowest unoccupied diffuse states in carbon nanostructures in density functional theory calculations using a minimal LCAO (linear combination of atomic orbitals) basis set. By comparing plane wave basis calculations, we show how these states can be captured by adding long-range orbitals to the standard LCAO basis sets for the extreme cases of planar sp 2 (graphene) and curved carbon (C 60 ). In particular, using Bessel functions with a long range as additional basis functions retain a minimal basis size. This provides a smaller and simpler atom-centered basis set compared to the standard pseudo-atomic orbitals (PAOs) with multiple polarization orbitals or by adding non-atom-centered states to the basis.

Simple and efficient LCAO basis sets for the diffuse states in carbon nanostructures

NASA Astrophysics Data System (ADS)

Papior, Nick R.; Calogero, Gaetano; Brandbyge, Mads

2018-06-01

We present a simple way to describe the lowest unoccupied diffuse states in carbon nanostructures in density functional theory calculations using a minimal LCAO (linear combination of atomic orbitals) basis set. By comparing plane wave basis calculations, we show how these states can be captured by adding long-range orbitals to the standard LCAO basis sets for the extreme cases of planar sp 2 (graphene) and curved carbon (C60). In particular, using Bessel functions with a long range as additional basis functions retain a minimal basis size. This provides a smaller and simpler atom-centered basis set compared to the standard pseudo-atomic orbitals (PAOs) with multiple polarization orbitals or by adding non-atom-centered states to the basis.

Mutations in Splicing Factor Genes Are a Major Cause of Autosomal Dominant Retinitis Pigmentosa in Belgian Families

PubMed Central

Coppieters, Frauke; Roels, Dimitri; De Jaegere, Sarah; Flipts, Helena; De Zaeytijd, Julie; Walraedt, Sophie; Claes, Charlotte; Fransen, Erik; Van Camp, Guy; Depasse, Fanny; Casteels, Ingele; de Ravel, Thomy

2017-01-01

Purpose Autosomal dominant retinitis pigmentosa (adRP) is characterized by an extensive genetic heterogeneity, implicating 27 genes, which account for 50 to 70% of cases. Here 86 Belgian probands with possible adRP underwent genetic testing to unravel the molecular basis and to assess the contribution of the genes underlying their condition. Methods Mutation detection methods evolved over the past ten years, including mutation specific methods (APEX chip analysis), linkage analysis, gene panel analysis (Sanger sequencing, targeted next-generation sequencing or whole exome sequencing), high-resolution copy number screening (customized microarray-based comparative genomic hybridization). Identified variants were classified following American College of Medical Genetics and Genomics (ACMG) recommendations. Results Molecular genetic screening revealed mutations in 48/86 cases (56%). In total, 17 novel pathogenic mutations were identified: four missense mutations in RHO, five frameshift mutations in RP1, six mutations in genes encoding spliceosome components (SNRNP200, PRPF8, and PRPF31), one frameshift mutation in PRPH2, and one frameshift mutation in TOPORS. The proportion of RHO mutations in our cohort (14%) is higher than reported in a French adRP population (10.3%), but lower than reported elsewhere (16.5–30%). The prevalence of RP1 mutations (10.5%) is comparable to other populations (3.5%-10%). The mutation frequency in genes encoding splicing factors is unexpectedly high (altogether 19.8%), with PRPF31 the second most prevalent mutated gene (10.5%). PRPH2 mutations were found in 4.7% of the Belgian cohort. Two families (2.3%) have the recurrent NR2E3 mutation p.(Gly56Arg). The prevalence of the recurrent PROM1 mutation p.(Arg373Cys) was higher than anticipated (3.5%). Conclusions Overall, we identified mutations in 48 of 86 Belgian adRP cases (56%), with the highest prevalence in RHO (14%), RP1 (10.5%) and PRPF31 (10.5%). Finally, we expanded the molecular spectrum of PRPH2, PRPF8, RHO, RP1, SNRNP200, and TOPORS-associated adRP by the identification of 17 novel mutations. PMID:28076437

CSR: Constrained Selfish Routing in Ad-Hoc Networks

NASA Astrophysics Data System (ADS)

Bassem, Christine; Bestavros, Azer

Routing protocols for ad-hoc networks assume that the nodes forming the network are either under a single authority, or else that they would be altruistically forwarding data for other nodes with no expectation of a return. These assumptions are unrealistic since in ad-hoc networks, nodes are likely to be autonomous and rational (selfish), and thus unwilling to help unless they have an incentive to do so. Providing such incentives is an important aspect that should be considered when designing ad-hoc routing protocols. In this paper, we propose a dynamic, decentralized routing protocol for ad-hoc networks that provides incentives in the form of payments to intermediate nodes used to forward data for others. In our Constrained Selfish Routing (CSR) protocol, game-theoretic approaches are used to calculate payments (incentives) that ensure both the truthfulness of participating nodes and the fairness of the CSR protocol. We show through simulations that CSR is an energy efficient protocol and that it provides lower communication overhead in the best and average cases compared to existing approaches.

Nanotechnology in Mexico: Key Findings Based on OECD Criteria

ERIC Educational Resources Information Center

Foladori, Guillermo; Arteaga Figueroa, Edgar; Záyago Lau, Edgar; Appelbaum, Richard; Robles-Belmont, Eduardo; Villa, Liliana; Parker, Rachel; Leos, Vanessa

2015-01-01

This analysis of Mexico's nanotechnology policies utilizes indicators developed by the Organization for Economic Co-operation and Development, which in 2008 conducted a pilot survey comparing the nanotechnology policies of 24 countries. In this paper, we apply the same questionnaire to the Mexican case, adding business information derived from the…

Selective Vulnerability of Brainstem Nuclei in Distinct Tauopathies: A Postmortem Study.

PubMed

Eser, Rana A; Ehrenberg, Alexander J; Petersen, Cathrine; Dunlop, Sara; Mejia, Maria B; Suemoto, Claudia K; Walsh, Christine M; Rajana, Hima; Oh, Jun; Theofilas, Panos; Seeley, William W; Miller, Bruce L; Neylan, Thomas C; Heinsen, Helmut; Grinberg, Lea T

2018-02-01

The brainstem nuclei of the reticular formation (RF) are critical for regulating homeostasis, behavior, and cognition. RF degenerates in tauopathies including Alzheimer disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). Although the burden of phopho-tau inclusion is high across these diseases, suggesting a similar vulnerability pattern, a distinct RF-associated clinical phenotype in these diseases indicates the opposite. To compare patterns of RF selective vulnerability to tauopathies, we analyzed 5 RF nuclei in tissue from 14 AD, 14 CBD, 10 PSP, and 3 control cases. Multidimensional quantitative analysis unraveled discernable differences on how these nuclei are vulnerable to AD, CBD, and PSP. For instance, PSP and CBD accrued more tau inclusions than AD in locus coeruleus, suggesting a lower vulnerability to AD. However, locus coeruleus neuronal loss in AD was so extreme that few neurons remained to develop aggregates. Likewise, tau burden in gigantocellular nucleus was low in AD and high in PSP, but few GABAergic neurons were present in AD. This challenges the hypothesis that gigantocellular nucleus neuronal loss underlies REM behavioral disorders because REM behavioral disorders rarely manifests in AD. This study provides foundation for characterizing the clinical consequences of RF degeneration in tauopathies and guiding customized treatment. © 2018 American Association of Neuropathologists, Inc. All rights reserved.

The effects of verbal reaction time in Alzheimer's disease.

PubMed

Midi, Ipek; Doǧan, Müzeyyen; Pata, Yavuz Selim; Kocak, Ismail; Mollahasanoglu, Aynur; Tuncer, Nese

2011-07-01

Verbal fluency deteriorates with normal aging, but is much more severe in Alzheimer's Disease (AD). Verbal functions were analyzed to find differences between normal aging subjects in patients with mild cognitive impairment (MCI), and in patients with early and moderate stages of AD. This study measured the verbal response time in patients with AD, MCI, and in control subjects This study measured the verbal response time in patients with AD, MCI, and in control subjects Fifteen patients with MCI, 15 patients with early AD, 8 patients with moderate AD, and 15 subjects for controls were included in the study. Word length in milliseconds, reaction time to a phoneme, word, or sentence and acoustic analysis of voice quality and speech diadochokinetic rate (DDK) were measured. Reaction time for a phoneme, word, or sentence especially the initiation period for them were longer in patients with early AD compared to patients with MCI (P < .001). The mean DDK rate was lower with increased severity of the disease, and was much more severe in patients with moderate AD. Clinical discrimination of the early stages of AD and MCI is challenging. Unfortunately, there are no laboratory markers present for the diagnosis of preclinical cases of AD. With the results of this study, the assessments of verbal reaction time may helpful for diagnosis of early AD. Copyright © 2011 The American Laryngological, Rhinological, and Otological Society, Inc.

Frequency of Alzheimer's Disease Pathology at Autopsy in Patients with Clinical Normal Pressure Hydrocephalus

PubMed Central

Cabral, Danielle; Beach, Thomas G; Vedders, Linda; Sue, Lucia I; Jacobson, Sandra; Myers, Kent; Sabbagh, Marwan N

2011-01-01

Background Normal pressure hydrocephalus (NPH) is considered potentially treatable with the placement of a cerebrospinal fluid (CSF) shunt. Yet, the procedure has had variable success, particularly with respect to improving the cognitive impairment in NPH. The presence of neurologic co-morbidities, particularly Alzheimer's Disease (AD), may contribute to shunt responsiveness. Uncovering the extent to which AD and NPH co-occur has implications for diagnosis and treatment of NPH. Autopsy studies of patients with NPH during life would elucidate the frequency of such co-morbidities. Methods We conducted a search of the Sun Health Research Institute Brain Donation Program database between 1/1/1997 and 4/1/09 to identify all cases with neuropathologic evidence of dementia as well as those cases of clinically diagnosed NPH. We reviewed the medical records and brain findings of each NPH case. Results Of the 761 cases autopsied over the study interval, 563 cases were found to have neuropathological evidence meeting criteria for a dementing illness. AD was found exclusively in 313/563 (56%) cases with 94/563 cases having a secondary diagnosis of dementia. We identified 9/761 cases with a clinical diagnosis of NPH, all nine cases were among the 563 cases with neuropathology of dementing illness at autopsy, representing 1.6% (9/563). Upon review of brain autopsy reports, 8/9 (89%) cases were found to have AD and 1/9 (11%) had progressive supranuclear palsy. Review of the medical records of the nine NPH cases revealed the following clinical co-morbidities: 5/9 with AD; 1/9 with Parkinson's Disease (PD); 1/9 with Mild Cognitive Impairment (MCI); 1/9 with seizure disorder. Conclusions Given the findings of our study, we support the AD-NPH theory and posit that AD is a common pathological co-morbidity in the setting of NPH and may preclude cognitive improvement post-shunt placement. This may have influence on selection of cases for shunting in the future. PMID:21723206

Inside out: meet the operators inside the horizon. On bulk reconstruction behind causal horizons

NASA Astrophysics Data System (ADS)

Almheiri, Ahmed; Anous, Tarek; Lewkowycz, Aitor

2018-01-01

Based on the work of Heemskerk, Marolf, Polchinski and Sully (HMPS), we study the reconstruction of operators behind causal horizons in time dependent geometries obtained by acting with shockwaves on pure states or thermal states. These geometries admit a natural basis of gauge invariant operators, namely those geodesically dressed to the boundary along geodesics which emanate from the bifurcate horizon at constant Rindler time. We outline a procedure for obtaining operators behind the causal horizon but inside the entanglement wedge by exploiting the equality between bulk and boundary time evolution, as well as the freedom to consider the operators evolved by distinct Hamiltonians. This requires we carefully keep track of how the operators are gravitationally dressed and that we address issues regarding background dependence. We compare this procedure to reconstruction using modular flow, and illustrate some formal points in simple cases such as AdS2 and AdS3.

Abnormally phosphorylated tau protein in senile dementia of Lewy body type and Alzheimer disease: evidence that the disorders are distinct.

PubMed

Strong, C; Anderton, B H; Perry, R H; Perry, E K; Ince, P G; Lovestone, S

1995-01-01

The relationship between Alzheimer disease (AD) and dementia with Lewy bodies (senile dementia Lewy body type, or SDLT) and dementia in Parkinson's disease is unclear. AD pathology is characterised by both amyloid deposition and abnormal phosphorylation of tau in paired helical filaments (PHF-tau). In AD, abnormally phosphorylated PHF-tau is present in neurofibrillary tangles, in neuritic processes of senile plaques, and also in neuropil threads dispersed throughout the cerebral cortex. Cortical homogenates from 12 cases each of AD and SDLT, 13 cases of Parkinson's disease, and 11 normal controls were examined by Western blot analysis with antibodies that detect PHF-tau. No PHF-tau was found in Parkinson's disease or control cortex. No PHF-tau was found in SDLT cases without histological evidence of tangles. PHF-tau was detectable in SDLT cases with a low density of tangles, and large amounts of PHF-tau were present in AD cases. This study demonstrates that abnormally phosphorylated PHF-tau is only present where tangles are found and not in SDLT cases without tangles or with only occasional tangles. It is concluded that Lewy body dementias are distinct at a molecular level from AD.

Alzheimer's disease - a neurospirochetosis. Analysis of the evidence following Koch's and Hill's criteria

PubMed Central

2011-01-01

It is established that chronic spirochetal infection can cause slowly progressive dementia, brain atrophy and amyloid deposition in late neurosyphilis. Recently it has been suggested that various types of spirochetes, in an analogous way to Treponema pallidum, could cause dementia and may be involved in the pathogenesis of Alzheimer's disease (AD). Here, we review all data available in the literature on the detection of spirochetes in AD and critically analyze the association and causal relationship between spirochetes and AD following established criteria of Koch and Hill. The results show a statistically significant association between spirochetes and AD (P = 1.5 × 10-17, OR = 20, 95% CI = 8-60, N = 247). When neutral techniques recognizing all types of spirochetes were used, or the highly prevalent periodontal pathogen Treponemas were analyzed, spirochetes were observed in the brain in more than 90% of AD cases. Borrelia burgdorferi was detected in the brain in 25.3% of AD cases analyzed and was 13 times more frequent in AD compared to controls. Periodontal pathogen Treponemas (T. pectinovorum, T. amylovorum, T. lecithinolyticum, T. maltophilum, T. medium, T. socranskii) and Borrelia burgdorferi were detected using species specific PCR and antibodies. Importantly, co-infection with several spirochetes occurs in AD. The pathological and biological hallmarks of AD were reproduced in vitro by exposure of mammalian cells to spirochetes. The analysis of reviewed data following Koch's and Hill's postulates shows a probable causal relationship between neurospirochetosis and AD. Persisting inflammation and amyloid deposition initiated and sustained by chronic spirochetal infection form together with the various hypotheses suggested to play a role in the pathogenesis of AD a comprehensive entity. As suggested by Hill, once the probability of a causal relationship is established prompt action is needed. Support and attention should be given to this field of AD research. Spirochetal infection occurs years or decades before the manifestation of dementia. As adequate antibiotic and anti-inflammatory therapies are available, as in syphilis, one might prevent and eradicate dementia. PMID:21816039

General practice performance in referral for suspected cancer: influence of number of cases and case-mix on publicly reported data.

PubMed

Murchie, P; Chowdhury, A; Smith, S; Campbell, N C; Lee, A J; Linden, D; Burton, C D

2015-05-26

Publicly available data show variation in GPs' use of urgent suspected cancer (USC) referral pathways. We investigated whether this could be due to small numbers of cancer cases and random case-mix, rather than due to true variation in performance. We analysed individual GP practice USC referral detection rates (proportion of the practice's cancer cases that are detected via USC) and conversion rates (proportion of the practice's USC referrals that prove to be cancer) in routinely collected data from GP practices in all of England (over 4 years) and northeast Scotland (over 7 years). We explored the effect of pooling data. We then modelled the effects of adding random case-mix to practice variation. Correlations between practice detection rate and conversion rate became less positive when data were aggregated over several years. Adding random case-mix to between-practice variation indicated that the median proportion of poorly performing practices correctly identified after 25 cancer cases were examined was 20% (IQR 17 to 24) and after 100 cases was 44% (IQR 40 to 47). Much apparent variation in GPs' use of suspected cancer referral pathways can be attributed to random case-mix. The methods currently used to assess the quality of GP-suspected cancer referral performance, and to compare individual practices, are misleading. These should no longer be used, and more appropriate and robust methods should be developed.

Adenomatous-Dominant Benign Prostatic Hyperplasia (AdBPH) as a Predictor for Clinical Success Following Prostate Artery Embolization: An Age-Matched Case–Control Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Little, M. W., E-mail: m.little@doctors.org.uk; Boardman, P.; Macdonald, A. C.

PurposeTo investigate the clinical impact of performing prostate artery embolization (PAE) on patients with adenomatous-dominant benign prostatic hyperplasia (AdBPH).Materials and MethodsTwelve patients from the ongoing proSTatic aRtery EmbolizAtion for the treatMent of benign prostatic hyperplasia (STREAM) trial were identified as having AdBPH; defined as two or more adenomas within the central gland of ≥1 cm diameter on multi-parametric MRI (MP-MRI). These patients were age-matched with patients from the STREAM cohort, without AdBPH. Patients were followed up with repeat MP-MRI at 3 months and 1 year. International prostate symptom score (IPSS), international index for erectile function (IIEF), and quality of life assessment from themore » IPSS and EQ-5D-5S questionnaires were recorded pre-PAE and at 6 weeks, 3 months, and 1 year.ResultsThe mean age of patients was 68 (61–76). All patients had PAE as a day-case procedure. The technical success in the cohort was 23/24 (96%). There was a significant reduction in prostate volume following embolization with a median reduction of 34% (30–55) in the AdBPH group, compared to a mean volume reduction of 22% (9–44) in the non-AdBPH group (p = 0.04). There was a significant reduction in IPSS in the AdBPH group following PAE when compared with the control group [AdBPH median IPSS 8 (3–15) vs. non-AdBPH median IPSS 13 (8–18), p = 0.01]. IPSS QOL scores significantly improved in the AdBPH group (p = 0.007). There was no deterioration in sexual function in either group post-PAE.ConclusionsThis is the first time that AdBPH has been identified as being a predictor of clinical success following PAE.« less

Association of Plasma Neurofilament Light With Neurodegeneration in Patients With Alzheimer Disease.

PubMed

Mattsson, Niklas; Andreasson, Ulf; Zetterberg, Henrik; Blennow, Kaj

2017-05-01

Existing cerebrospinal fluid (CSF) or imaging (tau positron emission tomography) biomarkers for Alzheimer disease (AD) are invasive or expensive. Biomarkers based on standard blood test results would be useful in research, drug development, and clinical practice. Plasma neurofilament light (NFL) has recently been proposed as a blood-based biomarker for neurodegeneration in dementias. To test whether plasma NFL concentrations are increased in AD and associated with cognitive decline, other AD biomarkers, and imaging evidence of neurodegeneration. In this prospective case-control study, an ultrasensitive assay was used to measure plasma NFL concentration in 193 cognitively healthy controls, 197 patients with mild cognitive impairment (MCI), and 180 patients with AD dementia from the Alzheimer's Disease Neuroimaging Initiative. The study dates were September 7, 2005, to February 13, 2012. The plasma NFL analysis was performed in September 2016. Associations were tested between plasma NFL and diagnosis, Aβ pathologic features, CSF biomarkers of neuronal injury, cognition, brain structure, and metabolism. Among 193 cognitively healthy controls, 197 patients with mild cognitive impairment, and 180 patients with AD with dementia, plasma NFL correlated with CSF NFL (Spearman ρ = 0.59, P < .001). Plasma NFL was increased in patients with MCI (mean, 42.8 ng/L) and patients with AD dementia (mean, 51.0 ng/L) compared with controls (mean, 34.7 ng/L) (P < .001) and had high diagnostic accuracy for patients with AD with dementia vs controls (area under the receiver operating characteristic curve, 0.87, which is comparable to established CSF biomarkers). Plasma NFL was particularly high in patients with MCI and patients with AD dementia with Aβ pathologic features. High plasma NFL correlated with poor cognition and AD-related atrophy (at baseline and longitudinally) and with brain hypometabolism (longitudinally). Plasma NFL is associated with AD diagnosis and with cognitive, biochemical, and imaging hallmarks of the disease. This finding implies a potential usefulness for plasma NFL as a noninvasive biomarker in AD.

Differentiating cognitive impairment due to corticobasal degeneration and Alzheimer disease

PubMed Central

Day, Gregory S.; Lim, Tae Sung; Hassenstab, Jason; Goate, Alison M.; Grant, Elizabeth A.; Roe, Catherine M.; Cairns, Nigel J.

2017-01-01

Objective: To identify clinical features that reliably differentiate individuals with cognitive impairment due to corticobasal degeneration (CBD) and Alzheimer disease (AD). Methods: Clinical features were compared between individuals with autopsy-proven CBD (n = 17) and AD (n = 16). All individuals presented with prominent cognitive complaints and were evaluated annually with semistructured interviews, detailed neurologic examinations, and neuropsychological testing. Results: Substantial overlap was observed between individuals with dementia due to CBD and AD concerning presenting complaints, median (range) duration of symptoms before assessment (CBD = 3.0 [0–5.0] years, AD = 2.5 [0–8.0] years; p = 0.96), and median (range) baseline dementia severity (Clinical Dementia Rating Sum of Boxes: CBD = 3.5 [0–12.0], AD = 4.25 [0.5–9.0], p = 0.49). Subsequent emergence of asymmetric motor/sensory signs, hyperreflexia, gait abnormalities, parkinsonism, falls, urinary incontinence, and extraocular movement abnormalities identified individuals with CBD, with ≥3 discriminating features detected in 80% of individuals within 3.1 years (95% confidence interval 2.9–3.3) of the initial assessment. Individuals with CBD exhibited accelerated worsening of illness severity and declines in episodic memory, executive functioning, and letter fluency. Semiquantitative pathologic assessment revealed prominent tau pathology within the frontal and parietal lobes of CBD cases. Comorbid AD neuropathologic change was present in 59% (10 of 17) of CBD cases but did not associate with the clinical phenotype, rate of dementia progression, or dementia duration. Conclusions: CBD may mimic AD dementia early in its disease course. Interval screening for discriminating clinical features may improve antemortem diagnosis in individuals with CBD and prominent cognitive symptoms. PMID:28235814

Economic Evaluation of Dupilumab for the Treatment of Moderate-to-Severe Atopic Dermatitis in Adults.

PubMed

Kuznik, Andreas; Bégo-Le-Bagousse, Gaëlle; Eckert, Laurent; Gadkari, Abhijit; Simpson, Eric; Graham, Christopher N; Miles, LaStella; Mastey, Vera; Mahajan, Puneet; Sullivan, Sean D

2017-12-01

Dupilumab significantly improves signs and symptoms of atopic dermatitis (AD), including pruritus, symptoms of anxiety and depression, and health-related quality of life versus placebo in adults with moderate-to-severe AD. Since the cost-effectiveness of dupilumab has not been evaluated, the objective of this analysis was to estimate a value-based price range in which dupilumab would be considered cost-effective compared with supportive care (SC) for treatment of moderate-to-severe AD in an adult population. A health economic model was developed to evaluate from the US payer perspective the long-term costs and benefits of dupilumab treatment administered every other week (q2w). Dupilumab q2w was compared with SC; robustness of assumptions and results were tested using sensitivity and scenario analyses. Clinical data were derived from the dupilumab LIBERTY AD SOLO trials; healthcare use and cost data were from health insurance claims histories of adult patients with AD. The annual price of maintenance therapy with dupilumab to be considered cost-effective was estimated for decision thresholds of US$100,000 and $150,000 per quality-adjusted life-year (QALY) gained. In the base case, the annual maintenance price for dupilumab therapy to be considered cost-effective would be $28,770 at a $100,000 per QALY gained threshold, and $39,940 at a $150,000 threshold. Results were generally robust to parameter variations in one-way and probabilistic sensitivity analyses. Dupilumab q2w compared with SC is cost-effective for the treatment of moderate-to-severe AD in US adults at an annual price of maintenance therapy in the range of $29,000-$40,000 at the $100,000-$150,000 per QALY thresholds. Sanofi and Regeneron Pharmaceuticals, Inc.

Diagnostic performance of an automated analysis software for the diagnosis of Alzheimer’s dementia with 18F FDG PET

PubMed Central

Partovi, Sasan; Yuh, Roger; Pirozzi, Sara; Lu, Ziang; Couturier, Spencer; Grosse, Ulrich; Schluchter, Mark D; Nelson, Aaron; Jones, Robert; O’Donnell, James K; Faulhaber, Peter

2017-01-01

The objective of this study was to assess the ability of a quantitative software-aided approach to improve the diagnostic accuracy of 18F FDG PET for Alzheimer’s dementia over visual analysis alone. Twenty normal subjects (M:F-12:8; mean age 80.6 years) and twenty mild AD subjects (M:F-12:8; mean age 70.6 years) with 18F FDG PET scans were obtained from the ADNI database. Three blinded readers interpreted these PET images first using a visual qualitative approach and then using a quantitative software-aided approach. Images were classified on two five-point scales based on normal/abnormal (1-definitely normal; 5-definitely abnormal) and presence of AD (1-definitely not AD; 5-definitely AD). Diagnostic sensitivity, specificity, and accuracy for both approaches were compared based on the aforementioned scales. The sensitivity, specificity, and accuracy for the normal vs. abnormal readings of all readers combined were higher when comparing the software-aided vs. visual approach (sensitivity 0.93 vs. 0.83 P = 0.0466; specificity 0.85 vs. 0.60 P = 0.0005; accuracy 0.89 vs. 0.72 P<0.0001). The specificity and accuracy for absence vs. presence of AD of all readers combined were higher when comparing the software-aided vs. visual approach (specificity 0.90 vs. 0.70 P = 0.0008; accuracy 0.81 vs. 0.72 P = 0.0356). Sensitivities of the software-aided and visual approaches did not differ significantly (0.72 vs. 0.73 P = 0.74). The quantitative software-aided approach appears to improve the performance of 18F FDG PET for the diagnosis of mild AD. It may be helpful for experienced 18F FDG PET readers analyzing challenging cases. PMID:28123864

Supergravity backgrounds for deformations of AdS n × S n supercoset string models

DOE PAGES

Lunin, O.; Roiban, R.; Tseytlin, A. A.

2014-12-11

We considermore » type IIB supergravity backgrounds corresponding to the deformed AdS n × S n × T 10 - 2 n supercoset string models of the type constructed in arXiv:1309.5850[2] which depend on one deformation parameter κ. In AdS 2 × S 2 case we find that the deformed metric can be extended to a full supergravity solution with non-trivial dilaton, RR scalar and RR 5-form strength. The solution depends on a free parameter a that should be chosen as a particular function of κ to correspond to the deformed supercoset model. In AdS 3 × S 3 case the full solution supported by the dilaton, RR scalar and RR 3-form strength exists only in the two special cases, a = 0 and a = 1 . We conjecture that there may be a more general one-parameter solution supported by several RR fields that for particular a = a ( κ ) corresponds to the supercoset model. In the most complicated deformed AdS 5 × S 5 case we were able to find only the expressions for the dilaton and the RR scalar. The full solution is likely to be supported by a combination of the 5-form and 3-form field strengths. We comment on the singularity structure of the resulting metric and exact dilaton field.« less

Supergravity backgrounds for deformations of AdS n × S n supercoset string models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lunin, O.; Roiban, R.; Tseytlin, A. A.

We considermore » type IIB supergravity backgrounds corresponding to the deformed AdS n × S n × T 10 - 2 n supercoset string models of the type constructed in arXiv:1309.5850[2] which depend on one deformation parameter κ. In AdS 2 × S 2 case we find that the deformed metric can be extended to a full supergravity solution with non-trivial dilaton, RR scalar and RR 5-form strength. The solution depends on a free parameter a that should be chosen as a particular function of κ to correspond to the deformed supercoset model. In AdS 3 × S 3 case the full solution supported by the dilaton, RR scalar and RR 3-form strength exists only in the two special cases, a = 0 and a = 1 . We conjecture that there may be a more general one-parameter solution supported by several RR fields that for particular a = a ( κ ) corresponds to the supercoset model. In the most complicated deformed AdS 5 × S 5 case we were able to find only the expressions for the dilaton and the RR scalar. The full solution is likely to be supported by a combination of the 5-form and 3-form field strengths. We comment on the singularity structure of the resulting metric and exact dilaton field.« less

APOε2 and education in cognitively normal older subjects with high levels of AD pathology at autopsy: findings from the Nun Study.

PubMed

Iacono, Diego; Zandi, Peter; Gross, Myron; Markesbery, William R; Pletnikova, Olga; Rudow, Gay; Troncoso, Juan C

2015-06-10

Asymptomatic Alzheimer's disease (ASYMAD) subjects are individuals characterized by preserved cognition before death despite substantial AD pathology at autopsy. ASYMAD subjects show comparable levels of AD pathology, i.e. β-amyloid neuritic plaques (Aβ-NP) and tau-neurofibrillary tangles (NFT), to those observed in mild cognitive impairment (MCI) and some definite AD cases. Previous clinicopathologic studies on ASYMAD subjects have shown specific phenomena of hypertrophy in the cell bodies, nuclei, and nucleoli of hippocampal pyramidal neurons and other cerebral areas. Since it is well established that the allele APOε4 is a major genetic risk factor for AD, we examined whether specific alleles of APOE could be associated with the different clinical outcomes between ASYMAD and MCI subjects despite equivalent AD pathology. A total of 523 brains from the Nun Study were screened for this investigation. The results showed higher APOε2 frequency (p < 0.001) in ASYMAD (19.2%) vs. MCI (0%) and vs. AD (4.7%). Furthermore, higher education in ASYMAD vs. MCI and AD (p < 0.05) was found. These novel autopsy-verified findings support the hypothesis of the beneficial effect of APOε2 and education, both which seem to act as contributing factors in delaying or forestalling the clinical manifestations of AD despite consistent levels of AD pathology.

APOε2 and education in cognitively normal older subjects with high levels of AD pathology at autopsy: findings from the Nun Study

PubMed Central

Iacono, Diego; Zandi, Peter; Gross, Myron; Markesbery, William R.; Pletnikova, Olga; Rudow, Gay; Troncoso, Juan C.

2015-01-01

Asymptomatic Alzheimer's disease (ASYMAD) subjects are individuals characterized by preserved cognition before death despite substantial AD pathology at autopsy. ASYMAD subjects show comparable levels of AD pathology, i.e. β-amyloid neuritic plaques (Aβ-NP) and tau-neurofibrillary tangles (NFT), to those observed in mild cognitive impairment (MCI) and some definite AD cases. Previous clinicopathologic studies on ASYMAD subjects have shown specific phenomena of hypertrophy in the cell bodies, nuclei, and nucleoli of hippocampal pyramidal neurons and other cerebral areas. Since it is well established that the allele APOε4 is a major genetic risk factor for AD, we examined whether specific alleles of APOE could be associated with the different clinical outcomes between ASYMAD and MCI subjects despite equivalent AD pathology. A total of 523 brains from the Nun Study were screened for this investigation. The results showed higher APOε2 frequency (p < 0.001) in ASYMAD (19.2%) vs. MCI (0%) and vs. AD (4.7%). Furthermore, higher education in ASYMAD vs. MCI and AD (p < 0.05) was found. These novel autopsy-verified findings support the hypothesis of the beneficial effect of APOε2 and education, both which seem to act as contributing factors in delaying or forestalling the clinical manifestations of AD despite consistent levels of AD pathology. PMID:26101858

Has the increase in private health insurance uptake affected the Victorian public hospital surgical waiting list?

PubMed

Hanning, Brian

2002-01-01

It was anticipated that increase uptake of Private Health Insurance (PHI) would reduce demand on public sector surgical waiting lists. The best measure of changed demand is the comparison of the actual cases added to that projected given previous trends in PHI uptake. Detailed Victorian data is available up to 2000-1. The total waiting list has varied little, reflecting significant decreases in both in patients added to and removed. There was a marked increase in private sector elective surgery cases coinciding with the fall in additions to the public sector waiting list and in public sector elective surgical cases. The June 2001 Victorian surgical waiting list would have been 69,599 not 41,838 if the PHI uptake rate had continued to fall in line with pre-1999 trends, and that of June 2002 about 100,000 compared to 40,458 in March 2002. Limited data from other states suggests the Victorian trends are representative of all Australia.

Index of Theta/Alpha Ratio of the Quantitative Electroencephalogram in Alzheimer's Disease: A Case-Control Study.

PubMed

Fahimi, Golshan; Tabatabaei, Seyed Mahmoud; Fahimi, Elnaz; Rajebi, Hamid

2017-08-01

Alzheimer's disease (AD) is a devastating neurodegenerative disorder in human beings associated with cognitive, behavioral and motor impairments. The main symptom of AD is dementia, which causes difficulties in carrying out daily practices. Brain waves are altered in people with AD. Relative indices of brain waves can be beneficial in the diagnosis of AD. In this case-control study, 50 patients with AD and 50 matched healthy individuals were enrolled in case and control groups respectively. With recording and analyzing of brain waves with the utilization of quantitative electroencephalogram (QEEG), index of theta/alpha ratio was assessed in both groups. The index of theta/alpha ratio was significantly higher in patients with AD in comparison to healthy individuals (P<0.05). Index of theta/alpha ratio obtained by QEEG provides a non-invasive diagnostic marker of AD, which may be helpful in identification of non-advanced disease in susceptible individuals.

Comparison of digital mammography and digital breast tomosynthesis in the detection of architectural distortion.

PubMed

Dibble, Elizabeth H; Lourenco, Ana P; Baird, Grayson L; Ward, Robert C; Maynard, A Stanley; Mainiero, Martha B

2018-01-01

To compare interobserver variability (IOV), reader confidence, and sensitivity/specificity in detecting architectural distortion (AD) on digital mammography (DM) versus digital breast tomosynthesis (DBT). This IRB-approved, HIPAA-compliant reader study used a counterbalanced experimental design. We searched radiology reports for AD on screening mammograms from 5 March 2012-27 November 2013. Cases were consensus-reviewed. Controls were selected from demographically matched non-AD examinations. Two radiologists and two fellows blinded to outcomes independently reviewed images from two patient groups in two sessions. Readers recorded presence/absence of AD and confidence level. Agreement and differences in confidence and sensitivity/specificity between DBT versus DM and attendings versus fellows were examined using weighted Kappa and generalised mixed modeling, respectively. There were 59 AD patients and 59 controls for 1,888 observations (59 × 2 (cases and controls) × 2 breasts × 2 imaging techniques × 4 readers). For all readers, agreement improved with DBT versus DM (0.61 vs. 0.37). Confidence was higher with DBT, p = .001. DBT achieved higher sensitivity (.59 vs. .32), p < .001; specificity remained high (>.90). DBT achieved higher positive likelihood ratio values, smaller negative likelihood ratio values, and larger ROC values. DBT decreases IOV, increases confidence, and improves sensitivity while maintaining high specificity in detecting AD. • Digital breast tomosynthesis decreases interobserver variability in the detection of architectural distortion. • Digital breast tomosynthesis increases reader confidence in the detection of architectural distortion. • Digital breast tomosynthesis improves sensitivity in the detection of architectural distortion.

Malassezia Yeast and Cytokine Gene Polymorphism in Atopic Dermatitis

PubMed Central

Das, Shukla; Ramachandran, V.G.; Saha, Rumpa; Bhattacharya, S.N.; Dar, Sajad

2017-01-01

Introduction Atopic Dermatitis (AD) is a recurrent chronic condition associated with microorganism and their interaction with the susceptible host. Malassezia yeast is a known commensal which is thought to provoke the recurrent episodes of symptoms in atopic dermatitis patients. Malassezia immunomodulatory properties along with defective skin barrier in such host, results in disease manifestation. Here, we studied Single Nucleotide Polymorphism (SNP) in IL10 and IFN γ genes of the host and its relation with susceptibility to Malassezia infection. Aim To isolate Malassezia yeast from AD patients and compare the genetic susceptibility of the host by correlating the cytokine gene polymorphism with the control subjects. Materials and Methods Study was conducted from January 2012 to January 2013. It was a prospective observational study done in Department of Microbiology and Department of Dermatology and Venereology in University College of Medical Sciences and GTB Hospital, Delhi. Sample size comprised of 38 cases each of AD. Skin scrapings were used for fungal culture on Sabouraud Dextrose Agar (SDA) and Modified Dixon Agar (MDA) and isolated were identified as per conventional phenotypic methods. Genomic DNA was extracted from blood samples collected from all study subjects. Cytokine genotyping was carried out by Amplification Refractory Mutations System- Polymerase Chain Reaction (ARMS-PCR) with sequence specific primers. Three SNPs (IL10-1082A/G; IL10-819/592C/T; IFN-γ+874A/T) in two cytokine genes were assessed in all the patients and healthy controls. Statistical Analysis Chi-Square Test or Fisher’s-Exact Test and Bonferroni’s correction. Results In AD group, Malassezia yeasts were cultured in 24 out of 38 samples and thus the identification rate was 63.1 percent as compared to healthy group, 52.6 percent (20/38). Significant difference in allele, or genotype distribution were observed in IL10-819/592C/T and IFN-γ+874A/T gene polymorphism in AD group. Conclusion Higher isolation rate in cases as compared to control group highlights the implication of Malassezia in AD. Association between specific cytokine gene polymorphism and clinical outcome was found to be significant in study group. The result of cytokine gene polymorphism in the present study demonstrated susceptibility of host to Malassezia infection. PMID:28511379

Autism in children and adolescents with cancer.

PubMed

Blatt, Julie; Deal, Allison M; Mesibov, Gary

2010-01-01

The causes of autistic disorders (AD) are not known. Abnormalities of tumor suppressor genes have suggested that these genes may be important to the development of autism in some cases, and result in an increased risk of developing cancer or other neoplasms. We explore possible associations between AD and childhood cancer. We reviewed our institutional pediatric cancer database for all new cancer diagnoses 1997-2007. Medical records from patients older than 2 years at last visit were reviewed for a diagnosis of AD. The prevalence of AD was estimated for neoplasms overall and for specific tumor types, and compared with that in the general pediatric population. Of 702 eligible patients, 7 (1%; 95% CI: (0.4%, 2.04%)) were labeled as AD, not different than the prevalence of AD in North Carolina's general population (0.65%, P = 0.35). Cancer diagnoses for these 7 children were acute lymphoblastic leukemia (n = 1), acute nonlymphocytic leukemia (n = 2), non-Hodgkin lymphoma (n = 1), Hodgkin Disease (n = 1), brain tumor (n = 1), osteogenic sarcoma (n = 1). These data do not suggest that there is a high concordance between AD and childhood cancer. However, studies of large rigorously characterized AD cohorts will be needed to definitively address this issue. Copyright 2009 Wiley-Liss, Inc.

[Atopic dermatitis and prolonged exclusive breast-feeding].

PubMed

Amri, M; Elhani, I; Doussari, S; Amir, A

2012-04-01

We sought to compare the prevalence of exclusive breastfeeding throughout at least the first 6 months of life in patients presenting atopic dermatitis (AD) with a control group, and to check for a correlation between the duration of exclusive breastfeeding and the severity of AD. We conducted a case-control study with prospective inclusion over a period of 3 years. The study group consisted of 114 patients aged less than 15 years, from an urban area, presenting AD but with no personal or family history of atopy. Each patient was compared with two controls from the same town, matched for age and gender, with no personal or family history of atopy, and free of AD. Data analysis was performed using the SPSS software package, version 15.0. A P-value of less than 0.05 was considered as statistically significant. The prevalence of exclusive breastfeeding for at least the first 6 months of life in the patient group was significantly lower than in the control group (P=0.0413). On the other hand, AD was significantly less severe in patients exclusively breastfed for longer than 9 months (P=0.0079). The correlations recorded in our study do not allow us to draw any definite conclusions about a protective effect of exclusive breastfeeding with regard to AD. However, other benefits of extended exclusive breastfeeding justify supporting breastfeeding in a community with an existing sociocultural predisposition for this feeding method. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Understanding Effective High Schools: Evidence for Personalization for Academic and Social Emotional Learning

ERIC Educational Resources Information Center

Rutledge, Stacey A.; Cohen-Vogel, Lora; Osborne-Lampkin, La'Tara; Roberts, Ronnie L.

2015-01-01

This article presents findings from a year-long multilevel comparative case study exploring the characteristics of effective urban high schools. We developed a comprehensive framework from the school effectiveness research that guided our data collection and analysis at the four high schools. Using value-added methodology, we identified two higher…

Reduction of aggregated Tau in neuronal processes but not in the cell bodies after Abeta42 immunisation in Alzheimer's disease.

PubMed

Boche, Delphine; Donald, Jane; Love, Seth; Harris, Scott; Neal, James W; Holmes, Clive; Nicoll, James A R

2010-07-01

Alzheimer's disease (AD) pathology is characterised by aggregation in the brain of amyloid-beta (Abeta) peptide and hyperphosphorylated tau (phospho-tau), although how these proteins interact in disease pathogenesis is unclear. Abeta immunisation results in removal of Abeta from the brain but cognitive decline continues to progress, possibly due to persistent phospho-tau. We quantified phospho-tau and Abeta42 in the brains of 10 AD patients (iAD) who were actively immunised with Abeta42 (AN1792, Elan Pharmaceuticals) compared with 28 unimmunised AD cases (cAD). The phospho-tau load was lower in the iAD than the cAD group in the cerebral cortex (cAD 1.08% vs. iAD 0.72%, P = 0.048), CA1 hippocampus (cAD 2.26% vs. iAD 1.05%; P = 0.001), subiculum (cAD 1.60% vs. iAD 0.31%; P = 0.001) and entorhinal cortex (cAD 1.10% vs. iAD 0.18%; P < 0.001). Assessment of the localisation within neurons of phospho-tau indicated that the Abeta immunotherapy-associated reduction was confined to neuronal processes, i.e. neuropil threads and dystrophic neurites. However, the phospho-tau accumulation in the neuronal cell bodies, contributing to neurofibrillary tangles, appeared not to be affected. In showing that Abeta immunisation can influence phospho-tau pathology, we confirm the position of Abeta as a target for modifying tau accumulation in AD and demonstrate a link between these proteins. However, the continuing progression of cognitive decline in AD patients after Abeta immunisation may be explained by its lack of apparent effect on tangles.

Caspase-6 Activation in Familial Alzheimer Disease Brains Carrying Amyloid Precursor Protein, Presenilin I or Presenilin II Mutations

PubMed Central

Albrecht, Steffen; Bogdanovic, Nenad; Ghetti, Bernardino; Winblad, Bengt; LeBlanc, Andréa C.

2010-01-01

We previously demonstrated the activation of Caspase-6 in the hippocampus and cortex in cases of mild, moderate, severe and very severe Alzheimer disease (AD). To determine whether Caspase-6 is also activated in familial AD, we performed an immunohistochemical analysis of active Caspase-6 and Tau cleaved by Caspase-6 in temporal cortex and hippocampal tissue sections from cases of familial AD. The cases included 5 carrying the amyloid precursor protein K670N, M671L Swedish mutation, 1 carrying the amyloid precursor protein E693G Arctic mutation, 2 each carrying the Presenilin I M146V, F105L, A431E, V261F, Y115C mutations, and 1 with the Presenilin II N141I mutation. Active Caspase-6 immunoreactivity was found in all cases. Caspase-6 immunoreactivity was observed in neuritic plaques or cotton wool plaques in some cases, neuropil threads and neurofibrillary tangles. These results indicate that Caspase-6 is activated in familial forms of AD, as previously observed in sporadic forms. Since sporadic and familial AD cases have similar pathological features, these results support a fundamental role of Caspase-6 in the pathophysiology of both familial and sporadic AD. PMID:19915487

Computer-aided diagnostic method for classification of Alzheimer's disease with atrophic image features on MR images

NASA Astrophysics Data System (ADS)

Arimura, Hidetaka; Yoshiura, Takashi; Kumazawa, Seiji; Tanaka, Kazuhiro; Koga, Hiroshi; Mihara, Futoshi; Honda, Hiroshi; Sakai, Shuji; Toyofuku, Fukai; Higashida, Yoshiharu

2008-03-01

Our goal for this study was to attempt to develop a computer-aided diagnostic (CAD) method for classification of Alzheimer's disease (AD) with atrophic image features derived from specific anatomical regions in three-dimensional (3-D) T1-weighted magnetic resonance (MR) images. Specific regions related to the cerebral atrophy of AD were white matter and gray matter regions, and CSF regions in this study. Cerebral cortical gray matter regions were determined by extracting a brain and white matter regions based on a level set based method, whose speed function depended on gradient vectors in an original image and pixel values in grown regions. The CSF regions in cerebral sulci and lateral ventricles were extracted by wrapping the brain tightly with a zero level set determined from a level set function. Volumes of the specific regions and the cortical thickness were determined as atrophic image features. Average cortical thickness was calculated in 32 subregions, which were obtained by dividing each brain region. Finally, AD patients were classified by using a support vector machine, which was trained by the image features of AD and non-AD cases. We applied our CAD method to MR images of whole brains obtained from 29 clinically diagnosed AD cases and 25 non-AD cases. As a result, the area under a receiver operating characteristic (ROC) curve obtained by our computerized method was 0.901 based on a leave-one-out test in identification of AD cases among 54 cases including 8 AD patients at early stages. The accuracy for discrimination between 29 AD patients and 25 non-AD subjects was 0.840, which was determined at the point where the sensitivity was the same as the specificity on the ROC curve. This result showed that our CAD method based on atrophic image features may be promising for detecting AD patients by using 3-D MR images.

Argyrophilic grain disease as a neurodegenerative substrate in late-onset schizophrenia and delusional disorders.

PubMed

Nagao, Shigeto; Yokota, Osamu; Ikeda, Chikako; Takeda, Naoya; Ishizu, Hideki; Kuroda, Shigetoshi; Sudo, Koichiro; Terada, Seishi; Murayama, Shigeo; Uchitomi, Yosuke

2014-06-01

To study the relationship between neurodegenerative diseases including argyrophilic grain disease (AGD) and late-onset schizophrenia and delusional disorders (LOSD; onset ≥40 years of age), we pathologically examined 23 patients with LOSD, 71 age-matched normal controls, and 22 psychiatric disease controls (11 depression, six personality disorder, two bipolar disorders, and three neurotic disorders cases). In all LOSD cases (compared to age-matched normal controls), the frequencies of Lewy body disease (LBD), AGD, and corticobasal degeneration (CBD) were 26.1 % (11.3 %), 21.7 % (8.5 %), and 4.3 % (0.0 %), respectively. There was no case of pure Alzheimer's disease (AD). The total frequency of LBD, AGD, and CBD was significantly higher in LOSD cases than in normal controls. Argyrophilic grains were significantly more severe in LOSD than in controls, but were almost completely restricted to the limbic system and adjacent temporal cortex. In LOSD patients whose onset occurred at ≥65 years of age (versus age-matched normal controls), the frequencies of LBD and AGD were 36.4 % (19.4 %) and 36.4 % (8.3 %), respectively, and AGD was significantly more frequent in LOSD patients than in normal controls. In LOSD patients whose onset occurred at <65 years of age, the frequencies of LBD, AGD, and CBD were 16.7, 8.3, and 8.3 %, comparable to those of age-matched normal controls (10.2, 5.1, and 0.0 %). In all psychiatric cases, delusion was significantly more frequent in AGD cases than in cases bearing minimal AD pathology alone. Given these findings, LOSD patients may have heterogeneous pathological backgrounds, and AGD may be associated with the occurrence of LOSD especially after 65 years of age.

[Relationship between multi-slice spiral CT angiography imaging features and in-hospital death of patients with aortic dissection].

PubMed

Xiao, Z Y; Wang, H J; Yao, C L; Gu, G R; Xue, Y; Yin, J; Chen, J; Zhang, C; Tong, C Y; Song, Z J

2017-03-24

Objective: To explore the imaging manifestations of multi-slice spiral CT angiography (CTA) and relationship with in-hospital death in patients with aortic dissection (AD). Methods: The clinical data of 429 patients with AD who underwent CTA in Zhongshan Hospital of Fudan University between January 2009 and January 2016 were retrospectively analyzed. AD patients were divided into 2 groups, including operation group who underwent surgery or interventional therapy (370 cases) and non-operation group who underwent medical conservative treatment(59 cases). The multi-slice spiral CTA imaging features of AD were analyzed, and multivariate logistic regression analysis was used to investigate the relationship between imaging manifestations and in-hospital death in AD patients. Results: There were 12 cases (3.24%) of in-hospital death in operation group, and 28 cases (47.46%) of in-hospital death in non-operation group( P <0.001). AD involved different vascular branches. Multi-slice spiral CTA can clearly show the dissection of true and false lumen, and intimal tear was detected in 363 (84.62%) cases, outer wall calcification was revealed in 63 (14.69%) cases, and thrombus formation was present in 227 (52.91%) cases. The multivariate logistic regression analysis showed that the number of branch vessels involved ( OR =1.374, 95% CI 1.081-1.745, P =0.009) and tearing false lumen range( OR =2.059, 95% CI 1.252-3.385, P =0.004) were independent risk factors of in-hospital death in AD patients, and the number of branch vessels involved ( OR =1.600, 95% CI 1.062-2.411, P =0.025) was independent risk factor of in-hospital death in the operation group, while the tearing false lumen range ( OR =2.315, 95% CI 1.019-5.262, P =0.045) was independent risk factor of in-hospital death of non-operation group. Conclusions: Multi-slice spiral CTA can clearly show the entire AD, true and false lumen, intimal tear, wall calcification and thrombosis of AD patients. The number of branch vessels involved and tearing false lumen range are the independent risk factors of in-hospital death in AD patients.

Atopic dermatitis in older adults: A viewpoint from geriatric dermatology.

PubMed

Tanei, Ryoji; Hasegawa, Yasuko

2016-03-01

Atopic dermatitis (AD) in older adults represents a newly defined subgroup of AD. The prevalence of elderly AD is approximately 1-3% among elderly populations in industrialized countries. Elderly patients with AD show some common clinical characteristics, such as a male predominance, a lower incidence of lichenified eczema at the elbow and knee folds, and particular patterns of onset and clinical course. Both immunoglobulin (Ig)E-allergic and non-IgE-allergic types are observed in elderly AD. Elderly patients with IgE-allergic AD show high rates of positivity for specific IgE antibodies against house dust mites, associations with IgE allergic and asthmatic complications, histopathological features with a predominance of IgE-mediated allergic inflammation in the lesional skin, and a significantly lower incidence of malignancy as compared with control subjects. The etiology of elderly AD might be associated with immunosenescence, age-related changes to the sex hormone milieu, age-related barrier dysfunctions in the skin and gut, functional disturbance of sweat production, and environmental stimuli in the lifestyle of elderly individuals. Powerful anti-inflammatory treatments, such as oral corticosteroids, might be required together with standard treatments to manage moderate to severe cases of elderly AD. Finally, most elderly patients with AD reach the end of life with this disease, which should now be considered a lifelong allergic disease. © 2016 Japan Geriatrics Society.

Costs and cost-effectiveness of 9-valent human papillomavirus (HPV) vaccination in two East African countries.

PubMed

Kiatpongsan, Sorapop; Kim, Jane J

2014-01-01

Current prophylactic vaccines against human papillomavirus (HPV) target two of the most oncogenic types, HPV-16 and -18, which contribute to roughly 70% of cervical cancers worldwide. Second-generation HPV vaccines include a 9-valent vaccine, which targets five additional oncogenic HPV types (i.e., 31, 33, 45, 52, and 58) that contribute to another 15-30% of cervical cancer cases. The objective of this study was to determine a range of vaccine costs for which the 9-valent vaccine would be cost-effective in comparison to the current vaccines in two less developed countries (i.e., Kenya and Uganda). The analysis was performed using a natural history disease simulation model of HPV and cervical cancer. The mathematical model simulates individual women from an early age and tracks health events and resource use as they transition through clinically-relevant health states over their lifetime. Epidemiological data on HPV prevalence and cancer incidence were used to adapt the model to Kenya and Uganda. Health benefit, or effectiveness, from HPV vaccination was measured in terms of life expectancy, and costs were measured in international dollars (I$). The incremental cost of the 9-valent vaccine included the added cost of the vaccine counterbalanced by costs averted from additional cancer cases prevented. All future costs and health benefits were discounted at an annual rate of 3% in the base case analysis. We conducted sensitivity analyses to investigate how infection with multiple HPV types, unidentifiable HPV types in cancer cases, and cross-protection against non-vaccine types could affect the potential cost range of the 9-valent vaccine. In the base case analysis in Kenya, we found that vaccination with the 9-valent vaccine was very cost-effective (i.e., had an incremental cost-effectiveness ratio below per-capita GDP), compared to the current vaccines provided the added cost of the 9-valent vaccine did not exceed I$9.7 per vaccinated girl. To be considered very cost-effective, the added cost per vaccinated girl could go up to I$5.2 and I$16.2 in the worst-case and best-case scenarios, respectively. At a willingness-to-pay threshold of three times per-capita GDP where the 9-valent vaccine would be considered cost-effective, the thresholds of added costs associated with the 9-valent vaccine were I$27.3, I$14.5 and I$45.3 per vaccinated girl for the base case, worst-case and best-case scenarios, respectively. In Uganda, vaccination with the 9-valent vaccine was very cost-effective when the added cost of the 9-valent vaccine did not exceed I$8.3 per vaccinated girl. To be considered very cost-effective, the added cost per vaccinated girl could go up to I$4.5 and I$13.7 in the worst-case and best-case scenarios, respectively. At a willingness-to-pay threshold of three times per-capita GDP, the thresholds of added costs associated with the 9-valent vaccine were I$23.4, I$12.6 and I$38.4 per vaccinated girl for the base case, worst-case and best-case scenarios, respectively. This study provides a threshold range of incremental costs associated with the 9-valent HPV vaccine that would make it a cost-effective intervention in comparison to currently available HPV vaccines in Kenya and Uganda. These prices represent a 71% and 61% increase over the price offered to the GAVI Alliance ($5 per dose) for the currently available 2- and 4-valent vaccines in Kenya and Uganda, respectively. Despite evidence of cost-effectiveness, critical challenges around affordability and feasibility of HPV vaccination and other competing needs in low-resource settings such as Kenya and Uganda remain.

Costs and Cost-Effectiveness of 9-Valent Human Papillomavirus (HPV) Vaccination in Two East African Countries

PubMed Central

Kiatpongsan, Sorapop; Kim, Jane J.

2014-01-01

Background Current prophylactic vaccines against human papillomavirus (HPV) target two of the most oncogenic types, HPV-16 and -18, which contribute to roughly 70% of cervical cancers worldwide. Second-generation HPV vaccines include a 9-valent vaccine, which targets five additional oncogenic HPV types (i.e., 31, 33, 45, 52, and 58) that contribute to another 15–30% of cervical cancer cases. The objective of this study was to determine a range of vaccine costs for which the 9-valent vaccine would be cost-effective in comparison to the current vaccines in two less developed countries (i.e., Kenya and Uganda). Methods and Findings The analysis was performed using a natural history disease simulation model of HPV and cervical cancer. The mathematical model simulates individual women from an early age and tracks health events and resource use as they transition through clinically-relevant health states over their lifetime. Epidemiological data on HPV prevalence and cancer incidence were used to adapt the model to Kenya and Uganda. Health benefit, or effectiveness, from HPV vaccination was measured in terms of life expectancy, and costs were measured in international dollars (I$). The incremental cost of the 9-valent vaccine included the added cost of the vaccine counterbalanced by costs averted from additional cancer cases prevented. All future costs and health benefits were discounted at an annual rate of 3% in the base case analysis. We conducted sensitivity analyses to investigate how infection with multiple HPV types, unidentifiable HPV types in cancer cases, and cross-protection against non-vaccine types could affect the potential cost range of the 9-valent vaccine. In the base case analysis in Kenya, we found that vaccination with the 9-valent vaccine was very cost-effective (i.e., had an incremental cost-effectiveness ratio below per-capita GDP), compared to the current vaccines provided the added cost of the 9-valent vaccine did not exceed I$9.7 per vaccinated girl. To be considered very cost-effective, the added cost per vaccinated girl could go up to I$5.2 and I$16.2 in the worst-case and best-case scenarios, respectively. At a willingness-to-pay threshold of three times per-capita GDP where the 9-valent vaccine would be considered cost-effective, the thresholds of added costs associated with the 9-valent vaccine were I$27.3, I$14.5 and I$45.3 per vaccinated girl for the base case, worst-case and best-case scenarios, respectively. In Uganda, vaccination with the 9-valent vaccine was very cost-effective when the added cost of the 9-valent vaccine did not exceed I$8.3 per vaccinated girl. To be considered very cost-effective, the added cost per vaccinated girl could go up to I$4.5 and I$13.7 in the worst-case and best-case scenarios, respectively. At a willingness-to-pay threshold of three times per-capita GDP, the thresholds of added costs associated with the 9-valent vaccine were I$23.4, I$12.6 and I$38.4 per vaccinated girl for the base case, worst-case and best-case scenarios, respectively. Conclusions This study provides a threshold range of incremental costs associated with the 9-valent HPV vaccine that would make it a cost-effective intervention in comparison to currently available HPV vaccines in Kenya and Uganda. These prices represent a 71% and 61% increase over the price offered to the GAVI Alliance ($5 per dose) for the currently available 2- and 4-valent vaccines in Kenya and Uganda, respectively. Despite evidence of cost-effectiveness, critical challenges around affordability and feasibility of HPV vaccination and other competing needs in low-resource settings such as Kenya and Uganda remain. PMID:25198104

Rare variant association analysis in case-parents studies by allowing for missing parental genotypes.

PubMed

Li, Yumei; Xiang, Yang; Xu, Chao; Shen, Hui; Deng, Hongwen

2018-01-15

The development of next-generation sequencing technologies has facilitated the identification of rare variants. Family-based design is commonly used to effectively control for population admixture and substructure, which is more prominent for rare variants. Case-parents studies, as typical strategies in family-based design, are widely used in rare variant-disease association analysis. Current methods in case-parents studies are based on complete case-parents data; however, parental genotypes may be missing in case-parents trios, and removing these data may lead to a loss in statistical power. The present study focuses on testing for rare variant-disease association in case-parents study by allowing for missing parental genotypes. In this report, we extended the collapsing method for rare variant association analysis in case-parents studies to allow for missing parental genotypes, and investigated the performance of two methods by using the difference of genotypes between affected offspring and their corresponding "complements" in case-parent trios and TDT framework. Using simulations, we showed that, compared with the methods just only using complete case-parents data, the proposed strategy allowing for missing parental genotypes, or even adding unrelated affected individuals, can greatly improve the statistical power and meanwhile is not affected by population stratification. We conclude that adding case-parents data with missing parental genotypes to complete case-parents data set can greatly improve the power of our strategy for rare variant-disease association.

Cross-sector surveys assessing perceptions of key stakeholders towards barriers, concerns and facilitators to the appropriate use of adaptive designs in confirmatory trials.

PubMed

Dimairo, Munyaradzi; Julious, Steven A; Todd, Susan; Nicholl, Jonathan P; Boote, Jonathan

2015-12-23

Appropriately conducted adaptive designs (ADs) offer many potential advantages over conventional trials. They make better use of accruing data, potentially saving time, trial participants, and limited resources compared to conventional, fixed sample size designs. However, one can argue that ADs are not implemented as often as they should be, particularly in publicly funded confirmatory trials. This study explored barriers, concerns, and potential facilitators to the appropriate use of ADs in confirmatory trials among key stakeholders. We conducted three cross-sectional, online parallel surveys between November 2014 and January 2015. The surveys were based upon findings drawn from in-depth interviews of key research stakeholders, predominantly in the UK, and targeted Clinical Trials Units (CTUs), public funders, and private sector organisations. Response rates were as follows: 30(55 %) UK CTUs, 17(68 %) private sector, and 86(41 %) public funders. A Rating Scale Model was used to rank barriers and concerns in order of perceived importance for prioritisation. Top-ranked barriers included the lack of bridge funding accessible to UK CTUs to support the design of ADs, limited practical implementation knowledge, preference for traditional mainstream designs, difficulties in marketing ADs to key stakeholders, time constraints to support ADs relative to competing priorities, lack of applied training, and insufficient access to case studies of undertaken ADs to facilitate practical learning and successful implementation. Associated practical complexities and inadequate data management infrastructure to support ADs were reported as more pronounced in the private sector. For funders of public research, the inadequate description of the rationale, scope, and decision-making criteria to guide the planned AD in grant proposals by researchers were all viewed as major obstacles. There are still persistent and important perceptions of individual and organisational obstacles hampering the use of ADs in confirmatory trials research. Stakeholder perceptions about barriers are largely consistent across sectors, with a few exceptions that reflect differences in organisations' funding structures, experiences and characterisation of study interventions. Most barriers appear connected to a lack of practical implementation knowledge and applied training, and limited access to case studies to facilitate practical learning.

Reducing Added Sugars in the Food Supply Through a Cap-and-Trade Approach

PubMed Central

Lewis, Kristina

2014-01-01

Objectives. We estimated the effect of a simulated cap-and-trade policy to reduce added sugar in the food supply. Methods. Using nationally representative data on added-sugar content and consumption, we constructed a mathematical model of a cap-and-trade policy and compared its health implications to those of proposals to tax sugar sweetened beverages or added sugars. Results. Capping added-sugar emissions into the food supply by food manufacturers at a rate of 1% per year would be expected to reduce the prevalence of obesity by 1.7 percentage points (95% confidence interval [CI] = 0.9, 2.4; a 4.6% decline) and the incidence of type 2 diabetes by 21.7 cases per 100 000 people (95% CI = 12.9, 30.6; a 4.2% decline) over 20 years, averting approximately $9.7 billion in health care spending. Racial and ethnic minorities would be expected to experience the largest declines. By comparison, equivalent price penalties through excise taxes would be expected to generate smaller health benefits. Conclusions. A cap-and-trade policy to reduce added-sugar intake may reduce obesity and type 2 diabetes to a greater extent than currently-proposed excise taxes. PMID:25365146

Reducing added sugars in the food supply through a cap-and-trade approach.

PubMed

Basu, Sanjay; Lewis, Kristina

2014-12-01

We estimated the effect of a simulated cap-and-trade policy to reduce added sugar in the food supply. Using nationally representative data on added-sugar content and consumption, we constructed a mathematical model of a cap-and-trade policy and compared its health implications to those of proposals to tax sugar sweetened beverages or added sugars. Capping added-sugar emissions into the food supply by food manufacturers at a rate of 1% per year would be expected to reduce the prevalence of obesity by 1.7 percentage points (95% confidence interval [CI] = 0.9, 2.4; a 4.6% decline) and the incidence of type 2 diabetes by 21.7 cases per 100 000 people (95% CI = 12.9, 30.6; a 4.2% decline) over 20 years, averting approximately $9.7 billion in health care spending. Racial and ethnic minorities would be expected to experience the largest declines. By comparison, equivalent price penalties through excise taxes would be expected to generate smaller health benefits. A cap-and-trade policy to reduce added-sugar intake may reduce obesity and type 2 diabetes to a greater extent than currently-proposed excise taxes.

Alzheimer's disease and the law: positive and negative consequences of structural stigma and labeling in the legal system.

PubMed

Werner, Perla; Doron, Israel Issi

2017-11-01

To explore the meaning and consequences of labeling on structural stigma in the context of Alzheimer's disease (AD) in the legal system. This qualitative study was made up of three focus groups including social workers and lawyers (n = 26). Participants were asked to report their experience in circumstances in which persons with AD and their family members engage with the legal system. Thematic analysis using the constant comparative method was used. The discussions in the focus groups raised two overall themes. (1) The significance of the medical diagnostic labeling of AD in the legal system and (2) the consequences of labeling of AD within the legal system. This last theme included four sub-themes: (a) negative consequences of labeling; (b) reasons associated with negative consequences of labeling; (c) positive consequences of labeling; and (d) reasons associated with positive consequences of labeling. Findings of the study provide a first foundation for future research on the meaning and consequences of labeling in legal cases involving persons with AD. They suggest that increasing judges' knowledge about AD and reforming the existing 'status-based' legal capacity legislation might benefit by limiting the legal weight given today to the medical diagnosis.

The Pattern of Brain Amyloid Load in Posterior Cortical Atrophy Using 18F-AV45: Is Amyloid the Principal Actor in the Disease?

PubMed Central

Beaufils, Emilie; Ribeiro, Maria Joao; Vierron, Emilie; Vercouillie, Johnny; Dufour-Rainfray, Diane; Cottier, Jean-Philippe; Camus, Vincent; Mondon, Karl; Guilloteau, Denis; Hommet, Caroline

2014-01-01

Background Posterior cortical atrophy (PCA) is characterized by progressive higher-order visuoperceptual dysfunction and praxis declines. This syndrome is related to a number of underlying diseases, including, in most cases, Alzheimer's disease (AD). The aim of this study was to compare the amyloid load with 18F-AV45 positron emission tomography (PET) between PCA and AD subjects. Methods We performed 18F-AV45 PET, cerebrospinal fluid (CSF) biomarker analysis and a neuropsychological assessment in 11 PCA patients and 12 AD patients. Results The global and regional 18F-AV45 uptake was similar in the PCA and AD groups. No significant correlation was observed between global 18F-AV45 uptake and CSF biomarkers or between regional 18F-AV45 uptake and cognitive and affective symptoms. Conclusion This 18F-AV45 PET amyloid imaging study showed no specific regional pattern of cortical 18F-AV45 binding in PCA patients. These results confirm that a distinct clinical phenotype in amnestic AD and PCA is not related to amyloid distribution. PMID:25538727

Frequency of Alzheimer's disease pathology at autopsy in patients with clinical normal pressure hydrocephalus.

PubMed

Cabral, Danielle; Beach, Thomas G; Vedders, Linda; Sue, Lucia I; Jacobson, Sandra; Myers, Kent; Sabbagh, Marwan N

2011-09-01

Normal pressure hydrocephalus (NPH) is considered to be potentially treatable with the placement of a cerebrospinal fluid (CSF) shunt. However, the procedure has been reported to have variable success, particularly with respect to improving the cognitive impairment in NPH. The presence of neurologic comorbidities, particularly Alzheimer's disease (AD), may contribute to shunt responsiveness. Uncovering the extent to which AD and NPH co-occur has implications for diagnosis and treatment of NPH. Autopsy studies of patients with NPH during their lifetime would elucidate the frequency of such comorbidities. A search of the Sun Health Research Institute Brain Donation Program database was conducted between January 1, 1997 and April 1, 2009 to identify all cases with neuropathologic evidence of dementia as well as those of clinically diagnosed NPH. We reviewed the medical records and brain findings of each NPH case. Of the 761 cases autopsied over the study interval, 563 were found to have neuropathologic evidence meeting criteria for a dementing illness. Of 563 cases, AD was found exclusively in 313 (56%), and 94 suffered from secondary diagnosis of dementia. Nine of 761 cases were identified with a clinical diagnosis of NPH, which were among the 563 cases with neuropathology of dementing illness at autopsy, representing 1.6% (9/563) of the cases. On review of brain autopsy reports of these nine patients, eight (89%) were found to have AD and one (11%) had progressive supranuclear palsy. Review of the medical records of the nine NPH cases revealed the following clinical comorbidities: five suffered from AD, one from Parkinson's Disease, one from mild cognitive impairment, and one from seizure disorder. Given the findings of the present study, we support the AD-NPH theory and posit that AD is a common pathologic comorbidity in the setting of NPH and may preclude cognitive improvement postshunt placement. This may influence the selection of cases for shunting in the future. Copyright © 2011 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Is Sugar the new Tobacco? Insights from Laboratory Studies, Consumer Surveys and Public Health.

PubMed

Le Bodo, Yann; Paquette, Marie-Claude; Vallières, Maggie; Alméras, Natalie

2015-03-01

In the Americas, mean energy intake from added sugar exceeds recent World Health Organization recommendations for free sugars in the diet. As a leading contributor to this excess, sugar-sweetened beverage (SSB) overconsumption represents a risk for the population's health. This article provides an overview of clinical and epidemiological evidence, marketing practices, corporate influence and prevention strategies related to added sugar and SSB. For each aspect of this multidimensional profile, we briefly compare SSB to the case of tobacco pointing to similarities but also major differences. Tobacco control has demonstrated the effectiveness of long term multifaceted prevention strategies in multiple settings supported by strong public policies which may be applied to the consumption of SSB. However, translating these policies to the specific case of SSB is urgently needed, to inform preventive actions, decide which intervention mix will be used, and evaluate the process and impact of the chosen strategy.

Senile dementia of Lewy body type and Alzheimer type are biochemically distinct in terms of paired helical filaments and hyperphosphorylated tau protein.

PubMed

Harrington, C R; Perry, R H; Perry, E K; Hurt, J; McKeith, I G; Roth, M; Wischik, C M

1994-01-01

We have used biochemical assays to examine cingulate and occipital cortices from age-matched cases of Alzheimer's disease (AD; n = 12), senile dementia of the Lewy body type (SDLT; n = 13), Parkinson's disease (PD; 5 non-demented cases and 7 cognitively impaired cases) and controls (n = 11) for paired helical filaments (PHFs), phosphorylated and normal tau protein and beta/A4-protein. Whereas cingulate cortex is characterised by relatively high densities of cortical Lewy bodies in the SDLT cases and lower numbers in PD, these inclusion bodies were absent in the cingulate cortex from AD and control cases. Protease-resistant PHFs and hyperphosphorylated tau protein were found in AD and, at low levels, in a minority of SDLT cases. Qualitatively, both of these preparations were indistinguishable in SDLT from those found in AD but levels of both parameters in SDLT were less than 5% of those in AD. SDLT, PD and control groups did not differ from each other in terms of the quantity of protease-resistant PHFs or the level of hyperphosphorylated tau. Furthermore, PHF accumulation did not distinguish between PD cases with or without dementia. The levels of normal tau protein did not differ between the four groups. beta/A4 protein levels did not distinguish between PD and control groups, between AD and SDLT groups, or between SDLT and control groups for either cingulate or occipital cortices. Thus extensive accumulation of PHFs in either neurofibrillary tangles or dystrophic neurites is not a feature of either SDLT or PD. Our findings provide molecular support for the neuropathological and clinical separation of SDLT as a form of dementia that is distinct from AD.

Dysregulation of Leptin Signaling in Alzheimer Disease: Evidence for Neuronal Leptin Resistance

PubMed Central

Bonda, David J.; Stone, Jeremy G.; Torres, Sandy L.; Siedlak, Sandra L.; Perry, George; Kryscio, Richard; Jicha, Gregory; Casadesus, Gemma; Smith, Mark A.; Zhu, Xiongwei; Lee, Hyoung-gon

2013-01-01

Leptin signaling has received considerable attention in the Alzheimer disease (AD) field. Within the past decade, the peptide hormone has been demonstrated to attenuate tau hyperphosphorylation in neuronal cells and to be modulated by amyloid-β. Moreover, a role in neuroprotection and neurogenesis within the hippocampus has been shown in animal models. To further characterize the association between leptin signaling and vulnerable regions in AD, we assessed the profile of leptin and the leptin receptor in AD and control patients. We analyzed leptin levels in cerebrospinal fluid (CSF), and the concentration and localization of leptin and leptin receptor in the hippocampus. Significant elevations in leptin levels in both CSF and hippocampal tissue of AD patients, compared to age-matched control cases, indicate a physiological upregulation of leptin in AD. However, the level of leptin receptor mRNA decreased in AD brain and the leptin receptor protein was localized to neurofibrillary tangles, suggesting a severe discontinuity in the leptin signaling pathway. Collectively, our results suggest that leptin resistance in the hippocampus may play a role in the characteristic changes associated with the disease. These findings are the first to demonstrate such dysregulated leptin-signaling circuitry and provide novel insights into the possible role of aberrant leptin signaling in AD. PMID:23895348

An Interdisciplinary Approach to Teaching International Law: Using the Tools of the Law School Classroom in Political Science

ERIC Educational Resources Information Center

Zartner, Dana

2009-01-01

As the world has grown more interconnected, many political science programs have added courses on international law, international organizations, the laws of war and peace, international human rights, and comparative judicial politics. While in many cases these are relatively new offerings within international studies, all of these subjects have…

Detecting At-Risk Alzheimer's Disease Cases.

PubMed

Fladby, Tormod; Pålhaugen, Lene; Selnes, Per; Waterloo, Knut; Bråthen, Geir; Hessen, Erik; Almdahl, Ina Selseth; Arntzen, Kjell-Arne; Auning, Eirik; Eliassen, Carl Fredrik; Espenes, Ragna; Grambaite, Ramune; Grøntvedt, Gøril Rolfseng; Johansen, Krisztina Kunszt; Johnsen, Stein Harald; Kalheim, Lisa Flem; Kirsebom, Bjørn-Eivind; Müller, Kai Ivar; Nakling, Arne Exner; Rongve, Arvid; Sando, Sigrid Botne; Siafarikas, Nikias; Stav, Ane Løvli; Tecelao, Sandra; Timon, Santiago; Bekkelund, Svein Ivar; Aarsland, Dag

2017-01-01

While APOEɛ4 is the major genetic risk factor for Alzheimer's disease (AD), amyloid dysmetabolism is an initial or early event predicting clinical disease and is an important focus for secondary intervention trials. To improve identification of cases with increased AD risk, we evaluated recruitment procedures using pathological CSF concentrations of Aβ42 (pAβ) and APOEɛ4 as risk markers in a multi-center study in Norway. In total, 490 subjects aged 40-80 y were included after response to advertisements and media coverage or memory clinics referrals. Controls (n = 164) were classified as normal controls without first-degree relatives with dementia (NC), normal controls with first-degree relatives with dementia (NCFD), or controls scoring below norms on cognitive screening. Patients (n = 301) were classified as subjective cognitive decline or mild cognitive impairment. Subjects underwent a clinical and cognitive examination and MRI according to standardized protocols. Core biomarkers in CSF from 411 and APOE genotype from 445 subjects were obtained. Cases (both self-referrals (n = 180) and memory clinics referrals (n = 87)) had increased fractions of pAβ and APOEɛ4 frequency compared to NC. Also, NCFD had higher APOEɛ4 frequencies without increased fraction of pAβ compared to NC, and cases recruited from memory clinics had higher fractions of pAβ and APOEɛ4 frequency than self-referred. This study shows that memory clinic referrals are pAβ enriched, whereas self-referred and NCFD cases more frequently are pAβ negative but at risk (APOEɛ4 positive), suitable for primary intervention.

Genome-wide Analysis of Genetic Loci Associated with Alzheimer’s Disease

PubMed Central

Seshadri, Sudha; Fitzpatrick, Annette L.; Arfan Ikram, M; DeStefano, Anita L.; Gudnason, Vilmundur; Boada, Merce; Bis, Joshua C.; Smith, Albert V.; Carassquillo, Minerva M.; Charles Lambert, Jean; Harold, Denise; Schrijvers, Elisabeth M. C.; Ramirez-Lorca, Reposo; Debette, Stephanie; Longstreth, W.T.; Janssens, A. Cecile J.W.; Shane Pankratz, V.; Dartigues, Jean François; Hollingworth, Paul; Aspelund, Thor; Hernandez, Isabel; Beiser, Alexa; Kuller, Lewis H.; Koudstaal, Peter J.; Dickson, Dennis W.; Tzourio, Christophe; Abraham, Richard; Antunez, Carmen; Du, Yangchun; Rotter, Jerome I.; Aulchenko, Yurii S.; Harris, Tamara B.; Petersen, Ronald C.; Berr, Claudine; Owen, Michael J.; Lopez-Arrieta, Jesus; Varadarajan, Badri N.; Becker, James T.; Rivadeneira, Fernando; Nalls, Michael A.; Graff-Radford, Neill R.; Campion, Dominique; Auerbach, Sanford; Rice, Kenneth; Hofman, Albert; Jonsson, Palmi V.; Schmidt, Helena; Lathrop, Mark; Mosley, Thomas H.; Au, Rhoda; Psaty, Bruce M.; Uitterlinden, Andre G.; Farrer, Lindsay A.; Lumley, Thomas; Ruiz, Agustin; Williams, Julie; Amouyel, Philippe; Younkin, Steve G.; Wolf, Philip A.; Launer, Lenore J.; Lopez, Oscar L.; van Duijn, Cornelia M.; Breteler, Monique M. B.

2010-01-01

Context Genome wide association studies (GWAS) have recently identified CLU, PICALM and CR1 as novel genes for late-onset Alzheimer’s disease (AD). Objective In a three-stage analysis of new and previously published GWAS on over 35000 persons (8371 AD cases), we sought to identify and strengthen additional loci associated with AD and confirm these in an independent sample. We also examined the contribution of recently identified genes to AD risk prediction. Design, Setting, and Participants We identified strong genetic associations (p<10−3) in a Stage 1 sample of 3006 AD cases and 14642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (1367 AD cases (973 incident)) with previously reported results from the Translational Genomics Research Institute (TGEN) and Mayo AD GWAS. We identified 2708 single nucleotide polymorphisms (SNPs) with p-values<10−3, and in Stage 2 pooled results for these SNPs with the European AD Initiative (2032 cases, 5328 controls) to identify ten loci with p-values<10−5. In Stage 3, we combined data for these ten loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases, 6995 controls) to identify four SNPs with a p-value<1.7×10−8. These four SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls). Main outcome measure Alzheimer’s Disease. Results We showed genome-wide significance for two new loci: rs744373 near BIN1 (OR:1.13; 95%CI:1.06–1.21 per copy of the minor allele; p=1.6×10−11) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (OR:1.18; 95%CI1.07–1.29; p=6.5×10−9). Associations of CLU, PICALM, BIN1 and EXOC3L2 with AD were confirmed in the Spanish sample (p<0.05). However, CLU and PICALM did not improve incident AD prediction beyond age, sex, and APOE (improvement in area under receiver-operating-characteristic curve <0.003). Conclusions Two novel genetic loci for AD are reported that for the first time reach genome-wide statistical significance; these findings were replicated in an independent population. Two recently reported associations were also confirmed, but these loci did not improve AD risk prediction, although they implicate biological pathways that may be useful targets for potential interventions. PMID:20460622

Behavioral comparisons in autistic individuals from multiplex and singleton families.

PubMed

Cuccaro, Michael L; Shao, Yujun; Bass, Meredyth P; Abramson, Ruth K; Ravan, Sarah A; Wright, Harry H; Wolpert, Chantelle M; Donnelly, Shannon L; Pericak-Vance, Margaret A

2003-02-01

Autistic disorder (AD) is a complex neurodevelopmental disorder. The role of genetics in AD etiology is well established, and it is postulated that anywhere from 2 to 10 genes could be involved. As part of a larger study to identify these genetic effects we have ascertained a series of AD families: Sporadic (SP, 1 known AD case per family and no known history of AD) and multiplex (MP, > or = 2 cases per family). The underlying etiology of both family types is unknown. It is possible that MP families may constitute a unique subset of families in which the disease phenotype is more likely due to genetic factors. Clinical differences between the two family types could represent underlying genetic heterogeneity. We examined ADI-R data for 69 probands from MP families and 88 from SP families in order to compare and contrast the clinical phenotypes for each group as a function of verbal versus nonverbal status. Multivariate analysis controlling for covariates of age at examination, gender, and race (MANCOVA) revealed no differences between either the verbal or nonverbal MP and SP groups for the three ADI-R area scores: social interaction, communication, and restricted/repetitive interests or behaviors. These data failed to find clinical heterogeneity between MP and SP family types. This supports previous work that indicated that autism features are not useful as tools to index genetic heterogeneity. Thus, although there may be different underlying etiologic mechanisms in the SP and MP probands, there are no distinct behavioral patterns associated with probands from MP families versus SP families. These results suggests the possibility that common etiologic mechanisms, either genetic and/or environmental, could underlie all of AD.

Added sugars and sugar-sweetened beverage consumption, dietary carbohydrate index and depression risk in the Seguimiento Universidad de Navarra (SUN) Project.

PubMed

Sanchez-Villegas, Almudena; Zazpe, Itziar; Santiago, Susana; Perez-Cornago, Aurora; Martinez-Gonzalez, Miguel A; Lahortiga-Ramos, Francisca

2018-01-01

The association between added sugars or sugar-sweetened beverage consumption and the risk of depression, as well as the role of carbohydrate quality in depression risk, remains unclear. Among 15 546 Spanish university graduates from the Seguimiento Universidad de Navarra (SUN) prospective cohort study, diet was assessed with a validated 136-item semi-quantitative FFQ at baseline and at 10-year follow-up. Cumulative average consumption of added sugars, sweetened drinks and an overall carbohydrate quality index (CQI) were calculated. A better CQI was associated with higher whole-grain consumption and fibre intake and lower glycaemic index and consumption of solid (instead of liquid) carbohydrates. Clinical diagnoses of depression during follow-up were classified as incident cases. Multivariable time-dependent Cox regression models were used to estimate hazard ratios (HR) of depression according to consumption of added sugars, sweetened drinks and CQI. We observed 769 incident cases of depression. Participants in the highest quartile of added sugars consumption showed a significant increment in the risk of depression (HR=1·35; 95 % CI 1·09, 1·67, P=0·034), whereas those in the highest quartile of CQI (upper quartile of the CQI) showed a relative risk reduction of 30 % compared with those in the lowest quartile of the CQI (HR=0·70; 95 % CI 0·56, 0·88). No significant association between sugar-sweetened beverage consumption and depression risk was found. Higher added sugars and lower quality of carbohydrate consumption were associated with depression risk in the SUN Cohort. Further studies are necessary to confirm the reported results.

Human papillomavirus-related carcinoma with adenoid cystic-like features: a series of five cases expanding the pathological spectrum.

PubMed

Hang, Jen-Fan; Hsieh, Min-Shu; Li, Wing-Yin; Chen, Jo-Yu; Lin, Shih-Yao; Liu, Shih-Hao; Pan, Chin-Chen; Kuo, Ying-Ju

2017-12-01

Human papillomavirus (HPV)-related carcinoma with adenoid cystic-like features is a newly described entity of the sinonasal tract. In this study, we evaluated histomorphology, immunophenotype and molecular testing to identify potentially helpful features in distinguishing it from classic adenoid cystic carcinoma (AdCC). We retrospectively collected five HPV-related carcinomas with adenoid cystic-like features and 14 AdCCs of the sinonasal tract. All histological slides were retrieved for morphological evaluation. As comparing with AdCC, HPV-related carcinomas with adenoid cystic-like features were associated with squamous dysplasia of surface epithelium (80% versus 0%, P < 0.01) and the presence of a solid growth pattern (100% versus 29%, P = 0.01), but less densely hyalinized tumour stroma (20% versus 86%, P = 0.02). Squamous differentiation in the invasive tumour was seen in three HPV-related carcinomas with adenoid cystic-like features, two of them showing abrupt keratinization and one with scattered non-keratinizing squamous nests. Diffuse p16 staining in ≥75% of tumour cells was noted in all HPV-related carcinomas with adenoid cystic-like features but in only one AdCC (100% versus 7%, P < 0.01). High-risk HPV testing gave positive results in all HPV-related carcinomas with adenoid cystic-like features (four associated with type 33 and one associated with type 16) but not in AdCCs. MYB rearrangement was tested in four HPV-related carcinomas with adenoid cystic-like features, and all were negative. This study has further clarified the histological spectrum of this tumour type, and reports the first HPV type 16-related case. Diffuse p16 staining followed by HPV molecular testing is useful in distinguishing HPV-related carcinomas with adenoid cystic features from classic AdCCs. © 2017 John Wiley & Sons Ltd.

Protein signature in cerebrospinal fluid and serum of Alzheimer's disease patients: The case of apolipoprotein A-1 proteoforms.

PubMed

Fania, Chiara; Arosio, Beatrice; Capitanio, Daniele; Torretta, Enrica; Gussago, Cristina; Ferri, Evelyn; Mari, Daniela; Gelfi, Cecilia

2017-01-01

In the diagnosis of Alzheimer's disease (AD) total tau (T-tau), tau phosphorylated at threonine 181 (P-tau181), and the 42 amino acid isoform of alpha β-amyloid (Aβ) are well established surrogate CSF markers. However, there is a constant need for new diagnostic markers to identify the disease at a very early stage. The identification of new molecules for AD diagnosis and monitoring in CSF is hampered by several "confounding" factors including intra- and inter-individual, pre-analytical and analytical variabilities. In an attempt to partially overcome patient's variability and to determine new molecules significantly dysregulated in CSF, we assessed the proteome profile of low molecular weight protein species in CSF and serum of the same patients. CSFs and sera from 36 ADs, 32 iNPHs (idiopathic normal pressure hydrocephalus) and 12 controls were compared by MALDI profiling (non-parametric statistics, CV<20%, AUC>0.750). After protein identification by mass spectrometry, the proteoform composition was assessed by 2-D DIGE/MS. Results indicated that CSF of iNPH can be used as control. Serum and CSF of AD patients shows a specific protein profile compared to iNPH samples. A variation (p<0.01) of Apo A-1 levels in AD, together with a specific dysregulation of Apo A-1 proteoforms was observed. The profiling of CSF and serum of the same patients, suggests that the decrement of total Apo A-1 occurs specifically in CSF. Serum and CSF of AD shows a characteristic Apo A-1 proteoform pattern suggesting it as potential marker which can support the clinical workflow adopted for AD diagnosis and progression.

Hippocampal sclerosis of aging is a key Alzheimer's disease mimic: clinical-pathologic correlations and comparisons with both alzheimer's disease and non-tauopathic frontotemporal lobar degeneration.

PubMed

Brenowitz, Willa D; Monsell, Sarah E; Schmitt, Frederick A; Kukull, Walter A; Nelson, Peter T

2014-01-01

Hippocampal sclerosis of aging (HS-Aging) neuropathology was observed in more than 15% of aged individuals in prior studies. However, much remains unknown about the clinical correlates of HS-Aging pathology or the association(s) between HS-Aging, Alzheimer's disease (AD), and frontotemporal lobar degeneration (FTLD) pathology. Clinical and comorbid pathological features linked to HS-Aging pathology were analyzed using National Alzheimer's Coordinating Center (NACC) data. From autopsy data extending back to 1990 (n = 9,817 participants), the neuropathological diagnoses were evaluated from American AD Centers (ADCs). Among participants who died between 2005-2012 (n = 1,422), additional analyses identified clinical and pathological features associated with HS-Aging pathology. We also compared cognitive testing and longevity outcomes between HS-Aging cases and a subsample with non-tauopathy FTLD (n = 210). Reporting of HS-Aging pathology increased dramatically among ADCs in recent years, to nearly 20% of autopsies in 2012. Participants with relatively "pure" HS-Aging pathology were often diagnosed clinically as having probable (68%) or possible (15%) AD. However, the co-occurrence of HS-Aging pathology and AD neuropathology (AD-NP) did not indicate any pattern of correlation between the two pathologies. Compared with other pathologies, participants with HS-Aging pathology had higher overall cognitive/functional ability (versus AD-NP) and verbal fluency (versus both AD-NP and FTLD) but similar episodic memory impairment at one clinic visit 2-5 years prior to death. Patients with HS-Aging live considerably longer than patients with non-tauopathy FTLD. We conclude that the manifestations of HS-Aging, increasingly recognized in recent years, probably indicate a separate disease process of direct relevance to patient care, dementia research, and clinical trials.

Theory of mind difficulties in patients with alcohol dependence: beyond the prefrontal cortex dysfunction hypothesis.

PubMed

Maurage, François; de Timary, Philippe; Tecco, Juan Martin; Lechantre, Stéphane; Samson, Dana

2015-06-01

Previous studies have shown that alcohol-dependent (AD) individuals have difficulties inferring other people's emotion, understanding humor, and detecting a faux pas. This study aimed at further understanding the nature of such "Theory of Mind" (ToM) difficulties. A total of 34 recently detoxified AD and 34 paired controls were compared based on 2 nonverbal and video-based false belief tasks. These tasks were designed to identify 3 different types of deficits: (i) a deficit in dealing with the general task demands, (ii) a selective deficit in self-perspective inhibition, and (iii) a deficit in tracking the other person's mental state. (i) and (ii) are compatible with the hypothesis of a prefrontal cortex dysfunction being at the origin of AD individuals' social difficulties, while (iii) would suggest the possible contribution of a dysfunction of the temporo-parietal junction in explaining the social difficulties. Group analyses highlighted that AD individuals performed worse on the 2 false belief tasks than controls. Individual analyses showed, however, that just under half of the AD individuals were impaired compared to controls. Moreover, most of the AD individuals who were impaired showed a deficit in tracking the other person's belief. This deficit was linked to disease-related factors such as illness duration, average alcohol consumption, and craving but not to general reasoning abilities, depression, anxiety, or demographic variables. Just under half of the AD individuals tested showed a ToM deficit, and in most cases, the deficit concerned the tracking of other people's mental states. Such a type of deficit has previously been associated with lesions to the temporo-parietal brain areas, indicating that a prefrontal cortex dysfunction may not be the sole origin of the social cognition deficits observed in alcohol dependence. Copyright © 2015 by the Research Society on Alcoholism.

Hippocampal sclerosis of aging is a key Alzheimer's disease mimic: clinical-pathologic correlations and comparisons with both Alzheimer's disease and non-tauopathic frontotemporal lobar degeneration

PubMed Central

Brenowitz, Willa D.; Monsell, Sarah E.; Schmitt, Frederick A.; Kukull, Walter A.; Nelson, Peter T.

2013-01-01

Hippocampal sclerosis of aging (HS-Aging) neuropathology was observed in more than 15% of aged individuals in prior studies. However, much remains unknown about the clinical correlates of HS-Aging pathology or the association(s) between HS-Aging, Alzheimer's disease (AD), and frontotemporal lobar degeneration (FTLD) pathology. Clinical and comorbid pathological features linked to HS-Aging pathology were analyzed using National Alzheimer's Coordinating Center (NACC) data. From autopsy data extending back to 1990 (N=9,817 participants), the neuropathologic diagnoses were evaluated from American AD Centers (ADCs). Among participants who died between 2005-2012 (N=1,422), additional analyses identified clinical and pathological features associated with HS-Aging pathology. We also compared cognitive testing and longevity outcomes between HS-Aging cases and a subsample with non-tauopathy FTLD (N=210). Reporting of HS pathology increased dramatically among ADCs in recent years, to nearly 20% of autopsies in 2012. Participants with relatively “pure” HS-Aging pathology were often diagnosed clinically as having probable (68%) or possible (15%) AD. However, the co-occurrence of HS-Aging pathology and AD neuropathology (AD-NP) did not indicate any pattern of correlation between the two pathologies. Compared other pathologies, participants with HS-Aging pathology had higher overall cognitive/functional ability (versus AD-NP) and verbal fluency (versus both AD-NP and FTLD) but similar episodic memory impairment at one clinic visit 2 -5 years prior to death. Patients with HS-Aging live considerably longer than patients with non-tauopathy FTLD. We conclude that the manifestations of HS-Aging, increasingly recognized in recent years, probably indicate a separate disease process of direct relevance to patient care, dementia research, and clinical trials. PMID:24270205

γ-Secretase binding sites in aged and Alzheimer’s disease human cerebrum: The choroid plexus as a putative origin of CSF Aβ

PubMed Central

Liu, Fei; Xue, Zhi-Qin; Deng, Si-Hao; Kun, Xiong; Luo, Xue-Gang; Patrylo, Peter R.; Rose, Gregory M.; Cai, Huaibin; Struble, Robert G.; Cai, Yan; Yan, Xiao-Xin

2013-01-01

Deposition of β-amyloid (Aβ) peptides, cleavage products of β-amyloid precursor protein (APP) by β-secretase-1 (BACE1) and γ-secretase, is a neuropathological hallmark of Alzheimer’s disease (AD). γ-Secretase inhibition is a therapeutical anti-Aβ approach, although less is clear about the change of the enzyme’s activity in AD brain. Cerebrospinal fluid (CSF) Aβ peptides are considered to derive from brain parenchyma, thus may serve as biomarkers for assessing cerebral amyloidosis and anti-Aβ efficacy. The present study compared active γ-secretase binding sites with Aβ deposition in aged and AD human cerebrum, and explored a possibility of Aβ production and secretion by the choroid plexus (CP). Specific binding density of [3H]-L-685,458, a radiolabeled high affinity γ-secretase inhibitor, in the temporal neocortex and hippocampal formation was similar for AD and control cases with comparable ages and postmortem delays. The CP in postmortem samples exhibited exceptionally high [3H]-L-685,458 binding density, with the estimated maximal binding sites (Bmax) reduced in the AD relative to control groups. Surgically resected human CP exhibited APP, BACE1 and presenilin-1 immunoreactivity, and β-site APP cleavage enzymatic activity. In primary culture, human CP cells also expressed these amyloidogenic proteins but released Aβ40 and Aβ42 into the medium. These results suggest that γ-secretase activity appears not altered in the cerebrum in AD related to aged control, nor correlated with regional amyloid plaque pathology. The choroid plexus appears to represent a novel non-neuronal source in the brain that may contribute Aβ into cerebrospinal fluid, probably at reduced levels in AD. PMID:23432732

Overlapping but distinct TDP-43 and tau pathologic patterns in aged hippocampi.

PubMed

Smith, Vanessa D; Bachstetter, Adam D; Ighodaro, Eseosa; Roberts, Kelly; Abner, Erin L; Fardo, David W; Nelson, Peter T

2018-03-01

Intracellular proteinaceous aggregates (inclusion bodies) are almost always detectable at autopsy in brains of elderly individuals. Inclusion bodies composed of TDP-43 and tau proteins often coexist in the same brain, and each of these pathologic biomarkers is associated independently with cognitive impairment. However, uncertainties remain about how the presence and neuroanatomical distribution of inclusion bodies correlate with underlying diseases including Alzheimer's disease (AD). To address this knowledge gap, we analyzed data from the University of Kentucky AD Center autopsy series (n = 247); none of the brains had frontotemporal lobar degeneration. A specific question for this study was whether neurofibrillary tangle (NFT) pathology outside of the Braak NFT staging scheme is characteristic of brains with TDP-43 pathology but lacking AD, that is those with cerebral age-related TDP-43 with sclerosis (CARTS). We also tested whether TDP-43 pathology is associated with comorbid AD pathology, and whether argyrophilic grains are relatively likely to be present in cases with, vs. without, TDP-43 pathology. Consistent with prior studies, hippocampal TDP-43 pathology was associated with advanced AD - Braak NFT stages V/VI. However, argyrophilic grain pathology was not more common in cases with TDP-43 pathology in this data set. In brains with CARTS (TDP-43[+]/AD[-] cases), there were more NFTs in dentate granule neurons than were seen in TDP-43[-]/AD[-] cases. These dentate granule cell NFTs could provide a proxy indicator of CARTS pathology in cases lacking substantial AD pathology. Immunofluorescent experiments in a subsample of cases found that, in both advanced AD and CARTS, approximately 1% of dentate granule neurons were PHF-1 immunopositive, whereas ∼25% of TDP-43 positive cells showed colocalized PHF-1 immunoreactivity. We conclude that NFTs in hippocampal dentate granule neurons are often present in CARTS, and TDP-43 pathology may be secondary to or occurring in parallel with tauopathy. © 2017 International Society of Neuropathology.

Effect of soil-added cadmium on several plant species

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miles, L.J.; Parker, G.R.

Several species (Andropogon scoparius, Rhus radicans, Rudbeckia hirta, Anemone cylindrica, Monarda fistulosa, Poa pratensis, and Liatris spicata) native to northwestern Indiana were grown from seed in the greenhouse for 6 weeks. An uncontaminated sandy soil was utilized as the substrate with four levels of soil-added Cd. The concentrations added ranged from 0 to 100 ..mu..g Cd/g soil and were comparable to surface soil Cd concentration levels found in the urban-industrial region of northwestern Indiana. Data on germination, survival, height, and dry weight were collected. Germination, survival, and weight were found to exhibit a negative response to increasing soil Cd concentrationmore » over all species. Height, however, was not found to be a consistently good indicator of Cd response. While overall species' differences were noted, no differences could be conclusively shown among the species for Cd tolerance, although there were indications that this was the case. All effects noted were of a low level for the soil-added Cd concentrations utilized.« less

An improved scheme on decoy-state method for measurement-device-independent quantum key distribution.

PubMed

Wang, Dong; Li, Mo; Guo, Guang-Can; Wang, Qin

2015-10-14

Quantum key distribution involving decoy-states is a significant application of quantum information. By using three-intensity decoy-states of single-photon-added coherent sources, we propose a practically realizable scheme on quantum key distribution which approaches very closely the ideal asymptotic case of an infinite number of decoy-states. We make a comparative study between this scheme and two other existing ones, i.e., two-intensity decoy-states with single-photon-added coherent sources, and three-intensity decoy-states with weak coherent sources. Through numerical analysis, we demonstrate the advantages of our scheme in secure transmission distance and the final key generation rate.

Optical Coherence Tomography in Alzheimer's Disease: A Meta-Analysis.

PubMed

Coppola, Gianluca; Di Renzo, Antonio; Ziccardi, Lucia; Martelli, Francesco; Fadda, Antonello; Manni, Gianluca; Barboni, Piero; Pierelli, Francesco; Sadun, Alfredo A; Parisi, Vincenzo

2015-01-01

Alzheimer's disease (AD) is a neurodegenerative disorder, which is likely to start as mild cognitive impairment (MCI) several years before the its full-blown clinical manifestation. Optical coherence tomography (OCT) has been used to detect a loss in peripapillary retina nerve fiber layer (RNFL) and a reduction in macular thickness and volume of people affected by MCI or AD. Here, we performed an aggregate meta-analysis combining results from different studies. Data sources were case-control studies published between January 2001 and August 2014 (identified through PubMed and Google Scholar databases) that examined the RNFL thickness by means of OCT in AD and MCI patients compared with cognitively healthy controls. 11 studies were identified, including 380 patients with AD, 68 with MCI and 293 healthy controls (HC). The studies suggest that the mean RNFL thickness is reduced in MCI (weighted mean differences in μm, WMD = -13.39, 95% CI: -17.34 to -9.45, p = 0.031) and, even more so, in AD (WMD = -15.95, 95% CI: -21.65 to -10.21, p<0.0001) patients compared to HC. RNFL in the 4 quadrants were all significantly thinner in AD superior (superior WMD = -24.0, 95% CI: -34.9 to -13.1, p<0.0001; inferior WMD = -20.8, 95% CI: -32.0 to -9.7, p<0.0001; nasal WMD = -14.7, 95% CI: -23.9 to -5.5, p<0.0001; and temporal WMD = -10.7, 95% CI: -19.9 to -1.4, p<0.0001); the same significant reduction in quadrant RNFL was observed in MCI patients compared with HC (Inferior WMD = -20.22, 95% CI: -30.41 to -10.03, p = 0.0001; nasal WMD = -7.4, 95% CI: -10.08 to -4.7, p = 0.0000; and temporal WMD = -6.88, 95% CI: -12.62 to -1.13, p = 0.01), with the exception of superior quadrant (WMD = -19.45, 95% CI: -40.23 to 1.32, p = 0.06). Results from the meta-analysis support the important role of OCT for RNFL analysis in monitoring the progression of AD and in assessing the effectiveness of purported AD treatments.

Alpha-1-antichymotrypsin (ACT or SERPINA3) polymorphism may affect age-at-onset and disease duration of Alzheimer's disease.

PubMed

Kamboh, M Ilyas; Minster, Ryan L; Kenney, Margaret; Ozturk, Ayla; Desai, Purnima P; Kammerer, Candace M; DeKosky, Steven T

2006-10-01

In addition to genetic effects on disease risk, age-at-onset (AAO) of Alzheimer's disease (AD) is also genetically controlled. Using AAO as a covariate, a linkage signal for AD has been detected on chromosome 14q32 near the alpha1-antichymotrypsin (ACT) gene. Previously, a signal peptide polymorphism (codon -17A>T) in the ACT gene has been suggested to affect AD risk, but with inconsistent findings. Given that a linkage signal for AAO has been detected near ACT, we hypothesized that ACT genetic variation affects AAO rather than disease risk and this may explain the previous inconsistent findings between ACT genetic variation and AD risk. We examined the impact of the ACT signal peptide polymorphism on mean AAO in 909 AD cases. The ACT polymorphism was significantly associated with AAO and this effect was independent of the APOE polymorphism. Mean AAO among ACT/AA homozygotes was significantly lower than that in the combined AT+TT genotype group (p = 0.019) and this difference was confined to male AD patients (p = 0.002). Among male AD patients, the ACT/AA genotype was also associated with shorter disease duration before death as compared to the ACT/AT+TT genotypes (p = 0.012). These data suggest that the ACT gene may affect AAO and disease duration of AD.

Alpha-1-antichymotrypsin (ACT or SERPINA3) polymorphism may affect age-at-onset and disease duration of Alzheimer’s disease

PubMed Central

Kamboh, M. Ilyas; Minster, Ryan L.; Kenney, Margaret; Ozturk, Ayla; Desai, Purnima P.; Kammerer, Candace M.; DeKosky, Steven T.

2006-01-01

In addition to genetic effects on disease risk, age-at-onset (AAO) of Alzheimer’s disease (AD) is also genetically controlled. Using AAO as a covariate, a linkage signal for AD has been detected on chromosome 14q32 near the a1-antichymotrypsin (ACT) gene. Previously, a signal peptide polymorphism (codon -17A>T) in the ACT gene has been suggested to affect AD risk, but with inconsistent findings. Given that a linkage signal for AAO has been detected near ACT, we hypothesized that ACT genetic variation affects AAO rather than disease risk and this may explain the previous inconsistent findings between ACT genetic variation and AD risk. We examined the impact of the ACT signal peptide polymorphism on mean AAO in 909 AD cases. The ACT polymorphism was significantly associated with AAO and this effect was independent of the APOE polymorphism. Mean AAO among ACT/AA homozygotes was significantly lower than that in the combined AT+TT genotype group (p=0.019) and this difference was confined to male AD patients (p=0.002). Among male AD patients, the ACT/AA genotype was also associated with shorter disease duration before death as compared to the ACT/AT + TT genotypes (p=0.012). These data suggest that the ACT gene may affect AAO and disease duration of AD. PMID:16137793

Influence of the Size of Cohorts in Adaptive Design for Nonlinear Mixed Effects Models: An Evaluation by Simulation for a Pharmacokinetic and Pharmacodynamic Model for a Biomarker in Oncology

PubMed Central

Lestini, Giulia; Dumont, Cyrielle; Mentré, France

2015-01-01

Purpose In this study we aimed to evaluate adaptive designs (ADs) by clinical trial simulation for a pharmacokinetic-pharmacodynamic model in oncology and to compare them with one-stage designs, i.e. when no adaptation is performed, using wrong prior parameters. Methods We evaluated two one-stage designs, ξ0 and ξ*, optimised for prior and true population parameters, Ψ0 and Ψ*, and several ADs (two-, three- and five-stage). All designs had 50 patients. For ADs, the first cohort design was ξ0. The next cohort design was optimised using prior information updated from the previous cohort. Optimal design was based on the determinant of the Fisher information matrix using PFIM. Design evaluation was performed by clinical trial simulations using data simulated from Ψ*. Results Estimation results of two-stage ADs and ξ* were close and much better than those obtained with ξ0. The balanced two-stage AD performed better than two-stage ADs with different cohort sizes. Three-and five-stage ADs were better than two-stage with small first cohort, but not better than the balanced two-stage design. Conclusions Two-stage ADs are useful when prior parameters are unreliable. In case of small first cohort, more adaptations are needed but these designs are complex to implement. PMID:26123680

Influence of the Size of Cohorts in Adaptive Design for Nonlinear Mixed Effects Models: An Evaluation by Simulation for a Pharmacokinetic and Pharmacodynamic Model for a Biomarker in Oncology.

PubMed

Lestini, Giulia; Dumont, Cyrielle; Mentré, France

2015-10-01

In this study we aimed to evaluate adaptive designs (ADs) by clinical trial simulation for a pharmacokinetic-pharmacodynamic model in oncology and to compare them with one-stage designs, i.e., when no adaptation is performed, using wrong prior parameters. We evaluated two one-stage designs, ξ0 and ξ*, optimised for prior and true population parameters, Ψ0 and Ψ*, and several ADs (two-, three- and five-stage). All designs had 50 patients. For ADs, the first cohort design was ξ0. The next cohort design was optimised using prior information updated from the previous cohort. Optimal design was based on the determinant of the Fisher information matrix using PFIM. Design evaluation was performed by clinical trial simulations using data simulated from Ψ*. Estimation results of two-stage ADs and ξ * were close and much better than those obtained with ξ 0. The balanced two-stage AD performed better than two-stage ADs with different cohort sizes. Three- and five-stage ADs were better than two-stage with small first cohort, but not better than the balanced two-stage design. Two-stage ADs are useful when prior parameters are unreliable. In case of small first cohort, more adaptations are needed but these designs are complex to implement.

A prime-boost immunization regimen based on a simian adenovirus 36 vectored multi-stage malaria vaccine induces protective immunity in mice.

PubMed

Fonseca, Jairo A; McCaffery, Jessica N; Kashentseva, Elena; Singh, Balwan; Dmitriev, Igor P; Curiel, David T; Moreno, Alberto

2017-05-31

Malaria remains a considerable burden on public health. In 2015, the WHO estimates there were 212 million malaria cases causing nearly 429,000 deaths globally. A highly effective malaria vaccine is needed to reduce the burden of this disease. We have developed an experimental vaccine candidate (PyCMP) based on pre-erythrocytic (CSP) and erythrocytic (MSP1) stage antigens derived from the rodent malaria parasite P. yoelii. Our protein-based vaccine construct induces protective antibodies and CD4 + T cell responses. Based on evidence that viral vectors increase CD8 + T cell-mediated immunity, we also have tested heterologous prime-boost immunization regimens that included human adenovirus serotype 5 vector (Ad5), obtaining protective CD8 + T cell responses. While Ad5 is commonly used for vaccine studies, the high prevalence of pre-existing immunity to Ad5 severely compromises its utility. Here, we report the use of the novel simian adenovirus 36 (SAd36) as a candidate for a vectored malaria vaccine since this virus is not known to infect humans, and it is not neutralized by anti-Ad5 antibodies. Our study shows that the recombinant SAd36PyCMP can enhance specific CD8 + T cell response and elicit similar antibody titers when compared to an immunization regimen including the recombinant Ad5PyCMP. The robust immune responses induced by SAd36PyCMP are translated into a lower parasite load following P. yoelii infectious challenge when compared to mice immunized with Ad5PyCMP. Copyright © 2017 Elsevier Ltd. All rights reserved.

Multicentered black holes with a negative cosmological constant

NASA Astrophysics Data System (ADS)

Chimento, Samuele; Klemm, Dietmar

2014-01-01

We present a recipe that allows us to construct multicentered black holes embedded in an arbitrary Friedmann-Lemaître-Robertson-Walker (FLRW) universe. These solutions are completely determined by a function satisfying the conformal Laplace equation on the spatial slices E3, S3, or H3. Since anti-de Sitter (AdS) space can be written in FLRW coordinates, this includes as a special case multicentered black holes in AdS, in the sense that, far away from the black holes, the energy density and the pressure approach the values given by a negative cosmological constant. We study in some detail the physical properties of the single-centered asymptotically AdS case, which does not coincide with the usual Reissner-Nordström-AdS black hole, but is highly dynamical. In particular, we determine the curvature singularities and trapping horizons of this solution, compute the surface gravity of the trapping horizons, and show that the generalized first law of black hole dynamics proposed by Hayward holds in this case. It turns out that the spurious big bang/big crunch singularities that appear when one writes AdS in FLRW form become real in the presence of these dynamical black holes. This implies that actually only one point of the usual conformal boundary of AdS survives in the solutions that we construct. Finally, a generalization to arbitrary dimension is also presented.

Conversion to dementia in mild cognitive impairment diagnosed with DSM-5 criteria and with Petersen's criteria.

PubMed

Marcos, G; Santabárbara, J; Lopez-Anton, R; De-la-Cámara, C; Gracia-García, P; Lobo, E; Pírez, G; Menchón, J M; Palomo, T; Stephan, B C M; Brayne, C; Lobo, A

2016-05-01

In a background of revision of criteria for states of increased risk for progression to dementia, we compare the conversion rate to dementia and Alzheimer's disease (AD) of mild cognitive impairment (MCI) as diagnosed using DSM-5 (DSM-5-MCI) and Petersen's (P-MCI) criteria. A population representative cohort of 4057 dementia-free individuals 55+ years of age was followed up at 2.5 and 4.5 years in Zaragoza, Spain (ZARADEMP). Using the Geriatric Mental State- AGECAT for assessment, research psychiatrists diagnosed DSM-5-MCI and P-MCI following operationalized criteria. 'Conversion rate' (CR), 'annual conversion rate' (ACR), and incidence rate (IR) were calculated along with incidence rate ratio (IRR) to compare the performance of the intermediate cognitive definitions. At 4.5-year follow-up, in individuals aged 65+ years, ACRs for non-cases, P-MCI, and DSM-5-MCI were 0.8, 1.9 and 3.4, respectively, for global dementia. The IRRs were 2.9 and 5.3 for P-MCI and DSM5-MCI, respectively, being the non-cases the reference category. The corresponding values were slightly lower for AD. Conversion rate to dementia and AD was higher using DSM-5-MCI criteria than using Petersen's criteria. However, prediction of the construct still has some way to go, as most MCI individuals did not convert at 4.5-year follow-up. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A disease state fingerprint for evaluation of Alzheimer's disease.

PubMed

Mattila, Jussi; Koikkalainen, Juha; Virkki, Arho; Simonsen, Anja; van Gils, Mark; Waldemar, Gunhild; Soininen, Hilkka; Lötjönen, Jyrki

2011-01-01

Diagnostic processes of Alzheimer's disease (AD) are evolving. Knowledge about disease-specific biomarkers is constantly increasing and larger volumes of data are being measured from patients. To gain additional benefits from the collected data, a novel statistical modeling and data visualization system is proposed for supporting clinical diagnosis of AD. The proposed system computes an evidence-based estimate of a patient's AD state by comparing his or her heterogeneous neuropsychological, clinical, and biomarker data to previously diagnosed cases. The AD state in this context denotes a patient's degree of similarity to previously diagnosed disease population. A summary of patient data and results of the computation are displayed in a succinct Disease State Fingerprint (DSF) visualization. The visualization clearly discloses how patient data contributes to the AD state, facilitating rapid interpretation of the information. To model the AD state from complex and heterogeneous patient data, a statistical Disease State Index (DSI) method underlying the DSF has been developed. Using baseline data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), the ability of the DSI to model disease progression from elderly healthy controls to AD and its ability to predict conversion from mild cognitive impairment (MCI) to AD were assessed. It was found that the DSI provides well-behaving AD state estimates, corresponding well with the actual diagnoses. For predicting conversion from MCI to AD, the DSI attains performance similar to state-of-the-art reference classifiers. The results suggest that the DSF establishes an effective decision support and data visualization framework for improving AD diagnostics, allowing clinicians to rapidly analyze large quantities of diverse patient data.

Neuropsychological Testing in Pathologically Verified Alzheimer Disease and Frontotemporal Dementia: How Well Do the Uniform Data Set Measures Differentiate Between Diseases?

PubMed

Ritter, Aaron R; Leger, Gabriel C; Miller, Justin B; Banks, Sarah J

2017-01-01

Differences in cognition between frontotemporal dementia (FTD) and Alzheimer disease (AD) are well described in clinical cohorts, but have rarely been confirmed in studies with pathologic verification. For emerging therapeutics to succeed, determining underlying pathology early in the disease course is increasingly important. Neuropsychological evaluation is an important component of the diagnostic workup for AD and FTD. Patients with FTD are thought to have greater deficits in language and executive function while patients with AD are more likely to have deficits in memory. To determine if performance on initial cognitive testing can reliably distinguish between patients with frontotemporal lobar degeneration (FTLD) and AD neuropathology. In addition, are there other factors of the neuropsychological assessment that can be used to enhance the accuracy of underlying pathology? Using a logistic regression we retrospectively compared neurocognitive performance on initial evaluation of 106 patients with pathologically verified FTLD (pvFTLD), with 558 pathologically verified AD (pvAD) patients from the National Alzheimer's Coordinating Center using data from the Uniform Data Set (UDS) and the neuropathology data set. As expected, pvFTLD patients were younger, demonstrated better memory performance, and had more neuropsychiatric symptoms than pvAD patients. Other results were less predictable: pvFTLD patients performed better on one test of executive function (trail making test part B) but worse on another (digit span backward). Performance on language testing did not strongly distinguish the 2 groups. To determine what factors led to a misdiagnosis of AD in patients with FTLD, we further analyzed a small group of pvFTLD patients. These patients demonstrated older age and lower Neuropsychiatric Inventory Questionnaire counts compared with accurately diagnosed cases. Other than memory, numerical scores of neurocognitive performance on the UDS are of limited value in differentiating FTLD from AD at the initial visit. These results highlight the difficulty of obtaining an accurate early diagnosis of FTLD and argue for adding supplemental tests to those included in the UDS to assess cognition in FTD and AD patients.

Role of Pro-Inflammatory Cytokines and Vitamin D in Probable Alzheimer's Disease with Depression

PubMed Central

Banerjee, Anindita; Khemka, Vineet Kumar; Roy, Debashree; Dhar, Aparajita; Sinha Roy, Tapan Kumar; Biswas, Atanu; Mukhopadhyay, Barun; Chakrabarti, Sasanka

2017-01-01

Symptoms of depression are present in a significant proportion of Alzheimer's disease (AD) patients. While epidemiological studies have shown a strong association between depression and AD, it has not been established whether depression is a risk factor or merely a co-morbidity of AD. It is also uncertain if depression affects the pathogenesis of AD. In this paper, we address these questions by measuring the serum levels of two common metabolic risk factors of AD and depression, inflammatory cytokines (IL 6 and TNF alpha) and serum 25-hydroxyvitamin D, in a case-control study. We measured the serum levels of IL 6, TNF α and 25-hydroxyvitamin D in age-matched healthy controls (n= 60) and in AD patients without depression (n=26) or AD patients with depression (n=34), and statistically analyzed the changes in these parameters among different groups under this study. Our results show that in AD there is a significant increase in IL 6 and TNF α and a marked decrease in 25-hydroxyvitamin D in the peripheral circulation compared to age-matched healthy controls. Furthermore, AD patients with depression have even significantly higher levels of IL 6 or TNF α and a lower level of 25-hydroxyvitamin D in circulation than in AD patients without depression. We also found a strong statistical correlation between the disease severity and the serum levels of IL 6, TNF α and 25-hydroxyvitamin D in AD patients with depression. These results suggest that altered circulating levels of common metabolic risk factors lead to the co-existence of depression with AD in many patients, and when they co-exist, the depression presumably affects the severity of AD presentations through more aggravated changes in these risk factors. PMID:28580183

The Added Value of a Single-photon Emission Computed Tomography-Computed Tomography in Sentinel Lymph Node Mapping in Patients with Breast Cancer and Malignant Melanoma.

PubMed

Bennie, George; Vorster, Mariza; Buscombe, John; Sathekge, Mike

2015-01-01

Single-photon emission computed tomography-computed tomography (SPECT-CT) allows for physiological and anatomical co-registration in sentinel lymph node (SLN) mapping and offers additional benefits over conventional planar imaging. However, the clinical relevance when considering added costs and radiation burden of these reported benefits remains somewhat uncertain. This study aimed to evaluate the possible added value of SPECT-CT and intra-operative gamma-probe use over planar imaging alone in the South African setting. 80 patients with breast cancer or malignant melanoma underwent both planar and SPECT-CT imaging for SLN mapping. We assessed and compared the number of nodes detected on each study, false positive and negative findings, changes in surgical approach and or patient management. In all cases where a sentinel node was identified, SPECT-CT was more accurate anatomically. There was a significant change in surgical approach in 30 cases - breast cancer (n = 13; P 0.001) and malignant melanoma (n = 17; P 0.0002). In 4 cases a node not identified on planar imaging was seen on SPECT-CT. In 16 cases additional echelon nodes were identified. False positives were excluded by SPECT-CT in 12 cases. The addition of SPECT-CT and use of intra-operative gamma-probe to planar imaging offers important benefits in patients who present with breast cancer and melanoma. These benefits include increased nodal detection, elimination of false positives and negatives and improved anatomical localization that ultimately aids and expedites surgical management. This has been demonstrated in the context of industrialized country previously and has now also been confirmed in the setting of a emerging-market nation.

Computation of iodine species concentrations in water

NASA Technical Reports Server (NTRS)

Schultz, John R.; Mudgett, Paul D.; Flanagan, David T.; Sauer, Richard L.

1994-01-01

During an evaluation of the use of iodine as a water disinfectant and the development of methods for measuring various iodine species in water onboard Space Freedom, it became necessary to compute the concentration of the various species based on equilibrium principles alone. Of particular concern was the case when various amounts of iodine, iodide, strong acid, and strong base are added to water. Such solutions can be used to evaluate the performance of various monitoring methods being considered. The authors of this paper present an overview of aqueous iodine chemistry, a set of nonlinear equations which can be used to model the above case, and a computer program for solving this system of equations using the Newton-Raphson method. The program was validated by comparing results over a range of concentrations and pH values with those previously presented by Gottardi for a given pH. Use of this program indicated that there are multiple roots to many cases and selecting an appropriate initial guess is important. Comparison of program results with laboratory results for the case when only iodine is added to water indicates the program gives high pH values for the iodine concentrations normally used for water disinfection. Extending the model to include the effects of iodate formation results in the computer pH values being closer to those observed, but the model with iodate does not agree well for the case in which base is added in addition to iodine to raise the pH. Potential explanations include failure to obtain equilibrium conditions in the lab, inaccuracies in published values for the equilibrium constants, and inadequate model of iodine chemistry and/or the lack of adequate analytical methods for measuring the various iodine species in water.

Pediatric Contact Dermatitis Registry Data on Contact Allergy in Children With Atopic Dermatitis.

PubMed

Jacob, Sharon E; McGowan, Maria; Silverberg, Nanette B; Pelletier, Janice L; Fonacier, Luz; Mousdicas, Nico; Powell, Doug; Scheman, Andrew; Goldenberg, Alina

2017-08-01

Atopic dermatitis (AD) and allergic contact dermatitis (ACD) have a dynamic relationship not yet fully understood. Investigation has been limited thus far by a paucity of data on the overlap of these disorders in pediatric patients. To use data from the Pediatric Contact Dermatitis Registry to elucidate the associations and sensitizations among patients with concomitant AD and ACD. This retrospective case review examined 1142 patch test cases of children younger than 18 years, who were registered between January 1, 2015, and December 31, 2015, by 84 health care providers (physicians, nurse practitioners, physician assistants) from across the United States. Data were gathered electronically from multidisciplinary providers within outpatient clinics throughout the United States on pediatric patients (ages 0-18 years). All participants were patch-tested to assess sensitizations to various allergens; history of AD was noted by the patch-testing providers. Primary outcomes were sensitization rates to various patch-tested allergens. A total of 1142 patients were evaluated: 189 boys (34.2%) and 363 girls (65.8%) in the AD group and 198 boys (36.1%) and 350 girls (63.9%) in the non-AD group (data on gender identification were missing for 17 patients). Compared with those without AD, patch-tested patients with AD were 1.3 years younger (10.5 vs 11.8 years; P < .001) and had longer history of dermatitis (3.5 vs 1.8 years; P < .001). Patch-tested patients designated as Asian or African American were more likely to have concurrent AD (odds ratio [OR], 1.92; 95% CI, 1.20-3.10; P = .008; and OR, 4.09; 95% CI, 2.70-6.20; P <.001, respectively). Patients with AD with generalized distribution were the most likely to be patch tested (OR, 4.68; 95% CI, 3.50-6.30; P < .001). Patients with AD had different reaction profiles than those without AD, with increased frequency of reactions to cocamidopropyl betaine, wool alcohol, lanolin, tixocortol pivalate, and parthenolide. Patients with AD were also noted to have lower frequency of reaction to methylisothiazolinone, cobalt, and potassium dichromate. Children with AD showed significant reaction patterns to allergens notable for their use in skin care preparations. This study adds to the current understanding of AD in ACD, and the continued need to investigate the interplay between these disease processes to optimize care for pediatric patients with these conditions.

Pediatric Contact Dermatitis Registry Data on Contact Allergy in Children With Atopic Dermatitis

PubMed Central

Jacob, Sharon E.; McGowan, Maria; Silverberg, Nanette B.; Pelletier, Janice L.; Fonacier, Luz; Mousdicas, Nico; Powell, Doug; Scheman, Andrew

2017-01-01

Importance Atopic dermatitis (AD) and allergic contact dermatitis (ACD) have a dynamic relationship not yet fully understood. Investigation has been limited thus far by a paucity of data on the overlap of these disorders in pediatric patients. Objective To use data from the Pediatric Contact Dermatitis Registry to elucidate the associations and sensitizations among patients with concomitant AD and ACD. Design, Setting, and Participants This retrospective case review examined 1142 patch test cases of children younger than 18 years, who were registered between January 1, 2015, and December 31, 2015, by 84 health care providers (physicians, nurse practitioners, physician assistants) from across the United States. Data were gathered electronically from multidisciplinary providers within outpatient clinics throughout the United States on pediatric patients (ages 0-18 years). Exposures All participants were patch-tested to assess sensitizations to various allergens; history of AD was noted by the patch-testing providers. Main Outcomes and Measures Primary outcomes were sensitization rates to various patch-tested allergens. Results A total of 1142 patients were evaluated: 189 boys (34.2%) and 363 girls (65.8%) in the AD group and 198 boys (36.1%) and 350 girls (63.9%) in the non-AD group (data on gender identification were missing for 17 patients). Compared with those without AD, patch-tested patients with AD were 1.3 years younger (10.5 vs 11.8 years; P < .001) and had longer history of dermatitis (3.5 vs 1.8 years; P < .001). Patch-tested patients designated as Asian or African American were more likely to have concurrent AD (odds ratio [OR], 1.92; 95% CI, 1.20-3.10; P = .008; and OR, 4.09; 95% CI, 2.70-6.20; P <.001, respectively). Patients with AD with generalized distribution were the most likely to be patch tested (OR, 4.68; 95% CI, 3.50-6.30; P < .001). Patients with AD had different reaction profiles than those without AD, with increased frequency of reactions to cocamidopropyl betaine, wool alcohol, lanolin, tixocortol pivalate, and parthenolide. Patients with AD were also noted to have lower frequency of reaction to methylisothiazolinone, cobalt, and potassium dichromate. Conclusions and Relevance Children with AD showed significant reaction patterns to allergens notable for their use in skin care preparations. This study adds to the current understanding of AD in ACD, and the continued need to investigate the interplay between these disease processes to optimize care for pediatric patients with these conditions. PMID:28241280

Mosaic Loss of Chromosome Y in Blood Is Associated with Alzheimer Disease.

PubMed

Dumanski, Jan P; Lambert, Jean-Charles; Rasi, Chiara; Giedraitis, Vilmantas; Davies, Hanna; Grenier-Boley, Benjamin; Lindgren, Cecilia M; Campion, Dominique; Dufouil, Carole; Pasquier, Florence; Amouyel, Philippe; Lannfelt, Lars; Ingelsson, Martin; Kilander, Lena; Lind, Lars; Forsberg, Lars A

2016-06-02

Men have a shorter life expectancy compared with women but the underlying factor(s) are not clear. Late-onset, sporadic Alzheimer disease (AD) is a common and lethal neurodegenerative disorder and many germline inherited variants have been found to influence the risk of developing AD. Our previous results show that a fundamentally different genetic variant, i.e., lifetime-acquired loss of chromosome Y (LOY) in blood cells, is associated with all-cause mortality and an increased risk of non-hematological tumors and that LOY could be induced by tobacco smoking. We tested here a hypothesis that men with LOY are more susceptible to AD and show that LOY is associated with AD in three independent studies of different types. In a case-control study, males with AD diagnosis had higher degree of LOY mosaicism (adjusted odds ratio = 2.80, p = 0.0184, AD events = 606). Furthermore, in two prospective studies, men with LOY at blood sampling had greater risk for incident AD diagnosis during follow-up time (hazard ratio [HR] = 6.80, 95% confidence interval [95% CI] = 2.16-21.43, AD events = 140, p = 0.0011). Thus, LOY in blood is associated with risks of both AD and cancer, suggesting a role of LOY in blood cells on disease processes in other tissues, possibly via defective immunosurveillance. As a male-specific risk factor, LOY might explain why males on average live shorter lives than females. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Improved multimodal biomarkers for Alzheimer's disease and mild cognitive impairment diagnosis: data from ADNI

NASA Astrophysics Data System (ADS)

Martinez-Torteya, Antonio; Treviño-Alvarado, Víctor; Tamez-Peña, José

2013-02-01

The accurate diagnosis of Alzheimer's disease (AD) and mild cognitive impairment (MCI) confers many clinical research and patient care benefits. Studies have shown that multimodal biomarkers provide better diagnosis accuracy of AD and MCI than unimodal biomarkers, but their construction has been based on traditional statistical approaches. The objective of this work was the creation of accurate AD and MCI diagnostic multimodal biomarkers using advanced bioinformatics tools. The biomarkers were created by exploring multimodal combinations of features using machine learning techniques. Data was obtained from the ADNI database. The baseline information (e.g. MRI analyses, PET analyses and laboratory essays) from AD, MCI and healthy control (HC) subjects with available diagnosis up to June 2012 was mined for case/controls candidates. The data mining yielded 47 HC, 83 MCI and 43 AD subjects for biomarker creation. Each subject was characterized by at least 980 ADNI features. A genetic algorithm feature selection strategy was used to obtain compact and accurate cross-validated nearest centroid biomarkers. The biomarkers achieved training classification accuracies of 0.983, 0.871 and 0.917 for HC vs. AD, HC vs. MCI and MCI vs. AD respectively. The constructed biomarkers were relatively compact: from 5 to 11 features. Those multimodal biomarkers included several widely accepted univariate biomarkers and novel image and biochemical features. Multimodal biomarkers constructed from previously and non-previously AD associated features showed improved diagnostic performance when compared to those based solely on previously AD associated features.

Hippocampus and Basal Forebrain Volumetry for Dementia and Mild Cognitive Impairment Diagnosis: Could It Be Useful in Primary Care?

PubMed

Teipel, Stefan J; Keller, Felix; Thyrian, Jochen R; Strohmaier, Urs; Altiner, Attila; Hoffmann, Wolfgang; Kilimann, Ingo

2017-01-01

Once a patient or a knowledgeable informant has noticed decline in memory or other cognitive functions, initiation of early dementia assessment is recommended. Hippocampus and cholinergic basal forebrain (BF) volumetry supports the detection of prodromal and early stages of Alzheimer's disease (AD) dementia in highly selected patient populations. To compare effect size and diagnostic accuracy of hippocampus and BF volumetry between patients recruited in highly specialized versus primary care and to assess the effect of white matter lesions as a proxy for cerebrovascular comorbidity on diagnostic accuracy. We determined hippocampus and BF volumes and white matter lesion load from MRI scans of 71 participants included in a primary care intervention trial (clinicaltrials.gov identifier: NCT01401582) and matched 71 participants stemming from a memory clinic. Samples included healthy controls and people with mild cognitive impairment (MCI), AD dementia, mixed dementia, and non-AD related dementias. Volumetric measures reached similar effect sizes and cross-validated levels of accuracy in the primary care and the memory clinic samples for the discrimination of AD and mixed dementia cases from healthy controls. In the primary care MCI cases, volumetric measures reached only random guessing levels of accuracy. White matter lesions had only a modest effect on effect size and diagnostic accuracy. Hippocampus and BF volumetry may usefully be employed for the identification of AD and mixed dementia, but the detection of MCI does not benefit from the use of these volumetric markers in a primary care setting.

Chromosomal DNA damage measured using the cytokinesis-block micronucleus cytome assay is significantly associated with cognitive impairment in South Australians.

PubMed

Lee, Sau Lai; Thomas, Philip; Hecker, Jane; Faunt, Jeffrey; Fenech, Michael

2015-01-01

Loss of genome integrity may be associated with increased risk for neurodegenerative disease. The aim of this study was to investigate whether mild cognitive impairment (MCI) or Alzheimer's disease (AD) individuals have increased DNA damage relative to age- and gender- matched controls using the cytokinesis-block micronucleus cytome (CBMN-Cyt) assay. DNA damage was measured as micronuclei (MN), nucleoplasmic bridges (NPB), and nuclear buds (NBUD) in binucleated cells. The assay was performed on blood samples from 80 participants consisting of (i) MCI cases (N = 20) and age- and gender- matched controls (N = 20), and (ii) AD cases (N = 20) and age- and gender- matched controls (N = 20). There was a significant increase in MCI NBUD frequency (P = 0.006) relative to controls, which was also observed in male (P = 0.03) and female (P = 0.04) subgroups. For AD cases, there were no significant differences in assay biomarkers relative to controls. There was a significant negative correlation between Mini Mental State Examination (MMSE) and (i) MN in all controls, (R = -0.3, P = 0.04), and AD cases (R = -0.4, P = 0.03), (ii) NPB in all controls, (R = -0.4, P = 0.006) and AD cases (R = -0.5, P = 0.01), and (iii) NBUD in MCI cases (R = -0.5, P = 0.007) and AD cases (R = -0.7, P = 0.0002). The results suggest that an increase in lymphocyte CBMN-Cyt DNA damage biomarkers may be associated with cognitive decline. © 2014 Wiley Periodicals, Inc.

Higher Spin Fields in Three-Dimensional Gravity

NASA Astrophysics Data System (ADS)

Lepage-Jutier, Arnaud

In this thesis, we study the effects of massless higher spin fields in three-dimensional gravity with a negative cosmological constant. First, we introduce gravity in Anti-de Sitter (AdS) space without the higher spin gauge symmetry. We recapitulate the semi-classical analysis that outlines the duality between quantum gravity in three dimensions with a negative cosmological constant and a conformal field theory on the asymptotic boundary of AdS 3. We review the statistical interpretation of the black hole entropy via the AdS/CFT correspondence and the modular invariance of the partition function of a CFT on a torus. For the case of higher spin theories in AdS 3 we use those modular properties to bound the amount of gauge symmetry present. We then discuss briefly cases that can evade this bound.

Computer-aided classification of patients with dementia of Alzheimer's type based on cerebral blood flow determined with arterial spin labeling technique

NASA Astrophysics Data System (ADS)

Yamashita, Yasuo; Arimura, Hidetaka; Yoshiura, Takashi; Tokunaga, Chiaki; Magome, Taiki; Monji, Akira; Noguchi, Tomoyuki; Toyofuku, Fukai; Oki, Masafumi; Nakamura, Yasuhiko; Honda, Hiroshi

2010-03-01

Arterial spin labeling (ASL) is one of promising non-invasive magnetic resonance (MR) imaging techniques for diagnosis of Alzheimer's disease (AD) by measuring cerebral blood flow (CBF). The aim of this study was to develop a computer-aided classification system for AD patients based on CBFs measured by the ASL technique. The average CBFs in cortical regions were determined as functional image features based on the CBF map image, which was non-linearly transformed to a Talairach brain atlas by using a free-form deformation. An artificial neural network (ANN) was trained with the CBF functional features in 10 cortical regions, and was employed for distinguishing patients with AD from control subjects. For evaluation of the method, we applied the proposed method to 20 cases including ten AD patients and ten control subjects, who were scanned a 3.0-Tesla MR unit. As a result, the area under the receiver operating characteristic curve obtained by the proposed method was 0.893 based on a leave-one-out-by-case test in identification of AD cases among 20 cases. The proposed method would be feasible for classification of patients with AD.

Strong evidence for a genetic contribution to late-onset Alzheimer's disease mortality: a population-based study.

PubMed

Kauwe, John S K; Ridge, Perry G; Foster, Norman L; Cannon-Albright, Lisa A

2013-01-01

Alzheimer's disease (AD) is an international health concern that has a devastating effect on patients and families. While several genetic risk factors for AD have been identified much of the genetic variance in AD remains unexplained. There are limited published assessments of the familiality of Alzheimer's disease. Here we present the largest genealogy-based analysis of AD to date. We assessed the familiality of AD in The Utah Population Database (UPDB), a population-based resource linking electronic health data repositories for the state with the computerized genealogy of the Utah settlers and their descendants. We searched UPDB for significant familial clustering of AD to evaluate the genetic contribution to disease. We compared the Genealogical Index of Familiality (GIF) between AD individuals and randomly selected controls and estimated the Relative Risk (RR) for a range of family relationships. Finally, we identified pedigrees with a significant excess of AD deaths. The GIF analysis showed that pairs of individuals dying from AD were significantly more related than expected. This excess of relatedness was observed for both close and distant relationships. RRs for death from AD among relatives of individuals dying from AD were significantly increased for both close and more distant relatives. Multiple pedigrees had a significant excess of AD deaths. These data strongly support a genetic contribution to the observed clustering of individuals dying from AD. This report is the first large population-based assessment of the familiality of AD mortality and provides the only reported estimates of relative risk of AD mortality in extended relatives to date. The high-risk pedigrees identified show a true excess of AD mortality (not just multiple cases) and are greater in depth and width than published AD pedigrees. The presence of these high-risk pedigrees strongly supports the possibility of rare predisposition variants not yet identified.

Clinical features of squamous cell lung cancer with anaplastic lymphoma kinase (ALK)-rearrangement: a retrospective analysis and review

PubMed Central

Watanabe, Junko; Togo, Shinsaku; Sumiyoshi, Issei; Namba, Yukiko; Suina, Kentaro; Mizuno, Takafumi; Kadoya, Kotaro; Motomura, Hiroaki; Iwai, Moe; Nagaoka, Tetsutaro; Sasaki, Shinichi; Hayashi, Takuo; Uekusa, Toshimasa; Abe, Kanae; Urata, Yasuo; Sakurai, Fuminori; Mizuguchi, Hiroyuki; Kato, Shunsuke; Takahashi, Kazuhisa

2018-01-01

Anti-anaplastic lymphoma kinase (ALK)-targeted therapy dramatically improves therapeutic responses in patients with ALK-rearranged lung adenocarcinoma (Ad-LC). A few cases of squamous cell lung carcinoma (Sq-LC) with ALK rearrangement have been reported; however, the clinicopathological features and clinical outcomes following treatment with ALK inhibitors are unknown. We addressed this in the present study by retrospectively comparing the clinical characteristics of five patients with ALK-rearranged Sq-LC with those of patients with ALK-rearranged Ad-LC and by evaluating representative cases of ALK inhibitor responders and non-responders. The prevalence of ALK rearrangement in Sq-LCs was 1.36%. Progression-free survival (PFS) after initial treatment with crizotinib was significantly shorter in Sq-LC than in Ad-LC with ALK rearrangement (p = 0.033). Two ALK rearrangements assayed by fluorescence in situ hybridization (FISH)-positive/immunohistochemistry-negative cases did not respond to crizotinb, and PFS decreased following alectinib treatment of ALK-rearranged Sq-LC (p = 0.045). A rebiopsy revealed that responders to ceritinib harbored the L1196M mutation, which causes resistance to other ALK inhibitors. However, non-responders were resistant to all ALK inhibitors, despite the presence of ALK rearrangement in FISH-positive circulating tumor cells and circulating free DNA and absence of the ALK inhibitor resistance mutation. These results indicate that ALK inhibitors remain a reasonable therapeutic option for ALK-rearranged Sq-LC patients who have worse outcomes than ALK-rearranged Ad-LC patients and that resistance mechanisms are heterogeneous. Additionally, oncologists should be aware of the possibility of ALK-rearranged Sq-LC based on clinicopathological features, and plan second-line therapeutic strategies based on rebiopsy results in order to improve patient outcome. PMID:29844868

Meta-analysis of the brain-derived neurotrophic factor gene (BDNF) Val66Met polymorphism in anxiety disorders and anxiety-related personality traits.

PubMed

Frustaci, Alessandra; Pozzi, Gino; Gianfagna, Francesco; Manzoli, Lamberto; Boccia, Stefania

2008-01-01

Brain-derived neurotrophic factor (BDNF) is potentially involved in the pathogenesis of anxiety. We carried out meta-analyses to evaluate the relationship between the BDNF Val66Met (valine, methionine) polymorphism and anxiety disorders (AD) or anxiety-related personality traits (ARPT). Medline, Embase and PsycINFO were searched up to December 2007. We investigated 3 outcomes related to BDNF Val66Met polymorphisms: (1) clinically diagnosed cases of AD; (2) ARPT in subjects without psychiatric diagnoses, assessed either by the Neuroticism scale of NEO-Personality Inventory forms (NEO-PI, NEO-PI-R, NEO-FFI), or by (3) the Harm Avoidance (HA) scale of Tridimensional Personality Questionnaire (TPQ) or its extended version Temperament and Character Inventory (TCI). Seven case-control studies were selected for AD, including 1,092 cases and 8,394 controls, while 5 cross-sectional studies for Neuroticism (n = 1,633) and 4 for HA (n = 607). Both Met/Met and Val/Met individuals, as compared to Val/Val, showed a statistically significant lower Neuroticism score [SMD = -0.24 (95% CI: -0.44, -0.04), and -0.11 (95% CI: -0.22, -0.01), respectively]. No significant association was found between BDNF Val66Met polymorphism and AD [OR = 1.13 (95% CI: 0.85-1.52) for Met/Met versus Val/Val] or HA [SMD = 0.11 (95% CI: -0.19, 0.42) for Met/Met vs. Val/Val]. The low number of studies on this topic and their limited sample size, along with the inner limits in the definition of anxiety phenotypes, suggest caution in the interpretation of these results. Larger additional studies possibly investigating the interaction with other genes and environmental exposures are required to confirm these results. 2008 S. Karger AG, Basel.

Paediatric acquired demyelinating syndromes: incidence, clinical and magnetic resonance imaging features.

PubMed

Absoud, Michael; Lim, Ming J; Chong, Wui K; De Goede, Christian G; Foster, Katharine; Gunny, Roxana; Hemingway, Cheryl; Jardine, Philip E; Kneen, Rachel; Likeman, Marcus; Nischal, Ken K; Pike, Michael G; Sibtain, Naomi A; Whitehouse, William P; Cummins, Carole; Wassmer, Evangeline

2013-01-01

Changing trends in multiple sclerosis (MS) epidemiology may first be apparent in the childhood population affected with first onset acquired demyelinating syndromes (ADSs). We aimed to determine the incidence, clinical, investigative and magnetic resonance imaging (MRI) features of childhood central nervous system ADSs in the British Isles for the first time. We conducted a population active surveillance study. All paediatricians, and ophthalmologists (n = 4095) were sent monthly reporting cards (September 2009-September 2010). International Paediatric MS Study Group 2007 definitions and McDonald 2010 MS imaging criteria were used for acute disseminated encephalomyelitis (ADEM), clinically isolated syndrome (CIS) and neuromyelitis optica (NMO). Clinicians completed a standard questionnaire and provided an MRI copy for review. Card return rates were 90%, with information available for 200/222 positive notifications (90%). After exclusion of cases, 125 remained (age range 1.3-15.9), with CIS in 66.4%, ADEM in 32.0% and NMO in 1.6%. The female-to-male ratio in children older than 10 years (n = 63) was 1.52:1 (p = 0.045). The incidence of first onset ADS in children aged 1-15 years old was 9.83 per million children per year (95% confidence interval [CI] 8.18-11.71). A trend towards higher incidence rates of ADS in children of South Asian and Black ethnicity was observed compared with White children. Importantly, a number of MRI characteristics distinguished ADEM from CIS cases. Of CIS cases with contrast imaging, 26% fulfilled McDonald 2010 MS diagnostic criteria. We report the highest surveillance incidence rates of childhood ADS. Paediatric MS diagnosis at first ADS presentation has implications for clinical practice and clinical trial design.

Clinical features of squamous cell lung cancer with anaplastic lymphoma kinase (ALK)-rearrangement: a retrospective analysis and review.

PubMed

Watanabe, Junko; Togo, Shinsaku; Sumiyoshi, Issei; Namba, Yukiko; Suina, Kentaro; Mizuno, Takafumi; Kadoya, Kotaro; Motomura, Hiroaki; Iwai, Moe; Nagaoka, Tetsutaro; Sasaki, Shinichi; Hayashi, Takuo; Uekusa, Toshimasa; Abe, Kanae; Urata, Yasuo; Sakurai, Fuminori; Mizuguchi, Hiroyuki; Kato, Shunsuke; Takahashi, Kazuhisa

2018-05-08

Anti-anaplastic lymphoma kinase (ALK)-targeted therapy dramatically improves therapeutic responses in patients with ALK-rearranged lung adenocarcinoma (Ad-LC). A few cases of squamous cell lung carcinoma (Sq-LC) with ALK rearrangement have been reported; however, the clinicopathological features and clinical outcomes following treatment with ALK inhibitors are unknown. We addressed this in the present study by retrospectively comparing the clinical characteristics of five patients with ALK-rearranged Sq-LC with those of patients with ALK-rearranged Ad-LC and by evaluating representative cases of ALK inhibitor responders and non-responders. The prevalence of ALK rearrangement in Sq-LCs was 1.36%. Progression-free survival (PFS) after initial treatment with crizotinib was significantly shorter in Sq-LC than in Ad-LC with ALK rearrangement ( p = 0.033). Two ALK rearrangements assayed by fluorescence in situ hybridization (FISH)-positive/immunohistochemistry-negative cases did not respond to crizotinb, and PFS decreased following alectinib treatment of ALK-rearranged Sq-LC ( p = 0.045). A rebiopsy revealed that responders to ceritinib harbored the L1196M mutation, which causes resistance to other ALK inhibitors. However, non-responders were resistant to all ALK inhibitors, despite the presence of ALK rearrangement in FISH-positive circulating tumor cells and circulating free DNA and absence of the ALK inhibitor resistance mutation. These results indicate that ALK inhibitors remain a reasonable therapeutic option for ALK-rearranged Sq-LC patients who have worse outcomes than ALK-rearranged Ad-LC patients and that resistance mechanisms are heterogeneous. Additionally, oncologists should be aware of the possibility of ALK-rearranged Sq-LC based on clinicopathological features, and plan second-line therapeutic strategies based on rebiopsy results in order to improve patient outcome.

Unusual Onset of Celiac Disease and Addison's Disease in a 12-Year-Old Boy.

PubMed

Miconi, Francesco; Savarese, Emanuela; Miconi, Giovanni; Cabiati, Gabriele; Rapaccini, Valentina; Principi, Nicola; Esposito, Susanna

2017-07-29

Celiac disease (CD) is an autoimmune disorder deriving from an aberrant adaptive immune response against gluten-containing grains in genetically predisposed subjects. In a number of patients, CD is associated with one or more other autoimmune diseases. Primary Addison's disease (AD) and CD may co-exist, although this association is relatively uncommon in children. In addition, it is not precisely defined whether a gluten-free diet influences the course of AD. A case of CD in a 12-year-old boy presenting as acute adrenal insufficiency is described here. A gluten-free diet had a significant therapeutic role in this case, wherein most of the clinical signs and symptoms of AD disappeared in a few days. In addition, the dosage of cortisol acetate, initially administered to treat the AD, was able to be rapidly reduced. This case highlights that CD can be associated with AD in children, and a gluten-free diet seems to positively influence the course of AD.

Skin reaction and regeneration after single sodium lauryl sulfate exposure stratified by filaggrin genotype and atopic dermatitis phenotype.

PubMed

Bandier, J; Carlsen, B C; Rasmussen, M A; Petersen, L J; Johansen, J D

2015-06-01

Filaggrin is key for the integrity of the stratum corneum. Mutations in the filaggrin gene (FLGnull) play a prominent role in atopic dermatitis (AD) pathogenesis. People with AD have increased susceptibility to irritants. However, little is known about the effect of filaggrin genotype and AD phenotype on irritant response and skin regeneration. To investigate the role of FLGnull and AD groups for skin reaction and recovery after sodium lauryl sulfate (SLS) irritation. This is a case-control study comprising 67 subjects, including healthy controls and patients with and without FLGnull and AD. Reactivity to different doses of SLS at 24, 48, 72 and 145 h after SLS application was measured by transepidermal water loss (TEWL) and laser Doppler flowmetry (LDF). Reactivity was assessed univariately and by pattern analysis. All patient groups showed a higher degree of skin-barrier disruption and inflammation than did controls in response to SLS. Assessing reactivity by the delta value of the area under the curve for both TEWL and LDF showed significant differences between healthy controls and those with the AD phenotype, irrespective of filaggrin mutation. The poorest regeneration was among those with the AD phenotype. The two AD phenotype groups were separated by multivariate technique, due to earlier inflammatory reactivity among subjects with FLGnullplus AD compared with the AD phenotype alone. Both skin reaction and regeneration were significantly different between the patient population and the healthy controls. Additionally, response severity and regeneration depended more on AD phenotype than on filaggrin genotype, whereas the response was more rapid among the FLGnullplus AD individuals. © 2015 British Association of Dermatologists.

Conserved Sequences at the Origin of Adenovirus DNA Replication

PubMed Central

Stillman, Bruce W.; Topp, William C.; Engler, Jeffrey A.

1982-01-01

The origin of adenovirus DNA replication lies within an inverted sequence repetition at either end of the linear, double-stranded viral DNA. Initiation of DNA replication is primed by a deoxynucleoside that is covalently linked to a protein, which remains bound to the newly synthesized DNA. We demonstrate that virion-derived DNA-protein complexes from five human adenovirus serological subgroups (A to E) can act as a template for both the initiation and the elongation of DNA replication in vitro, using nuclear extracts from adenovirus type 2 (Ad2)-infected HeLa cells. The heterologous template DNA-protein complexes were not as active as the homologous Ad2 DNA, most probably due to inefficient initiation by Ad2 replication factors. In an attempt to identify common features which may permit this replication, we have also sequenced the inverted terminal repeated DNA from human adenovirus serotypes Ad4 (group E), Ad9 and Ad10 (group D), and Ad31 (group A), and we have compared these to previously determined sequences from Ad2 and Ad5 (group C), Ad7 (group B), and Ad12 and Ad18 (group A) DNA. In all cases, the sequence around the origin of DNA replication can be divided into two structural domains: a proximal A · T-rich region which is partially conserved among these serotypes, and a distal G · C-rich region which is less well conserved. The G · C-rich region contains sequences similar to sequences present in papovavirus replication origins. The two domains may reflect a dual mechanism for initiation of DNA replication: adenovirus-specific protein priming of replication, and subsequent utilization of this primer by host replication factors for completion of DNA synthesis. Images PMID:7143575

An International Multi-center Study on Self-assessed and Family Quality of Life in Children with Atopic Dermatitis.

PubMed

Chernyshov, Pavel V; Ho, Roger C; Monti, Fiorella; Jirakova, Anna; Velitchko, Svitlana S; Hercogova, Jana; Neri, Erica

2015-01-01

Atopic dermatitis (AD) is a common childhood chronic inflammatory skin condition that greatly affects the quality of life (QoL) of affected children and their families. The aim of our study was to assess QoL and family QoL of children with AD from 4 different countries and then compare the data, evaluating the effects of AD severity and age of children. Data on the Children's Dermatology Life Quality Index (CDLQI) and the Dermatitis Family Impact (DFI) questionnaires and the SCORAD index of 167 AD children 5-16 years old from Ukraine, Czech Republic, Singapore, and Italy was used for the study. SCORAD correlated with the CDLQI in all 4 countries and with DFI in all countries except Singapore. Only in Czech children did the CDLQI correlate with their age. No significant correlations between age and DFI results were found. AD symptoms and expenditures related to AD were highly scored in all countries. Impact of AD on friendship and relations between family members were among the lower scored items, and family problems did not increase proportionately with duration of AD in any of the four countries. Self-assessed health-related QoL of children with AD in our study correlated better in most cases with disease severity than family QoL results. Parents of school children with AD were generally less stressed, tired, and exhausted than parents of preschool children. These data together with results showing that duration of AD in children does not affect relations between parents and other family members is optimistic news for families with children with AD who did not recover until adolescence.

Comparing colon cancer outcomes: The impact of low hospital case volume and case-mix adjustment.

PubMed

Fischer, C; Lingsma, H F; van Leersum, N; Tollenaar, R A E M; Wouters, M W; Steyerberg, E W

2015-08-01

When comparing performance across hospitals it is essential to consider the noise caused by low hospital case volume and to perform adequate case-mix adjustment. We aimed to quantify the role of noise and case-mix adjustment on standardized postoperative mortality and anastomotic leakage (AL) rates. We studied 13,120 patients who underwent colon cancer resection in 85 Dutch hospitals. We addressed differences between hospitals in postoperative mortality and AL, using fixed (ignoring noise) and random effects (incorporating noise) logistic regression models with general and additional, disease specific, case-mix adjustment. Adding disease specific variables improved the performance of the case-mix adjustment models for postoperative mortality (c-statistic increased from 0.77 to 0.81). The overall variation in standardized mortality ratios was similar, but some individual hospitals changed considerably. For the standardized AL rates the performance of the adjustment models was poor (c-statistic 0.59 and 0.60) and overall variation was small. Most of the observed variation between hospitals was actually noise. Noise had a larger effect on hospital performance than extended case-mix adjustment, although some individual hospital outcome rates were affected by more detailed case-mix adjustment. To compare outcomes between hospitals it is crucial to consider noise due to low hospital case volume with a random effects model. Copyright © 2015 Elsevier Ltd. All rights reserved.

Autopsy-confirmed hippocampal-sparing Alzheimer's disease with delusional jealousy as initial manifestation.

PubMed

Fujishiro, Hiroshige; Iritani, Shuji; Hattori, Miho; Sekiguchi, Hirotaka; Matsunaga, Shinji; Habuchi, Chikako; Torii, Youta; Umeda, Kentaro; Ozaki, Norio; Yoshida, Mari; Fujita, Kiyoshi

2015-09-01

Alzheimer's disease (AD) is clinically characterized by gradual onset over years with worsening of cognition. The initial and most prominent cognitive deficit is commonly memory dysfunction. However, a subset of AD cases has less hippocampal atrophy than would be expected relative to the predominance of cortical atrophy. These hippocampal-sparing cases have distinctive clinical features, including the presence of focal cortical clinical syndromes. Given that previous studies have indicated that severe hippocampal atrophy corresponds to prominent loss of episodic memory, it is likely that memory impairment is initially absent in hippocampal-sparing AD cases. Here, we report on a patient with an 8-year history of delusional jealousy with insidious onset who was clinically diagnosed as possible AD and pathologically confirmed to have AD with relatively preserved neurons in the hippocampus. This patient had delusional jealousy with a long pre-dementia stage, which initially was characterized by lack of memory impairment. Head magnetic resonance imaging findings showed preserved hippocampal volume with bilateral enlarged ventricles and mild-to-moderate cortical atrophy. Head single-photon emission computed tomography revealed severely decreased regional cerebral blood flow in the right temporal lobe. The resolution of the delusion was attributed to pharmacotherapy by an acetylcholinesterase inhibitor, suggesting that the occurrence of delusional jealousy was due to the disease process of AD. Although the neural basis of delusional jealousy remains unclear, this hippocampal-sparing AD case may be classified as an atypical presentation of AD. © 2015 The Authors. Psychogeriatrics © 2015 Japanese Psychogeriatric Society.

Preferential accumulation of amyloid-beta in presynaptic glutamatergic terminals (VGluT1 and VGluT2) in Alzheimer's disease cortex.

PubMed

Sokolow, Sophie; Luu, Sanh H; Nandy, Karabi; Miller, Carol A; Vinters, Harry V; Poon, Wayne W; Gylys, Karen H

2012-01-01

Amyloid-beta (Aβ) is thought to play a central role in synaptic dysfunction (e.g. neurotransmitter release) and synapse loss. Glutamatergic dysfunction is involved in the pathology of Alzheimer's disease (AD) and perhaps plays a central role in age-related cognitive impairment. Yet, it is largely unknown whether Aβ accumulates in excitatory boutons. To assess the possibility that glutamatergic terminals are lost in AD patients, control and AD synaptosomes were immunolabeled for the most abundant vesicular glutamate transporters (VGluT1 and VGluT2) and quantified by flow cytometry and immunoblot methods. In post-mortem parietal cortex from aged control subjects, glutamatergic boutons are fairly abundant as approximately 40% were immunoreactive for VGluT1 (37%) and VGluT2 (39%). However, the levels of these specific markers of glutamatergic synapses were not significantly different among control and AD cases. To test the hypothesis that Aβ is associated with excitatory terminals, AD synaptosomes were double-labeled for Aβ and for VGluT1 and VGluT2, and analyzed by flow cytometry and confocal microscopy. Our study demonstrated that Aβ immunoreactivity (IR) was present in glutamatergic terminals of AD patients. Quantification of Aβ and VGluT1 in a large population of glutamatergic nerve terminals was performed by flow cytometry, showing that 42% of VGluT1 synaptosomes were immunoreactive for Aβ compared to 9% of VGluT1 synaptosomes lacking Aβ-IR. Percentage of VGluT2 synaptosomes immunoreactive for Aβ (21%) was significantly higher than VGluT2 synaptosomes lacking Aβ-IR (9%). Moreover, Aβ preferentially affects VGluT1 (42% positive) compared to VGluT2 terminals (21%). These data represent the first evidence of high levels of Aβ in excitatory boutons in AD cortex and support the hypothesis that Aβ may play a role in modulating glutamate transmission in AD terminals. Copyright © 2011 Elsevier Inc. All rights reserved.

Preferential accumulation of amyloid-beta in presynaptic glutamatergic terminals (VGluT1 and VGluT2) in Alzheimer’s disease cortex

PubMed Central

Sokolow, Sophie; Luu, Sanh H.; Nandy, Karabi; Miller, Carol A.; Vinters, Harry V.; Poon, Wayne W.; Gylys, Karen H.

2011-01-01

Amyloid-beta (Aβ) is thought to play a central role in synaptic dysfunction (e.g. neurotransmitter release) and synapse loss. Glutamatergic dysfunction is involved in the pathology of Alzheimer’s disease (AD) and perhaps plays a central role in age-related cognitive impairment. Yet, it is largely unknown whether Aβ accumulates in excitatory boutons. To assess the possibility that glutamatergic terminals are lost in AD patients, control and AD synaptosomes were immunolabeled for the most abundant vesicular glutamate transporters (VGluT1 and VGluT2) and quantified by flow cytometry and immunoblot methods. In post-mortem parietal cortex from aged control subjects, glutamatergic boutons are fairly abundant as approximately 40% were immunoreactive for VGluT1 (37%) and VGluT2 (39%). However, the levels of these specific markers of glutamatergic synapses were not significantly different among control and AD cases. To test the hypothesis that Aβ is associated with excitatory terminals, AD synaptosomes were double-labeled for Aβ and for VGluT1 and VGluT2, and analyzed by flow cytometry and confocal microscopy. Our study demonstrated that Aβ immunoreactivity (IR) was present in glutamatergic terminals of AD patients. Quantification of Aβ and VGluT1 in a large population of glutamatergic nerve terminals was performed by flow cytometry, showing that 42% of VGluT1 synaptosomes were immunoreactive for Aβ compared to 9% of VGluT1 synaptosomes lacking Aβ-IR. Percentage of VGluT2 synaptosomes immunoreactive for Aβ (21%) was significantly higher than VGluT2 synaptosomes lacking Aβ-IR (9%). Moreover, Aβ preferentially affects VGluT1 (42% positive) compared to VGluT2 terminals (21%). These data represent the first evidence of high levels of Aβ in excitatory boutons in AD cortex and support the hypothesis that Aβ may play a role in modulating glutamate transmission in AD terminals. PMID:21914482

Accuracy of geographically targeted internet advertisements on Google AdWords for recruitment in a randomized trial.

PubMed

Jones, Ray B; Goldsmith, Lesley; Williams, Christopher J; Kamel Boulos, Maged N

2012-06-20

Google AdWords are increasingly used to recruit people into research studies and clinical services. They offer the potential to recruit from targeted control areas in cluster randomized controlled trials (RCTs), but little is known about the feasibility of accurately targeting ads by location and comparing with control areas. To examine the accuracy and contamination of control areas by a location-targeted online intervention using Google AdWords in a pilot cluster RCT. Based on previous use of online cognitive behavioral therapy for depression and population size, we purposively selected 16 of the 121 British postcode areas and randomized them to three intervention and one (do-nothing) control arms. Two intervention arms included use of location-targeted AdWords, and we compared these with the do-nothing control arm. We did not raise the visibility of our research website to normal Web searches. Users who clicked on the ad were directed to our project website, which collected the computer Internet protocol (IP) address, date, and time. Visitors were asked for their postcode area and to complete the Patient Health Questionnaire (depression). They were then offered links to several online depression resources. Google Analytics largely uses IP methods to estimate location, but AdWords uses additional information. We compared locations assessed by (1) Analytics, and (2) as self-identified by users. Ads were shown 300,523 times with 4207 click-throughs. There were few site visits except through AdWord click-throughs. Both methods of location assessment agreed there was little contamination of control areas. According to Analytics, 69.75% (2617/3752) of participants were in intervention areas, only 0% (8/3752) in control areas, but 30.04% (1127/3752) in other areas. However, according to user-stated postcodes, only 20.7% (463/2237) were in intervention areas, 1% (22/2236) in control areas, but 78.31% (1751/2236) in other areas. Both location assessments suggested most leakage from the intervention arms was to nearby postcode areas. Analytics data differed from postcodes reported by participants. Analysis of a subset of 200/2236 records over 10 days comparing IP-estimated location with stated postcode suggested that Google AdWords targeted correctly in just half the cases. Analytics agreed with our assessment that, overall, one-third were wrongly targeted by AdWords. There appeared little evidence that people who bothered to give their postcode did not answer truthfully. Although there is likely to be substantial leakage from the targeted areas, if intervention and control areas are a sufficient distance apart, it is feasible to conduct a cluster RCT using online ads to target British postcode areas without significant contamination. Clinicaltrials.gov NCT01469689; http://clinicaltrials.gov/ct2/show/NCT01469689 (Archived by WebCite at http://www.webcitation.org/681iro5OU).

Atomoxetine Augmentation in a Case of Treatment Resistant Panic Disorder with Multiple Augments Failure: A Case Report

PubMed Central

Ram, Dushad; Patil, Shwetha; Gowdappa, Basavana; Rajalakshmi, Iyshwarya

2015-01-01

Atomoxetine, a selective norepinephrine inhibitor, is effective in comorbid anxiety and attention deficit hyperactivity disorder, however its role in panic disorder is unknown. We are presenting a case of panic disorder, who initially partially responded to clonazepam. When clonazepam was added with sertraline, escitalopram, desvenlafaxin, she did not improve significantly until paroxetine was added. When clonazepam-paroxetine combination was added with propranolol, etizolam, olanzepine, risperidone and amisulpride the symptom remission did not occur until a trial of Atomoxetine was done. PMID:26598594

The Effect of Adding Comorbidities to Current Centers for Disease Control and Prevention Central-Line-Associated Bloodstream Infection Risk-Adjustment Methodology.

PubMed

Jackson, Sarah S; Leekha, Surbhi; Magder, Laurence S; Pineles, Lisa; Anderson, Deverick J; Trick, William E; Woeltje, Keith F; Kaye, Keith S; Stafford, Kristen; Thom, Kerri; Lowe, Timothy J; Harris, Anthony D

2017-09-01

BACKGROUND Risk adjustment is needed to fairly compare central-line-associated bloodstream infection (CLABSI) rates between hospitals. Until 2017, the Centers for Disease Control and Prevention (CDC) methodology adjusted CLABSI rates only by type of intensive care unit (ICU). The 2017 CDC models also adjust for hospital size and medical school affiliation. We hypothesized that risk adjustment would be improved by including patient demographics and comorbidities from electronically available hospital discharge codes. METHODS Using a cohort design across 22 hospitals, we analyzed data from ICU patients admitted between January 2012 and December 2013. Demographics and International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) discharge codes were obtained for each patient, and CLABSIs were identified by trained infection preventionists. Models adjusting only for ICU type and for ICU type plus patient case mix were built and compared using discrimination and standardized infection ratio (SIR). Hospitals were ranked by SIR for each model to examine and compare the changes in rank. RESULTS Overall, 85,849 ICU patients were analyzed and 162 (0.2%) developed CLABSI. The significant variables added to the ICU model were coagulopathy, paralysis, renal failure, malnutrition, and age. The C statistics were 0.55 (95% CI, 0.51-0.59) for the ICU-type model and 0.64 (95% CI, 0.60-0.69) for the ICU-type plus patient case-mix model. When the hospitals were ranked by adjusted SIRs, 10 hospitals (45%) changed rank when comorbidity was added to the ICU-type model. CONCLUSIONS Our risk-adjustment model for CLABSI using electronically available comorbidities demonstrated better discrimination than did the CDC model. The CDC should strongly consider comorbidity-based risk adjustment to more accurately compare CLABSI rates across hospitals. Infect Control Hosp Epidemiol 2017;38:1019-1024.

Adenovirus infection in pediatric transplant recipients: are effective antiviral agents coming our way?

PubMed

Lopez, Santiago M C; Michaels, Marian G; Green, Michael

2018-05-24

Adenoviruses (AdVs) infection is a self-limited disease in the majority of immunocompetent children and adults, but can cause disseminated and life-threatening illness in immunocompromised hosts. This article will discuss therapeutic strategies for AdV infection in the pediatrics transplant recipient. Currently, there is no FDA approved antiviral therapy for AdV infection. Accordingly, the primary initial therapy would be decreasing immunosuppression, whenever possible. Cidofovir (CDV) is an antiviral drug whose use has been associated with significant reductions of AdV viral load and, in some series improved survival in recipients of solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT). However, its use is also associated with significant toxicity. Brincidofovir (BCV) is a lipid formulation of CDV, which has an improved oral bioavailability and favorable toxicity profile compared with CDV. However, studies have only shown modest benefit from BCV for AdV disease or viremia. Immunotherapy is a growing field in the management of this virus infection on HSCT patients with promising results. Current evidence support the use of CDV and BCV, as rescue therapy, on SOT and HSCT transplant patients. Immunotherapy had only been proven successful in HSCT patients, as an option for refractory cases or rescue therapy for AdV infection.

Optimizing the Logistics of Anaerobic Digestion of Manure

NASA Astrophysics Data System (ADS)

Ghafoori, Emad; Flynn, Peter C.

Electrical power production from the combustion of biogas from anaerobic digestion (AD) of manure is a means of recovering energy from animal waste. We evaluate the lowest cost method of moving material to and from centralized AD plants serving multiple confined feeding operations. Two areas are modeled, Lethbridge County, Alberta, Canada, an area of concentrated beef cattle feedlots, and Red Deer County, Alberta, a mixed-farming area with hog, dairy, chicken and beef cattle farms, and feedlots. We evaluate two types of AD plant: ones that return digestate to the source confined feeding operation for land spreading (current technology), and ones that process digestate to produce solid fertilizer and a dischargeable water stream (technology under development). We evaluate manure and digestate trucking, trucking of manure with return of digestate by pipelines, and pipelining of manure plus digestate. We compare the overall cost of power from these scenarios to farm or feedlot-based AD units. For a centralized AD plant with digestate return for land spreading the most economical transport option for manure plus digestate is by truck for the mixed-farming area and by pipelines for the concentrated feedlot area. For a centralized AD plant with digestate processing, the most economical transport option is trucking of manure for both cases.

Sensitivity derivatives for advanced CFD algorithm and viscous modelling parameters via automatic differentiation

NASA Technical Reports Server (NTRS)

Green, Lawrence L.; Newman, Perry A.; Haigler, Kara J.

1993-01-01

The computational technique of automatic differentiation (AD) is applied to a three-dimensional thin-layer Navier-Stokes multigrid flow solver to assess the feasibility and computational impact of obtaining exact sensitivity derivatives typical of those needed for sensitivity analyses. Calculations are performed for an ONERA M6 wing in transonic flow with both the Baldwin-Lomax and Johnson-King turbulence models. The wing lift, drag, and pitching moment coefficients are differentiated with respect to two different groups of input parameters. The first group consists of the second- and fourth-order damping coefficients of the computational algorithm, whereas the second group consists of two parameters in the viscous turbulent flow physics modelling. Results obtained via AD are compared, for both accuracy and computational efficiency with the results obtained with divided differences (DD). The AD results are accurate, extremely simple to obtain, and show significant computational advantage over those obtained by DD for some cases.

STM-induced light emission enhanced by weakly coupled organic ad-layers

NASA Astrophysics Data System (ADS)

Cottin, M. C.; Ekici, E.; Bobisch, C. A.

2018-03-01

We analyze the light emission induced by the tunneling current flowing in a scanning tunneling microscopy experiment. In particular, we study the influence of organic ad-layers on the light emission on the initial monolayer of bismuth (Bi) on Cu(111) in comparison to the well-known case of organic ad-layers on Ag(111). On the Bi/Cu(111)-surface, we find that the scanning tunneling microscopy-induced light emission is considerably enhanced if an organic layer, e.g., the fullerene C60 or the perylene derivate perylene-tetracarboxylic-dianhydride, is introduced into the tip-sample junction. The enhancement can be correlated with a peculiarly weak interaction between the adsorbed molecules and the underlying Bi/Cu(111) substrate as compared to the Ag(111) substrate. This allows us to efficiently enhance and tune the coupling of the tunneling current to localized excitations of the tip-sample junction, which in turn couple to radiative decay channels.

Hypothermia and Alzheimer's disease neuropathogenic pathways.

PubMed

Whittington, R A; Papon, M-A; Chouinard, F; Planel, E

2010-12-01

Alzheimer's disease (AD) remains a major health problem, and accounts for 50 to 60% of all cases of dementia. The two histopathological hallmarks of AD are senile plaques, composed of the β-amyloid peptide (Aβ), and intraneuronal neurofibrillary tangles composed of abnormally hyperphosphorylated tau protein. Only a small proportion of AD is due to mutations in the genome of patients, the large majority of cases being of late onset and sporadic in origin. The relative contribution of genetics and environment to the sporadic cases is unclear, but they are accepted to be of multifactorial origin. This means that genetic and environmental factors can interact together to induce or accelerate the disease. Among environmental factors, studies suggest that hypothermia may contribute to the development and exacerbation AD. Here, we review the preclinical data involving hypothermia with tau and Aβ, as well as clinical evidence implicating hypothermia in the development of AD.

Systematic Analysis of Long Noncoding RNAs in the Senescence-accelerated Mouse Prone 8 Brain Using RNA Sequencing.

PubMed

Zhang, Shuai; Qin, Chunxia; Cao, Guoqiong; Xin, Wenfeng; Feng, Chengqiang; Zhang, Wensheng

2016-08-02

Long noncoding RNAs (lncRNAs) may play an important role in Alzheimer's disease (AD) pathogenesis. However, despite considerable research in this area, the comprehensive and systematic understanding of lncRNAs in AD is still limited. The emergence of RNA sequencing provides a predictor and has incomparable advantage compared with other methods, including microarray. In this study, we identified lncRNAs in a 7-month-old mouse brain through deep RNA sequencing using the senescence-accelerated mouse prone 8 (SAMP8) and senescence-accelerated mouse resistant 1 (SAMR1) models. A total of 599,985,802 clean reads and 23,334 lncRNA transcripts were obtained. Then, we identified 97 significantly upregulated and 114 significantly downregulated lncRNA transcripts from all cases in SAMP8 mice relative to SAMR1 mice. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses revealed that these significantly dysregulated lncRNAs were involved in regulating the development of AD from various angles, such as nerve growth factor term (GO: 1990089), mitogen-activated protein kinase signaling pathway, and AD pathway. Furthermore, the most probable AD-associated lncRNAs were predicted and listed in detail. Our study provided the systematic dissection of lncRNA profiling in SAMP8 mouse brain and accelerated the development of lncRNA biomarkers in AD. These attracting biomarkers could provide significant insights into AD therapy in the future.

Association of GSK3B With Alzheimer Disease and Frontotemporal Dementia

PubMed Central

Schaffer, Barbara A. J.; Bertram, Lars; Miller, Bruce L.; Mullin, Kristina; Weintraub, Sandra; Johnson, Nancy; Bigio, Eileen H.; Mesulam, Marsel; Wiedau-Pazos, Martina; Jackson, George R.; Cummings, Jeffrey L.; Cantor, Rita M.; Levey, Allan I.; Tanzi, Rudolph E.; Geschwind, Daniel H.

2009-01-01

Background Deposits of abnormally hyperphosphorylated tau are a hallmark of several dementias, including Alzheimer disease (AD), and about 10% of familial frontotemporal dementia (FTD) cases are caused by mutations in the tau gene. As a known tau kinase, GSK3B is a promising candidate gene in the remaining cases of FTD and in AD, for which tau mutations have not been found. Objective To examine the promoter of GSK3B and all 12 exons, including the surrounding intronic sequence, in patients with FTD, patients with AD, and aged healthy subjects to identify single-nucleotide polymorphisms associated with disease. Design, Setting, and Participants Single-nucleotide polymorphism frequency was examined in a case-control cohort of 48 patients with probable AD, 102 patients with FTD, 38 patients with primary progressive aphasia, and 85 aged healthy subjects. Results were followed up in 2 independent AD family samples consisting of 437 multiplex families with AD (National Institute of Mental Health Genetics Initiative AD Study) or 150 sibships discordant for AD (Consortium on Alzheimer’s Genetics Study). Results Several rare sequence variants in GSK3B were identified in the case-control study. An intronic polymorphism (IVS2−68G>A) occurred at more than twice the frequency among patients with FTD (10.8%) and patients with AD (14.6%) than in aged healthy subjects (4.1%). The polymorphism showed association with disease in both follow-up samples independently, although only the Consortium on Alzheimer’s Genetics sample showed the same direction of association as the case-control sample. Conclusions To our knowledge, this is the first evidence that a gene known to be involved in tau phosphorylation, GSK3B, is associated with risk for primary neurodegenerative dementias. This supports previous work in animal models suggesting that such genes are therapeutic targets. PMID:18852354

Capillary CAA and perivascular Aβ-deposition: two distinct features of Alzheimer's disease pathology.

PubMed

Attems, Johannes; Yamaguchi, Haruyasu; Saido, Takaomi C; Thal, Dietmar Rudolf

2010-12-15

Cerebral amyloid angiopathy (CAA) is frequently seen in Alzheimer's disease (AD) cases and represents one of its histopathological hallmarks. CAA is characterized by amyloid β-protein (Aβ) deposits within vessel walls. In addition to arteries and veins capillaries can also be affected. Aβ deposition into the capillary wall is, thereby, known as capillary CAA (capCAA) and strongly associated with the apolipoprotein E APOEε4 allele as a risk factor. Aβ deposits along the pericapillary glia limitans are described as pericapillary Aβ (pericapAβ: synonymous with pericapillary CAA in other studies). Here, we studied the relationship between pericapAβ and capCAA in 58 human autopsy cases. Although pericapAβ and capCAA were more frequently found in AD cases compared to controls and although they exhibited a correlation to one another, detailed analysis revealed that there is a significant number of cases with pericapAβ lacking capCAA and vice versa. Moreover, single capillaries show either both pathologies or pericapAβ or capCAA only. There was no local association between these pathologies when analyzing multiple capillaries in each given case. Moreover, pericapAβ predominantly exhibited Aβ(42) whereas capCAA contained both Aβ(42) and Aβ(40). These differences as well as differences in the related astroglial reaction indicate that pericapAβ and capCAA are not directly linked. PericapAβ appears to represent initial Aβ accumulation along the glia limitans that is involved in the perivascular drainage of apoE and Aβ regardless of the APOE genotype whereas capCAA could be explained by a limited transendothelial clearance of apoE4-Aβ complexes compared to apoE2/3-Aβ complexes. Copyright © 2010 Elsevier B.V. All rights reserved.

The Legal System and Alzheimer's Disease: Social Workers and Lawyers' Perceptions and Experiences.

PubMed

Werner, Perla; Doron, Israel Issi

2016-01-01

The expected increase in the number of people living with Alzheimer's disease (AD) worldwide will be accompanied by an increase in the number of cases involving persons with AD brought up to the courts. This study examined the perceptions and experiences of social workers and lawyers regarding these cases. Three focus groups including social workers and lawyers (n = 26) were conducted. Two main themes were raised by the participants: (a) the role of social workers and lawyers in court cases regarding AD, and (b) the need for improving legal encounters involving persons with AD. Similarities and differences were found in both professionals' interpretations of these shared themes. Results of this study emphasize the need for increasing the knowledge and interprofessional training provided to social workers and lawyers involved in legal cases dealing with issues involving persons with Alzheimer's disease.

Neuropsychiatric symptoms in Alzheimer's disease and vascular dementia.

PubMed

Echávarri, Carmen; Burgmans, Saartje; Uylings, Harry; Cuesta, Manuel J; Peralta, Victor; Kamphorst, Wouter; Rozemuller, Annemieke J M; Verhey, Frans R J

2013-01-01

Neuropsychiatric symptoms (NPSs) have a large impact on the quality of life of patients with dementia. A few studies have compared neuropsychiatric disturbances between dementia subtypes, but the results were conflicting. In the present study, we investigated whether the prevalence of NPSs differs between Alzheimer's disease (AD) and vascular dementia (VaD). The merit of our study is that we used clinical as well as histopathological information to differentiate between dementia subtypes. This retrospective descriptive study comprised 80 brains obtained from donors to the Netherlands Brain Bank between 1984 and 2010. These donors were diagnosed postmortem with AD (n = 40) or VaD (n = 40). We assessed the presence of NPSs by reviewing the information found in the patients' medical files. The most prevalent symptom in the sample as a whole was agitation (45 cases, 57.0%), followed by depression (33, 41.2%) and anxiety (28, 35.4%). Our study tried to contribute to the discussion by including, for the first time in the literature, a sample of AD and VaD patients with neuropathologically confirmed diagnoses. Since no significant differences were found between AD and VaD patients, we suggest that the prevalence of NPSs cannot be predicted from the diagnosis of AD or VaD.

Rare coding variants in Phospholipase D3 (PLD3) confer risk for Alzheimer's disease

PubMed Central

Cruchaga, Carlos; Benitez, Bruno A.; Cai, Yefei; Guerreiro, Rita; Harari, Oscar; Norton, Joanne; Budde, John; Bertelsen, Sarah; Jeng, Amanda T.; Cooper, Breanna; Skorupa, Tara; Carrell, David; Levitch, Denise; Hsu, Simon; Choi, Jiyoon; Ryten, Mina; Sassi, Celeste; Bras, Jose; Gibbs, Raphael J.; Hernandez, Dena G.; Lupton, Michelle K.; Powell, John; Forabosco, Paola; Ridge, Perry G.; Corcoran, Christopher D.; Tschanz, JoAnn T.; Norton, Maria C.; Munger, Ronald G.; Schmutz, Cameron; Leary, Maegan; Demirci, F. Yesim; Bamne, Mikhil N.; Wang, Xingbin; Lopez, Oscar L.; Ganguli, Mary; Medway, Christopher; Turton, James; Lord, Jenny; Braae, Anne; Barber, Imelda; Brown, Kristelle; Pastor, Pau; Lorenzo-Betancor, Oswaldo; Brkanac, Zoran; Scott, Erick; Topol, Eric; Morgan, Kevin; Rogaeva, Ekaterina; Singleton, Andy; Hardy, John; Kamboh, M. Ilyas; George-Hyslop, Peter St; Cairns, Nigel; Morris, John C.; Kauwe, John S.K.; Goate, Alison M.

2014-01-01

Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimer's disease (LOAD)1,2. These common variants have replicable but small effects on LOAD risk and generally do not have obvious functional effects. Low-frequency coding variants, not detected by GWAS, are predicted to include functional variants with larger effects on risk. To identify low frequency coding variants with large effects on LOAD risk, we performed whole exome-sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large case-control datasets. A rare variant in PLD3 (phospholipase-D family, member 3, rs145999145; V232M) segregated with disease status in two independent families and doubled risk for AD in seven independent case-control series (V232M meta-analysis; OR= 2.10, CI=1.47-2.99; p= 2.93×10-5, 11,354 cases and controls of European-descent). Gene-based burden analyses in 4,387 cases and controls of European-descent and 302 African American cases and controls, with complete sequence data for PLD3, indicate that several variants in this gene increase risk for AD in both populations (EA: OR= 2.75, CI=2.05-3.68; p=1.44×10-11, AA: OR= 5.48, CI=1.77-16.92; p=1.40×10-3). PLD3 is highly expressed in brain regions vulnerable to AD pathology, including hippocampus and cortex, and is expressed at lower levels in neurons from AD brains compared to control brains (p=8.10×10-10). Over-expression of PLD3 leads to a significant decrease in intracellular APP and extracellular Aβ42 and Aβ40, while knock-down of PLD3 leads to a significant increase in extracellular Aβ42 and Aβ40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a two-fold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may be used to identify rare variants with large effects on risk for disease or other complex traits. PMID:24336208

The added benefits and efficacy of atherectomy in the lower limb.

PubMed

VAN DEN Berg, Jos C

2016-08-01

Atherectomy has been used as an adjunct therapy for balloon angioplasty and/or stent placement in the superficial femoral artery for many years, but has never gained global popularity in the treatment of peripheral arterial disease, most probably related to the conflicting results as published in the literature. Novel techniques that have been developed over the past years are yielding promising results in the infrainguinal region. This paper will describe the added benefits of atherectomy as compared to plain old balloon angioplasty and bail-out bare-metal stenting, both in the treatment of primary lesions of the superficial femoral artery as well as in cases of in-stent restenosis.

Probability of identity by descent in metapopulations.

PubMed Central

Kaj, I; Lascoux, M

1999-01-01

Equilibrium probabilities of identity by descent (IBD), for pairs of genes within individuals, for genes between individuals within subpopulations, and for genes between subpopulations are calculated in metapopulation models with fixed or varying colony sizes. A continuous-time analog to the Moran model was used in either case. For fixed-colony size both propagule and migrant pool models were considered. The varying population size model is based on a birth-death-immigration (BDI) process, to which migration between colonies is added. Wright's F statistics are calculated and compared to previous results. Adding between-island migration to the BDI model can have an important effect on the equilibrium probabilities of IBD and on Wright's index. PMID:10388835

An improved scheme on decoy-state method for measurement-device-independent quantum key distribution

PubMed Central

Wang, Dong; Li, Mo; Guo, Guang-Can; Wang, Qin

2015-01-01

Quantum key distribution involving decoy-states is a significant application of quantum information. By using three-intensity decoy-states of single-photon-added coherent sources, we propose a practically realizable scheme on quantum key distribution which approaches very closely the ideal asymptotic case of an infinite number of decoy-states. We make a comparative study between this scheme and two other existing ones, i.e., two-intensity decoy-states with single-photon-added coherent sources, and three-intensity decoy-states with weak coherent sources. Through numerical analysis, we demonstrate the advantages of our scheme in secure transmission distance and the final key generation rate. PMID:26463580

New categories for traditional medicine in the Economic Botany Data Collection Standard.

PubMed

Gruca, Marta; Cámara-Leret, Rodrigo; Macía, Manuel J; Balslev, Henrik

2014-09-11

The Economic Botany Data Collection Standard (EBDCS) has been successfully followed by ethnobotanists investigating plant uses in many parts of the world. However, we have encountered some cases in our study of traditional medicine where the standard seems incomplete and inaccurate when it is applied to plant uses of rural or indigenous societies in developing countries. We propose two categories to be added to the EBDCS: Cultural Diseases and Disorders, and Ritual/Magical Uses. Adding these categories, we believe will give a more accurate insight into traditional medicine and will contribute to developing an integrative ethnomedicinal data collection protocol, which will make ethnomedicinal studies more comparable. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Computer aided system engineering and analysis (CASE/A) modeling package for ECLS systems - An overview

NASA Technical Reports Server (NTRS)

Dalee, Robert C.; Bacskay, Allen S.; Knox, James C.

1990-01-01

An overview of the CASE/A-ECLSS series modeling package is presented. CASE/A is an analytical tool that has supplied engineering productivity accomplishments during ECLSS design activities. A components verification program was performed to assure component modeling validity based on test data from the Phase II comparative test program completed at the Marshall Space Flight Center. An integrated plotting feature has been added to the program which allows the operator to analyze on-screen data trends or get hard copy plots from within the CASE/A operating environment. New command features in the areas of schematic, output, and model management, and component data editing have been incorporated to enhance the engineer's productivity during a modeling program.

Mitochondrial DNA copy numbers in pyramidal neurons are decreased and mitochondrial biogenesis transcriptome signaling is disrupted in Alzheimer's disease hippocampi.

PubMed

Rice, Ann C; Keeney, Paula M; Algarzae, Norah K; Ladd, Amy C; Thomas, Ravindar R; Bennett, James P

2014-01-01

Alzheimer's disease (AD) is the major cause of adult-onset dementia and is characterized in its pre-diagnostic stage by reduced cerebral cortical glucose metabolism and in later stages by reduced cortical oxygen uptake, implying reduced mitochondrial respiration. Using quantitative PCR we determined the mitochondrial DNA (mtDNA) gene copy numbers from multiple groups of 15 or 20 pyramidal neurons, GFAP(+) astrocytes and dentate granule neurons isolated using laser capture microdissection, and the relative expression of mitochondrial biogenesis (mitobiogenesis) genes in hippocampi from 10 AD and 9 control (CTL) cases. AD pyramidal but not dentate granule neurons had significantly reduced mtDNA copy numbers compared to CTL neurons. Pyramidal neuron mtDNA copy numbers in CTL, but not AD, positively correlated with cDNA levels of multiple mitobiogenesis genes. In CTL, but not in AD, hippocampal cDNA levels of PGC1α were positively correlated with multiple downstream mitobiogenesis factors. Mitochondrial DNA copy numbers in pyramidal neurons did not correlate with hippocampal Aβ1-42 levels. After 48 h exposure of H9 human neural stem cells to the neurotoxic fragment Aβ25-35, mtDNA copy numbers were not significantly altered. In summary, AD postmortem hippocampal pyramidal neurons have reduced mtDNA copy numbers. Mitochondrial biogenesis pathway signaling relationships are disrupted in AD, but are mostly preserved in CTL. Our findings implicate complex alterations of mitochondria-host cell relationships in AD.

Prevalence of Hippocampal Sclerosis in a Clinicopathologically Characterized Cohort.

PubMed

Malek-Ahmadi, Michael; Kahlon, Vickram; Adler, Charles H; Obradov, Aleksandra; Thind, Kabir; Shill, Holly A; Sue, Lucia I; Caviness, John N; Jacobson, Sandra; Sabbagh, Marwan N

2013-01-01

Hippocampal sclerosis (HS) is a neuropathological finding that frequently occurs with pathologies, such as Alzheimer's disease (AD). Prevalence estimates of HS in autopsy-confirmed dementia samples have varied between 0.4% and 24.5%. However, the prevalence of HS within other pathologic groups has not been well characterized. Utilizing a sample of 910 prospectively followed and clinicopathologically confirmed dementia cases, we determined the prevalence of HS among the sample and within specific pathologic groups. HS prevalence of the sample was compared to reported HS prevalence rates in other autopsy-confirmed dementia samples. The age range of the sample was 43 to 106 years, with a mean of 81.49±8.45. Of the 910 cases, 505 were male and 405 were female. For the entire sample, the average educational level was 14.59±2.65years. Of the 910 individuals, 47 (5.16%) cases had HS pathology present at autopsy. Among the 561 AD cases, 26 (4.43%) had HS pathology present. The frontotemporal dementia (FTD)/Pick's group had the highest percentage of cases with HS pathology (23.08%) followed by primary progressive aphasia (PPA) (16.67%) and Parkinson's disease with dementia (PDD) (5.34%). The HS prevalence rate of this study was not significantly different from all but 2 studies. The prevalence of HS pathology in this sample of autopsy-confirmed dementia cases was similar to other reported HS prevalence rates. This study is the first to report the presence of HS pathology in PDD cases.

Analysis of copy number variation in Alzheimer's disease in a cohort of clinically characterized and neuropathologically verified individuals.

PubMed

Swaminathan, Shanker; Huentelman, Matthew J; Corneveaux, Jason J; Myers, Amanda J; Faber, Kelley M; Foroud, Tatiana; Mayeux, Richard; Shen, Li; Kim, Sungeun; Turk, Mari; Hardy, John; Reiman, Eric M; Saykin, Andrew J

2012-01-01

Copy number variations (CNVs) are genomic regions that have added (duplications) or deleted (deletions) genetic material. They may overlap genes affecting their function and have been shown to be associated with disease. We previously investigated the role of CNVs in late-onset Alzheimer's disease (AD) and mild cognitive impairment using Alzheimer's Disease Neuroimaging Initiative (ADNI) and National Institute of Aging-Late Onset AD/National Cell Repository for AD (NIA-LOAD/NCRAD) Family Study participants, and identified a number of genes overlapped by CNV calls. To confirm the findings and identify other potential candidate regions, we analyzed array data from a unique cohort of 1617 Caucasian participants (1022 AD cases and 595 controls) who were clinically characterized and whose diagnosis was neuropathologically verified. All DNA samples were extracted from brain tissue. CNV calls were generated and subjected to quality control (QC). 728 cases and 438 controls who passed all QC measures were included in case/control association analyses including candidate gene and genome-wide approaches. Rates of deletions and duplications did not significantly differ between cases and controls. Case-control association identified a number of previously reported regions (CHRFAM7A, RELN and DOPEY2) as well as a new gene (HLA-DRA). Meta-analysis of CHRFAM7A indicated a significant association of the gene with AD and/or MCI risk (P = 0.006, odds ratio = 3.986 (95% confidence interval 1.490-10.667)). A novel APP gene duplication was observed in one case sample. Further investigation of the identified genes in independent and larger samples is warranted.

Biological evaluation of partially stabilized zirconia added HA/HDPE composites with osteoblast and fibroblast cell lines.

PubMed

Yari Sadi, Amir; Shokrgozar, Mohammad Ali; Homaeigohar, Seyed Shahin; Khavandi, Alireza

2008-06-01

In the present study, the biocompatibility of partially stabilized zirconia (PSZ) added hydroxyapatite (HA)--high density polyethylene (HDPE) composites was evaluated by proliferation and cell attachment assays on two osteoblast cell lines (G-292, Saos-2) and a type of fibroblast cell isolated from bone tissue namely HBF in different time intervals. Cell-material interactions on the surface of the composites were observed by scanning electron microscopy (SEM). The effect of composites on the behavior of osteoblast and fibroblast cells was compared with those of HDPE and Tissue Culture Poly Styrene (TPS) (as negative control) samples. Results showed that the composite samples supported a higher proliferation rate of osteoblast cells in the presence of composite samples as compared to the HDPE and TPS samples after 3, 7 and 14 days of incubation period. It was showed that an equal or in some cases an even higher proliferation rate of G-292 and Saos-2 osteoblast cells on composite samples in compare to negative controls in culture period (P < 0.05). The number of adhered cells on the composite samples was equal and in some cases higher than the number adhered on the HDPE and TPS samples after the above mentioned incubation periods (P < 0.05). Adhered cells presented a normal morphology by SEM and many of the cells were seen to be undergoing cell division.

Antipsychotic Use and Risk of Hospitalization or Death Due to Pneumonia in Persons With and Those Without Alzheimer Disease.

PubMed

Tolppanen, Anna-Maija; Koponen, Marjaana; Tanskanen, Antti; Lavikainen, Piia; Sund, Reijo; Tiihonen, Jari; Hartikainen, Sirpa; Taipale, Heidi

2016-12-01

The use of antipsychotic agents has been associated with increased pneumonia risk, but although people with dementia are particularly susceptible to pneumonia, only one small study has assessed the risk of pneumonia in relation to the use of antipsychotic agents among people with Alzheimer disease (AD). We investigated whether the incident use of antipsychotic agents, or specific antipsychotic agents, are related to a higher risk of hospitalization or death due to pneumonia in the Medication and Alzheimer Disease (MEDALZ) cohort. The cohort includes all individuals with AD who received a clinically verified AD diagnosis in Finland in 2005 to 2011 (N = 60,584; incident pneumonia, n = 12,225). A matched comparison cohort without AD (N = 60,584; incident pneumonia, n = 6,195) was used to compare the magnitude of risk. Results were adjusted for a propensity score derived from comorbidities, concomitant medications, and sociodemographic characteristics. Sensitivity analyses with case-crossover design were conducted. The use of antipsychotic agents was associated with a higher risk of pneumonia (adjusted hazard ratio [HR], 2.01; 95% CI, 1.90-2.13) in the AD cohort and a somewhat higher risk in the non-AD cohort (adjusted HR, 3.43; 95% CI, 2.99-3.93). Similar results were observed with case-crossover analyses (OR, 2.02; 95% CI, 1.75-2.34 in the AD cohort and OR, 2.59; 95% CI, 1.77-3.79 in the non-AD cohort). The three most commonly used antipsychotic agents (quetiapine, risperidone, haloperidol) had similar associations with pneumonia risk. Regardless of applied study design, treatment duration, or the choice of drug, the use of antipsychotic agents was associated with a higher risk of pneumonia. With observational data, we cannot fully rule out a shared causality between pneumonia and the use of antipsychotic agents, but the risk to benefit balance should be considered when antipsychotic agents are prescribed. Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Analysis of neurodegenerative Mendelian genes in clinically diagnosed Alzheimer Disease

PubMed Central

Fernández, Maria Victoria; Kim, Jong Hun; Budde, John P.; Black, Kathleen; Medvedeva, Alexandra; Saef, Ben; Del-Aguila, Jorge; Ibañez, Laura; Dube, Umber; Harari, Oscar; Norton, Joanne; Chasse, Rachel; Morris, John C.; Goate, Alison

2017-01-01

Alzheimer disease (AD), Frontotemporal lobar degeneration (FTD), Amyotrophic lateral sclerosis (ALS) and Parkinson disease (PD) have a certain degree of clinical, pathological and molecular overlap. Previous studies indicate that causative mutations in AD and FTD/ALS genes can be found in clinical familial AD. We examined the presence of causative and low frequency coding variants in the AD, FTD, ALS and PD Mendelian genes, in over 450 families with clinical history of AD and over 11,710 sporadic cases and cognitive normal participants from North America. Known pathogenic mutations were found in 1.05% of the sporadic cases, in 0.69% of the cognitively normal participants and in 4.22% of the families. A trend towards enrichment, albeit non-significant, was observed for most AD, FTD and PD genes. Only PSEN1 and PINK1 showed consistent association with AD cases when we used ExAC as the control population. These results suggest that current study designs may contain heterogeneity and contamination of the control population, and that current statistical methods for the discovery of novel genes with real pathogenic variants in complex late onset diseases may be inadequate or underpowered to identify genes carrying pathogenic mutations. PMID:29091718

Analysis of neurodegenerative Mendelian genes in clinically diagnosed Alzheimer Disease.

PubMed

Fernández, Maria Victoria; Kim, Jong Hun; Budde, John P; Black, Kathleen; Medvedeva, Alexandra; Saef, Ben; Deming, Yuetiva; Del-Aguila, Jorge; Ibañez, Laura; Dube, Umber; Harari, Oscar; Norton, Joanne; Chasse, Rachel; Morris, John C; Goate, Alison; Cruchaga, Carlos

2017-11-01

Alzheimer disease (AD), Frontotemporal lobar degeneration (FTD), Amyotrophic lateral sclerosis (ALS) and Parkinson disease (PD) have a certain degree of clinical, pathological and molecular overlap. Previous studies indicate that causative mutations in AD and FTD/ALS genes can be found in clinical familial AD. We examined the presence of causative and low frequency coding variants in the AD, FTD, ALS and PD Mendelian genes, in over 450 families with clinical history of AD and over 11,710 sporadic cases and cognitive normal participants from North America. Known pathogenic mutations were found in 1.05% of the sporadic cases, in 0.69% of the cognitively normal participants and in 4.22% of the families. A trend towards enrichment, albeit non-significant, was observed for most AD, FTD and PD genes. Only PSEN1 and PINK1 showed consistent association with AD cases when we used ExAC as the control population. These results suggest that current study designs may contain heterogeneity and contamination of the control population, and that current statistical methods for the discovery of novel genes with real pathogenic variants in complex late onset diseases may be inadequate or underpowered to identify genes carrying pathogenic mutations.

77 FR 11421 - Airworthiness Directives; Pratt & Whitney Canada, Auxiliary Power Units

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-27

... separation of the rear gas generator case and release of high energy debris. This proposed AD would require modifications of the rear gas generator case, exhaust duct support, and turbine exhaust duct flanges. We are proposing this AD to prevent separation of the rear gas generator case and release of high energy debris...

Vitamin D, Homocysteine, and Folate in Subcortical Vascular Dementia and Alzheimer Dementia.

PubMed

Moretti, Rita; Caruso, Paola; Dal Ben, Matteo; Conti, Corrado; Gazzin, Silvia; Tiribelli, Claudio

2017-01-01

Dementia is a worldwide health problem which affects millions of patients; Alzheimer's disease (AD) and subcortical vascular dementia (sVAD) are the two most frequent forms of its presentation. As no definite therapeutic options have been discovered, different risk factors for cognitive impairment have been searched for potential therapies. This report focuses on the possible evidence that vitamin D deficiency and hyper-homocysteinemia can be considered as two important factors for the development or the progression of neurodegenerative or vascular pathologies. To this end, we assessed: the difference in vascular risk factors and vitamin D-OH25 levels among groups of sVAD, AD, and healthy age-matched controls; the association of folate, B12, homocysteine, and vitamin D with sVAD/AD and whether a deficiency of vitamin D and an increment in homocysteine levels may be related to neurodegenerative or vessel damages. The commonly-considered vascular risk factors were collected in 543 patients and compared with those obtained from a healthy old volunteer population. ANOVA group comparison showed that vitamin D deficiency was present in demented cases, as well as low levels of folate and high levels of homocysteine, more pronounced in sVAD cases. The statistical models we employed, with regression models built, and adjustments for biochemical, demographic and neuropsychiatric scores, confirmed the association between the three measures (folate decrease, hyperhomocysteinemia and vitamin D decrease) and dementia, more pronounced in sVAD than in AD.

Longitudinal MR cortical thinning of individuals and its correlation with PET metabolic reduction: a measurement consistency and correctness studies

NASA Astrophysics Data System (ADS)

Lin, Zhongmin S.; Avinash, Gopal; McMillan, Kathryn; Yan, Litao; Minoshima, Satoshi

2014-03-01

Cortical thinning and metabolic reduction can be possible imaging biomarkers for Alzheimer's disease (AD) diagnosis and monitoring. Many techniques have been developed for the cortical measurement and widely used for the clinical statistical studies. However, the measurement consistency of individuals, an essential requirement for a clinically useful technique, requires proper further investigation. Here we leverage our previously developed BSIM technique 1 to measure cortical thickness and thinning and use it with longitudinal MRI from ADNI to investigate measurement consistency and spatial resolution. 10 normal, 10 MCI, and 10 AD subjects in their 70s were selected for the study. Consistent cortical thinning patterns were observed in all baseline and follow up images. Rapid cortical thinning was shown in some MCI and AD cases. To evaluate the correctness of the cortical measurement, we compared longitudinal cortical thinning with clinical diagnosis and longitudinal PET metabolic reduction measured using 3D-SSP technique2 for the same person. Longitudinal MR cortical thinning and corresponding PET metabolic reduction showed high level pattern similarity revealing certain correlations worthy of further studies. Severe cortical thinning that might link to disease conversion from MCI to AD was observed in two cases. In summary, our results suggest that consistent cortical measurements using our technique may provide means for clinical diagnosis and monitoring at individual patient's level and MR cortical thinning measurement can complement PET metabolic reduction measurement.

Survival in Alzheimer disease

PubMed Central

Helzner, E P.; Scarmeas, N; Cosentino, S; Tang, M X.; Schupf, N; Stern, Y

2008-01-01

Objective: To describe factors associated with survival in Alzheimer disease (AD) in a multiethnic, population-based longitudinal study. Methods: AD cases were identified in the Washington Heights Inwood Columbia Aging Project, a longitudinal, community-based study of cognitive aging in Northern Manhattan. The sample comprised 323 participants who were initially dementia-free but developed AD during study follow-up (incident cases). Participants were followed for an average of 4.1 (up to 12.6) years. Possible factors associated with shorter lifespan were assessed using Cox proportional hazards models with attained age as the time to event (time from birth to death or last follow-up). In subanalyses, median postdiagnosis survival durations were estimated using postdiagnosis study follow-up as the timescale. Results: The mortality rate was 10.7 per 100 person-years. Mortality rates were higher among those diagnosed at older ages, and among Hispanics compared to non-Hispanic whites. The median lifespan of the entire sample was 92.2 years (95% CI: 90.3, 94.1). In a multivariable-adjusted Cox model, history of diabetes and history of hypertension were independently associated with a shorter lifespan. No differences in lifespan were seen by race/ethnicity after multivariable adjustment. The median postdiagnosis survival duration was 3.7 years among non-Hispanic whites, 4.8 years among African Americans, and 7.6 years among Hispanics. Conclusion: Factors influencing survival in Alzheimer disease include race/ethnicity and comorbid diabetes and hypertension. GLOSSARY AD = Alzheimer disease; NDI = National Death Index; WHICAP = Washington Heights Inwood Columbia Aging Project. PMID:18981370

Extended phenotype and clinical subgroups in unilateral Meniere disease: A cross-sectional study with cluster analysis.

PubMed

Frejo, L; Martin-Sanz, E; Teggi, R; Trinidad, G; Soto-Varela, A; Santos-Perez, S; Manrique, R; Perez, N; Aran, I; Almeida-Branco, M S; Batuecas-Caletrio, A; Fraile, J; Espinosa-Sanchez, J M; Perez-Guillen, V; Perez-Garrigues, H; Oliva-Dominguez, M; Aleman, O; Benitez, J; Perez, P; Lopez-Escamez, J A

2017-12-01

To define clinical subgroups by cluster analysis in patients with unilateral Meniere disease (MD) and to compare them with the clinical subgroups found in bilateral MD. A cross-sectional study with a two-step cluster analysis. A tertiary referral multicenter study. Nine hundred and eighty-eight adult patients with unilateral MD. best predictors to define clinical subgroups with potential different aetiologies. We established five clusters in unilateral MD. Group 1 is the most frequently found, includes 53% of patients, and it is defined as the sporadic, classic MD without migraine and without autoimmune disorder (AD). Group 2 is found in 8% of patients, and it is defined by hearing loss, which antedates the vertigo episodes by months or years (delayed MD), without migraine or AD in most of cases. Group 3 involves 13% of patients, and it is considered familial MD, while group 4, which includes 15% of patients, is linked to the presence of migraine in all cases. Group 5 is found in 11% of patients and is defined by a comorbid AD. We found significant differences in the distribution of AD in clusters 3, 4 and 5 between patients with uni- and bilateral MD. Cluster analysis defines clinical subgroups in MD, and it extends the phenotype beyond audiovestibular symptoms. This classification will help to improve the phenotyping in MD and facilitate the selection of patients for randomised clinical trials. © 2017 John Wiley & Sons Ltd.

Accuracy of Geographically Targeted Internet Advertisements on Google Adwords for Recruitment in a Randomized Trial

PubMed Central

Goldsmith, Lesley; Williams, Christopher J; Kamel Boulos, Maged N

2012-01-01

Background Google AdWords are increasingly used to recruit people into research studies and clinical services. They offer the potential to recruit from targeted control areas in cluster randomized controlled trials (RCTs), but little is known about the feasibility of accurately targeting ads by location and comparing with control areas. Objective To examine the accuracy and contamination of control areas by a location-targeted online intervention using Google AdWords in a pilot cluster RCT. Methods Based on previous use of online cognitive behavioral therapy for depression and population size, we purposively selected 16 of the 121 British postcode areas and randomized them to three intervention and one (do-nothing) control arms. Two intervention arms included use of location-targeted AdWords, and we compared these with the do-nothing control arm. We did not raise the visibility of our research website to normal Web searches. Users who clicked on the ad were directed to our project website, which collected the computer Internet protocol (IP) address, date, and time. Visitors were asked for their postcode area and to complete the Patient Health Questionnaire (depression). They were then offered links to several online depression resources. Google Analytics largely uses IP methods to estimate location, but AdWords uses additional information. We compared locations assessed by (1) Analytics, and (2) as self-identified by users. Results Ads were shown 300,523 times with 4207 click-throughs. There were few site visits except through AdWord click-throughs. Both methods of location assessment agreed there was little contamination of control areas. According to Analytics, 69.75% (2617/3752) of participants were in intervention areas, only 0% (8/3752) in control areas, but 30.04% (1127/3752) in other areas. However, according to user-stated postcodes, only 20.7% (463/2237) were in intervention areas, 1% (22/2236) in control areas, but 78.31% (1751/2236) in other areas. Both location assessments suggested most leakage from the intervention arms was to nearby postcode areas. Analytics data differed from postcodes reported by participants. Analysis of a subset of 200/2236 records over 10 days comparing IP-estimated location with stated postcode suggested that Google AdWords targeted correctly in just half the cases. Analytics agreed with our assessment that, overall, one-third were wrongly targeted by AdWords. There appeared little evidence that people who bothered to give their postcode did not answer truthfully. Conclusions Although there is likely to be substantial leakage from the targeted areas, if intervention and control areas are a sufficient distance apart, it is feasible to conduct a cluster RCT using online ads to target British postcode areas without significant contamination. Trial Registration Clinicaltrials.gov NCT01469689; http://clinicaltrials.gov/ct2/show/NCT01469689 (Archived by WebCite at http://www.webcitation.org/681iro5OU) PMID:22718043

The Effect of Comparatively-Framed versus Similarity-Framed E-Cigarette and Snus Print Ads on Young Adults’ Ad and Product Perceptions

PubMed Central

Banerjee, Smita C.; Greene, Kathryn; Li, Yuelin; Ostroff, Jamie S.

2016-01-01

Objectives This study examined the effects of comparative-framing [C-F; ads highlighting differences between the advertised product and conventional cigarettes and/or smokeless tobacco products] versus similarity-framing (S-F; ads highlighting congruence with conventional cigarettes and/or smokeless tobacco products) in e-cigarette and snus ads on young adult smokers’ and non-smokers’ ad- and product-related perceptions. Methods One thousand fifty one (1,051) young adults (18–24 years; 76% women; 50% smokers) from existing consumer panels were recruited in a within-subjects quasi-experiment. Each participant viewed 4 online advertisements, varied by tobacco product type (e-cigarette or snus) and ad framing (C-F or S-F). The dependent measures for this study were ad-related (ad perceptions, ad credibility) and product-related perceptions (absolute and comparative risk perceptions, product appeal, and product use intentions). Results Former and current smokers rated C-F ads as more persuasive than S-F ads, as evidenced by favorable ad perceptions and high product use intentions. Former and current smokers also rated e-cigarette ads with more favorable ad perceptions, low absolute and comparative risk perceptions, high product appeal, and high product use intentions as compared to snus ads. However, the effect sizes of the significant differences are less than.2, indicating small magnitude of difference between the study variables. Conclusions Unless FDA regulates e-cig and snus advertising, there is a potential of decreasing risk perceptions and increasing use of e-cigs among young adults. Further research on implicit/explicit comparative claims in e-cigarettes and snus advertisements that encourage risk misperceptions is recommended. PMID:28042597

The Effect of Comparatively-Framed versus Similarity-Framed E-Cigarette and Snus Print Ads on Young Adults' Ad and Product Perceptions.

PubMed

Banerjee, Smita C; Greene, Kathryn; Li, Yuelin; Ostroff, Jamie S

2016-07-01

This study examined the effects of comparative-framing [C-F; ads highlighting differences between the advertised product and conventional cigarettes and/or smokeless tobacco products] versus similarity-framing (S-F; ads highlighting congruence with conventional cigarettes and/or smokeless tobacco products) in e-cigarette and snus ads on young adult smokers' and non-smokers' ad- and product-related perceptions. One thousand fifty one (1,051) young adults (18-24 years; 76% women; 50% smokers) from existing consumer panels were recruited in a within-subjects quasi-experiment. Each participant viewed 4 online advertisements, varied by tobacco product type (e-cigarette or snus) and ad framing (C-F or S-F). The dependent measures for this study were ad-related (ad perceptions, ad credibility) and product-related perceptions (absolute and comparative risk perceptions, product appeal, and product use intentions). Former and current smokers rated C-F ads as more persuasive than S-F ads, as evidenced by favorable ad perceptions and high product use intentions. Former and current smokers also rated e-cigarette ads with more favorable ad perceptions, low absolute and comparative risk perceptions, high product appeal, and high product use intentions as compared to snus ads. However, the effect sizes of the significant differences are less than.2, indicating small magnitude of difference between the study variables. Unless FDA regulates e-cig and snus advertising, there is a potential of decreasing risk perceptions and increasing use of e-cigs among young adults. Further research on implicit/explicit comparative claims in e-cigarettes and snus advertisements that encourage risk misperceptions is recommended.

PubMed

Ströhle, Alexander; Löser, Christian; Behrendt, Isabel; Leitzmann, Claus; Hahn, Andreas

2018-02-01

Alternative diets (AD) differ from the current common mixed diet; AD are recommended as a permanent diet. These diets are based on ethical, philosophical and health promoting principles and lead to very different recommendations for food selection. Even within a particular AD there is usually a broad spectrum of versions, so that a general evaluation is only possible to a limited extent. This is also true for single AD. Vegetarian diets and partly paleo-diets have been investigated to a reasonable extent. Plant based diets are appropriate as permanent diets and offer health benefits as compared with currently practiced diets (risk reduction of cancers by 10-18% and of heart diseases by 30%; favorable effect on blood pressure and lipid profile; no risk reduction on cancer and total mortality). Vegan diets have to be critically assessed: they are linked to an increased risk of deficits for single nutrients (vitamin B 12 , iodine and as the case may be. calcium and long chain omega-3 fatty acids), if suitable supplements or fortified foods are not consumed. © Georg Thieme Verlag KG Stuttgart · New York.

A new approach for concurrently improving performance of South Korean food waste valorization and renewable energy recovery via dry anaerobic digestion under mesophilic and thermophilic conditions.

PubMed

Nguyen, Dinh Duc; Yeop, Jeong Seong; Choi, Jaehoon; Kim, Sungsu; Chang, Soon Woong; Jeon, Byong-Hun; Guo, Wenshan; Ngo, Huu Hao

2017-08-01

Dry semicontinuous anaerobic digestion (AD) of South Korean food waste (FW) under four solid loading rates (SLRs) (2.30-9.21kg total solids (TS)/m 3 day) and at a fixed TS content was compared between two digesters, one each under mesophilic and thermophilic conditions. Biogas production and organic matter reduction in both digesters followed similar trends, increasing with rising SLR. Inhibitor (intermediate products of the anaerobic fermentation process) effects on the digesters' performance were not observed under the studied conditions. In all cases tested, the digesters' best performance was achieved at the SLR of 9.21kg TS/m 3 day, with 74.02% and 80.98% reduction of volatile solids (VS), 0.87 and 0.90m 3 biogas/kg VS removed , and 0.65 (65% CH 4 ) and 0.73 (60.02% CH 4 ) m 3 biogas/kg VS fed , under mesophilic and thermophilic conditions, respectively. Thermophilic dry AD is recommended for FW treatment in South Korea because it is more efficient and has higher energy recovery potential when compared to mesophilic dry AD. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cholinergic and dopaminergic activities in senile dementia of Lewy body type.

PubMed

Perry, E K; Marshall, E; Perry, R H; Irving, D; Smith, C J; Blessed, G; Fairbairn, A F

1990-01-01

Analyses of brain tissue in a recently identified group of elderly demented patients suggest a neurochemical basis for some of the clinical features. Senile dementia of the Lewy body type (SDLT) can be distinguished from classical Alzheimer disease (AD) clinically by its acute presentation with confusion frequently accompanied by visual hallucinations, and neuropathologically by the presence of Lewy bodies and senile plaques (but not generally neurofibrillary tangles) in the cerebral cortex. Reductions in the cortical cholinergic enzyme choline acetyltransferase were more pronounced in individuals with (80%) compared to those without (50%) hallucinations and correlated strongly with mental test scores in the group as a whole. In the caudate nucleus, dopamine levels were related to the number of neurons in the substantia nigra, there being a 40-60% loss of both in SDLT--probably accounting for mild extrapyramidal features in some of these cases--compared with an 80% loss in Parkinson disease and no change in AD. The cholinergic correlates of mental impairment in SDLT together with the relative absence of cortical neurofibrillary tangles and evidence for postsynaptic cholinergic receptor compensation raise the question of whether this type of dementia may be more amenable to cholinotherapy than classical AD.

Activity-dependent neuroprotective protein (ADNP): a case study for highly conserved chordata-specific genes shaping the brain and mutated in cancer.

PubMed

Gozes, Illana; Yeheskel, Adva; Pasmanik-Chor, Metsada

2015-01-01

The recent finding of activity-dependent neuroprotective protein (ADNP) as a protein decreased in serum of patients with Alzheimer's disease (AD) compared to controls, alongside with the discovery of ADNP mutations in autism and coupled with the original description of cancer mutations, ignited an interest for a comparative analysis of ADNP with other AD/autism/cancer-associated genes. We strive toward a better understanding of the molecular structure of key players in psychiatric/neurodegenerative diseases including autism, schizophrenia, and AD. This article includes data mining and bioinformatics analysis on the ADNP gene and protein, in addition to other related genes, with emphasis on recent literature. ADNP is discovered here as unique to chordata with specific autism mutations different from cancer-associated mutation. Furthermore, ADNP exhibits similarities to other cancer/autism-associated genes. We suggest that key genes, which shape and maintain our brain and are prone to mutations, are by in large unique to chordata. Furthermore, these brain-controlling genes, like ADNP, are linked to cell growth and differentiation, and under different stress conditions may mutate or exhibit expression changes leading to cancer propagation. Better understanding of these genes could lead to better therapeutics.

The development and application of multi-criteria decision-making tool with consideration of uncertainty: the selection of a management strategy for the bio-degradable fraction in the municipal solid waste.

PubMed

El Hanandeh, Ali; El-Zein, Abbas

2010-01-01

A modified version of the multi-criteria decision aid, ELECTRE III has been developed to account for uncertainty in criteria weightings and threshold values. The new procedure, called ELECTRE-SS, modifies the exploitation phase in ELECTRE III, through a new definition of the pre-order and the introduction of a ranking index (RI). The new approach accommodates cases where incomplete or uncertain preference data are present. The method is applied to a case of selecting a management strategy for the bio-degradable fraction in the municipal solid waste of Sydney. Ten alternatives are compared against 11 criteria. The results show that anaerobic digestion (AD) and composting of paper are less environmentally sound options than recycling. AD is likely to out-perform incineration where a market for heating does not exist. Moreover, landfilling can be a sound alternative, when considering overall performance and conditions of uncertainty.

Hospital-treated mental and behavioral disorders and risk of Alzheimer's disease: A nationwide nested case-control study.

PubMed

Tapiainen, V; Hartikainen, S; Taipale, H; Tiihonen, J; Tolppanen, A-M

2017-06-01

Studies investigating psychiatric disorders as Alzheimer's disease (AD) risk factors have yielded heterogeneous findings. Differences in time windows between the exposure and outcome could be one explanation. We examined whether (1) mental and behavioral disorders in general or (2) specific mental and behavioral disorder categories increase the risk of AD and (3) how the width of the time window between the exposure and outcome affects the results. A nationwide nested case-control study of all Finnish clinically verified AD cases, alive in 2005 and their age, sex and region of residence matched controls (n of case-control pairs 27,948). History of hospital-treated mental and behavioral disorders was available since 1972. Altogether 6.9% (n=1932) of the AD cases and 6.4% (n=1784) of controls had a history of any mental and behavioral disorder. Having any mental and behavioral disorder (adjusted OR=1.07, 95% CI=1.00-1.16) or depression/other mood disorder (adjusted OR=1.17, 95% CI=1.05-1.30) were associated with higher risk of AD with 5-year time window but not with 10-year time window (adjusted OR, 95% CI 0.99, 0.91-1.08 for any disorder and 1.08, 0.96-1.23 for depression). The associations between mental and behavioral disorders and AD were modest and dependent on the time window. Therefore, some of the disorders may represent misdiagnosed prodromal symptoms of AD, which underlines the importance of proper differential diagnostics among older persons. These findings also highlight the importance of appropriate time window in psychiatric and neuroepidemiology research. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Physical activity, diet, and risk of Alzheimer disease.

PubMed

Scarmeas, Nikolaos; Luchsinger, Jose A; Schupf, Nicole; Brickman, Adam M; Cosentino, Stephanie; Tang, Ming X; Stern, Yaakov

2009-08-12

Both higher adherence to a Mediterranean-type diet and more physical activity have been independently associated with lower Alzheimer disease (AD) risk but their combined association has not been investigated. To investigate the combined association of diet and physical activity with AD risk. Prospective cohort study of 2 cohorts comprising 1880 community-dwelling elders without dementia living in New York, New York, with both diet and physical activity information available. Standardized neurological and neuropsychological measures were administered approximately every 1.5 years from 1992 through 2006. Adherence to a Mediterranean-type diet (scale of 0-9; trichotomized into low, middle, or high; and dichotomized into low or high) and physical activity (sum of weekly participation in various physical activities, weighted by the type of physical activity [light, moderate, vigorous]; trichotomized into no physical activity, some, or much; and dichotomized into low or high), separately and combined, were the main predictors in Cox models. Models were adjusted for cohort, age, sex, ethnicity, education, apolipoprotein E genotype, caloric intake, body mass index, smoking status, depression, leisure activities, a comorbidity index, and baseline Clinical Dementia Rating score. Time to incident AD. A total of 282 incident AD cases occurred during a mean (SD) of 5.4 (3.3) years of follow-up. When considered simultaneously, both Mediterranean-type diet adherence (compared with low diet score, hazard ratio [HR] for middle diet score was 0.98 [95% confidence interval {CI}, 0.72-1.33]; the HR for high diet score was 0.60 [95% CI, 0.42-0.87]; P = .008 for trend) and physical activity (compared with no physical activity, the HR for some physical activity was 0.75 [95% CI, 0.54-1.04]; the HR for much physical activity was 0.67 [95% CI, 0.47-0.95]; P = .03 for trend) were associated with lower AD risk. Compared with individuals neither adhering to the diet nor participating in physical activity (low diet score and no physical activity; absolute AD risk of 19%), those both adhering to the diet and participating in physical activity (high diet score and high physical activity) had a lower risk of AD (absolute risk, 12%; HR, 0.65 [95% CI, 0.44-0.96]; P = .03 for trend). In this study, both higher Mediterranean-type diet adherence and higher physical activity were independently associated with reduced risk for AD.

Polygenic Overlap Between C-Reactive Protein, Plasma Lipids, and Alzheimer Disease.

PubMed

Desikan, Rahul S; Schork, Andrew J; Wang, Yunpeng; Thompson, Wesley K; Dehghan, Abbas; Ridker, Paul M; Chasman, Daniel I; McEvoy, Linda K; Holland, Dominic; Chen, Chi-Hua; Karow, David S; Brewer, James B; Hess, Christopher P; Williams, Julie; Sims, Rebecca; O'Donovan, Michael C; Choi, Seung Hoan; Bis, Joshua C; Ikram, M Arfan; Gudnason, Vilmundur; DeStefano, Anita L; van der Lee, Sven J; Psaty, Bruce M; van Duijn, Cornelia M; Launer, Lenore; Seshadri, Sudha; Pericak-Vance, Margaret A; Mayeux, Richard; Haines, Jonathan L; Farrer, Lindsay A; Hardy, John; Ulstein, Ingun Dina; Aarsland, Dag; Fladby, Tormod; White, Linda R; Sando, Sigrid B; Rongve, Arvid; Witoelar, Aree; Djurovic, Srdjan; Hyman, Bradley T; Snaedal, Jon; Steinberg, Stacy; Stefansson, Hreinn; Stefansson, Kari; Schellenberg, Gerard D; Andreassen, Ole A; Dale, Anders M

2015-06-09

Epidemiological findings suggest a relationship between Alzheimer disease (AD), inflammation, and dyslipidemia, although the nature of this relationship is not well understood. We investigated whether this phenotypic association arises from a shared genetic basis. Using summary statistics (P values and odds ratios) from genome-wide association studies of >200 000 individuals, we investigated overlap in single-nucleotide polymorphisms associated with clinically diagnosed AD and C-reactive protein (CRP), triglycerides, and high- and low-density lipoprotein levels. We found up to 50-fold enrichment of AD single-nucleotide polymorphisms for different levels of association with C-reactive protein, low-density lipoprotein, high-density lipoprotein, and triglyceride single-nucleotide polymorphisms using a false discovery rate threshold <0.05. By conditioning on polymorphisms associated with the 4 phenotypes, we identified 55 loci associated with increased AD risk. We then conducted a meta-analysis of these 55 variants across 4 independent AD cohorts (total: n=29 054 AD cases and 114 824 healthy controls) and discovered 2 genome-wide significant variants on chromosome 4 (rs13113697; closest gene, HS3ST1; odds ratio=1.07; 95% confidence interval=1.05-1.11; P=2.86×10(-8)) and chromosome 10 (rs7920721; closest gene, ECHDC3; odds ratio=1.07; 95% confidence interval=1.04-1.11; P=3.38×10(-8)). We also found that gene expression of HS3ST1 and ECHDC3 was altered in AD brains compared with control brains. We demonstrate genetic overlap between AD, C-reactive protein, and plasma lipids. By conditioning on the genetic association with the cardiovascular phenotypes, we identify novel AD susceptibility loci, including 2 genome-wide significant variants conferring increased risk for AD. © 2015 American Heart Association, Inc.

A mitocentric view of Alzheimer's disease suggests multi-faceted treatments.

PubMed

Gibson, Gary E; Shi, Qingli

2010-01-01

Alzheimer's disease (AD) is defined by senile plaques made of amyloid-beta peptide (Abeta), neurofibrillary tangles made of hyperphosphorylated tau proteins, and memory deficits. Thus, the events initiating the cascade leading to these end points may be more effective therapeutic targets than treating each facet individually. In the small percentage of cases of AD that are genetic (or animal models that reflect this form of AD), the factor initiating AD is clear (e.g., genetic mutations lead to high Abeta1-42 or hyperphosphorylated tau proteins). In the vast majority of AD cases, the cause is unknown. Substantial evidence now suggests that abnormalities in glucose metabolism/mitochondrial function/oxidative stress (GMO) are an invariant feature of AD and occur at an early stage of the disease process in both genetic and non-genetic forms of AD. Indeed, decreases in brain glucose utilization are diagnostic for AD. Changes in calcium homeostasis also precede clinical manifestations of AD. Abnormal GMO can lead to plaques, tangles, and the calcium abnormalities that accompany AD. Abnormalities in GMO diminish the ability of the brain to adapt. Therapies targeting mitochondria may ameliorate abnormalities in plaques, tangles, calcium homeostasis, and cognition that comprise AD.

Association Between Olfactory Dysfunction and Amnestic Mild Cognitive Impairment and Alzheimer Disease Dementia

PubMed Central

Roberts, Rosebud O.; Christianson, Teresa J. H.; Kremers, Walter K.; Mielke, Michelle M.; Machulda, Mary M.; Vassilaki, Maria; Alhurani, Rabe E.; Geda, Yonas E.; Knopman, David S.; Petersen, Ronald C.

2015-01-01

IMPORTANCE To increase the opportunity to delay or prevent mild cognitive impairment (MCI) or dementia due to Alzheimer's disease (AD), markers of early detection are essential. Olfactory impairment may be an important clinical marker and predictor of these conditions and may help identify persons at increased risk. OBJECTIVE To examine associations of impaired olfaction with incident MCI subtypes, and progression from MCI subtypes to AD dementia. DESIGN, SETTING, AND PARTICIPANTS Participants enrolled in the population-based, prospective Mayo Clinic Study of Aging were clinically evaluated at baseline and every 15-months thereafter, and classified as having normal cognition, MCI (amnestic, aMCI and nonamnestic, naMCI), and dementia. We administered the Brief Smell Identification Test (B-SIT) to assess olfactory function. MAIN OUTCOMES AND MEASURES Mild cognitive impairment, AD dementia, longitudinal change in cognitive performance measures. RESULTS Over a mean 3.5 years of follow-up, there were 250 incident cases of MCI among 1430 cognitively normal participants. We observed an association between decreasing olfactory identification, as measured by decrease in number of correct responses in B-SIT score, and an increased risk of aMCI. Compared to the upper B-SIT quartile (Q4, best scores), hazard ratios (HR) were 1.12; P = 0.68 for Q3; HR, 1.95; P =0.003 for Q2; and HR, 2.18; P = 0.001 (worst scores; p for trend <0.001) after adjustment for sex and education, with age as the time scale. There was no association with naMCI. There were 64 incident dementia cases among 221 prevalent MCI cases. The B-SIT score also predicted progression from aMCI to AD, with a significant dose-response with worsening B-SIT quartiles. Compared to Q4, HR estimates were 3.02, P = 0.038 for Q3; HR, 3.63; P = 0.024 for Q2; and HR, 5.20; P = 0.001 for Q1. After adjusting for key predictors of MCI risk, B-SIT (as a continuous measure) remained a significant predictor of MCI (HR, 1.10; p < 0.001), and improved the model concordance. CONCLUSIONS AND RELEVANCE Olfactory impairment predicts incident aMCI and progression from aMCI to AD. These findings are consistent with previous studies that have reported associations of olfactory impairment with cognitive impairment in late life, and suggest that olfactory tests have potential utility for screening for MCI and MCI that is likely to progress. PMID:26569387

Effects of comparative claims in prescription drug direct-to-consumer advertising on consumer perceptions and recall.

PubMed

O'Donoghue, Amie C; Williams, Pamela A; Sullivan, Helen W; Boudewyns, Vanessa; Squire, Claudia; Willoughby, Jessica Fitts

2014-11-01

Although pharmaceutical companies cannot make comparative claims in direct-to-consumer (DTC) ads for prescription drugs without substantial evidence, the U.S. Food and Drug Administration permits some comparisons based on labeled attributes of the drug, such as dosing. Researchers have examined comparative advertising for packaged goods; however, scant research has examined comparative DTC advertising. We conducted two studies to determine if comparative claims in DTC ads influence consumers' perceptions and recall of drug information. In Experiment 1, participants with osteoarthritis (n=1934) viewed a fictitious print or video DTC ad that had no comparative claim or made an efficacy comparison to a named or unnamed competitor. Participants who viewed print (but not video) ads with named competitors had greater efficacy and lower risk perceptions than participants who viewed unnamed competitor and noncomparative ads. In Experiment 2, participants with high cholesterol or high body mass index (n=5317) viewed a fictitious print or video DTC ad that had no comparative claim or made a comparison to a named or unnamed competitor. We varied the type of comparison (of indication, dosing, or mechanism of action) and whether the comparison was accompanied by a visual depiction. Participants who viewed print and video ads with named competitors had greater efficacy perceptions than participants who viewed unnamed competitor and noncomparative ads. Unlike Experiment 1, named competitors in print ads resulted in higher risk perceptions than unnamed competitors. In video ads, participants who saw an indication comparison had greater benefit recall than participants who saw dosing or mechanism of action comparisons. In addition, visual depictions of the comparison decreased risk recall for video ads. Overall, the results suggest that comparative claims in DTC ads could mislead consumers about a drug's efficacy and risk; therefore, caution should be used when presenting comparative claims in DTC ads. Published by Elsevier Ltd.

Phenotypic Variability in Autosomal Dominant Familial Alzheimer Disease due to the S170F Mutation of Presenilin-1.

PubMed

Tiedt, Hannes O; Benjamin, Beate; Niedeggen, Michael; Lueschow, Andreas

2018-02-22

In rare cases, patients with Alzheimer disease (AD) present at an early age and with a family history suggestive of an autosomal dominant mode of inheritance. Mutations of the presenilin-1 (PSEN1) gene are the most common causes of dementia in these patients. Early-onset and particularly familial AD patients frequently present with variable non-amnestic cognitive symptoms such as visual, language or behavioural changes as well as non-cognitive, e.g. motor, symptoms. To investigate the phenotypic variability in carriers of the PSEN1 S170F mutation. We report a family with 4 patients carrying the S170F mutation of whom 2 underwent detailed clinical examinations. We discuss our current findings in the context of previously reported S170F cases. The clinical phenotype was consistent regarding initial memory impairment and early onset in the late twenties found in all S170F patients. There were frequent non-amnestic cognitive changes and, at early stages of the disease, indications of a more pronounced disturbance of visuospatial abilities as compared to face and object recognition. Non-cognitive symptoms most often included myoclonus and cerebellar ataxia. A review of the available case reports indicates some phenotypic variability associated with the S170F mutation including different constellations of symptoms such as parkinsonism and delusions. The variable clinical findings associated with the S170F mutation highlight the relevance of atypical phenotypes in the context of research and under a clinical perspective. CSF sampling and detection of Aβ species may be essential to indicate AD pathology in unclear cases presenting with cognitive and motor symptoms at a younger age. © 2018 S. Karger AG, Basel.

Polygenic Scores for Major Depressive Disorder and Risk of Alcohol Dependence.

PubMed

Andersen, Allan M; Pietrzak, Robert H; Kranzler, Henry R; Ma, Li; Zhou, Hang; Liu, Xiaoming; Kramer, John; Kuperman, Samuel; Edenberg, Howard J; Nurnberger, John I; Rice, John P; Tischfield, Jay A; Goate, Alison; Foroud, Tatiana M; Meyers, Jacquelyn L; Porjesz, Bernice; Dick, Danielle M; Hesselbrock, Victor; Boerwinkle, Eric; Southwick, Steven M; Krystal, John H; Weissman, Myrna M; Levinson, Douglas F; Potash, James B; Gelernter, Joel; Han, Shizhong

2017-11-01

Major depressive disorder (MDD) and alcohol dependence (AD) are heritable disorders with significant public health burdens, and they are frequently comorbid. Common genetic factors that influence the co-occurrence of MDD and AD have been sought in family, twin, and adoption studies, and results to date have been promising but inconclusive. To examine whether AD and MDD overlap genetically, using a polygenic score approach. Association analyses were conducted between MDD polygenic risk score (PRS) and AD case-control status in European ancestry samples from 4 independent genome-wide association study (GWAS) data sets: the Collaborative Study on the Genetics of Alcoholism (COGA); the Study of Addiction, Genetics, and Environment (SAGE); the Yale-Penn genetic study of substance dependence; and the National Health and Resilience in Veterans Study (NHRVS). Results from a meta-analysis of MDD (9240 patients with MDD and 9519 controls) from the Psychiatric Genomics Consortium were applied to calculate PRS at thresholds from P < .05 to P ≤ .99 in each AD GWAS data set. Association between MDD PRS and AD. Participants analyzed included 788 cases (548 [69.5%] men; mean [SD] age, 38.2 [10.8] years) and 522 controls (151 [28.9.%] men; age [SD], 43.9 [11.6] years) from COGA; 631 cases (333 [52.8%] men; age [SD], 35.0 [7.7] years) and 756 controls (260 [34.4%] male; age [SD] 36.1 [7.7] years) from SAGE; 2135 cases (1375 [64.4%] men; age [SD], 39.4 [11.5] years) and 350 controls (126 [36.0%] men; age [SD], 43.5 [13.9] years) from Yale-Penn; and 317 cases (295 [93.1%] men; age [SD], 59.1 [13.1] years) and 1719 controls (1545 [89.9%] men; age [SD], 64.5 [13.3] years) from NHRVS. Higher MDD PRS was associated with a significantly increased risk of AD in all samples (COGA: best P = 1.7 × 10-6, R2 = 0.026; SAGE: best P = .001, R2 = 0.01; Yale-Penn: best P = .035, R2 = 0.0018; and NHRVS: best P = .004, R2 = 0.0074), with stronger evidence for association after meta-analysis of the 4 samples (best P = 3.3 × 10-9). In analyses adjusted for MDD status in 3 AD GWAS data sets, similar patterns of association were observed (COGA: best P = 7.6 × 10-6, R2 = 0.023; Yale-Penn: best P = .08, R2 = 0.0013; and NHRVS: best P = .006, R2 = 0.0072). After recalculating MDD PRS using MDD GWAS data sets without comorbid MDD-AD cases, significant evidence was observed for an association between the MDD PRS and AD in the meta-analysis of 3 GWAS AD samples without MDD cases (best P = .007). These results suggest that shared genetic susceptibility contributes modestly to MDD and AD comorbidity. Individuals with elevated polygenic risk for MDD may also be at risk for AD.

Disease-specific direct-to-consumer advertising of pharmaceuticals: An examination of endorser type and gender effects on consumers' attitudes and behaviors.

PubMed

Bhutada, Nilesh S; Rollins, Brent L

2015-01-01

Direct-to-consumer (DTC) advertising is still a controversial topic for pharmaceutical manufacturers' and researchers, and while numerous studies have examined the DTC phenomenon, little research has examined the effect of gender, particularly gender of the endorser and consumer. The objective of this research was to assess the impact of the endorser (celebrity vs. expert vs. non-celebrity) and gender - both gender of the endorser and gender of the consumer - on consumers' attitudes and behaviors in response to a print disease-specific direct-to-consumer advertisement. Using Qualtrics consumer panel, data were obtained for 514 US adults (age 18 years and above) who demonstrated at least minimal symptoms of depression and need for monitoring based on the Patient Health Questionnaire (PHQ) score. Data were analyzed using a 3 (Endorser Type: Celebrity/Expert/Non-Celebrity) × 2 (Endorser Gender: Male/Female) × 2 (Consumer Gender: Male/Female) full factorial between subjects multivariate analysis of variance (MANOVA) and necessary univariate analysis. Only the type of the endorser (celebrity vs. expert vs. non-celebrity) used in the ad had a significant main effect on the dependent variables. Further univariate analyses revealed that, of the several dependent variables, endorser type had a significant influence only on attitude towards the ad, attention paid to the ad, and endorser credibility, with gender being non-significant in all cases. Expert endorser generated significantly more favorable levels of attitude towards the ad, and endorser credibility compared to the non-celebrity endorser. Celebrity endorser attracted more consumer attention towards the ad and generated favorable endorser credibility perceptions compared to the non-celebrity endorser. However, celebrity and expert endorsers did not significantly differ from each other on the abovementioned ad effectiveness variables. Lastly, endorser gender and consumer gender did not have a significant influence on ad effectiveness. Copyright © 2015 Elsevier Inc. All rights reserved.

Two rare AKAP9 variants are associated with Alzheimer disease in African Americans

PubMed Central

Logue, Mark W.; Schu, Matthew; Vardarajan, Badri N.; Farrell, John; Bennett, David A.; Buxbaum, Joseph D.; Byrd, Goldie S.; Ertekin-Taner, Nilufer; Evans, Denis; Foroud, Tatiana; Goate, Alison; Graff-Radford, Neill R.; Kamboh, M. Ilyas; Kukull, Walter A.; Manly, Jennifer J.; Haines, Jonathan L.; Mayeux, Richard; Pericak-Vance, Margaret A.; Schellenberg, Gerard D.; Lunetta, Kathryn L.; Baldwin, Clinton T.; Fallin, M. Daniele; Farrer, Lindsay A.

2014-01-01

Background Less is known about the genetic basis of Alzheimer disease (AD) in African Americans (AAs) than in non-Hispanic whites. Methods Whole exome sequencing (WES) was performed on seven AA AD cases. Disease association with potentially AD-related variants from WES was assessed in an AA discovery cohort of 422 cases and 394 controls. Replication was sought in an AA sample of 1,037 cases and 1,869 controls from the Alzheimer Disease Genetics Consortium (ADGC). Results Forty-four SNPs from WES passed filtering criteria and were successfully genotyped, Nominally significant (p<0.05) association to AD was observed with two African-descent specific AKAP9 SNPs in tight linkage disequilibrium: rs144662445 (p=0.014) and rs149979685 (p=0.037). These associations were replicated in the ADGC sample (rs144662445: p=0.0022, odds ratio [OR]=2.75; rs149979685: p=0.0022, OR=3.61). Conclusions Because AKAP9 was not previously linked to AD risk, this study indicates a potential new disease mechanism. PMID:25172201

Multiple cytokines are involved in the early events leading to the Alzheimer’s disease pathology

PubMed Central

Wilberding, Akiko; Morimoto, Kaori; Satoh, Haruhisa; Harano, Keiko; Harano, Teruo; Arita, Seizaburo; Tooyama, Ikuo; Konishi, Yoshihiro

2009-01-01

It is likely that neuroinflammation begins well before detectable cognitive impairment in Alzheimer’s disease (AD) occurs. Clarifying the alterations occurring prior to the clinical manifestation of overt AD dementia may provide valuable insight into the early diagnosis and management of AD. Herein, to address the issue that neuroinflammation precedes development of AD pathology, we analyzed cytokine expression profiles of the brain, with focus on non-demented control patients with increasing AD pathology, referred to as high pathology control (HPC) cases, who provide an intermediate subset between AD and normal control cases referred to as low pathology control (LPC) cases. With a semi-quantitative analysis of cytokine mRNA, among 15 cytokines and their related molecules tested, we found the involvement of eight: interleukin-1(IL-1) receptor antagonist (IL-1ra), IL-1 converting enzyme (ICE), IL-2, IL-6, IL-8, tumor necrosis factor (TNF) α, macrophage-colony stimulating factor (M-CSF) and transforming growth factor (TGF) β1 during the development from LPC to HPC, while decreases in IL-1ra, IL-8, MCP-1 and TNFα, and an increase in TACE were implicated in the later development from HPC to AD. These findings indicate that neuroinflammation precedes the clinical manifestation of overt dementia, rather than being involved at the later stages of AD. PMID:22586434

Aleutian Disease: An Emerging Disease in Free-Ranging Striped Skunks (Mephitis mephitis) From California.

PubMed

LaDouceur, E E B; Anderson, M; Ritchie, B W; Ciembor, P; Rimoldi, G; Piazza, M; Pesti, D; Clifford, D L; Giannitti, F

2015-11-01

Aleutian disease virus (ADV, Amdovirus, Parvoviridae) primarily infects farmed mustelids (mink and ferrets) but also other fur-bearing animals and humans. Three Aleutian disease (AD) cases have been described in captive striped skunks; however, little is known about the relevance of AD in free-ranging carnivores. This work describes the pathological findings and temporospatial distribution in 7 cases of AD in free-ranging striped skunks. All cases showed neurologic disease and were found in a 46-month period (2010-2013) within a localized geographical region in California. Lesions included multisystemic plasmacytic and lymphocytic inflammation (ie, interstitial nephritis, myocarditis, hepatitis, meningoencephalitis, pneumonia, and splenitis), glomerulonephritis, arteritis with or without fibrinoid necrosis in several organs (ie, kidney, heart, brain, and spleen), splenomegaly, ascites/hydrothorax, and/or encephalomalacia with cerebral microangiopathy. ADV infection was confirmed in all cases by specific polymerase chain reaction and/or in situ hybridization. The results suggest that AD is an emerging disease in free-ranging striped skunks in California. © The Author(s) 2014.

Autoimmune diseases in a Nigerian woman--a case report.

PubMed

Talabi, O A; Owolabi, M O; Osotimehin, B O

2003-12-01

Autoimmune diseases (AD) are conditions in which there is the development of antibodies against self cells/ organs. AD could either be organ-specific or non-organ specific (systemic) in clinical presentation. Commonly reported ADs includes: Myasthenia gravis, Hashimoto thyroiditis, Guillian-Barre syndrome, vitiligo, type 1 diabetes mellitus, Graves diseases, Goodpastures syndrome, pemphigus, rheumatoid arthritis, systemic lupus erythematosis, Addisons disease, multiple sclerosis, pernicious anaemia, autoimmune haemolytic anaemia, chronic active hepatitis, idiopathic thrombocytopenic purpura. There is paucity of locally documented information on the occurrence of AD in same patient in our environment. We therefore report the case of a 66 year old woman who presented at the University College Hospital (UCH), Ibadan, with a spectrum of the AD, Vitiligo, rheumatoid arthritis, myasthenia gravis, impaired glucose tolerance.

Mature thunderstorm cloud-top structure and dynamics - A three-dimensional numerical simulation study

NASA Technical Reports Server (NTRS)

Schlesinger, R. E.

1984-01-01

The present investigation is concerned with results from an initial set of comparative experiments in a project which utilize a three-dimensional convective storm model. The modeling results presented are related to four comparative experiments, designated Cases A through D. One of two scientific questions considered involves the dynamical processes, either near the cloud top or well within the cloud interior, which contribute to organize cloud thermal patterns such as those revealed by IR satellite imagery for some storms having strong internal cloud-scale rotation. The second question is concerned with differences, in cloud-top height and temperature field characteristics, between thunderstorms with and without significant internal cloud-scale rotation. The four experiments A-D are compared with regard to both interior and cloud-top configurations in the context of the second question. A particular strong-shear experiment, Case B, is analyzed to address question one.

Humor and Comparatives in Ads for High- and Low-Involvement Products.

ERIC Educational Resources Information Center

Wu, Bob T. W.; And Others

1989-01-01

Investigates the effectiveness of humor in advertising, comparative advertising, and consumer involvement with the product. Finds that humorous ads are more eye catching but less impressive and less sufficient in information than nonhumorous ads. Finds the performance of comparative ads is generally negative and especially so in the high…

Splenic manifestations of chronic autoimmune disorder: a report of five cases with histiocytic necrotizing change in four cases.

PubMed

Auerbach, Aaron; Summers, Thomas A; Zhang, Binxue; Aguilera, Nadine S

2013-07-01

Autoimmune diseases (AD) are associated with lymphadenopathy and splenomegaly. Changes in the spleen have not been characterized completely in AD; we describe splenectomy specimens from five patients with chronic AD, highlighting the presence of necrotizing histiocytosis. Of the patients (three males and two females; mean 40 years), four had systemic lupus erythematosus; one had rheumatoid arthritis. All had moderate splenomegaly (213-803 g, mean 421 g). Four cases exhibited necrosis with apoptosis and karyorrhectic debris occurring in the white pulp and minimal acute inflammation; one showed florid follicular hyperplasia. Splenic involvement ranged from focal to extensive. Plasma cells were negative for IgG4. Haematoxylin bodies were not identified. Stains for infectious organisms were negative. Immunohistochemical studies showed that lymphocytes surrounding the necrosis were a mixture of CD4(+) and CD8(+) T cells; CD123-positive plasmacytoid dendritic cells were not present, and staining for kappa and lambda light chains showed no clonality. 16S rDNA PCR was performed; no amplification was seen in three of four cases tested for bacteria specific rDNA. Epstein-Barr virus-encoded RNA (EBER) in situ hybridization studies highlighted rare positive cells in four cases. Splenomegaly in AD is thought to be hyperplasic, but we present four cases showing histiocytic necrosis, a finding which should be considered part of the spectrum of AD in the spleen. © 2013 John Wiley & Sons Ltd.

Defense Acquisition and the Case of the Joint Capabilities Technology Demonstration Office: Ad Hoc Problem Solving as a Mechanism for Adaptive Change

DTIC Science & Technology

2013-04-01

Capabilities Technology Demonstration Office: Ad Hoc Problem Solving as a Mechanism for Adaptive Change Kathryn Aten and John T. Dillard Naval...Defense Acquisition and the Case of the Joint Capabilities Technology Demonstration Office: Ad Hoc Problem Solving as a Mechanism for Adaptive Change...describes the preliminary analysis and findings of our study exploring what drives successful organizational adaptation in the context of technology

Defense Acquisition and the Case of the Joint Capabilities Technology Demonstration Office: Ad Hoc Problem Solving as a Mechanism for Adaptive Change

DTIC Science & Technology

2013-10-01

pmlkploba=obmloq=pbofbp= Defense Acquisition and the Case of the Joint Capabilities Technology Demonstration Office: Ad Hoc Problem Solving as a...of the Joint Capabilities Technology Demonstration Office: Ad Hoc Problem Solving as a Mechanism for Adaptive Change 5a. CONTRACT NUMBER 5b. GRANT...findings of our study exploring what drives successful organizational adaptation in the context of technology transition and acquisition within the

Comparing hospital costs: what is gained by accounting for more than a case-mix index?

PubMed

Hvenegaard, Anne; Street, Andrew; Sørensen, Torben Højmark; Gyrd-Hansen, Dorte

2009-08-01

We explore what effect controlling for various patient characteristics beyond a case-mix index (DRG) has on inferences drawn about the relative cost performance of hospital departments. We estimate fixed effect cost models in which 3754 patients are clustered within six Danish vascular departments. We compare a basic model including a DRG index only with models also including age and gender, health related characteristics, such as smoking status, diabetes, and American Society of Anesthesiogists score (ASA-score), and socioeconomic characteristics such as income, employment and whether the patient lives alone. We find that the DRG index is a robust and important explanatory factor and adding other routinely collected characteristics such as age and gender and other health related or socioeconomic characteristics do not seem to alter the results significantly. The results are more sensitive to choice of functional form, i.e. in particular to whether costs are log transformed. Our results suggest that the routinely collected characteristics such as DRG index, age and gender are sufficient when drawing inferences about relative cost performance. Adding health related or socioeconomic patient characteristics only slightly improves our model in terms of explanatory power but not when drawing inferences about relative performance. The results are, however, sensitive to whether costs are log transformed.

Mutation analysis of the chromosome 14q24.3 dihydrolipoyl succinyltransferase (DLST) gene in patients with early-onset Alzheimer disease.

PubMed

Cruts, M; Backhovens, H; Van Gassen, G; Theuns, J; Wang, S Y; Wehnert, A; van Duijn, C M; Karlsson, T; Hofman, A; Adolfsson, R

1995-10-13

Linkage analysis studies have indicated that the chromosome band 14q24.3 harbours a major gene for familial early-onset Alzheimer's disease (AD). Recently we localized the chromosome 14 AD gene (AD3) in the 6.4 cM interval between the markers D14S289 and D14S61. We mapped the gene encoding dihydrolipoyl succinyltransferase (DLST), the E2k component of human alpha-ketoglutarate dehydrogenase complex (KGDHC), in the AD3 candidate region using yeast artificial chromosomes (YACs). The DLST gene is a candidate for the AD3 gene since deficiencies in KGDHC activity have been observed in brain tissue and fibroblasts of AD patients. The 15 exons and the promoter region of the DLST gene were analysed for mutations in chromosome 14 linked AD cases and in two series of unrelated early-onset AD cases (onset age < 55 years). Sequence variations in intronic sequences (introns 3, 5 and 10) or silent mutations in exonic sequences (exons 8 and 14) were identified. However, no AD related mutations were observed, suggesting that the DLST gene is not the chromosome 14 AD3 gene.

Molecular Analysis of Malassezia Microflora on the Skin of Atopic Dermatitis Patients and Healthy Subjects

PubMed Central

Sugita, Takashi; Suto, Hajime; Unno, Tetsushi; Tsuboi, Ryoji; Ogawa, Hideoki; Shinoda, Takako; Nishikawa, Akemi

2001-01-01

Members of the genus Malassezia, lipophilic yeasts, are considered to be one of the exacerbating factors in atopic dermatitis (AD). We examined variation in cutaneous colonization by Malassezia species in AD patients and compared it with variation in healthy subjects. Samples were collected by applying transparent dressings to the skin lesions of AD patients. DNA was extracted directly from the dressings and amplified in a specific nested PCR assay. Malassezia-specific DNA was detected in all samples obtained from 32 AD patients. In particular, Malassezia globosa and M. restricta were detected in approximately 90% of the AD patients and M. furfur and M. sympodialis were detected in approximately 40% of the cases. The detection rate was not dependent on the type of skin lesion. In healthy subjects, Malassezia DNA was detected in 78% of the samples, among which M. globosa, M. restricta, and M. sympodialis were detected at frequencies ranging from 44 to 61%, with M. furfur at 11%. The diversity of Malassezia species found in AD patients was greater (2.7 species detected in each individual) than that found in healthy subjects (1.8 species per individual). Our results suggest that M. furfur, M. globosa, M. restricta, and M. sympodialis are common inhabitants of the skin of both AD patients and healthy subjects, while the skin microflora of AD patients shows more diversity than that of healthy subjects. To our knowledge, this is the first report of the use of a nested PCR as an alternative to fungal culture for analysis of the distribution of cutaneous Malassezia spp. PMID:11574560

Factors influencing accuracy of cortical thickness in the diagnosis of Alzheimer's disease.

PubMed

Belathur Suresh, Mahanand; Fischl, Bruce; Salat, David H

2018-04-01

There is great value to use of structural neuroimaging in the assessment of Alzheimer's disease (AD). However, to date, predictive value of structural imaging tend to range between 80% and 90% in accuracy and it is unclear why this is the case given that structural imaging should parallel the pathologic processes of AD. There is a possibility that clinical misdiagnosis relative to the gold standard pathologic diagnosis and/or additional brain pathologies are confounding factors contributing to reduced structural imaging classification accuracy. We examined potential factors contributing to misclassification of individuals with clinically diagnosed AD purely from cortical thickness measures. Correctly classified and incorrectly classified groups were compared across a range of demographic, biological, and neuropsychological data including cerebrospinal fluid biomarkers, amyloid imaging, white matter hyperintensity (WMH) volume, cognitive, and genetic factors. Individual subject analyses suggested that at least a portion of the control individuals misclassified as AD from structural imaging additionally harbor substantial AD biomarker pathology and risk, yet are relatively resistant to cognitive symptoms, likely due to "cognitive reserve," and therefore clinically unimpaired. In contrast, certain clinical control individuals misclassified as AD from cortical thickness had increased WMH volume relative to other controls in the sample, suggesting that vascular conditions may contribute to classification accuracy from cortical thickness measures. These results provide examples of factors that contribute to the accuracy of structural imaging in predicting a clinical diagnosis of AD, and provide important information about considerations for future work aimed at optimizing structural based diagnostic classifiers for AD. © 2017 Wiley Periodicals, Inc.

Divergences in holographic complexity

NASA Astrophysics Data System (ADS)

Reynolds, Alan; Ross, Simon F.

2017-05-01

We study the UV divergences in the action of the ‘Wheeler-de Witt patch’ in asymptotically AdS spacetimes, which has been conjectured to be dual to the computational complexity of the state of the dual field theory on a spatial slice of the boundary. We show that including a surface term in the action on the null boundaries which ensures invariance under coordinate transformations has the additional virtue of removing a stronger than expected divergence, making the leading divergence proportional to the proper volume of the boundary spatial slice. We compare the divergences in the action to divergences in the volume of a maximal spatial slice in the bulk, finding that the qualitative structure is the same, but subleading divergences have different relative coefficients in the two cases.

TDP-43 pathology in primary progressive aphasia and frontotemporal dementia with pathologic Alzheimer disease

PubMed Central

Mishra, Manjari; Hatanpaa, Kimmo J.; White, Charles L.; Johnson, Nancy; Rademaker, Alfred; Weitner, Bing Bing; Deng, Han-Xiang; Dubner, Steven D.; Weintraub, Sandra; Mesulam, Marsel

2010-01-01

The clinical syndrome of primary progressive aphasia (PPA) can be associated with a variety of neuropathologic diagnoses at autopsy. Thirty percent of cases have Alzheimer disease (AD) pathology, most often in the usual distribution, which defies principles of brain–behavior organization, in that aphasia is not symptomatic of limbic disease. The present study investigated whether concomitant TDP-43 pathology could resolve the lack of clinicoanatomic concordance. In this paper, 16 cases of clinical PPA and 10 cases of primarily non-aphasic frontotemporal dementia (FTD), all with AD pathology, were investigated to determine whether their atypical clinical phenotypes reflected the presence of additional TDP-43 pathology. A comparison group consisted of 27 cases of pathologic AD with the typical amnestic clinical phenotype of probable AD. Concomitant TDP-43 pathology was discovered in only three of the FTD and PPA but in more than half of the typical amnestic clinical phenotypes. Hippocampal sclerosis (HS) was closely associated with TDP-43 pathology when all groups were combined for analysis. Therefore, the clinical phenotypes of PPA and FTD in cases with pathologic AD are only rarely associated with TDP-43 proteinopathy. Furthermore, medial temporal TDP-43 pathology is more tightly linked to HS than to clinical phenotype. These findings challenge the current notions about clinicopathologic correlation, especially about the role of multiple pathologies. PMID:20361198

Comparison of the yield of tuberculosis among contacts of multidrug-resistant and drug-sensitive tuberculosis patients in Ethiopia using GeneXpert as a primary diagnostic test.

PubMed

Hiruy, Nebiyu; Melese, Muluken; Habte, Dereje; Jerene, Degu; Gashu, Zewdu; Alem, Genetu; Jemal, Ilili; Tessema, Belay; Belayneh, Beza; Suarez, Pedro G

2018-06-01

This study compared the yield of tuberculosis (TB) among contacts of multidrug-resistant tuberculosis (MDR-TB) index cases with that in drug-sensitive TB (DS-TB) index cases in a program setting. A comparative cross-sectional study was conducted among contacts of sputum smear-positive new DS-TB index cases and MDR-TB index cases. After contacts were screened, GeneXpert was used for the diagnosis of TB. The study included 111 MDR-TB and 119 DS-TB index cases. A total of 340 and 393 contacts of MDR-TB and DS-TB index cases, respectively, were traced, of whom 331 among MDR-TB contacts and 353 among DS-TB contacts were screened. There were 20 (6%) presumptive TB cases for MDR-TB contacts and 41 (11%) for DS-TB contacts. The prevalence of TB among MDR-TB contacts was 2.7% and among DS-TB contacts was 4.0%. The majority of the MDR-TB contacts diagnosed with TB had MDR-TB; the reverse was true for DS-TB. The yield of TB among contacts of MDR-TB and DS-TB patients using GeneXpert was high as compared to the population-level prevalence. The likelihood of diagnosing rifampicin-resistant TB among contacts of MDR-TB index cases was higher in comparison with contacts of DS-TB index cases. The use of GeneXpert in DS-TB contact investigation has the added advantage of diagnosing rifampicin-resistant TB cases when compared to the use of the nationally recommended acid-fast bacillus (AFB) microscopy for DS-TB contact investigation. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

320-row CT renal perfusion imaging in patients with aortic dissection: A preliminary study.

PubMed

Liu, Dongting; Liu, Jiayi; Wen, Zhaoying; Li, Yu; Sun, Zhonghua; Xu, Qin; Fan, Zhanming

2017-01-01

To investigate the clinical value of renal perfusion imaging in patients with aortic dissection (AD) using 320-row computed tomography (CT), and to determine the relationship between renal CT perfusion imaging and various factors of aortic dissection. Forty-three patients with AD who underwent 320-row CT renal perfusion before operation were prospectively enrolled in this study. Diagnosis of AD was confirmed by transthoracic echocardiography. Blood flow (BF) of bilateral renal perfusion was measured and analyzed. CT perfusion imaging signs of AD in relation to the type of AD, number of entry tears and the false lumen thrombus were observed and compared. The BF values of patients with type A AD were significantly lower than those of patients with type B AD (P = 0.004). No significant difference was found in the BF between different numbers of intimal tears (P = 0.288), but BF values were significantly higher in cases with a false lumen without thrombus and renal arteries arising from the true lumen than in those with thrombus (P = 0.036). The BF values measured between the true lumen, false lumen and overriding groups were different (P = 0.02), with the true lumen group having the highest. Also, the difference in BF values between true lumen and false lumen groups was statistically significant (P = 0.016), while no statistical significance was found in the other two groups (P > 0.05). The larger the size of intimal entry tears, the greater the BF values (P = 0.044). This study shows a direct correlation between renal CT perfusion changes and AD, with the size, number of intimal tears, different types of AD, different renal artery origins and false lumen thrombosis, significantly affecting the perfusion values.

The Use of Profanity During Letter Fluency Tasks in Frontotemporal Dementia and Alzheimer's Disease

PubMed Central

Ringman, John M.; Kwon, Eunice; Flores, Deborah L.; Rotko, Carol; Mendez, Mario F.; Lu, Po

2012-01-01

Objective To assess whether the production of profanity during letter fluency testing distinguishes frontotemporal dementia (FTD) and Alzheimer's disease (AD) patients. Background Alterations in language and social behavior typify FTD spectrum disorders. Nonetheless, in can be difficult to distinguish pathologically-defined frontotemporal lobar degeneration (FTLD) from AD clinically. Assessing verbal fluency by having patients generate as many words as they can beginning with specific letters in a given period of time can yield diverse information of diagnostic utility. Method Words produced during FAS letter fluency testing were reviewed and instances of the use of "f*ck", "*ss", and "sh*t" and other words felt to be inappropriate were sought. The frequency of these words was compared between clinically diagnosed FTD and AD patients using chi-square tests. Results We found that 6/32 (18.8%) patients with FTD generated the word "f*ck" during the "F" trial as opposed to none of 38 patients with AD (p = 0.007). Patients who said "f*ck" had diagnoses of either behavioral variant FTD (3/15), progressive non-fluent aphasia (2/8), or semantic dementia (1/3). Conclusions Though the specific neuropathology in these cases is uncertain, generation of "f*ck" during letter fluency testing appears to have utility in differentiating FTD from AD. PMID:20829665

Oral infections and orofacial pain in Alzheimer's disease: a case-control study.

PubMed

de Souza Rolim, Thaís; Fabri, Gisele Maria Campos; Nitrini, Ricardo; Anghinah, Renato; Teixeira, Manoel Jacobsen; de Siqueira, José Tadeu T; Cestari, José Augusto Ferrari; de Siqueira, Silvia Regina Dowgan T

2014-01-01

Dental infections are frequent and have recently been implicated as a possible risk factor for Alzheimer's disease (AD). Despite a lack of studies investigating orofacial pain in this patient group, dental conditions are known to be a potential cause of pain and to affect quality of life and disease progression. To evaluate oral status, mandibular function and orofacial pain in patients with mild AD versus healthy subjects matched for age and gender. Twenty-nine patients and 30 control subjects were evaluated. The protocol comprised a clinical questionnaire and dental exam, research diagnostic criteria for temporomandibular disorders, the McGill Pain Questionnaire, the decayed, missing, and filled teeth index, and included a full periodontal evaluation. AD signs and symptoms as well as associated factors were evaluated by a trained neurologist. A higher prevalence of orofacial pain (20.7%, p < 0.001), articular abnormalities in temporomandibular joints (p < 0.05), and periodontal infections (p = 0.002) was observed in the study group compared to the control group. Orofacial pain and periodontal infections were more frequent in patients with mild AD than in healthy subjects. Orofacial pain screening and dental and oral exams should be routinely performed in AD patients in order to identify pathological conditions that need treatment thus improving quality of life compromised due to dementia.

[11C]PK11195 binding in Alzheimer disease and progressive supranuclear palsy

PubMed Central

Rodríguez, Patricia Vázquez; Hong, Young T.; Allinson, Kieren S.J.; Bevan-Jones, W. Richard; Williamson, David; Jones, P. Simon; Arnold, Robert; Borchert, Robin J.; Surendranathan, Ajenthan; Mak, Elijah; Su, Li; Fryer, Tim D.; Aigbirhio, Franklin I.; O'Brien, John T.; Rowe, James B.

2018-01-01

Objective We tested whether in vivo neuroinflammation relates to the distinctive distributions of pathology in Alzheimer disease (AD) and progressive supranuclear palsy (PSP). Methods Sixteen patients with symptomatic AD (including amnestic mild cognitive impairment with amyloid-positive PET scan), 16 patients with PSP–Richardson syndrome, and 13 age-, sex-, and education-matched healthy controls were included in this case-control study. Participants underwent [11C]PK11195 PET scanning, which was used as an in vivo index of neuroinflammation. Results [11C]PK11195 binding in the medial temporal lobe and occipital, temporal, and parietal cortices was increased in patients with AD, relative both to patients with PSP and to controls. Compared to controls, patients with PSP showed elevated [11C]PK11195 binding in the thalamus, putamen, and pallidum. [11C]PK11195 binding in the cuneus/precuneus correlated with episodic memory impairment in AD, while [11C]PK11195 binding in the pallidum, midbrain, and pons correlated with disease severity in PSP. Conclusions Together, our results suggest that neuroinflammation has an important pathogenic role in the 2 very different human neurodegenerative disorders of AD and PSP. The increase and distribution of microglial activation suggest that immunotherapeutic strategies may be useful in slowing the progression of both diseases. PMID:29703774

Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status.

PubMed

Piccio, Laura; Deming, Yuetiva; Del-Águila, Jorge L; Ghezzi, Laura; Holtzman, David M; Fagan, Anne M; Fenoglio, Chiara; Galimberti, Daniela; Borroni, Barbara; Cruchaga, Carlos

2016-06-01

Low frequency coding variants in TREM2 are associated with increased Alzheimer disease (AD) risk, while loss of functions mutations in the gene lead to an autosomal recessive early-onset dementia, named Nasu-Hakola disease (NHD). TREM2 can be detected as a soluble protein in cerebrospinal fluid (CSF) and plasma, and its CSF levels are elevated in inflammatory CNS diseases. We measured soluble TREM2 (sTREM2) in the CSF of a large AD case-control dataset (n = 180) and 40 TREM2 risk variant carriers to determine whether CSF sTREM2 levels are associated with AD status or mutation status. We also performed genetic studies to identify genetic variants associated with CSF sTREM2 levels. CSF, but not plasma, sTREM2 was highly correlated with CSF total tau and phosphorylated-tau levels (r = 0.35, P < 1×10(-4); r = 0.40, P < 1×10(-4), respectively), but not with CSF Aβ42. AD cases presented higher CSF sTREM2 levels than controls (P = 0.01). Carriers of NHD-associated TREM2 variants presented significantly lower CSF sTREM2 levels, supporting the hypothesis that these mutations lead to reduced protein production/function (R136Q, D87N, Q33X or T66M; P = 1×10(-3)). In contrast, CSF sTREM2 levels were significantly higher in R47H carriers compared to non-carriers (P = 6×10(-3)), suggesting that this variant does not impact protein expression and increases AD risk through a different pathogenic mechanism than NHD variants. In GWAS analyses for CSF sTREM2 levels the most significant signal was located on the MS4A gene locus (P = 5.45 × 10(-07)) corresponding to one of the SNPs reported to be associated with AD risk in this locus. Furthermore, SNPs involved in pathways related to virus cellular entry and vesicular trafficking were overrepresented, suggesting that CSF sTREM2 levels could be an informative phenotype for AD.

Functional microRNAs in Alzheimer’s disease and cancer: differential regulation of common mechanisms and pathways

PubMed Central

Holohan, Kelly N.; Lahiri, Debomoy K.; Schneider, Bryan P.; Foroud, Tatiana; Saykin, Andrew J.

2013-01-01

Two of the main research priorities in the United States are cancer and neurodegenerative diseases, which are attributed to abnormal patterns of cellular behavior. MicroRNAs (miRNA) have been implicated as regulators of cellular metabolism, and thus are an active topic of investigation in both disease areas. There is presently a more extensive body of work on the role of miRNAs in cancer compared to neurodegenerative diseases, and therefore it may be useful to examine whether there is any concordance between the functional roles of miRNAs in these diseases. As a case study, the roles of miRNAs in Alzheimer’s disease (AD) and their functions in various cancers will be compared. A number of miRNA expression patterns are altered in individuals with AD compared with healthy older adults. Among these, some have also been shown to correlate with neuropathological changes including plaque and tangle accumulation, as well as expression levels of other molecules known to be involved in disease pathology. Importantly, these miRNAs have also been shown to have differential expression and or functional roles in various types of cancer. To examine possible intersections between miRNA functions in cancer and AD, we review the current literature on these miRNAs in cancer and AD, focusing on their roles in known biological pathways. We propose a pathway-driven model in which some molecular processes show an inverse relationship between cancer and neurodegenerative disease (e.g., proliferation and apoptosis) whereas others are more parallel in their activity (e.g., immune activation and inflammation). A critical review of these and other molecular mechanisms in cancer may shed light on the pathophysiology of AD, and highlight key areas for future research. Conclusions from this work may be extended to other neurodegenerative diseases for which some molecular pathways have been identified but which have not yet been extensively researched for miRNA involvement. PMID:23335942

A fast optimization approach for treatment planning of volumetric modulated arc therapy.

PubMed

Yan, Hui; Dai, Jian-Rong; Li, Ye-Xiong

2018-05-30

Volumetric modulated arc therapy (VMAT) is widely used in clinical practice. It not only significantly reduces treatment time, but also produces high-quality treatment plans. Current optimization approaches heavily rely on stochastic algorithms which are time-consuming and less repeatable. In this study, a novel approach is proposed to provide a high-efficient optimization algorithm for VMAT treatment planning. A progressive sampling strategy is employed for beam arrangement of VMAT planning. The initial beams with equal-space are added to the plan in a coarse sampling resolution. Fluence-map optimization and leaf-sequencing are performed for these beams. Then, the coefficients of fluence-maps optimization algorithm are adjusted according to the known fluence maps of these beams. In the next round the sampling resolution is doubled and more beams are added. This process continues until the total number of beams arrived. The performance of VMAT optimization algorithm was evaluated using three clinical cases and compared to those of a commercial planning system. The dosimetric quality of VMAT plans is equal to or better than the corresponding IMRT plans for three clinical cases. The maximum dose to critical organs is reduced considerably for VMAT plans comparing to those of IMRT plans, especially in the head and neck case. The total number of segments and monitor units are reduced for VMAT plans. For three clinical cases, VMAT optimization takes < 5 min accomplished using proposed approach and is 3-4 times less than that of the commercial system. The proposed VMAT optimization algorithm is able to produce high-quality VMAT plans efficiently and consistently. It presents a new way to accelerate current optimization process of VMAT planning.

Added value of second biopsy target in screen-detected widespread suspicious breast calcifications.

PubMed

Falkner, Nathalie M; Hince, Dana; Porter, Gareth; Dessauvagie, Ben; Jeganathan, Sanjay; Bulsara, Max; Lo, Glen

2018-06-01

There is controversy on the optimal work-up of screen-detected widespread breast calcifications: whether to biopsy a single target or multiple targets. This study evaluates agreement between multiple biopsy targets within the same screen-detected widespread (≥25 mm) breast calcification to determine if the second biopsy adds value. Retrospective observational study of women screened in a statewide general population risk breast cancer mammographic screening program from 2009 to 2016. Screening episodes recalled for widespread calcifications where further views indicated biopsy, and two or more separate target areas were sampled within the same lesion were included. Percentage agreement and Cohen's Kappa were calculated. A total of 293317 women were screened during 761124 separate episodes with recalls for widespread calcifications in 2355 episodes. In 171 women, a second target was biopsied within the same lesion. In 149 (86%) cases, the second target biopsy result agreed with the first biopsy (κ = 0.6768). Agreement increased with increasing mammography score (85%, 86% and 92% for score 3, 4 and 5 lesions). Same day multiple biopsied lesions were three times more likely to yield concordant results compared to post-hoc second target biopsy cases. While a single target biopsy is sufficient to discriminate a benign vs. malignant diagnosis in most cases, in 14% there is added value in performing a second target biopsy. Biopsies performed prospectively are more likely to yield concordant results compared to post-hoc second target biopsy cases, suggesting a single prospective biopsy may be sufficient when results are radiological-pathological concordant; discordance still requires repeat sampling. © 2018 The Royal Australian and New Zealand College of Radiologists.

No association of SORL1 SNPs with Alzheimer's disease.

PubMed

Minster, Ryan L; DeKosky, Steven T; Kamboh, M Ilyas

2008-08-01

SORL1 is an element of the amyloid precursor protein processing pathway and is therefore a good candidate for affecting Alzheimer's disease (AD) risk. Indeed, there have been reports of associations between variation in SORL1 and AD risk. We examined six statistically significant single-nucleotide polymorphisms from the initial observation in a large Caucasian American case-controls cohort (1000 late-onset AD [LOAD] cases and 1000 older controls). Analysis of allele, genotype and haplotype frequencies revealed no association with LOAD risk in our cohort.

SU-E-T-230: Creating a Large Number of Focused Beams with Variable Patient Head Tilt to Improve Dose Fall-Off for Brain Radiosurgery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chiu, J; Ma, L

2015-06-15

Purpose: To develop a treatment delivery and planning strategy by increasing the number of beams to minimize dose to brain tissue surrounding a target, while maximizing dose coverage to the target. Methods: We analyzed 14 different treatment plans via Leksell PFX and 4C. For standardization, single tumor cases were chosen. Original treatment plans were compared with two optimized plans. The number of beams was increased in treatment plans by varying tilt angles of the patient head, while maintaining original isocenter and the beam positions in the x-, y- and z-axes, collimator size, and beam blocking. PFX optimized plans increased beammore » numbers with three pre-set tilt angles, 70, 90, 110, and 4C optimized plans increased beam numbers with tilt angles increasing arbitrarily from range of 30 to 150 degrees. Optimized treatment plans were compared dosimetrically with original treatment plans. Results: Comparing total normal tissue isodose volumes between original and optimized plans, the low-level percentage isodose volumes decreased in all plans. Despite the addition of multiple beams up to a factor of 25, beam-on times for 1 tilt angle versus 3 or more tilt angles were comparable (<1 min.). In 64% (9/14) of the studied cases, the volume percentage decrease by >5%, with the highest value reaching 19%. The addition of more tilt angles correlates to a greater decrease in normal brain irradiated volume. Selectivity and coverage for original and optimized plans remained comparable. Conclusion: Adding large number of additional focused beams with variable patient head tilt shows improvement for dose fall-off for brain radiosurgery. The study demonstrates technical feasibility of adding beams to decrease target volume.« less

Exploring the effect of previous inactivated influenza vaccination on seasonal influenza vaccine effectiveness against medically attended influenza: Results of the European I-MOVE multicentre test-negative case-control study, 2011/2012-2016/2017.

PubMed

Valenciano, Marta; Kissling, Esther; Larrauri, Amparo; Nunes, Baltazar; Pitigoi, Daniela; O'Donnell, Joan; Reuss, Annicka; Horváth, Judit Krisztina; Paradowska-Stankiewicz, Iwona; Rizzo, Caterina; Falchi, Alessandra; Daviaud, Isabelle; Brytting, Mia; Meijer, Adam; Kaic, Bernard; Gherasim, Alin; Machado, Ausenda; Ivanciuc, Alina; Domegan, Lisa; Schweiger, Brunhilde; Ferenczi, Annamária; Korczyńska, Monika; Bella, Antonino; Vilcu, Ana-Maria; Mosnier, Anne; Zakikhany, Katherina; de Lange, Marit; Kurečić Filipovićović, Sanja; Johansen, Kari; Moren, Alain

2018-04-16

Results of previous influenza vaccination effects on current season influenza vaccine effectiveness (VE) are inconsistent. To explore previous influenza vaccination effects on current season VE among population targeted for vaccination. We used 2011/2012 to 2016/2017 I-MOVE primary care multicentre test-negative data. For each season, we compared current season adjusted VE (aVE) between individuals vaccinated and unvaccinated in previous season. Using unvaccinated in both seasons as a reference, we then compared aVE between vaccinated in both seasons, current only, and previous only. We included 941, 2645 and 959 influenza-like illness patients positive for influenza A(H1N1)pdm09, A(H3N2) and B, respectively, and 5532 controls. In 2011/2012, 2014/2015 and 2016/2017, A(H3N2) aVE point estimates among those vaccinated in previous season were -68%, -21% and -19%, respectively; among unvaccinated in previous season, these were 33%, 48% and 46%, respectively (aVE not computable for influenza A(H1N1)pdm09 and B). Compared to current season vaccination only, VE for both seasons' vaccination was (i) similar in two of four seasons for A(H3N2) (absolute difference [ad] 6% and 8%); (ii) lower in three of four seasons for influenza A(H1N1)pdm09 (ad 18%, 26% and 29%), in two seasons for influenza A(H3N2) (ad 27% and 39%) and in two of three seasons for influenza B (ad 26% and 37%); (iii) higher in one season for influenza A(H1N1)pdm09 (ad 20%) and influenza B (ad 24%). We did not identify any pattern of previous influenza vaccination effect. Prospective cohort studies documenting influenza infections, vaccinations and vaccine types are needed to understand previous influenza vaccinations' effects. © 2018 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.

Genetically Predicted Body Mass Index and Alzheimer’s Disease Related Phenotypes in Three Large Samples: Mendelian Randomization Analyses

PubMed Central

Mukherjee, Shubhabrata; Walter, Stefan; Kauwe, John S.K.; Saykin, Andrew J.; Bennett, David A.; Larson, Eric B.; Crane, Paul K.; Glymour, M. Maria

2015-01-01

Observational research shows that higher body mass index (BMI) increases Alzheimer’s disease (AD) risk, but it is unclear whether this association is causal. We applied genetic variants that predict BMI in Mendelian Randomization analyses, an approach that is not biased by reverse causation or confounding, to evaluate whether higher BMI increases AD risk. We evaluated individual level data from the AD Genetics Consortium (ADGC: 10,079 AD cases and 9,613 controls), the Health and Retirement Study (HRS: 8,403 participants with algorithm-predicted dementia status) and published associations from the Genetic and Environmental Risk for AD consortium (GERAD1: 3,177 AD cases and 7,277 controls). No evidence from individual SNPs or polygenic scores indicated BMI increased AD risk. Mendelian Randomization effect estimates per BMI point (95% confidence intervals) were: ADGC OR=0.95 (0.90, 1.01); HRS OR=1.00 (0.75, 1.32); GERAD1 OR=0.96 (0.87, 1.07). One subscore (cellular processes not otherwise specified) unexpectedly predicted lower AD risk. PMID:26079416

Comparing the Nutritional Impact of Dietary Strategies to Reduce Discretionary Choice Intake in the Australian Adult Population: A Simulation Modelling Study.

PubMed

Grieger, Jessica A; Johnson, Brittany J; Wycherley, Thomas P; Golley, Rebecca K

2017-05-03

Dietary strategies to reduce discretionary choice intake are commonly utilized in practice, but evidence on their relative efficacy is lacking. The aim was to compare the potential impact on nutritional intake of three strategies to reducing discretionary choices intake in the Australian adult (19-90 years) population. Dietary simulation modelling using data from the National Nutrition and Physical Activity Survey 2011-2012 was conducted ( n = 9341; one 24 h dietary recall). Strategies modelled were: moderation (reduce discretionary choices by 50%, with 0%, 25% or 75% energy compensation); substitution (replace 50% of discretionary choices with core choices); reformulation (replace 50% SFA with unsaturated fats, reduce added sugars by 25%, and reduce sodium by 20%). Compared to the base case (observed) intake, modelled intakes in the moderation scenario showed: -17.3% lower energy (sensitivity analyses, 25% energy compensation -14.2%; 75% energy compensation -8.0%), -20.9% lower SFA (-17.4%; -10.5%), -43.3% lower added sugars (-41.1%; -36.7%) and 17.7% lower sodium (-14.3%; -7.5%). Substitution with a range of core items, or with fruits, vegetables and core beverages only, resulted in similar changes in energy intake (-13.5% and -15.4%), SFA (-17.7% and -20.1%), added sugars (-42.6% and -43%) and sodium (-13.7% and -16.5%), respectively. Reformulating discretionary choices had minimal impact on reducing energy intake but reduced SFA (-10.3% to -30.9%), added sugars (-9.3% to -52.9%), and alcohol (-25.0% to -49.9%) and sodium (-3.3% to -13.2%). The substitution and reformulation scenarios minimized negative changes in fiber, protein and micronutrient intakes. While each strategy has strengths and limitations, substitution of discretionary choices with core foods and beverages may optimize the nutritional impact.

Clustering and switching processes in semantic verbal fluency in the course of Alzheimer's disease subjects: results from the PAQUID longitudinal study.

PubMed

Raoux, Nadine; Amieva, Hélène; Le Goff, Mélanie; Auriacombe, Sophie; Carcaillon, Laure; Letenneur, Luc; Dartigues, Jean-François

2008-10-01

Reduced semantic fluency performances have been reported in the preclinical phase of Alzheimer's disease (AD). To investigate the cognitive processes underlying this early deficit, this study analyzed the verbal production of predemented subjects for the animals category with the qualitative parameters related to clustering (i.e. the ability to generate words belonging to semantic subcategories of animals) and switching (i.e. the ability to shift from one subcategory to another) proposed by Troyer. This qualitative analysis was applied to the PAQUID (Personnes Agées QUID) cohort, a 17-year longitudinal population-based study. The performances on the animal verbal fluency task of 51 incident cases of possible and probable AD were analyzed at the onset of dementia, 2 years and 5 years before dementia onset. Each case was matched for age, sex and education to two control subjects leading to a sample of 153 subjects. The mean cluster size and the raw number of switches were compared in the two samples. The results revealed a significantly lower switching index in the future AD subjects than in the elderly controls including 5 years before dementia incidence. A significant decline in this parameter was evidenced all along the prodromal phase until the clinical diagnosis of dementia. In contrast, the mean cluster size could not discriminate the two groups. Therefore the results support the hypothesis that impaired shifting abilities - rather than semantic memory storage degradation - could explain the early decline in semantic fluency performance occurring in the predementia phase of AD.

The added value of mifepristone to non-surgical treatment regimens for uterine evacuation in case of early pregnancy failure: a systematic review of the literature.

PubMed

van den Berg, Joyce; Gordon, Bernardus B M; Snijders, Marcus P M L; Vandenbussche, Frank P H A; Coppus, Sjors F P J

2015-12-01

Early pregnancy failure (EPF) is a common complication of pregnancy. Surgical intervention carries a risk of complications and, therefore, medical treatment appears to be a safe alternative. Unfortunately, the current medical treatment with misoprostol alone has complete evacuation rates between 53% and 87%. Some reports suggest that sequential treatment with mifepristone and misoprostol leads to higher success rates than misoprostol alone. To evaluate the added value of mifepristone to current non-surgical treatment regimens in women with EPF we performed a systematic literature search. Electronic databases were searched: PubMed, Cochrane Library, Current Controlled Trials, and ClinicalTrials.gov. Clinical studies, both randomised and non-randomised trials, reporting on the added value of mifepristone to current non-surgical treatment regimens in women with EPF were included. Data of sixteen studies were extracted using a data extraction sheet (based on the Cochrane Consumers and Communication Review Group's data extraction template). The methodological quality was assessed using the Cochrane Collaboration Risk of Bias tool. In five randomised and eleven non-randomised trials, success rates of sequential treatment with mifepristone and misoprostol in case of EPF varied between 52% and 95%. Large heterogeneity existed in treatment regimens and comparators between studies. The existing evidence is insufficient to draw firm conclusions about the added value of mifepristone to misoprostol alone. A sufficiently powered randomised, double blinded placebo-controlled trial is urgently required to test whether, in EPF, the sequential combination of mifepristone with misoprostol is superior to misoprostol only. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Numerical analysis of wall shear stress in ascending aorta before tearing in type A aortic dissection.

PubMed

Chi, Qingzhuo; He, Ying; Luan, Yong; Qin, Kairong; Mu, Lizhong

2017-10-01

Although the incidence of many cardiovascular diseases has declined as medical treatments have improved, the prevalence of aortic dissection (AD) has increased. Compared to type B dissections, type A dissections are more severe, and most patients with type A dissections require surgical treatment. The objective of this study was to investigate the relationships between the wall shear stress (WSS) on the aortic endothelium and the frequent tearing positions using computational fluid dynamics. Five type A dissection cases and two normal aortas were included in the study. First, the structures of the aortas before the type A dissection were reconstructed on the basis of the original imaging data. Analyses of flow in the reconstructed premorbid structures reveals that the rupture positions in three of the five cases corresponded to the area of maximum elevated WSS. Moreover, the WSS at the junction of the aortic arch and descending aorta was found to be elevated, which is considered to be related to the locally disturbed helical flow. Meanwhile, the highest WSS in the patients with premorbid AD was found to be almost double that of the control group. Due to the noticeable morphological differences between the AD cases and the control group, the WSSs in the premorbid structures without vasodilation in the ascending part were estimated. The computational results revealed that the WSS was lower in the aorta without vasodilation, but the pressure drop in this situation was higher than that with vasodilation in the ascending aorta. Significant differences were seen between the AD cases and the control group in the angles of the side branches of the aortic arch and its bending degree. Dilation of the ascending aorta and alterations in the branching angles may be the key determinants of a high WSS that leads to type A dissection. Greater tortuosity of the aortic arch leads to stronger helical flow through the distal aortic arch, which may be related to tears in this region. Copyright © 2017 Elsevier Ltd. All rights reserved.

Big Missiles and Big Decks: The Viability of Aircraft Carriers in an A2/AD World

DTIC Science & Technology

2016-06-01

RESEARCH DESIGN This thesis centers on a historical case study of two periods in which the United States and its carrier fleet faced some degree...19 3. Lessons Learned ...........................................................................21 C. APPLICABILITY OF CASE STUDIES ...employed the strategic concepts behind A2/AD since the Persian War of 480 BC. In his analysis of several historic case studies , Tangredi notes that a

Expression of cellular prion protein in the frontal and occipital lobe in Alzheimer's disease, diffuse Lewy body disease, and in normal brain: an immunohistochemical study.

PubMed

Rezaie, Payam; Pontikis, Charlie C; Hudson, Lance; Cairns, Nigel J; Lantos, Peter L

2005-08-01

Cellular prion protein (PrP(c)) is a glycoprotein expressed at low to moderate levels within the nervous system. Recent studies suggest that PrP(c) may possess neuroprotective functions and that its expression is upregulated in certain neurodegenerative disorders. We investigated whether PrP(c) expression is altered in the frontal and occipital cortex in two well-characterized neurodegenerative disorders--Alzheimer's disease (AD) and diffuse Lewy body disease (DLBD)--compared with that in normal human brain using immunohistochemistry and computerized image analysis. The distribution of PrP(c) was further tested for correlation with glial reactivity. We found that PrP(c) was localized mainly in the gray matter (predominantly in neurons) and expressed at higher levels within the occipital cortex in the normal human brain. Image analysis revealed no significant variability in PrP(c) expression between DLBD and control cases. However, blood vessels within the white matter of DLBD cases showed immunoreactivity to PrP(c). By contrast, this protein was differentially expressed in the frontal and occipital cortex of AD cases; it was markedly overexpressed in the former and significantly reduced in the latter. Epitope specificity of antibodies appeared important when detecting PrP(c). The distribution of PrP(c) did not correlate with glial immunoreactivity. In conclusion, this study supports the proposal that regional changes in expression of PrP(c) may occur in certain neurodegenerative disorders such as AD, but not in other disorders such as DLBD.

Alcohol dependence associated with increased utilitarian moral judgment: a case control study.

PubMed

Khemiri, Lotfi; Guterstam, Joar; Franck, Johan; Jayaram-Lindström, Nitya

2012-01-01

Recent studies indicate that emotional processes, mediated by the ventromedial prefrontal cortex (VMPC), are of great importance for moral judgment. Neurological patients with VMPC dysfunction have been shown to generate increased utilitarian moral judgments, i.e. are more likely to endorse emotionally aversive actions in order to maximize aggregate welfare, when faced with emotionally salient personal moral dilemmas. Patients with alcohol dependence (AD) also exhibit impairments in functions mediated by the prefrontal cortex, but whether they exhibit increased utilitarian moral reasoning has not previously been investigated. The aim of this study was to investigate moral judgment in AD patients (n = 20) compared to healthy controls (n = 20) matched by sex, age and education years. Each subject responded to a battery of 50 hypothetical dilemmas categorized as non-moral, moral impersonal and moral personal. They also responded to a questionnaire evaluating explicit knowledge of social and moral norms. Results confirmed our hypothesis that AD patients generated increased utilitarian moral judgment compared to controls when faced with moral personal dilemmas. Crucially, there was no difference in their responses to non-moral or impersonal moral dilemmas, nor knowledge of explicit social and moral norms. One possible explanation is that damage to the VMPC, caused by long term repeated exposure to alcohol results in emotional dysfunction, predisposing to utilitarian moral judgment. This work elucidates a novel aspect of the neuropsychological profile of AD patients, namely a tendency to generate utilitarian moral judgment when faced with emotionally salient moral personal dilemmas.

Could Alkali Production Be Considered an Approach for Caries Control?

PubMed Central

Gordan, V.V.; Garvan, C.W.; Ottenga, M.E.; Schulte, R.; Harris, P.A.; McEdward, D.; Magnusson, I.

2011-01-01

This study investigated the relationship of arginine deiminase (ADS) and urease activities with dental caries through a case-control study. ADS and urease activities were measured in dental smooth-surface supragingival plaque and whole saliva samples from 93 subjects, who were in three different groups: caries-free (n = 31), caries-active (n = 30), and caries-experienced (n = 32). ADS activity was measured by quantification of the ammonia generated from the incubation of plaque and saliva samples in a mixture containing 50 mM arginine-HCl and 50 mM Tris-maleate buffer, pH 6.0. ADS-specific activity was defined as nanomoles of ammonia generated per minute per milligram of protein. Urease activity was determined by quantification of ammonia produced from 50 mM urea. For bacterial identification and enumeration real-time qPCR analysis was used. Groups were compared using Kruskal-Wallis tests. Spearman correlations were used to analyze plaque metabolic activity and bacterial relationships. The results revealed significantly higher ammonia production from arginine in saliva (1.06 vs. 0.18; p < 0.0001) and plaque samples (1.74 vs. 0.58; p < 0.0001) from caries-free subjects compared to caries-active subjects. Urease levels were about 3-fold higher in the plaque of caries-free subjects (p < 0.0001). Although higher urease activity in saliva of caries-experienced and caries-free subjects was evident, no significant difference was found between the groups. PMID:21071940

Alcohol Dependence Associated with Increased Utilitarian Moral Judgment: A Case Control Study

PubMed Central

Khemiri, Lotfi; Guterstam, Joar; Franck, Johan; Jayaram-Lindström, Nitya

2012-01-01

Recent studies indicate that emotional processes, mediated by the ventromedial prefrontal cortex (VMPC), are of great importance for moral judgment. Neurological patients with VMPC dysfunction have been shown to generate increased utilitarian moral judgments, i.e. are more likely to endorse emotionally aversive actions in order to maximize aggregate welfare, when faced with emotionally salient personal moral dilemmas. Patients with alcohol dependence (AD) also exhibit impairments in functions mediated by the prefrontal cortex, but whether they exhibit increased utilitarian moral reasoning has not previously been investigated. The aim of this study was to investigate moral judgment in AD patients (n = 20) compared to healthy controls (n = 20) matched by sex, age and education years. Each subject responded to a battery of 50 hypothetical dilemmas categorized as non-moral, moral impersonal and moral personal. They also responded to a questionnaire evaluating explicit knowledge of social and moral norms. Results confirmed our hypothesis that AD patients generated increased utilitarian moral judgment compared to controls when faced with moral personal dilemmas. Crucially, there was no difference in their responses to non-moral or impersonal moral dilemmas, nor knowledge of explicit social and moral norms. One possible explanation is that damage to the VMPC, caused by long term repeated exposure to alcohol results in emotional dysfunction, predisposing to utilitarian moral judgment. This work elucidates a novel aspect of the neuropsychological profile of AD patients, namely a tendency to generate utilitarian moral judgment when faced with emotionally salient moral personal dilemmas. PMID:22761922

Thermodynamics of Newman-Unti-Tamburino charged spaces

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mann, Robert; Department of Physics, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, N2L 3G1; Stelea, Cristian

We discuss and compare at length the results of two methods used recently to describe the thermodynamics of Taub-Newman-Unti-Tamburino (NUT) solutions in a de Sitter background. In the first approach (C approach), one deals with an analytically continued version of the metric while in the second approach (R approach), the discussion is carried out using the unmodified metric with Lorentzian signature. No analytic continuation is performed on the coordinates and/or the parameters that appear in the metric. We find that the results of both these approaches are completely equivalent modulo analytic continuation and we provide the exact prescription that relatesmore » the results in both methods. The extension of these results to the AdS/flat cases aims to give a physical interpretation of the thermodynamics of NUT-charged spacetimes in the Lorentzian sector. We also briefly discuss the higher-dimensional spaces and note that, analogous with the absence of hyperbolic NUTs in AdS backgrounds, there are no spherical Taub-NUT-dS solutions.« less

Economic analysis of fuel ethanol production from winter hulled barley by the EDGE (Enhanced Dry Grind Enzymatic) process.

PubMed

Nghiem, Nhuan P; Ramírez, Edna C; McAloon, Andrew J; Yee, Winnie; Johnston, David B; Hicks, Kevin B

2011-06-01

A process and cost model was developed for fuel ethanol production from winter barley based on the EDGE (Enhanced Dry Grind Enzymatic) process. In this process, in addition to β-glucanases, which are added to reduce the viscosity of the mash, β-glucosidase is also added to completely hydrolyze the oligomers obtained during the hydrolysis of β-glucans to glucose. The model allows determination of capital costs, operating costs, and ethanol production cost for a plant producing 40 million gallons of denatured fuel ethanol annually. A sensitivity study was also performed to examine the effects of β-glucosidase and barley costs on the final ethanol production cost. The results of this study clearly demonstrate the economic benefit of adding β-glucosidase. Lower ethanol production cost was obtained compared to that obtained without β-glucosidase addition in all cases except one where highest β-glucosidase cost allowance and lowest barley cost were used. Copyright © 2011 Elsevier Ltd. All rights reserved.

Oral infections and orofacial pain in Alzheimer’s disease: Case report and review

PubMed Central

de Siqueira, Silvia Regina Dowgan T.; Rolim, Thaís de Souza; Teixeira, Manoel Jacobsen; Nitrini, Ricardo; Anghinah, Renato; de Siqueira, José Tadeu T.

2010-01-01

Dental infections, frequent in the general population, are a common cause of inflammation with systemic impact, and are the most common cause of orofacial pain. Temporomandibular disorders are also frequent in the elderly and represent an important cause of secondary headache. Both inflammation and pain can also contribute to cognitive, functional and behavioral impairment of the elderly and aggravate symptoms of patients with Alzheimer’s disease (AD). We report a case of a 74-year-old woman with AD and chronic facial pain who had a significant improvement in functional activities as well as in cognition and depressive symptoms after successful treatment of her facial pain. Patients with AD have higher compromise of oral health with infections and teeth loss. The investigation of orofacial pain should be performed in patients with AD, because of the associations reviewed and given the potential for improvement as highlighted by this case. PMID:29213678

C-reactive protein and serum creatinine, but not haemoglobin A1c, are independent predictors of coronary heart disease risk in non-diabetic Chinese.

PubMed

Salim, Agus; Tai, E Shyong; Tan, Vincent Y; Welsh, Alan H; Liew, Reginald; Naidoo, Nasheen; Wu, Yi; Yuan, Jian-Min; Koh, Woon P; van Dam, Rob M

2016-08-01

In western populations, high-sensitivity C-reactive protein (hsCRP), and to a lesser degree serum creatinine and haemoglobin A1c, predict risk of coronary heart disease (CHD). However, data on Asian populations that are increasingly affected by CHD are sparse and it is not clear whether these biomarkers can be used to improve CHD risk classification. We conducted a nested case-control study within the Singapore Chinese Health Study cohort, with incident 'hard' CHD (myocardial infarction or CHD death) as an outcome. We used data from 965 men (298 cases, 667 controls) and 528 women (143 cases, 385 controls) to examine the utility of hsCRP, serum creatinine and haemoglobin A1c in improving the prediction of CHD risk over and above traditional risk factors for CHD included in the ATP III model. For each sex, the performance of models with only traditional risk factors used in the ATP III model was compared with models with the biomarkers added using weighted Cox proportional hazards analysis. The impact of adding these biomarkers was assessed using the net reclassification improvement index. For men, loge hsCRP (hazard ratio 1.25, 95% confidence interval: 1.05; 1.49) and loge serum creatinine (hazard ratio 4.82, 95% confidence interval: 2.10; 11.04) showed statistically significantly associations with CHD risk when added to the ATP III model. We did not observe a significant association between loge haemoglobin A1c and CHD risk (hazard ratio 1.83, 95% confidence interval: 0.21; 16.06). Adding hsCRP and serum creatinine to the ATP III model improved risk classification in men with a net gain of 6.3% of cases (p-value = 0.001) being reclassified to a higher risk category, while it did not significantly reduce the accuracy of classification for non-cases. For women, squared hsCRP was borderline significantly (hazard ratio 1.01, 95% confidence interval: 1.00; 1.03) and squared serum creatinine was significantly (hazard ratio 1.81, 95% confidence interval: 1.49; 2.21) associated with CHD risk. However, the association between squared haemoglobin A1c and CHD risk was not significant (hazard ratio 1.05, 95% confidence interval: 0.99; 1.12). The addition of hsCRP and serum creatinine to the ATP III model resulted in 3.7% of future cases being reclassified to a higher risk category (p-value = 0.025), while it did not significantly reduce the accuracy of classification for non-cases. Adding hsCRP and serum creatinine, but not haemoglobin A1c, to traditional risk factors improved CHD risk prediction among non-diabetic Singaporean Chinese. The improved risk estimates will allow better identification of individuals at high risk of CHD than existing risk calculators such as the ATP III model. © The European Society of Cardiology 2016.

AdS5 solutions from M5-branes on Riemann surface and D6-branes sources

DOE PAGES

Bah, Ibrahima

2015-09-24

Here, we describe the gravity duals of four-dimensional N = 1 superconformal field theories obtained by wrapping M5-branes on a punctured Riemann surface. The internal geometry, normal to the AdS 5 factor, generically preserves two U(1)s, with generators (J +, J –), that are fibered over the Riemann surface. The metric is governed by a single potential that satisfies a version of the Monge-Ampère equation. The spectrum of N = 1 punctures is given by the set of supersymmetric sources of the potential that are localized on the Riemann surface and lead to regular metrics near a puncture. We usemore » this system to study a class of punctures where the geometry near the sources corresponds to M-theory description of D6-branes. These carry a natural (p, q) label associated to the circle dual to the killing vector pJ + + qJ – which shrinks near the source. In the generic case the world volume of the D6-branes is AdS 5 × S 2 and they locally preserve N = 2 supersymmetry. When p = –q, the shrinking circle is dual to a flavor U(1). The metric in this case is non-degenerate only when there are co-dimension one sources obtained by smearing M5-branes that wrap the AdS 5 factor and the circle dual the superconformal R-symmetry. The D6-branes are extended along the AdS 5 and on cups that end on the co-dimension one branes. In the special case when the shrinking circle is dual to the R-symmetry, the D6-branes are extended along the AdS 5 and wrap an auxiliary Riemann surface with an arbitrary genus. When the Riemann surface is compact with constant curvature, the system is governed by a Monge-Ampère equation.« less

Euclidean Wilson loops and minimal area surfaces in lorentzian AdS 3

DOE PAGES

Irrgang, Andrew; Kruczenski, Martin

2015-12-14

The AdS/CFT correspondence relates Wilson loops in N=4 SYM theory to minimal area surfaces in AdS 5 × S 5 space. If the Wilson loop is Euclidean and confined to a plane (t, x) then the dual surface is Euclidean and lives in Lorentzian AdS 3 c AdS 5. In this paper we study such minimal area surfaces generalizing previous results obtained in the Euclidean case. Since the surfaces we consider have the topology of a disk, the holonomy of the flat current vanishes which is equivalent to the condition that a certain boundary Schrödinger equation has all its solutionsmore » anti-periodic. If the potential for that Schrödinger equation is found then reconstructing the surface and finding the area become simpler. In particular we write a formula for the Area in terms of the Schwarzian derivative of the contour. Finally an infinite parameter family of analytical solutions using Riemann Theta functions is described. In this case, both the area and the shape of the surface are given analytically and used to check the previous results.« less

The free and cued selective reminding test for predicting progression to Alzheimer's disease in patients with mild cognitive impairment: A prospective longitudinal study.

PubMed

Lemos, Raquel; Marôco, João; Simões, Mário R; Santiago, Beatriz; Tomás, José; Santana, Isabel

2017-03-01

Amnestic mild cognitive impairment (aMCI) patients carry a greater risk of conversion to Alzheimer's disease (AD). Therefore, the International Working Group (IWG) on AD aims to consider some cases of aMCI as symptomatic prodromal AD. The core diagnostic marker of AD is a significant and progressive memory deficit, and the Free and Cued Selective Reminding Test (FCSRT) was recommended by the IWG to test memory in cases of possible prodromal AD. This study aims to investigate whether the performance on the FCSRT would enhance the ability to predict conversion to AD in an aMCI group. A longitudinal study was conducted on 88 aMCI patients, and neuropsychological tests were analysed on the relative risk of conversion to AD. During follow-up (23.82 months), 33% of the aMCI population converted to AD. An impaired FCSRT TR was significantly associated with the risk of conversion to dementia, with a mean time to conversion of 25 months. The FCSRT demonstrates utility for detecting AD at its prodromal stage, thus supporting its use as a valid clinical marker. © 2015 The British Psychological Society.

Using CSF biomarkers to replicate genetic associations in Alzheimer's disease.

PubMed

Schott, Jonathan M

2012-07-01

Defining cases and controls on the basis of biomarkers rather than clinical diagnosis may reduce sample sizes required for genetic studies. The aim of this study was to assess whether characterizing case/control status on the basis of cerebrospinal fluid (CSF) profile would increase power to replicate known genetic associations for Alzheimer's disease (AD). Independent of clinical diagnosis, Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects with 2 CSF biomarkers for AD (Aβ1-42 < 192 pg/mL and tau phosphorylated at threonine 181 (p-tau) > 23 pg/mL, "CSF-positive") were compared with those without CSF evidence for AD (Aβ1-42 > 192 pg/mL and 181-phosphorylated tau < 23 pg/mL, "CSF-negative"). Minor allele frequency (MAF) and odds ratios (ORs) between these 2 groups were calculated for 7 single-nucleotide polymorphisms (SNPs) of interest. Two hundred thirty-two individuals were CSF-positive and 94 CSF-negative. There were no differences in age (74.7 ± 7.2 vs. 75.0 ± 6.5 years, p = 0.7), but significant differences in Mini Mental State Examination (MMSE) (25.9 ± 2.6 vs. 28.2 ± 1.7, p < 0.001) between the CSF-positive and CSF-negative groups. Significant differences in MAF (p < 0.05, uncorrected) were seen for CR1 (rs1408077; OR, 1.59; 95% confidence interval [CI], 1.01-2.49), PICALM (rs541458; OR, 0.68, 95% CI, 0.47-0.98), TOMM40 (rs2075650; OR, 4.30; 95% CI, 2.61-7.06); and possession of 1 or more APOE ε4 alleles (OR, 9.84; 95% CI, 5.48-17.67). These results suggest that using biomarkers of AD pathology to define case and control status may increase power in genetic association studies. Copyright © 2012 Elsevier Inc. All rights reserved.

Reduced Mitochondrial Activity is Early and Steady in the Entorhinal Cortex but it is Mainly Unmodified in the Frontal Cortex in Alzheimer's Disease.

PubMed

Armand-Ugon, Mercedes; Ansoleaga, Belen; Berjaoui, Sara; Ferrer, Isidro

2017-01-01

It is well established that mitochondrial damage plays a role in the pathophysiology of Alzheimer's disease (AD). However, studies carried out in humans barely contemplate regional differences with disease progression. To study the expression of selected nuclear genes encoding subunits of the mitochondrial complexes and the activity of mitochondrial complexes in AD, in two regions: the entorhinal cortex (EC) and frontal cortex area 8 (FC). Frozen samples from 148 cases processed for gene expression by qRT-PCR and determination of individual activities of mitochondrial complexes I, II, IV and V using commercial kits and home-made assays. Decreased expression of NDUFA2, NDUFB3, UQCR11, COX7C, ATPD, ATP5L and ATP50, covering subunits of complex I, II, IV and V, occurs in total homogenates of the EC in AD stages V-VI when compared with stages I-II. However reduced activity of complexes I, II and V of isolated mitochondria occurs as early as stages I-II when compared with middle-aged individuals in the EC. In contrast, no alterations in the expression of the same genes and no alterations in the activity of mitochondrial complexes are found in the FC in the same series. Different mechanisms of impaired energy metabolism may occur in AD, one of them, represented by the EC, is the result of primary and early alteration of mitochondria; the other one is probably the result, at least in part, of decreased functional input and is represented by hypometabolism in the FC in AD patients aged 86 or younger. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Relative risk of Alzheimer disease and age-at-onset distributions, based on APOE genotypes among elderly African Americans, caucasians, and hispanics in New York City

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tang, M.X.; Liu, X.H.; Stern, Y.

1996-03-01

Apolipoprotein-E {epsilon}4 (APOE-{epsilon}4) has been consistently associated with Alzheimer disease (AD) and may be responsible for an earlier age at onset. We have previously reported a diminished association between APOE-{epsilon}4 and AD in African Americans. Using a new method, which allows inclusion of censored information, we compared relative risks by APOE genotypes in an expanded collection of cases and controls from three ethnic groups in a New York community. The relative risk for AD associated with APOE-{epsilon}4 homozygosity was increased in all ethnic groups (African American relative risk [RR] = 3.0; 95% confidence interval [CI] = 1.5-5.9; Caucasian RR =more » 7.3, 95% CI = 2.5-21.6; and Hispanic RR = 2.5, 95% CI = 1.1-5.7), compared with those with APOE-{epsilon}3/{epsilon}3 genotypes. The risk was also increased for APOE-{epsilon}4 heterozygous Caucasians (RR = 2.9, 95% CI = 1.7-5.1) and Hispanics (RR = 1.6,95% CI = 1.1-2.3), but not for African Americans (RR = 0.6, 95% CI = 0.4-0.9). The age distribution of the proportion of Caucasians and Hispanics without AD was consistently lower for APOE-{epsilon}4 homozygous and APOE-{epsilon}4 heterozygous individuals than for those with other APOE genotypes. In African Americans this relationship was observed only in APOE-{epsilon}4 homozygotes. These results confirm that APOE genotypes influence the RR of AD in Caucasians and Hispanics. Differences in risk among APOE-{epsilon}4 heterozygote African Americans suggest that other genetic or environmental factors may modify the effect of APOE-{epsilon}4 in some populations. 58 refs., 3 figs., 4 tabs.« less

Platelet rich fibrin in jaw defects

NASA Astrophysics Data System (ADS)

Nica, Diana; Ianes, Emilia; Pricop, Marius

2016-03-01

Platelet rich fibrin (PRF) is a tissue product of autologous origin abundant in growth factors, widely used in regenerative procedures. Aim of the study: Evaluation of the regenerative effect of PRF added in the bony defects (after tooth removal or after cystectomy) Material and methods: The comparative nonrandomized study included 22 patients divided into 2 groups. The first group (the test group) included 10 patients where the bony defects were treated without any harvesting material. The second group included 12 patients where the bony defects were filled with PRF. The bony defect design was not critical, with one to two walls missing. After the surgeries, a close clinically monitoring was carried out. The selected cases were investigated using both cone beam computer tomography (CBCT) and radiographic techniques after 10 weeks postoperatively. Results: Faster bone regeneration was observed in the bony defects filled with PRF comparing with the not grafted bony defects. Conclusions: PRF added in the bony defects accelerates the bone regeneration. This simplifies the surgical procedures and decreases the economic costs.

Three SNPs in the GSTO1, GSTO2 and PRSS11 genes on chromosome 10 are not associated with age-at-onset of Alzheimer's disease.

PubMed

Ozturk, Ayla; Desai, Purnima P; Minster, Ryan L; Dekosky, Steven T; Kamboh, M Ilyas

2005-01-01

Linkage studies suggest the presence of putative risk and/or age-at-onset genes for Alzheimer's disease on Chromosome 10. Recently, a genomic converging approach using a combination of linkage, expression and association studies has reported significant associations of the glutathione S-transferase omega 1 and 2 (GSTO1 and GSTO2) genes and possibly the protease serine 11 (PRSS11) gene on chromosome 10 with age-at-onset, but not risk, for Alzheimer's disease (AD) and Parkinson disease. We investigated the association of the reported three polymorphisms in 990 sporadic late-onset AD cases (26% autopsy confirmed) and 735 controls. In our sample, we found no association either with age-at-onset in AD cases or with disease risk in the case-control cohort. However, haplotype analysis revealed a modest association of one haplotype with AD risk (p = 0.04). Additional markers in these genes need to be screened to explore their role in the etiology of AD.

Fermionic halos at finite temperature in AdS/CFT

NASA Astrophysics Data System (ADS)

Argüelles, Carlos R.; Grandi, Nicolás E.

2018-05-01

We explore the gravitational backreaction of a system consisting in a very large number of elementary fermions at finite temperature, in asymptotically AdS space. We work in the hydrodynamic approximation, and solve the Tolman-Oppenheimer-Volkoff equations with a perfect fluid whose equation of state takes into account both the relativistic effects of the fermionic constituents, as well as its finite temperature effects. We find a novel dense core-diluted halo structure for the density profiles in the AdS bulk, similarly as recently reported in flat space, for the case of astrophysical dark matter halos in galaxies. We further study the critical equilibrium configurations above which the core undergoes gravitational collapse towards a massive black hole, and calculate the corresponding critical central temperatures, for two qualitatively different central regimes of the fermions: the diluted-Fermi case, and the degenerate case. As a probe for the dual CFT, we construct the holographic two-point correlator of a scalar operator with large conformal dimension in the worldline limit, and briefly discuss on the boundary CFT effects at the critical points.

A Better State of War: Surmounting the Ethical Cliff in Cyber Warfare

DTIC Science & Technology

2014-06-01

This study analyzes the emergent field of cyber warfare through the lens of commonly-accepted tenets of ethical warfare. By comparing the...foundational understanding of concepts that determine the justice of wars (jus ad bellum) and justice in war (jus en bello) with the capabilities cyber warfare offers...analyzing how cyber warfare affects each of the core concepts introduced above. The fourth chapter presents a case study that tests the theoretical

Features of Vocal Fold Adductor Paralysis and the Management of Posterior Muscle in Thyroplasty.

PubMed

Konomi, Ujimoto; Tokashiki, Ryoji; Hiramatsu, Hiroyuki; Motohashi, Ray; Sakurai, Eriko; Toyomura, Fumimasa; Nomoto, Masaki; Kawada, Yuri; Suzuki, Mamoru

2016-03-01

To present the pathologic characteristics of unilateral recurrent nerve adductor branch paralysis (AdBP), and to investigate the management of posterior cricoarytenoid (PCA) muscle on the basis of our experience of surgical treatment for AdBP. This is a retrospective review of clinical records Four cases of AdBP, in which surgical treatment was performed, are presented. AdBP shows disorders of vocal fold adduction because of paralysis of the thyroarytenoid and lateral cricoarytenoid muscles. The PCA muscle, dominated by the recurrent nerve PCA muscle branch, does not show paralysis. Thus, this type of partial recurrent nerve paresis retains the abductive function and is difficult to distinguish from arytenoid cartilage dislocation because of their similar endoscopic findings. The features include acute onset, and all cases were idiopathic etiology. Thyroarytenoid muscle paralysis was determined by electromyography and stroboscopic findings. The adduction and abduction of paralytic arytenoids were evaluated from 3 dimensional computed tomography (3DCT). In all cases, surgical treatments were arytenoid adduction combined with thyroplasty. When we adducted the arytenoid cartilage during inspiration, strong resistance was observed. In the two cases where we could cut the PCA muscle sufficiently, the maximum phonation time was improved to ≥30 seconds after surgery, from 2 to 3 seconds preoperatively, providing good postoperative voices. In contrast, in the two cases of insufficient resection, the surgical outcomes were poorer. Because the preoperative voice in AdBP patients is typically very coarse, surgical treatment is needed, as well as ordinary recurrent nerve paralysis. In our experience, adequate PCA muscle resection might be helpful in surgical treatment of AdBP. Copyright © 2016 The Voice Foundation. Published by Elsevier Inc. All rights reserved.

Remembering childhood atopic dermatitis as an adult: factors that influence recollection.

PubMed

Moberg, C; Meding, B; Stenberg, B; Svensson, A; Lindberg, M

2006-09-01

Atopic dermatitis (AD) is common in the population, and studies have shown that the disease is on the increase. Studies based on hospital records reflect selected populations and may miss less severe cases of AD, and the use of self-reported questionnaires has the drawback of recall bias. To investigate some possible factors influencing recall bias when questionnaires are used to establish the prevalence of childhood eczema in an adult population. A questionnaire regarding past and present eczema was sent to 557 cases (with signs suggesting the diagnosis AD) and 554 matched controls (subjects lacking signs of AD) born during 1960-1969 and identified in school health medical records. Cases and controls were aged 31-42 years at the time of the study and 70.5% returned the questionnaire. Of 403 cases, 29% did not report childhood eczema in the questionnaire. There was a difference between those who did recall their childhood AD (remembering group, RG), and those who did not (forgetful group, FG) in who had documented the diagnostic signs in the school health records. In the RG the signs were reported by both parents and school health personnel in 51% of cases, and in the FG this was true of only 16%. The RG had a higher prevalence of eczema after 15 years of age and of hand eczema. The RG also reported more visits to physicians after the age of 15 years and more time taken as sick leave due to eczema. Several factors influence how well people remember their AD in childhood. These factors include disease activity in adult life, disease severity, and who noticed the eczema in childhood.

Characteristics of Adenovirus Pneumonia in Korean Military Personnel, 2012–2016

PubMed Central

Yoon, Hee; Yoo, Hongseok; Park, Sung Bum

2017-01-01

Adenovirus (AdV) can cause severe pneumonia in non-immunocompromised host, but limited data exist on the distinctive characteristics of AdV pneumonia in non-immunocompromised patients. We evaluated distinctive clinico-laboratory and radiological characteristics and outcomes of AdV pneumonia (n = 179), compared with non-AdV pneumonia (n = 188) in Korean military personnel between 2012 and 2016. AdV pneumonia patients had a higher rate of consolidation with ground-glass opacity (101/152) in lobar distribution (89/152) on computed tomography (CT) (P < 0.001). Laboratory findings showed a higher incidence of unusual blood profiles such as leukopenia (55/179, P < 0.001) or thrombocytopenia (100/179, P < 0.001). The patients had more systemic symptoms such as myalgia (82/179, P = 0.001) or diarrhea (23/179, P < 0.001), compared with non-AdV pneumonia patients. Bacterial co-infection was identified in 28.5% of AdV pneumonia. Most of the AdV isolates typed (69/72, 95.8%) were AdV-55. Patients with a pneumonia severity index ≥ class III were more commonly observed in AdV pneumonia patients compared with non-AdV pneumonia patients (11.2% vs. 2.1%, P < 0.001), and time to clinical stabilization from admission was longer in the AdV pneumonia patients compared with the non-AdV pneumonia patients (3.8 vs. 2.6 days, P < 0.001). Mechanical ventilation (n = 6) was only required in AdV pneumonia patients, one of whom died due to AdV-55. Our data showed that AdV pneumonia in non-immunocompromised patients had distinct characteristics and most of the isolates typed in our study were AdV-55. It is suggested that AdV-55 is an important pathogen of pneumonia in Korean military personnel. PMID:28049240

Characteristics of Adenovirus Pneumonia in Korean Military Personnel, 2012-2016.

PubMed

Yoon, Hee; Jhun, Byung Woo; Kim, Hojoong; Yoo, Hongseok; Park, Sung Bum

2017-02-01

Adenovirus (AdV) can cause severe pneumonia in non-immunocompromised host, but limited data exist on the distinctive characteristics of AdV pneumonia in non-immunocompromised patients. We evaluated distinctive clinico-laboratory and radiological characteristics and outcomes of AdV pneumonia (n = 179), compared with non-AdV pneumonia (n = 188) in Korean military personnel between 2012 and 2016. AdV pneumonia patients had a higher rate of consolidation with ground-glass opacity (101/152) in lobar distribution (89/152) on computed tomography (CT) (P < 0.001). Laboratory findings showed a higher incidence of unusual blood profiles such as leukopenia (55/179, P < 0.001) or thrombocytopenia (100/179, P < 0.001). The patients had more systemic symptoms such as myalgia (82/179, P = 0.001) or diarrhea (23/179, P < 0.001), compared with non-AdV pneumonia patients. Bacterial co-infection was identified in 28.5% of AdV pneumonia. Most of the AdV isolates typed (69/72, 95.8%) were AdV-55. Patients with a pneumonia severity index ≥ class III were more commonly observed in AdV pneumonia patients compared with non-AdV pneumonia patients (11.2% vs. 2.1%, P < 0.001), and time to clinical stabilization from admission was longer in the AdV pneumonia patients compared with the non-AdV pneumonia patients (3.8 vs. 2.6 days, P < 0.001). Mechanical ventilation (n = 6) was only required in AdV pneumonia patients, one of whom died due to AdV-55. Our data showed that AdV pneumonia in non-immunocompromised patients had distinct characteristics and most of the isolates typed in our study were AdV-55. It is suggested that AdV-55 is an important pathogen of pneumonia in Korean military personnel.

Government Workers Adding Societal Value: The Ohio Workforce Development Program

ERIC Educational Resources Information Center

Guerra, Ingrid; Bernardez, Mariano; Jones, Michael; Zidan, Suhail

2005-01-01

This case study illustrates the application of Mega--adding measurable value for all stakeholders including society--as the central and ultimate focus for needs assessment. In this case, two needs assessment studies were conducted within a five-year period (1999-2003) with the State of Ohio's Workforce Development (WD) program. An initial needs…

Scalability enhancement of AODV using local link repairing

NASA Astrophysics Data System (ADS)

Jain, Jyoti; Gupta, Roopam; Bandhopadhyay, T. K.

2014-09-01

Dynamic change in the topology of an ad hoc network makes it difficult to design an efficient routing protocol. Scalability of an ad hoc network is also one of the important criteria of research in this field. Most of the research works in ad hoc network focus on routing and medium access protocols and produce simulation results for limited-size networks. Ad hoc on-demand distance vector (AODV) is one of the best reactive routing protocols. In this article, modified routing protocols based on local link repairing of AODV are proposed. Method of finding alternate routes for next-to-next node is proposed in case of link failure. These protocols are beacon-less, means periodic hello message is removed from the basic AODV to improve scalability. Few control packet formats have been changed to accommodate suggested modification. Proposed protocols are simulated to investigate scalability performance and compared with basic AODV protocol. This also proves that local link repairing of proposed protocol improves scalability of the network. From simulation results, it is clear that scalability performance of routing protocol is improved because of link repairing method. We have tested protocols for different terrain area with approximate constant node densities and different traffic load.

Annual precipitation in the Yellowstone National Park region since AD 1173

USGS Publications Warehouse

Gray, Stephen T.; Graumlich, Lisa J.; Betancourt, Julio L.

2007-01-01

Cores and cross sections from 133 limber pine (Pinus flexilis James) and Douglas fir (Pseudotsuga menziesii (Mirbel) Franco) at four sites were used to estimate annual (July to June) precipitation in the Yellowstone National Park region for the period from AD 1173 to 1998. Examination of the long-term record shows that the early 20th century was markedly wet compared to the previous 700 yr. Extreme wet and dry years within the instrumental period fall within the range of past variability, and the magnitude of the worst-case droughts of the 20th century (AD 1930s and 1950s) was likely equaled or exceeded on numerous occasions before AD 1900. Spectral analysis showed significant decadal to multidecadal precipitation variability. At times this lower frequency variability produces strong regime-like behavior in regional precipitation, with the potential for rapid, high-amplitude switching between predominately wet and predominately dry conditions. Over multiple time scales, strong Yellowstone region precipitation anomalies were almost always associated with spatially extensive events spanning various combinations of the central and southern U.S. Rockies, the northern U.S.-Southern Canadian Rockies and the Pacific Northwest.

Annual precipitation in the Yellowstone National Park region since AD 1173

USGS Publications Warehouse

Gray, S.T.; Graumlich, L.J.; Betancourt, J.L.

2007-01-01

Cores and cross sections from 133 limber pine (Pinus flexilis James) and Douglas fir (Pseudotsuga menziesii (Mirbel) Franco) at four sites were used to estimate annual (July to June) precipitation in the Yellowstone National Park region for the period from AD 1173 to 1998. Examination of the long-term record shows that the early 20th century was markedly wet compared to the previous 700??yr. Extreme wet and dry years within the instrumental period fall within the range of past variability, and the magnitude of the worst-case droughts of the 20th century (AD 1930s and 1950s) was likely equaled or exceeded on numerous occasions before AD 1900. Spectral analysis showed significant decadal to multidecadal precipitation variability. At times this lower frequency variability produces strong regime-like behavior in regional precipitation, with the potential for rapid, high-amplitude switching between predominately wet and predominately dry conditions. Over multiple time scales, strong Yellowstone region precipitation anomalies were almost always associated with spatially extensive events spanning various combinations of the central and southern U.S. Rockies, the northern U.S.-Southern Canadian Rockies and the Pacific Northwest. ?? 2007 University of Washington.

Facile Modification of Reverse Osmosis Membranes by Surfactant-Assisted Acrylate Grafting for Enhanced Selectivity.

PubMed

Baransi-Karkaby, Katie; Bass, Maria; Levchenko, Stanislav; Eitan, Shahar; Freger, Viatcheslav

2017-02-21

The top polyamide layer of composite reverse osmosis (RO) membranes has a fascinatingly complex structure, yet nanoscale nonuniformities inherently present in polyamide layer may reduce selectivity, e.g., for boron rejection. This study examines improving selectivity by in situ "caulking" such nonuniformities using concentration polarization-enhanced graft-polymerization with a surfactant added to the reactive solution. The surfactant appears to enhance both polarization (via monomer solubilization in surfactant micelles) and adherence of graft-polymer to the membrane surface, which facilitates grafting and reduces monomer consumption. The effect of surfactant was particularly notable for a hydrophobic monomer glycidyl methacrylate combined with a nonionic surfactant Triton X-100. With Triton added at an optimal level, close to critical micellization concentration (CMC), monomer gets solubilized and highly concentrated within micelles, which results in a significantly increased degree of grafting and uniformity of the coating compared to a procedure with no surfactant added. Notably, no improvement was obtained for an anionic surfactant SDS or the cationic surfactant DTAB, in which cases the high CMC of surfactant precludes high monomer concentration within micelles. The modification procedure was also up-scalable to membranes elements and resulted in elements with permeability comparable to commercial brackish water RO elements with superior boric acid rejection.

Characterization of pathogenic SORL1 genetic variants for association with Alzheimer’s disease: a clinical interpretation strategy

PubMed Central

Holstege, Henne; van der Lee, Sven J; Hulsman, Marc; Wong, Tsz Hang; van Rooij, Jeroen GJ; Weiss, Marjan; Louwersheimer, Eva; Wolters, Frank J; Amin, Najaf; Uitterlinden, André G; Hofman, Albert; Ikram, M Arfan; van Swieten, John C; Meijers-Heijboer, Hanne; van der Flier, Wiesje M; Reinders, Marcel JT; van Duijn, Cornelia M; Scheltens, Philip

2017-01-01

Accumulating evidence suggests that genetic variants in the SORL1 gene are associated with Alzheimer disease (AD), but a strategy to identify which variants are pathogenic is lacking. In a discovery sample of 115 SORL1 variants detected in 1908 Dutch AD cases and controls, we identified the variant characteristics associated with SORL1 variant pathogenicity. Findings were replicated in an independent sample of 103 SORL1 variants detected in 3193 AD cases and controls. In a combined sample of the discovery and replication samples, comprising 181 unique SORL1 variants, we developed a strategy to classify SORL1 variants into five subtypes ranging from pathogenic to benign. We tested this pathogenicity screen in SORL1 variants reported in two independent published studies. SORL1 variant pathogenicity is defined by the Combined Annotation Dependent Depletion (CADD) score and the minor allele frequency (MAF) reported by the Exome Aggregation Consortium (ExAC) database. Variants predicted strongly damaging (CADD score >30), which are extremely rare (ExAC-MAF <1 × 10−5) increased AD risk by 12-fold (95% CI 4.2–34.3; P=5 × 10−9). Protein-truncating SORL1 mutations were all unknown to ExAC and occurred exclusively in AD cases. More common SORL1 variants (ExAC-MAF≥1 × 10−5) were not associated with increased AD risk, even when predicted strongly damaging. Findings were independent of gender and the APOE-ε4 allele. High-risk SORL1 variants were observed in a substantial proportion of the AD cases analyzed (2%). Based on their effect size, we propose to consider high-risk SORL1 variants next to variants in APOE, PSEN1, PSEN2 and APP for personalized risk assessments in clinical practice. PMID:28537274

Strongly Correlated Electron Systems: An Operatorial Perspective

NASA Astrophysics Data System (ADS)

Di Ciolo, Andrea; Avella, Adolfo

2018-05-01

We discuss the operatorial approach to the study of strongly correlated electron systems and show how the exact solution of target models on small clusters chosen ad-hoc (minimal models) can suggest very efficient bulk approximations. We use the Hubbard model as case study (target model) and we analyze and discuss the crucial role of spin fluctuations in its 2-site realization (minimal model). Accordingly, we devise a novel three-pole approximation for the 2D case, including in the basic field an operator describing the dressing of the electronic one by the nearest-neighbor spin-fluctuations. Such a solution is in very good agreement with the exact one in the minimal model (2-site case) and performs very well once compared to advanced (semi-)numerical methods in the 2D case, being by far less computational-resource demanding.

Holographic helical superconductor with higher curvature corrections

NASA Astrophysics Data System (ADS)

Mukhopadhyay, Subir; Paul, Chandrima

2018-01-01

We study SU(2) × U(1) gauge theory with Chern-Simons term, coupled to scalar field in adjoint, in Einstein-Gauss-Bonnet gravity. We explore phases of holographic superconductor in terms of the condensates and free energies in the background of AdS black hole and AdS soliton. In the case of black hole, we find with increasing strength of higher curvature terms, transition temperature decreases. For AdS soliton, the critical value of chemical potential increases as the higher curvature terms dominate.

Hamiltonian adaptive resolution molecular dynamics simulation of infrared dielectric functions of liquids

NASA Astrophysics Data System (ADS)

Wang, C. C.; Tan, J. Y.; Liu, L. H.

2018-05-01

Hamiltonian adaptive resolution scheme (H-AdResS), which allows to simulate materials by treating different domains of the system at different levels of resolution, is a recently proposed atomistic/coarse-grained multiscale model. In this work, a scheme to calculate the dielectric functions of liquids on account of H-AdResS is presented. In the proposed H-AdResS dielectric-function calculation scheme (DielectFunctCalS), the corrected molecular dipole moments are calculated by multiplying molecular dipole moment by the weighting fraction of the molecular mapping point. As the widths of all-atom and hybrid regions show different degrees of influence on the dielectric functions, a prefactor is multiplied to eliminate the effects of all-atom and hybrid region widths. Since one goal of using the H-AdResS method is to reduce computational costs, widths of the all-atom region and the hybrid region can be reduced considering that the coarse-grained simulation is much more timesaving compared to atomistic simulation. Liquid water and ethanol are taken as test cases to validate the DielectFunctCalS. The H-AdResS DielectFunctCalS results are in good agreement with all-atom molecular dynamics simulations. The accuracy of the H-AdResS results, together with all-atom molecular dynamics results, depends heavily on the choice of the force field and force field parameters. The H-AdResS DielectFunctCalS allows us to calculate the dielectric functions of macromolecule systems with high efficiency and makes the dielectric function calculations of large biomolecular systems possible.

The co-occurrence of Alzheimer's disease and Huntington's disease: a neuropathological study of 15 elderly Huntington's disease subjects.

PubMed

Davis, Marie Y; Keene, C Dirk; Jayadev, Suman; Bird, Thomas

2014-01-01

Dementia is a common feature in both Huntington's disease (HD) and Alzheimer's disease (AD), as well as in the general elderly population. Few studies have examined elderly HD patients with dementia for neuropathologic evidence of both HD and AD. We present neuropathological findings in a retrospective case series of 15 elderly HD patients (ages 60-91 years), 11 of whom had prominent clinical dementia. Post-mortem brain tissue was examined and stained for evidence of both HD and AD including Vonsattel grading and Htt-repeat expansion, Bielskowsky, tau, β amyloid, and TDP43 immunostaining. Mean age at death was 76.8 years, mean disease duration was 18.6 years, and mean CAG repeat expansion was 42. Evidence of AD in addition to HD pathology was present in 9 of 11 (82%) patients with prominent dementia, suggesting that AD may be more commonly co-occurring with HD than previously appreciated. Two patients had only HD as the basis of dementia and four patients did not have prominent dementia. One patient with marked parkinsonian features was not L-dopa responsive and had no substantia nigra Lewy bodies at autopsy. Our study suggests that AD may frequently contribute to cognitive decline in elderly HD patients which complicates the assessment and management of such individuals. Further study is needed to determine if there is a higher incidence of AD in persons with HD compared to the general population. In addition, our series includes one HD patient whose clinical features masqueraded as Parkinson's disease but was not responsive to levodopa therapy.

Altered enzymatic activity and allele frequency of OMI/HTRA2 in Alzheimer's disease

PubMed Central

Westerlund, Marie; Behbahani, Homira; Gellhaar, Sandra; Forsell, Charlotte; Belin, Andrea Carmine; Anvret, Anna; Zettergren, Anna; Nissbrandt, Hans; Lind, Charlotta; Sydow, Olof; Graff, Caroline; Olson, Lars; Ankarcrona, Maria; Galter, Dagmar

2011-01-01

The serine-protease OMI/HTRA2, required for several cellular processes, including mitochondrial function, autophagy, chaperone activity, and apoptosis, has been implicated in the pathogenesis of both Alzheimer's disease (AD) and Parkinson's disease (PD). Western blot quantification of OMI/HTRA2 in frontal cortex of patients with AD (n=10) and control subjects (n=10) in two separate materials indicated reduced processed (active, 35 kDa) OMI/HTRA2 levels, whereas unprocessed (50 kDa) enzyme levels were not significantly different between the groups. Interestingly, the specific protease activity of OMI/HTRA2 was found to be significantly increased in patients with AD (n=10) compared to matched control subjects (n=10) in frontal cortex in two separate materials. Comparison of OMI/HTRA2 mRNA levels in frontal cortex and hippocampus, two brain areas particularly affected by AD, indicated similar levels in patients with AD (n=10) and matched control subjects (n=10). In addition, we analyzed the occurrence of the OMI/HTRA2 variants A141S and G399S in Swedish case-control materials for AD and PD and found a weak association of A141S with AD, but not with PD. In conclusion, our genetic, histological, and biochemical findings give further support to an involvement of OMI/HTRA2 in the pathology of AD; however, further studies are needed to clarify the role of this gene in neurodegeneration.—Westerlund, M., Behbahani, H., Gellhaar, S., Forsell, C., Carmine Belin, A., Anvret, A., Zettergren, A., Nissbrandt, H., Lind, C., Sydow, O., Graff, C., Olson, L., Ankarcrona, M., Galter, D. Altered enzymatic activity and allele frequency of OMI/HTRA2 in Alzheimer's disease. PMID:21163861

Abundant immunoglobulin E-positive cells in skin lesions support an allergic etiology of atopic dermatitis in the elderly

PubMed Central

Tanei, R; Hasegawa, Y; Sawabe, M

2013-01-01

Background/Objectives Atopic dermatitis (AD) in the elderly is gradually increasing in industrialized countries in association with the aging of society. We report herein four cases of elderly AD {three extrinsic [immunoglobulin (Ig)E-mediated allergy]; one intrinsic (non-IgE-allergy)} in which we investigated the presence of IgE+ cells in lesional skin. Methods/Results Single immunohistochemical and double immunofluorescence stainings were performed for skin biopsy specimens from AD patients and non-atopic control subjects with chronic eczema. In the lesional lichenified skin of patients with extrinsic elderly AD, numerous IgE+ cells were found among inflammatory cells infiltrates in the upper dermis. Comparative analysis of single immunohistochemistry results using serial paraffin and/or frozen sections found that many IgE+ cells showed identical distributions to tryptase+ mast cells. IgE+ cells coincident with CD1a+ Langerhans cells in the epidermis were found in small numbers only in frozen sections. Double immunofluorescence staining for IgE and CD11c revealed cells coexpressing IgE and CD11c with a dendritic morphology in the papillary and upper dermis. These IgE+ mast cells and IgE+ CD11c+ cells were also found in cured normal-looking skin from a patient with extrinsic elderly AD after successful treatment. Although only a few weakly positive IgE+ cells were detected, no IgE+CD11c+ cells were found in specimens from patients with intrinsic elderly AD or non-atopic chronic eczema. Conclusion IgE-mediated allergic inflammation may play an important role in the pathobiology of elderly AD, similar to other age groups of AD. PMID:22702954

TMEM106B expression is reduced in Alzheimer’s disease brains

PubMed Central

2014-01-01

Introduction TMEM106B is a transmembrane glycoprotein of unknown function located within endosome/lysosome compartments expressed ubiquitously in various cell types. Previously, the genome-wide association study (GWAS) identified a significant association of TMEM106B single nucleotide polymorphisms (SNPs) with development of frontotemporal lobar degeneration with ubiquitinated TAR DNA-binding protein-43 (TDP-43)-positive inclusions (FTLD-TDP), particularly in the patients exhibiting the progranulin (PGRN) gene (GRN) mutations. Recent studies indicate that TMEM106B plays a pathological role in various neurodegenerative diseases, including Alzheimer’s disease (AD). However, at present, the precise levels of TMEM106B expression in AD brains remain unknown. Methods By quantitative reverse transcription (RT)-PCR (qPCR), western blot and immunohistochemistry, we studied TMEM106B and PGRN expression levels in a series of AD and control brains, including amyotrophic lateral sclerosis, Parkinson’s disease, multiple system atrophy and non-neurological cases. Results In AD brains, TMEM106B mRNA and protein levels were significantly reduced, whereas PGRN mRNA levels were elevated, compared with the levels in non-AD brains. In all brains, TMEM106B was expressed in the majority of cortical neurons, hippocampal neurons, and some populations of oligodendrocytes, reactive astrocytes and microglia with the location in the cytoplasm. In AD brains, surviving neurons expressed intense TMEM106B immunoreactivity, while senile plaques, neurofibrillary tangles and the perivascular neuropil, almost devoid of TMEM106B, intensely expressed PGRN. Conclusions We found an inverse relationship between TMEM106B (downregulation) and PGRN (upregulation) expression levels in AD brains, suggesting a key role of TMEM106B in the pathological processes of AD. PMID:24684749

DEPRESSION AND INCIDENT ALZHEIMER’S DISEASE: THE IMPACT OF DEPRESSION SEVERITY

PubMed Central

Gracia-García, Patricia; de-la-Cámara, Concepción; Santabárbara, Javier; Lopez-Anton, Raúl; Quintanilla, Miguel Angel; Ventura, Tirso; Marcos, Guillermo; Campayo, Antonio; Saz, Pedro; Lyketsos, Constantine; Lobo, Antonio

2014-01-01

Objective We test the hypothesis that clinically significant depression, severe depression in particular, increases the risk of Alzheimer’s Disease (AD). Design A longitudinal, three-wave epidemiological enquiry was implemented in a sample of individuals aged ≥55 years (n = 4,803) followed-up at 2.5 years and 4.5 years. Setting Population-based cohort drawn from the ZARADEMP Project, in Zaragoza, Spain. Participants Cognitively intact individuals at baseline (n = 3,864). Main outcome measures Depression was assessed by a standardized diagnostic interview (Geriatric Mental State, GMS-AGECAT). A panel of research psychiatrist diagnosed AD according to DSM-IV criteria. Fine and Gray multivariate regression model was used in the analysis, accounting for mortality. Results At baseline, clinically significant depression was diagnosed in 452 participants (11.7%). Among the depressed, 16.4% had severe depression. Seventy incident cases of AD were found at follow-up. Compared with non-depressed individuals, the incidence rate of AD was significantly higher in the depressed (incidence rate ratio, IRR = 1.91 (95%CI: 1.04–3.51) and particularly in the severely depressed (IRR = 3.59 (95%CI: 1.30–9.94). A consistent, significant association was observed between severe depression at baseline and incident AD in the multivariate model (hazard ratio, HR = 4.30 (95%CI: 1.39–13.33). Untreated depression was associated with incident AD in the unadjusted model, although in the final model this association was attenuated and non-significant. Conclusions Severe depression increases the risk of AD, even after controlling for the competing risk of death. This finding may stimulate studies about the effect of treating depression in relation to the risk of AD. PMID:23791538

Evaluation of MRI acquisition workflow with lean six sigma method: case study of liver and knee examinations.

PubMed

Roth, Christopher J; Boll, Daniel T; Wall, Lisa K; Merkle, Elmar M

2010-08-01

The purpose of this investigation was to assess workflow for medical imaging studies, specifically comparing liver and knee MRI examinations by use of the Lean Six Sigma methodologic framework. The hypothesis tested was that the Lean Six Sigma framework can be used to quantify MRI workflow and to identify sources of inefficiency to target for sequence and protocol improvement. Audio-video interleave streams representing individual acquisitions were obtained with graphic user interface screen capture software in the examinations of 10 outpatients undergoing MRI of the liver and 10 outpatients undergoing MRI of the knee. With Lean Six Sigma methods, the audio-video streams were dissected into value-added time (true image data acquisition periods), business value-added time (time spent that provides no direct patient benefit but is requisite in the current system), and non-value-added time (scanner inactivity while awaiting manual input). For overall MRI table time, value-added time was 43.5% (range, 39.7-48.3%) of the time for liver examinations and 89.9% (range, 87.4-93.6%) for knee examinations. Business value-added time was 16.3% of the table time for the liver and 4.3% of the table time for the knee examinations. Non-value-added time was 40.2% of the overall table time for the liver and 5.8% for the knee examinations. Liver MRI examinations consume statistically significantly more non-value-added and business value-added times than do knee examinations, primarily because of respiratory command management and contrast administration. Workflow analyses and accepted inefficiency reduction frameworks can be applied with use of a graphic user interface screen capture program.

Genetic Retargeting of Adenovirus: Novel Strategy Employing “Deknobbing” of the Fiber

PubMed Central

Magnusson, Maria K.; Hong, Saw See; Boulanger, Pierre; Lindholm, Leif

2001-01-01

For efficient and versatile use of adenovirus (Ad) as an in vivo gene therapy vector, modulation of the viral tropism is highly desirable. In this study, a novel method to genetically alter the Ad fiber tropism is described. The knob and the last 15 shaft repeats of the fiber gene were deleted and replaced with an external trimerization motif and a new cell-binding ligand, in this case the integrin-binding motif RGD. The corresponding recombinant fiber retained the basic biological functions of the natural fiber, i.e., trimerization, nuclear import, penton formation, and ligand binding. The recombinant fiber bound to integrins but failed to react with antiknob antibody. For virus production, the recombinant fiber gene was rescued into the Ad genome at the exact position of the wild-type (WT) fiber to make use of the native regulation of fiber expression. The recombinant virus Ad5/FibR7-RGD yielded plaques on 293 cells, but the spread through the monolayer was two to three times delayed compared to WT, and the ratio of infectious to physical particles was 20 times lower. Studies on virus tropism showed that Ad5/FibR7-RGD was able to infect cells which did not express the coxsackie-adenovirus receptor (CAR), but did express integrins. Ad5/FibR7-RGD virus infectivity was unchanged in the presence of antiknob antibody, which neutralized the WT virus. Ad5/FibR7-RGD virus showed an expanded tropism, which is useful when gene transfer to cells not expressing CAR is needed. The described method should also make possible the construction of Ad genetically retargeted via ligands other than RGD. PMID:11462000

Using unassisted ecosystem development to restore marginal land case study of post mining areas

NASA Astrophysics Data System (ADS)

Frouz, Jan

2017-04-01

When we evaluate efficiency of individual restoration measures we typically compare individual restoration treatments or compare them with initial state or similar ecosystem in surrounding landscape. We argue that sensible way to show added value of restoration measure is to compare them with unassisted ecosystem development. Case study of ecosystem development in Sokolov post mining district (Czech Republic) show that spontaneous succession of ecosystem can be, in many parameters, comparable with various reclamation approaches. In suitable substrates the succession is driven mainly by site topography. In sites which were leveled grassy vegetation develops. In sites where original wave like topography was preserved the ecosystem develops towards forest. In forest sites the development on most of the investigated ecosystem parameters (cower, biomass soil developments, water holding capacity, carbon storage) in succession sites is little bit slower compare to reclaimed plantation during first 15-20 years. However in older sites differences disappear and succession sites show similarity with restored sites. Despite similarity in these ecosystem functions possibilities of spontaneous sites for commercial use has to be explored.

The Effect of Water on the Work of Adhesion at Epoxy Interfaces by Molecular Dynamics Simulation

NASA Technical Reports Server (NTRS)

Hinkley, J.A.; Frankland, S.J.V.; Clancy, T.C.

2009-01-01

Molecular dynamics simulation can be used to explore the detailed effects of chemistry on properties of materials. In this paper, two different epoxies found in aerospace resins are modeled using molecular dynamics. The first material, an amine-cured tetrafunctional epoxy, represents a composite matrix resin, while the second represents a 177 C-cured adhesive. Surface energies are derived for both epoxies and the work of adhesion values calculated for the epoxy/epoxy interfaces agree with experiment. Adding water -- to simulate the effect of moisture exposure -- reduced the work of adhesion in one case, and increased it in the other. To explore the difference, the various energy terms that make up the net work of adhesion were compared and the location of the added water was examined.

Combining select neuropsychological assessment with blood-based biomarkers to detect mild Alzheimer's disease: a molecular neuropsychology approach.

PubMed

Edwards, Melissa; Balldin, Valerie Hobson; Hall, James; O'Bryant, Sid

2014-01-01

Current work has sought to establish a rapid and cost effective means of screening for Alzheimer's disease (AD) with the most recent findings showing utility of integrating blood-based biomarkers with cognitive measures. The current project sought to create a combined biomarker-cognitive profile to detect mild AD. Data was analyzed from 266 participants (129 AD cases [Early AD n = 93; Very Early AD n = 36]; 137 controls) enrolled in the Texas Alzheimer's Research and Care Consortium (TARCC). Non-fasting serum samples were collected from each participant and assayed via a multi-plex biomarker assay platform using electrochemiluminescence. Logistic Regression was utilized to detect early AD using two serum biomarkers (TNFα and IL7), demographic information (age), and one neuropsychological measure (Clock 4-point) as predictor variable. Disease severity was determined via Clinical Dementia Rating (CDR) scale global scores. In the total sample (all levels of CDR scores), the combination of biomarkers, cognitive test score, and demographics yielded the obtained sensitivity (SN) of 0.94, specificity (SP) of 0.90, and an overall accuracy of 0.92. When examining early AD cases (i.e.m CDR = 0.5-1), the biomarker-cognitive profile yielded SN of 0.94, SP of 0.85, and an overall accuracy of 0.91. When restricted to very early AD cases (i.e., CDR = 0.5), the biomarker-cognitive profile yielded SN of 0.97 and SP of 0.72, with an overall accuracy of 0.91. The combination of demographics, two biomarkers, and one cognitive test created a biomarker-cognitive profile that was highly accurate in detecting the presence of AD, even in the very early stages.

Associations between dietary fiber and colorectal polyp risk differ by polyp type and smoking status.

PubMed

Fu, Zhenming; Shrubsole, Martha J; Smalley, Walter E; Ness, Reid M; Zheng, Wei

2014-05-01

The association of dietary fiber intake with colorectal cancer risk is established. However, the association may differ between cigarette smokers and nonsmokers. We evaluated this hypothesis in a large colonoscopy-based case-control study. Dietary fiber intakes were estimated by self-administered food frequency questionnaire. Unconditional logistic regression analysis was used to estimate ORs and 95% CIs with adjustment for potential confounders. Analysis also was stratified by cigarette smoking and sex. High dietary fiber intake was associated with reduced risk of colorectal polyps (P-trend = 0.003). This association was found to be stronger among cigarette smokers (P-trend = 0.006) than nonsmokers (P-trend = 0.21), although the test for multiplicative interaction was not statistically significant (P = 0.11). This pattern of association was more evident for high-risk adenomatous polyps (ADs), defined as advanced or multiple ADs (P-interaction smoking and dietary fiber intake = 0.09). Among cigarette smokers who smoked ≥23 y, a 38% reduced risk of high-risk ADs was found to be associated with high intake of dietary fiber compared with those in the lowest quartile fiber intake group (P-trend = 0.004). No inverse association with dietary fiber intake was observed for low-risk ADs, defined as single nonadvanced ADs. Cigarette smoking may modify the association of dietary fiber intake with the risk of colorectal polyps, especially high-risk ADs, a well-established precursor of colorectal cancer.

Cholinesterase targeting by polyphenols: A therapeutic approach for the treatment of Alzheimer's disease.

PubMed

Jabir, Nasimudeen R; Khan, Fayaz Rahman; Tabrez, Shams

2018-05-16

Alzheimer's disease (AD) is a progressive irreversible neurodegenerative disorder characterized by excessive deposition of β-amyloid (Aβ) oligomers, and neurofibrillary tangles (NFTs), comprising of hyperphosphorylated tau proteins. The cholinergic system has been suggested as the earliest and most affected molecular mechanism that describes AD pathophysiology. Moreover, cholinesterase inhibitors (ChEIs) are the potential class of drugs that can amplify cholinergic activity to improve cognition and global performance and reduce psychiatric and behavioral disturbances. Approximately, 60%-80% of all cases of dementia in the world are patients with AD. In view of the continuous rise of this disease especially in the aged population, there is a dire need to come up with a novel compound and/or mixture that could work against this devastating disease. In this regard, the best is to rely on natural compounds rather than synthetic ones, because natural compounds are easily available, cost-effective, and comparatively less toxic. To serve this purpose, lately, scientific community has started exploring the possibility of using different polyphenols either solitary or in combination that can serve as therapeutics against AD. In the current article, we have summarized the role of various polyphenols, namely quercetin, resveratrol, curcumin, gallocatechins, cinnamic acid, caffeine, and caffeic acid as an inhibitor of cholinesterase for the treatment of AD. We have also tried to uncover the mechanistic insight on the action of these polyphenols against AD pathogenicity. © 2018 John Wiley & Sons Ltd.

Free and Cued Selective Reminding Identifies Very Mild Dementia in Primary Care

PubMed Central

Grober, Ellen; Sanders, Amy E.; Hall, Charles; Lipton, Richard B.

2010-01-01

The Free and Cued Selective Reminding Test (FCSRT) is used widely to identify very mild dementia; three alternative scoring procedures have been proposed based on free recall, total recall, and cue efficiency. We compared the predictive validity of these scoring procedures for the identification of very mild prevalent dementia (CDR=0.5), of incident dementia and for distinguishing AD and nonAD dementias. We tested 244 elderly African American and Caucasian primary care patients at 18 month intervals using a screening neuropsychological battery that included the FCSRT and a comprehensive diagnostic neuropsychological battery. Median follow-up was 2.6 years. Dementia diagnoses were assigned using standard criteria without access to the results of the screening battery. There were 50 prevalent and 28 incident dementia cases. At scores selected to provide specificities of 90%, free recall was more sensitive to incident and prevalent dementia than the other two measures. Patients with impaired free recall were 15 times more likely to have a prevalent dementia and their risk of future dementia was four times higher than patients with intact free recall. Neither race nor education affected prediction though older patients were at increased risk of future dementia. Total recall was more impaired in AD dementia than in nonAD dementias. The results indicate that using the FCSRT, free recall is best measure for detecting prevalent dementia and predicting future dementia. Total recall impairment supports the diagnosis of AD rather than nonAD dementia. PMID:20683186

Identification of VaD and AD prodromes: the Cache County Study.

PubMed

Hayden, K M; Warren, L H; Pieper, C F; Østbye, T; Tschanz, J T; Norton, M C; Breitner, J C S; Welsh-Bohmer, K A

2005-07-01

It is unclear whether vascular dementia (VaD) has a cognitive prodrome, akin to the mild cognitive impairment (MCI) prodrome to Alzheimer's dementia (AD). To evaluate whether VaD has a cognitive prodrome, and if it can be differentiated from prodromal AD, we examined neuropsychological test performance of participants in a nested case-control study within a population-based cohort aged 65 or older. Participants (n = 485) were identified from the Cache County Study, a large population-based study of aging and dementia. After an average of 3 years of follow-up, a total of 62 incident dementia cases were identified (14 VaD, 48 AD). We identified a number of neuropsychological tests (executive and memory) that discriminated between diagnosed VaD and AD cases. Multivariate analyses sought to differentiate between these same groups 3 years before clinical diagnosis. The Consortium to Establish a Registry for Alzheimer's Disease Word List Recognition Test correct recognition of foils (mean difference, 1.25; 95% confidence interval [CI], 0.42 to 2.07; p < 0.01), Logical Memory I (mean difference, 7.16; 95% CI, 0.78 to 13.55, p < 0.05), Logical Memory II delayed recall (mean difference, 8.67; 95% CI, 1.59 to 15.74, p < 0.05), and percent savings (mean difference, 51.07; 95% CI, 32.58 to 69.56, p < 0.0001) differentiated VaD from AD cases after adjustment for age, sex, education, and dementia severity. Three years before dementia diagnosis, word list recognition ("no" responses mean difference, 1.40; 95% CI, 0.64 to 2.17; p < 0.001, and "yes" responses mean difference, -1.14; 95% CI, -2.14 to -0.13; p < 0.03) discriminated between prodromal VaD and AD. These results suggest that VaD has a prodromal syndrome, the cognitive features of which are distinguishable from the cognitive prodrome of AD.

Streptozotocin Intracerebroventricular-Induced Neurotoxicity and Brain Insulin Resistance: a Therapeutic Intervention for Treatment of Sporadic Alzheimer's Disease (sAD)-Like Pathology.

PubMed

Kamat, Pradip K; Kalani, Anuradha; Rai, Shivika; Tota, Santosh Kumar; Kumar, Ashok; Ahmad, Abdullah S

2016-09-01

Alzheimer's disease (AD) is a neurodegenerative disorder that is remarkably characterized by pathological hallmarks which include amyloid plaques, neurofibrillary tangles, neuronal loss, and progressive cognitive loss. Several well-known genetic mutations which are being used for the development of a transgenic model of AD lead to an early onset familial AD (fAD)-like condition. However, these settings are only reasons for a small percentage of the total AD cases. The large majorities of AD cases are considered as a sporadic in origin and are less influenced by a single mutation of a gene. The etiology of sporadic Alzheimer's disease (sAD) remains unclear, but numerous risk factors have been identified that increase the chance of developing AD. Among these risk factors are insulin desensitization/resistance state, oxidative stress, neuroinflammation, synapse dysfunction, tau hyperphosphorylation, and deposition of Aβ in the brain. Subsequently, these risk factors lead to development of sAD. However, the underlying molecular mechanism is not so clear. Streptozotocin (STZ) produces similar characteristic pathology of sAD such as altered glucose metabolism, insulin signaling, synaptic dysfunction, protein kinases such as protein kinase B/C, glycogen synthase-3β (GSK-3β) activation, tau hyperphosphorylation, Aβ deposition, and neuronal apoptosis. Further, STZ also leads to inhibition of Akt/PKB, insulin receptor (IR) signaling molecule, and insulin resistance in brain. These alterations mediated by STZ can be used to explore the underlying molecular and pathophysiological mechanism of AD (especially sAD) and their therapeutic intervention for drug development against AD pathology.

Risk, treatment duration, and recurrence risk of postpartum affective disorder in women with no prior psychiatric history: A population-based cohort study.

PubMed

Rasmussen, Marie-Louise H; Strøm, Marin; Wohlfahrt, Jan; Videbech, Poul; Melbye, Mads

2017-09-01

Some 5%-15% of all women experience postpartum depression (PPD), which for many is their first psychiatric disorder. The purpose of this study was to estimate the incidence of postpartum affective disorder (AD), duration of treatment, and rate of subsequent postpartum AD and other affective episodes in a nationwide cohort of women with no prior psychiatric history. Linking information from several Danish national registers, we constructed a cohort of 457,317 primiparous mothers with first birth (and subsequent births) from 1 January 1996 to 31 December 2013 (a total of 789,068 births) and no prior psychiatric hospital contacts and/or use of antidepressants. These women were followed from 1 January 1996 to 31 December 2014. Postpartum AD was defined as use of antidepressants and/or hospital contact for PPD within 6 months after childbirth. The main outcome measures were risk of postpartum AD, duration of treatment, and recurrence risk. We observed 4,550 (0.6%) postpartum episodes of AD. The analyses of treatment duration showed that 1 year after the initiation of treatment for their first episode, 27.9% of women were still in treatment; after 4 years, 5.4%. The recurrence risk of postpartum AD for women with a PPD hospital contact after first birth was 55.4 per 100 person-years; for women with postpartum antidepressant medication after first birth, it was 35.0 per 100 person-years. The rate of postpartum AD after second birth for women with no history of postpartum AD was 1.2 per 100 person-years. After adjusting for year of birth and mother's age, women with PPD hospital contact after first birth had a 46.4 times higher rate (95% CI 31.5-68.4) and women with postpartum antidepressant medication after their first birth had a 26.9 times higher rate (95% CI 21.9-33.2) of a recurrent postpartum episode after their second birth compared to women with no postpartum AD history. Limitations include the use of registry data to identify cases and limited confounder control. In this study, an episode of postpartum AD was observed for 0.6% of childbirths among women with no prior psychiatric history. The observed episodes were characterized by a relatively short treatment duration, yet the women had a notably high rate of later AD and recurrent episodes of postpartum AD. The recurrence risk of postpartum AD was markedly higher among women with PPD hospital contact after first birth compared to women with postpartum antidepressant medication after first birth. Our results underline the necessity of measures targeted at specific vulnerable groups, such as women who experience PPD as a first psychiatric episode.

The Use of a School Value-Added Model for Educational Improvement: A Case Study from the Portuguese Primary Education System

ERIC Educational Resources Information Center

Ferrão, Maria Eugénia; Couto, Alcino Pinto

2014-01-01

This article focuses on the use of a value-added approach for promoting school improvement. It presents yearly value-added estimates, analyses their stability over time, and discusses the contribution of this methodological approach for promoting school improvement programmes in the Portuguese system of evaluation. The value-added model is applied…

How One School Implements and Experiences Ohio's Value-Added Model: A Case Study

ERIC Educational Resources Information Center

Quattrochi, David

2009-01-01

Ohio made value-added law in 2003 and incorporated value-added assessment to its operating standards for teachers and administrators in 2006. Value-added data is used to determine if students are making a year's growth at the end of each school year. Schools and districts receive a rating of "Below Growth, Met Growth, or Above Growth" on…

Effect of adding powder on joint properties of laser penetration welding for dual phase steel and aluminum alloy

NASA Astrophysics Data System (ADS)

Zhou, D. W.; Liu, J. S.; Lu, Y. Z.; Xu, S. H.

2017-09-01

The experiments of laser penetration welding for dual phase steel and aluminum alloy were carried out, and the effect of adding Mn or Si powder on mechanical properties and microstructure of the weld was investigated. Some defects, such as spatter, inclusion, cracks and softening in heat affected zone (HAZ), can be avoided in welding joints, and the increased penetration depth is obtained by adding Mn or Si powder. The average tensile-shear strength of Si-added joint is 3.84% higher than that of Mn-added joint, and the strength of both joints exceeds that of no-added joint. In the case of adding Mn powder, small amount of liquid Al is mixed into steel molten pool, and the Al content increases in both sides of the weld, which leads to the increased weld width in aluminum molten pool. Thus, transverse area increases in jointing steel to aluminum, which is significant for the improved tensile-shear strength of joints. As far as adding Si powder is concerned, it is not the case, the enhancement of the joint properties benefits from improvement of metallurgical reaction.

Proximal pulmonary vein stenosis detection in pediatric patients: value of multiplanar and 3-D VR imaging evaluation.

PubMed

Lee, Edward Y; Jenkins, Kathy J; Muneeb, Muhammad; Marshall, Audrey C; Tracy, Donald A; Zurakowski, David; Boiselle, Phillip M

2013-08-01

One of the important benefits of using multidetector computed tomography (MDCT) is its capability to generate high-quality two-dimensional (2-D) multiplanar (MPR) and three-dimensional (3-D) images from volumetric and isotropic axial CT data. However, to the best of our knowledge, no results have been published on the potential diagnostic role of multiplanar and 3-D volume-rendered (VR) images in detecting pulmonary vein stenosis, a condition in which MDCT has recently assumed a role as the initial noninvasive imaging modality of choice. The purpose of this study was to compare diagnostic accuracy and interpretation time of axial, multiplanar and 3-D VR images for detection of proximal pulmonary vein stenosis in children, and to assess the potential added diagnostic value of multiplanar and 3-D VR images. We used our hospital information system to identify all consecutive children (< 18 years of age) with proximal pulmonary vein stenosis who had both a thoracic MDCT angiography study and a catheter-based conventional angiography within 2 months from June 2005 to February 2012. Two experienced pediatric radiologists independently reviewed each MDCT study for the presence of proximal pulmonary vein stenosis defined as ≥ 50% of luminal narrowing on axial, multiplanar and 3-D VR images. Final diagnosis was confirmed by angiographic findings. Diagnostic accuracy was compared using the z-test. Confidence level of diagnosis (scale 1-5, 5 = highest), perceived added diagnostic value (scale 1-5, 5 = highest), and interpretation time of multiplanar or 3-D VR images were compared using paired t-tests. Interobserver agreement was measured using the chance-corrected kappa coefficient. The final study population consisted of 28 children (15 boys and 13 girls; mean age: 5.2 months). Diagnostic accuracy based on 116 individual pulmonary veins for detection of proximal pulmonary vein stenosis was 72.4% (84 of 116) for axial MDCT images, 77.5% (90 of 116 cases) for multiplanar MDCT images, and 93% (108 of 116 cases) for 3-D VR images with significantly higher accuracy with 3-D VR compared to axial (z = 4.17, P < 0.001) and multiplanar (z = 3.34, P < 0.001) images. Confidence levels for detection of proximal pulmonary vein stenosis were significantly higher with 3-D VR images (mean level: 4.6) compared to axial MDCT images (mean level: 1.7) and multiplanar MDCT images (mean level: 2.0) (paired t-tests, P < 0.001). Thus, 3-D VR images (mean added diagnostic value: 4.7) were found to provide added diagnostic value for detecting proximal pulmonary vein stenosis (paired t-test, P < 0.001); however, multiplanar MDCT images did not provide added value (paired t-test, P = 0.89). Interpretation time was significantly longer and interobserver agreement was higher when using 3-D VR images than using axial MDCT images or MPR MDCT images for diagnosing proximal pulmonary vein stenosis (paired t-tests, P < 0.001). Use of 3-D VR images in the diagnosis of proximal pulmonary vein stenosis in children significantly increases accuracy, confidence level, added diagnostic value and interobserver agreement. Thus, the routine use of this technique should be encouraged despite its increased interpretation time.

Comparative Analysis of the Magnitude, Quality, Phenotype and Protective Capacity of SIV Gag-Specific CD8+ T Cells Following Human-, Simian- and Chimpanzee-Derived Recombinant Adenoviral Vector Immunisation

PubMed Central

Quinn, Kylie M.; Costa, Andreia Da; Yamamoto, Ayako; Berry, Dana; Lindsay, Ross W.B.; Darrah, Patricia A.; Wang, Lingshu; Cheng, Cheng; Kong, Wing-Pui; Gall, Jason G.D.; Nicosia, Alfredo; Folgori, Antonella; Colloca, Stefano; Cortese, Riccardo; Gostick, Emma; Price, David A.; Gomez, Carmen E.; Esteban, Mariano; Wyatt, Linda S.; Moss, Bernard; Morgan, Cecilia; Roederer, Mario; Bailer, Robert T.; Nabel, Gary J.; Koup, Richard A.; Seder, Robert A.

2013-01-01

Recombinant adenoviral vectors (rAds) are the most potent recombinant vaccines for eliciting CD8+ T cell-mediated immunity in humans; however, prior exposure from natural adenoviral infection can decrease such responses. Here we show low seroreactivity in humans against simian- (sAd11, sAd16), or chimpanzee-derived (chAd3, chAd63) compared to human-derived (rAd5, rAd28, rAd35) vectors across multiple geographic regions. We then compared the magnitude, quality, phenotype and protective capacity of CD8+ T cell responses in mice vaccinated with rAds encoding SIV Gag. Using a dose range (1 × 107 to 109 PU), we defined a hierarchy among rAd vectors based on the magnitude and protective capacity of CD8+ T cell responses, from most to least as: rAd5 and chAd3, rAd28 and sAd11, chAd63, sAd16, and rAd35. Selection of rAd vector or dose could modulate the proportion and/or frequency of IFNγ+TNFα+IL-2+ and KLRG1+CD127- CD8+ T cells, but strikingly ~30–80% of memory CD8+ T cells co-expressed CD127 and KLRG1. To further optimise CD8+ T cell responses, we assessed rAds as part of prime-boost regimens. Mice primed with rAds and boosted with NYVAC generated Gag-specific responses that approached ~60% of total CD8+ T cells at peak. Alternatively, priming with DNA or rAd28 and boosting with rAd5 or chAd3 induced robust and equivalent CD8+ T cell responses compared to prime or boost alone. Collectively, these data provide the immunologic basis for using specific rAd vectors alone or as part of prime-boost regimens to induce CD8+ T cells for rapid effector function or robust long-term memory, respectively. PMID:23390298

Self-Report of Guardians Ad Litem: Provision of Information to Judges in Child Abuse and Neglect Cases.

ERIC Educational Resources Information Center

Goldman, Jacquelin; And Others

1993-01-01

This study of the reporting practices of 91 Guardians Ad Litem to Florida judges in child abuse and neglect cases found that information reported most often concerned the child's physical safety, interaction between parent and child, and parents' personality characteristics. Less frequently reported was information regarding conflict in the home…

Spatio-Temporal Fluctuations of Neural Dynamics in Mild Cognitive Impairment and Alzheimer's Disease.

PubMed

Poza, Jesús; Gómez, Carlos; García, María; Tola-Arribas, Miguel A; Carreres, Alicia; Cano, Mónica; Hornero, Roberto

2017-01-01

An accurate characterization of neural dynamics in mild cognitive impairment (MCI) is of paramount importance to gain further insights into the underlying neural mechanisms in Alzheimer's disease (AD). Nevertheless, there has been relatively little research on brain dynamics in prodromal AD. As a consequence, its neural substrates remain unclear. In the present research, electroencephalographic (EEG) recordings from patients with dementia due to AD, subjects with MCI due to AD and healthy controls (HC) were analyzed using relative power (RP) in conventional EEG frequency bands and a novel parameter useful to explore the spatio-temporal fluctuations of neural dynamics: the spectral flux (SF). Our results suggest that dementia due to AD is associated with a significant slowing of EEG activity and several significant alterations in spectral fluctuations at low (i.e. theta) and high (i.e. beta and gamma) frequency bands compared to HC (p < 0.05). Furthermore, subjects with MCI due to AD exhibited a specific frequency-dependent pattern of spatio-temporal abnormalities, which can help identify neural mechanisms involved in cognitive impairment preceding AD. Classification analyses using linear discriminant analysis with a leave-one-out cross-validation procedure showed that the combination of RP and within-electrode SF at the beta band was useful to obtain a 77.3 % of accuracy to discriminate between HC and AD patients. In the case of comparison between HC and MCI subjects, the classification accuracy reached a value of 79.2 %, combining within-electrode SF at beta and gamma bands. SF has proven to be a useful measure to obtain an original description of brain dynamics at different stages of AD. Consequently, SF may contribute to gain a more comprehensive understanding into neural substrates underlying MCI, as well as to develop potential early AD biomarkers. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Effect of a new marker, ADAM12, on Down risk figures in first trimester screening.

PubMed

Valinen, Yrtti; Laitinen, Paivi; Ranta, Jenni; Ignatius, Jaakko; Jarvela, Ilkka; Ryynänen, Markku

2009-07-01

To investigate whether incorporating the measurement of ADAM12 in the risk calculation program LifeCycle, can improve Down screening in the first trimester. In a retrospective case control study, maternal serum ADAM12 concentrations were measured and compared in Down syndrome cases (n = 53) and in controls (n = 226) obtained from first trimester (9-12 weeks) screening samples in Oulu and Kuopio University Hospitals. Median concentration ( microg/l), observed and regressed (weight corrected) MoMs of ADAM12 were calculated. There was a significant difference in ADAM12 levels between Downs and controls during the pregnancy weeks 9 + 0 to 10 + 6, but not thereafter. By adding ADAM12 to the marker set used in the risk calculation program, one screening false negative Down syndrome case occurred in the affected population, which did not alter false positive rate. Adding ADAM12 as a parameter in Down screening did not cause radical changes in the risk value. The test might be useful at 9 and 10 weeks in which it might have the potential to improve the performance of the risk assessment especially for women receiving a result close to the high-risk cut-off. The real influence of ADAM12 remains to be elucidated in larger studies incorporating ADAM12 to the risk calculation program.

Introducing universal ultrasound screening for developmental dysplasia of the hip doubled the treatment rate.

PubMed

Olsen, Stine F; Blom, Hans C; Rosendahl, Karen

2018-02-01

There is no evidence on the effect of universal ultrasound screening on developmental dysplasia of the hip. We examined the impact of adding an ultrasound examination to a one examiner clinical screening strategy on treatment, follow-up rates and the number of cases detected late in a low-prevalence population. All eligible babies born at Kongsberg Hospital, Norway, from 1998 to 2006 (n = 4245) underwent both clinical and ultrasound hip examinations within three days of life. Indications for immediate treatment were positive Barlow or Ortolani manoeuvres and, or, sonographic dysplasia. Sonographic immature hips were followed until normalisation. Treatment rates and rates from the 1989 to 1997 prestudy period (n = 3594), including late diagnoses, were collected from hospital records. Treatment was initiated in 90 (2.1%) infants (74 girls), 63 (70%) from birth, compared to 33 (0.9%) during the prestudy period. The follow-up rate did not change (11%). There were two (0.5/1000) and four (1.0/1000) cases detected late, respectively. No one underwent surgery during the first year of life and no avascular necrosis was seen. Adding universal ultrasound to clinical screening performed by the same, experienced paediatrician doubled the treatment rate, without influencing the already low numbers of late cases. ©2017 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

Alzheimer's Disease Sequencing Project discovery and replication criteria for cases and controls: Data from a community-based prospective cohort study with autopsy follow-up.

PubMed

Crane, Paul K; Foroud, Tatiana; Montine, Thomas J; Larson, Eric B

2017-12-01

The Alzheimer's Disease Sequencing Project (ADSP) used different criteria for assigning case and control status from the discovery and replication phases of the project. We considered data from a community-based prospective cohort study with autopsy follow-up where participants could be categorized as case, control, or neither by both definitions and compared the two sets of criteria. We used data from the Adult Changes in Thought (ACT) study including Diagnostic and Statistical Manual-IV criteria for dementia status, McKhann et al. criteria for clinical Alzheimer's disease, and Braak and Consortium to Establish a Registry for AD findings on neurofibrillary tangles and neuritic plaques to categorize the 621 ACT participants of European ancestry who died and came to autopsy. We applied ADSP discovery and replication definitions to identify controls, cases, and people who were neither controls nor cases. There was some agreement between the discovery and replication definitions. Major areas of discrepancy included the finding that only 40% of the discovery sample controls had sufficiently low levels of neurofibrillary tangles and neuritic plaques to be considered controls by the replication criteria and the finding that 16% of the replication phase cases were diagnosed with non-AD dementia during life and thus were excluded as cases for the discovery phase. These findings should inform interpretation of genetic association findings from the ADSP. Differences in genetic association findings between the two phases of the study may reflect these different phenotype definitions from the discovery and replication phase of the ADSP. Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Source Term Model for Steady Micro Jets in a Navier-Stokes Computer Code

NASA Technical Reports Server (NTRS)

Waithe, Kenrick A.

2005-01-01

A source term model for steady micro jets was implemented into a non-proprietary Navier-Stokes computer code, OVERFLOW. The source term models the mass flow and momentum created by a steady blowing micro jet. The model is obtained by adding the momentum and mass flow created by the jet to the Navier-Stokes equations. The model was tested by comparing with data from numerical simulations of a single, steady micro jet on a flat plate in two and three dimensions. The source term model predicted the velocity distribution well compared to the two-dimensional plate using a steady mass flow boundary condition, which was used to simulate a steady micro jet. The model was also compared to two three-dimensional flat plate cases using a steady mass flow boundary condition to simulate a steady micro jet. The three-dimensional comparison included a case with a grid generated to capture the circular shape of the jet and a case without a grid generated for the micro jet. The case without the jet grid mimics the application of the source term. The source term model compared well with both of the three-dimensional cases. Comparisons of velocity distribution were made before and after the jet and Mach and vorticity contours were examined. The source term model allows a researcher to quickly investigate different locations of individual or several steady micro jets. The researcher is able to conduct a preliminary investigation with minimal grid generation and computational time.

Is elevated norepinephrine an etiological factor in some cases of Alzheimer's disease?

PubMed

Fitzgerald, Paul J

2010-09-01

Loss of norepinephrine (NE) releasing neurons, in the locus coeruleus of the brainstem, is well documented to occur in Alzheimer's disease (AD). However, this process does not necessarily result in decreased release of NE, since compensatory mechanisms may produce increased release of this neurotransmitter. Independent of potential loss of locus coeruleus cells, brain NE levels may be elevated in some persons with AD, both before and during disease progression. Here I examine evidence that elevated, endogenous brain NE is an etiological factor in some cases of AD, and not merely an epiphenomenon of the disease. To explore this etiological hypothesis in AD, I examine the following eight lines of evidence: 1) direct evidence of elevated NE or its metabolites in AD; 2) studies of tricyclic antidepressants, which may principally boost NE; 3) studies of clonidine and other alpha2 adrenergic agonist drugs, which may principally lower the concentration of NE; 4) studies of beta adrenoceptor blocking drugs, including propranolol; 5) comorbidity of AD and bipolar disorder, where both disorders may involve elevated NE; 6) comorbidity of AD and hypertension; 7) comorbidity of AD and obesity; and 8) potential interaction between AD and psychological stress, where stressors are known to release NE. These lines of evidence tend to support the elevated NE etiological hypothesis.

Normal ultrasonic fetal growth ratios evaluated in cases of fetal disproportion.

PubMed

Crang-Svalenius, E; Jörgensen, C

1991-02-01

During a 2-year period, 5476 normal routine obstetrical ultrasound investigations were performed in the 2nd trimester (16th to 20th week). Data on biparietal diameter (BPD), abdominal diameter (AD) and femur length (FL) have been obtained from this material. Ratios between BPD/AD and BPD/FL have been calculated, and from these ratios, graphs were constructed. Only nine normal fetuses (0.2%) were found to be outside mean +/- 3 SD, and none of the normal cases were +/- 4 SD, so this is perhaps a better guideline for those warranting further investigation. To evaluate if these ratios could better reflect disproportional fetal growth, three cases of triploidy and four cases of dwarfism were tested against these ratios. Triploidy was obvious on the BPD/AD graph and dwarfism on the BPD/FL graph. The ratios were not found to be conclusive in the intrauterine diagnosis of trisomy 21 or of trisomy 18, as only 4 of 17 cases were obvious on the graphs.

Identifying patterns in signs and symptoms preceding the clinical diagnosis of Alzheimer's disease: Retrospective medical record review study and a nested case -control design.

PubMed

Bature, Fidelia; Pang, Dong; Robinson, Anthea; Polson, Norma; Pappas, Yannis; Guinn, Barbara

2018-04-04

Evidence suggests that individuals with Alzheimer's disease (AD) are often diagnosed in the later stages of their disease with a poor prognosis. This study aimed to identify patterns in signs and symptoms preceding the clinical diagnosis of AD to suggest a predictive model for earlier diagnosis of the disease in the primary care. A retrospective medical record review; nested case control design. Participants included one hundred and nine patients from three general practice (GP) surgeries in Milton Keynes and Luton Clinical Commissioning groups (CCG) (37 cases with AD and 72 controls without AD). A retrospective analysis using the logistic regression of the presence of signs and symptoms before the diagnosis of AD was attained. Identification of the timing and sequence of appearance of these presentations as first reported before the clinical diagnosis was measured. Episodic memory with an odds ratio of 1.85 was the most frequent presentation, documented in 1.38% of the controls and 75.6% in cases. Auditory disturbance with an odds ratio of 3.03, which has not previously been noted except in the form of auditory hallucination, could have a diagnostic value. Auditory disturbance, which occurred mostly in the Caucasian females, could discriminate individuals with AD from those without. The symptom, which presented up to 14.5 (mean time) years prior to clinical diagnosis, was identified in Caucasians and mixed race individuals only. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Anticholinergic Exposure and Risk of Pneumonia in Persons with Alzheimer's Disease: A Nested Case-Control Study.

PubMed

Lampela, Pasi; Tolppanen, Anna-Maija; Tanskanen, Antti; Tiihonen, Jari; Hartikainen, Sirpa; Taipale, Heidi

2017-01-01

Risk of pneumonia is increased in persons with Alzheimer's disease (AD). In some studies, anticholinergic drugs (AC) have been associated with an increased pneumonia risk. We analyzed the risk of pneumonia associated with ACs in persons with AD. We performed a nested case-control study using register-based data from a Finnish nationwide MEDALZ cohort including all community-dwelling persons diagnosed with AD during 2005-2011. Cases were identified based on pneumonia diagnoses (n = 12,442) from hospital discharge and causes of death registers. Up to two controls without pneumonia were matched based on time since AD diagnoses, age, and gender for each case; AC use was measured using Anticholinergic Drug Scale. Use of AC was associated with an increased risk of pneumonia (adjusted odds ratio (OR) 1.36, 95% confidence interval (CI) 1.29-1.43). However, there was no increased pneumonia risk in persons using level 3 ACs. Incident use was associated with higher risk of pneumonia (OR 2.68, 95% CI 2.15-3.34) than prevalent use (OR 1.48, 95% CI 1.40-1.57). Among persons using cholinesterase inhibitors (AChEIs), risk of pneumonia was increased in persons using also ACs (OR 1.53, 95% CI 1.41-1.66). ACs were associated with an increased risk of pneumonia in persons with AD, especially at the time of initiation of these drugs. AC use was associated with increased pneumonia risk also in persons using AChEIs. This risk should be carefully considered when treating AD patients.

The Alzheimer's Disease-Associated Amyloid β-Protein Is an Antimicrobial Peptide

PubMed Central

Soscia, Stephanie J.; Kirby, James E.; Washicosky, Kevin J.; Tucker, Stephanie M.; Ingelsson, Martin; Hyman, Bradley; Burton, Mark A.; Goldstein, Lee E.; Duong, Scott; Tanzi, Rudolph E.; Moir, Robert D.

2010-01-01

Background The amyloid β-protein (Aβ) is believed to be the key mediator of Alzheimer's disease (AD) pathology. Aβ is most often characterized as an incidental catabolic byproduct that lacks a normal physiological role. However, Aβ has been shown to be a specific ligand for a number of different receptors and other molecules, transported by complex trafficking pathways, modulated in response to a variety of environmental stressors, and able to induce pro-inflammatory activities. Methodology/Principal Findings Here, we provide data supporting an in vivo function for Aβ as an antimicrobial peptide (AMP). Experiments used established in vitro assays to compare antimicrobial activities of Aβ and LL-37, an archetypical human AMP. Findings reveal that Aβ exerts antimicrobial activity against eight common and clinically relevant microorganisms with a potency equivalent to, and in some cases greater than, LL-37. Furthermore, we show that AD whole brain homogenates have significantly higher antimicrobial activity than aged matched non-AD samples and that AMP action correlates with tissue Aβ levels. Consistent with Aβ-mediated activity, the increased antimicrobial action was ablated by immunodepletion of AD brain homogenates with anti-Aβ antibodies. Conclusions/Significance Our findings suggest Aβ is a hitherto unrecognized AMP that may normally function in the innate immune system. This finding stands in stark contrast to current models of Aβ-mediated pathology and has important implications for ongoing and future AD treatment strategies. PMID:20209079

Less common clinical manifestations of atopic dermatitis: prevalence by age.

PubMed

Julián-Gónzalez, Rolando Elias; Orozco-Covarrubias, Luz; Durán-McKinster, Carola; Palacios-Lopez, Carolina; Ruiz-Maldonado, Ramon; Sáez-de-Ocariz, Marimar

2012-01-01

The common manifestations of atopic dermatitis (AD) appear sequentially with involvement of the cheeks in infancy, flexural extremities in childhood, and hands in adulthood. Although less common clinical manifestations are well described, they have not been the subject of epidemiologic studies to describe their prevalence in specific age groups. This observational, cross-sectional, comparative study included 131 children younger than 18 of both sexes with AD who attended the clinics of the Dermatology Department of the National Institute of Pediatrics in Mexico City. Patients were examined to determine the presence of infrequent clinical manifestations of AD during infancy, preschool and school age, and adolescence and stratified according to sex, age, and number of clinical signs. A chi-square test was used to detect differences according to age and sex. Logistic regression analysis was also performed. The main findings according to age were genital dermatitis and papular-lichenoid dermatitis variant in infants; atopic feet, prurigo-like, nummular pattern, and erythroderma in preschool and school-aged children; and eyelid eczema and nipple dermatitis in adolescents. The risk of development of nipple dermatitis and eyelid eczema increased with age, and the development of genital dermatitis decreased with age. The knowledge of the prevalence of less common clinical manifestations of AD according to age in different populations might be helpful in diagnosing incipient cases of AD. © 2012 Wiley Periodicals, Inc.

Construction and comparative evaluation of different activity detection methods in brain FDG-PET.

PubMed

Buchholz, Hans-Georg; Wenzel, Fabian; Gartenschläger, Martin; Thiele, Frank; Young, Stewart; Reuss, Stefan; Schreckenberger, Mathias

2015-08-18

We constructed and evaluated reference brain FDG-PET databases for usage by three software programs (Computer-aided diagnosis for dementia (CAD4D), Statistical Parametric Mapping (SPM) and NEUROSTAT), which allow a user-independent detection of dementia-related hypometabolism in patients' brain FDG-PET. Thirty-seven healthy volunteers were scanned in order to construct brain FDG reference databases, which reflect the normal, age-dependent glucose consumption in human brain, using either software. Databases were compared to each other to assess the impact of different stereotactic normalization algorithms used by either software package. In addition, performance of the new reference databases in the detection of altered glucose consumption in the brains of patients was evaluated by calculating statistical maps of regional hypometabolism in FDG-PET of 20 patients with confirmed Alzheimer's dementia (AD) and of 10 non-AD patients. Extent (hypometabolic volume referred to as cluster size) and magnitude (peak z-score) of detected hypometabolism was statistically analyzed. Differences between the reference databases built by CAD4D, SPM or NEUROSTAT were observed. Due to the different normalization methods, altered spatial FDG patterns were found. When analyzing patient data with the reference databases created using CAD4D, SPM or NEUROSTAT, similar characteristic clusters of hypometabolism in the same brain regions were found in the AD group with either software. However, larger z-scores were observed with CAD4D and NEUROSTAT than those reported by SPM. Better concordance with CAD4D and NEUROSTAT was achieved using the spatially normalized images of SPM and an independent z-score calculation. The three software packages identified the peak z-scores in the same brain region in 11 of 20 AD cases, and there was concordance between CAD4D and SPM in 16 AD subjects. The clinical evaluation of brain FDG-PET of 20 AD patients with either CAD4D-, SPM- or NEUROSTAT-generated databases from an identical reference dataset showed similar patterns of hypometabolism in the brain regions known to be involved in AD. The extent of hypometabolism and peak z-score appeared to be influenced by the calculation method used in each software package rather than by different spatial normalization parameters.

S182 and STM2 gene missense mutations in sporadic alzheimer disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Higuchi, Susumu; Matsushita, Sachio; Hasegawa, Yoshio

1996-07-26

The linkage of genes S182 and STM2 to early-onset or late-onset sporadic Alzheimer disease (AD) was not found in a group of 97 clinically-diagnosed AD patients and 46 autopsy-confirmed AD cases, using PCR-RFLP methods. 7 refs.

Prevalence of Comorbidity in Patients With Young-Onset Alzheimer Disease Compared With Late-Onset: A Comparative Cohort Study.

PubMed

Gerritsen, Adrie A J; Bakker, Christian; Verhey, Frans R J; de Vugt, Marjolein E; Melis, René J F; Koopmans, Raymond T C M

2016-04-01

With the lack of a cure for Alzheimer disease (AD), the identification of comorbidity is important to reduce the possibility of excess disability. Although comorbidity in patients with late-onset AD (LO-AD) is common, for people with young-onset AD (YO-AD), it is unclear how often comorbidity occurs. Furthermore, it is uncertain whether comorbidity in patients with YO-AD differs from that in patients with LO-AD. The aim of this study was to explore the prevalence, types of morbidity, and morbidity profiles in patients with YO-AD compared with those of patients with LO-AD. Explorative cohort study from 2 separate Dutch cohorts (Needs in Young-onset Dementia [NeedYD] and the Clinical Course of Cognition and Comorbidity-Dementia Study [4C-Dementia study]). Participants were recruited in 2007 and 2008 from (1) the memory clinics of 3 Dutch Alzheimer centers, (2) the memory clinics of general hospitals, (3) mental health services in the southern part of the Netherlands, and (4) young-onset dementia specialized day care facilities. A comparison group of community-dwelling, elderly patients with AD was selected from the 4C-Dementia study. Patients in this study were recruited in 2010 and 2011 from the aforementioned Alzheimer centers. The prevalence rates of comorbidity were compared between 177 patients with YO-AD and 155 patients with LO-AD. Comorbidity was classified using the International Classification of Diseases, 10th Revision (ICD-10). The total amount of comorbidity was established by counting the number of existing diseases (ICD categories or chapters) and comorbidity was also dichotomized as present or absent. Furthermore, a hierarchical cluster analysis was performed to study clusters of comorbidity. Compared with LO-AD, patients with YO-AD showed less (P < .001) overall comorbidity (58.2% vs 86.5%) and had lower prevalence rates of diabetes, obesity, and circulatory diseases; however, the prevalence rates of diseases of the nervous system in YO-AD (6.2%) were higher compared with those of patients with LO-AD (4.5%). The cluster analysis revealed a distinctive group of patients with YO-AD with either no comorbidity or with a disease of the nervous system. Endocrine, nutritional, and metabolic diseases and diseases of the circulatory system were present in 34% of the patients with YO-AD. Comorbidity is less common in YO-AD than in LO-AD. However, general practitioners should be aware that approximately one-third of the patients with YO-AD suffer from or have endocrine, nutritional, and metabolic diseases and/or diseases of the circulatory system. Treatment should therefore not only focus on dementia but also on comorbidity. This attention may slow the functional decline in AD. These exploratory analyses suggested a higher prevalence of nervous system diseases in YO-AD compared with LO-AD. However, the finding did not reach statistical significance and in combination with the exploratory nature of the analyses justifies further investigation. If verified, this finding may help to decrease the time to diagnosis of AD and, subsequently, support in young patients with a neurological disease. Further investigation is needed to gain more insight into the association between comorbidity and AD in younger people. Copyright © 2016 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.

Impact of Interventions to Reduce Alzheimer’s Disease Pathology on the Prevalence of Dementia in the Oldest-Old

PubMed Central

Brookmeyer, Ron; Kawas, Claudia H.; Abdallah, Nada; Paganini-Hill, Annlia; Kim, Ronald C.; Corrada, Maria M.

2016-01-01

Introduction The number of persons aged over 90 years will grow significantly in coming decades. This group has the highest rates of dementia, most commonly Alzheimer’s disease (AD). Methods Using The 90+ Study we developed a statistical model for dementia risk based on brain pathologies. Intervention scenarios which reduce or eliminate AD pathology were considered and the numbers of dementia cases among the U.S. oldest-old that could be prevented were estimated. Results U.S. dementia prevalence among the oldest-old will increase from 1.35 million in 2015 to 4.72 million in 2050.If interventions eliminate AD pathology, dementia prevalence would be reduced by approximately 50%, averting nearly 2.4 million cases in 2050. However, large numbers of dementia cases would still remain. Discussion Reducing AD pathology would significantly decrease the public health burden of dementia. However, other interventions are needed to address the burden associated with other dementing pathologies prevalent in the oldest-old. PMID:26900132

Enhancement of pheochromocytoma nerve cell growth by consecutive fractionization of Angelica gigas Nakai extracts

PubMed Central

Jeong, Myoung Hoon; Kim, Ji Seon; Zou, Yunyun; Yoon, Chang Soon; Lim, Hye Won; Ahn, Juhee

2010-01-01

This work was to investigate the effect of flavonoids from Angelica gigas Nakai on the proliferation and differentiation of PC12 cells. Several solvents including hexane, chloroform, ethyl acetate, butanol and water consecutively partitioned. We determined the ethanol crude extract of Angelica gigas Nakai. The hexane fraction was shown to contain the highest number of flavonoids as follows; 21.48 mg/g and the composition of the flavonoids was as follows: 12.24 mg/g of quercetin, 4.39 mg/g of myricetin and 2.58 mg/g of catechin. In addition, this hexane fraction greatly increased both cell growth and outgrowth of the neurite, and whose effects were three times higher than those of the other fractions. The length of the neurites was measured as ca. 110 μm in adding 50 μg/mL of the hexane fraction, which was about the same as the case of adding 50 ng/mL of NGF as a positive control. This result indicates that the differentiation of PC12 cells by the addition of the hexane fraction was comparable to the case of adding NGF. The hexane fraction was also determined to prevent apoptosis of PC12 cells by suppressing DNA fragmentation. It is interesting that the mixture of three major flavonoids, quercetin, myricetin and catechin showed stronger activity on, both PC12 cell growth and neuritis outgrowth, than when adding each flavonoid alone. We believe this was due to the synergistic effects of the three flavonoids. The activities of these flavonoids from Angelica gigas Nakai are reported for the first time in this study. PMID:20936343

Effect of reactive agent and transesterification catalyst on properties of PLA/PBAT blends

NASA Astrophysics Data System (ADS)

Pitivut, S.; Suttiruengwong, S.; Seadan, M.

2015-07-01

This research aimed to study the properties of poly (lactic acid) (PLA)/poly (butylene adipate-co-terephthalate) (PBAT) blends with two different reactive systems: free radical reaction through peroxide (Perkadox) and transesterification catalyst (tetrabutyl titanate; TBT). Two blends composed of PLA as a matrix phase with the composition of 80 and 70 percent by weight. PLA/PBAT blends with Perkadox were prepared in twin screw extruder, whereas PLA/PBAT blends with TBT were prepared in an internal mixer. The morphology of the blends was investigated by scanning electron microscope (SEM). Tensile and impact testingsof the blends were reported. In case of the blends with Perkadox, SEM micrographs revealed that the size of particles was substantially reduced when adding more Perkadox. Young's modulus and the tensile strength of all blend ratios were insignificantly changed, whereas the elongation at break was decreased when compared to non-reactive blends due to the possible crosslinking reaction as observed from melt flow index (MFI) values. When adding Perkadox, the impact strength of PLA/PBAT (80/20) remained almost unchanged. However, the impact strength of PLA/PBAT (70/30) was enhanced, increasing to 110% for 0.05 phr Perkadox. In case of the blends with TBT, SEM micrographs showed the decrease in the particle size of PBAT phase when adding TBT. Young's modulus and the tensile strength of all blend ratios were not different, but the elongation at break was improved when adding TBT owing to the transesterification reaction. For PLA/PBAT (80/20), the elongation at break was increased by 39%, whereas the elongation at break was increased by 15% for PLA/PLA (70/30). The impact strength of all blend ratios unaffected.

Fast computation of derivative based sensitivities of PSHA models via algorithmic differentiation

NASA Astrophysics Data System (ADS)

Leövey, Hernan; Molkenthin, Christian; Scherbaum, Frank; Griewank, Andreas; Kuehn, Nicolas; Stafford, Peter

2015-04-01

Probabilistic seismic hazard analysis (PSHA) is the preferred tool for estimation of potential ground-shaking hazard due to future earthquakes at a site of interest. A modern PSHA represents a complex framework which combines different models with possible many inputs. Sensitivity analysis is a valuable tool for quantifying changes of a model output as inputs are perturbed, identifying critical input parameters and obtaining insight in the model behavior. Differential sensitivity analysis relies on calculating first-order partial derivatives of the model output with respect to its inputs. Moreover, derivative based global sensitivity measures (Sobol' & Kucherenko '09) can be practically used to detect non-essential inputs of the models, thus restricting the focus of attention to a possible much smaller set of inputs. Nevertheless, obtaining first-order partial derivatives of complex models with traditional approaches can be very challenging, and usually increases the computation complexity linearly with the number of inputs appearing in the models. In this study we show how Algorithmic Differentiation (AD) tools can be used in a complex framework such as PSHA to successfully estimate derivative based sensitivities, as is the case in various other domains such as meteorology or aerodynamics, without no significant increase in the computation complexity required for the original computations. First we demonstrate the feasibility of the AD methodology by comparing AD derived sensitivities to analytically derived sensitivities for a basic case of PSHA using a simple ground-motion prediction equation. In a second step, we derive sensitivities via AD for a more complex PSHA study using a ground motion attenuation relation based on a stochastic method to simulate strong motion. The presented approach is general enough to accommodate more advanced PSHA studies of higher complexity.

Assessment of Bowel Wall Enhancement for the Diagnosis of Intestinal Ischemia in Patients with Small Bowel Obstruction: Value of Adding Unenhanced CT to Contrast-enhanced CT.

PubMed

Chuong, Anh Minh; Corno, Lucie; Beaussier, Hélène; Boulay-Coletta, Isabelle; Millet, Ingrid; Hodel, Jérôme; Taourel, Patrice; Chatellier, Gilles; Zins, Marc

2016-07-01

Purpose To determine whether adding unenhanced computed tomography (CT) to contrast material-enhanced CT improves the diagnostic performance of decreased bowel wall enhancement as a sign of ischemia complicating mechanical small bowel obstruction (SBO). Materials and Methods This retrospective study was approved by the institutional review board, which waived the requirement for informed consent. Two gastrointestinal radiologists independently performed retrospective assessments of 164 unenhanced and contrast-enhanced CT studies from 158 consecutive patients (mean age, 71.2 years) with mechanical SBO. The reference standard was the intraoperative and/or histologic diagnosis (in 80 cases) or results from clinical follow-up in patients who did not undergo surgery (84 cases). Decreased bowel wall enhancement was evaluated with contrast-enhanced images then and both unenhanced and contrast-enhanced images 1 month later. Diagnostic performance of decreased bowel wall enhancement and confidence in the diagnosis were compared between the two readings by using McNemar and Wilcoxon signed rank tests. Interobserver agreement was assessed by using κ statistics and compared with bootstrapping. Results Ischemia was diagnosed in 41 of 164 (25%) episodes of SBO. For both observers, adding unenhanced images improved decreased bowel wall enhancement sensitivity (observer 1: 46.3% [19 of 41] vs 65.8% [27 of 41], P = .02; observer 2: 56.1% [23 of 41] vs 63.4% [26 of 41], P = .45), Youden index (from 0.41 to 0.58 for observer 1 and from 0.42 to 0.61 for observer 2), and confidence score (P < .001 for both). Specificity significantly increased for observer 2 (84.5% [104 of 123] vs 94.3% [116 of 123], P = .002), and interobserver agreement significantly increased, from moderate (κ = 0.48) to excellent (κ = 0.89; P < .0001). Conclusion Adding unenhanced CT to contrast-enhanced CT improved the sensitivity, diagnostic confidence, and interobserver agreement of the diagnosis of ischemia, a complication of mechanical SBO, on the basis of decreased bowel wall enhancement. (©) RSNA, 2016.

Absence of Alzheimer Disease Neuropathologic Changes in Eyes of Subjects With Alzheimer Disease.

PubMed

Williams, Erik A; McGuone, Declan; Frosch, Matthew P; Hyman, Bradley T; Laver, Nora; Stemmer-Rachamimov, Anat

2017-05-01

Alzheimer disease (AD) is the most common cause of dementia in the elderly, and is characterized by extracellular deposition of β-amyloid and intracellular accumulation of hyperphosphorylated tau protein in the brain. These pathologic findings are identified postmortem. Various visual deficits in AD have been reported and there have been conflicting reports, through imaging and pathology studies, regarding the presence of changes in the globe that mirror Alzheimer changes in the brain. Moreover, both macular degeneration and glaucoma have been variously characterized as having AD-related features. We examined one or both eyes from 19 autopsy cases, 17 of which had varying degrees of AD-related changes, and 2 of which were age-matched controls. Three cases had glaucoma and 4 had macular degeneration. Immunohistochemistry for tau, β-amyloid, TDP-43, ubiquitin, and α-synuclein showed no evidence of inclusions, deposits or other protein accumulation in any case, in any part of the globe. This finding suggests that regardless of the severity of changes seen in the brain in AD, there are no similar changes in the globe. © 2017 American Association of Neuropathologists, Inc. All rights reserved.

Head or brain injuries and Alzheimer's disease: A nested case-control register study.

PubMed

Tolppanen, Anna-Maija; Taipale, Heidi; Hartikainen, Sirpa

2017-12-01

Many previous studies have been limited by self- or proxy-reported injury or short follow-up. We investigated whether head or brain injuries are associated with Alzheimer's disease (AD), possible modifying factors and dose-response relationship. Nested register-based case-control study of all community dwellers who received clinically verified AD diagnosis in Finland in 2005 to 2011 (n = 70,719) and one to four matched controls for each case (n of controls = 282,862). The magnitude of association between hospital-treated head and/or brain injuries was strongly dependent on the lag time between exposure and outcome. With a 5-year lag time, head injury (adjusted odds ratio; 95% confidence interval 1.19; 1.15-1.23) or brain injury (1.23; 1.18-1.29) was associated with higher risk of AD. Dose-response relationship with number and severity of injuries was observed. Associations were stronger in those with earlier onset of AD. Stronger associations with shorter lag times indicate that head and/or brain injuries may also reflect the ongoing AD disease process. Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Financial modeling of current surgical robotic system in outpatient laparoscopic cholecystectomy: how should we think about the expense?

PubMed

Schwaitzberg, S D

2016-05-01

More than 500,000 robotically assisted procedures were performed worldwide in 2013. Despite broad adoption, there remains a lack of clarity concerning the added cost of the robotic system to the procedure especially in light of an increasing number of ambulatory procedures which are now marketed by hospitals, surgeons and the manufacturer. These procedures are associated with much less reimbursement than inpatient procedures. It is unclear whether these added expenses can be absorbed in these scenarios. Reports vary in opinion concerning the added net costs during robotically assisted laparoscopic hernia or cholecystectomy. The worldwide revenues, procedures, and the installed base of robotic system data were reviewed and reanalyzed from the 2013 Intuitive Surgical Investors report. This provided an opportunity to look cost per case projections from the vantage point of actual revenue. This analysis was based on revenue of 2.27 billion US dollars in the three categories of capital acquisition, instrumentation and accessories, and service revenue. These revenues were then spread across 523,000 cases with varying assumptions. Without regard to expense offsets, the additional cost ranges from $2908 to $8675 depending on what system was purchased and the ability to distribute costs against case volume. Estimates of commercial and government revenue were then compared against these expenses. The use of the extraordinary technology in the face of low-morbidity low-cost established minimally invasive procedures needs to withstand scrutiny of outcome assessment, revenue and expense considerations and appropriateness review in order to create financially viable approaches to high-volume minimally invasive procedures. Revenue estimates associated with outpatient reimbursement make it difficult to support these expenses, recognizing inpatient procedures represent a different net financial picture.

The risk of renal disease is increased in lambda myeloma with bone marrow amyloid deposits.

PubMed

Kozlowski, Piotr; Montgomery, Scott; Befekadu, Rahel; Hahn-Strömberg, Victoria

2017-01-01

Light chain amyloidosis (AL) is a rare deposition disease and is present in 10-15% of patients with myeloma (MM). In contrast to symptomatic AL in MM, presence of bone marrow (BM) amyloid deposits (AD) in MM is not connected to kidney damage. Renal AD but not BM-AD occur mostly in MM with lambda paraprotein (lambda MM). We investigated amyloid presence in BM clots taken at diagnosis in 84 patients with symptomatic MM and compared disease characteristics in MM with kappa paraprotein (kappa MM)/lambda MM with and without BM-AD. Lambda MM with BM-AD was compared with kappa MM without BM-AD, kappa MM with BM-AD, and lambda MM without BM-AD: lambda MM with BM-AD patients had a significantly higher mean creatinine level (4.23 mg/dL vs 1.69, 1.14, and 1.28 mg/dL, respectively) and a higher proportion presented with severe kidney failure (6/11 [55%] vs 6/32 [19%], 1/22 [5%], and 3/19 [16%], respectively). Proteinuria was more common in lambda MM with BM-AD patients compared with kappa MM without BM-AD patients (8/11 [73%] vs 5/32 [16%], respectively). Kidney damage was more common in lambda MM with BM-AD indicating presence of renal AD.

The burden of atopic dermatitis in US adults: Health care resource utilization data from the 2013 National Health and Wellness Survey.

PubMed

Eckert, Laurent; Gupta, Shaloo; Amand, Caroline; Gadkari, Abhijit; Mahajan, Puneet; Gelfand, Joel M

2018-01-01

There is a lack of data on the burden of atopic dermatitis (AD) in adults relative to the general population. To characterize the AD burden in adult patients relative to both matched non-AD controls and matched patients with psoriasis in terms of comorbidities, health care resource utilization (HCRU), and costs. Adults (≥18 years) who self-reported a diagnosis of AD or psoriasis and adult non-AD controls were identified from the 2013 US National Health and Wellness Survey. Patients with AD were propensity score-matched with non-AD controls and patients with psoriasis on demographic variables. Patient-reported outcomes were analyzed between matched cohorts. Patients with AD had a significantly greater risk for atopic comorbidities, as well as significantly greater HCRU and total cost compared with non-AD controls. The burden of AD was generally comparable to that of psoriasis, although patients with AD reported increased use of emergency room visits compared with patients with psoriasis. Patient-reported data are susceptible to recall bias and erroneous classification. Adult patients with AD reported a substantial disease burden, suggesting an unmet need for more effective AD treatment options. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Cellular, synaptic and biochemical features of resilient cognition in Alzheimer’s disease

PubMed Central

Arnold, Steven. E.; Louneva, Natalia; Cao, Kajia; Wang, Li-San; Han, Li-Ying; Wolk, David A.; Negash, Selamawit; Leurgans, Sue E.; Schneider, Julie A.; Buchman, Aron S.; Wilson, Robert S.; Bennett, David A.

2012-01-01

While neuritic plaques and neurofibrillary tangles in older adults are correlated with cognitive impairment and severity of dementia, it has long been recognized that the relationship is imperfect as some people exhibit normal cognition despite high levels of AD pathology. We compared the cellular, synaptic and biochemical composition of midfrontal cortices in female subjects from the Religious Orders Study who were stratified into three subgroups: 1) pathological AD with normal cognition (“AD-Resilient”), 2) pathological AD with AD-typical dementia (“AD-Dementia)” and 3) pathologically normal with normal cognition (“Normal Comparison”). The AD-Resilient group exhibited preserved densities of synaptophysin-labeled presynaptic terminals and synaptopodin-labeled dendritic spines compared to the AD-Dementia group, and increased densities of GFAP astrocytes compared to both the AD-Dementia and Normal Comparison group. Further, in a discovery antibody microarray protein analysis we identified a number of candidate protein abnormalities that were associated with diagnostic group. These data characterize cellular and synaptic features and identify novel biochemical targets that may be associated with resilient cognitive brain aging in the setting of pathological AD. PMID:22554416

Modification to the Capsid of the Adenovirus Vector That Enhances Dendritic Cell Infection and Transgene-Specific Cellular Immune Responses

PubMed Central

Worgall, Stefan; Busch, Annette; Rivara, Michael; Bonnyay, David; Leopold, Philip L.; Merritt, Robert; Hackett, Neil R.; Rovelink, Peter W.; Bruder, Joseph T.; Wickham, Thomas J.; Kovesdi, Imi; Crystal, Ronald G.

2004-01-01

Adenovirus (Ad) gene transfer vectors can be used to transfer and express antigens and function as strong adjuvants and thus are useful platforms for the development of genetic vaccines. Based on the hypothesis that Ad vectors with enhanced infectibility of dendritic cells (DC) may be able to evoke enhanced immune responses against antigens encoded by the vector in vivo, the present study analyzes the vaccine potential of an Ad vector expressing β-galactosidase as a model antigen and genetically modified with RGD on the fiber knob [AdZ.F(RGD)] to more selectively infect DC and consequently enhance immunity against the β-galactosidase antigen. Infection of murine DC in vitro with AdZ.F(RGD) showed an eightfold-increased transgene expression following infection compared to AdZ (also expressing β-galactosidase, but with a wild-type capsid). Binding, cellular uptake, and trafficking in DC were also increased with AdZ.F(RGD) compared to AdZ. To determine whether AdZ.F(RGD) could evoke enhanced immune responses to β-galactosidase in vivo, C57BL/6 mice were immunized with AdZ.F(RGD) or AdZ subcutaneously via the footpad. Humoral responses with both vectors were comparable, with similar anti-β-galactosidase antibody levels following vector administration. However, cellular responses to β-galactosidase were significantly enhanced, with the frequency of CD4+ as well as the CD8+ β-galactosidase-specific gamma interferon response in cells isolated from the draining lymph nodes increased following immunization with AdZ.F(RGD) compared to Ad.Z (P < 0.01). Importantly, this enhanced cellular immune response of the AdZ.F(RGD) vector was sufficient to evoke enhanced inhibition of the growth of preexisting tumors expressing β-galactosidase: BALB/c mice implanted with the CT26 syngeneic β-galactosidase-expressing colon carcinoma cell line and subsequently immunized with AdZ.F(RGD) showed decreased tumor growth and improved survival compared to mice immunized with AdZ. These data demonstrate that addition of an RGD motif to the Ad fiber knob increases the infectibility of DC and leads to enhanced cellular immune responses to the Ad-transferred transgene, suggesting that the RGD capsid modification may be useful in developing Ad-based vaccines. PMID:14963160

Loops in AdS from conformal field theory

DOE PAGES

Aharony, Ofer; Alday, Luis F.; Bissi, Agnese; ...

2017-07-10

We propose and demonstrate a new use for conformal field theory (CFT) crossing equations in the context of AdS/CFT: the computation of loop amplitudes in AdS, dual to non-planar correlators in holographic CFTs. Loops in AdS are largely unexplored, mostly due to technical difficulties in direct calculations. We revisit this problem, and the dual 1=N expansion of CFTs, in two independent ways. The first is to show how to explicitly solve the crossing equations to the first subleading order in 1=N 2, given a leading order solution. This is done as a systematic expansion in inverse powers of the spin, to all orders. These expansions can be resummed, leading to the CFT data for nite values of the spin. Our second approach involves Mellin space. We show how the polar part of the four-point, loop-level Mellin amplitudes can be fully reconstructed from the leading-order data. The anomalous dimensions computed with both methods agree. In the case ofmore » $$\\phi$$ 4 theory in AdS, our crossing solution reproduces a previous computation of the one-loop bubble diagram. We can go further, deriving the four-point scalar triangle diagram in AdS, which had never been computed. In the process, we show how to analytically derive anomalous dimensions from Mellin amplitudes with an in nite series of poles, and discuss applications to more complicated cases such as the N = 4 super-Yang-Mills theory.« less

Loops in AdS from conformal field theory

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aharony, Ofer; Alday, Luis F.; Bissi, Agnese

We propose and demonstrate a new use for conformal field theory (CFT) crossing equations in the context of AdS/CFT: the computation of loop amplitudes in AdS, dual to non-planar correlators in holographic CFTs. Loops in AdS are largely unexplored, mostly due to technical difficulties in direct calculations. We revisit this problem, and the dual 1=N expansion of CFTs, in two independent ways. The first is to show how to explicitly solve the crossing equations to the first subleading order in 1=N 2, given a leading order solution. This is done as a systematic expansion in inverse powers of the spin, to all orders. These expansions can be resummed, leading to the CFT data for nite values of the spin. Our second approach involves Mellin space. We show how the polar part of the four-point, loop-level Mellin amplitudes can be fully reconstructed from the leading-order data. The anomalous dimensions computed with both methods agree. In the case ofmore » $$\\phi$$ 4 theory in AdS, our crossing solution reproduces a previous computation of the one-loop bubble diagram. We can go further, deriving the four-point scalar triangle diagram in AdS, which had never been computed. In the process, we show how to analytically derive anomalous dimensions from Mellin amplitudes with an in nite series of poles, and discuss applications to more complicated cases such as the N = 4 super-Yang-Mills theory.« less

Identification of pre-clinical Alzheimer’s disease by a profile of pathogenic proteins in neurally-derived blood exosomes: a case-control study

PubMed Central

Fiandaca, Massimo S.; Kapogiannis, Dimitrios; Mapstone, Mark; Boxer, Adam; Eitan, Erez; Schwartz, Janice B.; Abner, Erin L.; Petersen, Ronald C.; Federoff, Howard J.; Miller, Bruce L.; Goetzl, Edward J.

2014-01-01

Background Proteins pathogenic in Alzheimer’s disease (AD) were extracted from neurally-derived blood exosomes and quantified to develop biomarkers for staging of sporadic AD. Methods Blood exosomes obtained at one time-point from patients with AD (n=57) or frontotemporal dementia (FTD) (n=16), and at two time-points from others (n=24) when cognitively normal and one-ten years later when diagnosed with AD were enriched for neural sources by immunoabsorption. AD-pathogenic exosomal proteins were extracted and quantified by ELISAs. Results Mean exosomal levels of total Tau, P-T181-tau, P-S396-tau and Aβ1-42 for AD and levels of P-T181-tau and Aβ1-42 for FTD were significantly higher than for case-controls. Stepwise discriminant modeling incorporated P-T181-tau, P-S396-tau and Aβ1-42 in AD, but only P-T181-tau in FTD. Classification of 96.4% of AD patients and 87.5% of FTD patients was correct. In 24 AD patients, exosomal levels of P-S396-tau, P-T181-tau and Aβ1-42 were significantly higher than for controls both one to ten years before and when diagnosed with AD. Conclusions Levels of P-S396-tau, P-T181-tau and Aβ1-42 in extracts of neurally-derived blood exosomes predict development of AD up to 10 years prior to clinical onset. PMID:25130657

Loops in AdS from conformal field theory

NASA Astrophysics Data System (ADS)

Aharony, Ofer; Alday, Luis F.; Bissi, Agnese; Perlmutter, Eric

2017-07-01

We propose and demonstrate a new use for conformal field theory (CFT) crossing equations in the context of AdS/CFT: the computation of loop amplitudes in AdS, dual to non-planar correlators in holographic CFTs. Loops in AdS are largely unexplored, mostly due to technical difficulties in direct calculations. We revisit this problem, and the dual 1 /N expansion of CFTs, in two independent ways. The first is to show how to explicitly solve the crossing equations to the first subleading order in 1 /N 2, given a leading order solution. This is done as a systematic expansion in inverse powers of the spin, to all orders. These expansions can be resummed, leading to the CFT data for finite values of the spin. Our second approach involves Mellin space. We show how the polar part of the four-point, loop-level Mellin amplitudes can be fully reconstructed from the leading-order data. The anomalous dimensions computed with both methods agree. In the case of ϕ 4 theory in AdS, our crossing solution reproduces a previous computation of the one-loop bubble diagram. We can go further, deriving the four-point scalar triangle diagram in AdS, which had never been computed. In the process, we show how to analytically derive anomalous dimensions from Mellin amplitudes with an infinite series of poles, and discuss applications to more complicated cases such as the N = 4 super-Yang-Mills theory.

Malonyl-CoA decarboxylase (MCD) is differentially regulated in subcellular compartments by 5'AMP-activated protein kinase (AMPK). Studies using H9c2 cells overexpressing MCD and AMPK by adenoviral gene transfer technique.

PubMed

Sambandam, Nandakumar; Steinmetz, Michael; Chu, Angel; Altarejos, Judith Y; Dyck, Jason R B; Lopaschuk, Gary D

2004-07-01

Malonyl-CoA, a potent inhibitor of carnitine pamitoyl transferase-I (CPT-I), plays a pivotal role in fuel selection in cardiac muscle. Malonyl-CoA decarboxylase (MCD) catalyzes the degradation of malonyl-CoA, removes a potent allosteric inhibition on CPT-I and thereby increases fatty acid oxidation in the heart. Although MCD has several Ser/Thr phosphorylation sites, whether it is regulated by AMP-activated protein kinase (AMPK) has been controversial. We therefore overexpressed MCD (Ad.MCD) and constitutively active AMPK (Ad.CA-AMPK) in H9c2 cells, using an adenoviral gene delivery approach in order to examine if MCD is regulated by AMPK. Cells infected with Ad.CA-AMPK demonstrated a fourfold increase in AMPK activity as compared with control cells expressing green fluorescent protein (Ad.GFP). MCD activity increased 40- to 50-fold in Ad.MCD + Ad.GFP cells when compared with Ad.GFP control. Co-expressing AMPK with MCD further augmented MCD expression and activity in Ad.MCD + Ad.CA-AMPK cells compared with the Ad.MCD + Ad.GFP control. Subcellular fractionation further revealed that 54.7 kDa isoform of MCD expression was significantly higher in cytosolic fractions of Ad.MCD + Ad.CA-AMPK cells than of the Ad.MCD +Ad.GFP control. However, the MCD activities in cytosolic fractions were not different between the two groups. Interestingly, in the mitochondrial fractions, MCD activity significantly increased in Ad.MCD + Ad.CA-AMPK cells when compared with Ad.MCD + Ad.GFP cells. Using phosphoserine and phosphothreonine antibodies, no phosphorylation of MCD by AMPK was observed. The increase in MCD activity in mitochondria-rich fractions of Ad.MCD + Ad.CA-AMPK cells was accompanied by an increase in the level of the 50.7 kDa isoform of MCD protein in the mitochondria. This differential regulation of MCD expression and activity in the mitochondria by AMPK may potentially regulate malonyl-CoA levels at sites nearby CPT-I on the mitochondria.

Prominent microglial activation in cortical white matter is selectively associated with cortical atrophy in primary progressive aphasia.

PubMed

Ohm, D T; Kim, G; Gefen, T; Rademaker, A; Weintraub, S; Bigio, E H; Mesulam, M-M; Rogalski, E; Geula, C

2018-04-21

Primary progressive aphasia (PPA) is a clinical syndrome characterized by selective language impairments associated with focal cortical atrophy favouring the language dominant hemisphere. PPA is associated with Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) and significant accumulation of activated microglia. Activated microglia can initiate an inflammatory cascade that may contribute to neurodegeneration, but their quantitative distribution in cortical white matter and their relationship with cortical atrophy remain unknown. We investigated white matter activated microglia and their association with grey matter atrophy in 10 PPA cases with either AD or FTLD-TDP pathology. Activated microglia were quantified with optical density measures of HLA-DR immunoreactivity in two regions with peak cortical atrophy, and one nonatrophied region within the language dominant hemisphere of each PPA case. Nonatrophied contralateral homologues of the language dominant regions were examined for hemispheric asymmetry. Qualitatively, greater densities of activated microglia were observed in cortical white matter when compared to grey matter. Quantitative analyses revealed significantly greater densities of activated microglia in the white matter of atrophied regions compared to nonatrophied regions in the language dominant hemisphere (P < 0.05). Atrophied regions of the language dominant hemisphere also showed significantly more activated microglia compared to contralateral homologues (P < 0.05). White matter activated microglia accumulate more in atrophied regions in the language dominant hemisphere of PPA. While microglial activation may constitute a response to neurodegenerative processes in white matter, the resultant inflammatory processes may also exacerbate disease progression and contribute to cortical atrophy. © 2018 British Neuropathological Society.

Dietary sugar/starches intake and Barrett's esophagus: a pooled analysis.

PubMed

Li, Nan; Petrick, Jessica Leigh; Steck, Susan Elizabeth; Bradshaw, Patrick Terrence; McClain, Kathleen Michele; Niehoff, Nicole Michelle; Engel, Lawrence Stuart; Shaheen, Nicholas James; Corley, Douglas Allen; Vaughan, Thomas Leonard; Gammon, Marilie Denise

2017-11-01

Barrett's esophagus (BE) is the key precursor lesion of esophageal adenocarcinoma, a lethal cancer that has increased rapidly in westernized countries over the past four decades. Dietary sugar intake has also been increasing over time, and may be associated with these tumors by promoting hyperinsulinemia. The study goal was to examine multiple measures of sugar/starches intake in association with BE. This pooled analysis included 472 BE cases and 492 controls from two similarly conducted case-control studies in the United States. Dietary intake data, collected by study-specific food frequency questionnaires, were harmonized across studies by linking with the University of Minnesota Nutrient Database, and pooled based on study-specific quartiles. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for age, sex, race, total energy intake, study indicator, body mass index, frequency of gastro-esophageal reflux, and fruit/vegetable intake. In both studies, intake of sucrose (cases vs. controls, g/day: 36.07 vs. 33.51; 36.80 vs. 35.06, respectively) and added sugar (46.15 vs. 41.01; 44.18 vs. 40.68, respectively) were higher in cases than controls. BE risk was increased 79% and 71%, respectively, for associations comparing the fourth to the first quartile of intake of sucrose (OR Q4vs.Q1  = 1.79, 95% CI = 1.07-3.02, P trend  = 0.01) and added sugar (OR Q4vs.Q1  = 1.71, 95% CI = 1.05-2.80, P trend  = 0.15). Intake of sweetened desserts/beverages was associated with 71% increase in BE risk (OR Q4vs.Q1  = 1.71, 95% CI = 1.07-2.73, P trend  = 0.04). Limiting dietary intake of foods and beverages that are high in added sugar, especially refined table sugar, may reduce the risk of developing BE.

Creutzfeldt-Jakob disease with Alzheimer pathology, presenting with status epilepticus following repeated partial seizures: a case report and literature review.

PubMed

Miyake, Keita; Hara, Takashi; Oshima, Etsuko; Kawada, Kiyohiro; Ishizu, Hideki; Yamauchi, Yuko; Satoh, Katsuya; Kitamoto, Tetsuyuki; Takenoshita, Shintaro; Terada, Seishi; Yamada, Norihito

2018-04-25

Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disease. Common first symptoms are dementia, cerebellar ataxia, visual disturbance, and psychiatric symptoms. Seizure as the first symptom of CJD is a very rare finding. We experienced an elderly woman who presented initially with status epilepticus following repeated partial seizures in the course of Alzheimer disease (AD) dementia. Anti-convulsive therapy had no effect. Autopsy revealed definite CJD with AD pathology. This is the first reported CJD case presenting with status epilepticus in the course of AD dementia.

A Comparative Study of Academic Dishonesty among University Students in Mainland China and Taiwan

ERIC Educational Resources Information Center

Yang, Shu Ching; Chiang, Feng Kuang; Huang, Chiao Ling

2017-01-01

The purpose of this study was to compare the academic dishonesty (AD) experience of students from Mainland China and Taiwan. Specifically, we investigated students' current self-reported personal AD, their perception of peers' AD, the climate of academic integrity and their awareness of AD's seriousness. Furthermore, we sought to explore the…

Treatment for Rheumatoid Arthritis and Risk of Alzheimer's Disease: A Nested Case-Control Analysis.

PubMed

Chou, Richard C; Kane, Michael; Ghimire, Sanjay; Gautam, Shiva; Gui, Jiang

2016-11-01

It is increasingly becoming accepted that inflammation may play an important role in the pathogenesis of Alzheimer's disease (AD), as several immune-related genes have been associated with AD. Among these is tumor necrosis factor (TNF)-α, a proinflammatory cytokine known to play an important role in autoimmune disorders, including rheumatoid arthritis (RA). Although AD and RA appear to involve similar pathological mechanisms through the production of TNF-α, the relationship between AD and RA remains unknown. To determine the relative risk of AD among RA patients and non-RA patients, and whether anti-TNF therapy for RA was associated with a lower risk of AD in RA patients. We performed a nested case-control study of more than 8.5 million commercially insured adults (aged ≥18 years) in all 50 US states, Puerto Rico, and US Virgin Islands in the Verisk Health claims database. We derived a sub-cohort of subjects with a diagnosis of RA (controls), or RA and AD (cases), matching cases and controls based on age, sex, exposure assessment period, and methotrexate treatment. We also assessed relative risk of AD following exposure to standard RA therapies, including anti-TNF agents (infliximab, adalimumab, etanercept), methotrexate, prednisone, sulfasalazine, and rituximab. Odds ratios were adjusted for comorbidities, including coronary artery disease, diabetes mellitus, and peripheral vascular disease. AD was more prevalent (p < 0.0001) among RA patients (0.79 %) than among those without RA (0.11 %). Chronic conditions such as coronary artery disease (odds ratio [OR] 1.48; 95 % confidence interval [CI] 1.04-2.05; p = 0.03), diabetes (OR 1.86; 95 % CI 1.32-2.62; p = 0.0004), and peripheral vascular disease (OR 1.61; 95 % CI 1.06-2.43; p = 0.02) significantly increased the relative risk of AD among RA patients. Exposure to anti-TNF agents as a class, but not other immunosuppressive drugs studied, was associated with lowered risk of AD among RA patients (unadjusted OR 0.44; 95 % CI 0.22-0.87; p = 0.02; adjusted OR 0.45; 95 % CI 0.23-0.90; p = 0.02). Sub-group analysis demonstrated that of the three anti-TNF agents studied, only etanercept (unadjusted OR, 0.33; 95 % CI 0.08-0.94; p = 0.03; adjusted OR 0.30; 95 % CI 0.08-0.89; p = 0.02) was associated with a decreased risk of AD in RA patients. There is an increased risk of AD in the studied RA population. The relative risk of AD among RA subjects was lowered in those exposed to etanercept. Anti-TNF therapy with etanercept shows promise as a potential treatment for AD.

Analysis of functional polymorphisms in three synaptic plasticity-related genes (BDNF, COMT AND UCHL1) in Alzheimer's disease in Colombia.

PubMed

Forero, Diego A; Benítez, Bruno; Arboleda, Gonzalo; Yunis, Juan J; Pardo, Rodrigo; Arboleda, Humberto

2006-07-01

In recent years, it has been proposed that synaptic dysfunction may be an important etiological factor for Alzheimer's disease (AD). This hypothesis has important implications for the analysis of AD genetic risk in case-control studies. In the present work, we analyzed common functional polymorphisms in three synaptic plasticity-related genes (brain-derived neurotrophic factor, BDNF Val66Met; catechol-O-methyl transferase, COMT Val158; ubiquitin carboxyl-terminal hydroxylase, UCHL1 S18Y) in a sample of 102 AD cases and 168 age and sex matched controls living in Bogotá, Colombia. There was not association between UCHL1 polymorphism and AD in our sample. We have found an initial association with BDNF polymorphism in familial cases and with COMT polymorphism in male and sporadic patients. These initial associations were lost after Bonferroni correction for multiple testing. Unadjusted results may be compatible with the expected functional effect of variations in these genes on pathological memory and cognitive dysfunction, as has been implicated in animal and cell models and also from neuropsychological analysis of normal subjects carriers of the AD associated genotypes. An exploration of functional variants in these and in other synaptic plasticity-related genes (a synaptogenomics approach) in independent larger samples will be important to discover new genes associated with AD.

The clinical and economic burden of newly diagnosed Alzheimer's disease in a medicare advantage population.

PubMed

Suehs, Brandon T; Davis, Cralen D; Alvir, Jose; van Amerongen, Derek; Pharmd, Nick C Patel; Joshi, Ashish V; Faison, Warachal E; Shah, Sonali N

2013-06-01

Alzheimer's disease (AD) represents a serious public health issue affecting approximately 5.4 million individuals in the United States and is projected to affect up to 16 million by 2050. This study examined health care resource utilization (HCRU), costs, and comorbidity burden immediately preceding new diagnosis of AD and 2 years after diagnosis. This study utilized a claims-based, retrospective cohort design. Medicare Advantage members newly diagnosed with AD (n = 3374) were compared to matched non-AD controls (n = 6748). All patients with AD were required to have 12 months of continuous enrollment prior to AD diagnosis (International Classification of Diseases, Clinical Modification [ICD-9] 331.0), during which time no diagnosis of AD, a related dementia, or an AD medication was observed. Non-AD controls demonstrated no diagnosis of AD, a related dementia, or a prescription claim for an AD medication treatment during their health plan enrollment. Medical and pharmacy claims data were used to measure HCRU, costs, and comorbidity burden over a period of 36 months (12 months pre-diagnosis and 24 months post-diagnosis). The HCRU and costs were greater for AD members during the year prior to diagnosis and during postdiagnosis years 1 and 2 compared to controls. The AD members also displayed greater comorbidity than their non-AD counterparts during postdiagnosis years 1 and 2, as measured by 2 different comorbidity indices. Members newly diagnosed with AD demonstrated greater HCRU, health care costs, and comorbidity burden compared to matched non-AD controls.

TNF-alpha and antibodies to periodontal bacteria discriminate between Alzheimer's disease patients and normal subjects.

PubMed

Kamer, Angela R; Craig, Ronald G; Pirraglia, Elizabeth; Dasanayake, Ananda P; Norman, Robert G; Boylan, Robert J; Nehorayoff, Andrea; Glodzik, Lidia; Brys, Miroslaw; de Leon, Mony J

2009-11-30

The associations of inflammation/immune responses with clinical presentations of Alzheimer's disease (AD) remain unclear. We hypothesized that TNF-alpha and elevated antibodies to periodontal bacteria would be greater in AD compared to normal controls (NL) and their combination would aid clinical diagnosis of AD. Plasma TNF-alpha and antibodies against periodontal bacteria were elevated in AD patients compared with NL and independently associated with AD. The number of positive IgG to periodontal bacteria incremented the TNF-alpha classification of clinical AD and NL. This study shows that TNF-alpha and elevated numbers of antibodies against periodontal bacteria associate with AD and contribute to the AD diagnosis.

Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals

PubMed Central

Ghani, Mahdi; Reitz, Christiane; Cheng, Rong; Vardarajan, Badri Narayan; Jun, Gyungah; Sato, Christine; Naj, Adam; Rajbhandary, Ruchita; Wang, Li-San; Valladares, Otto; Lin, Chiao-Feng; Larson, Eric B.; Graff-Radford, Neill R.; Evans, Denis; De Jager, Philip L.; Crane, Paul K.; Buxbaum, Joseph D.; Murrell, Jill R.; Raj, Towfique; Ertekin-Taner, Nilufer; Logue, Mark; Baldwin, Clinton T.; Green, Robert C.; Barnes, Lisa L.; Cantwell, Laura B.; Fallin, M. Daniele; Go, Rodney C. P.; Griffith, Patrick A.; Obisesan, Thomas O.; Manly, Jennifer J.; Lunetta, Kathryn L.; Kamboh, M. Ilyas; Lopez, Oscar L.; Bennett, David A.; Hendrie, Hugh; Hall, Kathleen S.; Goate, Alison M.; Byrd, Goldie S.; Kukull, Walter A.; Foroud, Tatiana M.; Haines, Jonathan L.; Farrer, Lindsay A.; Pericak-Vance, Margaret A.; Lee, Joseph H.; Schellenberg, Gerard D.; St. George-Hyslop, Peter; Mayeux, Richard; Rogaeva, Ekaterina

2015-01-01

IMPORTANCE Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays. OBJECTIVE To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals. DESIGN, SETTING, AND PARTICIPANTS Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-based ROH measurements were analyzed using raw or imputed genotype data. We studied the raw genotypes from 2 case-control subsets grouped based on SNP array: Alzheimer’s Disease Genetics Consortium data set (871 cases and 1620 control individuals) and Chicago Health and Aging Project–Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals). We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals. MAIN OUTCOMES AND MEASURES The ROHs larger than 1 Mb, 2 Mb, or 3 Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses. RESULTS The African American cohort had a low degree of inbreeding (F ~ 0.006). In the Alzheimer’s Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2 Mb (P = .004) or greater than 3 Mb (P = .02), as well as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2 = .04; ROHs >2 Mb). In the Chicago Health and Aging Project–Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2 = .02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2 = .03; ROHs >3 Mb). A total of 43 of 49 nominally significant genes common for both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs >1 Mb in cases vs 12.11 in controls; 2.986 Mb average size of ROHs >2 Mb in cases vs 2.889 Mb in controls; and 22% of cases with ROHs >3 Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2 = .006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2 = .01; ROHs >1 Mb), encoding a protein from the Claudin family, members of which were previously suggested as AD biomarkers. CONCLUSIONS AND RELEVANCE To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals. PMID:26366463

Biomarkers in Sporadic and Familial Alzheimer's Disease.

PubMed

Lista, Simone; O'Bryant, Sid E; Blennow, Kaj; Dubois, Bruno; Hugon, Jacques; Zetterberg, Henrik; Hampel, Harald

2015-01-01

Most forms of Alzheimer's disease (AD) are sporadic (sAD) or inherited in a non-Mendelian fashion, and less than 1% of cases are autosomal-dominant. Forms of sAD do not exhibit familial aggregation and are characterized by complex genetic and environmental interactions. Recently, the expansion of genomic methodologies, in association with substantially larger combined cohorts, has resulted in various genome-wide association studies that have identified several novel genetic associations of AD. Currently, the most effective methods for establishing the diagnosis of AD are defined by multi-modal pathways, starting with clinical and neuropsychological assessment, cerebrospinal fluid (CSF) analysis, and brain-imaging procedures, all of which have significant cost- and access-to-care barriers. Consequently, research efforts have focused on the development and validation of non-invasive and generalizable blood-based biomarkers. Among the modalities conceptualized by the systems biology paradigm and utilized in the "exploratory biomarker discovery arena", proteome analysis has received the most attention. However, metabolomics, lipidomics, transcriptomics, and epigenomics have recently become key modalities in the search for AD biomarkers. Interestingly, biomarker changes for familial AD (fAD), in many but not all cases, seem similar to those for sAD. The integration of neurogenetics with systems biology/physiology-based strategies and high-throughput technologies for molecular profiling is expected to help identify the causes, mechanisms, and biomarkers associated with the various forms of AD. Moreover, in order to hypothesize the dynamic trajectories of biomarkers through disease stages and elucidate the mechanisms of biomarker alterations, updated and more sophisticated theoretical models have been proposed for both sAD and fAD.

Affective disorders as potential complication of anti-acne treatment with isotretinoin: A case series.

PubMed

Hanna, Karakula-Juchnowicz; Agnieszka, Kowal-Popczak; Michal, Dzikowski; Dariusz, Juchnowicz; Izabela, Dzikowska; Agata, Makarewicz; Halina, Dubas-Slemp

2016-11-01

To analyse cases of 9 patients (18-27 yo) who were consequently admitted to our department and treated with affective disorders (AD) while undergoing isotretinoin (INN) therapy. A semi-structured questionnaire designed by the authors was used to analyse many variables related to demographic characteristics, dermatologic and psychiatrics symptoms, AD course and treatment, family history of mental disorders, building on medical histories of patients and their families, and available medical records. Patients were diagnosed (DSM-IV-TR) with: a major depressive episode (4 patients), a recurrent major depressive episode (3), a bipolar mixed episode (1), and rapid cycling bipolar I disorder (1). The mean time from the first use of INN to: I. the onset of mental disorders was approximately 2 months (1-6 months), II. a visit with a psychiatrist was about 12 months (1-38 months). The predictors of occurrence of AD included a family history of AD and a prior episode of mental disorders. The onset of AD was in most cases preceded by prodromal symptoms such as headaches, sleep disorders, fatigue, drowsiness, or general weakness. Five patients reported suicidal ideation, four patients showed suicidal tendencies, and two persons attempted to commit suicide during the treatment. Psychiatrists should pay special attention to isotretinoin as a drug that may trigger episodes of AD, particularly in patients with a family history of AD or prior episodes of mental disorders. Isotretinoin therapy of patients with acne and a family history of AD or prior episodes of mental disorders requires special care and, if symptoms of depression develop or worsen during the INN treatment, collaboration between a dermatologist and a psychiatrist is needed. Copyright © 2016 Elsevier B.V. All rights reserved.

Management of atopic dermatitis: safety and efficacy of phototherapy

PubMed Central

Patrizi, Annalisa; Raone, Beatrice; Ravaioli, Giulia Maria

2015-01-01

Atopic dermatitis (AD) is a common chronic inflammatory skin disease that can affect all age groups. It is characterized by a relapsing course and a dramatic impact on quality of life for patients. Environmental interventions together with topical devices represent the mainstay of treatment for AD, in particular emollients, corticosteroids, and calcineurin inhibitors. Systemic treatments are reserved for severe cases. Phototherapy represents a valid second-line intervention in those cases where non-pharmacological and topical measures have failed. Different forms of light therapy are available, and have showed varying degrees of beneficial effect against AD: natural sunlight, narrowband (NB)-UVB, broadband (BB)-UVB, UVA, UVA1, cold-light UVA1, UVA and UVB (UVAB), full-spectrum light (including UVA, infrared and visible light), saltwater bath plus UVB (balneophototherapy), Goeckerman therapy (coal tar plus UVB radiation), psoralen plus UVA (PUVA), and other forms of phototherapy. In particular, UVA1 and NB-UVB have gained importance in recent years. This review illustrates the main trials comparing the efficacy and safety of the different forms of phototherapy. No sufficiently large randomized controlled studies have been performed as yet, and no light modality has been defined as superior to all. Parameters and dosing protocols may vary, although clinicians mainly refer to the indications included in the American Academy of Dermatology psoriasis guidelines devised by Menter et al in 2010. The efficacy of phototherapy (considering all forms) in AD has been established in adults and children, as well as for acute (UVA1) and chronic (NB-UVB) cases. Its use is suggested with strength of recommendation B and level of evidence II. Home phototherapy can also be performed; this technique is recommended with strength C and level of evidence III. Phototherapy is generally considered to be safe and well tolerated, with a low but established percentage of short-term and long-term adverse effects, with the most common being photodamage, xerosis, erythema, actinic keratosis, sunburn, and tenderness. A carcinogenic risk related to UV radiation has not been excluded. Phototherapy also has some limitations related to costs, availability, and patient compliance. In conclusion, phototherapy is an optimal second-line treatment for AD. It can be used as monotherapy or in combination with systemic drugs, in particular corticosteroids. It must be performed conscientiously, especially in children, and must take into account the patient’s features and overall condition. PMID:26491366

Vacuum degeneracy and Conformal Mass in Lovelock AdS gravity

NASA Astrophysics Data System (ADS)

Arenas-Henriquez, Gabriel; Miskovic, Olivera; Olea, Rodrigo

2017-11-01

It is shown that the notion of Conformal Mass can be defined within a given anti-de Sitter (AdS) branch of a Lovelock gravity theory as long as the corresponding vacuum is not degenerate. Indeed, conserved charges obtained by the addition of Kounterterms to the bulk action turn out to be proportional to the electric part of the Weyl tensor, when the fall-off of a generic solution in that AdS branch is considered. The factor of proportionality is the degeneracy condition for the vacua in the particular Lovelock AdS theory under study. This last feature explains the obstruction to define Conformal Mass in the degenerate case.

Diffuse idiopathic skeletal hyperostosis from Roman Hungary.

PubMed

Hlavenková, Lucia; Gábor, Olivér; Benus, Radoslav; Smrcka, Václav; Jambor, Jaroslav; Hajdu, Tamás

2013-01-01

This paper deals with cases of diffuse idiopathic skeletal hyperostosis (DISH) found at the Late Roman Age necropolis in Pécs, Hungary (4th century AD). The skeletal remains of two male individuals, aged between 60-70 years and 45-55 years, displayed right-sided ossification of the anterior longitudinal ligament with extra-spinal manifestations typical in DISH cases. It is presumed that both male individuals were middle-class citizens. Their social status was supplemented with trace element analysis in order to reconstruct the dietary habits of the urban population. Concentrations of Sr and Zn indicated a predominantly vegetal diet. Potential DISH risk factors and associations were subsequently discussed and compared with our findings.

Impact of Flexibility Options on Grid Economic Carrying Capacity of Solar and Wind: Three Case Studies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Denholm, Paul; Novacheck, Joshua; Jorgenson, Jennie

In this study, we attempt to quantify the benefits of various options of grid flexibility by measuring their impact on two measures: economic carrying capacity and system costs. Flexibility can increase ECC and reduce overall system costs. In some cases, options that provide a limited increase in ECC can provide significant operational savings, thus demonstrating the need to evaluate flexibility options using multiple metrics. The value of flexibility options varies regionally due to different generation mixes and types of renewables. The more rapid decline in PV value compared to wind makes PV more dependent on adding flexibility options, including transmissionmore » and energy storage.« less

Identification of age- and disease-related alterations in circulating miRNAs in a mouse model of Alzheimer's disease

PubMed Central

Garza-Manero, Sylvia; Arias, Clorinda; Bermúdez-Rattoni, Federico; Vaca, Luis; Zepeda, Angélica

2015-01-01

Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by the progressive decline of memory and cognition. Histopathologically, two main hallmarks have been identified in AD: amyloid-β peptide extracellular neuritic plaques and neurofibrillary tangles formed by posttranslational modified tau protein. A definitive diagnosis can only be achieved after the post mortem verification of the histological mentioned alterations. Therefore, the development of biomarkers that allow an early diagnosis and/or predict disease progression is imperative. The prospect of a blood-based biomarker is possible with the finding of circulating microRNAs (miRNAs), a class of small non-coding RNAs of 22–25 nucleotides length that regulate mRNA translation rate. miRNAs travel through blood and recent studies performed in potential AD cases suggest the possibility of finding pathology-associated differences in circulating miRNA levels that may serve to assist in early diagnosis of the disease. However, these studies analyzed samples at a single time-point, limiting the use of miRNAs as biomarkers in AD progression. In this study we evaluated miRNA levels in plasma samples at different time-points of the evolution of an AD-like pathology in a transgenic mouse model of the disease (3xTg-AD). We performed multiplex qRT-PCR and compared the plasmatic levels of 84 miRNAs previously associated to central nervous system development and disease. No significant differences were detected between WT and transgenic young mice. However, age-related significant changes in miRNA abundance were observed for both WT and transgenic mice, and some of these were specific for the 3xTg-AD. In agreement, variations in the levels of particular miRNAs were identified between WT and transgenic old mice thus suggesting that the age-dependent evolution of the AD-like pathology, rather than the presence and expression of the transgenes, modifies the circulating miRNA levels in the 3xTg-AD mice. PMID:25745387

Identification of age- and disease-related alterations in circulating miRNAs in a mouse model of Alzheimer's disease.

PubMed

Garza-Manero, Sylvia; Arias, Clorinda; Bermúdez-Rattoni, Federico; Vaca, Luis; Zepeda, Angélica

2015-01-01

Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by the progressive decline of memory and cognition. Histopathologically, two main hallmarks have been identified in AD: amyloid-β peptide extracellular neuritic plaques and neurofibrillary tangles formed by posttranslational modified tau protein. A definitive diagnosis can only be achieved after the post mortem verification of the histological mentioned alterations. Therefore, the development of biomarkers that allow an early diagnosis and/or predict disease progression is imperative. The prospect of a blood-based biomarker is possible with the finding of circulating microRNAs (miRNAs), a class of small non-coding RNAs of 22-25 nucleotides length that regulate mRNA translation rate. miRNAs travel through blood and recent studies performed in potential AD cases suggest the possibility of finding pathology-associated differences in circulating miRNA levels that may serve to assist in early diagnosis of the disease. However, these studies analyzed samples at a single time-point, limiting the use of miRNAs as biomarkers in AD progression. In this study we evaluated miRNA levels in plasma samples at different time-points of the evolution of an AD-like pathology in a transgenic mouse model of the disease (3xTg-AD). We performed multiplex qRT-PCR and compared the plasmatic levels of 84 miRNAs previously associated to central nervous system development and disease. No significant differences were detected between WT and transgenic young mice. However, age-related significant changes in miRNA abundance were observed for both WT and transgenic mice, and some of these were specific for the 3xTg-AD. In agreement, variations in the levels of particular miRNAs were identified between WT and transgenic old mice thus suggesting that the age-dependent evolution of the AD-like pathology, rather than the presence and expression of the transgenes, modifies the circulating miRNA levels in the 3xTg-AD mice.

A founder mutation in presenilin 1 causing early-onset Alzheimer disease in unrelated Caribbean Hispanic families.

PubMed

Athan, E S; Williamson, J; Ciappa, A; Santana, V; Romas, S N; Lee, J H; Rondon, H; Lantigua, R A; Medrano, M; Torres, M; Arawaka, S; Rogaeva, E; Song, Y Q; Sato, C; Kawarai, T; Fafel, K C; Boss, M A; Seltzer, W K; Stern, Y; St George-Hyslop, P; Tycko, B; Mayeux, R

2001-11-14

Genetic determinants of Alzheimer disease (AD) have not been comprehensively examined in Caribbean Hispanics, a population in the United States in whom the frequency of AD is higher compared with non-Hispanic whites. To identify variant alleles in genes related to familial early-onset AD among Caribbean Hispanics. Family-based case series conducted in 1998-2001 at an AD research center in New York, NY, and clinics in the Dominican Republic. Among 206 Caribbean Hispanic families with 2 or more living members with AD who were identified, 19 (9.2%) had at least 1 individual with onset of AD before the age of 55 years. The entire coding region of the presenilin 1 gene and exons 16 and 17 of the amyloid precursor protein gene were sequenced in probands from the 19 families and their living relatives. A G-to-C nucleotide change resulting in a glycine-alanine amino acid substitution at codon 206 (Gly206Ala) in exon 7 of presenilin 1 was observed in 23 individuals from 8 (42%) of the 19 families. A Caribbean Hispanic individual with the Gly206Ala mutation and early-onset familial disease was also found by sequencing the corresponding genes of 319 unrelated individuals in New York City. The Gly206Ala mutation was not found in public genetic databases but was reported in 5 individuals from 4 Hispanic families with AD referred for genetic testing. None of the members of these families were related to one another, yet all carriers of the Gly206Ala mutation tested shared a variant allele at 2 nearby microsatellite polymorphisms, indicating a common ancestor. No mutations were found in the amyloid precursor protein gene. The Gly206Ala mutation was found in 8 of 19 unrelated Caribbean Hispanic families with early-onset familial AD. This genetic change may be a prevalent cause of early-onset familial AD in the Caribbean Hispanic population.

A high incidence of Staphylococcus aureus colonization in the external eyes of patients with atopic dermatitis.

PubMed

Nakata, K; Inoue, Y; Harada, J; Maeda, N; Watanabe, H; Tano, Y; Shimomura, Y; Harino, S; Sawa, M

2000-12-01

To determine the frequency distribution of bacteria on the external surface of eyes of patients with atopic dermatitis (AD) and to investigate the relationship between the frequency of bacterial colonization and the grade of atopy or ocular diseases associated with AD. Comparative cross-sectional study. Thirty-six AD patients (mean age, 24.5 years) and 16 nonatopic, age-matched control participants (mean age, 25.5 years). The eyelid margins and conjunctival sacs were scraped with sterile swabs. These samples were inoculated into aerobic and anaerobic culture media. The frequency distribution of bacteria isolated from the eyelid margins and conjunctival sacs. Bacteria isolated from AD patients were: Staphylococcus aureus in 21 of 36 patients (including methicillin-resistant Staphylococcus aureus in two patients); Staphylococcus epidermidis in two patients (including methicillin-resistant Staphylococcus epidermidis in one patient); other coagulase-negative Staphylococcus in six patients;alpha-streptococcus in three patients; Corynebacterium species in three patients; Neisseria species in two patients; and Propionibacterium acnes in one patient. From the nonatopic control participants, we isolated S. aureus in one patient, S. epidermidis in two patients and alpha-streptococcus in one patient. S. aureus was isolated from 67% of the AD patients, and any type of bacteria was isolated from 86% of the patients. These rates were significantly higher than those of nonatopic control participants (6% S. aureus and 25% any bacteria). There was no significant relationship between the frequency distribution of bacteria and the grade of atopy or associated ocular diseases. High rates of bacterial colonization, especially S. aureus, were found in the conjunctival sacs and eyelid margins of AD patients. In case management of AD patients, this unique distribution of bacteria must be carefully considered.

Identification of Physician-Diagnosed Alzheimer's Disease and Related Dementias in Population-Based Administrative Data: A Validation Study Using Family Physicians' Electronic Medical Records.

PubMed

Jaakkimainen, R Liisa; Bronskill, Susan E; Tierney, Mary C; Herrmann, Nathan; Green, Diane; Young, Jacqueline; Ivers, Noah; Butt, Debra; Widdifield, Jessica; Tu, Karen

2016-08-10

Population-based surveillance of Alzheimer's and related dementias (AD-RD) incidence and prevalence is important for chronic disease management and health system capacity planning. Algorithms based on health administrative data have been successfully developed for many chronic conditions. The increasing use of electronic medical records (EMRs) by family physicians (FPs) provides a novel reference standard by which to evaluate these algorithms as FPs are the first point of contact and providers of ongoing medical care for persons with AD-RD. We used FP EMR data as the reference standard to evaluate the accuracy of population-based health administrative data in identifying older adults with AD-RD over time. This retrospective chart abstraction study used a random sample of EMRs for 3,404 adults over 65 years of age from 83 community-based FPs in Ontario, Canada. AD-RD patients identified in the EMR were used as the reference standard against which algorithms identifying cases of AD-RD in administrative databases were compared. The highest performing algorithm was "one hospitalization code OR (three physician claims codes at least 30 days apart in a two year period) OR a prescription filled for an AD-RD specific medication" with sensitivity 79.3% (confidence interval (CI) 72.9-85.8%), specificity 99.1% (CI 98.8-99.4%), positive predictive value 80.4% (CI 74.0-86.8%), and negative predictive value 99.0% (CI 98.7-99.4%). This resulted in an age- and sex-adjusted incidence of 18.1 per 1,000 persons and adjusted prevalence of 72.0 per 1,000 persons in 2010/11. Algorithms developed from health administrative data are sensitive and specific for identifying older adults with AD-RD.

γ-secretase binding sites in aged and Alzheimer's disease human cerebrum: the choroid plexus as a putative origin of CSF Aβ.

PubMed

Liu, Fei; Xue, Zhi-Qin; Deng, Si-Hao; Kun, Xiong; Luo, Xue-Gang; Patrylo, Peter R; Rose, Gregory M; Cai, Huaibin; Struble, Robert G; Cai, Yan; Yan, Xiao-Xin

2013-05-01

Deposition of β -amyloid (Aβ) peptides, cleavage products of β-amyloid precursor protein (APP) by β-secretase-1 (BACE1) and γ-secretase, is a neuropathological hallmark of Alzheimer's disease (AD). γ-Secretase inhibition is a therapeutical anti-Aβ approach, although changes in the enzyme's activity in AD brain are unclear. Cerebrospinal fluid (CSF) Aβ peptides are thought to derive from brain parenchyma and thus may serve as biomarkers for assessing cerebral amyloidosis and anti-Aβ efficacy. The present study compared active γ-secretase binding sites with Aβ deposition in aged and AD human cerebrum, and explored the possibility of Aβ production and secretion by the choroid plexus (CP). The specific binding density of [(3) H]-L-685,458, a radiolabeled high-affinity γ-secretase inhibitor, in the temporal neocortex and hippocampal formation was similar for AD and control cases with similar ages and post-mortem delays. The CP in post-mortem samples exhibited exceptionally high [(3) H]-L-685,458 binding density, with the estimated maximal binding sites (Bmax) reduced in the AD relative to control groups. Surgically resected human CP exhibited APP, BACE1 and presenilin-1 immunoreactivity, and β-site APP cleavage enzymatic activity. In primary culture, human CP cells also expressed these amyloidogenic proteins and released Aβ40 and Aβ42 into the medium. Overall, our results suggest that γ-secretase activity appears unaltered in the cerebrum in AD and is not correlated with regional amyloid plaque pathology. The CP appears to be a previously unrecognised non-neuronal contributor to CSF Aβ, probably at reduced levels in AD. © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Comparing three knowledge communication strategies - Diffusion, Dissemination and Translation - through randomized controlled studies.

PubMed

Lane, Joseph P; Stone, Vathsala I

2015-01-01

This paper describes a series of three randomized controlled case studies comparing the effectiveness of three strategies for communicating new research-based knowledge (Diffusion, Dissemination, Translation), to different Assistive Technology (AT) stakeholder groups. Pre and post intervention measures for level of knowledge use (unaware, aware, interested, using) via the LOKUS instrument, assessed the relative effectiveness of the three strategies. The latter two approaches were both more effective than diffusion but also equally effective. The results question the value added by tailoring research findings to specific audiences, and instead supports the critical yet neglected role for relevance in determining knowledge use by stakeholders.

Abnormal amyloid β42 expression and increased oxidative stress in plasma of CKD patients with cognitive dysfunction: A small scale case control study comparison with Alzheimer's disease.

PubMed

Vinothkumar, G; Kedharnath, C; Krishnakumar, S; Sreedhar, S; Preethikrishnan, K; Dinesh, S; Sundaram, A; Balakrishnan, D; Shivashekar, G; Sureshkumar; Venkataraman, P

2017-12-01

Cognitive dysfunction has been increasingly recognized in chronic kidney disease (CKD) patients. Senile plaques are important pathophysiological characteristic of cognitive dysfunction. The major component of plaques is the amyloid β (Aβ) peptide released from proteolytic cleavage of amyloid precursor protein (APP). Plasma Aβ has been a focus of the growing literature on blood based biomarkers for cognitive dysfunction. Oxidative stress is prevalent in CKD and it plays an important role in cognitive dysfunction. Increased oxidative stress leads to cause cleavage of APP and Aβ production. The aim of this study is to assess the antioxidant status and Aβ 42 levels in plasma of CKD patients with cognitive dysfunction compared to CKD without cognitive dysfunction. A total of 60 subjects divided into 30 CKD without cognitive dysfunction and 30 CKD with cognitive dysfunction based on neuropsychological assessment tests. To compare antioxidant status and Aβ 42 levels in plasma, the following groups such as healthy subjects (n = 30), normocytic normochromic anemia (n = 30) and Alzheimer's disease (AD, n = 10) patients were also maintained. Plasma Superoxide dismutase (SOD), Catalase (CAT), Glutathione peroxidase (GPx), Reduced glutathione (GSH) and lipid peroxidation (LPO) were determined by spectrophotometrically. Aβ level was determined by immunoblotting method. The parameters were statistically compared with healthy, normocytic normochromic anemia and AD subjects. Like AD subjects, significantly increased Aβ and LPO level while decreased SOD, CAT, GPx and GSH levels were observed in plasma of CKD patients with cognitive dysfunction when compared to healthy, CKD without cognitive dysfunction and normocytic normochromic anemic subjects. Results suggest that elevated plasma oxidative stress and Aβ were seen in CKD patients with cognitive dysfunction may be attributed to pathological changes within the brain.

Consumer perceptions of prescription and over-the-counter drug advertisements with promotional offers.

PubMed

Aikin, Kathryn J; Sullivan, Helen W; O'Donoghue, Amie C; Betts, Kevin R

2016-01-01

Information on the effects of promotional offers in direct-to-consumer prescription drug ads is limited. In two studies, we examined the effect of promotional offers (e.g., money-back guarantee) and ad type (creating prescription and over-the-counter drug ads by varying the presence of benefit and risk information). We found little effect of promotional offers. Adding benefit (risk) information to the ad increased consumers' knowledge of the benefit (risk) information and their efficacy (risk) perceptions. In most cases, adding risk information to an ad with benefit information increased risk knowledge and perceptions without decreasing benefit knowledge or perceptions.

Declining brain glucose metabolism in normal individuals with a maternal history of Alzheimer disease.

PubMed

Mosconi, L; Mistur, R; Switalski, R; Brys, M; Glodzik, L; Rich, K; Pirraglia, E; Tsui, W; De Santi, S; de Leon, M J

2009-02-10

At cross-section, cognitively normal individuals (NL) with a maternal history of late-onset Alzheimer disease (AD) have reduced glucose metabolism (CMRglc) on FDG-PET in the same brain regions as patients with clinical AD as compared to those with a paternal and a negative family history (FH) of AD. This longitudinal FDG-PET study examines whether CMRglc reductions in NL subjects with a maternal history of AD are progressive. Seventy-five 50- to 82-year-old NL received 2-year follow-up clinical, neuropsychological, and FDG-PET examinations. These included 37 subjects with negative family history of AD (FH-), 9 with paternal (FHp), and 20 with maternal AD (FHm). Two subjects had parents with postmortem confirmed AD. Statistical parametric mapping was used to compare CMRglc across FH groups at baseline, follow-up, and longitudinally. At both time points, the FH groups were comparable for demographic and neuropsychological characteristics. At baseline and at follow-up, FHm subjects showed CMRglc reductions in the parieto-temporal, posterior cingulate, and medial temporal cortices as compared to FH- and FHp (p < 0.001). Longitudinally, FHm had significant CMRglc declines in these regions, which were significantly greater than those in FH- and FHp (p < 0.05). A maternal history of Alzheimer disease (AD) predisposes normal individuals to progressive CMRglc reductions in AD-vulnerable brain regions, which may be related to a higher risk for developing AD.

Cytomorphological identification of advanced pulmonary adenocarcinoma harboring KRAS mutation in lymph node fine-needle aspiration specimens: Comparative investigation of adenocarcinoma with KRAS and EGFR mutations.

PubMed

Song, Dae Hyun; Lee, Boram; Shin, Yooju; Choi, In Ho; Ha, Sang Yun; Lee, Jae Jun; Hong, Min Eui; Choi, Yoon-La; Han, Joungho; Um, Sang-Won

2015-07-01

Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutation in pulmonary adenocarcinoma is clinically important due to its association with resistance to EGFR inhibitors and poor prognosis. To our knowledge, there has not been a comparative study focusing on cytological nuclear features of pulmonary adenocarcinoma harboring KRAS mutation (KRAS-AD). Hence, we compared the cytomorphology of metastatic KRAS-AD and EGFR-positive adenocarcinoma (EGFR-AD) in aspiration specimens from lymph nodes. Forty lymph node aspiration specimens from forty KRAS-AD patients were collected at Samsung Medical Center (Seoul, Korea) from 2009 to 2013. As a control group, 40 EBUS-FNA lymph node specimens from 20 EGFR-AD patients were collected. EGFR-AD specimens were evaluated at Samsung Medical Center (Seoul, Korea) from 2012 to 2013. All 80 specimens were histologically confirmed to metastatic adenocarcinoma. Two pathologists performed a blinded review of all specimens. Compared with EGFR-AD, KRAS-AD exhibited more severe nuclear pleomorphism (P < 0.001), coarse chromatin (P = 0.001), cherry-red nucleoli (P < 0.001) and naked tumor cells (P = 0.002) with necrotic (P < 0.001) and neutrophilic (P = 0.008) background. Our study provides the first demonstration of cytomorphologic differentiation between metastatic KRAS-AD and metastatic EGFR-AD in lymph node aspiration specimens. © 2014 Wiley Periodicals, Inc.

Meta-Prediction of the Effect of Methylenetetrahydrofolate Reductase Polymorphisms and Air Pollution on Alzheimer's Disease Risk.

PubMed

Wu, Suh-Mian; Chen, Zhao-Feng; Young, Lufei; Shiao, S Pamela K

2017-01-11

Background : Alzheimer's disease (AD) is a significant public health issue. AD has been linked with methylenetetrahydrofolate reductase ( MTHFR ) C677T polymorphism, but the findings have been inconsistent. The purpose of this meta-predictive analysis is to examine the associations between MTHFR polymorphisms and epigenetic factors, including air pollution, with AD risk using big data analytics approaches. Methods and Results : Forty-three studies (44 groups) were identified by searching various databases. MTHFR C677T TT and CT genotypes had significant associations with AD risk in all racial populations (RR = 1.13, p = 0.0047; and RR = 1.12, p < 0.0001 respectively). Meta-predictive analysis showed significant increases of percentages of MTHFR C677T polymorphism with increased air pollution levels in both AD case group and control group ( p = 0.0021-0.0457); with higher percentages of TT and CT genotypes in the AD case group than that in the control group with increased air pollution levels. Conclusions : The impact of MTHFR C677T polymorphism on susceptibility to AD was modified by level of air pollution. Future studies are needed to further examine the effects of gene-environment interactions including air pollution on AD risk for world populations.

Meta-Prediction of the Effect of Methylenetetrahydrofolate Reductase Polymorphisms and Air Pollution on Alzheimer’s Disease Risk

PubMed Central

Wu, Suh-Mian; Chen, Zhao-Feng; Young, Lufei; Shiao, S. Pamela K.

2017-01-01

Background: Alzheimer’s disease (AD) is a significant public health issue. AD has been linked with methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, but the findings have been inconsistent. The purpose of this meta-predictive analysis is to examine the associations between MTHFR polymorphisms and epigenetic factors, including air pollution, with AD risk using big data analytics approaches. Methods and Results: Forty-three studies (44 groups) were identified by searching various databases. MTHFR C677T TT and CT genotypes had significant associations with AD risk in all racial populations (RR = 1.13, p = 0.0047; and RR = 1.12, p < 0.0001 respectively). Meta-predictive analysis showed significant increases of percentages of MTHFR C677T polymorphism with increased air pollution levels in both AD case group and control group (p = 0.0021–0.0457); with higher percentages of TT and CT genotypes in the AD case group than that in the control group with increased air pollution levels. Conclusions: The impact of MTHFR C677T polymorphism on susceptibility to AD was modified by level of air pollution. Future studies are needed to further examine the effects of gene-environment interactions including air pollution on AD risk for world populations. PMID:28085050

Depletion of TDP-43 decreases fibril and plaque β-amyloid and exacerbates neurodegeneration in an Alzheimer's mouse model.

PubMed

LaClair, Katherine D; Donde, Aneesh; Ling, Jonathan P; Jeong, Yun Ha; Chhabra, Resham; Martin, Lee J; Wong, Philip C

2016-12-01

TDP-43 proteinopathy, initially associated with ALS and FTD, is also found in 30-60% of Alzheimer's disease (AD) cases and correlates with worsened cognition and neurodegeneration. A major component of this proteinopathy is depletion of this RNA-binding protein from the nucleus, which compromises repression of non-conserved cryptic exons in neurodegenerative diseases. To test whether nuclear depletion of TDP-43 may contribute to the pathogenesis of AD cases with TDP-43 proteinopathy, we examined the impact of depletion of TDP-43 in populations of neurons vulnerable in AD, and on neurodegeneration in an AD-linked context. Here, we show that some populations of pyramidal neurons that are selectively vulnerable in AD are also vulnerable to TDP-43 depletion in mice, while other forebrain neurons appear spared. Moreover, TDP-43 depletion in forebrain neurons of an AD mouse model exacerbates neurodegeneration, and correlates with increased prefibrillar oligomeric Aβ and decreased Aβ plaque burden. These findings support a role for nuclear depletion of TDP-43 in the pathogenesis of AD and provide strong rationale for developing novel therapeutics to alleviate the depletion of TDP-43 and functional antemortem biomarkers associated with its nuclear loss.

Blood-cerebrospinal fluid barrier permeability in Alzheimer's disease.

PubMed

Chalbot, Sonia; Zetterberg, Henrik; Blennow, Kaj; Fladby, Tormod; Andreasen, Niels; Grundke-Iqbal, Inge; Iqbal, Khalid

2011-01-01

The role of blood-cerebrospinal fluid barrier (BCB) dysfunction in Alzheimer's disease (AD) has been addressed but not yet established. We evaluated the BCB integrity in 179 samples of cerebrospinal fluid (CSF) retrospectively collected from AD patients and control cases using both CSF/serum albumin ratio (QAlb) and CSF secretory Ca2+-dependent phospholipase A2 (sPLA2) activity. These analyses were supplemented with the measurement of total tau, amyloid-β1-42 (Aβ1-42), and ubiquitin CSF levels. We found that due to its higher sensitivity, CSF sPLA2 activity could 1) discriminate AD from healthy controls and 2) showed BCB impairment in neurological control cases while QAlb could not. Moreover, the CSF sPLA2 activity measurement showed that around half of the AD patients were characterized by a BCB impairment. The BCB dysfunction observed in AD was independent from Mini-Mental State Examination score as well as CSF levels of total tau, Aβ1-42, and ubiquitin. Finally, the BCB dysfunction was not limited to any of the CSF biomarkers-based previously identified subgroups of AD. These results suggest that the BCB damage occurs independent of and probably precedes both Aβ and tau pathologies in a restricted subgroup of AD patients.

Discharge dynamics and plasma density recovery by on/off switches of additional gas

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Hyo-Chang, E-mail: lhc@kriss.re.kr; Department of Electrical Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763; Kwon, Deuk-Chul

2016-06-15

Measurement of the plasma density is investigated to study plasma dynamics by adding reactive gas (O{sub 2}) or rare gas (He) in Ar plasmas. When the O{sub 2} or He gas is added, plasma density is suddenly decreased, while the plasma density recovers slowly with gas off. It is found that the recovery time is strongly dependent on the gas flow rate, and it can be explained by effect of gas residence time. When the He gas is off in the Ar plasma, the plasma density is overshot compared to the case of the O{sub 2} gas pulsing due tomore » enhanced ionizations by metastable atoms. Analysis and calculation for correlation between the plasma density dynamics and the gas pulsing are also presented in detail.« less

Ad spending: maintaining market share.

PubMed

Jones, J P

1990-01-01

Accuracy in manufacturers' advertising budgeting is hampered by reliance on the case rate system, which ties budgets to sales. A better measure is a brand's market share compared with its share of voice (the brand's share of the total value of the main media exposure in that product category). New brands are often "investing" in the market: speaking in a louder voice than their market shares would justify. Popular brands are often "profit taking"--keeping their voices low but enjoying a disproportionately large market share. The interrelationship between market share and share of voice, with either "investing" or "profit taking" the desired result, is not usually considered when determining ad budgets. But as advertisers realize how market share can respond to advertising pressure through switches in the share of voice, this method of market testing should gain in importance.

Can We Talk through a Robot As if Face-to-Face? Long-Term Fieldwork Using Teleoperated Robot for Seniors with Alzheimer's Disease.

PubMed

Kuwamura, Kaiko; Nishio, Shuichi; Sato, Shinichi

2016-01-01

This work presents a case study on fieldwork in a group home for the elderly with dementia using a teleoperated robot called Telenoid. We compared Telenoid-mediated and face-to-face conditions with three residents with Alzheimer's disease (AD). The result indicates that two of the three residents with moderate AD showed a positive reaction to Telenoid. Both became less nervous while communicating with Telenoid from the time they were first introduced to it. Moreover, they started to use more body gestures in the face-to-face condition and more physical interactions in the Telenoid-mediated condition. In this work, we present all the results and discuss the possibilities of using Telenoid as a tool to provide opportunities for seniors to communicate over the long term.

Causality in criminal forensic and in civil disability cases: Legal and psychological comparison.

PubMed

Young, Gerald

2015-01-01

Causality (or causation) is central to every legal case, yet its underlying philosophical, legal, and psychological definitions and conceptions vary. In the criminal context, it refers to establishing the responsibility of the perpetrator of the criminal act at issue in terms of the person's mental state (mens rea), and whether the insanity defense applies. In the forensic disability and related context, it refers to whether the index event is a material or contributing cause in the multifactorial array that led to the psychological condition at issue. In both the criminal and tort contexts, the legal test is a counterfactual one. For the former, it refers to whether the outcome involved would have resulted absent the act (e.g., in cases of simultaneous criminal lethal action, which one is the but-for responsible one). For the latter, it concerns whether the claimed psychological condition would be present only because of the incident at issue. The latter event at issue is distinguished from the criminal one by its negligence compared to the voluntary intent in the criminal case. The psychological state of the perpetrator of criminal conduct can be analyzed from a biopsychosocial perspective as much as the civil one. In this regard, in the civil case, such as in forensic disability and related assessments, pre-existing, precipitating, and perpetuating factors need to be considered causally, with personal and social resilience and protective factors added, as well. In the criminal context, the same biopsychosocial model applies, but with mental competence and voluntariness added as a critical factor. The advent of neurolaw has led to use of neuroscience in court, but it risks reducing the complexity of criminal cases to unifactorial, biological models. Copyright © 2015 Elsevier Ltd. All rights reserved.

Alzheimer disease with cerebrovascular disease and vascular dementia: clinical features and course compared with Alzheimer disease.

PubMed

Bruandet, A; Richard, F; Bombois, S; Maurage, C A; Deramecourt, V; Lebert, F; Amouyel, P; Pasquier, F

2009-02-01

Vascular dementia (VaD) and Alzheimer disease with cerebrovascular disease (AD+CVD) are the leading causes of dementia after Alzheimer disease alone (AD). Little is known about the progression of either VaD or AD+CVD. The aim of this study was to compare demographic features, cognitive decline and survival of patients with VaD, AD+CVD and AD alone attending a memory clinic. This study included 970 patients who were followed at the Lille-Bailleul memory clinic, France. Cognitive functions were measured with the Mini Mental State Examination (MMSE) and the Dementia Rating Scale (DRS). Survival rate was analysed with a left-truncated Cox model. Analyses were adjusted for age, sex, education, hypertension, diabetes and baseline MMSE and DRS. Of 970 patients, 141 had VaD, 663 AD alone and 166 AD+CVD. The latter were significantly older than AD or VaD patients at onset (71 (SD 7) vs 69 (9) and 68 (9) years, p = 0.01) and at first visit (75 (6) vs 73 (8) and 72 (8) years, p = 0.0002). Baseline MMSE and DRS evaluations were highest for VaD compared with AD alone or AD+CVD patients (p<0.006). Cognitive decline during follow-up was slowest for VaD, intermediate for AD+CVD and fastest for AD alone (p = 0.03). After adjustment, compared with AD patients, mortality risk was similar for those with VaD (relative mortality risk (RR) = 0.7 (0.5 to 1.1)) and tended to be lower for AD+CVD (RR = 0.7 (0.5 to 1.0)). The shorter the delay between first symptoms and first visit, the longer patients survived. This clinical cohort study shows that patients with VaD, AD+CVD and AD present different characteristics at baseline and during follow-up, and underlines the need to distinguish between them.

CR1 rs3818361 Polymorphism Contributes to Alzheimer's Disease Susceptibility in Chinese Population.

PubMed

Li, Yongning; Song, Dongjing; Jiang, Yongshuai; Wang, Jingwei; Feng, Rennan; Zhang, Liangcai; Wang, Guangyu; Chen, Zugen; Wang, Renzhi; Jiang, Qinghua; Liu, Guiyou

2016-08-01

Recent genome-wide association studies (GWAS) reported CR1 rs3818361 polymorphism to be an Alzheimer's disease (AD) susceptibility variant in European ancestry. Three independent studies investigated this association in Chinese population. However, these studies reported weak or no significant association. Here, we reinvestigated the association using all the samples from three independent studies in Chinese population (N = 4047, 1244 AD cases and 2803 controls). We also selected three independent studies in European ancestry population (N = 11787, 3939 AD cases and 7848 controls) to evaluate the effect of rs3818361 polymorphism on AD risk in different ethnic backgrounds. In Chinese population, we did not identified significant heterogeneity using additive, recessive, and dominant genetic models. Meta-analysis showed significant association between rs3818361 and AD with P = 6.00E-03 and P = 5.00E-03. We further identified no heterogeneity of rs3818361 polymorphism between Chinese and European populations. We found that rs3818361 polymorphism contributed to AD with similar genetic risk in Chinese and European populations. In summary, this is the first study to show significant association between rs3818361 polymorphism and AD in Chinese population by a meta-analysis method. Our findings indicate that the effect of CR1 rs3818361 polymorphism on AD risk in Chinese cohorts is consistent with the increased risk observed in European AD cohorts.

Impaired mitochondrial energy metabolism as a novel risk factor for selective onset and progression of dementia in oldest-old subjects

PubMed Central

Zhao, Wei; Wang, Jun; Varghese, Merina; Ho, Lap; Mazzola, Paolo; Haroutunian, Vahram; Katsel, Pavel L; Gibson, Gary E; Levine, Samara; Dubner, Lauren; Pasinetti, Giulio Maria

2015-01-01

Recent evidence shows that Alzheimer disease (AD) dementia in the oldest-old subjects was associated with significantly less amyloid plaque and fibrillary tangle neuropathology than in the young-old population. In this study, using quantitative (q) PCR studies, we validated genome-wide microarray RNA studies previously conducted by our research group. We found selective downregulation of mitochondrial energy metabolism genes in the brains of oldest-old, but not young-old, AD dementia cases, despite a significant lack of classic AD neuropathology features. We report a significant decrease of genes associated with mitochondrial pyruvate metabolism, the tricarboxylic acid cycle (TCA), and glycolytic pathways. Moreover, significantly higher levels of nitrotyrosylated (3-NT)-proteins and 4-hydroxy-2-nonenal (HNE) adducts, which are indexes of cellular protein oxidation and lipid peroxidation, respectively, were detected in the brains of oldest-old subjects at high risk of developing AD, possibly suggesting compensatory mechanisms. These findings support the hypothesis that although oldest-old AD subjects, characterized by significantly lower AD neuropathology than young-old AD subjects, have brain mitochondrial metabolism impairment, which we hypothesize may selectively contribute to the development of dementia. Outcomes from this study provide novel insights into the molecular mechanisms underlying clinical dementia in young-old and oldest-old AD subjects and provide novel strategies for AD prevention and treatment in oldest-old dementia cases. PMID:25784811

Impaired mitochondrial energy metabolism as a novel risk factor for selective onset and progression of dementia in oldest-old subjects.

PubMed

Zhao, Wei; Wang, Jun; Varghese, Merina; Ho, Lap; Mazzola, Paolo; Haroutunian, Vahram; Katsel, Pavel L; Gibson, Gary E; Levine, Samara; Dubner, Lauren; Pasinetti, Giulio Maria

2015-01-01

Recent evidence shows that Alzheimer disease (AD) dementia in the oldest-old subjects was associated with significantly less amyloid plaque and fibrillary tangle neuropathology than in the young-old population. In this study, using quantitative (q) PCR studies, we validated genome-wide microarray RNA studies previously conducted by our research group. We found selective downregulation of mitochondrial energy metabolism genes in the brains of oldest-old, but not young-old, AD dementia cases, despite a significant lack of classic AD neuropathology features. We report a significant decrease of genes associated with mitochondrial pyruvate metabolism, the tricarboxylic acid cycle (TCA), and glycolytic pathways. Moreover, significantly higher levels of nitrotyrosylated (3-NT)-proteins and 4-hydroxy-2-nonenal (HNE) adducts, which are indexes of cellular protein oxidation and lipid peroxidation, respectively, were detected in the brains of oldest-old subjects at high risk of developing AD, possibly suggesting compensatory mechanisms. These findings support the hypothesis that although oldest-old AD subjects, characterized by significantly lower AD neuropathology than young-old AD subjects, have brain mitochondrial metabolism impairment, which we hypothesize may selectively contribute to the development of dementia. Outcomes from this study provide novel insights into the molecular mechanisms underlying clinical dementia in young-old and oldest-old AD subjects and provide novel strategies for AD prevention and treatment in oldest-old dementia cases.

Validation of the Italian Version of the Caregiver Abuse Screen among Family Caregivers of Older People with Alzheimer's Disease.

PubMed

Melchiorre, Maria Gabriella; Di Rosa, Mirko; Barbabella, Francesco; Barbini, Norma; Lattanzio, Fabrizia; Chiatti, Carlos

2017-01-01

Introduction . Elder abuse is often a hidden phenomenon and, in many cases, screening practices are difficult to implement among older people with dementia. The Caregiver Abuse Screen (CASE) is a useful tool which is administered to family caregivers for detecting their potential abusive behavior. Objectives . To validate the Italian version of the CASE tool in the context of family caregiving of older people with Alzheimer's disease (AD) and to identify risk factors for elder abuse in Italy. Methods . The CASE test was administered to 438 caregivers, recruited in the Up-Tech study. Validity and reliability were evaluated using Spearman's correlation coefficients, principal-component analysis, and Cronbach's alphas. The association between the CASE and other variables potentially associated with elder abuse was also analyzed. Results . The factor analysis suggested the presence of a single factor, with a strong internal consistency (Cronbach's alpha = 0.86). CASE score was strongly correlated with well-known risk factors of abuse. At multivariate level, main factors associated with CASE total score were caregiver burden and AD-related behavioral disturbances. Conclusions . The Italian version of the CASE is a reliable and consistent screening tool for tackling the risk of being or becoming perpetrators of abuse by family caregivers of people with AD.

Validation of the Italian Version of the Caregiver Abuse Screen among Family Caregivers of Older People with Alzheimer's Disease

PubMed Central

Di Rosa, Mirko; Barbabella, Francesco; Barbini, Norma; Chiatti, Carlos

2017-01-01

Introduction. Elder abuse is often a hidden phenomenon and, in many cases, screening practices are difficult to implement among older people with dementia. The Caregiver Abuse Screen (CASE) is a useful tool which is administered to family caregivers for detecting their potential abusive behavior. Objectives. To validate the Italian version of the CASE tool in the context of family caregiving of older people with Alzheimer's disease (AD) and to identify risk factors for elder abuse in Italy. Methods. The CASE test was administered to 438 caregivers, recruited in the Up-Tech study. Validity and reliability were evaluated using Spearman's correlation coefficients, principal-component analysis, and Cronbach's alphas. The association between the CASE and other variables potentially associated with elder abuse was also analyzed. Results. The factor analysis suggested the presence of a single factor, with a strong internal consistency (Cronbach's alpha = 0.86). CASE score was strongly correlated with well-known risk factors of abuse. At multivariate level, main factors associated with CASE total score were caregiver burden and AD-related behavioral disturbances. Conclusions. The Italian version of the CASE is a reliable and consistent screening tool for tackling the risk of being or becoming perpetrators of abuse by family caregivers of people with AD. PMID:28265571

The Evolution of Armed Forces Enlisted Personnel Management Policies: Executive Summary.

DTIC Science & Technology

1982-07-01

Navy were equally severe with such added cruelties as keel-hauling, by which a man was dragged from one side of the ship to the other under the keel...cheeked sons of New England and the West, who are subjected to degradation and cruelty , compared with which the servitude of the South is freedom, and...the Algerine cruelty is Christian kindness. Another senator cited the case of the training ship Pennsylvania: As a receiving ship it was tied up at a

Polymer Composite Using Aligned Carbon Nanotubes for Efficient Heat Transfer

DTIC Science & Technology

2012-01-17

ultrasonic sprayer system (Figs. 2 & 3). We will thermolyze ferrocene -benzylamine solutions at 850 °C under an Ar atmosphere. The material produced...C (center pannel). 1.4 Production of COxHy nanotubes We will use the same ultrasonic sprayer but in this case with solutions of ferrocene (FeCp2...more reactive when compared to standard CNTs. For example, when adding 2.5% by wt. of ethanol in a ferrocene -toluene solution containing 5% by wt. of

Stochastic quantization and holographic Wilsonian renormalization group of free massive fermion

NASA Astrophysics Data System (ADS)

Moon, Sung Pil

2018-06-01

We examine a suggested relation between stochastic quantization and the holographic Wilsonian renormalization group in the massive fermion case on Euclidean AdS space. The original suggestion about the general relation between the two theories is posted in arXiv:1209.2242. In the previous researches, it is already verified that scalar fields, U(1) gauge fields, and massless fermions are consistent with the relation. In this paper, we examine the relation in the massive fermion case. Contrary to the other case, in the massive fermion case, the action needs particular boundary terms to satisfy boundary conditions. We finally confirm that the proposed suggestion is also valid in the massive fermion case.

The Nun study: clinically silent AD, neuronal hypertrophy, and linguistic skills in early life.

PubMed

Iacono, D; Markesbery, W R; Gross, M; Pletnikova, O; Rudow, G; Zandi, P; Troncoso, J C

2009-09-01

It is common to find substantial Alzheimer disease (AD) lesions, i.e., neuritic beta-amyloid plaques and neurofibrillary tangles, in the autopsied brains of elderly subjects with normal cognition assessed shortly before death. We have termed this status asymptomatic AD (ASYMAD). We assessed the morphologic substrate of ASYMAD compared to mild cognitive impairment (MCI) in subjects from the Nun Study. In addition, possible correlations between linguistic abilities in early life and the presence of AD pathology with and without clinical manifestations in late life were considered. Design-based stereology was used to measure the volumes of neuronal cell bodies, nuclei, and nucleoli in the CA1 region of hippocampus (CA1). Four groups of subjects were compared: ASYMAD (n = 10), MCI (n = 5), AD (n = 10), and age-matched controls (n = 13). Linguistic ability assessed in early life was compared among all groups. A significant hypertrophy of the cell bodies (+44.9%), nuclei (+59.7%), and nucleoli (+80.2%) in the CA1 neurons was found in ASYMAD compared with MCI. Similar differences were observed with controls. Furthermore, significant higher idea density scores in early life were observed in controls and ASYMAD group compared to MCI and AD groups. 1) Neuronal hypertrophy may constitute an early cellular response to Alzheimer disease (AD) pathology or reflect compensatory mechanisms that prevent cognitive impairment despite substantial AD lesions; 2) higher idea density scores in early life are associated with intact cognition in late life despite the presence of AD lesions.

Impact of an automated dispensing system in outpatient pharmacies.

PubMed

Humphries, Tammy L; Delate, Thomas; Helling, Dennis K; Richardson, Bruce

2008-01-01

To evaluate the impact of an automated dispensing system (ADS) on pharmacy staff work activities and job satisfaction. Cross-sectional, retrospective study. Kaiser Permanente Colorado (KPCO) outpatient pharmacies in September 2005. Pharmacists and technicians from 18 outpatient pharmacies. All KPCO outpatient pharmacists (n = 136) and technicians (n = 160) were surveyed regarding demographics and work activities and pharmacist job satisfaction. Work activities and job satisfaction were compared between pharmacies with and without ADS. Historical prescription purchase records from ADS pharmacies were assessed for pre-ADS to post-ADS changes in productivity. Self-reported pharmacy staff work activities and pharmacist job satisfaction. Pharmacists who responded to the demographic questionnaire (n = 74) were primarily women (60%), had a bachelor's degree in pharmacy (68%), and had been in practice for 10 years or more (53%). Responding technicians (n = 72) were predominantly women (80%) with no postsecondary degree (90%) and fewer than 10 years (68%) in practice. Pharmacists in ADS pharmacies who responded to the work activities questionnaire (n = 50) reported equivalent mean hours spent in patient care activities and filling medication orders compared with non-ADS pharmacists (n = 33; P > 0.05). Similarly, technicians in ADS pharmacies who responded to the work activities questionnaire (n = 64) reported equivalent mean hours spent in filling medication orders compared with non-ADS technicians (n = 38; P > 0.05). An equivalent proportion of ADS pharmacists reported satisfaction with their current job compared with non-ADS pharmacies (P > 0.05). Mean productivity did not increase appreciably after automation (P >0.05). By itself, installing an ADS does not appear to shift pharmacist work activities from dispensing to patient counseling or to increase job satisfaction. Shifting pharmacist work activities from dispensing to counseling and monitoring drug therapy outcomes may be warranted in ADS pharmacies.

Erythropoietin promotes network formation of transplanted adipose tissue-derived microvascular fragments.

PubMed

Karschnia, P; Scheuer, C; Heß, A; Später, T; Menger, M D; Laschke, M W

2018-05-09

The seeding of tissue constructs with adipose tissue-derived microvascular fragments (ad-MVF) is an emerging pre-vascularisation strategy. Ad-MVF rapidly reassemble into new microvascular networks after in vivo implantation. Herein it was analysed whether this process was improved by erythropoietin (EPO). Ad-MVF were isolated from green fluorescent protein (GFP)+ as well as wild-type C57BL/6 mice and cultivated for 24 h in medium supplemented with EPO (20 IU/mL) or vehicle. Freshly isolated, non-cultivated ad-MVF served as controls. Protein expression, cell viability and proliferation of ad-MVF were assessed by proteome profiler array and fluorescence microscopy. GFP+ ad-MVF were seeded on collagen-glycosaminoglycan matrices, which were implanted into dorsal skinfold chambers of C57BL/6 mice, to analyse their vascularisation over 14 d by intravital fluorescence microscopy, histology and immunohistochemistry. Cultivation up-regulated the expression of pro- and anti-angiogenic factors within both vehicle- and EPO-treated ad-MVF when compared with non-cultivated controls. Moreover, EPO treatment suppressed cultivation-associated apoptosis and significantly increased the number of proliferating endothelial cells in ad-MVF when compared with vehicle-treated and non-cultivated ad-MVF. Accordingly, implanted matrices seeded with EPO-treated ad-MVF exhibited an improved vascularisation, as indicated by a significantly higher functional microvessel density. The matrices of the three groups contained a comparably large fraction of GFP+ microvessels originating from the ad-MVF, whereas the tissue surrounding the matrices seeded with EPO-treated ad-MVF exhibited a significantly increased microvessel density when compared with the other two groups. These findings indicated that EPO represents a promising cytokine to further boost the excellent vascularisation properties of ad-MVF in tissue-engineering applications.

Ensemble transcript interaction networks: a case study on Alzheimer's disease.

PubMed

Armañanzas, Rubén; Larrañaga, Pedro; Bielza, Concha

2012-10-01

Systems biology techniques are a topic of recent interest within the neurological field. Computational intelligence (CI) addresses this holistic perspective by means of consensus or ensemble techniques ultimately capable of uncovering new and relevant findings. In this paper, we propose the application of a CI approach based on ensemble Bayesian network classifiers and multivariate feature subset selection to induce probabilistic dependences that could match or unveil biological relationships. The research focuses on the analysis of high-throughput Alzheimer's disease (AD) transcript profiling. The analysis is conducted from two perspectives. First, we compare the expression profiles of hippocampus subregion entorhinal cortex (EC) samples of AD patients and controls. Second, we use the ensemble approach to study four types of samples: EC and dentate gyrus (DG) samples from both patients and controls. Results disclose transcript interaction networks with remarkable structures and genes not directly related to AD by previous studies. The ensemble is able to identify a variety of transcripts that play key roles in other neurological pathologies. Classical statistical assessment by means of non-parametric tests confirms the relevance of the majority of the transcripts. The ensemble approach pinpoints key metabolic mechanisms that could lead to new findings in the pathogenesis and development of AD. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Estimating the Added Utility of Highly Sensitive Histidine-Rich Protein 2 Detection in Outpatient Clinics in Sub-Saharan Africa.

PubMed

Plucinski, Mateusz M; Rogier, Eric; Dimbu, Pedro Rafael; Fortes, Filomeno; Halsey, Eric S; Aidoo, Michael

2017-10-01

Most malaria testing is by rapid diagnostic tests (RDTs) that detect Plasmodium falciparum histidine-rich protein 2 (HRP2). Recently, several RDT manufacturers have developed highly sensitive RDTs (hsRDTs), promising a limit of detection (LOD) orders of magnitude lower than conventional RDTs. To model the added utility of hsRDTs, HRP2 concentration in Angolan outpatients was measured quantitatively using an ultrasensitive bead-based assay. The distribution of HRP2 concentration was bimodal in both afebrile and febrile patients. The conventional RDT was able to detect 81% of all HRP2-positive febrile patients and 52-77% of HRP2-positive afebrile patients. The added utility of hsRDTs was estimated to be greater in afebrile patients, where an hsRDT with a LOD of 200 pg/mL would detect an additional 50-60% of HRP2-positive persons compared with a conventional RDT with a LOD of 3,000 pg/mL. In febrile patients, the hsRDT would detect an additional 10-20% of cases. Conventional RDTs already capture the vast majority of symptomatic HRP2-positive individuals, and hsRDTs would have to reach a sufficiently low LOD approaching 200 pg/mL to provide added utility in identifying HRP2-positive, asymptomatic individuals.

Development of petri net-based dynamic model for improved production of farnesyl pyrophosphate by integrating mevalonate and methylerythritol phosphate pathways in yeast.

PubMed

Baadhe, Rama Raju; Mekala, Naveen Kumar; Palagiri, Satwik Reddy; Parcha, Sreenivasa Rao

2012-07-01

In this case study, we designed a farnesyl pyrophosphate (FPP) biosynthetic network using hybrid functional Petri net with extension (HFPNe) which is derived from traditional Petri net theory and allows easy modeling with graphical approach of various types of entities in the networks together. Our main objective is to improve the production of FPP in yeast, which is further converted to amorphadiene (AD), a precursor of artemisinin (antimalarial drug). Natively, mevalonate (MEV) pathway is present in yeast. Methyl erythritol phosphate pathways (MEP) are present only in higher plant plastids and eubacteria, but not present in yeast. IPP and DAMP are common isomeric intermediate in these two pathways, which immediately yields FPP. By integrating these two pathways in yeast, we augmented the FPP synthesis approximately two folds higher (431.16 U/pt) than in MEV pathway alone (259.91 U/pt) by using HFPNe technique. Further enhanced FPP levels converted to AD by amorphadiene synthase gene yielding 436.5 U/pt of AD which approximately two folds higher compared to the AD (258.5 U/pt) synthesized by MEV pathway exclusively. Simulation and validation processes performed using these models are reliable with identified biological information and data.

The Porphyromonas gingivalis/Host Interactome Shows Enrichment in GWASdb Genes Related to Alzheimer's Disease, Diabetes and Cardiovascular Diseases

PubMed Central

Carter, Chris J.; France, James; Crean, StJohn; Singhrao, Sim K.

2017-01-01

Periodontal disease is of established etiology in which polymicrobial synergistic ecology has become dysbiotic under the influence of Porphyromonas gingivalis. Following breakdown of the host's protective oral tissue barriers, P. gingivalis migrates to developing inflammatory pathologies that associate with Alzheimer's disease (AD). Periodontal disease is a risk factor for cardiovascular disorders (CVD), type II diabetes mellitus (T2DM), AD and other chronic diseases, whilst T2DM exacerbates periodontitis. This study analyzed the relationship between the P. gingivalis/host interactome and the genes identified in genome-wide association studies (GWAS) for the aforementioned conditions using data from GWASdb (P < 1E-03) and, in some cases, from the NCBI/EBI GWAS database (P < 1E-05). Gene expression data from periodontitis or P. gingivalis microarray was compared to microarray datasets from the AD hippocampus and/or from carotid artery plaques. The results demonstrated that the host genes of the P. gingivalis interactome were significantly enriched in genes deposited in GWASdb genes related to cognitive disorders, AD and dementia, and its co-morbid conditions T2DM, obesity, and CVD. The P. gingivalis/host interactome was also enriched in GWAS genes from the more stringent NCBI-EBI database for AD, atherosclerosis and T2DM. The misregulated genes in periodontitis tissue or P. gingivalis infected macrophages also matched those in the AD hippocampus or atherosclerotic plaques. Together, these data suggest important gene/environment interactions between P. gingivalis and susceptibility genes or gene expression changes in conditions where periodontal disease is a contributory factor. PMID:29311898

The Porphyromonas gingivalis/Host Interactome Shows Enrichment in GWASdb Genes Related to Alzheimer's Disease, Diabetes and Cardiovascular Diseases.

PubMed

Carter, Chris J; France, James; Crean, StJohn; Singhrao, Sim K

2017-01-01

Periodontal disease is of established etiology in which polymicrobial synergistic ecology has become dysbiotic under the influence of Porphyromonas gingivalis . Following breakdown of the host's protective oral tissue barriers, P. gingivalis migrates to developing inflammatory pathologies that associate with Alzheimer's disease (AD). Periodontal disease is a risk factor for cardiovascular disorders (CVD), type II diabetes mellitus (T2DM), AD and other chronic diseases, whilst T2DM exacerbates periodontitis. This study analyzed the relationship between the P. gingivalis /host interactome and the genes identified in genome-wide association studies (GWAS) for the aforementioned conditions using data from GWASdb ( P < 1E-03) and, in some cases, from the NCBI/EBI GWAS database ( P < 1E-05). Gene expression data from periodontitis or P. gingivalis microarray was compared to microarray datasets from the AD hippocampus and/or from carotid artery plaques. The results demonstrated that the host genes of the P. gingivalis interactome were significantly enriched in genes deposited in GWASdb genes related to cognitive disorders, AD and dementia, and its co-morbid conditions T2DM, obesity, and CVD. The P. gingivalis /host interactome was also enriched in GWAS genes from the more stringent NCBI-EBI database for AD, atherosclerosis and T2DM. The misregulated genes in periodontitis tissue or P. gingivalis infected macrophages also matched those in the AD hippocampus or atherosclerotic plaques. Together, these data suggest important gene/environment interactions between P. gingivalis and susceptibility genes or gene expression changes in conditions where periodontal disease is a contributory factor.

Face-name association learning in early Alzheimer's disease: a comparison of learning methods and their underlying mechanisms.

PubMed

Bier, Nathalie; Van Der Linden, Martial; Gagnon, Lise; Desrosiers, Johanne; Adam, Stephane; Louveaux, Stephanie; Saint-Mleux, Julie

2008-06-01

This study compared the efficacy of five learning methods in the acquisition of face-name associations in early dementia of Alzheimer type (AD). The contribution of error production and implicit memory to the efficacy of each method was also examined. Fifteen participants with early AD and 15 matched controls were exposed to five learning methods: spaced retrieval, vanishing cues, errorless, and two trial-and-error methods, one with explicit and one with implicit memory task instructions. Under each method, participants had to learn a list of five face-name associations, followed by free recall, cued recall and recognition. Delayed recall was also assessed. For AD, results showed that all methods were efficient but there were no significant differences between them. The number of errors produced during the learning phases varied between the five methods but did not influence learning. There were no significant differences between implicit and explicit memory task instructions on test performances. For the control group, there were no differences between the five methods. Finally, no significant correlations were found between the performance of the AD participants in free recall and their cognitive profile, but generally, the best performers had better remaining episodic memory. Also, case study analyses showed that spaced retrieval was the method for which the greatest number of participants (four) obtained results as good as the controls. This study suggests that the five methods are effective for new learning of face-name associations in AD. It appears that early AD patients can learn, even in the context of error production and explicit memory conditions.

Suicide Risk Associated with Experience of Violence and Impulsivity in Alcohol Dependent Patients.

PubMed

Khemiri, Lotfi; Jokinen, Jussi; Runeson, Bo; Jayaram-Lindström, Nitya

2016-01-19

Alcohol dependence (AD) and aggression-impulsivity are both associated with increased suicide risk. There is a need to evaluate clinical tools in order to improve suicide risk assessment of AD patients. The present study consisted of 95 individuals with a diagnosis of AD, consecutively admitted for addiction treatment, compared with 95 healthy controls. Suicidal risk was assessed together with exposure of violence and impulsivity. AD patients reported significantly higher rates of exposure to violence in childhood, as measured by the Karolinska Interpersonal Violence Scale (KIVS), compared to HC. Within the AD group, individuals with history of suicidal ideation and suicidal behavior reported higher levels of violence experience compared to AD individuals without such history. AD patients with previous suicidal ideation scored higher on self-reported impulsivity as assessed by the Barratt Impulsivity Scale (BIS). Our main finding was that experience of trauma and expression of violent behavior, coupled with increased impulsivity are associated with an elevated suicide risk in AD patients. Future longitudinal studies assessing these traits are needed to evaluate their potential role in identifying AD patients at risk of future suicide.

Suicide Risk Associated with Experience of Violence and Impulsivity in Alcohol Dependent Patients

PubMed Central

Khemiri, Lotfi; Jokinen, Jussi; Runeson, Bo; Jayaram-Lindström, Nitya

2016-01-01

Alcohol dependence (AD) and aggression-impulsivity are both associated with increased suicide risk. There is a need to evaluate clinical tools in order to improve suicide risk assessment of AD patients. The present study consisted of 95 individuals with a diagnosis of AD, consecutively admitted for addiction treatment, compared with 95 healthy controls. Suicidal risk was assessed together with exposure of violence and impulsivity. AD patients reported significantly higher rates of exposure to violence in childhood, as measured by the Karolinska Interpersonal Violence Scale (KIVS), compared to HC. Within the AD group, individuals with history of suicidal ideation and suicidal behavior reported higher levels of violence experience compared to AD individuals without such history. AD patients with previous suicidal ideation scored higher on self-reported impulsivity as assessed by the Barratt Impulsivity Scale (BIS). Our main finding was that experience of trauma and expression of violent behavior, coupled with increased impulsivity are associated with an elevated suicide risk in AD patients. Future longitudinal studies assessing these traits are needed to evaluate their potential role in identifying AD patients at risk of future suicide. PMID:26784730

Dirac perturbations on Schwarzschild-anti-de Sitter spacetimes: Generic boundary conditions and new quasinormal modes

NASA Astrophysics Data System (ADS)

Wang, Mengjie; Herdeiro, Carlos; Jing, Jiliang

2017-11-01

We study Dirac quasinormal modes of Schwarzschild-anti-de Sitter (Schwarzschild-AdS) black holes, following the generic principle for allowed boundary conditions proposed in [M. Wang, C. Herdeiro, and M. O. P. Sampaio, Phys. Rev. D 92, 124006 (2015)., 10.1103/PhysRevD.92.124006]. After deriving the equations of motion for Dirac fields on the aforementioned background, we impose vanishing energy flux boundary conditions to solve these equations. We find a set of two Robin boundary conditions are allowed. These two boundary conditions are used to calculate Dirac normal modes on empty AdS and quasinormal modes on Schwarzschild-AdS black holes. In the former case, we recover the known normal modes of empty AdS; in the latter case, the two sets of Robin boundary conditions lead to two different branches of quasinormal modes. The impact on these modes of the black hole size, the angular momentum quantum number and the overtone number are discussed. Our results show that vanishing energy flux boundary conditions are a robust principle, applicable not only to bosonic fields but also to fermionic fields.

Genetic association between ghrelin polymorphisms and Alzheimer's disease in a Japanese population.

PubMed

Shibata, Nobuto; Ohnuma, Tohru; Kuerban, Bolati; Komatsu, Miwa; Arai, Heii

2011-01-01

Ghrelin has been reported to enter the hippocampus and to bind to the neurons of the hippocampal formation. This peptide also affects neuronal glucose uptake and decreases tau hyperphosphorylation. There is increasing evidence suggesting an association between ghrelin and Alzheimer's disease (AD) pathology. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) of the ghrelin gene are associated with AD. The SNPs were genotyped using TaqMan technology and were analyzed using a case-control study design. Our case-control dataset consisted of 182 AD patients and 143 age-matched controls. Hardy-Weinberg equilibrium and linkage disequilibrium analyses suggest that the region in and around the gene is highly polymorphic. One SNP, rs4684677 (Leu90Gln), showed a marginal association with age of AD onset. We did not detect any association between the other SNPs of the ghrelin gene and AD. There have been few genetic studies on the relationship between circulating ghrelin and functional SNPs. Further multifactorial studies are needed to clarify the relationship between ghrelin and AD. Copyright © 2011 S. Karger AG, Basel.

Added Value of Coronal Reformations for Duty Radiologists and for Referring Physicians or Surgeons in the CT Diagnosis of Acute Appendicitis

PubMed Central

Lee, Kyoung Ho; Hahn, Seokyung; Lee, Kyung Won; Lee, Hak Jong; Kim, Tae Jung; Kang, Sung-Bum; Shin, Joong Ho; Park, Byung Joo

2006-01-01

Objective To assess the added value of coronal reformation for radiologists and for referring physicians or surgeons in the CT diagnosis of acute appendicitis. Materials and Methods Contrast-enhanced CT was performed using 16-detector-row scanners in 110 patients, 46 of whom had appendicitis. Transverse (5-mm thickness, 4-mm increment), coronal (5-mm thickness, 4-mm increment), and combined transverse and coronal sections were interpreted by four radiologists, two surgeons and two emergency physicians. The area under the receiver operating characteristic curve (Az value), sensitivity, specificity (McNemar test), diagnostic confidence and appendiceal visualization (Wilcoxon signed rank test) were compared. Results For radiologists, the additional coronal sections tended to increase the Az value (0.972 vs. 0.986, p = 0.076) and pooled sensitivity (92% [95% CI: 88, 96] vs. 96% [93, 99]), and enhanced appendiceal visualization in true-positive cases (p = 0.031). For non-radiologists, no such enhancement was observed, and the confidence for excluding acute appendicitis declined (p = 0.013). Coronal sections alone were inferior to transverse sections for diagnostic confidence as well as appendiceal visualization for each reader group studied (p < 0.05). Conclusion The added value of coronal reformation is more apparent for radiologists compared to referring physicians or surgeons in the CT diagnosis of acute appendicitis. PMID:16799269

Comparative effectiveness of incorporating a hypothetical DCIS prognostic marker into breast cancer screening.

PubMed

Trentham-Dietz, Amy; Ergun, Mehmet Ali; Alagoz, Oguzhan; Stout, Natasha K; Gangnon, Ronald E; Hampton, John M; Dittus, Kim; James, Ted A; Vacek, Pamela M; Herschorn, Sally D; Burnside, Elizabeth S; Tosteson, Anna N A; Weaver, Donald L; Sprague, Brian L

2018-02-01

Due to limitations in the ability to identify non-progressive disease, ductal carcinoma in situ (DCIS) is usually managed similarly to localized invasive breast cancer. We used simulation modeling to evaluate the potential impact of a hypothetical test that identifies non-progressive DCIS. A discrete-event model simulated a cohort of U.S. women undergoing digital screening mammography. All women diagnosed with DCIS underwent the hypothetical DCIS prognostic test. Women with test results indicating progressive DCIS received standard breast cancer treatment and a decrement to quality of life corresponding to the treatment. If the DCIS test indicated non-progressive DCIS, no treatment was received and women continued routine annual surveillance mammography. A range of test performance characteristics and prevalence of non-progressive disease were simulated. Analysis compared discounted quality-adjusted life years (QALYs) and costs for test scenarios to base-case scenarios without the test. Compared to the base case, a perfect prognostic test resulted in a 40% decrease in treatment costs, from $13,321 to $8005 USD per DCIS case. A perfect test produced 0.04 additional QALYs (16 days) for women diagnosed with DCIS, added to the base case of 5.88 QALYs per DCIS case. The results were sensitive to the performance characteristics of the prognostic test, the proportion of DCIS cases that were non-progressive in the model, and the frequency of mammography screening in the population. A prognostic test that identifies non-progressive DCIS would substantially reduce treatment costs but result in only modest improvements in quality of life when averaged over all DCIS cases.

Brain Aging in the Oldest-Old

PubMed Central

von Gunten, A.; Ebbing, K.; Imhof, A.; Giannakopoulos, P.; Kövari, E.

2010-01-01

Nonagenarians and centenarians represent a quickly growing age group worldwide. In parallel, the prevalence of dementia increases substantially, but how to define dementia in this oldest-old age segment remains unclear. Although the idea that the risk of Alzheimer's disease (AD) decreases after age 90 has now been questioned, the oldest-old still represent a population relatively resistant to degenerative brain processes. Brain aging is characterised by the formation of neurofibrillary tangles (NFTs) and senile plaques (SPs) as well as neuronal and synaptic loss in both cognitively intact individuals and patients with AD. In nondemented cases NFTs are usually restricted to the hippocampal formation, whereas the progressive involvement of the association areas in the temporal neocortex parallels the development of overt clinical signs of dementia. In contrast, there is little correlation between the quantitative distribution of SP and AD severity. The pattern of lesion distribution and neuronal loss changes in extreme aging relative to the younger-old. In contrast to younger cases where dementia is mainly related to severe NFT formation within adjacent components of the medial and inferior aspects of the temporal cortex, oldest-old individuals display a preferential involvement of the anterior part of the CA1 field of the hippocampus whereas the inferior temporal and frontal association areas are relatively spared. This pattern suggests that both the extent of NFT development in the hippocampus as well as a displacement of subregional NFT distribution within the Cornu ammonis (CA) fields may be key determinants of dementia in the very old. Cortical association areas are relatively preserved. The progression of NFT formation across increasing cognitive impairment was significantly slower in nonagenarians and centenarians compared to younger cases in the CA1 field and entorhinal cortex. The total amount of amyloid and the neuronal loss in these regions were also significantly lower than those reported in younger AD cases. Overall, there is evidence that pathological substrates of cognitive deterioration in the oldest-old are different from those observed in the younger-old. Microvascular parameters such as mean capillary diameters may be key factors to consider for the prediction of cognitive decline in the oldest-old. Neuropathological particularities of the oldest-old may be related to “longevity-enabling” genes although little or nothing is known in this promising field of future research. PMID:20706534

Multiscale deep neural network based analysis of FDG-PET images for the early diagnosis of Alzheimer's disease.

PubMed

Lu, Donghuan; Popuri, Karteek; Ding, Gavin Weiguang; Balachandar, Rakesh; Beg, Mirza Faisal

2018-05-01

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases with a commonly seen prodromal mild cognitive impairment (MCI) phase where memory loss is the main complaint progressively worsening with behavior issues and poor self-care. However, not all individuals clinically diagnosed with MCI progress to AD. A fraction of subjects with MCI either progress to non-AD dementia or remain stable at the MCI stage without progressing to dementia. Although a curative treatment of AD is currently unavailable, it is extremely important to correctly identify the individuals in the MCI phase that will go on to develop AD so that they may benefit from a curative treatment when one becomes available in the near future. At the same time, it would be highly desirable to also correctly identify those in the MCI phase that do not have AD pathology so they may be spared from unnecessary pharmocologic interventions that, at best, may provide them no benefit, and at worse, could further harm them with adverse side-effects. Additionally, it may be easier and simpler to identify the cause of the cognitive impairment in these non-AD cases, and hence proper identification of prodromal AD will be of benefit to these individuals as well. Fluorodeoxy glucose positron emission tomography (FDG-PET) captures the metabolic activity of the brain, and this imaging modality has been reported to identify changes related to AD prior to the onset of structural changes. Prior work on designing classifier using FDG-PET imaging has been promising. Since deep-learning has recently emerged as a powerful tool to mine features and use them for accurate labeling of the group membership of given images, we propose a novel deep-learning framework using FDG-PET metabolism imaging to identify subjects at the MCI stage with presymptomatic AD and discriminate them from other subjects with MCI (non-AD / non-progressive). Our multiscale deep neural network obtained 82.51% accuracy of classification just using measures from a single modality (FDG-PET metabolism data) outperforming other comparable FDG-PET classifiers published in the recent literature. Copyright © 2018 Elsevier B.V. All rights reserved.

Comorbidity of Narcolepsy Type 1 With Autoimmune Diseases and Other Immunopathological Disorders: A Case-Control Study

PubMed Central

Martinez-Orozco, Francisco Javier; Vicario, Jose Luis; De Andres, Clara; Fernandez-Arquero, Miguel; Peraita-Adrados, Rosa

2016-01-01

Background Several evidences suggest that autoimmune diseases (ADs) tend to co-occur in an individual and within the same family. Narcolepsy type 1 (NT1) is a chronic sleep disorder caused by a selective loss of hypocretin-producing neurons due to a mechanism of neural destruction that indicates an autoimmune pathogenesis, although no evidence is available. We report on the comorbidity of ADs and other immunopathological diseases (including allergy diseases) in narcolepsy. Methods We studied 158 Caucasian NT1 patients (60.7% male; mean age 49.4 ± 19.7 years), in whom the diagnosis was confirmed by polysomnography followed by a multiple sleep latency test, or by hypocretin-1 levels measurements. Results Thirty out of 158 patients (18.99%; 53.3% female; 29 sporadic and one familial cases) had one or more immunopathological diseases associated. A control group of 151 subjects were matched by gender and age with the narcolepsy patients. Results demonstrated that there was a higher frequency of ADs in our series of narcolepsy patients compared to the sample of general population (odds ratio: 3.17; 95% confidence interval: 1.01 - 10.07; P = 0.040). A temporal relationship with the age at onset of the diseases was found. Conclusions Cataplexy was significantly more severe in NT1 patients with immunopathological diseases, and immunopathological diseases are a risk factor for severe forms of cataplexy in our series (odds ratio: 23.6; 95% confidence interval: 5.5 - 100.1). PMID:27298657

Multiple Gingival Recession Coverage Treated with Vestibular Incision Subperiosteal Tunnel Access Approach with or without Platelet-Rich Fibrin - A Case Series

PubMed Central

Garg, Surbhi; Arora, Sachit Anand; Chhina, Shivjot; Singh, Padam

2017-01-01

Background: Gingival recession involves both soft tissue and hard tissue loss. In this evolutionary era of dentistry, newer techniques have evolved for complete coverage of isolated recession defects. Since 2012, vestibular incision subperiosteal tunnel access (VISTA) technique was used with various regenerative membranes to treat multiple recession defects (MRDs). Platelet-rich fibrin (PRF) membrane, a pool of growth factors but have any added advantage to recession coverage techniques is controversial. Thus, in this case series, we compare the effect of VISTA with or without PRF-membrane for the treatment of Classes I and III MRDs. Subjects and Methods: Four patients between of age 30 and 40 years (two patients having bilateral Class I and another two having bilateral Class III MRDs) were selected from the Department of Periodontics, ITS Dental College, Greater Noida and designated as Case I–IV simultaneously. Recession defects at antagonist sites in each patient were corrected by VISTA approach with or without PRF-membrane. Recorded clinical parameters included recession depth, recession width, pocket probing depth, and clinical attachment level (CAL) at baseline and 6 months postoperatively. Results: Patients having Class I recession defects showed almost complete root coverage with VISTA technique alone and reflected no added advantage of PRF-membrane. However, patients with Class III recession defects treated with VISTA + PRF-membrane showed more reduction in recession depth and gain in CAL as compared to sites treated with VISTA only. Conclusion: VISTA alone is a convenient technique for treatment of Class I MRDs. Addition of PRF-membrane for Class III recession defects give better outcome in term of reduction of recession depth and gain in CAL 6 month postoperatively. PMID:29042736

Neuropathological diagnostic criteria for Alzheimer's disease.

PubMed

Murayama, Shigeo; Saito, Yuko

2004-09-01

Neuropathological diagnostic criteria for Alzheimer's disease (AD) are based on tau-related pathology: NFT or neuritic plaques (NP). The Consortium to Establish a Registry for Alzheimer's disease (CERAD) criterion evaluates the highest density of neocortical NP from 0 (none) to C (abundant). Clinical documentation of dementia and NP stage A in younger cases, B in young old cases and C in older cases fulfils the criterion of AD. The CERAD criterion is most frequently used in clinical outcome studies because of its inclusion of clinical information. Braak and Braak's criterion evaluates the density and distribution of NFT and classifies them into: I/II, entorhinal; III/IV, limbic; and V/VI, neocortical stage. These three stages correspond to normal cognition, cognitive impairment and dementia, respectively. As Braak's criterion is based on morphological evaluation of the brain alone, this criterion is usually adopted in the research setting. The National Institute for Aging and Ronald and Nancy Reagan Institute of the Alzheimer's Association criterion combines these two criteria and categorizes cases into NFT V/VI and NP C, NFT III/IV and NP B, and NFT I/II and NP A, corresponding to high, middle and low probability of AD, respectively. As most AD cases in the aged population are categorized into Braak tangle stage IV and CERAD stage C, the usefulness of this criterion has not yet been determined. The combination of Braak's NFT stage equal to or above IV and Braak's senile plaque Stage C provides, arguably, the highest sensitivity and specificity. In future, the criteria should include in vivo dynamic neuropathological data, including 3D MRI, PET scan and CSF biomarkers, as well as more sensitive and specific immunohistochemical and immunochemical grading of AD.

Aberrant distribution patterns of corneodesmosomal components of tape-stripped corneocytes in atopic dermatitis and related skin conditions (ichthyosis vulgaris, Netherton syndrome and peeling skin syndrome type B).

PubMed

Igawa, Satomi; Kishibe, Mari; Honma, Masaru; Murakami, Masamoto; Mizuno, Yuki; Suga, Yasushi; Seishima, Mariko; Ohguchi, Yuka; Akiyama, Masashi; Hirose, Kenji; Ishida-Yamamoto, Akemi; Iizuka, Hajime

2013-10-01

Atopic dermatitis (AD), Netherton syndrome (NS) and peeling skin syndrome type B (PSS) may show some clinical phenotypic overlap. Corneodesmosomes are crucial for maintaining stratum corneum integrity and the components' localization can be visualized by immunostaining tape-stripped corneocytes. In normal skin, they are detected at the cell periphery. To determine whether AD, NS, PSS and ichthyosis vulgaris (IV) have differences in the corneodesmosomal components' distribution and corneocytes surface areas. Corneocytes were tape-stripped from a control group (n=12) and a disease group (37 AD cases, 3 IV cases, 4 NS cases, and 3 PSS cases), and analyzed with immunofluorescent microscopy. The distribution patterns of corneodesmosomal components: desmoglein 1, corneodesmosin, and desmocollin 1 were classified into four types: peripheral, sparse diffuse, dense diffuse and partial diffuse. Corneocyte surface areas were also measured. The corneodesmosome staining patterns were abnormal in the disease group. Other than in the 3 PSS cases, all three components showed similar patterns in each category. In lesional AD skin, the dense diffuse pattern was prominent. A high rate of the partial diffuse pattern, loss of linear cell-cell contacts, and irregular stripping manners were unique to NS. Only in PSS was corneodesmosin staining virtually absent. The corneocyte surface areas correlated significantly with the rate of combined sparse and dense diffuse patterns of desmoglein 1. This method may be used to assess abnormally differentiated corneocytes in AD and other diseases tested. In PSS samples, tape stripping analysis may serve as a non-invasive diagnostic test. Copyright © 2013 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

Epidemiology, associated burden, and current clinical practice for the diagnosis and management of Alzheimer's disease in Japan.

PubMed

Montgomery, William; Ueda, Kaname; Jorgensen, Margaret; Stathis, Shari; Cheng, Yuanyuan; Nakamura, Tomomi

2018-01-01

The burden of dementia in Japan is large and growing. With the world's fastest aging population, it is estimated that one in five elderly people will be living with dementia in Japan by 2025. The most common form of dementia is Alzheimer's disease (AD), accounting for around two-thirds of dementia cases. A systematic review was conducted to examine the epidemiology and associated burden of AD in Japan and to identify how AD is diagnosed and managed in Japan. English and Japanese language databases were searched for articles published between January 2000 and November 2015. Relevant Japanese sources, clinical practice guideline registers, and reference lists were also searched. Systematic reviews and cohort and case-control studies were eligible for inclusion, with a total of 60 studies included. The most recent national survey conducted in six regions of Japan reported the mean prevalence of dementia in people aged ≥65 years to be 15.75% (95% CI: 12.4, 22.2%), which is much higher than the previous estimated rate of 10% in 2010. AD was confirmed as the predominant type of dementia, accounting for 65.8% of all cases. Advancing age and low education were the most consistently reported risk factors for AD dementia. Japanese guidelines for the management of dementia were released in 2010 providing specific guidance for AD about clinical signs, image findings, biochemical markers, and treatment approaches. Pharmacotherapies and non-pharmacotherapies to relieve cognitive symptoms were introduced, as were recommendations to achieve better patient care. No studies reporting treatment patterns were identified. Due to population aging and growing awareness of AD in Japan, health care expenditure and associated burden are expected to soar. This review highlights the importance of early detection, diagnosis, and treatment of AD as strategies to minimize the impact of AD on society in Japan.

Risk factors for atopic dermatitis in New Zealand children at 3.5 years of age.

PubMed

Purvis, D J; Thompson, J M D; Clark, P M; Robinson, E; Black, P N; Wild, C J; Mitchell, E A

2005-04-01

The prevalence of atopic dermatitis (AD) is increasing in Western societies. The hygiene hypothesis proposes that this is due to reduced exposure to environmental allergens and infections during early life. To examine factors associated with a diagnosis of AD at 3.5 years of age, especially those factors implicated by the hygiene hypothesis. The Auckland Birthweight Collaborative study is a case-control study of risk factors for small for gestational age babies. Cases were born at term with birthweight < or = 10th centile; controls were appropriate for gestational age, with birthweight > 10th centile. The infants were assessed at birth, 1 year and 3.5 years of age. Data were collected by parental interview and examination of the child. AD was defined as the presence of an itchy rash in the past 12 months with three or more of the following: history of flexural involvement; history of generally dry skin; history of atopic disease in parents or siblings; and visible flexural dermatitis as per photographic protocol. Statistical analyses took into account the disproportionate sampling of the study population. Analysis was restricted to European subjects. Eight hundred and seventy-one children were enrolled at birth, 744 (85.4%) participated at 1 year, and 550 (63.2%) at 3.5 years. AD was diagnosed in 87 (15.8%) children seen at 3.5 years. The prevalence of AD did not differ by birthweight. AD at 3.5 years was associated with raised serum IgE > 200 kU L(-1), and wheezing, asthma, rash or eczema at 1 year. In multivariate analysis, adjusted for parental atopy and breastfeeding, AD at 3.5 years was associated with atopic disease in the parents: maternal atopy only, adjusted odds ratio (OR) 3.83, 95% confidence interval (CI) 1.20-12.23; paternal atopy only, adjusted OR 3.59, 95% CI 1.09-11.75; both parents atopic, adjusted OR 6.12, 95% CI 2.02-18.50. There was a higher risk of AD with longer duration of breastfeeding: < 6 months, adjusted OR 6.13, 95% CI 1.45-25.86; > or = 6 months, adjusted OR 9.70, 95% CI 2.47-38.15 compared with never breastfed. These findings remained significant after adjusting for environmental factors and a personal history of atopy. AD at 3.5 years was associated with owning a cat at 3.5 years (adjusted OR 0.45, 95% CI 0.21-0.97) but not with owning a dog at 3.5 years, pets at 1 year, nor with older siblings. Furthermore, AD at 3.5 years was not associated with gender, socioeconomic status, maternal smoking, parity, damp, mould, immunizations, body mass index or antibiotic use in first year of life. A personal and a parental history of atopic disease are risk factors for AD at 3.5 years. Duration of breastfeeding was associated with an increased risk of AD. No association was found with those factors implicated by the hygiene hypothesis. This study suggests that breastfeeding should not be recommended for the prevention of AD.

Risk, treatment duration, and recurrence risk of postpartum affective disorder in women with no prior psychiatric history: A population-based cohort study

PubMed Central

Strøm, Marin; Wohlfahrt, Jan

2017-01-01

Background Some 5%–15% of all women experience postpartum depression (PPD), which for many is their first psychiatric disorder. The purpose of this study was to estimate the incidence of postpartum affective disorder (AD), duration of treatment, and rate of subsequent postpartum AD and other affective episodes in a nationwide cohort of women with no prior psychiatric history. Methods and findings Linking information from several Danish national registers, we constructed a cohort of 457,317 primiparous mothers with first birth (and subsequent births) from 1 January 1996 to 31 December 2013 (a total of 789,068 births) and no prior psychiatric hospital contacts and/or use of antidepressants. These women were followed from 1 January 1996 to 31 December 2014. Postpartum AD was defined as use of antidepressants and/or hospital contact for PPD within 6 months after childbirth. The main outcome measures were risk of postpartum AD, duration of treatment, and recurrence risk. We observed 4,550 (0.6%) postpartum episodes of AD. The analyses of treatment duration showed that 1 year after the initiation of treatment for their first episode, 27.9% of women were still in treatment; after 4 years, 5.4%. The recurrence risk of postpartum AD for women with a PPD hospital contact after first birth was 55.4 per 100 person-years; for women with postpartum antidepressant medication after first birth, it was 35.0 per 100 person-years. The rate of postpartum AD after second birth for women with no history of postpartum AD was 1.2 per 100 person-years. After adjusting for year of birth and mother’s age, women with PPD hospital contact after first birth had a 46.4 times higher rate (95% CI 31.5–68.4) and women with postpartum antidepressant medication after their first birth had a 26.9 times higher rate (95% CI 21.9–33.2) of a recurrent postpartum episode after their second birth compared to women with no postpartum AD history. Limitations include the use of registry data to identify cases and limited confounder control. Conclusions In this study, an episode of postpartum AD was observed for 0.6% of childbirths among women with no prior psychiatric history. The observed episodes were characterized by a relatively short treatment duration, yet the women had a notably high rate of later AD and recurrent episodes of postpartum AD. The recurrence risk of postpartum AD was markedly higher among women with PPD hospital contact after first birth compared to women with postpartum antidepressant medication after first birth. Our results underline the necessity of measures targeted at specific vulnerable groups, such as women who experience PPD as a first psychiatric episode. PMID:28949960

Prenatal diagnosis of congenital toxoplasmosis: comparative value of fetal blood and amniotic fluid using serological techniques and cultures.

PubMed

Fricker-Hidalgo, H; Pelloux, H; Muet, F; Racinet, C; Bost, M; Goullier-Fleuret, A; Ambroise-Thomas, P

1997-09-01

The prenatal diagnosis of congenital toxoplasmosis is mainly based on biological tests performed on fetal blood and amniotic fluid. We studied the performance of neonatal diagnosis procedures and the results of fetal blood and amniotic fluid analysis. Of 127 women who contracted toxoplasmosis and underwent prenatal diagnosis, the postnatal serological follow-up was long enough to definitively diagnose congenital toxoplasmosis in 19 cases and to exclude it in 27 cases. Prenatal diagnosis allowed the detection of 94.7 per cent (18/19) of the infected fetuses. The sensitivities of tests in amniotic fluid and fetal blood were equivalent, 88.2 per cent (15/17) and 87.5 per cent (14/16), respectively. In fetal blood, biological techniques were positive in 12/16 cases and in 2/16 cases, serological tests were the only positive sign. The specificities of tests in amniotic fluid and fetal blood were respectively 100 per cent (23/23) and 86.3 per cent (19/22) (three false-positive serological results). These results, added to the lower morbidity of amniocentesis compared with cordocentesis, might lead to cordocentesis being abandoned in the prenatal diagnosis of congenital toxoplasmosis.

A NOVEL ALZHEIMER DISEASE LOCUS LOCATED NEAR THE GENE ENCODING TAU PROTEIN

PubMed Central

Jun, Gyungah; Ibrahim-Verbaas, Carla A.; Vronskaya, Maria; Lambert, Jean-Charles; Chung, Jaeyoon; Naj, Adam C.; Kunkle, Brian W.; Wang, Li-San; Bis, Joshua C.; Bellenguez, Céline; Harold, Denise; Lunetta, Kathryn L.; Destefano, Anita L.; Grenier-Boley, Benjamin; Sims, Rebecca; Beecham, Gary W.; Smith, Albert V.; Chouraki, Vincent; Hamilton-Nelson, Kara L.; Ikram, M. Arfan; Fievet, Nathalie; Denning, Nicola; Martin, Eden R.; Schmidt, Helena; Kamatani, Yochiro; Dunstan, Melanie L; Valladares, Otto; Laza, Agustin Ruiz; Zelenika, Diana; Ramirez, Alfredo; Foroud, Tatiana M.; Choi, Seung-Hoan; Boland, Anne; Becker, Tim; Kukull, Walter A.; van der Lee, Sven J.; Pasquier, Florence; Cruchaga, Carlos; Beekly, Duane; Fitzpatrick, Annette L.; Hanon, Oliver; Gill, Michael; Barber, Robert; Gudnason, Vilmundur; Campion, Dominique; Love, Seth; Bennett, David A.; Amin, Najaf; Berr, Claudine; Tsolaki, Magda; Buxbaum, Joseph D.; Lopez, Oscar L.; Deramecourt, Vincent; Fox, Nick C; Cantwell, Laura B.; Tárraga, Lluis; Dufouil, Carole; Hardy, John; Crane, Paul K.; Eiriksdottir, Gudny; Hannequin, Didier; Clarke, Robert; Evans, Denis; Mosley, Thomas H.; Letenneur, Luc; Brayne, Carol; Maier, Wolfgang; De Jager, Philip; Emilsson, Valur; Dartigues, Jean-François; Hampel, Harald; Kamboh, M. Ilyas; de Bruijn, Renee F.A.G.; Tzourio, Christophe; Pastor, Pau; Larson, Eric B.; Rotter, Jerome I.; O’Donovan, Michael C; Montine, Thomas J.; Nalls, Michael A.; Mead, Simon; Reiman, Eric M.; Jonsson, Palmi V.; Holmes, Clive; St George-Hyslop, Peter H.; Boada, Mercè; Passmore, Peter; Wendland, Jens R.; Schmidt, Reinhold; Morgan, Kevin; Winslow, Ashley R.; Powell, John F; Carasquillo, Minerva; Younkin, Steven G.; Jakobsdóttir, Jóhanna; Kauwe, John SK; Wilhelmsen, Kirk C.; Rujescu, Dan; Nöthen, Markus M; Hofman, Albert; Jones, Lesley; Haines, Jonathan L.; Psaty, Bruce M.; Van Broeckhoven, Christine; Holmans, Peter; Launer, Lenore J.; Mayeux, Richard; Lathrop, Mark; Goate, Alison M.; Escott-Price, Valentina; Seshadri, Sudha; Pericak-Vance, Margaret A.; Amouyel, Philippe; Williams, Julie; van Duijn, Cornelia M.; Schellenberg, Gerard D.; Farrer, Lindsay A.

2015-01-01

APOE ε4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer’s Project (IGAP) Consortium in APOE ε4+ (10,352 cases and 9,207 controls) and APOE ε4− (7,184 cases and 26,968 controls) subgroups as well as in the total sample testing for interaction between a SNP and APOE ε4 status. Suggestive associations (P<1x10−4) in stage 1 were evaluated in an independent sample (stage 2) containing 4,203 subjects (APOE ε4+: 1,250 cases and 536 controls; APOE ε4-: 718 cases and 1,699 controls). Among APOE ε4− subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 datasets (best SNP, rs2732703, P=5·8x10−9). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100 kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ε4+ subjects (CR1 and CLU) or APOE ε4− subjects (MS4A6A/MS4A4A/ MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6x10−7) is noteworthy because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P≤1.3x10−8), frontal cortex (P≤1.3x10−9), and temporal cortex (P≤1.2x10−11). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2x10−6) and temporal cortex (P=2.6x10−6). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ε4 compared to persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted. PMID:25778476

A novel Alzheimer disease locus located near the gene encoding tau protein.

PubMed

Jun, G; Ibrahim-Verbaas, C A; Vronskaya, M; Lambert, J-C; Chung, J; Naj, A C; Kunkle, B W; Wang, L-S; Bis, J C; Bellenguez, C; Harold, D; Lunetta, K L; Destefano, A L; Grenier-Boley, B; Sims, R; Beecham, G W; Smith, A V; Chouraki, V; Hamilton-Nelson, K L; Ikram, M A; Fievet, N; Denning, N; Martin, E R; Schmidt, H; Kamatani, Y; Dunstan, M L; Valladares, O; Laza, A R; Zelenika, D; Ramirez, A; Foroud, T M; Choi, S-H; Boland, A; Becker, T; Kukull, W A; van der Lee, S J; Pasquier, F; Cruchaga, C; Beekly, D; Fitzpatrick, A L; Hanon, O; Gill, M; Barber, R; Gudnason, V; Campion, D; Love, S; Bennett, D A; Amin, N; Berr, C; Tsolaki, Magda; Buxbaum, J D; Lopez, O L; Deramecourt, V; Fox, N C; Cantwell, L B; Tárraga, L; Dufouil, C; Hardy, J; Crane, P K; Eiriksdottir, G; Hannequin, D; Clarke, R; Evans, D; Mosley, T H; Letenneur, L; Brayne, C; Maier, W; De Jager, P; Emilsson, V; Dartigues, J-F; Hampel, H; Kamboh, M I; de Bruijn, R F A G; Tzourio, C; Pastor, P; Larson, E B; Rotter, J I; O'Donovan, M C; Montine, T J; Nalls, M A; Mead, S; Reiman, E M; Jonsson, P V; Holmes, C; St George-Hyslop, P H; Boada, M; Passmore, P; Wendland, J R; Schmidt, R; Morgan, K; Winslow, A R; Powell, J F; Carasquillo, M; Younkin, S G; Jakobsdóttir, J; Kauwe, J S K; Wilhelmsen, K C; Rujescu, D; Nöthen, M M; Hofman, A; Jones, L; Haines, J L; Psaty, B M; Van Broeckhoven, C; Holmans, P; Launer, L J; Mayeux, R; Lathrop, M; Goate, A M; Escott-Price, V; Seshadri, S; Pericak-Vance, M A; Amouyel, P; Williams, J; van Duijn, C M; Schellenberg, G D; Farrer, L A

2016-01-01

APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P ⩽ 1.3 × 10(-8)), frontal cortex (P ⩽ 1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.

Comparison between Smoluchowski and Boltzmann approaches for self-propelled rods.

PubMed

Bertin, Eric; Baskaran, Aparna; Chaté, Hugues; Marchetti, M Cristina

2015-10-01

Considering systems of self-propelled polar particles with nematic interactions ("rods"), we compare the continuum equations describing the evolution of polar and nematic order parameters, derived either from Smoluchowski or Boltzmann equations. Our main goal is to understand the discrepancies between the continuum equations obtained so far in both frameworks. We first show that, in the simple case of point-like particles with only alignment interactions, the continuum equations obtained have the same structure in both cases. We further study, in the Smoluchowski framework, the case where an interaction force is added on top of the aligning torque. This clarifies the origin of the additional terms obtained in previous works. Our observations lead us to emphasize the need for a more involved closure scheme than the standard normal form of the distribution when dealing with active systems.

A study of methods of prediction and measurement of the transmission sound through the walls of light aircraft

NASA Technical Reports Server (NTRS)

Forssen, B.; Wang, Y. S.; Crocker, M. J.

1981-01-01

Several aspects were studied. The SEA theory was used to develop a theoretical model to predict the transmission loss through an aircraft window. This work mainly consisted of the writing of two computer programs. One program predicts the sound transmission through a plexiglass window (the case of a single partition). The other program applies to the case of a plexiglass window window with a window shade added (the case of a double partition with an air gap). The sound transmission through a structure was measured in experimental studies using several different methods in order that the accuracy and complexity of all the methods could be compared. Also, the measurements were conducted on the simple model of a fuselage (a cylindrical shell), on a real aircraft fuselage, and on stiffened panels.

A study of methods of prediction and measurement of the transmission sound through the walls of light aircraft

NASA Astrophysics Data System (ADS)

Forssen, B.; Wang, Y. S.; Crocker, M. J.

1981-12-01

Several aspects were studied. The SEA theory was used to develop a theoretical model to predict the transmission loss through an aircraft window. This work mainly consisted of the writing of two computer programs. One program predicts the sound transmission through a plexiglass window (the case of a single partition). The other program applies to the case of a plexiglass window window with a window shade added (the case of a double partition with an air gap). The sound transmission through a structure was measured in experimental studies using several different methods in order that the accuracy and complexity of all the methods could be compared. Also, the measurements were conducted on the simple model of a fuselage (a cylindrical shell), on a real aircraft fuselage, and on stiffened panels.

Importance of an intact dura in management of compound elevated fractures; a short series and literature review.

PubMed

Mohindra, Sandeep; Singh, Harnarayan; Savardekar, Amey

2012-01-01

To describe compound elevated fractures (CEFs) of the skull vault, with radiological pictures, management problems and prognosticative factors. The authors describe three cases of CEFs of the cranium, their mode of injury, clinical findings, radiological images and management problems. The authors have reviewed the existing literature regarding epidemiological data, neurological status, dural breech, methods of management and final outcome, in respect of CEFs. The first case had no dural breech, the second case had completely shattered dura, with extruding brain matter from the wound, while the third case had an elevated bone flap in consequence to large extradural haematoma. The patients with intact dura had relatively favourable outcome, when compared to patients with shattered dura. Three cases are added to the existing 10 such cases described in English literature. The major cause of unfavourable outcome remains sepsis and the presence of intact dura places these cases in the relatively safe category, regarding infective complications. The authors attempt at highlighting the importance of intact dura with such an injury. The review of literature supports favourable outcomes in patients having no dural breech.

Mortality among patients due to adverse drug reactions that lead to hospitalization: a meta-analysis.

PubMed

Patel, Tejas K; Patel, Parvati B

2018-06-01

The aim of this study was to estimate the prevalence of mortality among patients due to adverse drug reactions that lead to hospitalisation (fatal ADR Ad ), to explore the heterogeneity in its estimation through subgroup analysis of study characteristics, and to identify system-organ classes involved and causative drugs for fatal ADR Ad . We identified prospective ADR Ad -related studies via screening of the PubMed and Google Scholar databases with appropriate key terms. We estimated the prevalence of fatal ADR Ad using a double arcsine method and explored heterogeneity using the following study characteristics: age groups, wards, study region, ADR definitions, ADR identification methods, study duration and sample size. We examined patterns of fatal ADR Ad and causative drugs. Among 312 full-text articles assessed, 49 studies satisfied the selection criteria and were included in the analysis. The mean prevalence of fatal ADR Ad was 0.20% (95% CI: 0.13-0.27%; I 2  = 93%). The age groups and study wards were the important heterogeneity modifiers. The mean fatal ADR Ad prevalence varied from 0.01% in paediatric patients to 0.44% in the elderly. Subgroup analysis showed a higher prevalence of fatal ADR Ad in intensive care units, emergency departments, multispecialty wards and whole hospitals. Computer-based monitoring systems in combination with other methods detected higher mortality. Intracranial haemorrhage, renal failure and gastrointestinal bleeding accounted for more than 50% of fatal ADR Ad cases. Warfarin, aspirin, renin-angiotensin system (RAS) inhibitors and digoxin accounted for 60% of fatal ADR Ad . ADR Ad is an important cause of mortality. Strategies targeting the safer use of warfarin, aspirin, RAS inhibitors and digoxin could reduce the large number of fatal ADR Ad cases.

Identification of Differentially Expressed Genes through Integrated Study of Alzheimer's Disease Affected Brain Regions.

PubMed

Puthiyedth, Nisha; Riveros, Carlos; Berretta, Regina; Moscato, Pablo

2016-01-01

Alzheimer's disease (AD) is the most common form of dementia in older adults that damages the brain and results in impaired memory, thinking and behaviour. The identification of differentially expressed genes and related pathways among affected brain regions can provide more information on the mechanisms of AD. In the past decade, several studies have reported many genes that are associated with AD. This wealth of information has become difficult to follow and interpret as most of the results are conflicting. In that case, it is worth doing an integrated study of multiple datasets that helps to increase the total number of samples and the statistical power in detecting biomarkers. In this study, we present an integrated analysis of five different brain region datasets and introduce new genes that warrant further investigation. The aim of our study is to apply a novel combinatorial optimisation based meta-analysis approach to identify differentially expressed genes that are associated to AD across brain regions. In this study, microarray gene expression data from 161 samples (74 non-demented controls, 87 AD) from the Entorhinal Cortex (EC), Hippocampus (HIP), Middle temporal gyrus (MTG), Posterior cingulate cortex (PC), Superior frontal gyrus (SFG) and visual cortex (VCX) brain regions were integrated and analysed using our method. The results are then compared to two popular meta-analysis methods, RankProd and GeneMeta, and to what can be obtained by analysing the individual datasets. We find genes related with AD that are consistent with existing studies, and new candidate genes not previously related with AD. Our study confirms the up-regualtion of INFAR2 and PTMA along with the down regulation of GPHN, RAB2A, PSMD14 and FGF. Novel genes PSMB2, WNK1, RPL15, SEMA4C, RWDD2A and LARGE are found to be differentially expressed across all brain regions. Further investigation on these genes may provide new insights into the development of AD. In addition, we identified the presence of 23 non-coding features, including four miRNA precursors (miR-7, miR570, miR-1229 and miR-6821), dysregulated across the brain regions. Furthermore, we compared our results with two popular meta-analysis methods RankProd and GeneMeta to validate our findings and performed a sensitivity analysis by removing one dataset at a time to assess the robustness of our results. These new findings may provide new insights into the disease mechanisms and thus make a significant contribution in the near future towards understanding, prevention and cure of AD.

Effects of apolipoprotein E genotype on cortical neuropathology in senile dementia of the Lewy body and Alzheimer's disease.

PubMed

Benjamin, R; Leake, A; Ince, P G; Perry, R H; McKeith, I G; Edwardson, J A; Morris, C M

1995-12-01

Apolipoprotein E (APO E) genotypes were determined in a UK population of neuropathologically confirmed control cases, and in cases of Lewy body dementia (SDLT) and late onset Alzheimer's disease (AD). APO E epsilon 4 allele frequency was significantly elevated in both SDLT and AD groups with a concomitant reduction in the APO E epsilon 3 allele frequency. The epsilon 2 allele frequency in the AD group was only 25% of the control population, though because of the relatively small sample size this reduction was not significant; the epsilon 2 allele frequency in the SDLT group was normal. No significant association was found between senile plaque density and neurofibrillary tangle density in the neocortex and APO E allele dose in either SDLT or AD. Although the possession of APO E epsilon 4 is associated with an increased risk of developing SDLT and AD, actual APO E genotype does not appear to affect the burden of pathology.

Increased CNV-Region deletions in mild cognitive impairment (MCI) and Alzheimer's disease (AD) subjects in the ADNI sample

PubMed Central

Guffanti, Guia; Torri, Federica; Rasmussen, Jerod; Clark, Andrew P.; Lakatos, Anita; Turner, Jessica A.; Fallon, James H.; Saykin, Andrew J.; Weiner, Michael; Vawter, Marquis P.; Knowles, James A.; Potkin, Steven G.; Macciardi, Fabio

2014-01-01

We investigated the genome-wide distribution of CNVs in the Alzheimer's disease (AD) Neuroimaging Initiative (ADNI) sample (146 with AD, 313 with Mild Cognitive Impairment (MCI), and 181 controls). Comparison of single CNVs between cases (MCI and AD) and controls shows overrepresentation of large heterozygous deletions in cases (p-value < 0.0001). The analysis of CNV-Regions identifies 44 copy number variable loci of heterozygous deletions, with more CNV-Regions among affected than controls (p = 0.005). Seven of the 44 CNV-Regions are nominally significant for association with cognitive impairment. We validated and confirmed our main findings with genome re-sequencing of selected patients and controls. The functional pathway analysis of the genes putatively affected by deletions of CNV-Regions reveals enrichment of genes implicated in axonal guidance, cell–cell adhesion, neuronal morphogenesis and differentiation. Our findings support the role of CNVs in AD, and suggest an association between large deletions and the development of cognitive impairment PMID:23583670

Acrodermatitis dysmetabolica in an infant with maple syrup urine disease.

PubMed

Flores, K; Chikowski, R; Morrell, D S

2016-08-01

Acrodermatitis dysmetabolica (AD) is a rare, newly termed, and poorly understood disease that appears to be clinically similar to acrodermatitis enteropathica (AE). Both diseases are characterized by the triad of periorificial and acral dermatitis, diarrhoea, and alopecia. Unlike AE, which is caused by zinc deficiency, AD is caused by numerous metabolic disorders. One such disorder is maple syrup urine disease (MSUD), a genetic deficiency of branched chain α-ketoacid dehydrogenase, the enzyme that degrades the branched-chain amino acids (BCAAs) isoleucine, leucine and valine. Treatment involves restricting BCAAs to prevent accumulation. We report a case of an infant being treated for MSUD, who developed the triad of AE/AD after a period of poor BCAA formula intake. The child was found to have low isoleucine and normal zinc levels. Increasing the isoleucine dose improved the eruption, thus the diagnosis of AD secondary to isoleucine deficiency was made. This case emphasizes the importance of carefully balancing BCAA levels while treating MSUD, as deficiency can precipitate AD. © 2016 British Association of Dermatologists.

Comparing the Nutritional Impact of Dietary Strategies to Reduce Discretionary Choice Intake in the Australian Adult Population: A Simulation Modelling Study

PubMed Central

Grieger, Jessica A.; Johnson, Brittany J.; Wycherley, Thomas P.; Golley, Rebecca K.

2017-01-01

Dietary strategies to reduce discretionary choice intake are commonly utilized in practice, but evidence on their relative efficacy is lacking. The aim was to compare the potential impact on nutritional intake of three strategies to reducing discretionary choices intake in the Australian adult (19–90 years) population. Dietary simulation modelling using data from the National Nutrition and Physical Activity Survey 2011–2012 was conducted (n = 9341; one 24 h dietary recall). Strategies modelled were: moderation (reduce discretionary choices by 50%, with 0%, 25% or 75% energy compensation); substitution (replace 50% of discretionary choices with core choices); reformulation (replace 50% SFA with unsaturated fats, reduce added sugars by 25%, and reduce sodium by 20%). Compared to the base case (observed) intake, modelled intakes in the moderation scenario showed: −17.3% lower energy (sensitivity analyses, 25% energy compensation −14.2%; 75% energy compensation −8.0%), −20.9% lower SFA (−17.4%; −10.5%), −43.3% lower added sugars (−41.1%; −36.7%) and 17.7% lower sodium (−14.3%; −7.5%). Substitution with a range of core items, or with fruits, vegetables and core beverages only, resulted in similar changes in energy intake (−13.5% and −15.4%), SFA (−17.7% and −20.1%), added sugars (−42.6% and −43%) and sodium (−13.7% and −16.5%), respectively. Reformulating discretionary choices had minimal impact on reducing energy intake but reduced SFA (−10.3% to −30.9%), added sugars (−9.3% to −52.9%), and alcohol (−25.0% to −49.9%) and sodium (−3.3% to −13.2%). The substitution and reformulation scenarios minimized negative changes in fiber, protein and micronutrient intakes. While each strategy has strengths and limitations, substitution of discretionary choices with core foods and beverages may optimize the nutritional impact. PMID:28467387

Impact of interventions to reduce Alzheimer's disease pathology on the prevalence of dementia in the oldest-old.

PubMed

Brookmeyer, Ron; Kawas, Claudia H; Abdallah, Nada; Paganini-Hill, Annlia; Kim, Ronald C; Corrada, María M

2016-03-01

The number of persons aged >90 years will grow significantly in coming decades. This group has the highest rates of dementia, most commonly Alzheimer's disease (AD). Using The 90+ Study, we developed a statistical model for dementia risk based on brain pathologies. Intervention scenarios which reduce or eliminate AD pathology were considered, and the numbers of dementia cases among the U.S. oldest-old that could be prevented were estimated. The U.S. dementia prevalence among the oldest-old will increase from 1.35 million in 2015 to 4.72 million in 2050. If interventions eliminate AD pathology, dementia prevalence would be reduced by approximately 50%, averting nearly 2.4 million cases in 2050. However, large numbers of dementia cases would still remain. Reducing AD pathology would significantly decrease the public health burden of dementia. However, other interventions are needed to address the burden associated with other dementing pathologies prevalent in the oldest-old. Copyright © 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

The added value of a mobile application of Community Case Management on referral, re-consultation and hospitalization rates of children aged under 5 years in two districts in Northern Malawi: study protocol for a pragmatic, stepped-wedge cluster-randomized controlled trial.

PubMed

Hardy, Victoria; O'Connor, Yvonne; Heavin, Ciara; Mastellos, Nikolaos; Tran, Tammy; O'Donoghue, John; Fitzpatrick, Annette L; Ide, Nicole; Wu, Tsung-Shu Joseph; Chirambo, Griphin Baxter; Muula, Adamson S; Nyirenda, Moffat; Carlsson, Sven; Andersson, Bo; Thompson, Matthew

2017-10-11

There is evidence to suggest that frontline community health workers in Malawi are under-referring children to higher-level facilities. Integrating a digitized version of paper-based methods of Community Case Management (CCM) could strengthen delivery, increasing urgent referral rates and preventing unnecessary re-consultations and hospital admissions. This trial aims to evaluate the added value of the Supporting LIFE electronic Community Case Management Application (SL eCCM App) compared to paper-based CCM on urgent referral, re-consultation and hospitalization rates, in two districts in Northern Malawi. This is a pragmatic, stepped-wedge cluster-randomized trial assessing the added value of the SL eCCM App on urgent referral, re-consultation and hospitalization rates of children aged 2 months and older to up to 5 years, within 7 days of the index visit. One hundred and two health surveillance assistants (HSAs) were stratified into six clusters based on geographical location, and clusters randomized to the timing of crossover to the intervention using simple, computer-generated randomization. Training workshops were conducted prior to the control (paper-CCM) and intervention (paper-CCM + SL eCCM App) in assigned clusters. Neither participants nor study personnel were blinded to allocation. Outcome measures were determined by abstraction of clinical data from patient records 2 weeks after recruitment. A nested qualitative study explored perceptions of adherence to urgent referral recommendations and a cost evaluation determined the financial and time-related costs to caregivers of subsequent health care utilization. The trial was conducted between July 2016 and February 2017. This is the first large-scale trial evaluating the value of adding a mobile application of CCM to the assessment of children aged under 5 years. The trial will generate evidence on the potential use of mobile health for CCM in Malawi, and more widely in other low- and middle-income countries. ClinicalTrials.gov, ID: NCT02763345 . Registered on 3 May 2016.

Laparoendoscopic single-site adrenalectomy versus conventional laparoscopic surgery: a systematic review and meta-analysis of observational studies.

PubMed

Wang, Linhui; Wu, Zhenjie; Li, Mingmin; Cai, Chen; Liu, Bing; Yang, Qing; Sun, Yinghao

2013-06-01

To assess the surgical efficacy and potential advantages of laparoendoscopic single-site adrenalectomy (LESS-AD) compared with conventional laparoscopic adrenalectomy (CL-AD) based on published literature. An online systematic search in electronic databasesM including Pubmed, Embase, and the Cochrane Library, as well as manual bibliography searches were performed. All studies that compared LESS-AD with CL-AD were included. The outcome measures were the patient demographics, tumor size, blood loss, operative time, time to resumption of oral intake, hospital stay, postoperative pain, cosmesis satisfaction score, rates of complication, conversion, and transfusion. A meta-analysis of the results was conducted. A total of 443 patients were included: 171 patients in the LESS-AD group and 272 patients in the CL-AD group (nine studies). There was no significant difference between the two groups in any of the demographic parameters expect for lesion size (age: P=0.24; sex: P=0.35; body mass index: P=0.79; laterality: P=0.76; size: P=0.002). There was no significant difference in estimated blood loss, time to oral intake resumption, and length of stay between the two groups. The LESS-AD patients had a significantly lower postoperative visual analog pain score compared with the CL-AD group, but a longer operative time was noted. Both groups had a comparable cosmetic satisfaction score. The two groups had a comparable rate of complication, conversion, and transfusion. In early experience, LESS-AD appears to be a safe and feasible alternative to its conventional laparoscopic counterpart with decreased postoperative pain noted, albeit with a longer operative time. As a promising and emerging minimally invasive technique, however, the current evidence has not verified other potential advantages (ie, cosmesis, recovery time, convalescence, port-related complications, etc.) of LESS-AD.

Effect of Embedded Piezoelectric Sensors on Fracture Toughness and Fatigue Resistance of Composite Laminates Under Mode I Loading

NASA Technical Reports Server (NTRS)

Murri, Gretchen B.

2006-01-01

Double-cantilevered beam (DCB) specimens of a glass/epoxy composite material with embedded piezoelectric sensors were tested both statically and under fatigue loading to determine the effect of the embedded material on the Mode I fracture toughness and fatigue resistance compared to baseline data without the embedded elements. A material known as LaRC-Macrofiber Composite (LaRC-MFC (TradeMark)), or MFC, was embedded at the midplane of the specimen during the layup. Specimens were manufactured with the embedded MFC material either at the loaded end of the specimen to simulate an initial delamination; or with the MFC material located at the delaminating interface, with a Teflon film at the loaded end to simulate an initial delamination. There were three types of specimens with the embedded material at the delaminating interface: co-cured with no added adhesive; cured with a paste adhesive applied to the embedded element; or cured with a film adhesive added to the embedded material. Tests were conducted with the sensors in both the passive and active states. Results were compared to baseline data for the same material without embedded elements. Interlaminar fracture toughness values (G(sub Ic)) for the passive condition showed little change when the MFC was at the insert end. Passive results varied when the MFC was at the delaminating interface. For the co-cured case and with the paste adhesive, G(sub Ic) decreased compared to the baseline toughness, whereas, for the film adhesive case, G(sub Ic) was significantly greater than the baseline toughness, but the failure was always catastrophic. When the MFC was in the active state, G(sub Ic) was generally lower compared to the passive results. Fatigue tests showed little effect of the embedded material whether it was active or passive compared to baseline values.

Delay-dependent stability and added damping of SDOF real-time dynamic hybrid testing

NASA Astrophysics Data System (ADS)

Chi, Fudong; Wang, Jinting; Jin, Feng

2010-09-01

It is well-recognized that a transfer system response delay that reduces the test stability inevitably exists in real-time dynamic hybrid testing (RTDHT). This paper focuses on the delay-dependent stability and added damping of SDOF systems in RTDHT. The exponential delay term is transferred into a rational fraction by the Padé approximation, and the delay-dependent stability conditions and instability mechanism of SDOF RTDHT systems are investigated by the root locus technique. First, the stability conditions are discussed separately for the cases of stiffness, mass, and damping experimental substructure. The use of root locus plots shows that the added damping effect and instability mechanism for mass are different from those for stiffness. For the stiffness experimental substructure case, the instability results from the inherent mode because of an obvious negative damping effect of the delay. For the mass case, the delay introduces an equivalent positive damping into the inherent mode, and instability occurs at an added high frequency mode. Then, the compound stability condition is investigated for a general case and the results show that the mass ratio may have both upper and lower limits to remain stable. Finally, a high-emulational virtual shaking table model is built to validate the stability conclusions.

Meta-analytic Review of Memory Impairment in Behavioral Variant Frontotemporal Dementia.

PubMed

Poos, Jackie M; Jiskoot, Lize C; Papma, Janne M; van Swieten, John C; van den Berg, Esther

2018-03-19

A meta-analysis of the extent, nature and pattern of memory performance in behavioral variant frontotemporal dementia (bvFTD). Multiple observational studies have challenged the relative sparing of memory in bvFTD as stated in the current diagnostic criteria. We performed a meta-analytic review covering the period 1967 to February 2017 of case-control studies on episodic memory in bvFTD versus control participants (16 studies, 383 patients, 603 control participants), and patients with bvFTD versus those with Alzheimer's disease (AD) (20 studies, 452 bvFTD, 874 AD). Differences between both verbal and non-verbal working memory, episodic memory learning and recall, and recognition memory were examined. Data were extracted from the papers and combined into a common metric measure of effect, Hedges' d. Patients with bvFTD show large deficits in memory performance compared to controls (Hedges' d -1.10; 95% confidence interval [CI] [-1.23, -0.95]), but perform significantly better than patients with AD (Hedges' d 0.85; 95% CI [0.69, 1.03]). Learning and recall tests differentiate best between patients with bvFTD and AD (p<.01). There is 37-62% overlap in test scores between the two groups. This study points to memory disorders in patients with bvFTD, with performance at an intermediate level between controls and patients with AD. This indicates that, instead of being an exclusion criterion for bvFTD diagnosis, memory deficits should be regarded as a potential integral part of the clinical spectrum. (JINS, 2018, 24, 1-13).

The Climate and Human Impacts of Major Explosive Volcanism AD670-730, A Multi-proxy Assessment

NASA Astrophysics Data System (ADS)

Gao, C.; Ludlow, F.

2013-12-01

Chronologically secure volcanic events can provide an important tool to improve ice core dating as well as our understanding of volcano-climate responses. However, there is a substantial lack of reference horizons for ice-core dating during the first millennium, excepting the Taupo (New Zealand, AD186×10) and Vesuvius (Italy, AD 79) eruptions. In this exploratory case-study, we use a total of 20 ice core records, 9 from the Arctic and 11 from the Antarctic, together with historical records to examine the occurrence and climatic impact of explosive volcanism, AD 670-730. Sulfate signals comparable in magnitude to the sizeable 1815 Tambora eruption are detected in all of the ice-core time series, with different cores attributing the timing of eruptions to AD 676×2, 688×2, or 700×2, respectively. Historical records of widespread frost damage, anomalously warm winters, drought, famine and mortality from Chinese, European and Middle Eastern chronicles suggest substantial climate and social perturbations during AD 677-685 and AD 699-709. The distinctive double-peak feature seen in the majority of the volcanic signals from both poles at AD 676×2 and AD 688×2 suggests that these signals may belong to the same eruption, with those cores dating the signals to c.AD 676 generally considered to have a more precise chronology. Combining the evidence from natural and historical anthropogenic records and taking into account uncertainties (e.g. resolution, dating accuracy) associated with individual ice cores, we propose that a (most-likely) low-latitude eruption took place around AD676, followed by another possible eruption around AD700, identifiable by the significant acidity in polar ice-caps and historical documents. Unique historical observations of 'blood rain' in Ireland (often associated with Saharan sand deposition, but also plausibly with iron and manganese-rich tephra falls) also suggest a high-latitude eruption (possibly Icelandic) at AD693, corresponding to a GISP2 volcanic signal at 690.7×2.5. Results from this study attempt to characterize and reduce uncertainties in ice-core volcanic reconstructions, and make a contribution towards establishing a new reference horizon for this relatively under-studied period.

The Schooling Experience of Adolescent Boys with AD/HD: An Australian Case Study

ERIC Educational Resources Information Center

Gibbs, Kathryn; Mercer, K. Louise; Carrington, Suzanne

2016-01-01

This study explored the experience of schooling of six adolescent boys diagnosed with AD/HD from the perspectives of the boys, their mothers and their teachers. The study utilised social constructionism as the theoretical orientation and the Dynamic Developmental Theory (DDT) of AD/HD as the explanatory framework. Utilising a multiple,…

The combination of vestibular impairment and congenital sensorineural hearing loss predisposes patients to ocular anomalies, including Usher syndrome.

PubMed

Kletke, S; Batmanabane, V; Dai, T; Vincent, A; Li, S; Gordon, K A; Papsin, B C; Cushing, S L; Héon, E

2017-07-01

The co-occurrence of hearing impairment and visual dysfunction is devastating. Most deaf-blind etiologies are genetically determined, the commonest being Usher syndrome (USH). While studies of the congenitally deaf population reveal a variable degree of visual problems, there are no effective ophthalmic screening guidelines. We hypothesized that children with congenital sensorineural hearing loss (SNHL) and vestibular impairment were at an increased risk of having USH. A retrospective chart review of 33 cochlear implants recipients for severe to profound SNHL and measured vestibular dysfunction was performed to determine the ocular phenotype. All the cases had undergone ocular examination and electroretinogram (ERG). Patients with an abnormal ERG underwent genetic testing for USH. We found an underlying ocular abnormality in 81.81% (27/33) of cases; of which 75% had refractive errors, and 50% of those patients showed visual improvement with refractive correction. A total of 14 cases (42.42%; 14/33) had generalized rod-cone dysfunction on ERG suggestive of Usher syndrome type 1, confirmed by mutational analysis. This work shows that adding vestibular impairment as a criterion for requesting an eye exam and adding the ERG to detect USH increases the chances of detecting ocular anomalies, when compared with previous literature focusing only on congenital SNHL. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Infectious diseases and natural disasters: the effects of Hurricane Mitch over Villanueva municipal area, Nicaragua.

PubMed

Campanella, N

1999-01-01

A three month relief operation for the 25,303 people living in the municipal area of Villanueva, Nicaragua, hit by Hurricane Mitch, was carried out jointly by the staff of an international non-government organization and an Italian Regional Hospital's staff. Health Mobile Teams joined the local health facilities (Health Centers and Health Posts) in responding to the people's urgent health problems. From their files the thirty-day post-disaster incidence of acute diarrheas (AD), respiratory tract infectious diseases (ARD), and malaria were estimated and compared with off-crisis data. New cases of leptospirosis were searched, but no control group was available. The incidence of AD and ARD increased significantly in comparison with pre-disaster data (6,798 vs. 2,849 per 100,000 inhabitants (p < 0.01) and 1,205 vs. 295 per 100,000 inhabitants (p < 0.01)). The increase in incidence of malaria was not explicit. Only three cases of leptospirosis were ascertained. The relief operators used the gathered data to make decisions to allocate the poorly available resources. The feasibility of the infectious disease surveillance and the reliability of the results under such conditions may change according to the setting. In this case study the infectious disease surveillance was feasible, and the gathered data were reliable and of some help to the relief operators in order to allocate the resources efficiently.

Classical probes of string/gauge theory duality

NASA Astrophysics Data System (ADS)

Ishizeki, Riei

The AdS/CFT correspondence has played an important role in the recent development of string theory. The reason is that it proposes a description of certain gauge theories in terms of string theory. It is such that simple string theory computations give information about the strong coupling regime of the gauge theory. Vice versa, gauge theory computations give information about string theory and quantum gravity. Although much is known about AdS/CFT, the precise map between the two sides of the correspondence is not completely understood. In the unraveling of such map classical string solutions play a vital role. In this thesis, several classical string solutions are proposed to help understand the AdS/CFT duality. First, rigidly rotating strings on a two-sphere are studied. Taking special limits of such solutions leads to two cases: the already known giant magnon solution, and a new solution which we call the single spike solution. Next, we compute the scattering phase shift of the single spike solutions and compare the result with the giant magnon solutions. Intriguingly, the results are the same up to non-logarithmic terms, indicating that the single spike solution should have the same rich spin chain structure as the giant magnon solution. Afterward, we consider open string solutions ending on the boundary of AdS5. The lines traced by the ends of such open strings can be viewed as Wilson loops in N = 4 SYM theory. After applying an inversion transformation, the open Wilson loops become closed Wilson loops whose expectation value is consistent with previously conjectured results. Next, several Wilson loops for N = 4 SYM in an AdS5 pp-wave background are considered and translated to the pure AdS 5 background and their interpretation as forward quark-gluon scattering is suggested. In the last part of this thesis, a class of classical solutions for closed strings moving in AdS3 x S 1 ⊂ AdS5 x S5 with energy E and spin S in AdS3 and angular momentum J and winding m in S1 is explained. The relation between different limits of the spiky string solution with the Landau-Lifshitz model is of particular interest. The presented solutions provide new classes of string motion that are used to better understand the AdS/CFT correspondence, including the single spike solution and previously unknown examples of supersymmetric Wilson loops.

Multislice spiral CT angiography for evaluation of acute aortic syndrome.

PubMed

Zhao, De-Li; Liu, Xin-Ding; Zhao, Cheng-Lei; Zhou, Hai-Ting; Wang, Guo-Kun; Liang, Hong-Wei; Zhang, Jin-Ling

2017-10-01

To discuss the diagnostic value of multislice CT angiography (MSCTA) in acute aortic syndrome (AAS). The clinical and imaging data of 36 cases diagnosed as AAS by MSCTA were collected. The manifestations of the MSCTA images were reviewed retrospectively, and the average x-ray dose was calculated. Among 36 AAS cases, 16 cases had aortic dissection (AD), 8 cases had penetrating atherosclerotic ulcer (PAU), 7 cases had intramural hematoma (IMH), and 5 cases had unstable thoracic aneurysm (UTA). Of 16 cases with AD, type A and type B accounted for 43.7% (7/16) and 56.3% (9/16), respectively. Of 7 cases with IMH, type A and type B accounted for 42.9% (3/7) and 57.1% (4/7), respectively. In spite of the x-ray radiation, MSCTA proves to be a rapid and noninvasive imaging technique for the diagnosis of AAS. © 2017, Wiley Periodicals, Inc.

One-Loop Test of Quantum Black Holes in anti–de Sitter Space

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, James T.; Pando Zayas, Leopoldo A.; Rathee, Vimal

Within 11-dimensional supergravity we compute the logarithmic correction to the entropy of magnetically charged asymptotically AdS4 black holes with arbitrary horizon topology. We find perfect agreement with the expected microscopic result arising from the dual field theory computation of the topologically twisted index. Our result relies crucially on a particular limit to the extremal black hole case and clarifies some aspects of quantum corrections in asymptotically AdS spacetimes.

One-Loop Test of Quantum Black Holes in anti–de Sitter Space

DOE PAGES

Liu, James T.; Pando Zayas, Leopoldo A.; Rathee, Vimal; ...

2018-06-01

Within 11-dimensional supergravity we compute the logarithmic correction to the entropy of magnetically charged asymptotically AdS4 black holes with arbitrary horizon topology. We find perfect agreement with the expected microscopic result arising from the dual field theory computation of the topologically twisted index. Our result relies crucially on a particular limit to the extremal black hole case and clarifies some aspects of quantum corrections in asymptotically AdS spacetimes.

One-Loop Test of Quantum Black Holes in anti-de Sitter Space

NASA Astrophysics Data System (ADS)

Liu, James T.; Pando Zayas, Leopoldo A.; Rathee, Vimal; Zhao, Wenli

2018-06-01

Within 11-dimensional supergravity we compute the logarithmic correction to the entropy of magnetically charged asymptotically AdS4 black holes with arbitrary horizon topology. We find perfect agreement with the expected microscopic result arising from the dual field theory computation of the topologically twisted index. Our result relies crucially on a particular limit to the extremal black hole case and clarifies some aspects of quantum corrections in asymptotically AdS spacetimes.

One-Loop Test of Quantum Black Holes in anti-de Sitter Space.

PubMed

Liu, James T; Pando Zayas, Leopoldo A; Rathee, Vimal; Zhao, Wenli

2018-06-01

Within 11-dimensional supergravity we compute the logarithmic correction to the entropy of magnetically charged asymptotically AdS_{4} black holes with arbitrary horizon topology. We find perfect agreement with the expected microscopic result arising from the dual field theory computation of the topologically twisted index. Our result relies crucially on a particular limit to the extremal black hole case and clarifies some aspects of quantum corrections in asymptotically AdS spacetimes.

The generalization of charged AdS black hole specific volume and number density

NASA Astrophysics Data System (ADS)

Wang, Zi-Liang; He, Miao; Fang, Chao; Sun, Dao-Quan; Deng, Jian-Bo

2017-04-01

In this paper, by proposing a generalized specific volume, we restudy the P- V criticality of charged AdS black holes in the extended phase space. The results show that most of the previous conclusions can be generalized without change, but the ratio {\\tilde{ρ }}_c should be 3 {\\tilde{α }}/16 in general case. Further research on the thermodynamical phase transition of black hole leads us to a natural interpretation of our assumption, and more black hole properties can be generalized. Finally, we study the number density for charged AdS black hole in higher dimensions, the results show the necessity of our assumption.

Association of tagSNPs in the urokinase-plasminogen activator (PLAU) gene with Alzheimer's disease and associated quantitative traits.

PubMed

Ozturk, Ayla; Minster, Ryan L; DeKosky, Steven T; Kamboh, M Ilyas

2007-01-05

The gene coding for urokinase-plasminogen activator (PLAU) is a strong biological and positional candidate gene for Alzheimer's disease (AD). Previously some studies have examined the role of common variation in the PLAU gene with AD risk but the results have been inconsistent and this inconsistency could have been due to the use of relatively small sample sizes. In this study we evaluated the distribution of four tagSNPs (rs2227562 in intron 5, rs2227564 in exon 6, rs2227571 in intron 9, and rs4065 in 3'UTR) in the PLAU gene in a large case-control study consisting of up to 1,000 AD patients and 697 white control subjects. We examined the role of these tagSNPs with AD risk and quantitative traits of AD, including age-at-onset (AAO), disease duration, and mini-mental state examination (MMSE) scores. The 3'UTR SNP revealed modest significant association with risk (OR = 0.71, 95% CI: 0.53-0.95; P = 0.02), AAO (P = 0.036) and disease duration (P = 0.04) of AD. In addition, the intron 9 SNP also revealed a significant association with AAO (P = 0.01) and disease duration (P = 0.006). Our data on a large number of AD cases and controls suggest that genetic variation in PLAU may affect the risk and AAO of AD.

Vowels in infant-directed speech: More breathy and more variable, but not clearer.

PubMed

Miyazawa, Kouki; Shinya, Takahito; Martin, Andrew; Kikuchi, Hideaki; Mazuka, Reiko

2017-09-01

Infant-directed speech (IDS) is known to differ from adult-directed speech (ADS) in a number of ways, and it has often been argued that some of these IDS properties facilitate infants' acquisition of language. An influential study in support of this view is Kuhl et al. (1997), which found that vowels in IDS are produced with expanded first and second formants (F1/F2) on average, indicating that the vowels are acoustically further apart in IDS than in ADS. These results have been interpreted to mean that the way vowels are produced in IDS makes infants' task of learning vowel categories easier. The present paper revisits this interpretation by means of a thorough analysis of IDS vowels using a large-scale corpus of Japanese natural utterances. We will show that the expansion of F1/F2 values does occur in spontaneous IDS even when the vowels' prosodic position, lexical pitch accent, and lexical bias are accounted for. When IDS vowels are compared to carefully read speech (CS) by the same mothers, however, larger variability among IDS vowel tokens means that the acoustic distances among vowels are farther apart only in CS, but not in IDS when compared to ADS. Finally, we will show that IDS vowels are significantly more breathy than ADS or CS vowels. Taken together, our results demonstrate that even though expansion of formant values occurs in spontaneous IDS, this expansion cannot be interpreted as an indication that the acoustic distances among vowels are farther apart, as is the case in CS. Instead, we found that IDS vowels are characterized by breathy voice, which has been associated with the communication of emotional affect. Copyright © 2017 Elsevier B.V. All rights reserved.

A comparative study of methanol as a supplementary carbon source for enhancing denitrification in primary and secondary anoxic zones.

PubMed

Ginige, Maneesha P; Bowyer, Jocelyn C; Foley, Leah; Keller, Jürg; Yuan, Zhiguo

2009-04-01

A comparative study on the use of methanol as a supplementary carbon source to enhance denitrification in primary and secondary anoxic zones is reported. Three lab-scale sequencing batch reactors (SBR) were operated to achieve nitrogen and carbon removal from domestic wastewater. Methanol was added to the primary anoxic period of the first SBR, and to the secondary anoxic period of the second SBR. No methanol was added to the third SBR, which served as a control. The extent of improvement on the denitrification performance was found to be dependent on the reactor configuration. Addition to the secondary anoxic period is more effective when very low effluent nitrate levels are to be achieved and hence requires a relatively large amount of methanol. Adding a small amount of methanol to the secondary anoxic period may cause nitrite accumulation, which does not improve overall nitrogen removal. In the latter case, methanol should be added to the primary anoxic period. The addition of methanol can also improve biological phosphorus removal by creating anaerobic conditions and increasing the availability of organic carbon in wastewater for polyphosphate accumulating organisms. This potentially provides a cost-effective approach to phosphorus removal from wastewater with a low carbon content. New fluorescence in situ hybridisation (FISH) probes targeting methanol-utilising denitrifiers were designed using stable isotope probing. Microbial structure analysis of the sludges using the new and existing FISH probes clearly showed that the addition of methanol stimulated the growth of specific methanol-utilizing denitrifiers, which improved the capability of sludge to use methanol and ethanol for denitrification, but reduced its capability to use wastewater COD for denitrification. Unlike acetate, long-term application of methanol has no negative impact on the settling properties of the sludge.

Post-anaerobic digestion thermal hydrolysis of sewage sludge and food waste: Effect on methane yields, dewaterability and solids reduction.

PubMed

Svensson, Kine; Kjørlaug, Oda; Higgins, Matthew J; Linjordet, Roar; Horn, Svein J

2018-04-01

Post-anaerobic digestion (PAD) treatment technologies have been suggested for anaerobic digestion (AD) to improve process efficiency and assure hygenization of organic waste. Because AD reduces the amount of organic waste, PAD can be applied to a much smaller volume of waste compared to pre-digestion treatment, thereby improving efficiency. In this study, dewatered digestate cakes from two different AD plants were thermally hydrolyzed and dewatered, and the liquid fraction was recirculated to a semi-continuous AD reactor. The thermal hydrolysis was more efficient in relation to methane yields and extent of dewaterability for the cake from a plant treating waste activated sludge, than the cake from a plant treating source separated food waste (SSFW). Temperatures above 165 °C yielded the best results. Post-treatment improved volumetric methane yields by 7% and the COD-reduction increased from 68% to 74% in a mesophilic (37 °C) semi-continuous system despite lowering the solid retention time (from 17 to 14 days) compared to a conventional system with pre-treatment of feed substrates at 70 °C. Results from thermogravimetric analysis showed an expected increase in maximum TS content of dewatered digestate cake from 34% up to 46% for the SSFW digestate cake, and from 17% up to 43% in the sludge digestate cake, after the PAD thermal hydrolysis process (PAD-THP). The increased dewatering alone accounts for a reduction in wet mass of cake leaving the plant of 60% in the case of sludge digestate cake. Additionaly, the increased VS-reduction will contribute to further reduce the mass of wet cake. Copyright © 2018 Elsevier Ltd. All rights reserved.

Polymorphisms of CHAT but not TFAM or VR22 are Associated with Alzheimer Disease Risk.

PubMed

Gao, Lili; Zhang, Yan; Deng, Jinghua; Yu, Wenbing; Yu, Yunxia

2016-06-07

BACKGROUND Alzheimer disease (AD) is a chronic neurodegenerative disease that is one of the most prevalent health problems among seniors. The cause of AD has not yet been elucidated, but many risk factors have been identified that might contribute to the pathogenesis and prognosis of AD. We conducted a meta-analysis of studies involving CHAT, TFAM, and VR22 polymorphisms and AD susceptibility to further understand the pathogenesis of AD. MATERIAL AND METHODS PubMed/Medline, Embase, Web of Science, the Cochrane Library, and Google Scholar were searched for relevant articles. Rs1880676, rs2177369, rs3810950, and rs868750 of CHAT; rs1937 and rs2306604 of TFAM; and rs10997691 and rs7070570 of VR22 are studied in this meta-analysis. RESULTS A total of 51 case-control studies with 16 446 cases and 16 057 controls were enrolled. For CHAT, rs2177369 (G>A) in whites and rs3810950 (G>A) in Asians were found to be associated with AD susceptibility. No association was detected between rs1880676 and rs868750 and AD risk. For TFAM and VR22, no significant association was detected in studied single-nucleotide polymorphisms (SNPs). CONCLUSIONS Rs2177369 and rs3810950 of CHAT are associated with AD susceptibility, but rs1880676 and rs868750 are not. Rs1937 and rs2306604 of TFAM, and rs10997691 and rs7070570 of VR22 are not significantly associated with AD risk.

Does ear endoscopy provide advantages in the outpatient management of open mastoidectomy cavities?

PubMed

Freire, Gustavo Subtil Magalhães; Sampaio, Andre Luiz Lopes; Lopes, Rafaela Aquino Fernandes; Nakanishi, Márcio; de Oliveira, Carlos Augusto Costa Pires

2018-01-01

To evaluate the use of ear endoscopy in the postoperative management of open mastoidectomy cavities, and to test whether ear endoscopy improves inspection and cleaning compared with ear microscopy. Prospective study. Thirty-two ears were divided into two groups: group 1, examination and cleaning of mastoid cavities under endoscopic visualization after microscopic standard ear cleaning; group 2, examination and cleaning of mastoid cavities under microscopic visualization after endoscope-assisted ear cleaning. We assessed the ability of each method to provide exposure and facilitate cleaning, comparing the benefits of microscopy and endoscopy when used sequentially and vice-versa. Endoscopy provided additional benefits for exposure in 61.1% of cases and cleaning in 66.7%. Microscopy provided no additional benefits in terms of exposure in any case, and provided added benefit for cleaning in only 21.4% of cases. For outpatient postoperative care of open mastoidectomy cavities, ear endoscopy provides greater benefit over ear microscopy than vice-versa. In over half of all cases, endoscopy was able to expose areas not visualized under the microscope. Furthermore, in two-thirds of cases, endoscopy enabled removal of material that could not be cleared under microscopy. Ear endoscopy was superior to microscopy in terms of enabling exposure and cleaning of hard-to-reach sites, due to its wider field of vision. Ear endoscopy is a feasible technique for the postoperative management of open mastoidectomy cavities. Ear endoscopy provided superior advantages in terms of exposure and aural cleaning compared with microscopy.

Continuous thermal hydrolysis and anaerobic digestion of sludge. Energy integration study.

PubMed

Pérez-Elvira, S I; Fdz-Polanco, F

2012-01-01

Experimental data obtained from the operation in a pilot plant are used to perform mass and energy balances to a global process combining units of thermal hydrolysis (TH) of secondary sludge, anaerobic digestion (AD) of hydrolysed secondary sludge together with fresh primary sludge, and cogeneration from biogas by using a gas engine in which the biogas produces electricity and heat from the exhaust gases. Three scenarios were compared, corresponding to the three digesters operated: C (conventional AD, 17 days residence time), B (combined TH + AD, same time), and A (TH + AD at half residence time). The biogas production of digesters B and A was 33 and 24% better, respectively when compared with C. In the case of the combined TH + AD process (scenarios A and B), the key factors in the energy balance were the recovery of heat from hot streams, and the concentration of sludge. The results of the balances showed that for 8% DS concentration of the secondary sludge tested in the pilot plant, the process can be energetically self-sufficient, but a fraction of the biogas must by-pass the gas engine to be directly burned. From an economic point of view, scenario B is more profitable in terms of green energy and higher waste removal, while scenario A reduces the digester volume required by a half. Considering a population of 100,000 inhabitants, the economic benefit is 87,600 €/yr for scenario A and 132,373 €/yr for B. This value can be increased to 223,867 €/yr by increasing the sludge concentration of the feeding to the TH unit to a minimum value that allows use of all the biogas to produce green energy. This concentration is 13% DS, which is still possible from a practical point of view. Additional benefits gained with the combined TH + AD process are the enhancement of the digesters rheology and the possibility of getting Class A biosolids. The integration study presented here set the basis for the scale-up to a demonstration plant.

Imaging correlates of pathology in corticobasal syndrome(Podcast)

PubMed Central

Whitwell, J.L.; Jack, C.R.; Boeve, B.F.; Parisi, J.E.; Ahlskog, J.E.; Drubach, D.A.; Senjem, M.L.; Knopman, D.S.; Petersen, R.C.; Dickson, D.W.; Josephs, K.A.

2010-01-01

Background: Corticobasal syndrome (CBS) can be associated with different underlying pathologies that are difficult to predict based on clinical presentation. The aim of this study was to determine whether patterns of atrophy on imaging could be useful to help predict underlying pathology in CBS. Methods: This was a case-control study of 24 patients with CBS who had undergone MRI during life and came to autopsy. Pathologic diagnoses included frontotemporal lobar degeneration (FTLD) with TDP-43 immunoreactivity in 5 (CBS-TDP), Alzheimer disease (AD) in 6 (CBS-AD), corticobasal degeneration in 7 (CBS-CBD), and progressive supranuclear palsy in 6 (CBS-PSP). Voxel-based morphometry and atlas-based parcellation were used to assess atrophy across the CBS groups and compared to 24 age- and gender-matched controls. Results: All CBS pathologic groups showed gray matter loss in premotor cortices, supplemental motor area, and insula on imaging. However, CBS-TDP and CBS-AD showed more widespread patterns of loss, with frontotemporal loss observed in CBS-TDP and temporoparietal loss observed in CBS-AD. CBS-TDP showed significantly greater loss in prefrontal cortex than the other groups, whereas CBS-AD showed significantly greater loss in parietal lobe than the other groups. The focus of loss was similar in CBS-CBD and CBS-PSP, although more severe in CBS-CBD. Conclusions: Imaging patterns of atrophy in CBS vary according to pathologic diagnosis. Widespread atrophy points toward a pathologic diagnosis of FTLD-TDP or AD, with frontotemporal loss suggesting FTLD-TDP and temporoparietal loss suggesting AD. On the contrary, more focal atrophy predominantly involving the premotor and supplemental motor area suggests CBD or PSP pathology. GLOSSARY AAL = automated anatomic labeling; AD = Alzheimer disease; CBD = corticobasal degeneration; CBS = corticobasal syndrome; CDR-SB = Clinical Dementia Rating sum of boxes; FDR = false discovery rate; FTLD = frontotemporal lobar degeneration; MMSE = Mini-Mental State Examination; PSP = progressive supranuclear palsy; ROI = region of interest; SMA = supplemental motor area; TDP = TDP-43 immunoreactivity; TIV = total intracranial volume; VBM = voxel-based morphometry. PMID:21098403

Oxidative Stress Induces Mitochondrial Dysfunction in a Subset of Autism Lymphoblastoid Cell Lines in a Well-Matched Case Control Cohort

PubMed Central

Rose, Shannon; Frye, Richard E.; Slattery, John; Wynne, Rebecca; Tippett, Marie; Pavliv, Oleksandra; Melnyk, Stepan; James, S. Jill

2014-01-01

There is increasing recognition that mitochondrial dysfunction is associated with the autism spectrum disorders. However, little attention has been given to the etiology of mitochondrial dysfunction or how mitochondrial abnormalities might interact with other physiological disturbances associated with autism, such as oxidative stress. In the current study we used respirometry to examine reserve capacity, a measure of the mitochondrial ability to respond to physiological stress, in lymphoblastoid cell lines (LCLs) derived from children with autistic disorder (AD) as well as age and gender-matched control LCLs. We demonstrate, for the first time, that LCLs derived from children with AD have an abnormal mitochondrial reserve capacity before and after exposure to increasingly higher concentrations of 2,3-dimethoxy-1,4-napthoquinone (DMNQ), an agent that increases intracellular reactive oxygen species (ROS). Specifically, the AD LCLs exhibit a higher reserve capacity at baseline and a sharper depletion of reserve capacity when ROS exposure is increased, as compared to control LCLs. Detailed investigation indicated that reserve capacity abnormalities seen in AD LCLs were the result of higher ATP-linked respiration and maximal respiratory capacity at baseline combined with a marked increase in proton leak respiration as ROS was increased. We further demonstrate that these reserve capacity abnormalities are driven by a subgroup of eight (32%) of 25 AD LCLs. Additional investigation of this subgroup of AD LCLs with reserve capacity abnormalities revealed that it demonstrated a greater reliance on glycolysis and on uncoupling protein 2 to regulate oxidative stress at the inner mitochondria membrane. This study suggests that a significant subgroup of AD children may have alterations in mitochondrial function which could render them more vulnerable to a pro-oxidant microenvironment derived from intrinsic and extrinsic sources of ROS such as immune activation and pro-oxidant environmental toxicants. These findings are consistent with the notion that AD is caused by a combination of genetic and environmental factors. PMID:24416410

Mediterranean Diet, Alzheimer Disease, and Vascular Mediation

PubMed Central

Scarmeas, Nikolaos; Stern, Yaakov; Mayeux, Richard; Luchsinger, Jose A.

2011-01-01

Objectives To examine the association between the Mediterranean diet (MeDi) and Alzheimer disease (AD) in a different AD population and to investigate possible mediation by vascular pathways. Design, Setting, Patients, and Main Outcome Measures A case-control study nested within a community-based cohort in New York, NY. Adherence to the MeDi (0- to 9-point scale with higher scores indicating higher adherence) was the main predictor of AD status (194 patients with AD vs 1790 nondemented subjects) in logistic regression models that were adjusted for cohort, age, sex, ethnicity, education, apolipoprotein E genotype, caloric intake, smoking, medical comorbidity index, and body mass index (calculated as weight in kilograms divided by height in meters squared). We investigated whether there was attenuation of the association between MeDi and AD when vascular variables (stroke, diabetes mellitus, hypertension, heart disease, lipid levels) were simultaneously introduced in the models (which would constitute evidence of mediation). Results Higher adherence to the MeDi was associated with lower risk for AD (odds ratio, 0.76; 95% confidence interval, 0.67–0.87; P<.001). Compared with subjects in the lowest MeDi tertile, subjects in the middle MeDi tertile had an odds ratio of 0.47 (95% confidence interval, 0.29–0.76) and those at the highest tertile an odds ratio of 0.32 (95% confidence interval, 0.17–0.59) for AD (P for trend <.001). Introduction of the vascular variables in the model did not change the magnitude of the association. Conclusions We note once more that higher adherence to the MeDi is associated with a reduced risk for AD. The association does not seem to be mediated by vascular comorbidity. This could be the result of either other biological mechanisms (oxidative or inflammatory) being implicated or measurement error of the vascular variables. PMID:17030648

Content Analysis of Trends in Print Magazine Tobacco Advertisements.

PubMed

Banerjee, Smita; Shuk, Elyse; Greene, Kathryn; Ostroff, Jamie

2015-07-01

To provide a descriptive and comparative content analysis of tobacco print magazine ads, with a focus on rhetorical and persuasive themes. Print tobacco ads for cigarettes, cigars, e-cigarettes, moist snuff, and snus (N = 171) were content analyzed for the physical composition/ad format (e.g., size of ad, image, setting, branding, warning label) and the content of the ad (e.g., rhetorical themes, persuasive themes). The theme of pathos (that elicits an emotional response) was most frequently utilized for cigarette (61%), cigar (50%), and moist snuff (50%) ads, and the theme of logos (use of logic or facts to support position) was most frequently used for e-cigarette (85%) ads. Additionally, comparative claims were most frequently used for snus (e.g., "spit-free," "smoke-free") and e-cigarette ads (e.g., "no tobacco smoke, only vapor," "no odor, no ash"). Comparative claims were also used in cigarette ads, primarily to highlight availability in different flavors (e.g., "bold," "menthol"). This study has implications for tobacco product marketing regulation, particularly around limiting tobacco advertising in publications with a large youth readership and prohibiting false or misleading labels, labeling, and advertising for tobacco products, such as modified risk (unless approved by the FDA) or therapeutic claims.

Understanding casing flow in Pelton turbines by numerical simulation

NASA Astrophysics Data System (ADS)

Rentschler, M.; Neuhauser, M.; Marongiu, J. C.; Parkinson, E.

2016-11-01

For rehabilitation projects of Pelton turbines, the flow in the casing may have an important influence on the overall performance of the machine. Water sheets returning on the jets or on the runner significantly reduce efficiency, and run-away speed depends on the flow in the casing. CFD simulations can provide a detailed insight into this type of flow, but these simulations are computationally intensive. As in general the volume of water in a Pelton turbine is small compared to the complete volume of the turbine housing, a single phase simulation greatly reduces the complexity of the simulation. In the present work a numerical tool based on the SPH-ALE meshless method is used to simulate the casing flow in a Pelton turbine. Using improved order schemes reduces the numerical viscosity. This is necessary to resolve the flow in the jet and on the casing wall, where the velocity differs by two orders of magnitude. The results are compared to flow visualizations and measurement in a hydraulic laboratory. Several rehabilitation projects proved the added value of understanding the flow in the Pelton casing. The flow simulation helps designing casing insert, not only to see their influence on the flow, but also to calculate the stress in the inserts. In some projects, the casing simulation leads to the understanding of unexpected behavior of the flow. One such example is presented where the backsplash of a deflector hit the runner, creating a reversed rotation of the runner.

The role of food allergy in atopic dermatitis.

PubMed

Greenhawt, Matthew

2010-01-01

Atopic dermatitis (AD) affects ∼10% of children. Food allergy is a known provoking cause of AD in a subset of affected children. A literature search of PubMed and Medline was conducted to review the epidemiology and pathophysiology of AD, with special focus on the role of food allergy in the development of AD, its management, and its long-term preventive strategies. A literature search of PubMed and Medline was conducted. Food allergens readily provoke AD in ∼35% of patients, as proven through double-blind placebo-controlled food challenge studies. Milk, egg, wheat, soy, and peanut account for 75% of the cases of food-induced AD. However, the positive predictive values of the parental history, skin-prick tests, or serum tests for detecting food-specific IgE are low, making these unsuitable for use as single diagnostic modalities. Therefore, the use of a food challenge test is very helpful in objectively confirming the history or positive tests. Elimination diets are often helpful in challenge-proven cases, but care must be taken to evaluate the nutritional status of the child. There are few effective long-term strategies to prevent the development of food allergen-induced AD. Early onset of AD has been shown to be a risk factor for the development of other allergic diseases, including other food allergy/sensitization, as part of the atopic march. Treatment of other causes of AD, such as barrier dysfunction and cutaneous infection, are of equal importance to food allergen avoidance. Food allergy is an important provoking cause of AD, but it is only relevant in ∼35% of affected individuals.

Combining Select Neuropsychological Assessment With Blood-Based Biomarkers to detect Mild Alzheimer’s disease: A Molecular Neuropsychology approach

PubMed Central

Edwards, Melissa; Balldin, Valerie Hobson; Hall, James; O’Bryant, Sid

2015-01-01

Background The current project sought to create combined biomarker-cognitive profile to detect mild Alzheimer’s disease. Methods Data was analyzed from 266 participants (129 AD cases [Early AD n=93; Very Early AD n=36]; 137 controls) enrolled in the Texas Alzheimer’s Research and Care Consortium (TARCC). Non-fasting serum samples were collected from each participant and assayed via a multi-plex biomarker assay platform using electrochmiluminescence (ECL). Logistic Regression was utilized to detect early AD using two serum biomarkers (TNFα and IL7), demographic information (age) and one neuropsychological measure (Clock-4 point) as predictor variable. Disease severity was determined via Clinical Dementia Rating scale global scores. Results In the total sample (all levels of CDR scores), the combination of biomarkers, cognitive test score, and demographics yielded the obtained sensitivity (SN) of 0.94, specificity (SP) of 0.90 and an overall accuracy of 0.92. When examining early AD cases (i.e. CDR=0.5-1), the biomarker-cognitive profile yielded SN of 0.94, SP of 0.85 and an overall accuracy of 0.91. When restricted to very early AD cases (i.e CDR=0.5), the biomarker-cognitive profile yielded SN of 0.97, SP of 0.72 with an overall accuracy of 0.91. Conclusions The combination of demographics + 2 biomarkers + 1 cognitive test created a biomarker-cognitive profile that was highly accurate in detecting AD presence, even in the very early stages. This work demonstrates the complementary nature of each modality (blood biomarkers + neuropsychological assessment) and supports our previously proposed concept for Molecular Neuropsychology. PMID:24916542

Genetic variants of ABCA1 modify Alzheimer disease risk and quantitative traits related to beta-amyloid metabolism.

PubMed

Katzov, Hagit; Chalmers, Katy; Palmgren, Juni; Andreasen, Niels; Johansson, Boo; Cairns, Nigel J; Gatz, Margaret; Wilcock, Gordon K; Love, Seth; Pedersen, Nancy L; Brookes, Anthony J; Blennow, Kaj; Kehoe, Patrick G; Prince, Jonathan A

2004-04-01

Linkage studies have provided evidence that one or more loci on chromosome 9q influence Alzheimer disease (AD). The gene encoding the ATP-binding cassette A1 transporter (ABCA1) resides within proximity of previously identified linkage peaks and represents a plausible biological candidate for AD due to its central role in cellular lipid homeostasis. Several single nucleotide polymorphisms (SNPs) spanning ABCA1 have been genotyped and haplotype-based association analyses performed in four independent case-control samples, consisting of over 1,750 individuals from three European populations representing both early and late-onset AD. Prominent effects were observed for a common (H2) and rarer haplotype (H5) that were enriched in AD cases across studied populations (odds ratio [OR] 1.59, 95% confidence interval [CI] 1.36-1.82; P<0.00001 and OR 2.90; 95% CI 2.54-3.27; P<0.00001, respectively). Two other common haplotypes in the studied region (H1 and H3) were significantly under-represented in AD cases, suggesting that they may harbor alleles that decrease disease risk (OR 0.79, 95% CI 0.64-0.94; P=0.0065 and OR 0.70, 95% CI 0.46-0.93; P=0.011, respectively). While findings were significant in both early and late-onset samples, haplotype effects were more distinct in early-onset materials. For late-onset samples, ancillary evidence was obtained that both single marker alleles and haplotypes of ABCA1 contribute to variable cerebrospinal fluid tau and beta amyloid (Abeta42) protein levels, and brain Abeta load. Results indicate that variants of ABCA1 may affect the risk of AD, providing further support for a genetic link between AD and cholesterol metabolism. Copyright 2004 Wiley-Liss, Inc.

ABJ quadrality

NASA Astrophysics Data System (ADS)

Honda, Masazumi; Pang, Yi; Zhu, Yaodong

2017-11-01

We study physical consequences of adding orientifolds to the ABJ triality, which is among 3d N=6 superconformal Chern-Simons theory known as ABJ theory, type IIA string in AdS 4 × ℂℙ3 and N=6 supersymmetric (SUSY) Vasiliev higher spin theory in AdS 4. After adding the orientifolds, it is known that the gauge group of the ABJ theory becomes O( N 1) × USp(2 N 2) while the background of the string theory is replaced by AdS 4 × ℂℙ3/ Z 2, and the supersymmetries in the both theories reduce to N=5 . We propose that adding the orientifolds to the N=6 Vasiliev theory leads to N=5 SUSY Vasiliev theory. It turns out that the N=5 case is more involved because there are two formulations of the N=5 Vasiliev theory with either O or USp internal symmetry. We show that the two N=5 Vasiliev theories can be understood as certain projections of the N=6 Vasiliev theory, which we identify with the orientifold projections in the Vasiliev theory. We conjecture that the O( N 1) × USp(2 N 2) ABJ theory has the two vector model like limits: N 2 ≫ N 1 and N 1 ≫ N 2 which correspond to the semi-classical N=5 Vasiliev theories with O( N 1) and USp(2 N 2) internal symmetries respectively. These correspondences together with the standard AdS/CFT correspondence comprise the ABJ quadrality among the N=5 ABJ theory, string/M-theory and two N=5 Vasliev theories. We provide a precise holographic dictionary for the correspondences by comparing correlation functions of stress tensor and flavor currents. Our conjecture is supported by various evidence such as agreements of the spectra, one-loop free energies and SUSY enhancement on the both sides. We also predict the leading free energy of the N=5 Vasiliev theory from the CFT side. As a byproduct, we give a derivation of the relation between the parity violating phase in the N=6 Vasiliev theory and the parameters in the N=6 ABJ theory, which was conjectured in [1].

CYP46 T/C polymorphism is not associated with Alzheimer's dementia in a population from Hungary.

PubMed

Juhász, Anna; Rimanóczy, Agnes; Boda, Krisztina; Vincze, Gábor; Szlávik, Gyozo; Zana, Marianna; Bjelik, Annamária; Pákáski, Magdolna; Bódi, Nikoletta; Palotás, András; Janka, Zoltán; Kálmán, János

2005-08-01

Multiple genetic and environmental factors regulate the susceptibility to Alzheimer's disease (AD). Recently, several independent studies have reported that a locus on chromosome 14q32.1, where a gene encoding a cholesterol degrading enzyme of the brain, called 24-hydroxylase (CYP46A1) is located, has been linked with AD. The single nucleotide polymorphism (T/C) in intron 2 of CYP46 gene has been found to confer the risk for AD. The water soluble 24(S)-hydroxysterol is the product of the CYP46A1, and elevated plasma and cerebrospinal fluid hydroxysterol concentrations have been found in AD, reflecting increased brain cholesterol turnover or cellular degradation, due to the neurodegenerative process. A case-control study was performed on 125 AD and 102 age- and gender-matched control subjects (CNT) from Hungary, to test the association of CYP46 T/C and apolipoprotein E (ApoE) gene polymorphisms in AD. The frequency of the CYP46 C allele was similar (chi2=0.647, df=1, P=0.421, exact P=0.466, OR=0.845; 95% CI: 0.561-1.274) in both groups (CNT: 27%; 95% CI: 21.3-33.4; AD 30%; 95% CI: 25.0-36.3). The ApoE varepsilon4 allele was significantly over-represented (chi2=11.029, df=2, P=0.004) in the AD population (23.2%; 95% CI: 18.2-29.0) when compared with the CNT (11.3%; 95% CI: 7.4-16.6). The presence or absence of one or two CYP46C alleles together with the ApoE varepsilon4 allele did not increase the risk of AD (OR=3.492; 95% CI: 1.401-8.707; P<0.007 and OR=3.714; 95% CI: 1.549-8.908; P<0.003, respectively). Our results indicate that the intron 2 T/C polymorphism of CYP46 gene (neither alone, nor together with the varepsilon4 allele) does not increase the susceptibility to late-onset sporadic AD in the Hungarian population.

Expression of Nrf2 in neurodegenerative diseases.

PubMed

Ramsey, Chenere P; Glass, Charles A; Montgomery, Marshall B; Lindl, Kathryn A; Ritson, Gillian P; Chia, Luis A; Hamilton, Ronald L; Chu, Charleen T; Jordan-Sciutto, Kelly L

2007-01-01

In response to oxidative stress, the nuclear factor E2-related factor 2 (Nrf2) transcription factor translocates from the cytoplasm into the nucleus and transactivates expression of genes with antioxidant activity. Despite this cellular mechanism, oxidative damage is abundant in Alzheimer and Parkinson disease (AD and PD). To investigate mechanisms by which Nrf2 activity may be aberrant or insufficient in neurodegenerative conditions, we assessed Nrf2 localization in affected brain regions of AD, Lewy body variant of AD (LBVAD), and PD. By immunohistochemistry, Nrf2 is expressed in both the nucleus and the cytoplasm of neurons in normal hippocampi with predominant expression in the nucleus. In AD and LBVAD, Nrf2 was predominantly cytoplasmic in hippocampal neurons and was not a major component of beta amyloid plaques or neurofibrillary tangles. By immunoblotting, we observed a significant decrease in nuclear Nrf2 levels in AD cases. In contrast, Nrf2 was strongly nuclear in PD nigral neurons but cytoplasmic in substantia nigra of normal, AD, and LBVAD cases. These findings suggest that Nrf2-mediated transcription is not induced in neurons in AD despite the presence of oxidative stress. In PD, nuclear localization of Nrf2 is strongly induced, but this response may be insufficient to protect neurons from degeneration.

Expression of Nrf2 in Neurodegenerative Diseases

PubMed Central

Ramsey, Chenere P.; Glass, Charles A.; Montgomery, Marshall B.; Lindl, Kathryn A.; Ritson, Gillian P.; Chia, Luis A.; Hamilton, Ronald L.; Chu, Charleen T.; Jordan-Sciutto, Kelly L.

2008-01-01

In response to oxidative stress, the nuclear factor E2-related factor 2 (Nrf2) transcription factor translocates from the cytoplasm into the nucleus and transactivates expression of genes with antioxidant activity. Despite this cellular mechanism, oxidative damage is abundant in Alzheimer and Parkinson disease (AD and PD). To investigate mechanisms by which Nrf2 activity may be aberrant or insufficient in neurodegenerative conditions, we assessed Nrf2 localization in affected brain regions of AD, Lewy body variant of AD (LBVAD), and PD. By immunohistochemistry, Nrf2 is expressed in both the nucleus and the cytoplasm of neurons in normal hippocampi with predominant expression in the nucleus. In AD and LBVAD, Nrf2 was predominantly cytoplasmic in hippocampal neurons and was not a major component of beta amyloid plaques or neurofibrillary tangles. By immunoblotting, we observed a significant decrease in nuclear Nrf2 levels in AD cases. In contrast, Nrf2 was strongly nuclear in PD nigral neurons but cytoplasmic in substantia nigra of normal, AD, and LBVAD cases. These findings suggest that Nrf2-mediated transcription is not induced in neurons in AD despite the presence of oxidative stress. In PD, nuclear localization of Nrf2 is strongly induced, but this response may be insufficient to protect neurons from degeneration. PMID:17204939