Functional impairment in patients with major depressive disorder: the 2-year PERFORM study.

PubMed

Hammer-Helmich, Lene; Haro, Josep Maria; Jönsson, Bengt; Tanguy Melac, Audrey; Di Nicola, Sylvie; Chollet, Julien; Milea, Dominique; Rive, Benoît; Saragoussi, Delphine

2018-01-01

The Prospective Epidemiological Research on Functioning Outcomes Related to Major depressive disorder (PERFORM) study describes the course of depressive symptoms, perceived cognitive symptoms, and functional impairment over 2 years in outpatients with major depressive disorder (MDD) and investigates the patient-related factors associated with functional impairment. This was a 2-year observational study in 1,159 outpatients with MDD aged 18-65 years who were either initiating antidepressant monotherapy or undergoing their first switch of antidepressant. Functional impairment was assessed by the Sheehan Disability Scale and the Work Productivity and Activity Impairment questionnaire. Patients assessed depression severity using the nine-item Patient Health Questionnaire and severity of perceived cognitive symptoms using the five-item Perceived Deficit Questionnaire. To investigate which patient-related factors were associated with functional impairment, univariate analyses of variance were performed to identify relevant factors that were then included in multivariate analyses of covariance at baseline, month 2, months 6 and 12 combined, and months 18 and 24 combined. The greatest improvement in depressive symptoms, perceived cognitive symptoms, and functional impairment was seen immediately (within 2 months) following initiation or switch of antidepressant therapy, followed by more gradual improvement and long-term stabilization. Improvement in perceived cognitive symptoms was less marked than improvement in depressive symptoms during the acute treatment phase. Functional impairment in patients with MDD was not only associated with severity of depressive symptoms but also independently associated with severity of perceived cognitive symptoms when adjusted for depression severity throughout the 2 years of follow-up. These findings highlight the burden of functional impairment in MDD and the importance of recognizing and managing cognitive symptoms in daily practice.

Hyperhomocysteinemia impairs regional blood flow: involvements of endothelial and neuronal nitric oxide.

PubMed

Toda, Noboru; Okamura, Tomio

2016-09-01

Increasing evidence support the idea that hyperhomocysteinemia (HHcy) is responsible for pathogenesis underlying cerebral, coronary, renal, and other vascular circulatory disorders and for hypertension. Impaired synthesis of nitric oxide (NO) in the endothelium or increased production of asymmetric dimethylarginine and activated oxygen species are involved in the impairment of vasodilator effects of NO. Impaired circulation in the brain derived from reduced synthesis and actions of NO would be an important triggering factor to dementia and Alzheimer's disease. Reduced actions of NO and brain hypoperfusion trigger increased production of amyloid-β that inhibits endothelial function, thus establishing a vicious cycle for impairing brain circulation. HHcy is involved in the genesis of anginal attack and coronary myocardial infarction. HHcy is also involved in renal circulatory diseases. The homocysteine (Hcy)-induced circulatory failure is promoted by methionine and is prevented by increased folic acid and vitamin B6/B12. Eliminating poor life styles, such as smoking and being sedentary; keeping favorable dietary habits; and early treatment maintaining constitutive NOS functions healthy, reducing oxidative stresses would be beneficial in protecting HHcy-induced circulatory failures.

Respiratory symptoms and pulmonary function impairment among detergent plant workers in Jos, Northern Nigeria.

PubMed

Babashani, M; Iliyasu, Z; Ukoli, C O

2008-01-01

The industrial process of detergent production could be deleterious to lung function. This study describes respiratory symptoms and ventilatory function impairment among detergent workers in Jos, Northern Nigeria. Two hundred detergent plant workers and controls were studied for the presence of respiratory symptoms and ventilatory function impairment using the MRC questionnaire and Spirometry. A significantly higher proportion of exposed detergent workers 178 (87.0%) reported respiratory symptoms compared to 52 (26.0%) controls [OR=23; 95% CI=12.9-41.3] (P<0.001). Commonest symptoms include rhinitis (57.5% versus 11.0%) and cough (48.5% versus 15%). Symptoms were most prevalent in the packaging section. FEV1, FVC and PEFR were significantly reduced among exposed detergent workers. Similarly, the predicted values of PEFR, FVC and FEV1, were significantly reduced among smokers (P<0. 001). Respiratory symptoms are highly prevalent among detergent workers. This was associated with impaired pulmonary function. Protective equipment and periodic lung function tests could reduce these effects.

Loss of Mitochondrial Function Impairs Lysosomes.

PubMed

Demers-Lamarche, Julie; Guillebaud, Gérald; Tlili, Mouna; Todkar, Kiran; Bélanger, Noémie; Grondin, Martine; Nguyen, Angela P; Michel, Jennifer; Germain, Marc

2016-05-06

Alterations in mitochondrial function, as observed in neurodegenerative diseases, lead to disrupted energy metabolism and production of damaging reactive oxygen species. Here, we demonstrate that mitochondrial dysfunction also disrupts the structure and function of lysosomes, the main degradation and recycling organelle. Specifically, inhibition of mitochondrial function, following deletion of the mitochondrial protein AIF, OPA1, or PINK1, as well as chemical inhibition of the electron transport chain, impaired lysosomal activity and caused the appearance of large lysosomal vacuoles. Importantly, our results show that lysosomal impairment is dependent on reactive oxygen species. Given that alterations in both mitochondrial function and lysosomal activity are key features of neurodegenerative diseases, this work provides important insights into the etiology of neurodegenerative diseases. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

MUSCLE WEAKNESS, FATIGUE, AND TORQUE VARIABILITY: EFFECTS OF AGE AND MOBILITY STATUS

PubMed Central

KENT-BRAUN, JANE A.; CALLAHAN, DAMIEN M.; FAY, JESSICA L.; FOULIS, STEPHEN A.; BUONACCORSI, JOHN P.

2013-01-01

Introduction Whereas deficits in muscle function, particularly power production, develop in old age and are risk factors for mobility impairment, a complete understanding of muscle fatigue during dynamic contractions is lacking. We tested hypotheses related to torque-producing capacity, fatigue resistance, and variability of torque production during repeated maximal contractions in healthy older, mobility-impaired older, and young women. Methods Knee extensor fatigue (decline in torque) was measured during 4 min of dynamic contractions. Torque variability was characterized using a novel 4-component logistic regression model. Results Young women produced more torque at baseline and during the protocol than older women (P < 0.001). Although fatigue did not differ between groups (P = 0.53), torque variability differed by group (P = 0.022) and was greater in older impaired compared with young women (P = 0.010). Conclusions These results suggest that increased torque variability may combine with baseline muscle weakness to limit function, particularly in older adults with mobility impairments. PMID:23674266

Myocardial Perfusion and Function Are Distinctly Altered by Sevoflurane Anesthesia in Diet-Induced Prediabetic Rats.

PubMed

van den Brom, Charissa E; Boly, Chantal A; Bulte, Carolien S E; van den Akker, Rob F P; Kwekkeboom, Rick F J; Loer, Stephan A; Boer, Christa; Bouwman, R Arthur

2016-01-01

Preservation of myocardial perfusion during surgery is particularly important in patients with increased risk for perioperative complications, such as diabetes. Volatile anesthetics, like sevoflurane, have cardiodepressive effects and may aggravate cardiovascular complications. We investigated the effect of sevoflurane on myocardial perfusion and function in prediabetic rats. Rats were fed a western diet (WD; n = 18) or control diet (CD; n = 18) for 8 weeks and underwent (contrast) echocardiography to determine perfusion and function during baseline and sevoflurane exposure. Myocardial perfusion was estimated based on the product of microvascular filling velocity and blood volume. WD-feeding resulted in a prediabetic phenotype characterized by obesity, hyperinsulinemia, hyperlipidemia, glucose intolerance, and hyperglycemia. At baseline, WD-feeding impaired myocardial perfusion and systolic function compared to CD-feeding. Exposure of healthy rats to sevoflurane increased the microvascular filling velocity without altering myocardial perfusion but impaired systolic function. In prediabetic rats, sevoflurane did also not affect myocardial perfusion; however, it further impaired systolic function. Diet-induced prediabetes is associated with impaired myocardial perfusion and function in rats. While sevoflurane further impaired systolic function, it did not affect myocardial perfusion in prediabetic rats. Our findings suggest that sevoflurane anesthesia leads to uncoupling of myocardial perfusion and function, irrespective of the metabolic state.

iStimulation: Apple iPad Use with Children Who Are Visually Impaired, Including Those with Multiple Disabilities

ERIC Educational Resources Information Center

Campaña, Laura V.; Ouimet, Donald A.

2015-01-01

Since its creation in the early 1980s, Light Box, a product developed by the American Printing House for the Blind (APH) that is designed for working on functional vision tasks with children who have visual impairments or multiple disabilities, has been an effective tool to help teach children with visual impairments to locate and track items…

Grammatical Impairments in PPA

PubMed Central

Thompson, Cynthia K.; Mack, Jennifer E.

2015-01-01

Background Grammatical impairments are commonly observed in the agrammatic subtype of primary progressive aphasia (PPA-G), whereas grammatical processing is relatively preserved in logopenic (PPA-L) and semantic (PPA-S) subtypes. Aims We review research on grammatical deficits in PPA and associated neural mechanisms, with discussion focused on production and comprehension of four aspects of morphosyntactic structure: grammatical morphology, functional categories, verbs and verb argument structure, and complex syntactic structures. We also address assessment of grammatical deficits in PPA, with emphasis on behavioral tests of grammatical processing. Finally, we address research examining the effects of treatment for progressive grammatical impairments. Main Contribution PPA-G is associated with grammatical deficits that are evident across linguistic domains in both production and comprehension. PPA-G is associated with damage to regions including the left inferior frontal gyrus (IFG) and dorsal white matter tracts, which have been linked to impaired comprehension and production of complex sentences. Detailing grammatical deficits in PPA is important for estimating the trajectory of language decline and associated neuropathology. We, therefore, highlight several new assessment tools for examining different aspects of morphosyntactic processing in PPA. Conclusions Individuals with PPA-G present with agrammatic deficit patterns distinct from those associated with PPA-L and PPA-S, but similar to those seen in agrammatism resulting from stroke, and patterns of cortical atrophy and white matter changes associated with PPA-G have been identified. Methods for clinical evaluation of agrammatism, focusing on comprehension and production of grammatical morphology, functional categories, verbs and verb argument structure, and complex syntactic structures are recommended and tools for this are emerging in the literature. Further research is needed to investigate the real-time processes underlying grammatical impairments in PPA, as well as the structural and functional neural correlates of grammatical impairments across linguistic domains. Few studies have examined the effects of treatment for grammatical impairments in PPA; research in this area is needed to better understand how (or if) grammatical processing ability can be improved, the potential for spared neural tissue to be recruited to support this, and whether the neural connections within areas of dysfunctional tissue required for grammatical processing can be enhanced using cortical stimulation. PMID:25642014

Grammatical Impairments in PPA.

PubMed

Thompson, Cynthia K; Mack, Jennifer E

2014-09-01

Grammatical impairments are commonly observed in the agrammatic subtype of primary progressive aphasia (PPA-G), whereas grammatical processing is relatively preserved in logopenic (PPA-L) and semantic (PPA-S) subtypes. We review research on grammatical deficits in PPA and associated neural mechanisms, with discussion focused on production and comprehension of four aspects of morphosyntactic structure: grammatical morphology, functional categories, verbs and verb argument structure, and complex syntactic structures. We also address assessment of grammatical deficits in PPA, with emphasis on behavioral tests of grammatical processing. Finally, we address research examining the effects of treatment for progressive grammatical impairments. PPA-G is associated with grammatical deficits that are evident across linguistic domains in both production and comprehension. PPA-G is associated with damage to regions including the left inferior frontal gyrus (IFG) and dorsal white matter tracts, which have been linked to impaired comprehension and production of complex sentences. Detailing grammatical deficits in PPA is important for estimating the trajectory of language decline and associated neuropathology. We, therefore, highlight several new assessment tools for examining different aspects of morphosyntactic processing in PPA. Individuals with PPA-G present with agrammatic deficit patterns distinct from those associated with PPA-L and PPA-S, but similar to those seen in agrammatism resulting from stroke, and patterns of cortical atrophy and white matter changes associated with PPA-G have been identified. Methods for clinical evaluation of agrammatism, focusing on comprehension and production of grammatical morphology, functional categories, verbs and verb argument structure, and complex syntactic structures are recommended and tools for this are emerging in the literature. Further research is needed to investigate the real-time processes underlying grammatical impairments in PPA, as well as the structural and functional neural correlates of grammatical impairments across linguistic domains. Few studies have examined the effects of treatment for grammatical impairments in PPA; research in this area is needed to better understand how (or if) grammatical processing ability can be improved, the potential for spared neural tissue to be recruited to support this, and whether the neural connections within areas of dysfunctional tissue required for grammatical processing can be enhanced using cortical stimulation.

Does Severity of Depression Predict Magnitude of Productivity Loss?

PubMed Central

Beck, Arne; Crain, A. Lauren; Solberg, Leif I.; Unützer, Jürgen; Glasgow, Russell E.; Maciosek, Michael V.; Whitebird, Robin

2014-01-01

PURPOSE Depression is associated with lowered work functioning, including absence, productivity impairment, and decreased job retention. However, few studies have examined depression symptoms across a continuum of severity in relationship to the magnitude of work impairment in a large and heterogeneous patient population. This study assessed the relationship between depression symptom severity and productivity loss among patients initiated on antidepressants. METHODS Data were obtained from patients participating in the DIAMOND Initiative (Depression Improvement Across Minnesota: Offering a New Direction), a statewide quality improvement collaborative to provide enhanced depression care. Patients newly started on antidepressants were surveyed with the Patient Health Questionnaire (PHQ-9), a measure of depression symptom severity, the Work Productivity and Activity Impairment questionnaire (WPAI) a measure of productivity loss, and items on health status and demographics. RESULTS We analyzed data from the 771 patients who reported current employment. General linear models adjusting for demographics and health status showed a significant linear, monotonic relationship between depression symptom severity and productivity loss (p<.0001). Even minor levels of depression symptoms were associated with decrements in work function. Greater productivity loss also was associated with full-time vs. part-time employment status (p<.001), fair or poor health (p=.05), and “not coupled” marital status (p=.07). CONCLUSIONS This study illustrated the relationship between the severity of depression symptoms and work function, suggesting that even minor levels of depression are associated with productivity loss. Employers may find it beneficial to invest in effective treatments for employees across the continuum of depression severity. PMID:25295792

Acupuncture elicits neuroprotective effect by inhibiting NAPDH oxidase-mediated reactive oxygen species production in cerebral ischaemia.

PubMed

Shi, Guang-Xia; Wang, Xue-Rui; Yan, Chao-Qun; He, Tian; Yang, Jing-Wen; Zeng, Xiang-Hong; Xu, Qian; Zhu, Wen; Du, Si-Qi; Liu, Cun-Zhi

2015-12-10

In the current study, we aimed to investigate whether NADPH oxidase, a major ROS-producing enzyme, was involved in the antioxidant effect of acupuncture on cognitive impairment after cerebral ischaemia. The cognitive function, infract size, neuron cell loss, level of superoxide anion and expression of NADPH oxidase subunit in hippocampus of two-vessel occlusion (2VO) rats were determined after 2-week acupuncture. Furthermore, the cognitive function and production of O2(-) were determined in the presence and absence of NADPH oxidase agonist (TBCA) and antagonist (Apocynin). The effect of acupuncture on cognitive function after cerebral ischaemia in gp91phox-KO mice was evaluated by Morris water maze. Acupuncture reduced infarct size, attenuated overproduction of O2(-), and reversed consequential cognitive impairment and neuron cell loss in 2VO rats. The elevations of gp91phox and p47phox after 2VO were significantly decreased after acupuncture treatment. However, no differences of gp91phox mRNA were found among any experimental groups. Furthermore, these beneficial effects were reversed by TBCA, whereas apocynin mimicked the effect of acupuncture by improving cognitive function and decreasing O2(-) generation. Acupuncture failed to improve the memory impairment in gp91phox KO mice. Full function of the NADPH oxidase enzyme plays an important role in neuroprotective effects against cognitive impairment via inhibition of NAPDH oxidase-mediated oxidative stress.

Parametric Cognitive Modeling of Information and Computer Technology Usage by People with Aging- and Disability-Derived Functional Impairments

PubMed Central

García-Betances, Rebeca I.; Cabrera-Umpiérrez, María Fernanda; Ottaviano, Manuel; Pastorino, Matteo; Arredondo, María T.

2016-01-01

Despite the speedy evolution of Information and Computer Technology (ICT), and the growing recognition of the importance of the concept of universal design in all domains of daily living, mainstream ICT-based product designers and developers still work without any truly structured tools, guidance or support to effectively adapt their products and services to users’ real needs. This paper presents the approach used to define and evaluate parametric cognitive models that describe interaction and usage of ICT by people with aging- and disability-derived functional impairments. A multisensorial training platform was used to train, based on real user measurements in real conditions, the virtual parameterized user models that act as subjects of the test-bed during all stages of simulated disabilities-friendly ICT-based products design. An analytical study was carried out to identify the relevant cognitive functions involved, together with their corresponding parameters as related to aging- and disability-derived functional impairments. Evaluation of the final cognitive virtual user models in a real application has confirmed that the use of these models produce concrete valuable benefits to the design and testing process of accessible ICT-based applications and services. Parameterization of cognitive virtual user models allows incorporating cognitive and perceptual aspects during the design process. PMID:26907296

Work productivity is associated with disease activity and functional ability in Italian patients with early axial spondyloarthritis: an observational study from the SPACE cohort.

PubMed

de Hooge, Manouk; Ramonda, Roberta; Lorenzin, Mariagrazia; Frallonardo, Paola; Punzi, Leonardo; Ortolan, Augusta; Doria, Andrea

2016-11-16

Spondyloarthritis often affects young people, typically in their working years. The aim of our study was to investigate work productivity and its relationship with disease activity and physical functioning in Italian patients with axial spondyloarthritis (axSpA) with chronic back pain (CBP) for ≥3 months and ≤2 years, and onset  < 45 years of age. Baseline absenteeism, presenteeism, work productivity loss (assessed by the Work Productivity and Activity Impairment questionnaire (WPAI)), and disease activity (assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)/Ankylosing Spondylitis Disease Activity Score (ASDAS)) and functional ability (assessed by the Bath Ankylosing Spondylitis Disease Functional Index (BASFI)) of patients with axSpA (rheumatologist's diagnosis) included in the Italian section of the Spondyloarthritis Caught Early (SPACE) cohort were collected. Multivariate linear regression analysis was used to evaluate the associations between work productivity and disease activity/physical functioning. Absenteeism in 51 patients with axSpA was low (8.3 %). A decrease in work productivity was related to an increase in disease activity. Disease activity was strongly correlated with absenteeism (p < 0.01), presenteeism (p < 0.01) and work productivity loss (p < 0.001). In addition, decreased work productivity was related to a decrease in functional ability. Physical functioning was correlated with absenteeism (p < 0.001), presenteeism (p < 0.05) and work productivity loss (p < 0.001). Impairment of work productivity was correlated with disease activity and physical functioning in Italian patients with axSpA with CBP for ≥3 months and ≤2 years, with onset <45 years of age.

Production and Comprehension of Time Reference in Korean Nonfluent Aphasia

PubMed Central

Lee, Jiyeon; Kwon, Miseon; Na, Hae Ri; Bastiaanse, Roelien; Thompson, Cynthia K.

2015-01-01

Objectives Individuals with nonfluent agrammatic aphasia show impaired production and comprehension of time reference via verbal morphology. However, cross-linguistic findings to date suggest inconsistent evidence as to whether tense processing in general is impaired or time reference to the past is selectively difficult in this population. This study examined production and comprehension of time reference via verb morphology in Korean-speaking individuals with nonfluent aphasia. Methods A group of 9 healthy controls and 8 individuals with nonfluent aphasia (5 for the production task) participated in the study. Sentence priming production and auditory sentence to picture matching tasks were used, parallel with the previous cross-linguistic experiments in English, Chinese, Turkish, and others. Results The participants with nonfluent aphasia showed different patterns of impairment in production and comprehension. In production, they were impaired in all time references with errors being dominated by substitution of incorrect time references and other morpho-phonologically well-formed errors, indicating a largely intact morphological affixation process. In comprehension, they showed selective impairment of the past, consistent with the cross-linguistic evidence from English, Chinese, Turkish, and others. Conclusion The findings suggest that interpretation of past time reference poses particular difficulty in nonfluent aphasia irrespective of typological characteristics of languages; however, in production, language-specific morpho-semantic functions of verbal morphology may play a significant role in selective breakdowns of time reference. PMID:26290861

Comparing work productivity in obesity and binge eating.

PubMed

Striegel, Ruth H; Bedrosian, Richard; Wang, Chun

2012-12-01

To examine productivity impairment in individuals with obesity and/or binge eating. Based on current weight and eating behavior, 117,272 employees who had completed a health risk appraisal and psychosocial functioning questionnaire were classified into one of four groups. Gender-stratified analyses compared groups on four measures: absenteeism, presenteeism, total work productivity impairment, and (non-work) activity impairment. Overall group differences were statistically significant for all measures with lowest impairment in non-obese men and women without binge eating (n = 34,090, n = 39,198), higher levels in individuals without binge eating (n = 15,570, n = 16,625), yet higher levels in non-obese men and women with binge eating (n = 1,381, n = 2,674), and highest levels in obese men and women with binge eating (Group 4, n = 2,739, n = 4,176). Health initiatives for obese employees should include screening and interventions for employees with binge eating. Copyright © 2012 Wiley Periodicals, Inc.

Relationship of work disability between the disease activity, depression and quality of life in patients with ankylosing spondylitis.

PubMed

Sağ, Sinem; Nas, Kemal; Sağ, Mustafa Serdar; Tekeoğlu, İbrahim; Kamanlı, Ayhan

2018-02-02

In this study, our objective was to determine the work productivity and work disability of the patients with ankylosing spondylitis (AS) and to investigate the relation of these parameters with disease activity, anxiety, depression and quality of life. Fifty patients with the diagnosis of AS and 30 healthy control were included in the study. In patients with AS, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was used to evaluate the disease activity; Bath Ankylosing Spondylitis Metrology Index (BASMI) was used to evaluate the spinal mobility and Bath Ankylosing Spondylitis Functional Index (BASFI) was used to determine the functional status. In addition, the Ankylosing Spondylitis Quality of Life (ASQoL) questionnaire and The Short Form (SF-36) Health Survey was used to evaluate the health status, Hospital Anxiety and Depression Scale (HADS) was used for the evaluation of depression and anxiety and Work Productivity and Activity Impairment Questionnaire: Specific Health Problem v2.0 (WPAI:SHP) was used to evaluate the work productivity. In AS patients duration of disease at the diagnosis was 7.24 ± 6.23 years. The time lost at work due to the disease, decrease in the work productivity and impairment in the time off daily activities were worse in the patient group compared with the control group (p< 0.05). The impairment in the work productivity was correlated with BASDAI and depression; difficulty in time-off activities was correlated with BASFI and anxiety and depression was correlated with BASDAI (p< 0.05). While the impairment in work productivity was correlated with the subparameter vitality in SF-36, difficulty in time off activities was correlated with general health status, social functions, vitality and mental health (p< 0.05). In this study, we determined that AS had a significant influence on the working conditions and the factors related to the disease had a significant correlation with work productivity. Factors related to the psychology and the disease were also correlated with the working conditions.

Leptin concentration and risk of impaired physical function in older adults: the Seniors-ENRICA cohort.

PubMed

Lana, Alberto; Struijk, Ellen; Guallar-Castillón, Pilar; Martín-Moreno, Jose María; Rodríguez Artalejo, Fernando; Lopez-Garcia, Esther

2016-11-01

leptin resistance, which may develop during the ageing process, stimulates the production of pro-inflammatory cytokines and insulin resistance that could impair the muscle function. However, the role of leptin on physical functioning among older adults has not yet been elucidated. to examine the association between serum leptin levels and physical function impairment in older adults. prospective study of 1,556 individuals 60 years and older from the Seniors-ENRICA cohort, who were free of physical function limitation at baseline. serum leptin was measured in 2008-10, and incident functional limitation was assessed through 2012. Self-reported limitations in agility and mobility were assessed with the Rosow and Breslau scale, limitation in the lower extremity function was measured with the Short Physical Performance Battery, and impairment in the overall physical performance with the physical component summary of the SF-12. after adjustment for potential confounders and compared to individuals in the lowest quartile of leptin concentration, those in the highest quartile showed increased risk of impaired physical function; the odds ratio (95% confidence interval) and P-trend was: 1.95 (1.11-3.43), P = 0.006 for self-reported impaired mobility; 1.76 (1.08-2.87), P = 0.02 for self-reported impaired agility; 1.48 (1.02-2.15), P = 0.04 for limitation in the lower extremity function; and 1.97 (1.20-3.22), P = 0.01, for decreased overall physical performance. These associations were only modestly explained by C-reactive protein and insulin resistance. Moreover, the associations held across groups with varying health status and were independent of estimated total body fat. higher leptin concentration was associated with increased risk of impaired physical function. Preserving metabolic function during the old age could help delaying physical function decline. © The Author 2016. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Severity of depression and magnitude of productivity loss.

PubMed

Beck, Arne; Crain, A Lauren; Solberg, Leif I; Unützer, Jürgen; Glasgow, Russell E; Maciosek, Michael V; Whitebird, Robin

2011-01-01

Depression is associated with lowered work functioning, including absences, impaired productivity, and decreased job retention. Few studies have examined depression symptoms across a continuum of severity in relationship to the magnitude of work impairment in a large and heterogeneous patient population, however. We assessed the relationship between depression symptom severity and productivity loss among patients initiating treatment for depression. Data were obtained from patients participating in the DIAMOND (Depression Improvement Across Minnesota: Offering a New Direction) initiative, a statewide quality improvement collaborative to provide enhanced depression care. Patients newly started on antidepressants were surveyed with the Patient Health Questionnaire 9-item screen (PHQ-9), a measure of depression symptom severity; the Work Productivity and Activity Impairment (WPAI) questionnaire, a measure of loss in productivity; and items on health status and demographics. We analyzed data from the 771 patients who reported being currently employed. General linear models adjusting for demographics and health status showed a significant linear, monotonic relationship between depression symptom severity and productivity loss: with every 1-point increase in PHQ-9 score, patients experienced an additional mean productivity loss of 1.65% (P <.001). Even minor levels of depression symptoms were associated with decrements in work function. Full-time vs part-time employment status and self-reported fair or poor health vs excellent, very good, or good health were also associated with a loss of productivity (P <.001 and P=.045, respectively). This study shows a relationship between the severity of depression symptoms and work function, and suggests that even minor levels of depression are associated with a loss of productivity. Employers may find it beneficial to invest in effective treatments for depressed employees across the continuum of depression severity.

Fatty acid-binding protein 4 impairs the insulin-dependent nitric oxide pathway in vascular endothelial cells

PubMed Central

2012-01-01

Background Recent studies have shown that fatty acid-binding protein 4 (FABP4) plasma levels are associated with impaired endothelial function in type 2 diabetes (T2D). In this work, we analysed the effect of FABP4 on the insulin-mediated nitric oxide (NO) production by endothelial cells in vitro. Methods In human umbilical vascular endothelial cells (HUVECs), we measured the effects of FABP4 on the insulin-mediated endothelial nitric oxide synthase (eNOS) expression and activation and on NO production. We also explored the impact of exogenous FABP4 on the insulin-signalling pathway (insulin receptor substrate 1 (IRS1) and Akt). Results We found that eNOS expression and activation and NO production are significantly inhibited by exogenous FABP4 in HUVECs. FABP4 induced an alteration of the insulin-mediated eNOS pathway by inhibiting IRS1 and Akt activation. These results suggest that FABP4 induces endothelial dysfunction by inhibiting the activation of the insulin-signalling pathway resulting in decreased eNOS activation and NO production. Conclusion These findings provide a mechanistic linkage between FABP4 and impaired endothelial function in diabetes, which leads to an increased cardiovascular risk. PMID:22709426

Developmental trajectories of writing skills in first grade: Examining the effects of SES and language and/or speech impairments

PubMed Central

Kim, Young-Suk; Puranik, Cynthia; Otaiba, Stephanie Al

2013-01-01

We examined growth trajectories of writing and the relation of children's socio-economic status, and language and/or speech impairment to the growth trajectories. First grade children (N = 304) were assessed on their written composition in the fall, winter, and spring, and their vocabulary and literacy skills in the fall. Children's SES had a negative effect on writing quality and productivity. Children with language and/or speech impairment had lower scores than typically developing children in the quality and productivity of writing. Even after accounting for their vocabulary and literacy skills, students with language and/or speech impairment had lower scores in the quality and organization of writing. Growth rates in writing were not different as a function of children's SES and language/speech impairment status. Theoretical and practical implications are discussed. PMID:26146410

Inventory of Electronic Mobility Aids for Persons with Visual Impairments: A Literature Review

ERIC Educational Resources Information Center

Roentgen, Uta R.; Gelderblom, Gert Jan; Soede, Mathijs; de Witte, Luc P.

2008-01-01

This literature review of existing electronic mobility aids for persons who are visually impaired and recent developments in this field identified and classified 146 products, systems, and devices. The 21 that are currently available that can be used without environmental adaptation are described in functional terms. (Contains 2 tables.)

Unfolded protein response (UPR) signaling regulates arsenic trioxide-mediated macrophage innate immune function disruption

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

Srivastava, Ritesh K.; Li, Changzhao; Chaudhary, Sandeep C.

Arsenic exposure is known to disrupt innate immune functions in humans and in experimental animals. In this study, we provide a mechanism by which arsenic trioxide (ATO) disrupts macrophage functions. ATO treatment of murine macrophage cells diminished internalization of FITC-labeled latex beads, impaired clearance of phagocytosed fluorescent bacteria and reduced secretion of pro-inflammatory cytokines. These impairments in macrophage functions are associated with ATO-induced unfolded protein response (UPR) signaling pathway characterized by the enhancement in proteins such as GRP78, p-PERK, p-eIF2α, ATF4 and CHOP. The expression of these proteins is altered both at transcriptional and translational levels. Pretreatment with chemical chaperon,more » 4-phenylbutyric acid (PBA) attenuated the ATO-induced activation in UPR signaling and afforded protection against ATO-induced disruption of macrophage functions. This treatment also reduced ATO-mediated reactive oxygen species (ROS) generation. Interestingly, treatment with antioxidant N-acetylcysteine (NAC) prior to ATO exposure, not only reduced ROS production and UPR signaling but also improved macrophage functions. These data demonstrate that UPR signaling and ROS generation are interdependent and are involved in the arsenic-induced pathobiology of macrophage. These data also provide a novel strategy to block the ATO-dependent impairment in innate immune responses. - Highlights: • Inorganic arsenic to humans and experimental animals disrupt innate immune responses. • The mechanism underlying arsenic impaired macrophage functions involves UPR signaling. • Chemical chaperon attenuates arsenic-mediated macrophage function impairment. • Antioxidant, NAC blocks impairment in arsenic-treated macrophage functions.« less

Determinants of sick-leave length: still limited to diagnosis elements.

PubMed

Lévy, Yvan; Denis, Angélique; Fassier, Jean-Baptiste; Kellou, Nadir; Schott, Anne-Marie; Letrilliart, Laurent

2017-12-01

Sickness certification implies that a health problem impairs ability to work. However, its assessment is seldom performed by physicians. Our objective was, therefore, to assess the specific influence of functional and environmental limitations on the length of sick-leave prescriptions. We conducted a cross-sectional study in French general teaching practices and recorded 353 initial sick-leave certifications. For each of them, the functional and environmental limitations were collected using the ATCIF questionnaire, derived from the International Classification of Functioning. Data analysis was based on a linear regression multivariate model. Among the functional limitations, "pain" was the main body function impairment (22% of impairments) and "mobility" the main activity limitation (48%). An environmental barrier was identified in 39% of sick-listed patients, mainly relating to "products and technology" (20%), which refers to workplace factors. The prescription was longer in cases of activity limitations relating to "mobility" and in cases of environmental barriers relating to "products and technology". The multivariate model explained 27% of the variability of sick-leave length through diagnosis elements and only 7% through functional and contextual elements. In sick-leave prescription, a functional and contextual approach, in addition to the traditional diagnosis-based approach, could better support patients' shared understanding and follow-up, and accountability towards health authorities. Implication for Rehabilitation Although sickness certification implies that a health problem impairs ability to work, decision on sick-leave length in general practice is primarily based on diagnosis. A more functional and contextual approach could better support patients' and other health professionals' shared understanding and follow-up, and accountability towards health authorities. Such evolution requires a change of paradigm in medical education, and the way of reasoning of healthcare professionals.

Do tasks make a difference? Accounting for heterogeneity of performance of children with reading difficulties on tasks of executive function: findings from a meta-analysis.

PubMed

Booth, Josephine N; Boyle, James M E; Kelly, Steve W

2010-03-01

Research studies have implicated executive functions in reading difficulties (RD). But while some studies have found children with RD to be impaired on tasks of executive function other studies report unimpaired performance. A meta-analysis was carried out to determine whether these discrepant findings can be accounted for by differences in the tasks of executive function that are utilized. A total of 48 studies comparing the performance on tasks of executive function of children with RD with their typically developing peers were included in the meta-analysis, yielding 180 effect sizes. An overall effect size of 0.57 (SE .03) was obtained, indicating that children with RD have impairments on tasks of executive function. However, effect sizes varied considerably suggesting that the impairment is not uniform. Moderator analysis revealed that task modality and IQ-achievement discrepancy definitions of RD influenced the magnitude of effect; however, the age and gender of participants and the nature of the RD did not have an influence. While the children's RD were associated with executive function impairments, variation in effect size is a product of the assessment task employed, underlying task demands, and definitional criteria.

ASTM lights the way for tissue engineered medical products standards: jump start for combination medical products that restore biological function of human tissues.

PubMed

Picciolo, G L; Stocum, D L

2001-01-01

Everybody hopes for better health and restoration of impaired bodily function, and now that hope is illuminated by the promise of powerful biological tools that make human cells grow and replace human tissue. ASTM Committee F04 on Medical and Surgical Materials and Devices is taking the lead by defining some of those tools as standards that can be used for the development, production, testing, and regulatory approval of medical products.

Clinical progression and outcome of dysphagia following paediatric traumatic brain injury: a prospective study.

PubMed

Morgan, Angela; Ward, Elizabeth; Murdoch, Bruce

2004-04-01

To provide a preliminary clinical profile of the resolution and outcomes of oral-motor impairment and swallowing function in a group of paediatric dysphagia patients post-traumatic brain injury (TBI). To document the level of cognitive impairment parallel to the return to oral intake, and to investigate the correlation between the resolution of impaired swallow function versus the resolution of oral-motor impairment and cognitive impairment. Thirteen children admitted to an acute care setting for TBI. A series of oral-motor (Verbal Motor Production Assessment for Children, Frenchay Dysarthria Assessment, Schedule for Oral Motor Assessment) and swallowing (Paramatta Hospital's Assessment for Dysphagia) assessments, an outcome measure for swallowing (Royal Brisbane Hospital's Outcome Measure for Swallowing), and a cognitive rating scale (Rancho Level of Cognitive Functioning Scale). Across the patient group, oral-motor deficits resolved to normal status between 3 and 11 weeks post-referral (and at an average of 12 weeks post-injury) and swallowing function and resolution to normal diet status were achieved by 3-11 weeks post-referral (and at an average of 12 weeks post-injury). The resolution of dysphagia and the resolution of oral-motor impairment and cognitive impairment were all highly correlated. The provision of a preliminary profile of oral-motor functioning and dysphagia resolution, and data on the linear relationship between swallowing impairment and cognition, will provide baseline information on the course of rehabilitation of dysphagia in the paediatric population post-TBI. Such data will contribute to more informed service provision and rehabilitation planning for paediatric patients post-TBI.

Patients with Gout Treated with Conventional Urate-lowering Therapy: Association with Disease Control, Health-related Quality of Life, and Work Productivity.

PubMed

Wood, Robert; Fermer, Steve; Ramachandran, Sulabha; Baumgartner, Scott; Morlock, Robert

2016-10-01

Implications of inadequate gout control were assessed through health-related quality of life (HRQOL) and work productivity of patients with gout adequately controlled while taking conventional urate-lowering therapy (ULT) for ≥ 3 months vs those whose gout was inadequately controlled. Retrospective data were drawn from the Adelphi Disease Specific Programme (DSP), a cross-sectional survey of patients with gout in France, Germany, the United Kingdom, and the United States. Patients completed these questionnaires: EQ-5D (3L), Patient Reported Outcomes Measurement Information System (PROMIS) Health Assessment Questionnaire (HAQ), and Work Productivity and Activity Impairment. Inadequate control was defined as the most recent serum uric acid (SUA) level > 6 mg/dl (> 360 µmol/l) or ≥ 2 flares in the last 12 months; adequate control as SUA level ≤ 6 mg/dl (≤ 360 µmol/l) and 0 flares. Appropriate statistical tests were used to assess differences between groups. There were 836 (69%) inadequately and 368 (31%) adequately controlled gout cases. Mean age was 61 and 63 years and duration of current ULT was 32 and 57 months, respectively. Patients experiencing inadequate control reported significantly worse functioning and HRQOL, as measured by the EQ-5D (0.790 vs 0.877; difference: -0.087; p < 0.001) and PROMIS HAQ (13.21 vs 6.91; difference: 6.30; p < 0.001) scales. Productivity was also more impaired (work time missed: 4.5% vs 1.3%; impairment while working: 19.1% vs 5.2%; overall work impairment: 20.4% vs 5.6%; activity impairment: 20.3% vs 5.3%; all p < 0.001). Less than one-third of patients had gout that was adequately controlled. Those experiencing inadequately controlled gout reported significantly worse functioning, quality of life, and work productivity. Gout treatment strategies to improve disease control may lead to improvements in HRQOL and productivity.

Measuring Work Functioning: Validity of a Weighted Composite Work Functioning Approach.

PubMed

Boezeman, Edwin J; Sluiter, Judith K; Nieuwenhuijsen, Karen

2015-09-01

To examine the construct validity of a weighted composite work functioning measurement approach. Workers (health-impaired/healthy) (n = 117) completed a composite measure survey that recorded four central work functioning aspects with existing scales: capacity to work, quality of work performance, quantity of work, and recovery from work. Previous derived weights reflecting the relative importance of these aspects of work functioning were used to calculate the composite weighted work functioning score of the workers. Work role functioning, productivity, and quality of life were used for validation. Correlations were calculated and norms applied to examine convergent and divergent construct validity. A t test was conducted and a norm applied to examine discriminative construct validity. Overall the weighted composite work functioning measure demonstrated construct validity. As predicted, the weighted composite score correlated (p < .001) strongly (r > .60) with work role functioning and productivity (convergent construct validity), and moderately (.30 < r < .60) with physical quality of life and less strongly than work role functioning and productivity with mental quality of life (divergent validity). Further, the weighted composite measure detected that health-impaired workers show with a large effect size (Cohen's d > .80) significantly worse work functioning than healthy workers (discriminative validity). The weighted composite work functioning measurement approach takes into account the relative importance of the different work functioning aspects and demonstrated good convergent, fair divergent, and good discriminative construct validity.

Cigarette smoking impairs nitric oxide-mediated cerebral blood flow increase: Implications for Alzheimer's disease.

PubMed

Toda, Noboru; Okamura, Tomio

2016-08-01

Cerebral blood flow is mainly regulated by nitrergic (parasympathetic, postganglionic) nerves and nitric oxide (NO) liberated from endothelial cells in response to shear stress and stretch of vasculature, whereas sympathetic vasoconstrictor control is quite weak. On the other hand, peripheral vascular resistance and blood flow are mainly controlled by adrenergic vasoconstrictor nerves; endothelium-derived NO and nitrergic nerves play some roles as vasodilator factors. Cigarette smoking impairs NO synthesis in cerebral vascular endothelial cells and nitrergic nerves leading to interference with cerebral blood flow and glucose metabolism in the brain. Smoking-induced cerebral hypoperfusion is induced by impairment of synthesis and actions of NO via endothelial nitric oxide synthase (eNOS)/neuronal NOS (nNOS) inhibition and by increased production of oxygen radicals, resulting in decreased actions of NO on vascular smooth muscle. Nicotine acutely and chronically impairs the action of endothelial NO and also inhibits nitrergic nerve function in chronic use. Impaired cerebral blood supply promotes the synthesis of amyloid β that accelerates blood flow decrease. This vicious cycle is thought to be one of the important factors involving in Alzheimer's disease (AD). Quitting smoking is undoubtedly one of the important ways to prevent and delay the genesis or slow the progress of impaired cognitive function and AD. Copyright © 2016 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Fluoride Increases Superoxide Production and Impairs the Respiratory Chain in ROS 17/2.8 Osteoblastic Cells

PubMed Central

Fina, Brenda Lorena; Lombarte, Mercedes; Rigalli, Juan Pablo; Rigalli, Alfredo

2014-01-01

It is known that fluoride produces oxidative stress. Inflammation in bone tissue and an impairment of the respiratory chain of liver have been described in treatments with fluoride. Whether the impairment of the respiratory chain and oxidative stress are related is not known. The aim of this work was to study the effects of fluoride on the production of superoxide radical, the function of the respiratory chain and the increase in oxidative stress in ROS 17/2.8 osteoblastic cells. We measured the effect of fluoride (100 µM) on superoxide production, oxygen consumption, lipid peroxidation and antioxidant enzymes activities of cultured cells following the treatment with fluoride. Fluoride decreased oxygen consumption and increased superoxide production immediately after its addition. Furthermore, chronic treatment with fluoride increased oxidative stress status in osteoblastic cells. These results indicate that fluoride could damage bone tissue by inhibiting the respiratory chain, increasing the production of superoxide radicals and thus of the others reactive oxygen species. PMID:24964137

Fatigue contributes to work productivity impairment in patients with axial spondyloarthritis: a cross-sectional UK study.

PubMed

Espahbodi, Shima; Bassett, Paul; Cavill, Charlotte; Freeth, Mandy; Hole, John; Sengupta, Raj

2017-01-01

To determine factors associated with absenteeism, presenteeism, work productivity loss (WPL), and daily activity impairment in UK patients with AxSpA using standardised measures. 490 patients with AxSpA completed (1) Work Productivity and Impairment questionnaire (WPAI), providing measures for absenteeism, presenteeism, WPL and daily activity impairment, and (2) BASDAI, BASFI, BASMI, Jenkins Sleep scale, Patient Global Assessment disease activity (PGA), back pain night and anytime, EQ-5D for mobility, self-care, daily activities, pain/discomfort, anxiety/depression, EQ-VAS Health State Today, FACIT fatigue, for health-related disease factors. Multivariate linear and logistic regression determined associations between WPAI measures and health-related factors. 301(61%) patients provided WPAI measurements, 76% were male, 87% HLA-B27+. Mean (SD) WPAI scores for absenteeism were 5.1%(19.2), presenteeism 22%(24.3), WPL 23.2%(25.7), activity impairment 34.8%(27.3). Absenteeism was associated with higher fatigue levels and more likely in patients with nrAxSpA. Presenteeism and WPL were both associated higher fatigue levels, BASDAI, and BASFI respectively. Daily activity impairment was associated with higher fatigue levels, BASFI, PGA, EQ-VAS, and smoking. Work productivity and impairment are associated with fatigue, disease activity, and functional ability in UK patients with AxSpA. The strong association of fatigue with all work measures as well as with daily activity impairment emphasises the need to better understand the impact of fatigue on patients' quality of life. Improving fatigue may help to optimise work status.

Loss of Word-Meaning with Spared Object Semantics in a Case of Mixed Primary Progressive Aphasia

ERIC Educational Resources Information Center

Knels, Christina; Danek, Adrian

2010-01-01

This article provides a detailed assessment of patient HT with a history of progressive language deterioration of approximately 6 years presenting now as a fluent jargon aphasic with severe impairment of both speech production and comprehension. Neuropsychological testing of non-verbal cognitive functions showed no impairment, leading to the…

Caspase-2 cleavage of tau reversibly impairs memory.

PubMed

Zhao, Xiaohui; Kotilinek, Linda A; Smith, Benjamin; Hlynialuk, Chris; Zahs, Kathleen; Ramsden, Martin; Cleary, James; Ashe, Karen H

2016-11-01

In Alzheimer's disease (AD) and other tauopathies, the tau protein forms fibrils, which are believed to be neurotoxic. However, fibrillar tau has been dissociated from neuron death and network dysfunction, suggesting the involvement of nonfibrillar species. Here we describe a novel pathological process in which caspase-2 cleavage of tau at Asp314 impairs cognitive and synaptic function in animal and cellular models of tauopathies by promoting the missorting of tau to dendritic spines. The truncation product, Δtau314, resists fibrillation and is present at higher levels in brains from cognitively impaired mice and humans with AD. The expression of tau mutants that resisted caspase-2 cleavage prevented tau from infiltrating spines, dislocating glutamate receptors and impairing synaptic function in cultured neurons, and it prevented memory deficits and neurodegeneration in mice. Decreasing the levels of caspase-2 restored long-term memory in mice that had existing deficits. Our results suggest an overall treatment strategy for re-establishing synaptic function and restoring memory in patients with AD by preventing tau from accumulating in dendritic spines.

Deuterated methoxyflurane anesthesia and renal function in Fischer 344 rats

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

Baden, J.M.; Rice, S.A.; Mazze, R.I.

1982-03-01

Inorganic fluoride (F-) production and renal function were assessed in six groups of Fischer 344 rats administered either methoxyflurane (MOF) or deuterated methoxyflurane (d4-MOF). One untreated and one phenobarbital (PB)-treated group were exposed for two hours to either air, 0.5 per cent (V/v) MOF, or 0.5 per cent (v/v) d4-MOF. Serum and urinary F- and serum urea nitrogen and creatinine were measured. Urine volume and urinary F- excretion were only slightly greater among MOF than among d4-MOF exposed animals. Pretreatment with PB, however, greatly enhanced F- production in MOF-exposed animals leading to marked renal impairment but only slightly enhanced F-more » production in d4-MOF animals leading to mild renal impairment. Thus, only in PB-pretreated animals could a biologically significant difference in nephrotoxicity be demonstrated for MOF and d4-MOF.« less

Syntactic processing as a marker for cognitive impairment in amyotrophic lateral sclerosis

PubMed Central

Tsermentseli, Stella; Leigh, P. Nigel; Taylor, Lorna J.; Radunovic, Aleksandar; Catani, Marco; Goldstein, Laura H.

2016-01-01

Despite recent interest in cognitive changes in patients with amyotrophic lateral sclerosis (ALS), investigations of language function looking at the level of word, sentence and discourse processing are relatively scarce. Data were obtained from 26 patients with sporadic ALS and 26 healthy controls matched for age, education, gender, anxiety, depression and executive function performance. Standardized language tasks included confrontation naming, semantic access, and syntactic comprehension. Quantitative production analysis (QPA) was used to analyse connected speech samples of the Cookie Theft picture description task. Results showed that the ALS patients were impaired on standardized measures of grammatical comprehension and action/verb semantics. At the level of discourse, ALS patients were impaired on measures of syntactic complexity and fluency; however, the latter could be better explained by disease related factors. Discriminant analysis revealed that syntactic measures differentiated ALS patients from controls. In conclusion, patients with ALS exhibit deficits in receptive and expressive language on tasks of comprehension and connected speech production, respectively. Our findings suggest that syntactic processing deficits seem to be the predominant feature of language impairment in ALS and that these deficits can be detected by relatively simple language tests. PMID:26312952

Syntactic processing as a marker for cognitive impairment in amyotrophic lateral sclerosis.

PubMed

Tsermentseli, Stella; Leigh, P Nigel; Taylor, Lorna J; Radunovic, Aleksandar; Catani, Marco; Goldstein, Laura H

2015-01-01

Despite recent interest in cognitive changes in patients with amyotrophic lateral sclerosis (ALS), investigations of language function looking at the level of word, sentence and discourse processing are relatively scarce. Data were obtained from 26 patients with sporadic ALS and 26 healthy controls matched for age, education, gender, anxiety, depression and executive function performance. Standardized language tasks included confrontation naming, semantic access, and syntactic comprehension. Quantitative production analysis (QPA) was used to analyse connected speech samples of the Cookie Theft picture description task. Results showed that the ALS patients were impaired on standardized measures of grammatical comprehension and action/verb semantics. At the level of discourse, ALS patients were impaired on measures of syntactic complexity and fluency; however, the latter could be better explained by disease related factors. Discriminant analysis revealed that syntactic measures differentiated ALS patients from controls. In conclusion, patients with ALS exhibit deficits in receptive and expressive language on tasks of comprehension and connected speech production, respectively. Our findings suggest that syntactic processing deficits seem to be the predominant feature of language impairment in ALS and that these deficits can be detected by relatively simple language tests.

Broca's Aphasia, Verbs and the Mental Lexicon

ERIC Educational Resources Information Center

Bastiaanse, Roelien; van Zonneveld, Ron

2004-01-01

Verb production is notoriously difficult for individuals with Broca's aphasia, both at the word and at the sentence level. An intriguing question is at which level in the speech production these problems arise. The aim of the present study is to identify the functional locus of the impairment that results in verb production deficits in Broca's…

An advanced glycation end product (AGE)-receptor for AGEs (RAGE) axis restores adipogenic potential of senescent preadipocytes through modulation of p53 protein function.

PubMed

Chen, Chih-Yu; Abell, Allison Martorano; Moon, Yang Soo; Kim, Kee-Hong

2012-12-28

The impaired adipogenic potential of senescent preadipocytes is a hallmark of adipose aging and aging-related adipose dysfunction. Although advanced glycation end products (AGEs) derived from both foods and endogenous nonenzymatic glycation and AGE-associated signaling pathways are known to play a key role in aging and its related diseases, the role of AGEs in adipose aging remains elusive. We show a novel pro-adipogenic function of AGEs in replicative senescent preadipocytes and mouse embryonic fibroblasts, as well as primary preadipocytes isolated from aged mice. Using glycated bovine serum albumin (BSA) as a model protein of AGEs, we found that glycated BSA restores the impaired adipogenic potential of senescent preadipocytes in vitro and ex vivo. However, glycated BSA showed no effect on adipogenesis in nonsenescent preadipocytes. The AGE-induced receptor for AGE (RAGE) expression is required for the pro-adipogenic function of AGEs in senescent preadipocytes. RAGE is required for impairment of p53 expression and p53 function in regulating p21 expression in senescent preadipocytes. We also observed a direct binding between RAGE and p53 in senescent preadipocytes. Taken together, our findings reveal a novel pro-adipogenic function of the AGE-RAGE axis in p53-regulated adipogenesis of senescent preadipocytes, providing new insights into aging-dependent adiposity by diet-driven and/or endogenous glycated proteins.

An Advanced Glycation End Product (AGE)-Receptor for AGEs (RAGE) Axis Restores Adipogenic Potential of Senescent Preadipocytes through Modulation of p53 Protein Function*

PubMed Central

Chen, Chih-Yu; Abell, Allison Martorano; Moon, Yang Soo; Kim, Kee-Hong

2012-01-01

The impaired adipogenic potential of senescent preadipocytes is a hallmark of adipose aging and aging-related adipose dysfunction. Although advanced glycation end products (AGEs) derived from both foods and endogenous nonenzymatic glycation and AGE-associated signaling pathways are known to play a key role in aging and its related diseases, the role of AGEs in adipose aging remains elusive. We show a novel pro-adipogenic function of AGEs in replicative senescent preadipocytes and mouse embryonic fibroblasts, as well as primary preadipocytes isolated from aged mice. Using glycated bovine serum albumin (BSA) as a model protein of AGEs, we found that glycated BSA restores the impaired adipogenic potential of senescent preadipocytes in vitro and ex vivo. However, glycated BSA showed no effect on adipogenesis in nonsenescent preadipocytes. The AGE-induced receptor for AGE (RAGE) expression is required for the pro-adipogenic function of AGEs in senescent preadipocytes. RAGE is required for impairment of p53 expression and p53 function in regulating p21 expression in senescent preadipocytes. We also observed a direct binding between RAGE and p53 in senescent preadipocytes. Taken together, our findings reveal a novel pro-adipogenic function of the AGE-RAGE axis in p53-regulated adipogenesis of senescent preadipocytes, providing new insights into aging-dependent adiposity by diet-driven and/or endogenous glycated proteins. PMID:23150674

Concordance of Barthel Index, ECOG-PS, and Palliative Performance Scale in the assessment of functional status in patients with advanced medical diseases.

PubMed

Hernández-Quiles, C; Bernabeu-Wittel, M; Pérez-Belmonte, L M; Macías-Mir, P; Camacho-González, D; Massa, B; Maiz-Jiménez, M; Ollero-Baturone, M

2017-09-01

Analysing most relevant clinical features and concordance between different functional scales in patients with advanced medical diseases (PAMD). Cross-sectional multicentre study that included PAMD (heart, lung, kidney, liver, and neurological diseases) in hospital settings from February 2009 to October 2010. We analysed clinical, biological and functional features in performing activities of daily living (ADL) by medians of Barthel Index (BI); additionally we assessed their performance status by medians of Eastern Cooperative Oncology Group-Performance Status (ECOG-PS) and Palliative Performance Scale (PPS) scores. We evaluated the concordance of these instruments in assessing functional impairment by κ and intraclass correlation coefficient tests. 1847 patients were included (average age 79 years, 50.1% men). Most common symptoms were dyspnoea (62.31%), asthenia (23%) and delirium (20.14%). Functional assessment showed a high prevalence of severe or total impairment in performing basic ADL by medians of used instruments (BI median=35 (IQR=70), and 52.1% of patients with severe-total impairment; ECOG-PS median=2 (IQR 30), and 44% of patients with severe-total impairment; and PPS median=50 (IQR 30), and 32% of patients with severe-total impairment). Concordance among these instruments was acceptably good ( κ indexes ranging from 0.653 to 0.745 (p<0.0001)). PAMD represent a population with severe functional impairment, which requires a multidisciplinary approach for proper management. Assessment of functional ability in this population by BI, ECOG-PS, and PPS showed good concordance. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Endothelial cells of extremely premature infants display impaired immune response after proinflammatory stimulation.

PubMed

Wisgrill, Lukas; Muck, Martina; Wessely, Isabelle; Berger, Angelika; Spittler, Andreas; Förster-Waldl, Elisabeth; Sadeghi, Kambis

2018-01-01

BackgroundEndothelial cells (ECs) exert immunological functions such as production of proinflammatory cytokines/chemokines as well as facilitation of extravasation of immune cells into infected tissue. Limited data are available on the functionality of ECs from extremely preterm neonates during infection. Accordingly, the aim of our study was to investigate the immune response of premature ECs after proinflammatory stimulation.MethodsCell adhesion receptors' expression and function, nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NFκB) signaling, and chemokine production were analyzed in umbilical cord ECs from extremely preterm and term neonates after proinflammatory stimulation.ResultsP-selectin and E-selectin surface expression as well as NFκB signaling were lower after lipopolysaccharide (LPS) stimulation in premature ECs. Preterm ECs exhibited lower, but significant, cell-adhesive functions after LPS stimulation compared with term ECs. CCL2/CXCL8 chemokine secretion was significantly upregulated after proinflammatory stimulation in both groups. CXCL10 production was significantly increased in term but not in preterm ECs upon stimulation with tumor necrosis factor compared with unstimulated ECs.ConclusionExtremely premature ECs showed partly reduced expression levels and function of cell adhesion molecules. Both NFκB signaling and chemokine/cytokine production were reduced in premature ECs. The diminished endothelial proinflammatory immune response might result in impaired infection control of preterm newborns rendering them prone to severe infection.

Prolonged exposure of cortical neurons to oligomeric amyloid-β impairs NMDA receptor function via NADPH oxidase-mediated ROS production: protective effect of green tea (–)-epigallocatechin-3-gallate

PubMed Central

He, Yan; Cui, Jiankun; Lee, James C-M; Ding, Shinghua; Chalimoniuk, Malgorzata; Simonyi, Agnes; Sun, Albert Y; Gu, Zezong; Weisman∥, Gary A; Gibson Wood, W; Sun, Grace Y

2011-01-01

Excessive production of Aβ (amyloid β-peptide) has been shown to play an important role in the pathogenesis of AD (Alzheimer's disease). Although not yet well understood, aggregation of Aβ is known to cause toxicity to neurons. Our recent study demonstrated the ability for oligomeric Aβ to stimulate the production of ROS (reactive oxygen species) in neurons through an NMDA (N-methyl-d-aspartate)-dependent pathway. However, whether prolonged exposure of neurons to aggregated Aβ is associated with impairment of NMDA receptor function has not been extensively investigated. In the present study, we show that prolonged exposure of primary cortical neurons to Aβ oligomers caused mitochondrial dysfunction, an attenuation of NMDA receptor-mediated Ca2+ influx and inhibition of NMDA-induced AA (arachidonic acid) release. Mitochondrial dysfunction and the decrease in NMDA receptor activity due to oligomeric Aβ are associated with an increase in ROS production. Gp91ds-tat, a specific peptide inhibitor of NADPH oxidase, and Mn(III)-tetrakis(4-benzoic acid)-porphyrin chloride, an ROS scavenger, effectively abrogated Aβ-induced ROS production. Furthermore, Aβ-induced mitochondrial dysfunction, impairment of NMDA Ca2+ influx and ROS production were prevented by pre-treatment of neurons with EGCG [(−)-epigallocatechin-3-gallate], a major polyphenolic component of green tea. Taken together, these results support a role for NADPH oxidase-mediated ROS production in the cytotoxic effects of Aβ, and demonstrate the therapeutic potential of EGCG and other dietary polyphenols in delaying onset or retarding the progression of AD. PMID:21434871

Perceptual analysis of speech following traumatic brain injury in childhood.

PubMed

Cahill, Louise M; Murdoch, Bruce E; Theodoros, Deborah G

2002-05-01

To investigate perceptually the speech dimensions, oromotor function, and speech intelligibility of a group of individuals with traumatic brain injury (TBI) acquired in childhood. The speech of 24 children with TBI was analysed perceptually and compared with that of a group of non-neurologically impaired children matched for age and sex. The 16 dysarthric TBI subjects were significantly less intelligible than the control subjects, and demonstrated significant impairment in 12 of the 33 speech dimensions rated. In addition, the eight non-dysarthric TBI subjects were significantly impaired in many areas of oromotor function on the Frenchay Dysarthria Assessment, indicating some degree of pre-clinical speech impairment. The results of the perceptual analysis are discussed in terms of the possible underlying pathophysiological bases of the deviant speech features identified, and the need for a comprehensive instrumental assessment, to more accurately determine the level of breakdown in the speech production mechanism in children following TBI.

Production of Verb Tense in Agrammatic Aphasia: A Meta-Analysis and Further Data

PubMed Central

Faroqi-Shah, Yasmeen; Friedman, Laura

2015-01-01

In a majority of languages, the time of an event is expressed by marking tense on the verb. There is substantial evidence that the production of verb tense in sentences is more severely impaired than other functional categories in persons with agrammatic aphasia. The underlying source of this verb tense impairment is less clear, particularly in terms of the relative contribution of conceptual-semantic and processing demands. This study aimed to provide a more precise characterization of verb tense impairment by examining if there is dissociation within tenses (due to conceptual-semantic differences) and an effect of experimental task (mediated by processing limitations). Two sources of data were used: a meta-analysis of published research (which yielded 143 datasets) and new data from 16 persons with agrammatic aphasia. Tensed verbs were significantly more impaired than neutral (nonfinite) verbs, but there were no consistent differences between past, present, and future tenses. Overall, tense accuracy was mediated by task, such that picture description task was the most challenging, relative to sentence completion, sentence production priming, and grammaticality judgment. An interaction between task and tense revealed a past tense disadvantage for a sentence production priming task. These findings indicate that verb tense impairment is exacerbated by processing demands of the elicitation task and the conceptual-semantic differences between tenses are too subtle to show differential performance in agrammatism. PMID:26457004

Evaluation of impairment of the upper extremity.

PubMed

Blair, S J; McCormick, E; Bear-Lehman, J; Fess, E E; Rader, E

1987-08-01

Evaluation of impairment of the upper extremity is the product of a team effort by the physician, occupational therapist, physical therapist, and rehabilitation counselor. A careful recording of the anatomic impairment should be made because this is critical in determining the subsequent functional activities of the extremity. The measurement criteria for clinical and functional evaluation includes condition assessment instruments. Some assess the neurovascular system, others assess movements including the monitoring of articular motion and musculotendinous function. Sensibility assessment instruments measure sympathetic response and detect single joint stimulus, discrimination, quantification, and recognition abilities. A detailed description of each assessment is recorded and physical capacity evaluation is only one component of the entire vocational evaluation. This evaluation answers questions regarding the injured worker's ability to return to his previous job. The work simulator is a useful instrument that allows rehabilitation and testing of the injured upper extremity. Job site evaluation includes assessment criteria for work performance, work behavior, and work environment.

Changes in the immune system are conditioned by nutrition.

PubMed

Marcos, A; Nova, E; Montero, A

2003-09-01

Undernutrition due to insufficient intake of energy and macronutrients and/or due to deficiencies in specific micronutrients impairs the immune system, suppressing immune functions that are fundamental to host protection. The most consistent abnormalities are seen in cell-mediated immunity, complement system, phagocyte function, cytokine production, mucosal secretory antibody response, and antibody affinity. There is a number of physiological situations such as ageing and performance of intense physical exercise associated with an impairment of some immune parameters' response. Nutrition can influence the extent of immune alteration in both of them. There are also numerous pathological situations in which nutrition plays a role as a primary or secondary determinant of some underlying immunological impairments. This includes obesity, eating disorders (anorexia nervosa and bulimia nervosa), food hypersensitivity and gastrointestinal disorders as some examples. The implications of nutrition on immune function in these disorders are briefly reviewed.

Thidoredxin-2 overexpression fails to rescue chronic high calorie diet induced hippocampal dysfunction.

PubMed

Liu, Yong; Yang, Ying; Dong, Hui; Cutler, Roy G; Strong, Randy; Mattson, Mark P

2016-01-01

A high calorie diet (HCD) can impair hippocampal synaptic plasticity and cognitive function in animal models. Mitochondrial thioredoxin 2 (TRX-2) is critical for maintaining intracellular redox status, but whether it can protect against HCD-induced impairment of synaptic plasticity is unknown. We found that levels of TRX-2 are reduced in the hippocampus of wild type mice maintained for 8 months on a HCD, and that the mice on the HCD exhibit impaired hippocampal synaptic plasticity (long-term potentiation at CA1 synapses) and cognitive function (novel object recognition). Transgenic mice overexpressing human TRX-2 (hTRX-2) exhibit increased resistance to diquat-induced oxidative stress in peripheral tissues. However, neither the HCD nor hTRX-2 overexpression affected levels of lipid peroxidation products (F2 isoprostanes) in the hippocampus, and hTRX-2 transgenic mice were not protected against the adverse effects of the HCD on hippocampal synaptic plasticity and cognitive function. Our findings indicate that TRX-2 overexpression does not mitigate adverse effects of a HCD on synaptic plasticity, and also suggest that oxidative stress may not be a pivotal factor in the impairment of synaptic plasticity and cognitive function caused by HCDs. Published by Elsevier Inc.

Human TRAF3 adaptor molecule deficiency leads to impaired Toll-like receptor 3 response and susceptibility to herpes simplex encephalitis

PubMed Central

de Diego, Rebeca Pérez; Sancho-Shimizu, Vanessa; Lorenzo, Lazaro; Puel, Anne; Plancoulaine, Sabine; Picard, Capucine; Herman, Melina; Cardon, Annabelle; Durandy, Anne; Bustamante, Jacinta; Vallabhapurapu, Sivakumar; Bravo, Jerónimo; Warnatz, Klaus; Chaix, Yves; Cascarrigny, Françoise; Lebon, Pierre; Rozenberg, Flore; Karin, Michael; Tardieu, Marc; Al-Muhsen, Saleh; Jouanguy, Emmanuelle; Zhang, Shen-Ying; Abel, Laurent; Casanova, Jean-Laurent

2010-01-01

Tumor necrosis factor (TNF) receptor-associated factor 3 (TRAF3) functions downstream of multiple receptors that induce interferon-α (IFN-α), IFN–β and IFN-λ production, including Toll-like receptor 3 (TLR3), which is deficient in some patients with herpes simplex virus-1 encephalitis (HSE). Mice lacking TRAF3 die in the neonatal period, preventing direct investigation of the role of TRAF3 in immune responses and host defenses in vivo. Here we reported the autosomal dominant, human TRAF3 deficiency in a young adult with a history of HSE in childhood. The TRAF3 mutant allele was a loss-of-expression, loss-of-function, dominant-negative phenotype, and was associated with impaired, but not abolished TRAF3-dependent responses upon stimulation of both TNF receptors and receptors that induce IFN production. TRAF3 deficiency was associated with a clinical phenotype limited to HSE resulting from the impairment of TLR3-dependent induction of IFN. Thus, TLR3-mediated immunity against primary infection by HSV-1 in the central nervous system is critically dependent on TRAF3. Highlight sentence Autosomal dominant TRAF3 deficiency is a genetic etiology of herpes simplex encephalitis. Highlight sentence R118W TRAF3 allele is loss-of-function, loss-of-expression, and dominant-negative. Highlight sentence Human TRAF3 deficiency impairs the TLR3-dependent induction of anti-viral interferons. PMID:20832341

Impairments of Antigen-Presenting Cells in Pulmonary Tuberculosis

PubMed Central

Sakhno, Ludmila V.; Shevela, Ekaterina Ya.; Tikhonova, Marina A.; Nikonov, Sergey D.; Ostanin, Alexandr A.; Chernykh, Elena R.

2015-01-01

The phenotype and functional properties of antigen-presenting cells (APC), that is, circulating monocytes and generated in vitro macrophages and dendritic cells, were investigated in the patients with pulmonary tuberculosis (TB) differing in lymphocyte reactivity to M. tuberculosis antigens (PPD-reactive versus PPD-anergic patients). We revealed the distinct impairments in patient APC functions. For example, the monocyte dysfunctions were displayed by low CD86 and HLA-DR expression, 2-fold increase in CD14+CD16+ expression, the high numbers of IL-10-producing cells, and enhanced IL-10 and IL-6 production upon LPS-stimulation. The macrophages which were in vitro generated from peripheral blood monocytes under GM-CSF were characterized by Th1/Th2-balance shifting (downproduction of IFN-γ coupled with upproduction of IL-10) and by reducing of allostimulatory activity in mixed lymphocyte culture. The dendritic cells (generated in vitro from peripheral blood monocytes upon GM-CSF + IFN-α) were characterized by impaired maturation/activation, a lower level of IFN-γ production in conjunction with an enhanced capacity to produce IL-10 and IL-6, and a profound reduction of allostimulatory activity. The APC dysfunctions were found to be most prominent in PPD-anergic patients. The possible role of APC impairments in reducing the antigen-specific T-cell response to M. tuberculosis was discussed. PMID:26339660

Is semantic verbal fluency impairment explained by executive function deficits in schizophrenia?

PubMed

Berberian, Arthur A; Moraes, Giovanna V; Gadelha, Ary; Brietzke, Elisa; Fonseca, Ana O; Scarpato, Bruno S; Vicente, Marcella O; Seabra, Alessandra G; Bressan, Rodrigo A; Lacerda, Acioly L

2016-04-19

To investigate if verbal fluency impairment in schizophrenia reflects executive function deficits or results from degraded semantic store or inefficient search and retrieval strategies. Two groups were compared: 141 individuals with schizophrenia and 119 healthy age and education-matched controls. Both groups performed semantic and phonetic verbal fluency tasks. Performance was evaluated using three scores, based on 1) number of words generated; 2) number of clustered/related words; and 3) switching score. A fourth performance score based on the number of clusters was also measured. SZ individuals produced fewer words than controls. After controlling for the total number of words produced, a difference was observed between the groups in the number of cluster-related words generated in the semantic task. In both groups, the number of words generated in the semantic task was higher than that generated in the phonemic task, although a significant group vs. fluency type interaction showed that subjects with schizophrenia had disproportionate semantic fluency impairment. Working memory was positively associated with increased production of words within clusters and inversely correlated with switching. Semantic fluency impairment may be attributed to an inability (resulting from reduced cognitive control) to distinguish target signal from competing noise and to maintain cues for production of memory probes.

Soy food and isoflavone intake reduces the risk of cognitive impairment in elderly Japanese women.

PubMed

Nakamoto, Mariko; Otsuka, Rei; Nishita, Yukiko; Tange, Chikako; Tomida, Makiko; Kato, Yuki; Imai, Tomoko; Sakai, Tohru; Ando, Fujiko; Shimokata, Hiroshi

2018-01-18

Data were derived from the National Institute for Longevity Sciences-Longitudinal Study of Aging. Subjects comprised 403 men and 373 women aged 60-81 years at baseline who participated in the follow-up study at least once. Bean, soy product and soy isoflavone intake was assessed using a 3-day dietary record at baseline. Cognitive function was assessed by the Mini-Mental State Examination (MMSE). MMSE scores of ≤23 were used to define cognitive impairment. The relationship between bean, soy product and soy isoflavone intake and cognitive impairment was assessed using a generalized estimating equation. Multivariate-adjusted odds ratios (95% confidence intervals) for cognitive impairment with a 1 s.d. increase in total bean, total soybean and total soy isoflavone intakes were 0.48 (0.28-0.81; p = 0.006), 0.51 (0.32-0.83; p = 0.007), and 0.55 (0.32-0.93; p = 0.026), respectively, in women. Total soybean and soy isoflavone intake might decrease the risk of cognitive impairment in elderly Japanese women.

Management of a Statewide Textbook and Materials Center for the Visually Impaired.

ERIC Educational Resources Information Center

Rossi, Peter

1979-01-01

The activities described include production and/or procurement of special media textbooks (tape, large print, and braille) and specialized equipment, as well as the administrative service function. (Author)

Cutting Edge: Defective Aerobic Glycolysis Defines the Distinct Effector Function in Antigen-Activated CD8+ Recent Thymic Emigrants.

PubMed

Cunningham, Cody A; Bergsbaken, Tessa; Fink, Pamela J

2017-06-15

Recent thymic emigrants (RTEs) are the youngest peripheral T cells that have completed thymic selection and egress to the lymphoid periphery. RTEs are functionally distinct from their more mature but still naive T cell counterparts, because they exhibit dampened proliferation and reduced cytokine production upon activation. In this article, we show that, compared with more mature but still naive T cells, RTEs are impaired in their ability to perform aerobic glycolysis following activation. Impaired metabolism underlies the reduced IFN-γ production observed in activated RTEs. This failure to undergo Ag-induced aerobic glycolysis is caused by reduced mTORC1 activity and diminished Myc induction in RTEs. Critically, exogenous IL-2 restores Myc expression in RTEs, driving aerobic glycolysis and IFN-γ production to the level of mature T cells. These results reveal a previously unknown metabolic component to postthymic T cell maturation. Copyright © 2017 by The American Association of Immunologists, Inc.

The metabolic enhancer piracetam ameliorates the impairment of mitochondrial function and neurite outgrowth induced by beta-amyloid peptide.

PubMed

Kurz, C; Ungerer, I; Lipka, U; Kirr, S; Schütt, T; Eckert, A; Leuner, K; Müller, W E

2010-05-01

beta-Amyloid peptide (Abeta) is implicated in the pathogenesis of Alzheimer's disease by initiating a cascade of events from mitochondrial dysfunction to neuronal death. The metabolic enhancer piracetam has been shown to improve mitochondrial dysfunction following brain aging and experimentally induced oxidative stress. We used cell lines (PC12 and HEK cells) and murine dissociated brain cells. The protective effects of piracetam in vitro and ex vivo on Abeta-induced impairment of mitochondrial function (as mitochondrial membrane potential and ATP production), on secretion of soluble Abeta and on neurite outgrowth in PC12 cells were investigated. Piracetam improves mitochondrial function of PC12 cells and acutely dissociated brain cells from young NMRI mice following exposure to extracellular Abeta(1-42). Similar protective effects against Abeta(1-42) were observed in dissociated brain cells from aged NMRI mice, or mice transgenic for mutant human amyloid precursor protein (APP) treated with piracetam for 14 days. Soluble Abeta load was markedly diminished in the brain of those animals after treatment with piracetam. Abeta production by HEK cells stably transfected with mutant human APP was elevated by oxidative stress and this was reduced by piracetam. Impairment of neuritogenesis is an important consequence of Abeta-induced mitochondrial dysfunction and Abeta-induced reduction of neurite growth in PC12 cells was substantially improved by piracetam. Our findings strongly support the concept of improving mitochondrial function as an approach to ameliorate the detrimental effects of Abeta on brain function.

Influence of organic and functional dyspepsia on work productivity: the HEROES-DIP study.

PubMed

Sander, Guilherme Becker; Mazzoleni, Luiz Edmundo; Francesconi, Carlos Ferrnando de Magalhães; Balbinotto, Giácomo; Mazzoleni, Felipe; Wortmann, Andre Castagna; Cardoso, Israel de Quadros; Klamt, Alexandre Luis; Milbradt, Tobias Cancian

2011-01-01

Dyspepsia is defined as persistent or recurrent abdominal pain or discomfort centered in the upper abdomen. Dyspepsia represents up to 8.3% of all primary care physician visits and causes huge economic costs to patients and to the economy as a whole. The aim of this study was to measure the influence of dyspepsia on work productivity of people within the Brazilian workforce. Adult patients were enrolled if they met the Roma III criteria for uninvestigated dyspepsia. All patients answered a demographic questionnaire. Productivity impairment was measured by the Work Productivity and Activity Impairment questionnaire. Subjects underwent upper gastrointestinal endoscopy and were classified as having functional or organic dyspepsia. The study protocol was approved by the Ethics Committee of Hospital de Clínicas de Porto Alegre, Brazil. Eight hundred fifty patients with dyspepsia were evaluated: 628 were women (73.9%); mean age was 46.4 ± 12.9 years; 387 (45.5%) were active workers. Among active workers, 32.2% mentioned that dyspepsia had caused absenteeism from work during the preceding week and 78% reported a reduction of the work productivity (presenteeism). The lost work productivity score was 35.7% among all employed patients. The affect on work productivity was similar between patients with functional or organic dyspepsia. Our study showed an important influence of dyspepsia on work productivity. We did not find any statistically significant difference on the influence on work between patients with organic dyspepsia and functional dyspepsia. The social impact of these findings is underscored by taking into account the prevalence (up to 40%) of this condition in Brazil. Copyright © 2011 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Gossypol Toxicity from Cottonseed Products

PubMed Central

Gadelha, Ivana Cristina N.; Fonseca, Nayanna Brunna S.; Oloris, Silvia Catarina S.; Melo, Marília M.

2014-01-01

Gossypol is a phenolic compound produced by pigment glands in cotton stems, leaves, seeds, and flower buds (Gossypium spp.). Cottonseed meal is a by-product of cotton that is used for animal feeding because it is rich in oil and proteins. However, gossypol toxicity limits cottonseed use in animal feed. High concentrations of free gossypol may be responsible for acute clinical signs of gossypol poisoning which include respiratory distress, impaired body weight gain, anorexia, weakness, apathy, and death after several days. However, the most common toxic effects is the impairment of male and female reproduction. Another important toxic effect of gossypol is its interference with immune function, reducing an animal's resistance to infections and impairing the efficiency of vaccines. Preventive procedures to limit gossypol toxicity involve treatment of the cottonseed product to reduce the concentration of free gossypol with the most common treatment being exposure to heat. However, free gossypol can be released from the bound form during digestion. Agronomic selection has produced cotton varieties devoid of glands producing gossypol, but these varieties are not normally grown because they are less productive and are more vulnerable to attacks by insects. PMID:24895646

Mitochondrial Dysfunctions in Bipolar Disorder: Effect of the Disease and Pharmacotherapy.

PubMed

Cikankova, Tereza; Sigitova, Ekaterina; Zverova, Martina; Fisar, Zdenek; Raboch, Jiri; Hroudova, Jana

2017-01-01

Exact pathophysiological mechanisms of bipolar disorder have not been sufficiently clarified. We review the evidence of mitochondrial dysfunctions on the relation between both disease and pharmacotherapy. Mitochondria produce the most of energy-rich molecules of adenosine triphosphate (ATP), apart from energy production they are involved in other functions: regulation of free radicals, antioxidant defenses, lipid peroxidation, calcium metabolism and participate in the intrinsic pathway of apoptosis. According to increasing evidence dysfunctions of mitochondria are associated with affective disorders, a hypothesis of impaired mitochondrial functions has been proposed in bipolar disorder pathogenesis. Mitochondrial DNA mutations and/or polymorphisms, impaired phospholipid metabolism and glycolytic shift, decrease in ATP production, increased oxidative stress and changes of intracellular calcium are concerned in mood disorders and effects of mood stabilizers. Recent studies have also provided data about the positive effects of chronic treatment by mood stabilizers on mitochondrial functions. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Music and language in degenerative disease of the brain.

PubMed

Polk, M; Kertesz, A

1993-05-01

Music and language functions were studied in two musicians with degenerative disease. Both patients were tested on a standardized language battery and a series of music tasks. In the first case with left cortical atrophy and primary progressive aphasia, expressive music functions were spared with impaired reception of rhythm. The second case with posterior cortical atrophy, greater on the right, was nonaphasic, had spatial agraphia, a visuopractic deficit, and severe expressive music deficits, but intact rhythm repetition. The aphasic patient showed dissociations between music and language in fluency and content; continuous, organized, although reiterative music production was contrasted with nonfluent language. The nonaphasic patient showed the opposite pattern of deficits; unmusical production with impaired melody and rhythm organization that was contrasted with fluent, intelligible language. The double dissociation between language and music functions supports the existence of independent cognitive systems, one consistent with conventional left lateralization models of language, temporal sequence, and analytic music processing and another with a right lateralization model of implicit music cognition.

Mechanisms linking brain insulin resistance to Alzheimer's disease

PubMed Central

Matioli, Maria Niures P.S.; Nitrini, Ricardo

2015-01-01

Several studies have indicated that Diabetes Mellitus (DM) can increase the risk of developing Alzheimer's disease (AD). This review briefly describes current concepts in mechanisms linking DM and insulin resistance/deficiency to AD. Insulin/insulin-like growth factor (IGF) resistance can contribute to neurodegeneration by several mechanisms which involve: energy and metabolism deficits, impairment of Glucose transporter-4 function, oxidative and endoplasmic reticulum stress, mitochondrial dysfunction, accumulation of AGEs, ROS and RNS with increased production of neuro-inflammation and activation of pro-apoptosis cascade. Impairment in insulin receptor function and increased expression and activation of insulin-degrading enzyme (IDE) have also been described. These processes compromise neuronal and glial function, with a reduction in neurotransmitter homeostasis. Insulin/IGF resistance causes the accumulation of AβPP-Aβ oligomeric fibrils or insoluble larger aggregated fibrils in the form of plaques that are neurotoxic. Additionally, there is production and accumulation of hyper-phosphorylated insoluble fibrillar tau which can exacerbate cytoskeletal collapse and synaptic disconnection. PMID:29213950

NMDA receptor hypofunction in the dentate gyrus and impaired context discrimination in adult Fmr1 knockout mice.

PubMed

Eadie, Brennan D; Cushman, Jesse; Kannangara, Timal S; Fanselow, Michael S; Christie, Brian R

2012-02-01

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability in humans. This X-linked disorder is caused by the transcriptional repression of a single gene, Fmr1. The loss of Fmr1 transcription prevents the production of Fragile X mental retardation protein (FMRP) which in turn disrupts the expression of a variety of key synaptic proteins that appear to be important for intellectual ability. A clear link between synaptic dysfunction and behavioral impairment has been elusive, despite the fact that several animal models of FXS have been generated. Here we report that Fmr1 knockout mice exhibit impaired bidirectional synaptic plasticity in the dentate gyrus (DG) of the hippocampus. These deficits are associated with a novel decrease in functional NMDARs (N-methyl-D-aspartate receptors). In addition, mice lacking the Fmr1 gene show impaired performance in a context discrimination task that normally requires functional NMDARs in the DG. These data indicate that Fmr1 deletion results in significant NMDAR-dependent electrophysiological and behavioral impairments specific to the DG. Copyright © 2010 Wiley Periodicals, Inc.

The Use of Grammatical Morphemes by Mandarin-Speaking Children with High Functioning Autism

ERIC Educational Resources Information Center

Zhou, Peng; Crain, Stephen; Gao, Liqun; Tang, Ye; Jia, Meixiang

2015-01-01

The present study investigated the production of grammatical morphemes by Mandarin-speaking children with high functioning autism. Previous research found that a subgroup of English-speaking children with autism exhibit deficits in the use of grammatical morphemes that mark tense. In order to see whether this impairment in grammatical morphology…

Reductions in employee productivity impairment observed after implementation of web-based worksite health promotion programs.

PubMed

Silberman, Jordan; Schwartz, Steven; Giuseffi, Danielle L; Wang, Chun; Nevedal, Dana; Bedrosian, Richard

2011-12-01

To assess changes in employee productivity impairment observed after the implementation of several Web-based health promotion programs. Health risk assessments and self-report measures of productivity impairment were administered on-line to more than 43,000 participants of Web-based health promotion programs. Reductions in productivity impairment were observed after 1 month of program utilization. Productivity impairment at 90- and 180-day follow-ups also decreased relative to baseline. Improvements in employee health were associated with reductions in employee productivity impairment. The use of Web-based health promotion programs was associated with reductions in productivity impairment and improvements in employee health. After the implementation of Web-based health promotion programs, reductions in productivity impairment may be observed before reductions in direct health care costs.

Predictors of presenteeism and activity impairment outside work in patients with spondyloarthritis.

PubMed

Haglund, Emma; Petersson, Ingemar F; Bremander, Ann; Bergman, Stefan

2015-06-01

To assess predictors of presenteeism (reduced productivity at work) and activity impairment outside work in patients with spondyloarthritis (SpA). Multivariate logistic regression analysis was used to study predictors of presenteeism and activity impairment in 1,253 patients with SpA based on a 2.5 year follow-up questionnaire. The Work Productivity and Activity Impairment (WPAI) questionnaire was used as main outcome. Age, gender, lifestyle factors, subgroups, disease duration, and different patient reported outcome measures (PROMs) were studied as possible predictors. The association between presenteeism and WPAI activity impairment outside work was assessed. Out of 1,253 patients, 757 reported being in work and of these 720 responded to the WPAI questionnaire. The mean (confidence interval, CI) reported presenteeism was 25% (23-27%) and mean activity impairment 33% (31-35%) (0-100%, 0 = no reduction). Significant predictors of presenteeism and activity impairment at follow-up (controlled for gender, age, spondyloarthritis subgroups and presenteeism at baseline) were presenteeism at baseline, poor quality of life, worse disease activity, decreased physical function, lower self-efficacy pain and symptom, higher scores of anxiety, depression, smoking and low education level, and for activity impairment also female sex. There was a strong association between presenteeism and activity impairment outside work (OR 16.7; 95% CI 11.6-24.3; p < 0.001). Presenteeism and activity impairment were not only predicted by presenteeism at baseline, but also by several PROMs commonly used in clinical rheumatology practice. Impaired activity outside work could indicate problems also at work suggesting why both areas need to be addressed in the clinical situation.

Culture supernatants of oral cancer cells induce impaired IFN-α production of pDCs partly through the down-regulation of TLR-9 expression.

PubMed

Han, Nannan; Zhang, Zun; Jv, Houyu; Hu, Jingzhou; Ruan, Min; Zhang, Chenping

2018-06-05

The aim of the present study was to investigate whether tumor-derived supernatants down-regulate the immune function of plasmacytoid dendritic cells (pDCs) in oral cancer and the potential molecular mechanisms of this effect. Immunohistochemistry (IHC) and flow cytometry were used to detect tumor-infiltrating and peripheral blood pDCs. MTS and flow cytometry were employed to evaluate the immune response of CD4 + T cells. Real-time PCR and ELISA assays were used to identify TLR-7 and TLR-9 expression, IFN-α production and tumor-secreted soluble cytokines. The proportion of pDCs (0.121%±0.043%) was significantly higher in Oral squamous cell carcinoma (OSCC) samples than in normal tissue (0.023%±0.016%) (P = 0.021). TLR9 mRNA was significantly lower in tumor-infiltrating pDCs and positively correlated to low IFN-α production (r = 0.956; P<0.01). The supernatant of oral cancer cells negatively regulated TLR9 mRNA expression and the subsequent IFN-α production of pDCs, which inhibited the immune response of CD4 + T cells. The neutralizing antibodies blocking assay showed that the specific inhibitory effect of pDC functionality was associated with the soluble fraction of the oral cancer environment, which is mainly mediated by IL-10 and TGF-β cooperation. Tumor-derived supernatants may impair the function of tumor-infiltrating pDCs, which subsequently decreases the immune response of CD4 + T cells in human oral cancer through TGF-β- and IL-10- dependent mechanisms. Careful manipulation of these impaired pDCs may help develop an important alternative immunotherapy for the treatment of oral cancer. Copyright © 2018 Elsevier Ltd. All rights reserved.

Atypical speech lateralization in adults with developmental coordination disorder demonstrated using functional transcranial Doppler ultrasound.

PubMed

Hodgson, Jessica C; Hudson, John M

2017-03-01

Research using clinical populations to explore the relationship between hemispheric speech lateralization and handedness has focused on individuals with speech and language disorders, such as dyslexia or specific language impairment (SLI). Such work reveals atypical patterns of cerebral lateralization and handedness in these groups compared to controls. There are few studies that examine this relationship in people with motor coordination impairments but without speech or reading deficits, which is a surprising omission given the prevalence of theories suggesting a common neural network underlying both functions. We use an emerging imaging technique in cognitive neuroscience; functional transcranial Doppler (fTCD) ultrasound, to assess whether individuals with developmental coordination disorder (DCD) display reduced left-hemisphere lateralization for speech production compared to control participants. Twelve adult control participants and 12 adults with DCD, but no other developmental/cognitive impairments, performed a word-generation task whilst undergoing fTCD imaging to establish a hemispheric lateralization index for speech production. All participants also completed an electronic peg-moving task to determine hand skill. As predicted, the DCD group showed a significantly reduced left lateralization pattern for the speech production task compared to controls. Performance on the motor skill task showed a clear preference for the dominant hand across both groups; however, the DCD group mean movement times were significantly higher for the non-dominant hand. This is the first study of its kind to assess hand skill and speech lateralization in DCD. The results reveal a reduced leftwards asymmetry for speech and a slower motor performance. This fits alongside previous work showing atypical cerebral lateralization in DCD for other cognitive processes (e.g., executive function and short-term memory) and thus speaks to debates on theories of the links between motor control and language production. © 2016 The Authors. Journal of Neuropsychology published by John Wiley & Sons Ltd on behalf of British Psychological Society.

CLASSIFYING COASTAL WATERS:CURRENT NECESSITY AND HISTORICAL PERSPECTIVE

EPA Science Inventory

Coastal ecosystems are ecologically and commercially valuable, productive habitats that are experiencing escalating compromises of their structural and functional integrity. The Clean Water Act (USC 1972) requires identification of impaired water bodies and determination of the c...

The role of cognitive impairment in psychosocial functioning in remitted depression.

PubMed

Knight, Mattew J; Air, Tracy; Baune, Bernhard T

2018-08-01

Cognitive dysfunction is a prevalent and disabling symptom of Major Depressive Disorder (MDD), and is often retained in the remitted stage of illness. Emerging evidence suggests that cognitive impairment may be associated with dysfunction in a number of psychosocial domains (e.g., workplace productivity, social relationships). The current study explored the relationship between cognition and psychosocial functioning in remitted MDD and in healthy controls. Data were obtained from 182 participants of the Cognitive Function and Mood Study (CoFaM-S), a cross-sectional study of cognition, mood, and social cognition in mood disorders. Participants' (Remitted MDD n = 72, Healthy n = 110) cognition was assessed with a battery of cognitive tests including the Repeatable Battery for the Assessment of Neuropsychological Function (RBANS) and other standard measures of cognition (e.g., The Tower of London task). Psychosocial functioning was clinically evaluated with the Functioning Assessment Short Test (FAST). The results indicated that executive functioning was the strongest independent predictor of functioning in remitted MDD patients, whereas various cognitive domains predicted psychosocial functioning in healthy individuals. Psychosocial functioning was measured with a clinical interview, and was therefore reliant on clinicians' judgement of impairment, as opposed to more objective measures of functioning. These findings suggest that executive cognition plays an important role in functional recovery in remitted depression, and may be a crucial target in adjunctive treatment. Copyright © 2018 Elsevier B.V. All rights reserved.

Functional impairment of cytomegalovirus specific CD8 T cells predicts high-level replication after renal transplantation.

PubMed

Mattes, F M; Vargas, A; Kopycinski, J; Hainsworth, E G; Sweny, P; Nebbia, G; Bazeos, A; Lowdell, M; Klenerman, P; Phillips, R E; Griffiths, P D; Emery, V C

2008-05-01

Human cytomegalovirus (HCMV) remains an important cause of morbidity after allotransplantation, causing a range of direct effects including hepatitis, pneumonitis, enteritis and retinitis. A dominant risk factor for HCMV disease is high level viral replication in blood but it remains unexplained why only a subset of patients develop such diseases. In this detailed study of 25 renal transplant recipients, we show that functional impairment of HCMV specific CD8 T cells in the production of interferon gamma was associated with a 14-fold increased risk of progression to high level replication. The CD8 T-cell impairment persisted during the period of high level replication and was more prominent in patients above 40 years of age (odds ratio = 1.37, p = 0.01) and was also evident in dialysis patients. Threshold levels of functional impairment were associated with an increased risk of future HCMV replication and there was a direct relationship between the functional capacity of HCMV ppUL83 CD8 T cells and HCMV load (R(2)= 0.83). These results help to explain why a subset of seropositive individuals develop HCMV replication and are at risk of end-organ disease and may facilitate the early identification of individuals who would benefit from targeted anti-HCMV therapy after renal transplantation.

Stimulus Over-Selectivity and Extinction-Induced Recovery of Performance as a Product of Intellectual Impairment and Autism Severity

ERIC Educational Resources Information Center

Kelly, Michelle P.; Leader, Geraldine; Reed, Phil

2015-01-01

The current experiment investigated the extent to which three variables (autism severity, nonverbal intellectual functioning, and verbal intellectual functioning) are associated with over-selective responding in a group of children with Autism Spectrum Disorder. This paper also analyzed the association of these three variables with the recovery of…

Impaired plasmacytoid dendritic cell (PDC)-NK cell activity in viremic human immunodeficiency virus infection attributable to impairments in both PDC and NK cell function.

PubMed

Conry, Sara J; Milkovich, Kimberly A; Yonkers, Nicole L; Rodriguez, Benigno; Bernstein, Helene B; Asaad, Robert; Heinzel, Frederick P; Tary-Lehmann, Magdalena; Lederman, Michael M; Anthony, Donald D

2009-11-01

Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections impair plasmacytoid dendritic cell (PDC) and natural killer (NK) cell subset numbers and functions, though little is known about PDC-NK cell interactions during these infections. We evaluated PDC-dependent NK cell killing and gamma interferon (IFN-gamma) and granzyme B production, using peripheral blood mononuclear cell (PBMC)-based and purified cell assays of samples from HCV- and HIV-infected subjects. CpG-enhanced PBMC killing and IFN-gamma and granzyme B activity (dependent on PDC and NK cells) were impaired in viremic HIV infection. In purified PDC-NK cell culture experiments, CpG-enhanced, PDC-dependent NK cell activity was cell contact and IFN-alpha dependent, and this activity was impaired in viremic HIV infection but not in HCV infection. In heterologous PDC-NK cell assays, impaired PDC-NK cell killing activity was largely attributable to an NK cell defect, while impaired PDC-NK cell IFN-gamma-producing activity was attributable to both PDC and NK cell defects. Additionally, the response of NK cells to direct IFN-alpha stimulation was defective in viremic HIV infection, and this defect was not attributable to diminished IFN-alpha receptor expression, though IFN-alpha receptor and NKP30 expression was closely associated with killer activity in viremic HIV infection but not in healthy controls. These data indicate that during uncontrolled HIV infection, PDC-dependent NK cell function is impaired, which is in large part attributable to defective IFN-alpha-induced NK cell activity and not to altered IFN-alpha receptor, NKP30, NKP44, NKP46, or NKG2D expression.

The effect of personality dimensions on functional outcomes in mood disorders.

PubMed

Leen, Jessica; Soczynska, Joanna K; Gallaugher, Laura Ashley; Woldeyohannes, Hanna O; Alsuwaidan, Mohammad T; Cha, Danielle S; Dale, Roman M; Muzina, David J; Kennedy, Sidney H; McIntyre, Roger S

2013-07-01

Functional impairment associated with mood disorders may be related to a characteristic "profile" of normative personality dimensions. Individuals (age ≥ 18 years) with MDD (n = 400) or BD (n = 317), as defined by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR), were enrolled in the IMDCP. Personality was evaluated with the Neuroticism-Extraversion-Openness Five-Factor Inventory (NEO-FFI), and functionality with the Sheehan Disability Scale and Endicott Work Productivity Scale. Path analysis using linear multiple regressions was performed to identify direct and indirect effects of personality on functional impairment. Lower conscientiousness exerted a significant direct effect on global (p = 0.017) and family life dysfunction in individuals with MDD (p = 0.002), as well as lower work productivity in both MDD (p = 0.020) and BD (p = 0.018). Lower extraversion exerted a significant direct effect on social impairment in individuals with BD (p = 0.017). Higher neuroticism and agreeableness as well as lower extraversion exerted indirect effects on global and social dysfunction in individuals with MDD via their effects on depression severity. In BD, higher neuroticism and openness indirectly affected global dysfunction. Family dysfunction was indirectly affected by higher neuroticism and openness as well as lower extraversion in MDD and BD. The results suggest that discrete personality dimensions may exert direct and indirect effects on functional outcomes in individuals with mood disorders. Personalizing disease management approaches in mood disorders with emphasis on vocational rehabilitation may benefit from measurement and intervention targeting personality.

The impact of hearing loss on language performance in older adults with different stages of cognitive function

PubMed Central

Lodeiro-Fernández, Leire; Lorenzo-López, Laura; Maseda, Ana; Núñez-Naveira, Laura; Rodríguez-Villamil, José Luis; Millán-Calenti, José Carlos

2015-01-01

Purpose The possible relationship between audiometric hearing thresholds and cognitive performance on language tests was analyzed in a cross-sectional cohort of older adults aged ≥65 years (N=98) with different degrees of cognitive impairment. Materials and methods Participants were distributed into two groups according to Reisberg’s Global Deterioration Scale (GDS): a normal/predementia group (GDS scores 1–3) and a moderate/moderately severe dementia group (GDS scores 4 and 5). Hearing loss (pure-tone audiometry) and receptive and production-based language function (Verbal Fluency Test, Boston Naming Test, and Token Test) were assessed. Results Results showed that the dementia group achieved significantly lower scores than the predementia group in all language tests. A moderate negative correlation between hearing loss and verbal comprehension (r=−0.298; P<0.003) was observed in the predementia group (r=−0.363; P<0.007). However, no significant relationship between hearing loss and verbal fluency and naming scores was observed, regardless of cognitive impairment. Conclusion In the predementia group, reduced hearing level partially explains comprehension performance but not language production. In the dementia group, hearing loss cannot be considered as an explanatory factor of poor receptive and production-based language performance. These results are suggestive of cognitive rather than simply auditory problems to explain the language impairment in the elderly. PMID:25914528

Diabetes-related dysfunction of the small intestine and the colon: focus on motility.

PubMed

Horváth, Viktor József; Putz, Zsuzsanna; Izbéki, Ferenc; Körei, Anna Erzsébet; Gerő, László; Lengyel, Csaba; Kempler, Péter; Várkonyi, Tamás

2015-11-01

In contrast to gastric dysfunction, diabetes-related functional impairments of the small and large intestine have been studied less intensively. The gastrointestinal tract accomplishes several functions, such as mixing and propulsion of luminal content, absorption and secretion of ions, water, and nutrients, defense against pathogens, and elimination of waste products. Diverse functions of the gut are regulated by complex interactions among its functional elements, including gut microbiota. The network-forming tissues, the enteric nervous system) and the interstitial cells of Cajal, are definitely impaired in diabetic patients, and their loss of function is closely related to the symptoms in diabetes, but changes of other elements could also play a role in the development of diabetes mellitus-related motility disorders. The development of our understanding over the recent years of the diabetes-induced dysfunctions in the small and large intestine are reviewed in this article.

Mechanisms for impaired effector function in alveolar macrophages from marijuana and cocaine smokers.

PubMed

Roth, Michael D; Whittaker, Katherine; Salehi, Ken; Tashkin, Donald P; Baldwin, Gayle C

2004-02-01

Lung macrophages provide a first line of host defense against inhaled pathogens and their function is impaired in the lungs of inhaled substance abusers. In order to investigate the mechanism for this impairment, alveolar macrophages (AM) were recovered from nonsmokers (NS), regular tobacco smokers (TS), marijuana smokers (MS), or crack cocaine smokers (CS), and evaluated for their production of nitric oxide (NO) and the role of NO as an antimicrobial effector molecule. AM from NS and TS efficiently killed Staphylococcus aureus and their antibacterial activity correlated closely with the production of nitrite and the expression of mRNA encoding for inducible nitric oxide synthase (iNOS). In contrast, AM collected from MS and CS exhibited limited antimicrobial activity that was not affected by an inhibitor of iNOS, or associated with expression of iNOS. Treatment with either granulocyte/macrophage colony-stimulating factor (GM-CSF) or interferon-gamma restored the ability of these cells to produce NO and to kill bacteria. These findings confirm a significant role for NO as an antibacterial effector molecule used by normal human AM and suggest that this host defense mechanism is suppressed by habitual exposure to inhaled marijuana or crack cocaine in vivo.

Persistent impairment in working memory following severe hyperglycemia in newly diagnosed type 2 diabetes.

PubMed

Cerasuolo, Joseph; Izzo, Anthony

2017-01-01

Acute hyperglycemia has been shown to cause cognitive impairments in animal models. There is growing appreciation of the numerous effects of hyperglycemia on neuronal function as well as blood-brain barrier function. In humans, hypoglycemia is well known to cause cognitive deficits acutely, but hyperglycemia has been less well studied. We present a case of selective neurocognitive deficits in the setting of acute hyperglycemia. A 60-year-old man was admitted to the hospital for an episode of acute hyperglycemia in the setting of newly diagnosed diabetes mellitus precipitated by steroid use. He was managed with insulin therapy and discharged home, and later, presented with complaints of memory impairment. Deficits included impairment in his declarative and working memory, to the point of significant impairment in his overall functioning. The patient had no structural lesions on MRI imaging of the brain or other systemic illnesses to explain his specific deficits. We suggest that his acute hyperglycemia may have caused neurological injury, and may be responsible for our patient's memory complaints. Acute hyperglycemia has been associated with poor outcomes in several different central nervous system injuries including cerebrovascular accident and hypoxic injury.Hyperglycemia is responsible for accumulation of reactive oxygen species in the brain, resulting in advanced glycosylated end products and a proinflammatory response that may lead to cellular injury.Further research is needed to define the impact of both acute and chronic hyperglycemia on cognitive impairment and memory.

Functional impairment related to painful physical symptoms in patients with generalized anxiety disorder with or without comorbid major depressive disorder: post hoc analysis of a cross-sectional study

PubMed Central

2011-01-01

Background Generalized anxiety disorder (GAD) is the most frequent anxiety disorder in primary care patients. It is known that painful physical symptoms (PPS) are associated with GAD, regardless the presence of comorbid major depressive disorder (MDD). However the specific role of such symptoms in patients' functional impairment is not well understood. The objective of the present study is to assess functional impairment related to the presence of PPS in patients with GAD. Methods This is a post hoc analysis of a cross-sectional study. Functioning, in the presence (overall pain score >30; Visual Analog Scale) or absence of PPS, was assessed using the Sheehan Disability Scale (SDS) in three groups of patients; 1) GAD and comorbid MDD (GAD+MDD+), 2) GAD without comorbid MDD (GAD+MDD-), 3) controls (GAD-MDD-). ANCOVA models were used. Results Of those patients with GAD+MDD+ (n = 559), 436 (78.0%) had PPS, compared with GAD+MDD- (249 of 422, 59%) and controls (95 of 336, 28.3%). Functioning worsened in both GAD groups in presence of PPS (SDS least squares mean total score: 16.1 vs. 9.8, p < 0.0001, GAD+MDD+; 14.3 vs. 8.2, p < 0.0001, GAD+MDD-). The presence of PPS was significantly associated with less productivity. Conclusions Functional impairment related to the presence of PPS was relevant. Clinical implications should be considered. PMID:21510887

Induction of Inhibitory Receptors on T Cells During Plasmodium vivax Malaria Impairs Cytokine Production

PubMed Central

Costa, Pedro A. C.; Leoratti, Fabiana M. S.; Figueiredo, Maria M.; Tada, Mauro S.; Pereira, Dhelio B.; Junqueira, Caroline; Soares, Irene S.; Barber, Daniel L.; Gazzinelli, Ricardo T.; Antonelli, Lis R. V.

2015-01-01

The function and regulation of the immune response triggered during malaria is complex and poorly understood, and there is a particular paucity of studies conducted in humans infected with Plasmodium vivax. While it has been proposed that T-cell-effector responses are crucial for protection against blood-stage malaria in mice, the mechanisms behind this in humans remain poorly understood. Experimental models of malaria have shown that the regulatory molecules, cytotoxic T-lymphocyte attenuator-4 (CTLA-4), lymphocyte activation gene-3 (LAG-3), and programmed death-1 (PD-1) are involved in the functional impairment of T cells during infection. Our goal was to define the role of these molecules during P. vivax malaria. We demonstrate that infection triggers the expression of regulatory molecules on T cells. The pattern of expression differs in CD4+ and CD8+ T cells. Higher frequencies of CD4+ express more than 1 regulatory molecule compared to CD8+ T cells. Moreover, lower proportions of CD4+ T cells coexpress regulatory molecules, but are still able to proliferate. Importantly, simultaneously blockade of the CLTA-4, PD-1, and T-cell immunoglobulin and mucin–3 signaling restores the cytokine production by antigen-specific cells. These data support the hypothesis that upregulation of inhibitory receptors on T cells during P. vivax malaria impairs parasite-specific T-cell effector function. PMID:26019284

Dietary Patterns Associated with Cognitive Function among the Older People in Underdeveloped Regions: Finding from the NCDFaC Study.

PubMed

Yin, Zhaoxue; Chen, Jing; Zhang, Jian; Ren, Zeping; Dong, Kui; Kraus, Virginia B; Wang, Zhuoqun; Zhang, Mei; Zhai, Yi; Song, Pengkun; Zhao, Yanfang; Pang, Shaojie; Mi, Shengquan; Zhao, Wenhua

2018-04-09

Although dietary patterns are crucial to cognitive function, associations of dietary patterns with cognitive function have not yet been fully understood. This cross-sectional study explored dietary patterns associated with cognitive function among the older adults in underdeveloped regions, using 1504 community-dwelling older adults aged 60 and over. Diet was assessed using a food frequency questionnaire and 24-h dietary recall. Factor analysis was used to extract dietary patterns. Global cognitive function was assessed using the Mini-Mental State Examination (MMSE). Two dietary patterns, a "mushroom, vegetable, and fruits" (MVF) pattern and a "meat and soybean products" (MS) pattern, were identified. The MVF pattern, characterized by high consumption of mushrooms, vegetables, and fruits was significantly positively associated with cognitive function ( p < 0.05), with an odds ratio of (95% CIs) 0.60 (0.38, 0.94) for cognitive impairment and β (95% CIs) 0.15 (0.02, 0.29) for -log (31-MMSE score). The MS pattern, characterized by high consumption of soybean products and meat, was also associated with better cognitive function, with an odds ratio of 0.47 (95% CIs 0.30, 0.74) for cognitive impairment and β (95% CIs) 0.34 (0.21, 0.47) for -log (31-MMSE score). Our results suggested that both the MVF and MS patterns were positively associated with better cognitive function among older adults in underdeveloped regions.

Oxidative phosphorylation is essential for felid sperm function, but is substantially lower in cheetah (Acinonyx jubatus) compared to domestic cat (Felis catus) ejaculate.

PubMed

Terrell, Kimberly A; Wildt, David E; Anthony, Nicola M; Bavister, Barry D; Leibo, S P; Penfold, Linda M; Marker, Laurie L; Crosier, Adrienne E

2011-09-01

Compared with the normospermic domestic cat, sperm metabolic function is compromised in the teratospermic cat and cheetah, but the pathway(s) involved in this deficiency are unknown. Glycolysis is essential for sperm motility, yet it appears to function normally in spermatozoa of either species regardless of structural morphology. We conducted a comparative study to further understand the mechanisms of energy production in felid spermatozoa, with the hypothesis that oxidative phosphorylation is required for normal sperm function and is impaired in teratospermic ejaculates. Electroejaculates from both species were stained with MitoTracker to quantify mitochondrial membrane potential (MMP) or were incubated to assess changes in sperm function (motility, acrosomal integrity, and lactate production) after mitochondrial inhibition with myxothiazol. Sperm midpiece dimensions also were quantified. Sperm mitochondrial fluorescence (directly proportional to MMP) was ~95% lower in the cheetah compared with the normospermic and teratospermic cat, despite the cheetah having a 10% longer midpiece. In both species, MMP was increased 5-fold in spermatozoa with retained cytoplasm compared with structurally normal cells. Inhibition of oxidative phosphorylation impaired sperm function in both species, but a 100-fold higher inhibitor concentration was required in the cat compared with the cheetah. Collectively, findings revealed that oxidative phosphorylation was required for sperm function in the domestic cat and cheetah. This pathway of energy production appeared markedly less active in the cheetah, indicating a species-specific vulnerability to mitochondrial dysfunction. The unexpected, cross-species linkage between retained cytoplasmic droplets and elevated MMP may reflect increased concentrations of metabolic enzymes or substrates in these structures.

Impairment of speech production predicted by lesion load of the left arcuate fasciculus.

PubMed

Marchina, Sarah; Zhu, Lin L; Norton, Andrea; Zipse, Lauryn; Wan, Catherine Y; Schlaug, Gottfried

2011-08-01

Previous studies have suggested that patients' potential for poststroke language recovery is related to lesion size; however, lesion location may also be of importance, particularly when fiber tracts that are critical to the sensorimotor mapping of sounds for articulation (eg, the arcuate fasciculus) have been damaged. In this study, we tested the hypothesis that lesion loads of the arcuate fasciculus (ie, volume of arcuate fasciculus that is affected by a patient's lesion) and of 2 other tracts involved in language processing (the extreme capsule and the uncinate fasciculus) are inversely related to the severity of speech production impairments in patients with stroke with aphasia. Thirty patients with chronic stroke with residual impairments in speech production underwent high-resolution anatomic MRI and a battery of cognitive and language tests. Impairment was assessed using 3 functional measures of spontaneous speech (eg, rate, informativeness, and overall efficiency) as well as naming ability. To quantitatively analyze the relationship between impairment scores and lesion load along the 3 fiber tracts, we calculated tract-lesion overlap volumes for each patient using probabilistic maps of the tracts derived from diffusion tensor images of 10 age-matched healthy subjects. Regression analyses showed that arcuate fasciculus lesion load, but not extreme capsule or uncinate fasciculus lesion load or overall lesion size, significantly predicted rate, informativeness, and overall efficiency of speech as well as naming ability. A new variable, arcuate fasciculus lesion load, complements established voxel-based lesion mapping techniques and, in the future, may potentially be used to estimate impairment and recovery potential after stroke and refine inclusion criteria for experimental rehabilitation programs.

Phthalate-Induced Pathology in the Foetal Testis Involves More Than Decreased Testosterone Production

EPA Science Inventory

Foetal exposure to phthalates is known to adversely impact male reproductive development and function. Developmental anomalies of reproductive tract have been attributed to impaired testosterone synthesis. However, species differences in the ability to produce testosterone have...

46 CFR 160.057-4 - Approval and production tests.

Code of Federal Regulations, 2011 CFR

2011-10-01

....) above the surface of a body of water. The buoy is released and must cause the signal to ignite and fall... fashion that would impair their proper functioning. (8) Color of smoke. Ignite specimen in the open air in...

Directed evolution can rapidly improve the activity of chimeric assembly-line enzymes

PubMed Central

Fischbach, Michael A.; Lai, Jonathan R.; Roche, Eric D.; Walsh, Christopher T.; Liu, David R.

2007-01-01

Nonribosomal peptides (NRPs) are produced by NRP synthetase (NRPS) enzymes that function as molecular assembly lines. The modular architecture of NRPSs suggests that a domain responsible for activating a building block could be replaced with a domain from a foreign NRPS to create a chimeric assembly line that produces a new variant of a natural NRP. However, such chimeric NRPS modules are often heavily impaired, impeding efforts to create novel NRP variants by swapping domains from different modules or organisms. Here we show that impaired chimeric NRPSs can be functionally restored by directed evolution. Using rounds of mutagenesis coupled with in vivo screens for NRP production, we rapidly isolated variants of two different chimeric NRPSs with ≈10-fold improvements in enzyme activity and product yield, including one that produces new derivatives of the potent NRP/polyketide antibiotic andrimid. Because functional restoration in these examples required only modest library sizes (103 to 104 clones) and three or fewer rounds of screening, our approach may be widely applicable even for NRPSs from genetically challenging hosts. PMID:17620609

Activating transcription factor 4 underlies the pathogenesis of arsenic trioxide-mediated impairment of macrophage innate immune functions

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

Srivastava, Ritesh K.; Li, Changzhao

Chronic arsenic exposure to humans is considered immunosuppressive with augmented susceptibility to several infectious diseases. The exact molecular mechanisms, however, remain unknown. Earlier, we showed the involvement of unfolded protein response (UPR) signaling in arsenic-mediated impairment of macrophage functions. Here, we show that activating transcription factor 4 (ATF4), a UPR transcription factor, regulates arsenic trioxide (ATO)-mediated dysregulation of macrophage functions. In ATO-treated ATF4{sup +/+} wild-type mice, a significant down-regulation of CD11b expression was associated with the reduced phagocytic functions of peritoneal and lung macrophages. This severe immuno-toxicity phenotype was not observed in ATO-treated ATF4{sup +/−} heterozygous mice. To confirm thesemore » observations, we demonstrated in Raw 264.7 cells that ATF4 knock-down rescues ATO-mediated impairment of macrophage functions including cytokine production, bacterial engulfment and clearance of engulfed bacteria. Sustained activation of ATF4 by ATO in macrophages induces apoptosis, while diminution of ATF4 expression protects against ATO-induced apoptotic cell death. Raw 264.7 cells treated with ATO also manifest dysregulated Ca{sup ++} homeostasis. ATO induces Ca{sup ++}-dependent calpain-1 and caspase-12 expression which together regulated macrophage apoptosis. Additionally, apoptosis was also induced by mitochondria-regulated pathway. Restoring ATO-impaired Ca{sup ++} homeostasis in ER/mitochondria by treatments with the inhibitors of inositol 1,4,5-trisphosphate receptor (IP3R) and voltage-dependent anion channel (VDAC) attenuate innate immune functions of macrophages. These studies identify a novel role for ATF4 in underlying pathogenesis of macrophage dysregulation and immuno-toxicity of arsenic. - Highlights: • ATF4 regulates arsenic-mediated impairment in macrophage functions. • Arsenic-mediated alterations in pulmonary macrophage are diminished in ATF4{sup +/−} mice. • Changes in macrophage functions can be attenuated by Ca{sup ++} homeostasis regulators.« less

Melatonin reverses H-89 induced spatial memory deficit: Involvement of oxidative stress and mitochondrial function.

PubMed

Sharif, Rojin; Aghsami, Mehdi; Gharghabi, Mehdi; Sanati, Mehdi; Khorshidahmad, Tina; Vakilzadeh, Gelareh; Mehdizadeh, Hajar; Gholizadeh, Shervin; Taghizadeh, Ghorban; Sharifzadeh, Mohammad

2017-01-01

Oxidative stress and mitochondrial dysfunction play indispensable role in memory and learning impairment. Growing evidences have shed light on anti-oxidative role for melatonin in memory deficit. We have previously reported that inhibition of protein kinase A by H-89 can induce memory impairment. Here, we investigated the effect of melatonin on H-89 induced spatial memory deficit and pursued their interactive consequences on oxidative stress and mitochondrial function in Morris Water Maze model. Rats received melatonin (50 and 100μg/kg/side) and H-89(10μM) intra-hippocampally 30min before each day of training. Animals were trained for 4 consecutive days, each containing one block from four trials. Oxidative stress indices, including thiobarbituric acid (TBARS), reactive oxygen species (ROS), thiol groups, and ferric reducing antioxidant power (FRAP) were assessed using spectrophotometer. Mitochondrial function was evaluated through measuring ROS production, mitochondrial membrane potential (MMP), swelling, outer membrane damage, and cytochrome c release. As expected from our previous report, H-89 remarkably impaired memory by increasing the escape latency and traveled distance. Intriguingly, H-89 significantly augmented TBARS and ROS levels, caused mitochondrial ROS production, swelling, outer membrane damage, and cytochrome c release. Moreover, H-89 lowered thiol, FRAP, and MMP values. Intriguingly, melatonin pre-treatment not only effectively hampered H-89-mediated spatial memory deficit at both doses, but also reversed the H-89 effects on mitochondrial and biochemical indices upon higher dose. Collectively, these findings highlight a protective role for melatonin against H-89-induced memory impairment and indicate that melatonin may play a therapeutic role in the treatment of oxidative- related neurodegenerative disorders. Copyright © 2016 Elsevier B.V. All rights reserved.

Use of Oral Bisphosphonates by Older Adults with Fractures and Impaired Renal Function

PubMed Central

Sadowski, Cheryl A; Spencer, Tara; Yuksel, Nese

2011-01-01

Background: The manufacturers of oral bisphosphonates (alendronate, risedronate) recommend avoiding use of these drugs in patients with renal impairment. However, many patients who have osteoporosis or who are at risk of fracture are elderly and may have renal impairment. This situation poses a quandary for clinicians in deciding how best to manage osteoporosis in this high-risk population. Objective: To synthesize published evidence regarding the use and safety of oral bisphosphonates for patients with impaired renal function. Methods: The following databases were searched up to October 2010: PubMed, MEDLINE, Embase, the Cochrane Library, and International Pharmaceutical Abstracts. The following key words and terms were used for the searches: bisphosphonates, alendronate, risedronate, Fosamax, Actonel, “renal failure”, “renal insufficiency”, “chronic kidney disease”, and “end-stage renal disease”. The manufacturers of Fosamax and Actonel were asked to provide information about use of their products in patients with renal impairment, including unpublished pharmacokinetic studies or reports of adverse drug events. Results: The search yielded 2 post hoc analyses of safety data, 1 case–control study, 1 case series, 4 retrospective chart analyses, and 2 prospective studies. According to these publications, numerous patients with decreased renal function have received bisphosphonates and have experienced improvement in bone mineral density and/or reduction in risk of fractures, with no increase in adverse effects. Increased renal damage occurred in some individuals with underlying renal disorders, as described in case reports. Conclusions: Although the literature is limited, there is evidence that alendronate and risedronate are well tolerated and effective when used by individuals with renal impairment. Further research is required to confirm the benefits and risks of using these medications in patients with renal impairment. PMID:22479027

Biomarkers of Aging: From Function to Molecular Biology

PubMed Central

Wagner, Karl-Heinz; Cameron-Smith, David; Wessner, Barbara; Franzke, Bernhard

2016-01-01

Aging is a major risk factor for most chronic diseases and functional impairments. Within a homogeneous age sample there is a considerable variation in the extent of disease and functional impairment risk, revealing a need for valid biomarkers to aid in characterizing the complex aging processes. The identification of biomarkers is further complicated by the diversity of biological living situations, lifestyle activities and medical treatments. Thus, there has been no identification of a single biomarker or gold standard tool that can monitor successful or healthy aging. Within this short review the current knowledge of putative biomarkers is presented, focusing on their application to the major physiological mechanisms affected by the aging process including physical capability, nutritional status, body composition, endocrine and immune function. This review emphasizes molecular and DNA-based biomarkers, as well as recent advances in other biomarkers such as microRNAs, bilirubin or advanced glycation end products. PMID:27271660

Dietary Habits and Cognitive Impairment Risk Among Oldest-Old Chinese.

PubMed

An, Ruopeng; Liu, Gordon; Khan, Naiman; Yan, Hai; Wang, Youfa

2017-02-10

This study examined the longitudinal relationship between dietary habits and cognitive impairment among the oldest-old Chinese. Cognitively intact adults aged 80 or older (N = 4,749) came from the Chinese Longitudinal Healthy Longevity Survey. Cognitive impairment was assessed by Mini-mental State Examination. Cox regressions were performed to examine the relationship between dietary habits and cognitive impairment onset during follow-up period of 1998-2012, adjusting for various time-variant and time-invariant individual characteristics. Compared with those who rarely/never consumed fruit, vegetables, meat, and soybean-derived products, participants consuming such products almost every day were 21%, 25%, 17%, and 20% less likely to develop cognitive impairment during follow-up, respectively. Compared with those who rarely/never consumed sugar, participants consuming sugar almost every day were 17% more likely to develop cognitive impairment during follow-up. Consumption of fish, egg, salt-preserved vegetable, tea, and garlic was not found to be associated with cognitive impairment. Dietary habits might profoundly impact cognitive functioning among the oldest-old Chinese. This work has limitations pertaining to study design and measure. Future work adopting experimental design and refined dietary measures is warranted to confirm these findings and inform public nutrition practices aiming at preventing cognitive decline among the oldest-old Chinese population. © The Author 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Prospective study of recovery from copperhead snake envenomation: an observational study.

PubMed

Lavonas, Eric J; Gerardo, Charles J

2015-05-15

Although much is known about signs, symptoms, and management in the acute phase of crotaline snake envenomation, little is known about signs, symptoms, function, and quality of life during the recovery phase. The purpose of this observational pilot investigation is to evaluate the utility of several clinical outcome instruments in the setting of copperhead snakebite, and to characterize the clinical course of recovery. This is a multi-center prospective, open-label, observational study of patients envenomated by copperhead snakes. We administered the Disabilities of the Arm, Shoulder, and Hand (DASH), Lower Extremity Functional Scale (LEFS), Patient-Specific Functional Scale (PSFS), Work Productivity and Ability Impairment: Special Health Problem (WPAI: SHP), Patients' Global Impression of Change (PGIC), Patient's Global Assessment of Recovery (PGAR), and SF-36 instruments, obtained numeric pain rating scales, and measured grip strength, walking speed, and swelling prior to hospital discharge and 3, 7, 14, 21, and 28 days after envenomation. 20 subjects were enrolled; none were lost to follow-up. Most (80%) had moderate severity swelling, and most (75%) received antivenom. Across the broad range of measures, abnormalities of pain, swelling, impairments of physical and role function, and quality of life persisted for 7-14 days in most subjects. Validated self-reported outcome measures, such as the DASH, LEFS, PSFS, PGIC, SF-36, and the daily activities impairment portion of the WPAI: SHP were more responsive than measurements of swelling or walking speed. Data quality issues limited the utility of the work impairment portion of the WPAI: SHP. Residual signs, symptoms, and impairment in some subjects lasted through the 28-day study period. The study design precluded any assessment of the effectiveness of antivenom. Signs, symptoms, impaired function, and decreased quality of life typically last 7 - 14 days after copperhead envenomation. Several tools appear responsive and useful in studying recovery from pit viper envenomation. ClinicalTrials.gov NCT01651299.

Increased androgen levels in rats impair glucose-stimulated insulin secretion through disruption of pancreatic beta cell mitochondrial function.

PubMed

Wang, Hongdong; Wang, Xiaping; Zhu, Yunxia; Chen, Fang; Sun, Yujie; Han, Xiao

2015-11-01

Although insulin resistance is recognized to contribute to the reproductive and metabolic phenotypes of polycystic ovary syndrome (PCOS), pancreatic beta cell dysfunction plays an essential role in the progression from PCOS to the development of type 2 diabetes. However, the role of insulin secretory abnormalities in PCOS has received little attention. In addition, the precise changes in beta cells and the underlying mechanisms remain unclear. In this study, we therefore attempted to elucidate potential mechanisms involved in beta cell alterations in a rat model of PCOS. Glucose-induced insulin secretion was measured in islets isolated from DHT-treated and control rats. Oxygen consumption rate (OCR), ATP production, and mitochondrial copy number were assayed to evaluate mitochondrial function. Glucose-stimulated insulin secretion is significantly decreased in islets from DHT-treated rats. On the other hand, significant reductions are observed in the expression levels of several key genes involved in mitochondrial biogenesis and in mitochondrial OCR and ATP production in DHT-treated rat islets. Meanwhile, we found that androgens can directly impair beta cell function by inducing mitochondrial dysfunction in vitro in an androgen receptor dependent manner. For the first time, our study demonstrates that increased androgens in female rats can impair glucose-stimulated insulin secretion partly through disruption of pancreatic beta cell mitochondrial function. This work has significance for hyperandrogenic women with PCOS: excess activation of the androgen receptor by androgens may provoke beta cell dysfunction via mitochondrial dysfunction. Copyright © 2015 Elsevier Ltd. All rights reserved.

Mitochondrial reactive oxygen species production and respiratory complex activity in rats with pressure overload-induced heart failure

PubMed Central

Schwarzer, Michael; Osterholt, Moritz; Lunkenbein, Anne; Schrepper, Andrea; Amorim, Paulo; Doenst, Torsten

2014-01-01

We investigated the impact of cardiac reactive oxygen species (ROS) during the development of pressure overload-induced heart failure. We used our previously described rat model where transverse aortic constriction (TAC) induces compensated hypertrophy after 2 weeks, heart failure with preserved ejection fraction at 6 and 10 weeks, and heart failure with systolic dysfunction after 20 weeks. We measured mitochondrial ROS production rates, ROS damage and assessed the therapeutic potential of in vivo antioxidant therapies. In compensated hypertrophy (2 weeks of TAC) ROS production rates were normal at both mitochondrial ROS production sites (complexes I and III). Complex I ROS production rates increased with the appearance of diastolic dysfunction (6 weeks of TAC) and remained high thereafter. Surprisingly, maximal ROS production at complex III peaked at 6 weeks of pressure overload. Mitochondrial respiratory capacity (state 3 respiration) was elevated 2 and 6 weeks after TAC, decreased after this point and was significantly impaired at 20 weeks, when contractile function was also impaired and ROS damage was found with increased hydroxynonenal. Treatment with the ROS scavenger α-phenyl-N-tert-butyl nitrone or the uncoupling agent dinitrophenol significantly reduced ROS production rates at 6 weeks. Despite the decline in ROS production capacity, no differences in contractile function between treated and untreated animals were observed. Increased ROS production occurs early in the development of heart failure with a peak at the onset of diastolic dysfunction. However, ROS production may not be related to the onset of contractile dysfunction. PMID:24951621

Dietary restriction improves repopulation but impairs lymphoid differentiation capacity of hematopoietic stem cells in early aging

PubMed Central

Tang, Duozhuang; Tao, Si; Chen, Zhiyang; Koliesnik, Ievgen Oleksandrovich; Calmes, Philip Gerald; Hoerr, Verena; Han, Bing; Gebert, Nadja; Zörnig, Martin; Löffler, Bettina

2016-01-01

Dietary restriction (DR) improves health, delays tissue aging, and elongates survival in flies and worms. However, studies on laboratory mice and nonhuman primates revealed ambiguous effects of DR on lifespan despite improvements in health parameters. In this study, we analyzed consequences of adult-onset DR (24 h to 1 yr) on hematopoietic stem cell (HSC) function. DR ameliorated HSC aging phenotypes, such as the increase in number of HSCs and the skewing toward myeloid-biased HSCs during aging. Furthermore, DR increased HSC quiescence and improved the maintenance of the repopulation capacity of HSCs during aging. In contrast to these beneficial effects, DR strongly impaired HSC differentiation into lymphoid lineages and particularly inhibited the proliferation of lymphoid progenitors, resulting in decreased production of peripheral B lymphocytes and impaired immune function. The study shows that DR-dependent suppression of growth factors and interleukins mediates these divergent effects caused by DR. Supplementation of insulin-like growth factor 1 partially reverted the DR-induced quiescence of HSCs, whereas IL-6/IL-7 substitutions rescued the impairment of B lymphopoiesis exposed to DR. Together, these findings delineate positive and negative effects of long-term DR on HSC functionality involving distinct stress and growth signaling pathways. PMID:26951333

Bioenergetic Impairment in Congenital Muscular Dystrophy Type 1A and Leigh Syndrome Muscle Cells

PubMed Central

Fontes-Oliveira, Cibely C.; Steinz, Maarten; Schneiderat, Peter; Mulder, Hindrik; Durbeej, Madeleine

2017-01-01

Skeletal muscle has high energy requirement and alterations in metabolism are associated with pathological conditions causing muscle wasting and impaired regeneration. Congenital muscular dystrophy type 1A (MDC1A) is a severe muscle disorder caused by mutations in the LAMA2 gene. Leigh syndrome (LS) is a neurometabolic disease caused by mutations in genes related to mitochondrial function. Skeletal muscle is severely affected in both diseases and a common feature is muscle weakness that leads to hypotonia and respiratory problems. Here, we have investigated the bioenergetic profile in myogenic cells from MDC1A and LS patients. We found dysregulated expression of genes related to energy production, apoptosis and proteasome in myoblasts and myotubes. Moreover, impaired mitochondrial function and a compensatory upregulation of glycolysis were observed when monitored in real-time. Also, alterations in cell cycle populations in myoblasts and enhanced caspase-3 activity in myotubes were observed. Thus, we have for the first time demonstrated an impairment of the bioenergetic status in human MDC1A and LS muscle cells, which could contribute to cell cycle disturbance and increased apoptosis. Our findings suggest that skeletal muscle metabolism might be a promising pharmacological target in order to improve muscle function, energy efficiency and tissue maintenance of MDC1A and LS patients. PMID:28367954

Communicative-pragmatic disorders in traumatic brain injury: The role of theory of mind and executive functions.

PubMed

Bosco, Francesca M; Parola, Alberto; Sacco, Katiuscia; Zettin, Marina; Angeleri, Romina

2017-05-01

Previous research has shown that communicative-pragmatic ability, as well as executive functions (EF) and Theory of Mind (ToM), may be impaired in individuals with traumatic brain injury (TBI). However, the role of such cognitive deficits in explaining communicative-pragmatic difficulty in TBI has still not been fully investigated. The study examined the relationship between EF (working memory, planning and flexibility) and ToM and communicative-pragmatic impairment in patients with TBI. 30 individuals with TBI and 30 healthy controls were assessed using the Assessment Battery of Communication (ABaCo), and a set of cognitive, EF and ToM, tasks. The results showed that TBI participants performed poorly in comprehension and production tasks in the ABaCo, using both linguistic and extralinguistic means of expression, and that they were impaired in EF and ToM abilities. Cognitive difficulties were able to predict the pragmatic performance of TBI individuals, with both executive functions and ToM contributing to explaining patients' scores on the ABaCo. Copyright © 2017 Elsevier Inc. All rights reserved.

The schizophrenia risk gene product miR-137 alters presynaptic plasticity

PubMed Central

Siegert, Sandra; Seo, Jinsoo; Kwon, Ester J.; Rudenko, Andrii; Cho, Sukhee; Wang, Wenyuan; Flood, Zachary; Martorell, Anthony J.; Ericsson, Maria; Mungenast, Alison E.; Tsai, Li-Huei

2015-01-01

Non-coding variants in the human MIR137 gene locus increase schizophrenia risk at a genome-wide significance level. However, the functional consequence of these risk alleles is unknown. Here, we examined induced human neurons harboring the minor alleles of four disease-associated single nucleotide polymorphisms (SNPs) in MIR137, and observed increased MIR137 levels compared to major allele-carrying cells. We found that miR-137 gain-of-function causes downregulation of the presynaptic target genes, Complexin-1 (Cplx1), Nsf, and Synaptotagmin-1 (Syt1), leading to impaired vesicle release. In vivo, miR-137 gain-of-function results in changes in synaptic vesicle pool distribution, impaired mossy fiber-LTP induction and deficits in hippocampus-dependent learning and memory. By sequestering endogenous miR-137, we were able to ameliorate the synaptic phenotypes. Moreover, reinstatement of Syt1 expression partially restored synaptic plasticity, demonstrating the importance of Syt1 as a miR-137 target. Our data provide new insight into the mechanism by which miR-137 dysregulation can impair synaptic plasticity in the hippocampus. PMID:26005852

Work Productivity and Costs Related to Patients with Ankylosing Spondylitis, Rheumatoid Arthritis, and Psoriasis.

PubMed

Kruntorádová, Klára; Klimeš, Jiří; Šedová, Liliana; Štolfa, Jiří; Doležal, Tomáš; Petříková, Alena

2014-09-01

To determine and compare the impact of rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriasis on work productivity, to calculate the productivity costs (PC), and to map out factors that influence (functional status and disease activity) work productivity. The Work Productivity and Activity Impairment questionnaire was used to evaluate productivity losses of patients with RA (n = 77), AS (n = 230), and psoriasis (n = 93). Demographic data, patient-reported outcomes (PROs) (Health Assessment Questionnaire [HAQ] and Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]), and clinical parameters (Disease Activity Score in 28 joints [DAS28], body surface area [BSA], and Psoriasis Area and Severity Index [PASI]) were collected. The correlations among PROs, clinical parameters, and overall productivity loss were examined, and multiple regression models were used to examine relationships among parameters and productivity loss. PC were calculated using the friction cost approach. Mean patient age and disease duration were 47.1 and 15.7 years, respectively. The mean HAQ and DAS28 in patients with RA were 1.22 and 5.6, respectively. The mean BASDAI score in patients with AS was 4.43. The mean BSA and PASI score in patients with psoriasis were 21.1% and 12.9, respectively. The percentage of patients with psoriatic arthritis (in those with psoriasis) was 24.7%. We did not find significant differences in Work Productivity and Activity Impairment domains among various diagnoses. Patients with AS, RA, and psoriasis reported overall work productivity losses of 40.9%, 42.9%, and 42.8%, respectively. Daily activity impairments were approximately 50.0%. Overall work productivity loss strongly correlated with PROs, whereas correlations with clinical parameters were weak. The HAQ and BASDAI were identified as major predictors of productivity impairment. The greatest loss in productivity was in those with psoriatic arthritis; however, it was not significant. In contrast to clinical parameters (DAS28, BSA, and PASI score), PROs (HAQ and BASDAI score) significantly influence loss of productivity. The average annual lost PC per patient was estimated to be €2000. Copyright © 2014 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Tpl2 kinase regulates T cell interferon-γ production and host resistance to Toxoplasma gondii

PubMed Central

Watford, Wendy T.; Hissong, Bruce D.; Durant, Lydia R.; Yamane, Hidehiro; Muul, Linda M.; Kanno, Yuka; Tato, Cristina M.; Ramos, Haydeé L.; Berger, Alan E.; Mielke, Lisa; Pesu, Marko; Solomon, Benjamin; Frucht, David M.; Paul, William E.; Sher, Alan; Jankovic, Dragana; Tsichlis, Philip N.; O'Shea, John J.

2008-01-01

Tpl2 (Tumor progression locus 2), also known as Cot/MAP3K8, is a hematopoietically expressed serine-threonine kinase. Tpl2 is known to have critical functions in innate immunity in regulating tumor necrosis factor–α, Toll-like receptor, and G protein–coupled receptor signaling; however, our understanding of its physiological role in T cells is limited. We investigated the potential roles of Tpl2 in T cells and found that it was induced by interleukin-12 in human and mouse T cells in a Stat4-dependent manner. Deficiency of Tpl2 was associated with impaired interferon (IFN)-γ production. Accordingly, Tpl2−/− mice had impaired host defense against Toxoplasma gondii with reduced parasite clearance and decreased IFN-γ production. Furthermore, reconstitution of Rag2−/− mice with Tpl2-deficient T cells followed by T. gondii infection recapitulated the IFN-γ defect seen in the Tpl2-deficient mice, confirming a T cell–intrinsic defect. CD4+ T cells isolated from Tpl2−/− mice showed poor induction of T-bet and failure to up-regulate Stat4 protein, which is associated with impaired TCR-dependent extracellular signal-regulated kinase activation. These data underscore the role of Tpl2 as a regulator of T helper cell lineage decisions and demonstrate that Tpl2 has an important functional role in the regulation of Th1 responses. PMID:19001140

39 CFR 255.2 - Definitions.

Code of Federal Regulations, 2014 CFR

2014-07-01

... technology” and any equipment or interconnected system or subsystem of equipment that is used in the creation... embedded information technology that is used as an integral part of the product, but the principal function... an impairment. (f) Information technology means any equipment, or interconnected system or subsystem...

39 CFR 255.2 - Definitions.

Code of Federal Regulations, 2013 CFR

2013-07-01

... technology” and any equipment or interconnected system or subsystem of equipment that is used in the creation... embedded information technology that is used as an integral part of the product, but the principal function... an impairment. (f) Information technology means any equipment, or interconnected system or subsystem...

39 CFR 255.2 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-07-01

... technology” and any equipment or interconnected system or subsystem of equipment that is used in the creation... embedded information technology that is used as an integral part of the product, but the principal function... an impairment. (f) Information technology means any equipment, or interconnected system or subsystem...

39 CFR 255.2 - Definitions.

Code of Federal Regulations, 2012 CFR

2012-07-01

... technology” and any equipment or interconnected system or subsystem of equipment that is used in the creation... embedded information technology that is used as an integral part of the product, but the principal function... an impairment. (f) Information technology means any equipment, or interconnected system or subsystem...

Traditional Chinese Nootropic Medicine Radix Polygalae and Its Active Constituent Onjisaponin B Reduce β-Amyloid Production and Improve Cognitive Impairments

PubMed Central

Li, Xiaohang; Cui, Jin; Yu, Yang; Li, Wei; Hou, Yujun; Wang, Xin; Qin, Dapeng; Zhao, Cun; Yao, Xinsheng; Zhao, Jian; Pei, Gang

2016-01-01

Decline of cognitive function is the hallmark of Alzheimer’s disease (AD), regardless of the pathological mechanism. Traditional Chinese medicine has been used to combat cognitive impairments and has been shown to improve learning and memory. Radix Polygalae (RAPO) is a typical and widely used herbal medicine. In this study, we aimed to follow the β-amyloid (Aβ) reduction activity to identify active constituent(s) of RAPO. We found that Onjisaponin B of RAPO functioned as RAPO to suppress Aβ production without direct inhibition of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) and γ-secretase activities. Our mechanistic study showed that Onjisaponin B promoted the degradation of amyloid precursor protein (APP). Further, oral administration of Onjisaponin B ameliorated Aβ pathology and behavioral defects in APP/PS1 mice. Taken together, our results indicate that Onjisaponin B is effective against AD, providing a new therapeutic agent for further drug discovery. PMID:26954017

Traditional Chinese Nootropic Medicine Radix Polygalae and Its Active Constituent Onjisaponin B Reduce β-Amyloid Production and Improve Cognitive Impairments.

PubMed

Li, Xiaohang; Cui, Jin; Yu, Yang; Li, Wei; Hou, Yujun; Wang, Xin; Qin, Dapeng; Zhao, Cun; Yao, Xinsheng; Zhao, Jian; Pei, Gang

2016-01-01

Decline of cognitive function is the hallmark of Alzheimer's disease (AD), regardless of the pathological mechanism. Traditional Chinese medicine has been used to combat cognitive impairments and has been shown to improve learning and memory. Radix Polygalae (RAPO) is a typical and widely used herbal medicine. In this study, we aimed to follow the β-amyloid (Aβ) reduction activity to identify active constituent(s) of RAPO. We found that Onjisaponin B of RAPO functioned as RAPO to suppress Aβ production without direct inhibition of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) and γ-secretase activities. Our mechanistic study showed that Onjisaponin B promoted the degradation of amyloid precursor protein (APP). Further, oral administration of Onjisaponin B ameliorated Aβ pathology and behavioral defects in APP/PS1 mice. Taken together, our results indicate that Onjisaponin B is effective against AD, providing a new therapeutic agent for further drug discovery.

Neurocognitive Deficits in Attention-Deficit/Hyperactivity Disorder With and Without Comorbid Oppositional Defiant Disorder

PubMed Central

Noordermeer, Siri D. S.; Luman, Marjolein; Buitelaar, Jan K.; Hartman, Catharina A.; Hoekstra, Pieter J.; Franke, Barbara; Faraone, Stephen V.; Heslenfeld, Dirk J.; Oosterlaan, Jaap

2016-01-01

Objective Oppositional Defiant Disorder (ODD) is highly prevalent in Attention-Deficit/Hyperactivity Disorder (ADHD) and may account for inconsistencies in findings on neurocognitive functioning in ADHD. Our aim was to assess cool and hot executive functioning (EF) and temporal processing in ADHD with and without comorbid ODD to elucidate the effects of comorbid ODD. Method ADHD-only (n = 82), ADHD + ODD (n = 82), and controls (n = 82), with mean age 16 years (SD = 3.1), matched for age, gender, IQ, and ADHD type (clinical groups) were assessed on cool EF (inhibition, working memory), hot EF (reinforcement processing, emotion recognition), and temporal processing (time production and reproduction). Results Individuals with ADHD + ODD showed abnormalities in inhibition, working memory, facial emotion recognition, and temporal processing, whereas individuals with ADHD-only were solely impaired in working memory and time production. Conclusion Findings suggest that ODD carries a substantial part of the EF deficits observed in ADHD and contrast with current theories of neurocognitive impairments in ADHD. PMID:26486602

Longitudinal decline in speech production in Parkinson's disease spectrum disorders.

PubMed

Ash, Sharon; Jester, Charles; York, Collin; Kofman, Olga L; Langey, Rachel; Halpin, Amy; Firn, Kim; Dominguez Perez, Sophia; Chahine, Lama; Spindler, Meredith; Dahodwala, Nabila; Irwin, David J; McMillan, Corey; Weintraub, Daniel; Grossman, Murray

2017-08-01

We examined narrative speech production longitudinally in non-demented (n=15) and mildly demented (n=8) patients with Parkinson's disease spectrum disorder (PDSD), and we related increasing impairment to structural brain changes in specific language and motor regions. Patients provided semi-structured speech samples, describing a standardized picture at two time points (mean±SD interval=38±24months). The recorded speech samples were analyzed for fluency, grammar, and informativeness. PDSD patients with dementia exhibited significant decline in their speech, unrelated to changes in overall cognitive or motor functioning. Regression analysis in a subset of patients with MRI scans (n=11) revealed that impaired language performance at Time 2 was associated with reduced gray matter (GM) volume at Time 1 in regions of interest important for language functioning but not with reduced GM volume in motor brain areas. These results dissociate language and motor systems and highlight the importance of non-motor brain regions for declining language in PDSD. Copyright © 2017 Elsevier Inc. All rights reserved.

Structural equation modeling of motor impairment, gross motor function, and the functional outcome in children with cerebral palsy.

PubMed

Park, Eun-Young; Kim, Won-Ho

2013-05-01

Physical therapy intervention for children with cerebral palsy (CP) is focused on reducing neurological impairments, improving strength, and preventing the development of secondary impairments in order to improve functional outcomes. However, relationship between motor impairments and functional outcome has not been proved definitely. This study confirmed the construct of motor impairment and performed structural equation modeling (SEM) between motor impairment, gross motor function, and functional outcomes of regarding activities of daily living in children with CP. 98 children (59 boys, 39 girls) with CP participated in this cross-sectional study. Mean age was 11 y 5 mo (SD 1 y 9 mo). The Manual Muscle Test (MMT), the Modified Ashworth Scale (MAS), range of motion (ROM) measurement, and the selective motor control (SMC) scale were used to assess motor impairments. Gross motor function and functional outcomes were measured using the Gross Motor Function Measure (GMFM) and the Functional Skills domain of the Pediatric Evaluation of Disability Inventory (PEDI) respectively. Measurement of motor impairment was consisted of strength, spasticity, ROM, and SMC. The construct of motor impairment was confirmed though an examination of a measurement model. The proposed SEM model showed good fit indices. Motor impairment effected gross motor function (β=-.0869). Gross motor function and motor impairment affected functional outcomes directly (β=0.890) and indirectly (β=-0.773) respectively. We confirmed that the construct of motor impairment consist of strength, spasticity, ROM, and SMC and it was identified through measurement model analysis. Functional outcomes are best predicted by gross motor function and motor impairments have indirect effects on functional outcomes. Copyright © 2013 Elsevier Ltd. All rights reserved.

Deterioration of physical performance and cognitive function in rats with short-term high-fat feeding.

PubMed

Murray, Andrew J; Knight, Nicholas S; Cochlin, Lowri E; McAleese, Sara; Deacon, Robert M J; Rawlins, J Nicholas P; Clarke, Kieran

2009-12-01

Efficiency, defined as the amount of work produced for a given amount of oxygen consumed, is a key determinant of endurance capacity, and can be altered by metabolic substrate supply, in that fatty acid oxidation is less efficient than glucose oxidation. It is unclear, however, whether consumption of a high-fat diet would be detrimental or beneficial for endurance capacity, due to purported glycogen-sparing properties. In addition, a high-fat diet over several months leads to cognitive impairment. Here, we tested the hypothesis that short-term ingestion of a high-fat diet (55% kcal from fat) would impair exercise capacity and cognitive function in rats, compared with a control chow diet (7.5% kcal from fat) via mitochondrial uncoupling and energy deprivation. We found that rats ran 35% less far on a treadmill and showed cognitive impairment in a maze test with 9 d of high-fat feeding, with respiratory uncoupling in skeletal muscle mitochondria, associated with increased uncoupling protein (UCP3) levels. Our results suggest that high-fat feeding, even over short periods of time, alters skeletal muscle UCP3 expression, affecting energy production and physical performance. Optimization of nutrition to maximize the efficiency of mitochondrial ATP production could improve energetics in athletes and patients with metabolic abnormalities.

Traumatic Brain Injury Causes Endothelial Dysfunction in the Systemic Microcirculation through Arginase-1-Dependent Uncoupling of Endothelial Nitric Oxide Synthase.

PubMed

Villalba, Nuria; Sackheim, Adrian M; Nunez, Ivette A; Hill-Eubanks, David C; Nelson, Mark T; Wellman, George C; Freeman, Kalev

2017-01-01

Endothelial dysfunction is a hallmark of many chronic diseases, including diabetes and long-term hypertension. We show that acute traumatic brain injury (TBI) leads to endothelial dysfunction in rat mesenteric arteries. Endothelial-dependent dilation was greatly diminished 24 h after TBI because of impaired nitric oxide (NO) production. The activity of arginase, which competes with endothelial NO synthase (eNOS) for the common substrate l-arginine, were also significantly increased in arteries, suggesting that arginase-mediated depletion of l-arginine underlies diminished NO production. Consistent with this, substrate restoration by exogenous application of l-arginine or inhibition of arginase recovered endothelial function. Moreover, evidence for increased reactive oxygen species production, a consequence of l-arginine starvation-dependent eNOS uncoupling, was detected in endothelium and plasma. Collectively, our findings demonstrate endothelial dysfunction in a remote vascular bed after TBI, manifesting as impaired endothelial-dependent vasodilation, with increased arginase activity, decreased generation of NO, and increased O 2 - production. We conclude that blood vessels have a "molecular memory" of neurotrauma, 24 h after injury, because of functional changes in vascular endothelial cells; these effects are pertinent to understanding the systemic inflammatory response that occurs after TBI even in the absence of polytrauma.

Affected functional networks associated with sentence production in classic galactosemia.

PubMed

Timmers, Inge; van den Hurk, Job; Hofman, Paul Am; Zimmermann, Luc Ji; Uludağ, Kâmil; Jansma, Bernadette M; Rubio-Gozalbo, M Estela

2015-08-07

Patients with the inherited metabolic disorder classic galactosemia have language production impairments in several planning stages. Here, we assessed potential deviations in recruitment and connectivity across brain areas responsible for language production that may explain these deficits. We used functional magnetic resonance imaging (fMRI) to study neural activity and connectivity while participants carried out a language production task. This study included 13 adolescent patients and 13 age- and gender-matched healthy controls. Participants passively watched or actively described an animated visual scene using two conditions, varying in syntactic complexity (single words versus a sentence). Results showed that patients recruited additional and more extensive brain regions during sentence production. Both groups showed modulations with syntactic complexity in left inferior frontal gyrus (IFG), a region associated with syntactic planning, and in right insula. In addition, patients showed a modulation with syntax in left superior temporal gyrus (STG), whereas the controls did not. Further, patients showed increased activity in right STG and right supplementary motor area (SMA). The functional connectivity data showed similar patterns, with more extensive connectivity with frontal and motor regions, and restricted and weaker connectivity with superior temporal regions. Patients also showed higher baseline cerebral blood flow (CBF) in right IFG and trends towards higher CBF in bilateral STG, SMA and the insula. Taken together, the data demonstrate that language abnormalities in classic galactosemia are associated with specific changes within the language network. These changes point towards impairments related to both syntactic planning and speech motor planning in these patients. Copyright © 2015 Elsevier B.V. All rights reserved.

SHIP-1 Deficiency in AID+ B Cells Leads to the Impaired Function of B10 Cells with Spontaneous Autoimmunity.

PubMed

Chen, Yingjia; Hu, Fanlei; Dong, Xuejiao; Zhao, Meng; Wang, Jing; Sun, Xiaolin; Kim, Tae Jin; Li, Zhanguo; Liu, Wanli

2017-11-01

Unlike conventional B cells, regulatory B cells exhibit immunosuppressive functions to downregulate inflammation via IL-10 production. However, the molecular mechanism regulating the production of IL-10 is not fully understood. In this study, we report the finding that activation-induced cytidine deaminase (AID) is highly upregulated in the IL-10-competent B cell (B10) cell from Innp5d fl/fl Aicda Cre/+ mice, whereas the 5' inositol phosphatase SHIP-1 is downregulated. Notably, SHIP-1 deficiency in AID + B cells leads to a reduction in cell count and impaired IL-10 production by B10 cells. Furthermore, the Innp5d fl/fl Aicda Cre/+ mouse model shows B cell-dependent autoimmune lupus-like phenotypes, such as elevated IgG serum Abs, formation of spontaneous germinal centers, production of anti-dsDNA and anti-nuclear Abs, and the obvious deposition of IgG immune complexes in the kidney with age. We observe that these lupus-like phenotypes can be reversed by the adoptive transfer of B10 cells from control Innp5d fl/fl mice, but not from the Innp5d fl/fl Aicda Cre/+ mice. This finding highlights the importance of defective B10 cells in Innp5d fl/fl Aicda Cre/+ mice. Whereas p-Akt is significantly upregulated, MAPK and AP-1 activation is impaired in B10 cells from Innp5d fl/fl Aicda Cre/+ mice, resulting in the reduced production of IL-10. These results show that SHIP-1 is required for the maintenance of B10 cells and production of IL-10, and collectively suggests that SHIP-1 could be a new potential therapeutic target for the treatment of autoimmune diseases. Copyright © 2017 by The American Association of Immunologists, Inc.

Antipsychotics promote GABAergic interneuron genesis in the adult rat brain: Role of heat-shock protein production.

PubMed

Kaneta, Hiroo; Ukai, Wataru; Tsujino, Hanako; Furuse, Kengo; Kigawa, Yoshiyasu; Tayama, Masaya; Ishii, Takao; Hashimoto, Eri; Kawanishi, Chiaki

2017-09-01

Current antipsychotics reduce positive symptoms and reverse negative symptoms in conjunction with cognitive behavioral issues with the goal of restoring impaired occupational and social functioning. However, limited information is available on their influence on gliogenesis or their neurogenic properties in adult schizophrenia brains, particularly on GABAergic interneuron production. In the present study, we used young adult subventricular zone (SVZ)-derived progenitor cells expressing proteoglycan NG2 cultures to examine the oligodendrocyte and GABAergic interneuron genesis effects of several kinds of antipsychotics on changes in differentiation function induced by exposure to the NMDA receptor antagonist MK-801. We herein demonstrated that antipsychotics promoted or restored changes in the oligodendrocyte/GABAergic interneuron differentiation functions of NG2(+) cells induced by the exposure to MK-801, which was considered to be one of the drug-induced schizophrenia model. We also demonstrated that antipsychotics restored heat-shock protein (HSP) production in NG2(+) cells with differentiation impairment. The antipsychotics olanzapine, aripiprazole, and blonanserin, but not haloperidol increased HSP90 levels, which were reduced by the exposure to MK-801. Our results showed that antipsychotics, particularly those recently synthesized, exerted similar GABAergic interneuron genesis effects on NG2(+) neuronal/glial progenitor cells in the adult rat brain by increasing cellular HSP production, and also suggest that HSP90 may play a crucial role in the pathophysiology of schizophrenia and is a key target for next drug development. Copyright © 2017 Elsevier Ltd. All rights reserved.

Chronic inflammation in skeletal muscle impairs satellite cells function during regeneration: can physical exercise restore the satellite cell niche?

PubMed

Perandini, Luiz Augusto; Chimin, Patricia; Lutkemeyer, Diego da Silva; Câmara, Niels Olsen Saraiva

2018-06-01

Chronic inflammation impairs skeletal muscle regeneration. Although many cells are involved in chronic inflammation, macrophages seem to play an important role in impaired muscle regeneration since these cells are associated with skeletal muscle stem cell (namely, satellite cells) activation and fibro-adipogenic progenitor cell (FAP) survival. Specifically, an imbalance of M1 and M2 macrophages seems to lead to impaired satellite cell activation, and these are the main cells that function during skeletal muscle regeneration, after muscle damage. Additionally, this imbalance leads to the accumulation of FAPs in skeletal muscle, with aberrant production of pro-fibrotic factors (e.g., extracellular matrix components), impairing the niche for proper satellite cell activation and differentiation. Treatments aiming to block the inflammatory pro-fibrotic response are partially effective due to their side effects. Therefore, strategies reverting chronic inflammation into a pro-regenerative pattern are required. In this review, we first describe skeletal muscle resident macrophage ontogeny and homeostasis, and explain how macrophages are replenished after muscle injury. We next discuss the potential role of chronic physical activity and exercise in restoring the M1 and M2 macrophage balance and consequently, the satellite cell niche to improve skeletal muscle regeneration after injury. © 2018 Federation of European Biochemical Societies.

EP Profiles Inventor Mark Sherron

ERIC Educational Resources Information Center

Williams, John M.

2006-01-01

This article profiles Mark Jerome Sherron, inventor of the ALLIES Line of electronic sensors for blind and visually-impaired people. Featuring the American Liquid Level Indicator electronic sensor (ALLI), Sherron's ALLIES product line also includes the Light Intensity Level Indicator (LILI), a multi-function electronic light sensor for electronic…

Tone-deafness – a new disconnection syndrome?

PubMed Central

Loui, Psyche; Alsop, David; Schlaug, Gottfried

2009-01-01

Communicating with one’s environment requires efficient neural interaction between action and perception. Neural substrates ofsound perception and production are connected by the arcuate fasciculus (AF). While AF is known to be involved in language, its roles in non-linguistic functions are unexplored. Here we show that tone-deaf people, with impaired sound perception and production, have reduced AF connectivity. Diffusion tensor tractography and psychophysics were assessed in tone-deaf individuals and matched controls. Abnormally-reduced AF connectivity was observed in the tone-deaf. Furthermore, we observed relationships between AF and auditory-motor behavior: superior and inferior AF branches predict psychophysically-assessed pitch-discrimination and sound production-perception abilities respectively. This neural abnormality suggests that tone-deafness leads to a reduction in connectivity resulting in pitch-related impairments. Results support a dual-stream anatomy of sound production and perception implicated in vocal communications. By identifying white-matter differences and their psychophysical correlates, results contribute to our understanding of how neural connectivity subserves behavior. PMID:19692596

Precursor-product discrimination by La protein during tRNA metabolism

PubMed Central

Bayfield, Mark A.; Maraia, Richard J.

2009-01-01

SUMMARY La proteins bind pre-tRNAs at their UUU-3'OH ends, facilitating their maturation. While the mechanism by which La binds pre-tRNA 3' trailers is known, the function of the RNA-binding β-sheet surface of RRM1 is unknown. How La dissociates from UUU-3'OH-containing trailers after 3' processing is also unknown. La preferentially binds pre-tRNAs over processed tRNAs or 3' trailer products through coupled use of two sites: one on the La motif and another on the RRM1 β surface that binds elsewhere on tRNA. Two sites provide stable pre-tRNA binding while processed tRNA and 3' trailer are released from their single sites relatively fast. RRM1 loop-3 mutations decrease affinity for pre-tRNA and tRNA but not UUU-3'OH trailer, and impair tRNA maturation in vivo. We propose that RRM1 functions in activities that are more complex than UUU-3'OH binding. Accordingly, the RRM1 mutations also impair a RNA chaperone activity of La. The results suggest how La distinguishes precursor from product RNAs, allowing it to recycle onto a new pre-tRNA. PMID:19287396

Resistin impairs endothelium-dependent dilation to bradykinin, but not acetylcholine, in the coronary circulation.

PubMed

Dick, Gregory M; Katz, Paige S; Farias, Martin; Morris, Michael; James, Jeremy; Knudson, Jarrod D; Tune, Johnathan D

2006-12-01

Elevated plasma levels of fat-derived signaling molecules are associated with obesity, vascular endothelial dysfunction, and coronary heart disease; however, little is known about their direct coronary vascular effects. Accordingly, we examined mechanisms by which one adipokine, resistin, affects coronary vascular tone and endothelial function. Studies were conducted in anesthetized dogs and isolated coronary artery rings. Resistin did not change coronary blood flow, mean arterial pressure, or heart rate. Resistin had no effect on acetylcholine-induced relaxation of artery rings; however, resistin did impair bradykinin-induced relaxation. Selective impairment was also observed in vivo, as resistin attenuated vasodilation to bradykinin but not to acetylcholine. Resistin had no effect on dihydroethidium fluorescence, an indicator of superoxide (O(2)(-)) production, and the inhibitory effect of resistin on bradykinin-induced relaxation persisted in the presence of Tempol, a superoxide dismutase mimetic. To determine whether resistin impaired production of and/or responses to nitric oxide (NO) or prostaglandins (e.g., prostacyclin; PGI(2)), we performed experiments with N(omega)-nitro-L-arginine methyl ester (L-NAME) and indomethacin. The effect of resistin to attenuate bradykinin-induced vasodilation persisted in the presence of L-NAME or indomethacin, suggesting resistin may act at a cell signaling point upstream of NO or PGI(2) production. Resistin-induced endothelial dysfunction is not generalized, and it is not consistent with effects mediated by O(2)(-) or interference with NO or PGI(2) signaling. The site of the resistin-induced impairment is unknown but may be at the bradykinin receptor or a closely associated signal transduction machinery proximal to NO synthase or cyclooxygenase.

Exploring the Relationship between Physiological Measures of Cochlear and Brainstem Function

PubMed Central

Dhar, S.; Abel, R.; Hornickel, J.; Nicol, T.; Skoe, E.; Zhao, W.; Kraus, N.

2009-01-01

Objective Otoacoustic emissions and the speech-evoked auditory brainstem response are objective indices of peripheral auditory physiology and are used clinically for assessing hearing function. While each measure has been extensively explored, their interdependence and the relationships between them remain relatively unexplored. Methods Distortion product otoacoustic emissions (DPOAE) and speech-evoked auditory brainstem responses (sABR) were recorded from 28 normal-hearing adults. Through correlational analyses, DPOAE characteristics were compared to measures of sABR timing and frequency encoding. Data were organized into two DPOAE (Strength and Structure) and five brainstem (Onset, Spectrotemporal, Harmonics, Envelope Boundary, Pitch) composite measures. Results DPOAE Strength shows significant relationships with sABR Spectrotemporal and Harmonics measures. DPOAE Structure shows significant relationships with sABR Envelope Boundary. Neither DPOAE Strength nor Structure is related to sABR Pitch. Conclusions The results of the present study show that certain aspects of the speech-evoked auditory brainstem responses are related to, or covary with, cochlear function as measured by distortion product otoacoustic emissions. Significance These results form a foundation for future work in clinical populations. Analyzing cochlear and brainstem function in parallel in different clinical populations will provide a more sensitive clinical battery for identifying the locus of different disorders (e.g., language based learning impairments, hearing impairment). PMID:19346159

Work Outcomes in Patients Who Stay at Work Despite Musculoskeletal Pain.

PubMed

Cochrane, Andy; Higgins, Niamh M; Rothwell, Conor; Ashton, Jennifer; Breen, Roisin; Corcoran, Oriel; FitzGerald, Oliver; Gallagher, Pamela; Desmond, Deirdre

2017-12-13

Purpose To assess self-reported work impacts and associations between psychosocial risk factors and work impairment amongst workers seeking care for musculoskeletal pain while continuing to work. Methods Patients were recruited from Musculoskeletal Assessment Clinics at 5 hospitals across Ireland. Participants completed questionnaires including assessments of work impairment (Work Productivity and Activity Impairment Questionnaire), work ability (single item from the Work Ability Index) and work performance (Work Role Functioning Questionnaire; WRFQ). Logistic and hierarchical regressions were conducted to analyse the relation between psychosocial variables and work outcomes. Results 155 participants (53.5% female; mean age = 46.50 years) who were working at the time of assessment completed the questionnaires. Absenteeism was low, yet 62.6% were classified as functioning poorly according to the WRFQ; 52.3% reported having poor work ability. Logistic regression analyses indicated that higher work role functioning was associated with higher pain self-efficacy (OR 1.51); better work ability was associated with older age (OR 1.063) and lower functional restriction (OR 0.93); greater absenteeism was associated with lower pain self-efficacy (OR 0.65) and poorer work expectancy (OR 1.18). Multiple regression analysis indicated that greater presenteeism was associated with higher pain intensity (β = 0.259) and lower pain self-efficacy (β = - 0.385). Conclusions While individuals continue to work with musculoskeletal pain, their work performance can be adversely affected. Interventions that target mutable factors, such as pain self-efficacy, may help reduce the likelihood of work impairment.

High anion gap metabolic acidosis induced by cumulation of ketones, L- and D-lactate, 5-oxoproline and acute renal failure.

PubMed

Heireman, Laura; Mahieu, Boris; Helbert, Mark; Uyttenbroeck, Wim; Stroobants, Jan; Piqueur, Marian

2017-07-27

Frequent causes of high anion gap metabolic acidosis (HAGMA) are lactic acidosis, ketoacidosis and impaired renal function. In this case report, a HAGMA caused by ketones, L- and D-lactate, acute renal failure as well as 5-oxoproline is discussed. A 69-year-old woman was admitted to the emergency department with lowered consciousness, hyperventilation, diarrhoea and vomiting. The patient had suffered uncontrolled type 2 diabetes mellitus, underwent gastric bypass surgery in the past and was chronically treated with high doses of paracetamol and fosfomycin. Urosepsis was diagnosed, whilst laboratory analysis of serum bicarbonate concentration and calculation of the anion gap indicated a  HAGMA. L-lactate, D-lactate, β-hydroxybutyric acid, acetone and 5-oxoproline serum levels were markedly elevated and renal function was impaired. We concluded that this case of HAGMA was induced by a variety of underlying conditions: sepsis, hyperglycaemia, prior gastric bypass surgery, decreased renal perfusion and paracetamol intake. Risk factors for 5-oxoproline intoxication present in this case are female gender, sepsis, impaired renal function and uncontrolled type 2 diabetes mellitus. Furthermore, chronic antibiotic treatment with fosfomycin might have played a role in the increased production of 5-oxoproline. Paracetamol-induced 5-oxoproline intoxication should be considered as a cause of HAGMA in patients with female gender, sepsis, impaired renal function or uncontrolled type 2 diabetes mellitus, even when other more obvious causes of HAGMA such as lactate, ketones or renal failure can be identified.

Global cost of correcting vision impairment from uncorrected refractive error.

PubMed

Fricke, T R; Holden, B A; Wilson, D A; Schlenther, G; Naidoo, K S; Resnikoff, S; Frick, K D

2012-10-01

To estimate the global cost of establishing and operating the educational and refractive care facilities required to provide care to all individuals who currently have vision impairment resulting from uncorrected refractive error (URE). The global cost of correcting URE was estimated using data on the population, the prevalence of URE and the number of existing refractive care practitioners in individual countries, the cost of establishing and operating educational programmes for practitioners and the cost of establishing and operating refractive care facilities. The assumptions made ensured that costs were not underestimated and an upper limit to the costs was derived using the most expensive extreme for each assumption. There were an estimated 158 million cases of distance vision impairment and 544 million cases of near vision impairment caused by URE worldwide in 2007. Approximately 47 000 additional full-time functional clinical refractionists and 18 000 ophthalmic dispensers would be required to provide refractive care services for these individuals. The global cost of educating the additional personnel and of establishing, maintaining and operating the refractive care facilities needed was estimated to be around 20 000 million United States dollars (US$) and the upper-limit cost was US$ 28 000 million. The estimated loss in global gross domestic product due to distance vision impairment caused by URE was US$ 202 000 million annually. The cost of establishing and operating the educational and refractive care facilities required to deal with vision impairment resulting from URE was a small proportion of the global loss in productivity associated with that vision impairment.

The impact of fatigue and energy on work functioning and impairment in patients with major depressive disorder treated with desvenlafaxine.

PubMed

Sarfati, David; Evans, Vanessa C; Tam, Edwin M; Woo, Cindy; Iverson, Grant L; Yatham, Lakshmi N; Lam, Raymond W

2017-11-01

Fatigue and low energy are cardinal symptoms of major depressive disorder (MDD) that have an impact on work functioning. Antidepressants with noradrenergic activity have been hypothesized to improve symptoms of fatigue and low energy. We examined the impact of these symptoms on work functioning in patients with MDD treated with the serotonin and noradrenaline reuptake inhibitor, desvenlafaxine. A secondary analysis was carried out from a study of employed adult outpatients (n=35) with MDD and subjective cognitive complaints treated with desvenlafaxine 50-100 mg/day for 8 weeks. Multiple regression analyses modeled improvement in work functioning measures (Lam Employment Absence and Productivity Scale, Health and Work Performance Questionnaire, Sheehan Disability Scale) with measures of fatigue (Patient-Reported Outcomes Measurement Information System Fatigue scale and 20-item Hopkins Symptom Check List Energy scale). Patients showed a significant improvement in Montgomery-Åsberg Depression Rating Scale scores as well as in fatigue and work functioning measures following treatment. Fatigue measures were significantly associated with improvement in some (Lam Employment Absence and Productivity Scale, Sheehan Disability Scale), but not all (Health and Work Performance Questionnaire) work functioning measures, independent of improvement in overall depressive symptoms. The limitations of this study include the small sample size and the lack of a placebo or a comparison group. Fatigue and low energy are important symptoms that are associated with occupational impairment in MDD. Treatments that improve these symptoms are likely to improve work functioning.

Effect of moderate exercise on peritoneal neutrophils from juvenile rats.

PubMed

Braz, Glauber Ruda; Ferreira, Diorginis Soares; Pedroza, Anderson Apolonio; da Silva, Aline Isabel; Sousa, Shirley Maria; Pithon-Curi, Tania Cristina; Lagranha, Claudia

2015-09-01

Previous studies showed that moderate exercise in adult rats enhances neutrophil function, although no studies were performed in juvenile rats. We evaluated the effects of moderate exercise on the neutrophil function in juvenile rats. Viability and neutrophils function were evaluated. Moderate exercise did not impair the viability and mitochondrial transmembrane potential of neutrophils, whereas there was greater reactive oxygen species production (164%; p < 0.001) and phagocytic capacity (29%; p < 0.05). Our results suggest that moderate exercise in juvenile rats improves neutrophil function, similar to adults.

Extrarenal citrulline disposal in mice with impaired renal function

USDA-ARS?s Scientific Manuscript database

The endogenous synthesis of arginine, a semiessential amino acid, relies on the production of citrulline by the gut and its conversion into arginine by the kidney in what has been called the "intestinal-renal axis" for arginine synthesis. Although the kidney is the main site for citrulline disposal,...

Nicotinamide mononucleotide protects against pro-inflammatory cytokine-mediated impairment of mouse islet function.

PubMed

Caton, P W; Kieswich, J; Yaqoob, M M; Holness, M J; Sugden, M C

2011-12-01

Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD(+) biosynthesis, exists as intracellular NAMPT (iNAMPT) and extracellular NAMPT (eNAMPT). eNAMPT, secreted from adipose tissue, promotes insulin secretion. Administration of nicotinamide mononucleotide (NMN), a product of the eNAMPT reaction, corrects impaired islet function in Nampt ( +/- ) mice. One of its potential targets is the NAD(+)-dependent deacetylase sirtuin 1. We hypothesised that altered NAMPT activity might contribute to the suppression of islet function associated with inflammation, and aimed to determine whether NMN could improve cytokine-mediated islet dysfunction. Acute effects of NMN on cytokine-mediated islet dysfunction were examined in islets incubated with TNFα and IL1β, and in mice fed a fructose-rich diet (FRD) for 16 weeks. Changes in iNAMPT, eNAMPT and inflammation levels were determined in FRD-fed mice. FRD-fed mice displayed markedly lower levels of circulating eNAMPT, with impaired insulin secretion and raised islet expression of Il1b. NMN administration lowered Il1b expression and restored suppressed insulin secretion in FRD-fed mice. NMN also restored insulin secretion in islets cultured with pro-inflammatory cytokines. The changes in islet function corresponded with changes in key markers of islet function and differentiation. The anti-inflammatory effects of NMN were partially blocked by inhibition of sirtuin 1. Chronic fructose feeding causes severe islet dysfunction in mice. Onset of beta cell failure in FRD-fed mice may occur via lowered secretion of eNAMPT, leading to increased islet inflammation and impaired beta cell function. Administration of exogenous NMN to FRD-fed mice corrects inflammation-induced islet dysfunction. Modulation of this pathway may be an attractive target for amelioration of islet dysfunction associated with inflammation.

MRI-based comparative study of different mild cognitive impairment subtypes: protocol for an observational case-control study.

PubMed

Yu, Yang; Zhao, Weina; Li, Siou; Yin, Changhao

2017-03-08

Amnestic mild cognitive impairment (aMCI) and vascular mild cognitive impairment (VaMCI) comprise the 2 main types of mild cognitive impairment (MCI). The first condition generally progresses to Alzheimer's disease, whereas the second is likely to develop into vascular dementia (VD). The brain structure and function of patients with MCI differ from those of normal elderly individuals. However, whether brain structures or functions differ between these 2 MCI subtypes has not been studied. This study is designed to analyse neuroimages of brain in patients with VaMCI and aMCI using multimodality MRI (structural MRI (sMRI), functional MRI and diffusion tensor imaging (DTI)). In this study, 80 participants diagnosed with aMCI, 80 participants diagnosed with VaMCI, and 80 age-matched, gender-matched and education-matched normal controls (NCs) will be recruited to the Hongqi Hospital of Mudanjiang Medical University, Heilongjiang, China. All participants will undergo neuroimaging and neuropsychological evaluations. The primary outcome measures will be (1) microstructural alterations revealed by multimodal MRIs, including sMRI, resting-state functional MRI and DTI; and (2) a neuropsychological evaluation, including the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Auditory Verbal Learning Test (AVLT), Memory and Executive Screening (MES), trail making test, Stroop colour naming condition and Clinical Dementia Rating (CDR) scale, to evaluate global cognition, memory function, attention, visuospatial skills, processing speed, executive function and emotion, respectively. NCT02706210; Pre-results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Adolescent Binge Alcohol Exposure Affects the Brain Function Through Mitochondrial Impairment.

PubMed

Tapia-Rojas, Cheril; Carvajal, Francisco J; Mira, Rodrigo G; Arce, Camila; Lerma-Cabrera, José Manuel; Orellana, Juan A; Cerpa, Waldo; Quintanilla, Rodrigo A

2018-05-01

In the young population, binge drinking is a pattern of problematic alcohol consumption, characterized by a short period of heavy drinking followed by abstinence which is frequently repeated over time. This drinking pattern is associated with mental problems, use of other drugs, and an increased risk of excessive alcohol intake during adulthood. However, little is known about the effects of binge drinking on brain function in adolescents and its neurobiological impact during the adulthood. In the present study, we evaluated the effects of alcohol on hippocampal memory, synaptic plasticity, and mitochondrial function in adolescent rats after a binge drinking episode in vivo. These effects were analyzed at 1, 3, or 7 weeks post alcohol exposure. Our results showed that binge-like ethanol pre-treated (BEP) rats exhibited early alterations in learning and memory tests accompanied by an impairment of synaptic plasticity that was total and partially compensated, respectively. These changes could be attributed to a rapid increase in oxidative damage and a late inflammatory response induced by post ethanol exposure. Additionally, BEP alters the regulation of mitochondrial dynamics and modifies the expression of mitochondrial permeability transition pore (mPTP) components, such as cyclophilin D (Cyp-D) and the voltage-dependent anion channel (VDAC). These mitochondrial structural changes result in the impairment of mitochondrial bioenergetics, decreasing ATP production progressively until adulthood. These results strongly suggest that teenage alcohol binge drinking impairs the function of the adult hippocampus including memory and synaptic plasticity as a consequence of the mitochondrial damage induced by alcohol and that the recovery of hippocampal function could implicate the activation of alternative pathways that fail to reestablish mitochondrial function.

Worse cardiac remodeling in response to pressure overload in type 2 diabetes mellitus.

PubMed

Gonçalves, N; Gomes-Ferreira, C; Moura, C; Roncon-Albuquerque, R; Leite-Moreira, A F; Falcão-Pires, I

2016-08-15

Diabetic cardiomyopathy is characterized by cardiac structural and functional abnormalities. Additionally, chronic pressure overload conditions are highly prevalent amongst diabetic population and this association leads to a more severe myocardial impairment. The differences in myocardial pathophysiology between type 1 and type 2 diabetes mellitus (DM) still remain to be clarified. Thus, we aimed to investigate biventricular structural and functional changes promoted by the two types of DM and the impact of concomitant chronic pressure overload. Wistar rats were injected with streptozotocin (Type 1 DM, T1DM) or fed with a hypercaloric diet (Type 2 DM, T2DM). Pressure overload was imposed in DM animals by aortic constriction and after 5weeks of DM the cardiac function and structure were evaluated. Both types of DM promoted hypertrophy, increased fibrosis and advanced glycation end-products deposition, in the two ventricles. Interestingly, the induced myocardial alterations were distinct. While T1DM stimulated a pronounced hypertrophy and extracellular matrix remodeling, T2DM induced functional impairment. The negative impact of the association of DM with aortic constriction was more pronounced in T2DM, promoting impaired function and increased stiffness, particularly in the right ventricle. Our study demonstrated that the two types of diabetes induce distinct cardiac alterations per se or when combined with chronic pressure overload. T1DM promoted a more extensive remodeling in cardiac structure while T2DM significantly impaired ventricular function. The impact of pressure overload was more notorious in T2DM as observed by worse myocardial remodeling, suggesting a higher susceptibility to the deleterious effects of chronic pressure overload, namely hypertension, among this diabetic population. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Cognitive and psychosocial function in retired professional hockey players.

PubMed

Esopenko, Carrie; Chow, Tiffany W; Tartaglia, Maria Carmela; Bacopulos, Agnes; Kumar, Priya; Binns, Malcolm A; Kennedy, James L; Müller, Daniel J; Levine, Brian

2017-06-01

The relationship between repeated concussions and neurodegenerative disease has received significant attention, particularly research in postmortem samples. Our objective was to characterise retired professional ice hockey players' cognitive and psychosocial functioning in relation to concussion exposure and apolipoprotein ε4 status. Alumni athletes (N=33, aged 34-71 years) and an age-matched sample of comparison participants (N=18) were administered measures of cognitive function and questionnaires concerning psychosocial and psychiatric functioning. No significant group differences were found on neuropsychological measures of speeded attention, verbal memory or visuospatial functions, nor were significant differences observed on computerised measures of response speed, inhibitory control and visuospatial problem solving. Reliable group differences in cognitive performance were observed on tests of executive and intellectual function; performance on these measures was associated with concussion exposure. Group differences were observed for cognitive, affective and behavioural impairment on psychosocial questionnaires and psychiatric diagnoses. There was no evidence of differential effects associated with age in the alumni athletes. Possession of an apolipoprotein ε4 allele was associated with increased endorsement of psychiatric complaints, but not with objective cognitive performance. We found only subtle objective cognitive impairment in alumni athletes in the context of high subjective complaints and psychiatric impairment. Apolipoprotein ε4 status related to psychiatric, but not cognitive status. These findings provide benchmarks for the degree of cognitive and behavioural impairment in retired professional athletes and a point of comparison for future neuroimaging and longitudinal studies. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus

PubMed Central

Tangvarasittichai, Surapon

2015-01-01

Oxidative stress is increased in metabolic syndrome and type 2 diabetes mellitus (T2DM) and this appears to underlie the development of cardiovascular disease, T2DM and diabetic complications. Increased oxidative stress appears to be a deleterious factor leading to insulin resistance, dyslipidemia, β-cell dysfunction, impaired glucose tolerance and ultimately leading to T2DM. Chronic oxidative stress, hyperglycemia and dyslipidemia are particularly dangerous for β-cells from lowest levels of antioxidant, have high oxidative energy requirements, decrease the gene expression of key β-cell genes and induce cell death. If β-cell functioning is impaired, it results in an under production of insulin, impairs glucose stimulated insulin secretion, fasting hyperglycemia and eventually the development of T2DM. PMID:25897356

Malnutrition-associated liver steatosis and ATP depletion is caused by peroxisomal and mitochondrial dysfunction.

PubMed

van Zutphen, Tim; Ciapaite, Jolita; Bloks, Vincent W; Ackereley, Cameron; Gerding, Albert; Jurdzinski, Angelika; de Moraes, Roberta Allgayer; Zhang, Ling; Wolters, Justina C; Bischoff, Rainer; Wanders, Ronald J; Houten, Sander M; Bronte-Tinkew, Dana; Shatseva, Tatiana; Lewis, Gary F; Groen, Albert K; Reijngoud, Dirk-Jan; Bakker, Barbara M; Jonker, Johan W; Kim, Peter K; Bandsma, Robert H J

2016-12-01

Severe malnutrition in young children is associated with signs of hepatic dysfunction such as steatosis and hypoalbuminemia, but its etiology is unknown. Peroxisomes and mitochondria play key roles in various hepatic metabolic functions including lipid metabolism and energy production. To investigate the involvement of these organelles in the mechanisms underlying malnutrition-induced hepatic dysfunction we developed a rat model of malnutrition. Weanling rats were placed on a low protein or control diet (5% or 20% of calories from protein, respectively) for four weeks. Peroxisomal and mitochondrial structural features were characterized using immunofluorescence and electron microscopy. Mitochondrial function was assessed using high-resolution respirometry. A novel targeted quantitative proteomics method was applied to analyze 47 mitochondrial proteins involved in oxidative phosphorylation, tricarboxylic acid cycle and fatty acid β-oxidation pathways. Low protein diet-fed rats developed hypoalbuminemia and hepatic steatosis, consistent with the human phenotype. Hepatic peroxisome content was decreased and metabolomic analysis indicated peroxisomal dysfunction. This was followed by changes in mitochondrial ultrastructure and increased mitochondrial content. Mitochondrial function was impaired due to multiple defects affecting respiratory chain complex I and IV, pyruvate uptake and several β-oxidation enzymes, leading to strongly reduced hepatic ATP levels. Fenofibrate supplementation restored hepatic peroxisome abundance and increased mitochondrial β-oxidation capacity, resulting in reduced steatosis and normalization of ATP and plasma albumin levels. Malnutrition leads to severe impairments in hepatic peroxisomal and mitochondrial function, and hepatic metabolic dysfunction. We discuss the potential future implications of our findings for the clinical management of malnourished children. Severe malnutrition in children is associated with metabolic disturbances that are poorly understood. In order to study this further, we developed a malnutrition animal model and found that severe malnutrition leads to an impaired function of liver mitochondria which are essential for energy production and a loss of peroxisomes, which are important for normal liver metabolic function. Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Impaired IL-13-mediated functions of macrophages in STAT6-deficient mice.

PubMed

Takeda, K; Kamanaka, M; Tanaka, T; Kishimoto, T; Akira, S

1996-10-15

IL-13 shares many biologic responses with IL-4. In contrast to well-characterized IL-4 signaling pathways, which utilize STAT6 and 4PS/IRS2, IL-13 signaling pathways are poorly understood. Recent studies performed with STAT6-deficient mice have demonstrated that STAT6 plays an essential role in IL-4 signaling. In this study, the functions of peritoneal macrophages of STAT6-deficient mice in response to IL-13 were analyzed. In STAT6-deficient mice, neither morphologic changes nor augmentation of MHC class II expression in response to IL-13 was observed. In addition, IL-13 did not decrease the nitric oxide production by activated macrophages. Taken together, these results suggest that the macrophage functions in response to IL-13 were impaired in STAT6-deficient mice, indicating that IL-13 and IL-4 share the signaling pathway via STAT6.

The association of medical conditions and presenteeism.

PubMed

Burton, Wayne N; Pransky, Glenn; Conti, Daniel J; Chen, Chin-Yu; Edington, Dee W

2004-06-01

A self-reported measure of four domains of work impairment based on the Work Limitations Questionnaire was completed by 16,651 employees of a large financial services corporation. Using a multivariate model to control for coexisting conditions, age, and gender, significant relationships were observed between medical conditions and patterns of impaired work performance. Depression was highly associated with work limitations in time management (odds ratio [OR] = 2.05), interpersonal/mental functioning (OR = 2.50), and overall output (OR = 2.24). Arthritis (OR = 1.56) and low back pain (OR = 1.32) were associated with physical function limitations. These same two conditions were associated with limitations in mental/interpersonal functioning but with low back pain having the higher odds ratio (OR = 1.54 vs. 1.22). These results suggest that worksite interventions (eg, disease management programs) should be tailored to the unique effects observed with specific medical conditions. More targeted programs could have important benefits for productivity in the workplace.

Dammarane Sapogenins Ameliorates Neurocognitive Functional Impairment Induced by Simulated Long-Duration Spaceflight.

PubMed

Wu, Xiaorui; Li, Dong; Liu, Junlian; Diao, Lihong; Ling, Shukuan; Li, Yuheng; Gao, Jianyi; Fan, Quanchun; Sun, Weijia; Li, Qi; Zhao, Dingsheng; Zhong, Guohui; Cao, Dengchao; Liu, Min; Wang, Jiaping; Zhao, Shuang; Liu, Yu; Bai, Guie; Shi, Hongzhi; Xu, Zi; Wang, Jing; Xue, Chunmei; Jin, Xiaoyan; Yuan, Xinxin; Li, Hongxing; Liu, Caizhi; Sun, Huiyuan; Li, Jianwei; Li, Yongzhi; Li, Yingxian

2017-01-01

Increasing evidence indicates the occurrence of cognitive impairment in astronauts under spaceflight compound conditions, but the underlying mechanisms and countermeasures need to be explored. In this study, we found that learning and memory abilities were significantly reduced in rats under a simulated long-duration spaceflight environment (SLSE), which includes microgravity, isolation confinement, noises, and altered circadian rhythms. Dammarane sapogenins (DS), alkaline hydrolyzed products of ginsenosides, can enhance cognition function by regulating brain neurotransmitter levels and inhibiting SLSE-induced neuronal injury. Bioinformatics combined with experimental verification identified that the PI3K-Akt-mTOR pathway was inhibited and the MAPK pathway was activated during SLSE-induced cognition dysfunction, whereas DS substantially ameliorated the changes in brain. These findings defined the characteristics of SLSE-induced cognitive decline and the mechanisms by which DS improves it. The results provide an effective candidate for improving cognitive function in spaceflight missions.

Dammarane Sapogenins Ameliorates Neurocognitive Functional Impairment Induced by Simulated Long-Duration Spaceflight

PubMed Central

Wu, Xiaorui; Li, Dong; Liu, Junlian; Diao, Lihong; Ling, Shukuan; Li, Yuheng; Gao, Jianyi; Fan, Quanchun; Sun, Weijia; Li, Qi; Zhao, Dingsheng; Zhong, Guohui; Cao, Dengchao; Liu, Min; Wang, Jiaping; Zhao, Shuang; Liu, Yu; Bai, Guie; Shi, Hongzhi; Xu, Zi; Wang, Jing; Xue, Chunmei; Jin, Xiaoyan; Yuan, Xinxin; Li, Hongxing; Liu, Caizhi; Sun, Huiyuan; Li, Jianwei; Li, Yongzhi; Li, Yingxian

2017-01-01

Increasing evidence indicates the occurrence of cognitive impairment in astronauts under spaceflight compound conditions, but the underlying mechanisms and countermeasures need to be explored. In this study, we found that learning and memory abilities were significantly reduced in rats under a simulated long-duration spaceflight environment (SLSE), which includes microgravity, isolation confinement, noises, and altered circadian rhythms. Dammarane sapogenins (DS), alkaline hydrolyzed products of ginsenosides, can enhance cognition function by regulating brain neurotransmitter levels and inhibiting SLSE-induced neuronal injury. Bioinformatics combined with experimental verification identified that the PI3K-Akt-mTOR pathway was inhibited and the MAPK pathway was activated during SLSE-induced cognition dysfunction, whereas DS substantially ameliorated the changes in brain. These findings defined the characteristics of SLSE-induced cognitive decline and the mechanisms by which DS improves it. The results provide an effective candidate for improving cognitive function in spaceflight missions. PMID:28611667

Loss of Work Productivity and Quality of Life in Patients With Autoimmune Bullous Dermatoses.

PubMed

Heelan, K; Hitzig, S L; Knowles, S; Drucker, A M; Mittmann, N; Walsh, S; Shear, N H

2015-01-01

Little is known about quality of life and work productivity in autoimmune bullous dermatoses (AIBDs). To determine the impact of AIBDs on quality of life and work productivity. An observational cross-sectional study took place between February and May 2013 at an AIBD tertiary referral centre. Ninety-four patients were included. All participants completed the Dermatology Life Quality Index and the Work Productivity and Activity Impairment-Specific Health Problem questionnaires. Responders to treatment had less impairment (P<.001) than nonresponders. Patients with severe AIBD had significantly more impairment that those with mild (P<.001) and moderate (P=.002) AIBD. Greater impairment was associated with higher percentage of work missed. Those with a higher Dermatology Life Quality Index score had greater work impairment and overall activity impairment (P=.041, P=.024). Nonresponders had increased impairment while working (P<.001), overall work impairment (P<.001), and activity impairment (P<.001). Severely affected patients had worse impairment in all Work Productivity and Activity Impairment Questionnaire domains. AIBD has the potential to be a large burden on ability to work and quality of life. Larger studies are needed to clarify how these domains change over time and whether or not they improve with treatment. © The Author(s) 2015.

Contemporary Issues in Phoneme Production by Hearing-Impaired Persons: Physiological and Acoustic Aspects.

ERIC Educational Resources Information Center

McGarr, Nancy S.; Whitehead, Robert

1992-01-01

This paper on physiologic correlates of speech production in children and youth with hearing impairments focuses specifically on the production of phonemes and includes data on respiration for speech production, phonation, speech aerodynamics, articulation, and acoustic analyses of speech by hearing-impaired persons. (Author/DB)

ROLE OF CENTRAL NERVOUS SYSTEM INSULIN RESISTANCE IN FETAL ALCOHOL SPECTRUM DISORDERS

PubMed Central

de la Monte, Suzanne M; Wands, Jack R

2011-01-01

Fetal alcohol spectrum disorder (FASD) is the most common preventable cause of mental retardation in the USA. Ethanol impairs neuronal survival and function by two major mechanisms: 1) it inhibits insulin signaling required for viability, metabolism, synapse formation, and acetylcholine production; and 2) it functions as a neurotoxicant, causing oxidative stress, DNA damage and mitochondrial dysfunction. Ethanol inhibition of insulin signaling is mediated at the insulin receptor (IR) level and caused by both impaired receptor binding and increased activation of phosphatases that reverse IR tyrosine kinase activity. As a result, insulin activation of PI3K-Akt, which mediates neuronal survival, motility, energy metabolism, and plasticity, is impaired. The neurotoxicant effects of ethanol promote DNA damage, which could contribute to mitochondrial dysfunction and oxidative stress. Therefore, chronic in utero ethanol exposure produces a dual state of CNS insulin resistance and oxidative stress, which we postulate plays a major role in ethanol neurobehavioral teratogenesis. We propose that many of the prominent adverse effects of chronic prenatal exposure to ethanol on CNS development and function may be prevented or reduced by treatment with peroxisome-proliferated activated receptor (PPAR) agonists which enhance insulin sensitivity by increasing expression and function of insulin-responsive genes, and reducing cellular oxidative stress. PMID:21063035

Progesterone impairs antigen-non-specific immune protection by CD8 T memory cells via interferon-γ gene hypermethylation.

PubMed

Yao, Yushi; Li, Hui; Ding, Jie; Xia, Yixin; Wang, Lei

2017-11-01

Pregnant women and animals have increased susceptibility to a variety of intracellular pathogens including Listeria monocytogenes (LM), which has been associated with significantly increased level of sex hormones such as progesterone. CD8 T memory(Tm) cell-mediated antigen-non-specific IFN-γ responses are critically required in the host defense against LM. However, whether and how increased progesterone during pregnancy modulates CD8 Tm cell-mediated antigen-non-specific IFN-γ production and immune protection against LM remain poorly understood. Here we show in pregnant women that increased serum progesterone levels are associated with DNA hypermethylation of IFN-γ gene promoter region and decreased IFN-γ production in CD8 Tm cells upon antigen-non-specific stimulation ex vivo. Moreover, IFN-γ gene hypermethylation and significantly reduced IFN-γ production post LM infection in antigen-non-specific CD8 Tm cells are also observed in pregnant mice or progesterone treated non-pregnant female mice, which is a reversible phenotype following demethylation treatment. Importantly, antigen-non-specific CD8 Tm cells from progesterone treated mice have impaired anti-LM protection when adoptive transferred in either pregnant wild type mice or IFN-γ-deficient mice, and demethylation treatment rescues the adoptive protection of such CD8 Tm cells. These data demonstrate that increased progesterone impairs immune protective functions of antigen-non-specific CD8 Tm cells via inducing IFN-γ gene hypermethylation. Our findings thus provide insights into a new mechanism through which increased female sex hormone regulate CD8 Tm cell functions during pregnancy.

Progesterone impairs antigen-non-specific immune protection by CD8 T memory cells via interferon-γ gene hypermethylation

PubMed Central

Yao, Yushi; Li, Hui; Ding, Jie; Xia, Yixin

2017-01-01

Pregnant women and animals have increased susceptibility to a variety of intracellular pathogens including Listeria monocytogenes (LM), which has been associated with significantly increased level of sex hormones such as progesterone. CD8 T memory(Tm) cell-mediated antigen-non-specific IFN-γ responses are critically required in the host defense against LM. However, whether and how increased progesterone during pregnancy modulates CD8 Tm cell-mediated antigen-non-specific IFN-γ production and immune protection against LM remain poorly understood. Here we show in pregnant women that increased serum progesterone levels are associated with DNA hypermethylation of IFN-γ gene promoter region and decreased IFN-γ production in CD8 Tm cells upon antigen-non-specific stimulation ex vivo. Moreover, IFN-γ gene hypermethylation and significantly reduced IFN-γ production post LM infection in antigen-non-specific CD8 Tm cells are also observed in pregnant mice or progesterone treated non-pregnant female mice, which is a reversible phenotype following demethylation treatment. Importantly, antigen-non-specific CD8 Tm cells from progesterone treated mice have impaired anti-LM protection when adoptive transferred in either pregnant wild type mice or IFN-γ-deficient mice, and demethylation treatment rescues the adoptive protection of such CD8 Tm cells. These data demonstrate that increased progesterone impairs immune protective functions of antigen-non-specific CD8 Tm cells via inducing IFN-γ gene hypermethylation. Our findings thus provide insights into a new mechanism through which increased female sex hormone regulate CD8 Tm cell functions during pregnancy. PMID:29155896

HLA-E upregulation on IFN-gamma-activated AML blasts impairs CD94/NKG2A-dependent NK cytolysis after haplo-mismatched hematopoietic SCT.

PubMed

Nguyen, S; Beziat, V; Dhedin, N; Kuentz, M; Vernant, J P; Debre, P; Vieillard, V

2009-05-01

Natural killer (NK) cells generated after haploidentical hematopoietic SCT in patients with AML are characterized by specific phenotypic features and impaired functioning that may affect transplantation outcome. We show that IFN-gamma produced by immature CD56(bright) NK cells upregulates cell surface expression of HLA-E on AML blasts and that this upregulation protects leukemic cells from NK-mediated cell lysis through the mediation of CD94/NKG2A, an inhibitory receptor overexpressed on NK cells after haploidentical SCT. Two years after transplantation, however, maturing NK cells were functionally active, as evidenced by high cytotoxicity and poor IFN-gamma production. This implies that maturation of NK cells is the key to improved immune responses and transplantation outcome.

Functional Impairment and Changes in Depression Subtypes for Women in STAR*D: A Latent Transition Analysis

PubMed Central

Rothschild, Anthony J.; Lapane, Kate L.

2016-01-01

Abstract Objective: To characterize the association between functional impairment and major depression subtypes at baseline and to characterize changes in subtypes by functional impairment level in women receiving citalopram in level 1 of the Sequenced Treatment Alternatives to Relieve Depression trial. Method: Women who completed baseline and week 12 study visits were included. Items from the self-reported Quick Inventory of Depressive Symptomatology were used to define the latent depression subtypes. The Work and Social Adjustment Scale was used to classify baseline functional impairment. A latent transition analysis model provided estimates of the prevalence of subtype membership and transition probabilities by functional impairment level. Results: Of the 755 women included, 69% had major functional impairment at baseline. Regardless of functional impairment level, the subtypes were differentiated by depression severity, appetite changes, psychomotor disturbances, and insomnia. Sixty-seven percent of women with normal/significant functional impairment and 60% of women with major impairment were likely to transition to a symptom resolution subtype at week 12. Women with baseline major impairment who were in the severe with psychomotor agitation subtype at the beginning of the study were least likely to transition to the symptom resolution subtype (4% chance). Conclusions: Functional impairment level was related to both the baseline depression subtype and the likelihood of moving to a different subtype. These results underscore the need to incorporate not only depression symptoms but also functioning in the assessment and treatment of depression. PMID:26488110

Altered morphology and function of the lacrimal functional unit in protein kinase C{alpha} knockout mice.

PubMed

Chen, Zhuo; Li, Zhijie; Basti, Surendra; Farley, William J; Pflugfelder, Stephen C

2010-11-01

Protein kinase C (PKC) α plays a major role in the parasympathetic neural stimulation of lacrimal gland (LG) secretion. It also has been reported to have antiapoptotic properties and to promote cell survival. Therefore, the hypothesis for the present study was that PKCα knockout ((-/-)) mice have impaired ocular surface-lacrimal gland signaling, rendering them susceptible to desiccating stress and impaired corneal epithelial wound healing. In this study, the lacrimal function unit (LFU) and the stressed wound-healing response were examined in PKCα(-/-) mice. In PKCα(+/+) control mice and PKCα(-/-) mice, tear production, osmolarity, and clearance rate were evaluated before and after experimental desiccating stress. Histology and immunofluorescent staining of PKC and epidermal growth factor were performed in tissues of the LFU. Cornified envelope (CE) precursor protein expression and cell proliferation were evaluated. The time course of healing and degree of neutrophil infiltration was evaluated after corneal epithelial wounding. Compared with the PKCα(+/+) mice, the PKCα(-/-) mice were noted to have significantly increased lacrimal gland weight, with enlarged, carbohydrate-rich, PAS-positive acinar cells; increased corneal epithelia permeability, with reduced CE expression; and larger conjunctival epithelial goblet cells. The PKCα(-/-) mice showed more rapid corneal epithelial healing, with less neutrophil infiltration and fewer proliferating cells than did the PKCα(+/+) mice. The PKCα(-/-) mice showed lower tear production, which appeared to be caused by impaired secretion by the LG and conjunctival goblet cells. Despite their altered tear dynamics, the PKCα(-/-) mice demonstrated more rapid corneal epithelial wound healing, perhaps due to decreased neutrophil infiltration.

Induction of oxidative stress and human leukocyte/endothelial cell interactions in polycystic ovary syndrome patients with insulin resistance.

PubMed

Victor, Victor M; Rocha, Milagros; Bañuls, Celia; Alvarez, Angeles; de Pablo, Carmen; Sanchez-Serrano, Maria; Gomez, Marcelino; Hernandez-Mijares, Antonio

2011-10-01

Insulin resistance is a feature of polycystic ovary syndrome (PCOS) and is related to mitochondrial and endothelial function. We tested whether hyperandrogenic insulin-resistant women with PCOS, who have an increased risk of vascular disease, display impaired leukocyte-endothelium interactions, and mitochondrial dysfunction. This was a prospective controlled study conducted in an academic medical center. The study population consisted of 43 lean reproductive-age women with PCOS and 39 controls subjects. We evaluated anthropometric and metabolic parameters, adhesion molecules, and interactions between leukocytes and human umbilical vein endothelial cells. Mitochondrial function was studied by assessing mitochondrial oxygen consumption, membrane potential, reactive oxygen species production, glutathione levels (GSH), and the oxidized glutathione (GSSG)/GSH ratio in polymorphonuclear cells. Impairment of mitochondrial function was observed in the PCOS patients, evident in a decrease in oxygen consumption, an increase in reactive oxygen species production, a decrease in the GSH/GSSG ratio and GSH levels, and an undermining of the membrane potential. PCOS was related to a decrease in polymorphonuclear cell rolling velocity and an increase in rolling flux and adhesion. Increases in IL-6 and TNFα and adhesion molecules (vascular cell adhesion molecule-1 and E-selectin) were also observed. This study supports the hypothesis of an association between insulin resistance and an impaired endothelial and mitochondrial oxidative metabolism. The evidence obtained shows that the inflammatory state related to insulin resistance in PCOS induces a leukocyte-endothelium interaction. These findings may explain the increased risk of vascular disease in women with PCOS.

Neurocognition, functional competence and self-reported functional impairment in psychometrically defined schizotypy.

PubMed

Xavier, Shannon; Best, Michael W; Schorr, Emily; Bowie, Christopher R

2015-01-01

Schizotypy is phenologically and genetically related to schizophrenia-spectrum illness. Previous studies find cognitive function to be mildly impaired, but specific impairments and their relationship to functioning are not well understood. In this study, we sought to examine how cognitive load affects performance in schizotypy and to examine whether impairments might manifest in functional capacity and quality of life. Undergraduate students were screened for abnormally high levels of schizotypy (N = 72) and compared to those without psychopathology (N = 80) on a standard battery of neuropsychological tests, cognitive tests with varying cognitive load, functional capacity measures and quality of life. The high schizotypy group did not differ from controls on traditional measures of neuropsychological functioning, but an interaction of group by cognitive load was observed, where those with schizotypy manifested a greater decline in performance as information processing load was parametrically increased. Differences in functioning were observed and cognitive impairment was associated with impaired functioning. Cognitive and functional impairment can be observed in those with high schizotypal traits who are non-treatment seeking. The sensitivity of cognitive tests to impairment in this population might be a function of their ability to parametrically increase cognitive load.

Cytophysiological Changes in the Follicular Epithelium of the Thyroid Gland after Long-Term Exposure to Low Doses of Dichlorodiphenyltrichloroethane (DDT).

PubMed

Yaglova, N V; Yaglov, V V

2017-03-01

Exposure to endocrine disruptors is considered as a risk factor thyroid gland diseases. We analyzed cytophysiological changes in rat thyroid follicular epithelium after long-term exposure to low doses of the most widespread disruptor DDT. Analysis of thyroid hormone production and light and electron microscopy of thyroid gland samples revealed cytophysiological changes in thyroid epithelium related to impaired transport through the apical membrane, suppressed Golgi complex activity, and impaired thyrotrophic hormone regulation of the secretory functions of thyroid cells, which led to compensatory transition from merocrine to microapocrine secret release.

Forest Ecosystem Services As Production Inputs

Treesearch

Subhrendu Pattanayak; David T. Butry

2003-01-01

Are we cutting down tropical forests too rapidly and too extensively? If so, why? Answers to both questions are obscured in some ways by insufficient and unreliable data on the economic worth of forest ecosystem services. It is clear, however, that rapid, excessive cutting of forests can irreversibly and substantively impair ecosystem functions, thereby endangering the...

IMMUNE FUNCTION IS NOT IMPAIRED IN SPRAGUE-DAWLEY RATS EXPOSED TO DIMETHYLTIN DICHLORIDE (DMTC) DURING DEVELOPMENT OR ADULTHOOD

EPA Science Inventory

Abstract

Organotins are used commercially as pesticides, antifouling agents and stabilizers for polyvinyl chloride (PVC) pipe. Mono- and di-substituted butyltins, used in PVC pipe production, are of concern to the U.S. EPA because they leach from supply pipes into drinkin...

Evaluation of a Computer-Based Revision Prompting Intervention for Undergraduate Writers with Acquired Brain Injury

ERIC Educational Resources Information Center

Ledbetter, Alexander K.

2017-01-01

People with acquired brain injury (ABI) present with impairments in working memory and executive functions, and these cognitive deficits contribute to difficulty self-regulating the production of expository writing. Cognitive processes involved in carrying out complex writing tasks include planning, generating text, and reviewing or revising text…

Arthritis and Risk of Cognitive and Functional Impairment in Older Mexican Adults.

PubMed

Veeranki, Sreenivas P; Downer, Brian; Jupiter, Daniel; Wong, Rebeca

2017-04-01

This study investigated the risk of cognitive and functional impairment in older Mexicans diagnosed with arthritis. Participants included 2,681 Mexicans, aged ≥60 years, enrolled in the Mexican Health and Aging Study cohort. Participants were categorized into arthritis and no arthritis exposure groups. Primary outcome included participants categorized into "cognitively impaired" or "cognitively normal" groups. Secondary outcomes included participants categorized into Normal, Functionally Impaired only, Cognitively Impaired only, or Dementia (both cognitively and functionally impaired) groups. Multivariable logistic and multinomial regression models were used to assess the relationships. Overall, 16% or 7% were diagnosed with cognitive impairment or dementia. Compared with older Mexicans without arthritis, those who were diagnosed with arthritis had significantly increased risk of functional impairment (adjusted odds ratio [OR] 1.82, 95% confidence interval [CI] = [1.45, 2.29]), but not of dementia. Arthritis is associated with increased risk of functional impairment, but not with dementia after 11 years in older Mexicans.

PATHOPHYSIOLOGICAL CONSEQUENCES OF TAT-HKII PEPTIDE ADMINISTRATION ARE INDEPENDENT OF IMPAIRED VASCULAR FUNCTION AND ENSUING ISCHEMIA

PubMed Central

Nederlof, Rianne; Xie, Chaoqin; Eerbeek, Otto; Koeman, Anneke; Milstein, Dan MJ; Hollmann, Markus W; Mik, Egbert G; Warley, Alice; Southworth, Richard; Akar, Fadi G.; Zuurbier, Coert J

2013-01-01

Rationale We have shown that partial dissociation of HKII from mitochondria in the intact heart using low dose (200 nM) TAT-HKII prevents the cardioprotective effects of ischemic preconditioning (IPC) whereas high-dose (10 μM) TAT-HKII administration results in rapid myocardial dysfunction, mitochondrial depolarization and disintegration. In this issue of Circulation Research, Pasdois et al argue that the deleterious effects of TAT-HKII administration on cardiac function are likely due to vasoconstriction and ensuing ischemia. Objective To investigate whether altered vascular function and ensuing ischemia recapitulate the deleterious effects of TAT-HKII in intact myocardium. Methods and Results Using a variety of complementary techniques, including mitochondrial membrane potential (ΔΨm) imaging, high-resolution optical action potential (AP) mapping, analysis of lactate production, NADH epifluorescence, lactate dehydrogenase (LDH) release, and electron microscopy, we provide direct evidence that refutes the notion that acute myocardial dysfunction by high-dose TAT-HKII peptide administration is a consequence of impaired vascular function. Moreover, we demonstrate that low-dose TAT-HKII treatment, which abrogates the protective effects of IPC, is not associated with ischemia or ischemic-injury. Conclusions Our findings challenge the notion that the effects of TAT-HKII are attributable to impaired vascular function and ensuing ischemia; thereby, lending further credence to the role of mitochondria bound HKII as a critical regulator of cardiac function, ischemia-reperfusion (IR) injury, and cardioprotection by IPC. PMID:23329797

Effectiveness of the second-stage rehabilitation in stroke patients with cognitive impairment.

PubMed

Milinavičienė, Eglė; Rastenytė, Daiva; Kriščiūnas, Aleksandras

2011-01-01

The aim of this study was to evaluate the recovery of functional status and effectiveness of the second-stage rehabilitation depending on the degree of cognitive impairment in stroke patients. The study sample comprised 226 stroke patients at the Viršužiglis Hospital of rehabilitation, Hospital of Lithuanian University of Health Sciences. Functional status was evaluated with the Functional Independence Measure, cognitive function with the Mini-Mental Status Examination scale, and severity of neurologic condition with the National Institutes of Health Stroke Scale. The patients were divided into 4 study groups based on cognitive impairment: severe, moderate, mild, or no impairment. More than half (53%) of all cases were found to have cognitive impairment, while patients with different degree of cognitive impairment were equally distributed: mild impairment (18%), moderate impairment (17%), and severe impairment (18%). Improvement of functional status was observed in all study groups (P<0.001). In the patients with moderate and severe cognitive impairment, cognitive recovery was significantly more expressed than in other study groups (P<0.001). Insufficient recovery of functional status was significantly associated with hemiplegia (OR, 11.15; P=0.015), urinary incontinence (OR, 14.91; P<0.001), joint diseases (OR, 5.52; P=0.022), heart diseases (OR, 4.10; P=0.041), and severe cognitive impairment (OR, 15.18; P<0.001), while moderate and mild cognitive impairment was not associated with the recovery of functional status. During the second-stage rehabilitation of stroke patients, functional status as well as cognitive and motor skills were improved both in patients with and without cognitive impairment; however, the patients who were diagnosed with severe or moderate cognitive impairment at the beginning of second-stage rehabilitation showed worse neurological and functional status during the whole second-stage rehabilitation than the patients with mild or no cognitive impairment.

High CO2 levels impair alveolar epithelial function independently of pH.

PubMed

Briva, Arturo; Vadász, István; Lecuona, Emilia; Welch, Lynn C; Chen, Jiwang; Dada, Laura A; Trejo, Humberto E; Dumasius, Vidas; Azzam, Zaher S; Myrianthefs, Pavlos M; Batlle, Daniel; Gruenbaum, Yosef; Sznajder, Jacob I

2007-11-28

In patients with acute respiratory failure, gas exchange is impaired due to the accumulation of fluid in the lung airspaces. This life-threatening syndrome is treated with mechanical ventilation, which is adjusted to maintain gas exchange, but can be associated with the accumulation of carbon dioxide in the lung. Carbon dioxide (CO2) is a by-product of cellular energy utilization and its elimination is affected via alveolar epithelial cells. Signaling pathways sensitive to changes in CO2 levels were described in plants and neuronal mammalian cells. However, it has not been fully elucidated whether non-neuronal cells sense and respond to CO2. The Na,K-ATPase consumes approximately 40% of the cellular metabolism to maintain cell homeostasis. Our study examines the effects of increased pCO2 on the epithelial Na,K-ATPase a major contributor to alveolar fluid reabsorption which is a marker of alveolar epithelial function. We found that short-term increases in pCO2 impaired alveolar fluid reabsorption in rats. Also, we provide evidence that non-excitable, alveolar epithelial cells sense and respond to high levels of CO2, independently of extracellular and intracellular pH, by inhibiting Na,K-ATPase function, via activation of PKCzeta which phosphorylates the Na,K-ATPase, causing it to endocytose from the plasma membrane into intracellular pools. Our data suggest that alveolar epithelial cells, through which CO2 is eliminated in mammals, are highly sensitive to hypercapnia. Elevated CO2 levels impair alveolar epithelial function, independently of pH, which is relevant in patients with lung diseases and altered alveolar gas exchange.

IL-6-mediated environmental conditioning of defective Th1 differentiation dampens antitumour immune responses in old age.

PubMed

Tsukamoto, Hirotake; Senju, Satoru; Matsumura, Keiko; Swain, Susan L; Nishimura, Yasuharu

2015-04-07

Decline in immune function and inflammation concomitantly develop with ageing. Here we focus on the impact of this inflammatory environment on T cells, and demonstrate that in contrast to successful tumour elimination in young mice, replenishment of tumour-specific CD4(+) T cells fails to induce tumour regression in aged hosts. The impaired antitumour effect of CD4(+) T cells with their defective Th1 differentiation in an aged environment is restored by interleukin (IL)-6 blockade or IL-6 deficiency. IL-6 blockade also restores the impaired ability of CD4(+) T cells to promote CD8(+) T-cell-dependent tumour elimination in aged mice, which requires IFN-γ. Furthermore, IL-6-stimulated production of IL-4/IL-21 through c-Maf induction is responsible for impaired Th1 differentiation. IL-6 also contributes to IL-10 production from CD4(+) T cells in aged mice, causing attenuated responses of CD8(+) T cells. These findings suggest that IL-6 serves as an extrinsic factor counteracting CD4(+) T-cell-mediated immunity against tumour in old age.

Temporal processing impairment in children with attention-deficit-hyperactivity disorder.

PubMed

Huang, Jia; Yang, Bin-rang; Zou, Xiao-bing; Jing, Jin; Pen, Gang; McAlonan, Gráinne M; Chan, Raymond C K

2012-01-01

The current study aimed to investigate temporal processing in Chinese children with Attention-Deficit-Hyperactivity Disorder(ADHD) using time production, time reproduction paradigm and duration discrimination tasks. A battery of tests specifically designed to measure temporal processing was administered to 94 children with ADHD and 100 demographically matched healthy children. A multivariate analysis of variance (MANOVA) and a repeated measure MANOVA indicated that children with ADHD were impaired in time processing functions. The results of pairwise comparisons showed that the probands with a family history of ADHD performed significantly worse than those without family history in the time production tasks and the time reproduction task. Logistic regression analysis showed duration discrimination had a significant role in predicting whether the children were suffering from ADHD or not, while temporal processing had a significant role in predicting whether the ADHD children had a family history or not. This study provides further support for the existence of a generic temporal processing impairment in ADHD children and suggests that abnormalities in time processing and ADHD share some common genetic factors. Copyright © 2011 Elsevier Ltd. All rights reserved.

Association between pulmonary function and renal function: findings from China and Australia.

PubMed

Yu, Dahai; Chen, Tao; Cai, Yamei; Zhao, Zhanzheng; Simmons, David

2017-05-01

The relationship between obstructive lung function and impaired renal function is unclear. This study investigated the dose-response relationship between obstructive lung function and impaired renal function. Two independent cross-sectional studies with representative sampling were applied. 1454 adults from rural Victoria, Australia (1298 with normal renal function, 156 with impaired renal function) and 5824 adults from Nanjing, China (4313 with normal renal function, 1511 with impaired renal function). Pulmonary function measurements included forced expiratory volume in one second (FEV1) and forced vital capacity (FVC). Estimated glomerular filtration rate (eGFR), and impaired renal function marked by eGFR <60 mL/min/1.73m 2 were used as outcome. eGFR increased linearly with FEV1 in Chinese participants and with FVC in Australians. A non-linear relationship with peaked eGFR was found for FEV1 at 2.65 L among Australians and for FVC at 2.78 L among Chinese participants, respectively. A non-linear relationship with peaked eGFR was found for the predicted percentage value of forced expiratory volume in 1 s (PFEV1) at 81-82% and for the predicted percentage value of forced vital capacity (PFVC) at 83-84% among both Chinese and Australian participants, respectively. The non-linear dose-response relationships between lung capacity measurements (both for FEV1 and FVC) and risk of impaired renal function were consistently identified in both Chinese and Australian participants. An increased risk of impaired renal function was found below 3.05 L both for FEV1 and FVC, respectively. The non-linear relationship between PFEV and PVC and the risk of impaired renal function were consistently identified in both Chinese and Australian participants. An increased risk of impaired renal function was found below 76-77% for PFEV1 and 79-80% for PFVC, respectively. In both Australian and Chinese populations, the risk of impaired renal function increased both with FEV1 and FVC below 3.05 L, with PFEV1 below 76-77% or with PFVC below 79-80%, respectively. Obstructive lung function was associated with increased risk of reduced renal function. The screen for impaired renal function in patients with obstructive lung disease might be useful to ensure there was no impaired renal function before the commencement of potentially nephrotoxic medication where indicated (eg diuretics).

Structural Equation Modeling of Motor Impairment, Gross Motor Function, and the Functional Outcome in Children with Cerebral Palsy

ERIC Educational Resources Information Center

Park, Eun-Young; Kim, Won-Ho

2013-01-01

Physical therapy intervention for children with cerebral palsy (CP) is focused on reducing neurological impairments, improving strength, and preventing the development of secondary impairments in order to improve functional outcomes. However, relationship between motor impairments and functional outcome has not been proved definitely. This study…

Umbilical cord-derived mesenchymal stem cells reversed the suppressive deficiency of T regulatory cells from peripheral blood of patients with multiple sclerosis in a co-culture – a preliminary study

PubMed Central

Yang, Hongna; Sun, Jinhua; Wang, Feng; Li, Yan; Bi, Jianzhong; Qu, Tingyu

2016-01-01

The immunoregulatory function of T regulatory cells (Tregs) is impaired in multiple sclerosis (MS). Recent studies have shown that umbilical cord-derived mesenchymal stem cells (UC-MSCs) exert regulatory effect on the functions of immune cells. Thus, we investigated whether UC-MSCs could improve the impaired function of Tregs from MS patients. Co-cultures of UC-MSCs with PBMCs of MS patients were performed for 3 days. Flow cytometry was used to determine the frequency of Tregs. A cell proliferation assay was used to evaluate the suppressive capacity of Tregs. ELISA was conducted for cytokine analysis in the co-cultures. Our results showed that UC-MSCs significantly increased the frequency of CD4+CD25+CD127low/− Tregs in resting CD4+ T cells (p<0.01) from MS, accompanied by the significantly augmented production of cytokine prostaglandin E2, transforming growth factor (−β1, and interleukin-10, along with a reduced interferon-γ production in these co-cultures (p<0.05 - 0.01). More importantly, UC-MSC-primed Tregs of MS patients significantly inhibited the proliferation of PHA-stimulated autologous and allogeneic CD4+CD25− T effector cells (Teffs) from MS patients and healthy individuals compared to non-UC-MSC-primed (naïve) Tregs from the same MS patients (p<0.01). Furthermore, no remarkable differences in suppressing the proliferation of PHA-stimulated CD4+CD25− Teffs was observed in UC-MSC-primed Tregs from MS patients and naïve Tregs from healthy subjects. The impaired suppressive function of Tregs from MS can be completely reversed in a co-culture by UC-MSC modulation. This report is the first to demonstrate that functional defects of Tregs in MS can be repaired in vitro using a simple UC-MSC priming approach. PMID:27705922

The metabolic enhancer piracetam ameliorates the impairment of mitochondrial function and neurite outgrowth induced by ß-amyloid peptide

PubMed Central

Kurz, C; Ungerer, I; Lipka, U; Kirr, S; Schütt, T; Eckert, A; Leuner, K; Müller, WE

2010-01-01

Background and purpose: β-Amyloid peptide (Aβ) is implicated in the pathogenesis of Alzheimer's disease by initiating a cascade of events from mitochondrial dysfunction to neuronal death. The metabolic enhancer piracetam has been shown to improve mitochondrial dysfunction following brain aging and experimentally induced oxidative stress. Experimental approach: We used cell lines (PC12 and HEK cells) and murine dissociated brain cells. The protective effects of piracetam in vitro and ex vivo on Aβ-induced impairment of mitochondrial function (as mitochondrial membrane potential and ATP production), on secretion of soluble Aβ and on neurite outgrowth in PC12 cells were investigated. Key results: Piracetam improves mitochondrial function of PC12 cells and acutely dissociated brain cells from young NMRI mice following exposure to extracellular Aβ1-42. Similar protective effects against Aβ1-42 were observed in dissociated brain cells from aged NMRI mice, or mice transgenic for mutant human amyloid precursor protein (APP) treated with piracetam for 14 days. Soluble Aβ load was markedly diminished in the brain of those animals after treatment with piracetam. Aβ production by HEK cells stably transfected with mutant human APP was elevated by oxidative stress and this was reduced by piracetam. Impairment of neuritogenesis is an important consequence of Aβ-induced mitochondrial dysfunction and Aβ-induced reduction of neurite growth in PC12 cells was substantially improved by piracetam. Conclusion and implications: Our findings strongly support the concept of improving mitochondrial function as an approach to ameliorate the detrimental effects of Aβ on brain function. This article is commented on by Moncada, pp. 217–219 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2010.00706.x and to view related papers by Pravdic et al. and Puerta et al. visit http://dx.doi.org/10.1111/j.1476-5381.2010.00698.x and http://dx.doi.org/10.1111/j.1476-5381.2010.00663.x PMID:20218980

IL-23 signaling in Th17 cells is inhibited by HIV infection and is not restored by HAART: Implications for persistent immune activation.

PubMed

Fernandes, Jason R; Berthoud, Tamara K; Kumar, Ashok; Angel, Jonathan B

2017-01-01

HIV infection causes a profound depletion of gut derived Th17 cells, contributing to loss of mucosal barrier function and an increase in microbial translocation, thus driving systemic immune activation. Despite normalization of circulating CD4+ T cell counts with highly active antiretroviral therapy (HAART), Th17 frequency and function often remain impaired. Given the importance of interleukin (IL)-23 in the generation and stabilization of Th17 cells we hypothesized that impaired IL-23 signaling causes persistent Th17 dysfunction in HIV infection. The effects of in vitro HIV infection on responses to IL-23 in Th17 cells were examined. These included the production of IL-17, phosphorylated STAT3 (pSTAT3) and the transcription of retinoic acid orphan receptor C (RORC) gene. Blood derived Th17 cells from untreated and HAART-treated HIV-infected individuals were also examined for the IL-23 induced production of phosphorylated STAT3 (pSTAT3) and the expression of the IL-23 receptors. In vitro HIV infection significantly inhibited IL-17 production and IL-23 induced pSTAT3 while expression of RORC RNA was unaffected. Th17 cells isolated from untreated and HAART-treated HIV-infected individuals showed complete loss of IL-23 induced pSTAT3 without a decrease in the expression of the IL-23 receptors. This study is the first to demonstrate an effect of HIV on the IL-23 signaling pathway in Th17 cells. We show that in vitro and in vivo HIV infection results in impaired IL-23 signaling which is not reversed by HAART nor is it a result of reduced receptor expression, suggesting that HIV interferes with IL-23-activated signaling pathways. These findings may explain the inability of HAART to restore Th17 frequency and function and the resulting persistent chronic immune activation observed in HIV infected individuals.

Gender differences in associations between DSM-5 posttraumatic stress disorder symptom clusters and functional impairment in war veterans.

PubMed

Meyer, Eric C; Konecky, Brian; Kimbrel, Nathan A; DeBeer, Bryann B; Marx, Brian P; Schumm, Jeremiah; Penk, Walter E; Gulliver, Suzy Bird; Morissette, Sandra B

2018-05-01

Understanding the links between posttraumatic stress disorder (PTSD) symptoms and functional impairment is essential for assisting veterans in transitioning to civilian life. Moreover, there may be differences between men and women in the relationships between PTSD symptoms and functional impairment. However, no prior studies have examined the links between functional impairment and the revised symptom clusters as defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5; American Psychiatric Association, 2013) or whether the associations between PTSD symptom clusters and functional impairment differ by gender. We examined the associations between the DSM-5 PTSD symptom clusters and functional impairment in 252 trauma-exposed Iraq and Afghanistan war veterans (79 females). Regression analyses included demographic factors and exposure to both combat and military sexual trauma as covariates. In the total sample, both the intrusions cluster (β = .18, p = .045) and the negative alterations in cognition and mood cluster (β = .45, p < .001) were associated with global functional impairment. Among male veterans, global functional impairment was associated only with negative alterations in cognition and mood (β = .52, p < .001). However, by contrast, among female veterans, only marked alterations in arousal and reactivity were associated with global functional impairment (β = .35, p = .027). These findings suggest that there may be important gender differences with respect to the relationship between PTSD symptoms and functional impairment. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Eating disorder severity and functional impairment: moderating effects of illness duration in a clinical sample.

PubMed

Davidsen, Annika Helgadóttir; Hoyt, William T; Poulsen, Stig; Waaddegaard, Mette; Lau, Marianne

2017-09-01

The aim was to examine duration of illness and body mass index as possible moderators of the relationship between eating disorder severity and functional impairment, as well as psychological distress as a possible mediator of this relationship. The study included 159 patients diagnosed with bulimia nervosa, binge eating disorder or eating disorder not otherwise specified. Regression analysis was applied to assess the effect of the hypothesized moderators and mediators. Eating disorder severity was measured with the Eating Disorder Examination Questionnaire, functional impairment was measured with the Sheehan Disability Scale, and psychological distress was measured with the Symptom Check List-90-R. Duration of illness and body mass index were assessed clinically. Duration of illness significantly moderated the relationship between eating disorder severity and functional impairment; the relationship was strongest for patients with a shorter duration of illness. Psychological distress partly mediated the relationship between eating disorder severity and functional impairment. Duration of illness significantly moderated the relationship between psychological distress and functional impairment; the strongest relationship was seen for patients with a shorter duration of illness. Body mass index was not a significant moderator of the relationship between ED severity and functional impairment. Overall, this study established a link between ED severity, psychological distress and functional impairment indicating that both eating disorder severity and psychological distress are more strongly related to impaired role functioning for patients with more recent onset of an eating disorder. More research in the complex relationship between ED severity and functional impairment is needed.

Associations of smoking and alcohol consumption with impaired β-cell function in Chinese men.

PubMed

Xu, Min; Zhou, Yulin; Xu, Baihui; Sun, Jichao; Wang, Tiange; Lu, Jieli; Lai, Shenghan; Bi, Yufang; Wang, Weiqing; Ning, Guang

2016-05-01

The aims of the present study were to examine the association of cigarette smoking and alcohol consumption with impaired β-cell function in Chinese men, particularly the interaction of smoking and alcohol consumption on impaired insulin secretion. A population-based cross-sectional study was performed in 3957 Chinese men aged ≥40 years. The homeostatic model assessment of β-cell function (HOMA-β) was calculated, and impaired β-cell function was defined as less than the lowest quartile HOMA-βcut-off point. The prevalence of impaired β-cell function in current smokers and heavy drinkers (≥200 g/week) was significantly higher than in non-smokers and non-drinkers, respectively. Compared with non-smoking, current smoking had an exacerbating relationship with impaired β-cell function (odds ratio [OR] 1.78; 95% confidence interval [CI] 1.47-2.15; P < 0.001). No significant association was found between impaired β-cell function and former smoking (P = 0.21), although low and heavy drinking were associated with an increased risk of impaired β-cell function (OR 1.40 [95% CI 1.07-1.81] and 2.14 [95% CI 1.77-2.58], respectively) compared with non-drinking. The combination of current smoking and heavy drinking was associated with the highest risk of impaired β-cell function (OR 3.16; 95% CI 2.43-4.12; P < 0.0001) after adjustment for confounders. We did not detect an additive interaction between current smoking and heavy drinking on the association with impaired β-cell function. Cigarette smoking and alcohol consumption were significantly and independently associated with impaired β-cell function in Chinese men. © 2015 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

Conditional mutagenesis in vivo reveals cell type- and infection stage-specific requirements for LANA in chronic MHV68 infection

PubMed Central

Salinas, Eduardo; Sifford, Jeffrey M.; Oldenburg, Darby G.

2018-01-01

Gammaherpesvirus (GHV) pathogenesis is a complex process that involves productive viral replication, dissemination to tissues that harbor lifelong latent infection, and reactivation from latency back into a productive replication cycle. Traditional loss-of-function mutagenesis approaches in mice using murine gammaherpesvirus 68 (MHV68), a model that allows for examination of GHV pathogenesis in vivo, have been invaluable for defining requirements for specific viral gene products in GHV infection. But these approaches are insufficient to fully reveal how viral gene products contribute when the encoded protein facilitates multiple processes in the infectious cycle and when these functions vary over time and from one host tissue to another. To address this complexity, we developed an MHV68 genetic platform that enables cell-type-specific and inducible viral gene deletion in vivo. We employed this system to re-evaluate functions of the MHV68 latency-associated nuclear antigen (mLANA), a protein with roles in both viral replication and latency. Cre-mediated deletion in mice of loxP-flanked ORF73 demonstrated the necessity of mLANA in B cells for MHV68 latency establishment. Impaired latency during the transition from draining lymph nodes to blood following mLANA deletion also was observed, supporting the hypothesis that B cells are a major conduit for viral dissemination. Ablation of mLANA in infected germinal center (GC) B cells severely impaired viral latency, indicating the importance of viral passage through the GC for latency establishment. Finally, induced ablation of mLANA during latency resulted in complete loss of affected viral genomes, indicating that mLANA is critically important for maintenance of viral genomes during stable latency. Collectively, these experiments provide new insights into LANA homolog functions in GHV colonization of the host and highlight the potential of a new MHV68 genetic platform to foster a more complete understanding of viral gene functions at discrete stages of GHV pathogenesis. PMID:29364981

Precursor-product discrimination by La protein during tRNA metabolism.

PubMed

Bayfield, Mark A; Maraia, Richard J

2009-04-01

La proteins bind pre-tRNAs at their UUU-3'OH ends, facilitating their maturation. Although the mechanism by which La binds pre-tRNA 3' trailers is known, the function of the RNA binding beta-sheet surface of the RNA-recognition motif (RRM1) is unknown. How La dissociates from UUU-3'OH-containing trailers after 3' processing is also unknown. Here we show that La preferentially binds pre-tRNAs over processed tRNAs or 3' trailer products through coupled use of two sites: one on the La motif and another on the RRM1 beta-surface that binds elsewhere on tRNA. Two sites provide stable pre-tRNA binding, whereas the processed tRNA and 3' trailer are released from their single sites relatively fast. RRM1 loop-3 mutations decrease affinity for pre-tRNA and tRNA, but not for the UUU-3'OH trailer, and impair tRNA maturation in vivo. We propose that RRM1 functions in activities that are more complex than UUU-3'OH binding. Accordingly, the RRM1 mutations also impair an RNA chaperone activity of La. The results suggest how La distinguishes precursor from product RNAs, allowing it to recycle onto a new pre-tRNA.

Impact of Myeloproliferative neoplasms on patients' employment status and work productivity in the United States: results from the living with MPNs survey.

PubMed

Yu, Jingbo; Parasuraman, Shreekant; Paranagama, Dilan; Bai, Andrew; Naim, Ahmad; Dubinski, David; Mesa, Ruben

2018-04-13

Patients with the myeloproliferative neoplasms (MPNs) myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) are at increased risk for thrombotic and cardiovascular events and experience a variety of burdensome symptoms. However, there is a paucity of data in the biomedical literature about how MPNs impact productivity in the workplace. This analysis of the Living with MPNs survey was conducted to evaluate the impact of MPNs on employment, career potential, and work productivity. This cross-sectional online survey included respondents aged 18-70 years living in the United States with a diagnosis of MF, PV, or ET. The survey consisted of ~ 100 questions related to MPN diagnosis, disease-related medical history, MPN-related symptoms and functional status, changes in employment and work productivity, and impact on daily activities since diagnosis. The MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) was used to assess symptom burden. The Work Productivity and Activity Impairment Specific Health Problem questionnaire (WPAI-SHP) was used to assess the effects of MPNs on work productivity and activity (7-day recall) among currently employed respondents. Correlations between MPN-SAF TSS and WPAI-SHP scores were calculated using Spearman's coefficients. Of 904 respondents, 592 were employed (MF, n = 174; PV, n = 248; ET, n = 170) at the time of their MPN diagnosis. Approximately half (50.5%) of the 592 employed survey respondents reported ≥1 change in employment status because of their diagnosis, most commonly "left a job" (30.2%) "went on medical disability leave" (24.8%), and "had reductions in work hours for at least 3 months" (21.8%). Among respondents who remained employed at the time of survey participation (n = 398), mean WPAI-SHP scores were as follows: absenteeism, 6.9%; presenteeism, 27.4%; overall work impairment, 31.1%; and activity impairment, 32.8%. WPAI-SHP scores positively correlated with MPN-SAF TSS (correlation coefficients, 0.37-0.70; P < 0.001). Half of the employed respondents had an employment status change (eg, leaving a job, medical disability leave, early retirement) because of their disease since the diagnosis. Currently employed respondents reported meaningful impairments in work productivity and activities of daily living that were attributable to their MPNs, and the degree of impairments highlighted the severity of symptom burden.

Sensory Impairments and Cognitive Function in Middle-Aged Adults.

PubMed

Schubert, Carla R; Cruickshanks, Karen J; Fischer, Mary E; Chen, Yanjun; Klein, Barbara E K; Klein, Ronald; Pinto, A Alex

2017-08-01

Hearing, visual, and olfactory impairments have been associated with cognitive impairment in older adults but less is known about associations with cognitive function in middle-aged adults. Sensory and cognitive functions were measured on participants in the baseline examination (2005-2008) of the Beaver Dam Offspring Study. Cognitive function was measured with the Trail Making tests A (TMTA) and B (TMTB) and the Grooved Peg Board test. Pure-tone audiometry, Pelli-Robson letter charts, and the San Diego Odor Identification test were used to measure hearing, contrast sensitivity, and olfaction, respectively. There were 2,836 participants aged 21-84 years with measures of hearing, visual, olfactory, and cognitive function at the baseline examination. Nineteen percent of the cohort had one sensory impairment and 3% had multiple sensory impairments. In multivariable adjusted linear regression models that included all three sensory impairments, hearing impairment, visual impairment, and olfactory impairment were each independently associated with poorer performance on the TMTA, TMTB, and Grooved Peg Board (p < .05 for all sensory impairments in all models). Participants with a sensory impairment took on average from 2 to 10 seconds longer than participants without the corresponding sensory impairment to complete these tests. Results were similar in models that included adjustment for hearing aid use. Hearing, visual and olfactory impairment were associated with poorer performance on cognitive function tests independent of the other sensory impairments and factors associated with cognition. Sensory impairments in midlife are associated with subtle deficits in cognitive function which may be indicative of early brain aging. © The Author 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

The Fruiting Bodies, Submerged Culture Biomass, and Acidic Polysaccharide Glucuronoxylomannan of Yellow Brain Mushroom Tremella mesenterica Modulate the Immunity of Peripheral Blood Leukocytes and Splenocytes in Rats with Impaired Glucose Tolerance

PubMed Central

Hsu, Tai-Hao; Lee, Chien-Hsing; Lin, Fang-Yi; Wasser, Solomon P.; Lo, Hui-Chen

2014-01-01

The prevalence of diabetes mellitus (DM), a chronic disease with hyperglycemia and impaired immune function, is increasing worldwide. Progression from impaired glucose tolerance (IGT) to type 2 DM has recently become a target for early intervention. The fruiting bodies (FB) and submerged culture mycelium (CM) of Tremella mesenterica, an edible and medicinal mushroom, have been demonstrated to have antihyperglycemic and immunomodulatory activities in type 1 DM rats. Herein, we investigated the effects of acidic polysaccharide glucuronoxylomannan (GX) extracted from CM on the immunocyte responses. Male Wistar rats were injected with streptozotocin (65 mg/kg) plus nicotinamide (200 mg/kg) for the induction of IGT, and gavaged daily with vehicle, FB, CM, or GX (1 g/kg/day). Rats injected with saline and gavaged vehicle were used as controls. Two weeks later, peripheral blood leukocytes (PBLs) and splenocytes were collected. Ingestion of FB, CM, and GX significantly decreased blood glucose levels in the postprandial period and in oral glucose tolerance test, and partially reversed T-splenocytic proliferation in IGT rats. CM significantly decreased T-helper lymphocytes in the PBLs and B-splenocytes. In addition, FB, CM, and GX significantly reversed the IGT-induced decreases in tumor necrosis factor-α production; GX significantly increased interleukin-6 production in T-lymphocytes in the PBLs and splenocytes; and CM and GX significantly reversed IGT-induced decrease in interferon-γ production in T-lymphocytes in the spleen. In conclusion, FB, CM, and acidic polysaccharide GX of T. mesenterica may increase T-cell immunity via the elevation of proinflammatory and T-helper cytokine production in rats with impaired glucose tolerance. PMID:24872934

Effects of covalent modification by 4-hydroxy-2-nonenal on the noncovalent oligomerization of ubiquitin.

PubMed

Grasso, Giuseppe; Axelsen, Paul H

2017-01-01

When lipid membranes containing ω-6 polyunsaturated fatty acyl chains are subjected to oxidative stress, one of the reaction products is 4-hydroxy-2-nonenal (HNE)-a chemically reactive short chain alkenal that can covalently modify proteins. The ubiquitin proteasome system is involved in the clearing of proteins modified by oxidation products such as HNE, but the chemical structure, stability and function of ubiquitin may be impaired by HNE modification. To evaluate this possibility, the susceptibility of ubiquitin to modification by HNE has been characterized over a range of concentrations where ubiquitin forms non-covalent oligomers. Results indicate that HNE modifies ubiquitin at only two of the many possible sites, and that HNE modification at these two sites alters the ubiquitin oligomerization equilibrium. These results suggest that any role ubiquitin may have in clearing proteins damaged by oxidative stress may itself be impaired by oxidative lipid degradation products. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Working while unwell: Workplace impairment in people with severe asthma.

PubMed

Hiles, S A; Harvey, E S; McDonald, V M; Peters, M; Bardin, P; Reynolds, P N; Upham, J W; Baraket, M; Bhikoo, Z; Bowden, J; Brockway, B; Chung, L P; Cochrane, B; Foxley, G; Garrett, J; Hew, M; Jayaram, L; Jenkins, C; Katelaris, C; Katsoulotos, G; Koh, M S; Kritikos, V; Lambert, M; Langton, D; Lara Rivero, A; Marks, G B; Middleton, P G; Nanguzgambo, A; Radhakrishna, N; Reddel, H; Rimmer, J; Southcott, A M; Sutherland, M; Thien, F; Wark, P A B; Yang, I A; Yap, E; Gibson, P G

2018-06-01

Severe asthma affects quality of life; however, its impact on workplace productivity is poorly understood. To compare workplace productivity-absenteeism and presenteeism-and impairment in daily activities in severe and non-severe asthma over time and identify characteristics associated with presenteeism in severe asthma. The Severe Asthma Web-based Database is an ongoing observational registry from Australia, New Zealand and Singapore. At April 2017, 434 patients with severe asthma and 102 with non-severe asthma were enrolled (18-88 years; 59% female). Participants provided comprehensive clinical and questionnaire data at baseline and were followed-up every 6 months for 24 months. Absenteeism (percentage of time not at work), presenteeism (self-reported impairment at work) and impairment in daily activities outside work due to health problems in the last week were calculated. At baseline, 61.4% of participants with severe asthma and 66.2% with non-severe asthma under 65 years were employed. At younger ages (30-50 years), fewer severe asthma participants were employed (69% vs 100%). Presenteeism and impairment in daily activity were more frequently reported in severe asthma and in participants with poorer asthma control, poorer lung function and more past-year exacerbations (P < .01). Over time, deteriorating asthma control was associated with increasing presenteeism. Although absenteeism was not different between severe and non-severe asthma, worse asthma control was associated with absenteeism (P < .001). In participants with severe asthma, presenteeism was reported more frequently in those with poorer asthma control, poorer asthma-related quality of life and symptoms of depression or anxiety (P < .01). Severe asthma was associated with impairment at work and outside the workplace. Improving asthma control and mental health may be important targets for optimizing workplace productivity in severe asthma. Presenteeism and absenteeism may represent key metrics for assessing intervention efficacy in people with severe asthma of working age. © 2018 John Wiley & Sons Ltd.

Greater dyspnea is associated with lower health-related quality of life among European patients with COPD

PubMed Central

Gruenberger, Jean-Bernard; Vietri, Jeffrey; Keininger, Dorothy L; Mahler, Donald A

2017-01-01

Objective Dyspnea is a defining symptom in the classification and treatment of chronic obstructive pulmonary disease (COPD). However, the degree of variation in burden among symptomatic COPD patients and the possible correlates of burden remain unclear. This study was conducted to characterize patients in Europe currently being treated for COPD according to the level of dyspnea in terms of sociodemographics, health-related quality of life, work productivity impairment, and health care resource use assessed by patient reports. Methods Data were derived from the 5-EU 2013 National Health and Wellness Survey (N=62,000). Respondents aged ≥40 years who reported currently using a prescription for COPD were grouped according to their level of dyspnea as per the Global Initiative for Chronic Obstructive Lung Disease guidelines and compared on health status (revised Short Form 36 [SF-36]v2), work impairment (Work Productivity and Activity Impairment questionnaire), and number of health care visits in the past 6 months using generalized linear models with appropriate distributions and link functions. Results Of the 768 respondents who met the inclusion criteria, 245 (32%) were considered to have higher dyspnea (equivalent to modified Medical Research Council score ≥2). Higher dyspnea was associated with decrements ranging from 3.9 to 8.2 points in all eight domains of the SF-36 health profile after adjustment for sociodemographics, general health characteristics, and length of COPD diagnosis; mental component summary scores and Short Form-6D health utility scores were lower by 3.5 and 0.06 points, respectively. Adjusted mean activity impairment (55% vs 37%, P<0.001) and number of emergency room visits (0.61 vs 0.40, P=0.030) were higher in patients with greater dyspnea. Conclusion Many European patients with COPD continue to experience dyspnea despite treatment and at levels associated with notable impairments in the patients’ ability to function across a multitude of domains. These patients may benefit from more intense treatment of their symptoms. PMID:28360517

Greater dyspnea is associated with lower health-related quality of life among European patients with COPD.

PubMed

Gruenberger, Jean-Bernard; Vietri, Jeffrey; Keininger, Dorothy L; Mahler, Donald A

2017-01-01

Dyspnea is a defining symptom in the classification and treatment of chronic obstructive pulmonary disease (COPD). However, the degree of variation in burden among symptomatic COPD patients and the possible correlates of burden remain unclear. This study was conducted to characterize patients in Europe currently being treated for COPD according to the level of dyspnea in terms of sociodemographics, health-related quality of life, work productivity impairment, and health care resource use assessed by patient reports. Data were derived from the 5-EU 2013 National Health and Wellness Survey (N=62,000). Respondents aged ≥40 years who reported currently using a prescription for COPD were grouped according to their level of dyspnea as per the Global Initiative for Chronic Obstructive Lung Disease guidelines and compared on health status (revised Short Form 36 [SF-36]v2), work impairment (Work Productivity and Activity Impairment questionnaire), and number of health care visits in the past 6 months using generalized linear models with appropriate distributions and link functions. Of the 768 respondents who met the inclusion criteria, 245 (32%) were considered to have higher dyspnea (equivalent to modified Medical Research Council score ≥2). Higher dyspnea was associated with decrements ranging from 3.9 to 8.2 points in all eight domains of the SF-36 health profile after adjustment for sociodemographics, general health characteristics, and length of COPD diagnosis; mental component summary scores and Short Form-6D health utility scores were lower by 3.5 and 0.06 points, respectively. Adjusted mean activity impairment (55% vs 37%, P <0.001) and number of emergency room visits (0.61 vs 0.40, P =0.030) were higher in patients with greater dyspnea. Many European patients with COPD continue to experience dyspnea despite treatment and at levels associated with notable impairments in the patients' ability to function across a multitude of domains. These patients may benefit from more intense treatment of their symptoms.

Methyl Jasmonate Alleviates Cadmium-Induced Photosynthetic Damages through Increased S-Assimilation and Glutathione Production in Mustard

PubMed Central

Per, Tasir S.; Khan, Nafees A.; Masood, Asim; Fatma, Mehar

2016-01-01

The effect of methyl jasmonate (MeJA) in mitigation of 50 μM cadmium (Cd) toxicity on structure and function of photosynthetic apparatus in presence or absence of 1.0 mM SO42– was investigated in mustard (Brassica juncea L. cv. Ro Agro 4001) at 30 days after sowing. Plants exhibited increased oxidative stress, impaired photosynthetic function when grown with Cd, but MeJA in presence of sulfur (S) more prominently ameliorated Cd effects through increased S-assimilation and production of reduced glutathione (GSH) and promoted photosynthetic functions. The transmission electron microscopy showed that MeJA protected chloroplast structure against Cd-toxicity. The use of GSH biosynthetic inhibitor, buthionine sulfoximine (BSO) substantiated the findings that ameliorating effect of MeJA was through GSH production. MeJA could not alleviate Cd effects when BSO was used due to unavailability of GSH even with the input of S. The study shows that MeJA regulates S-assimilation and GSH production for protection of structure and function of photosynthetic apparatus in mustard plants under Cd stress. PMID:28066485

A prospective study of the impact of diabetes mellitus on restrictive and obstructive lung function impairment: The Saku study.

PubMed

Sonoda, Nao; Morimoto, Akiko; Tatsumi, Yukako; Asayama, Kei; Ohkubo, Takayoshi; Izawa, Satoshi; Ohno, Yuko

2018-05-01

To assess the impact of diabetes on restrictive and obstructive lung function impairment. This 5-year prospective study included 7524 participants aged 40-69years without lung function impairment at baseline who underwent a comprehensive medical check-up between April 2008 and March 2009 at Saku Central Hospital. Diabetes was defined by fasting plasma glucose ≥7.0mmol/l (126mg/dl), HbA1c≥6.5% (48mmol/mol), or a history of diabetes, as determined by interviews conducted by the physicians. Restrictive and obstructive lung function impairment were defined as forced vital capacity (FVC) <80% predicted and forced expiratory volume in 1s (FEV 1 ) to FVC ratio (FEV 1 /FVC) <0.70, respectively. Participants were screened until they developed restrictive or obstructive lung function impairment or until March 2014. During the follow-up period, 171 and 639 individuals developed restrictive and obstructive lung function impairment, respectively. Individuals with diabetes had a 1.6-fold higher risk of restrictive lung function impairment than those without diabetes after adjusting for sex, age, height, abdominal obesity, smoking status, exercise habits, systolic blood pressure, HDL-cholesterol, log-transformed high-sensitivity C-reactive protein, and baseline lung function [multivariable-adjusted HR and 95% CI; 1.57 (1.04-2.36)]. In contrast, individuals with diabetes did not have a significantly higher risk of obstructive lung function impairment [multivariable-adjusted HR and 95% CI; 0.93 (0.72-1.21)]. Diabetes was associated with restrictive lung function impairment but not obstructive lung function impairment. Copyright © 2017. Published by Elsevier Inc.

Policing the intestinal epithelial barrier: Innate immune functions of intraepithelial lymphocytes.

PubMed

Hu, Madeleine D; Jia, Luo; Edelblum, Karen L

2018-03-01

This review will explore the contribution of IELs to mucosal innate immunity and highlight the similarities in IEL functional responses to bacteria, viruses and protozoan parasite invasion. IELs rapidly respond to microbial invasion by activating host defense responses, including the production of mucus and antimicrobial peptides to prevent microbes from reaching the epithelial surface. During active infection, IELs promote epithelial cytolysis, cytokine and chemokine production to limit pathogen invasion, replication and dissemination. Commensal-induced priming of IEL effector function or continuous surveillance of the epithelium may be important contributing factors to the rapidity of response. Impaired microbial recognition, dysregulated innate immune signaling or microbial dysbiosis may limit the protective function of IELs and increase susceptibility to disease. Further understanding of the mechanisms regulating IEL surveillance and sentinel function may provide insight into the development of more effective targeted therapies designed to reinforce the mucosal barrier.

The association of fatigue, pain, depression and anxiety with work and activity impairment in immune mediated inflammatory diseases.

PubMed

Enns, Murray W; Bernstein, Charles N; Kroeker, Kristine; Graff, Lesley; Walker, John R; Lix, Lisa M; Hitchon, Carol A; El-Gabalawy, Renée; Fisk, John D; Marrie, Ruth Ann

2018-01-01

Impairment in work function is a frequent outcome in patients with chronic conditions such as immune-mediated inflammatory diseases (IMID), depression and anxiety disorders. The personal and economic costs of work impairment in these disorders are immense. Symptoms of pain, fatigue, depression and anxiety are potentially remediable forms of distress that may contribute to work impairment in chronic health conditions such as IMID. The present study evaluated the association between pain [Medical Outcomes Study Pain Effects Scale], fatigue [Daily Fatigue Impact Scale], depression and anxiety [Hospital Anxiety and Depression Scale] and work impairment [Work Productivity and Activity Impairment Scale] in four patient populations: multiple sclerosis (n = 255), inflammatory bowel disease (n = 248, rheumatoid arthritis (n = 154) and a depression and anxiety group (n = 307), using quantile regression, controlling for the effects of sociodemographic factors, physical disability, and cognitive deficits. Each of pain, depression symptoms, anxiety symptoms, and fatigue individually showed significant associations with work absenteeism, presenteeism, and general activity impairment (quantile regression standardized estimates ranging from 0.3 to 1.0). When the distress variables were entered concurrently into the regression models, fatigue was a significant predictor of work and activity impairment in all models (quantile regression standardized estimates ranging from 0.2 to 0.5). These findings have important clinical implications for understanding the determinants of work impairment and for improving work-related outcomes in chronic disease.

Epigallocatechin-3-gallate induces oxidative phosphorylation by activating cytochrome c oxidase in human cultured neurons and astrocytes

PubMed Central

Castellano-González, Gloria; Pichaud, Nicolas; Ballard, J. William O.; Bessede, Alban; Marcal, Helder; Guillemin, Gilles J.

2016-01-01

Mitochondrial dysfunction and resulting energy impairment have been identified as features of many neurodegenerative diseases. Whether this energy impairment is the cause of the disease or the consequence of preceding impairment(s) is still under discussion, however a recovery of cellular bioenergetics would plausibly prevent or improve the pathology. In this study, we screened different natural molecules for their ability to increase intracellular adenine triphosphate purine (ATP). Among them, epigallocatechin-3-gallate (EGCG), a polyphenol from green tea, presented the most striking results. We found that it increases ATP production in both human cultured astrocytes and neurons with different kinetic parameters and without toxicity. Specifically, we showed that oxidative phosphorylation in human cultured astrocytes and neurons increased at the level of the routine respiration on the cells pre-treated with the natural molecule. Furthermore, EGCG-induced ATP production was only blocked by sodium azide (NaN3) and oligomycin, inhibitors of cytochrome c oxidase (CcO; complex IV) and ATP synthase (complex V) respectively. These findings suggest that the EGCG modulates CcO activity, as confirmed by its enzymatic activity. CcO is known to be regulated differently in neurons and astrocytes. Accordingly, EGCG treatment is acting differently on the kinetic parameters of the two cell types. To our knowledge, this is the first study showing that EGCG promotes CcO activity in human cultured neurons and astrocytes. Considering that CcO dysfunction has been reported in patients having neurodegenerative diseases such as Alzheimer's disease (AD), we therefore suggest that EGCG could restore mitochondrial function and prevent subsequent loss of synaptic function. PMID:26760769

Interactive effects of diabetes and impaired kidney function on cognitive performance in old age: a population-based study.

PubMed

Yin, Zhaoxue; Yan, Zhongrui; Liang, Yajun; Jiang, Hui; Cai, Chuanzhu; Song, Aiqin; Feng, Lei; Qiu, Chengxuan

2016-01-12

The interactive effect between diabetes and impaired kidney function on cognitive impairment in older adults has not yet been reported. The aim of this study was to investigate the association of diabetes and impaired kidney function with cognitive impairment among Chinese older people living in a rural area. This cross-sectional study included 1,358 participants (age ≥60 years; 60.5% women) in the population-based Confucius Hometown Aging Project in Shandong, China. Data on demographics, lifestyle factors, health history, use of medications, global cognitive function, and kidney function were collected through structured interviews, clinical examinations, and blood tests. We defined diabetes as a fasting plasma glucose level ≥7.0 mmol/l or use of hypoglycemic agents, impaired kidney function as glomerular filtration rate estimated from cystatin C (eGFRcys) <60 ml/min/1.73 m(2). Cognitive impairment was defined using the education-based cut-off scores of Mini-Mental State Examination (MMSE). Data were analyzed using multiple general linear and logistic regression models. Cognitive impairment was defined in 197 (14.5%) persons. The multi-adjusted β coefficient of MMSE score associated with diabetes was -0.06 (95% confidence interval [CI], -0.16, 0.03); the corresponding figures associated with eGFRcys <60, 60-89.9, and ≥90 ml/min/1.73 m(2) were -0.15 (-0.28, -0.02), -0.01 (-0.10, 0.08), and 0 (reference) (Ptrend = 0.046), respectively. Diabetes and impaired kidney function showed an interactive effect on cognitive impairment ( interaction = 0.02). Compared with individuals having neither diabetes nor impaired kidney function, those with both conditions had a multi-adjusted odds ratio of 4.23 (95% CI, 2.10-8.49) for cognitive impairment. The relative excess risk due to interaction was 2.74. This study suggests that concurrent presence of diabetes and impaired kidney function is associated with a substantial likelihood for cognitive impairment in older adults.

Association between advanced glycation end-products and functional performance in Alzheimer's disease and mixed dementia.

PubMed

Drenth, Hans; Zuidema, Sytse U; Krijnen, Wim P; Bautmans, Ivan; van der Schans, Cees; Hobbelen, Hans

2017-09-01

People with Alzheimer's disease (AD) experience, in addition to the progressive loss of cognitive functions, a decline in functional performance such as mobility impairment and disability in activities of daily living (ADL). Functional decline in dementia is mainly linked to the progressive brain pathology. Peripheral biomechanical changes by advanced glycation end-products (AGEs) have been suggested but have yet to be thoroughly studied. A multi-center, longitudinal, one-year follow-up cohort study was conducted in 144 people with early stage AD or mixed Alzheimer's/Vascular dementia. Linear mixed model analyses was used to study associations between AGE-levels (AGE reader) and mobility (Timed Up and Go), and ADL (Groningen Activity Restriction Scale and Barthel index), respectively. A significant association between AGE levels and mobility (β = 3.57, 95%CI: 1.43-5.73) was revealed; however, no significant association between AGE levels and ADL was found. Over a one-year time span, mean AGE levels significantly increased, and mobility and ADL performance decreased. Change in AGE levels was not significantly correlated with change in mobility. This study indicates that high AGE levels could be a contributing factor to impaired mobility but lacks evidence for an association with ADL decline in people with early stage AD or mixed dementia. Future research is necessary on the reduction of functional decline in dementia regarding the effectiveness of interventions such as physical activity programs and dietary advice possibly in combination with pharmacologic strategies targeting AGE accumulation.

Disease-Associated Mutant Ubiquitin Causes Proteasomal Impairment and Enhances the Toxicity of Protein Aggregates

PubMed Central

Tank, Elizabeth M. H.; True, Heather L.

2009-01-01

Protein homeostasis is critical for cellular survival and its dysregulation has been implicated in Alzheimer's disease (AD) and other neurodegenerative disorders. Despite the growing appreciation of the pathogenic mechanisms involved in familial forms of AD, much less is known about the sporadic cases. Aggregates found in both familial and sporadic AD often include proteins other than those typically associated with the disease. One such protein is a mutant form of ubiquitin, UBB+1, a frameshift product generated by molecular misreading of a wild-type ubiquitin gene. UBB+1 has been associated with multiple disorders. UBB+1 cannot function as a ubiquitin molecule, and it is itself a substrate for degradation by the ubiquitin/proteasome system (UPS). Accumulation of UBB+1 impairs the proteasome system and enhances toxic protein aggregation, ultimately resulting in cell death. Here, we describe a novel model system to investigate how UBB+1 impairs UPS function and whether it plays a causal role in protein aggregation. We expressed a protein analogous to UBB+1 in yeast (Ubext) and demonstrated that it caused UPS impairment. Blocking ubiquitination of Ubext or weakening its interactions with other ubiquitin-processing proteins reduced the UPS impairment. Expression of Ubext altered the conjugation of wild-type ubiquitin to a UPS substrate. The expression of Ubext markedly enhanced cellular susceptibility to toxic protein aggregates but, surprisingly, did not induce or alter nontoxic protein aggregates in yeast. Taken together, these results suggest that Ubext interacts with more than one protein to elicit impairment of the UPS and affect protein aggregate toxicity. Furthermore, we suggest a model whereby chronic UPS impairment could inflict deleterious consequences on proper protein aggregate sequestration. PMID:19214209

Effects of low-dose hydrocortisone therapy on immune function in neonatal horses

PubMed Central

Hart, Kelsey A.; Barton, Michelle H.; Vandenplas, Michel L.; Hurley, David J.

2011-01-01

Low-dose hydrocortisone therapy modulates inflammatory responses in adults and improves outcomes in some septic adults and neonates, but its immunologic effects have not been evaluated in neonates. The objective of this study was to evaluate effects of low-dose hydrocortisone (LDHC) therapy on ex vivo immune function in neonatal horses (foals). We hypothesized that LDHC treatment would dampen pro-inflammatory responses without impairing neutrophil function. Hydrocortisone (1.3 mg/kg/day i.v.) was administered to foals in a tapering 3.5 day course. Peripheral blood leukocytes were collected from foals before, during and after hydrocortisone treatment. A separate group of age-matched untreated foals served as controls. Endotoxin-induced peripheral blood mononuclear cell gene expression of inflammatory cytokines was measured by real time quantitative RT-PCR. Neutrophils were incubated with labeled, killed S. aureus or E. coli for assessment of phagocytosis, and with phorbol myristate acetate, zymosan, or endotoxin for measurement of reactive oxygen species (ROS) production. Neutrophil phagocytosis and ROS production were similar in both groups. Foals receiving hydrocortisone had significantly decreased endotoxin-induced expression of TNF-α, IL-6, IL-8, and IL-1β. These data suggest that this LDHC treatment regimen ameliorates endotoxin-induced pro-inflammatory cytokine expression in neonatal foals without impairing innate immune responses needed to combat bacterial infection. PMID:21430601

Effects of aspirin on distortion product otoacoustic emission suppression in human adults: A comparison with neonatal data

NASA Astrophysics Data System (ADS)

Abdala, Carolina

2005-09-01

One of the distortion product otoacoustic emission (DPOAE) paradigms used to study cochlear function is DPOAE (2f1-f2) ipsilateral suppression. Newborns do not have adultlike DPOAE suppression. At 6000 Hz, infants show excessively narrow DPOAE suppression tuning and shallow growth of suppression for low-frequency suppressor tones. The source of this immaturity is not known but the outer hair cell (OHC) is one possible locus. In the present study, DPOAE suppression was measured at f2=1500 and 6000 Hz from two groups with impaired OHC function in an attempt to model the observed immaturity in neonates: adults with aspirin-induced OHC dysfunction and subjects with sensorineural hearing loss (SNHL). Their DPOAE suppression results were compared to those obtained from a group of term newborns to address whether infant DPOAE suppression resembles suppression from individuals with known OHC dysfunction. Results indicate that aspirin systematically alters DPOAE suppression in adults at f2=6000 Hz, but not 1500 Hz. However, neither aspirin-induced OHC dysfunction nor naturally occurring SNHL produces ``neonatal-like'' DPOAE suppression at either test frequency. This finding does not support the hypothesis that non-adultlike DPOAE suppression characterizing newborns can be explained by minor impairments or alterations of OHC function.

Arthritis and Risk of Cognitive and Functional Impairment in Older Mexican Adults

PubMed Central

Veeranki, Sreenivas P.; Downer, Brian; Jupiter, Daniel; Wong, Rebeca

2016-01-01

Objective This study investigated the risk of cognitive and functional impairment in older Mexicans diagnosed with arthritis. Participants included 2,681 Mexicans, aged ≥60 years, enrolled in the Mexican Health and Aging Study cohort. Method Participants were categorized into arthritis and no arthritis exposure groups. Primary outcome included participants categorized into “cognitively impaired” or “cognitively normal” groups. Secondary outcomes included participants categorized into Normal, Functionally Impaired only, Cognitively Impaired only, or Dementia (both cognitively and functionally impaired) groups. Multivariable logistic and multinomial regression models were used to assess the relationships. Results Overall, 16% or 7% were diagnosed with cognitive impairment or dementia. Compared with older Mexicans without arthritis, those who were diagnosed with arthritis had significantly increased risk of functional impairment (adjusted odds ratio [OR] 1.82, 95% confidence interval [CI] = [1.45, 2.29]), but not of dementia. Conclusion Arthritis is associated with increased risk of functional impairment, but not with dementia after 11 years in older Mexicans. PMID:26965081

Hepatitis B Virus Lacks Immune Activating Capacity, but Actively Inhibits Plasmacytoid Dendritic Cell Function

PubMed Central

Woltman, Andrea M.; Shi, Cui C.; Janssen, Harry L. A.

2011-01-01

Chronic hepatitis B virus (HBV) infection is caused by inadequate anti-viral immunity. Activation of plasmacytoid dendritic cells (pDC) leading to IFNα production is important for effective anti-viral immunity. Hepatitis B virus (HBV) infection lacks IFNα induction in animal models and patients and chronic HBV patients display impaired IFNα production by pDC. Therefore, HBV and HBV-derived proteins were examined for their effect on human pDC in vitro. In addition, the in vitro findings were compared to the function of pDC derived from chronic HBV patients ex vivo. In contrast to other viruses, HBV did not activate pDC. Moreover, HBV and HBsAg abrogated CpG-A/TLR9-induced, but not Loxoribine/TLR7-induced, mTOR-mediated S6 phosphorylation, subsequent IRF7 phosphorylation and IFNα gene transcription. HBV/HBsAg also diminished upregulation of co-stimulatory molecules, production of TNFα, IP-10 and IL-6 and pDC-induced NK cell function, whereas TLR7-induced pDC function was hardly affected. In line, HBsAg preferentially bound to TLR9-triggered pDC demonstrating that once pDC are able to bind HBV/HBsAg, the virus exerts its immune regulatory effect. HBV not only directly interfered with pDC function, but also indirectly by interfering with monocyte-pDC interaction. Also HBeAg diminished pDC function to a certain extent, but via another unknown mechanism. Interestingly, patients with HBeAg-positive chronic hepatitis B displayed impaired CpG-induced IFNα production by pDC without significant alterations in Loxoribine-induced pDC function compared to HBeAg-negative patients and healthy controls. The lack of activation and the active inhibition of pDC by HBV may both contribute to HBV persistence. The finding that the interaction between pDC and HBV may change upon activation may aid in the identification of a scavenging receptor supporting immunosuppressive effects of HBV and also in the design of novel treatment strategies for chronic HBV. PMID:21246041

Adaptor Protein-1 Complex Affects the Endocytic Trafficking and Function of Peptidylglycine α-Amidating Monooxygenase, a Luminal Cuproenzyme*

PubMed Central

Bonnemaison, Mathilde L.; Bäck, Nils; Duffy, Megan E.; Ralle, Martina; Mains, Richard E.; Eipper, Betty A.

2015-01-01

The adaptor protein-1 complex (AP-1), which transports cargo between the trans-Golgi network and endosomes, plays a role in the trafficking of Atp7a, a copper-transporting P-type ATPase, and peptidylglycine α-amidating monooxygenase (PAM), a copper-dependent membrane enzyme. Lack of any of the four AP-1 subunits impairs function, and patients with MEDNIK syndrome, a rare genetic disorder caused by lack of expression of the σ1A subunit, exhibit clinical and biochemical signs of impaired copper homeostasis. To explore the role of AP-1 in copper homeostasis in neuroendocrine cells, we used corticotrope tumor cells in which AP-1 function was diminished by reducing expression of its μ1A subunit. Copper levels were unchanged when AP-1 function was impaired, but cellular levels of Atp7a declined slightly. The ability of PAM to function was assessed by monitoring 18-kDa fragment-NH2 production from proopiomelanocortin. Reduced AP-1 function made 18-kDa fragment amidation more sensitive to inhibition by bathocuproine disulfonate, a cell-impermeant Cu(I) chelator. The endocytic trafficking of PAM was altered, and PAM-1 accumulated on the cell surface when AP-1 levels were reduced. Reduced AP-1 function increased the Atp7a presence in early/recycling endosomes but did not alter the ability of copper to stimulate its appearance on the plasma membrane. Co-immunoprecipitation of a small fraction of PAM and Atp7a supports the suggestion that copper can be transferred directly from Atp7a to PAM, a process that can occur only when both proteins are present in the same subcellular compartment. Altered luminal cuproenzyme function may contribute to deficits observed when the AP-1 function is compromised. PMID:26170456

Risk factors for impaired respiratory function during nurse-administered procedural sedation and analgesia in the cardiac catheterisation laboratory: a matched case-control study.

PubMed

Conway, Aaron; Page, Karen; Rolley, John; Fulbrook, Paul

2013-08-01

Side effects of the medications used for procedural sedation and analgesia in the cardiac catheterisation laboratory are known to cause impaired respiratory function. Impaired respiratory function poses considerable risk to patient safety as it can lead to inadequate oxygenation. Having knowledge about the conditions that predict impaired respiratory function prior to the procedure would enable nurses to identify at-risk patients and selectively implement intensive respiratory monitoring. This would reduce the possibility of inadequate oxygenation occurring. To identify pre-procedure risk factors for impaired respiratory function during nurse-administered procedural sedation and analgesia in the cardiac catheterisation laboratory. Retrospective matched case-control. 21 cases of impaired respiratory function were identified and matched to 113 controls from a consecutive cohort of patients over 18 years of age. Conditional logistic regression was used to identify risk factors for impaired respiratory function. With each additional indicator of acute illness, case patients were nearly two times more likely than their controls to experience impaired respiratory function (OR 1.78; 95% CI 1.19-2.67; p = 0.005). Indicators of acute illness included emergency admission, being transferred from a critical care unit for the procedure or requiring respiratory or haemodynamic support in the lead up to the procedure. Several factors that predict the likelihood of impaired respiratory function were identified. The results from this study could be used to inform prospective studies investigating the effectiveness of interventions for impaired respiratory function during nurse-administered procedural sedation and analgesia in the cardiac catheterisation laboratory.

Telephone Crisis Support Workers' Intentions to Use Recommended Skills While Experiencing Functional Impairment.

PubMed

Kitchingman, Taneile A; Wilson, Coralie J; Woodward, Alan; Caputi, Peter; Wilson, Ian

2018-05-01

Empathic engagement with distressed others can lead to elevated symptoms of psychological distress and functional impairment, which preclude helping professionals' delivery of optimal patient care. Whether telephone crisis support workers are impacted in a similar way is not currently reported in the literature. This study examined the relationship between functional impairment and intentions to use recommended support skills in a representative national sample of 210 telephone crisis support workers. Participants completed an online survey including measures of functional impairment and intentions to use recommended telephone crisis support skills with callers reporting suicidal ideation, symptoms of depression, and anxiety. As a group, participants who experienced greater functional impairment during the past month reported significantly lower intentions to use recommended support skills with callers than those who reported lower functional impairment. Future research is needed to clarify the extent to which results generalize to telephone crisis support workers from other organizations. Results warrant further research to (a) identify determinants of telephone crisis support workers' functional impairment, and (b) for the deliberate management of telephone crisis support workers' functional impairment through developing and/or modifying existing service strategies to optimize workers' psychological well-being and delivery of support to callers.

Restoring composition and structure in Southwestern frequent-fire forests: A science-based framework for improving ecosystem resiliency

Treesearch

Richard T. Reynolds; Andrew J. Sanchez Meador; James A. Youtz; Tessa Nicolet; Megan S. Matonis; Patrick L. Jackson; Donald G. DeLorenzo; Andrew D. Graves

2013-01-01

Ponderosa pine and dry mixed-conifer forests in the Southwest United States are experiencing, or have become increasingly susceptible to, large-scale severe wildfire, insect, and disease episodes resulting in altered plant and animal demographics, reduced productivity and biodiversity, and impaired ecosystem processes and functions. We present a management framework...

The Use of Visual Feedback during Signing: Evidence from Signers with Impaired Vision

ERIC Educational Resources Information Center

Emmorey, Karen; Korpics, Franco; Petronio, Karen

2009-01-01

The role of visual feedback during the production of American Sign Language was investigated by comparing the size of signing space during conversations and narrative monologues for normally sighted signers, signers with tunnel vision due to Usher syndrome, and functionally blind signers. The interlocutor for all groups was a normally sighted deaf…

DEVELOPMENTAL EXPOSURE TO 1.0 OR 2.5 MG/KG DIBUTYLTIN DICHLORIDE DOES NOT IMPAIR IMMUNE FUNCTION IN SPRAGUE-DAWLEY RATS

EPA Science Inventory

Organotins are used commercially as pesticides, antifouling agents and stabilizers for polyvinyl chloride (PVC) pipe. Mono- and di-substituted methyl and butyltins, used in PVC pipe production, are of concern to the U.S. EPA as they leach from supply pipes into drinking water an...

Practices of Assistive Technology Implementation and Facilitation: Experiences of Teachers of Students with Visual Impairments in Singapore

ERIC Educational Resources Information Center

Wong, Meng Ee; Law, Janet S. P.

2016-01-01

Assistive technology is defined by the Individuals With Disabilities Education Improvement Act (IDEIA) of 2004 as "any item, piece of equipment, or product system, whether acquired commercially off the shelf, modified, or customized, that is used to increase, maintain, or improve functional capabilities of a child with a disability"…

Disordered follicle development

PubMed Central

Chang, R. Jeffrey; Cook-Andersen, Heidi

2013-01-01

Alterations of ovarian follicle morphology and function have been well documented in women with PCOS. These include increased numbers of growing preantral follicles, failure of follicle growth beyond the mid-antral stage, evidence of granulosa call degeneration, and theca cell hyperplasia. Functional abnormalities include paradoxical granulosa cell hyperresponsiveness to FSH which is clinically linked to ovarian hyperstimulation during ovulation induction. In addition, there is likely a primary theca cell defect that accounts for the majority of excess androgen production in this disorder. The precise mechanisms responsible for altered follicle function are not completely clear. However, several factors appear to influence normal advancement of follicle development as well as impair ovarian steroidogenesis. These include intra- as well as extraovarian influences that distort normal ovarian growth and disrupt steroid production by follicle cells. PMID:22874072

Evaluating the role of functional impairment in personality psychopathology.

PubMed

Boland, Jennifer K; Damnjanovic, Tatjana; Anderson, Jaime L

2018-03-22

DSM-5's Section III Alternative Model for Personality Disorder (AMPD) model states that an individual must show impairment in self and interpersonal functioning for PD diagnosis. The current study investigated dimensional personality trait associations with impairment, including differential patterns of impairment across specific PDs, and whether traits have improved our assessment of functional impairment in PDs. Two-hundred and seventy-seven participants were administered measures of Antisocial PD, Avoidant PD, Borderline PD, Narcissistic PD, Obsessive-Compulsive PD, and Schizotypal PD from the perspectives of Section II (PDQ-4) and Section III (PID-5) PD models, as well as measures of functional impairment in interpersonal and intrapersonal domains. Pearson correlations showed associations between ratings of impairment and most Section II and Section III PDs and trait facets, with the exception of narcissistic PD. Hierarchical regression analyses revealed that Section III PDs added predictive validity beyond Section II PDs in predicting impairment, except narcissistic PD. These findings provide support both for the impairment criterion in the AMPD and for the association between trait-based PDs and impairment, and suggest that this trait-based measurement adds uniquely to the understanding of functional impairment. Copyright © 2018. Published by Elsevier B.V.

Obesity in Aging Exacerbates Neuroinflammation, Dysregulating Synaptic Function-related Genes and Altering Eicosanoid Synthesis in the Mouse Hippocampus: Potential Role in Impaired Synaptic Plasticity and Cognitive Decline.

PubMed

Valcarcel-Ares, Marta Noa; Tucsek, Zsuzsanna; Kiss, Tamas; Giles, Cory B; Tarantini, Stefano; Yabluchanskiy, Andriy; Balasubramanian, Priya; Gautam, Tripti; Galvan, Veronica; Ballabh, Praveen; Richardson, Arlan; Freeman, Willard M; Wren, Jonathan D; Deak, Ferenc; Ungvari, Zoltan; Csiszar, Anna

2018-06-08

There is strong evidence that obesity has deleterious effects on cognitive function of older adults. Previous preclinical studies demonstrate that obesity in aging is associated with a heightened state of systemic inflammation, which exacerbates blood brain barrier disruption, promoting neuroinflammation and oxidative stress. To test the hypothesis that synergistic effects of obesity and aging on inflammatory processes exert deleterious effects on hippocampal function, young and aged C57BL/6 mice were rendered obese by chronic feeding of a high fat diet followed by assessment of learning and memory function, measurement of hippocampal long-term potentiation (LTP), assessment of changes in hippocampal expression of genes relevant for synaptic function and determination of synaptic density. Because there is increasing evidence that altered production of lipid mediators modulate LTP, neuroinflammation and neurovascular coupling responses, the effects of obesity on hippocampal levels of relevant eicosanoid mediators were also assessed. We found that aging exacerbates obesity-induced microglia activation, which is associated with deficits in hippocampal-dependent learning and memory tests, impaired LTP, decreased synaptic density and dysregulation of genes involved in regulation of synaptic plasticity. Obesity in aging also resulted in an altered hippocampal eicosanoid profile, including decreases in vasodilator and pro-LTP epoxy-eicosatrienoic acids (EETs). Collectively, our results taken together with previous findings suggest that obesity in aging promotes hippocampal inflammation, which in turn may contribute to synaptic dysfunction and cognitive impairment.

4-Methylene-2-octyl-5-oxotetrahydrofuran-3-carboxylic Acid (C75), an Inhibitor of Fatty-acid Synthase, Suppresses the Mitochondrial Fatty Acid Synthesis Pathway and Impairs Mitochondrial Function*

PubMed Central

Chen, Cong; Han, Xiao; Zou, Xuan; Li, Yuan; Yang, Liang; Cao, Ke; Xu, Jie; Long, Jiangang; Liu, Jiankang; Feng, Zhihui

2014-01-01

4-Methylene-2-octyl-5-oxotetrahydrofuran-3-carboxylic acid (C75) is a synthetic fatty-acid synthase (FASN) inhibitor with potential therapeutic effects in several cancer models. Human mitochondrial β-ketoacyl-acyl carrier protein synthase (HsmtKAS) is a key enzyme in the newly discovered mitochondrial fatty acid synthesis pathway that can produce the substrate for lipoic acid (LA) synthesis. HsmtKAS shares conserved catalytic domains with FASN, which are responsible for binding to C75. In our study, we explored the possible effect of C75 on HsmtKAS and mitochondrial function. C75 treatment decreased LA content, impaired mitochondrial function, increased reactive oxygen species content, and reduced cell viability. HsmtKAS but not FASN knockdown had an effect that was similar to C75 treatment. In addition, an LA supplement efficiently inhibited C75-induced mitochondrial dysfunction and oxidative stress. Overexpression of HsmtKAS showed cellular protection against low dose C75 addition, whereas there was no protective effect upon high dose C75 addition. In summary, the mitochondrial fatty acid synthesis pathway has a vital role in mitochondrial function. Besides FASN, C75 might also inhibit HsmtKAS, thereby reducing LA production, impairing mitochondrial function, and potentially having toxic effects. LA supplements sufficiently ameliorated the toxicity of C75, showing that a combination of C75 and LA may be a reliable cancer treatment. PMID:24784139

Decreased Cerebellar-Orbitofrontal Connectivity Correlates with Stuttering Severity: Whole-Brain Functional and Structural Connectivity Associations with Persistent Developmental Stuttering.

PubMed

Sitek, Kevin R; Cai, Shanqing; Beal, Deryk S; Perkell, Joseph S; Guenther, Frank H; Ghosh, Satrajit S

2016-01-01

Persistent developmental stuttering is characterized by speech production disfluency and affects 1% of adults. The degree of impairment varies widely across individuals and the neural mechanisms underlying the disorder and this variability remain poorly understood. Here we elucidate compensatory mechanisms related to this variability in impairment using whole-brain functional and white matter connectivity analyses in persistent developmental stuttering. We found that people who stutter had stronger functional connectivity between cerebellum and thalamus than people with fluent speech, while stutterers with the least severe symptoms had greater functional connectivity between left cerebellum and left orbitofrontal cortex (OFC). Additionally, people who stutter had decreased functional and white matter connectivity among the perisylvian auditory, motor, and speech planning regions compared to typical speakers, but greater functional connectivity between the right basal ganglia and bilateral temporal auditory regions. Structurally, disfluency ratings were negatively correlated with white matter connections to left perisylvian regions and to the brain stem. Overall, we found increased connectivity among subcortical and reward network structures in people who stutter compared to controls. These connections were negatively correlated with stuttering severity, suggesting the involvement of cerebellum and OFC may underlie successful compensatory mechanisms by more fluent stutterers.

Altered Morphology and Function of the Lacrimal Functional Unit in Protein Kinase Cα Knockout Mice

PubMed Central

Chen, Zhuo; Li, Zhijie; Basti, Surendra; Farley, William J.

2010-01-01

Purpose. Protein kinase C (PKC) α plays a major role in the parasympathetic neural stimulation of lacrimal gland (LG) secretion. It also has been reported to have antiapoptotic properties and to promote cell survival. Therefore, the hypothesis for the present study was that PKCα knockout (−/−) mice have impaired ocular surface–lacrimal gland signaling, rendering them susceptible to desiccating stress and impaired corneal epithelial wound healing. In this study, the lacrimal function unit (LFU) and the stressed wound-healing response were examined in PKCα−/− mice. Methods. In PKCα+/+ control mice and PKCα−/− mice, tear production, osmolarity, and clearance rate were evaluated before and after experimental desiccating stress. Histology and immunofluorescent staining of PKC and epidermal growth factor were performed in tissues of the LFU. Cornified envelope (CE) precursor protein expression and cell proliferation were evaluated. The time course of healing and degree of neutrophil infiltration was evaluated after corneal epithelial wounding. Results. Compared with the PKCα+/+ mice, the PKCα−/− mice were noted to have significantly increased lacrimal gland weight, with enlarged, carbohydrate-rich, PAS-positive acinar cells; increased corneal epithelia permeability, with reduced CE expression; and larger conjunctival epithelial goblet cells. The PKCα−/− mice showed more rapid corneal epithelial healing, with less neutrophil infiltration and fewer proliferating cells than did the PKCα+/+ mice. Conclusions. The PKCα−/− mice showed lower tear production, which appeared to be caused by impaired secretion by the LG and conjunctival goblet cells. Despite their altered tear dynamics, the PKCα−/− mice demonstrated more rapid corneal epithelial wound healing, perhaps due to decreased neutrophil infiltration. PMID:20505191

Gain-of-function STAT1 mutations impair STAT3 activity in patients with chronic mucocutaneous candidiasis (CMC).

PubMed

Zheng, Jie; van de Veerdonk, Frank L; Crossland, Katherine L; Smeekens, Sanne P; Chan, Chun M; Al Shehri, Tariq; Abinun, Mario; Gennery, Andrew R; Mann, Jelena; Lendrem, Dennis W; Netea, Mihai G; Rowan, Andrew D; Lilic, Desa

2015-10-01

Signal transducer and activator of transcription 3 (STAT3) triggered production of Th-17 cytokines mediates protective immunity against fungi. Mutations affecting the STAT3/interleukin 17 (IL-17) pathway cause selective susceptibility to fungal (Candida) infections, a hallmark of chronic mucocutaneous candidiasis (CMC). In patients with autosomal dominant CMC, we and others previously reported defective Th17 responses and underlying gain-of-function (GOF) STAT1 mutations, but how this affects STAT3 function leading to decreased IL-17 is unclear. We also assessed how GOF-STAT1 mutations affect STAT3 activation, DNA binding, gene expression, cytokine production, and epigenetic modifications. We excluded impaired STAT3 phosphorylation, nuclear translocation, and sequestration of STAT3 into STAT1/STAT3 heterodimers and confirm significantly reduced transcription of STAT3-inducible genes (RORC/IL-17/IL-22/IL-10/c-Fos/SOCS3/c-Myc) as likely underlying mechanism. STAT binding to the high affinity sis-inducible element was intact but binding to an endogenous STAT3 DNA target was impaired. Reduced STAT3-dependent gene transcription was reversed by inhibiting STAT1 activation with fludarabine or enhancing histone, but not STAT1 or STAT3 acetylation with histone deacetylase (HDAC) inhibitors trichostatin A or ITF2357. Silencing HDAC1, HDAC2, and HDAC3 indicated a role for HDAC1 and 2. Reduced STAT3-dependent gene transcription underlies low Th-17 responses in GOF-STAT1 CMC, which can be reversed by inhibiting acetylation, offering novel targets for future therapies. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Examining the association of smoking with work productivity and associated costs in Japan.

PubMed

Suwa, Kiyomi; Flores, Natalia M; Yoshikawa, Reiko; Goto, Rei; Vietri, Jeffrey; Igarashi, Ataru

2017-09-01

Smoking is associated with significant health and economic burden globally, including an increased risk of many leading causes of mortality and significant impairments in work productivity. This burden is attenuated by successful tobacco cessation, including reduced risk of disease and improved productivity. The current study aimed to show the benefits of smoking cessation for workplace productivity and decreased costs associated with loss of work impairment. The data source was the 2011 Japan National Health and Wellness Survey (n = 30,000). Respondents aged 20-64 were used in the analyses (n = 23,738) and were categorized into: current smokers, former smokers, and never smokers. Generalized linear models controlling for demographics and health characteristics examined the relationship of smoking status with the Work Productivity and Activity Impairment questionnaire (WPAI-GH) endpoints, as well as estimated indirect costs. Current smokers reported the greatest overall work impairment, including absenteeism (i.e. work time missed) and presenteeism (i.e. impairment while at work); however, after controlling for covariates, there were no significant differences between former smokers and never smokers on overall work impairment. Current smokers and former smokers had greater activity impairment (i.e. impairment in daily activities) than never smokers. Current smokers reported the highest indirect costs (i.e. costs associated with work impairment); however, after controlling for covariates, there were no significant differences between former smokers and never smokers on indirect costs. Smoking exerts a large health and economic burden; however, smoking cessation attenuates this burden. The current study provides important further evidence of this association, with former smokers appearing statistically indistinguishable from never smokers in terms of work productivity loss and associated indirect costs among a large representative sample of Japanese workers. This report highlights the workplace benefits of smoking cessation across productivity markers and cost-savings.

Treatment of Functional Impairment in Patients with Bipolar Disorder.

PubMed

Sanchez-Moreno, Jose; Martinez-Aran, Anabel; Vieta, Eduard

2017-01-01

Traditionally, functional impairment has received little attention in bipolar disorder, despite the fact that many patients experience significant impairments in daily life. In the last decade, research has changed its focus from clinical remission to functional recovery in bipolar patients as a priority. A literature review of this topic will allow us provide an overview of the relevance of functional impairment as well as the potential factors that can predict or contribute to low functioning in bipolar disorder (BD). Treatment approaches should consider not only euthymia as a goal but also cognitive and functional improvement of patients with such a complex disorder. Functional remediation and psychoeducation among psychological interventions may help to enhance functioning. The combination of cognitive enhancers and cognitive/functional remediation programs may help in improving cognitive and functional impairments. Early interventions are essential to prevent cognitive deficits and disability.

Physiological reactions of a passenger to transportation conditions

NASA Technical Reports Server (NTRS)

Lakshin, A. M.; Novoselov, V. P.

1980-01-01

The effect of transportation conditions on the performance capacity of a passenger were studied, in order to establish the time for his most rapid inclusion in production activity after the trip. It was concluded that the transportation conditions impair the functional condition of the passenger's organism. The restoration of the functional state to the initial level occurs mainly in the space of one day. It is shown that it is necessary to take into consideration the adaptation of the organism during transfer to another climate zone.

Quality of life and cost factors in panic disorder.

PubMed

Davidson, J R

1996-01-01

Quality of life encompasses domains of personal happiness, role fulfillment, and health status. Increasing attention has been paid to the relationship between quality of life and panic disorder, with accumulating evidence now available to suggest impairment in several domains among subjects with panic disorder. This review summarizes the results of community-based and treatment-seeking populations of subjects with panic disorder. Impaired personal happiness, restricted role functioning, and increased use of health services are all described. Evidence suggests that accurate diagnosis and effective treatment can significantly lessen health service utilization, resulting in substantial cost offset and also leading to increased work productivity and personal effectiveness.

Factors influencing work disability in psoriatic arthritis: first results from a large UK multicentre study.

PubMed

Tillett, William; Shaddick, Gavin; Askari, Ayman; Cooper, Annie; Creamer, Paul; Clunie, Gavin; Helliwell, Philip S; Kay, Lesley; Korendowych, Eleanor; Lane, Suzanne; Packham, Jonathan; Shaban, Ragai; Williamson, Lyn; McHugh, Neil

2015-01-01

The aim of this study was to determine the extent to which structural damage, clinical disease activity, demographic and social factors are associated with work disability (WD) in PsA. Four hundred patients fulfilling CASPAR (Classification Criteria for Psoriatic Arthritis) criteria for PsA were recruited from 23 hospitals across the UK. Demographic, socio-economic, work, clinical and radiographic data were collected. WD was assessed with the Work Productivity and Activity Impairment Specific Health Problem (WPAI-SHP) questionnaire reporting WD as a percentage of absenteeism (work time missed), presenteeism (impairment at work/reduced effectiveness) and work productivity loss (overall work impairment/absenteeism plus presenteeism). Logistic and linear regressions were conducted to investigate associations with WD. Two hundred and thirty-six participants of any age were in work. Absenteeism, presenteeism and productivity loss rates were 14% (s.d. 29.0), 39% (s.d. 27.2) and 46% (s.d. 30.4), respectively. Ninety-two (26%) participants of working age were unemployed. Greater age, disease duration of 2-5 years and worse physical function were associated with unemployment. Patients reported that employer awareness and helpfulness exerted a strongly positive influence on remaining in employment. Higher levels of global and joint-specific disease activity and worse physical function were associated with greater levels of presenteeism and productivity loss among those who remained in work. Reduced effectiveness at work was associated with measures of disease activity, whereas unemployment, considered the endpoint of WD, was associated with employer factors, age and disease duration. A longitudinal study is under way to determine whether treatment to reduce disease activity ameliorates WD in the real-world setting. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Results of a real-world study on vortioxetine in patients with major depressive disorder in South East Asia (REVIDA).

PubMed

Chin, Cheuk Ngen; Zain, Azhar; Hemrungrojn, Solaphat; Ung, Eng Khean; Kwansanit, Patanon; Au Yong, Koon Choong; Chong, Marvin Swee Woon; Inpa, Chalowat; Yen, Teck Hoe; Yeoh, Boon Beng David; Tay, Liam Kai; Bernardo, Carmina; Lim, Lionel Chee-Chong; Yap, Chin Hong; Fones, Calvin; Nayak, Ashwini; Nelleman, Lars

2018-06-14

The REVIDA study aimed to assess the evolution of major depression symptoms in South East Asian (SEA) patients treated with vortioxetine for major depression in real-world clinical practice. This non-interventional study was conducted from August 2016 to April 2017. A total of 138 patients (aged 18-65 years) with an active episode of major depression were recruited from Malaysia, Philippines, Singapore and Thailand. Vortioxetine was initiated on the first visit and patients were followed for 3 months. Depression severity was assessed using the PHQ-9 questionnaire (patient assessed) and CGI-S scale (physician assessed); cognitive function was assessed with the PDQ-D questionnaire; work productivity and activity impairment (WPAI) was assessed with the WPAI questionnaire. At baseline, 89.9% of patients were moderately to severely depressed (PHQ-9 score ≥10). During the 3 month treatment period, mean ± SD PHQ-9 score decreased from 18.7 ± 5.7 to 5.0 ± 5.3, mean ± SD CGI-S score decreased from 4.4 ± 0.7 to 2.2 ± 1.1 and mean ± SD PDQ-D score decreased from 42.1 ± 18.8 to 13.4 ± 13.0. By Month 3, response and remission rates reached 80.8% and 59.0%, respectively. Work productivity loss decreased from 73.6% to 30.5%, while activity impairment decreased from 71.5% to 24.6%. Positive correlations were observed between PHQ-9, PDQ-D, and WPAI work productivity loss and activity impairment. By Month 3, 82.0% of patients were either not depressed or only mildly depressed (PHQ-9 score ≤9). In real-world clinical settings, vortioxetine was effective in reducing depression severity and improving cognitive function and work productivity in SEA patients with major depression.

SIRT1 inhibits NADPH oxidase activation and protects endothelial function in the rat aorta: implications for vascular aging.

PubMed

Zarzuelo, María José; López-Sepúlveda, Rocío; Sánchez, Manuel; Romero, Miguel; Gómez-Guzmán, Manuel; Ungvary, Zoltan; Pérez-Vizcaíno, Francisco; Jiménez, Rosario; Duarte, Juan

2013-05-01

Vascular aging is characterized by up-regulation of NADPH oxidase, oxidative stress and endothelial dysfunction. Previous studies demonstrate that the activity of the evolutionarily conserved NAD(+)-dependent deacetylase SIRT1 declines with age and that pharmacological activators of SIRT1 confer significant anti-aging cardiovascular effects. To determine whether dysregulation of SIRT1 promotes NADPH oxidase-dependent production of reactive oxygen species (ROS) and impairs endothelial function we assessed the effects of three structurally different inhibitors of SIRT1 (nicotinamide, sirtinol, EX527) in aorta segments isolated from young Wistar rats. Inhibition of SIRT1 induced endothelial dysfunction, as shown by the significantly reduced relaxation to the endothelium-dependent vasodilators acetylcholine and the calcium ionophore A23187. Endothelial dysfunction induced by SIRT1 inhibition was prevented by treatment of the vessels with the NADPH oxidase inhibitor apocynin or superoxide dismutase. Inhibition of SIRT1 significantly increased vascular superoxide production, enhanced NADPH oxidase activity, and mRNA expression of its subunits p22(phox) and NOX4, which were prevented by resveratrol. Peroxisome proliferator-activated receptor-α (PPARα) activation mimicked the effects of resveratrol while PPARα inhibition prevented the effects of this SIRT1 activator. SIRT1 co-precipitated with PPARα and nicotinamide increased the acetylation of the PPARα coactivator PGC-1α, which was suppressed by resveratrol. In conclusion, impaired activity of SIRT1 induces endothelial dysfunction and up-regulates NADPH oxidase-derived ROS production in the vascular wall, mimicking the vascular aging phenotype. Moreover, a new mechanism for controlling endothelial function after SIRT1 activation involves a decreased PGC-1α acetylation and the subsequent PPARα activation, resulting in both decreased NADPH oxidase-driven ROS production and NO inactivation. Copyright © 2013 Elsevier Inc. All rights reserved.

Combination of soya pulp and Bacillus coagulans lilac-01 improves intestinal bile acid metabolism without impairing the effects of prebiotics in rats fed a cholic acid-supplemented diet.

PubMed

Lee, Yeonmi; Yoshitsugu, Reika; Kikuchi, Keidai; Joe, Ga-Hyun; Tsuji, Misaki; Nose, Takuma; Shimizu, Hidehisa; Hara, Hiroshi; Minamida, Kimiko; Miwa, Kazunori; Ishizuka, Satoshi

2016-08-01

Intestinal bacteria are involved in bile acid (BA) deconjugation and/or dehydroxylation and are responsible for the production of secondary BA. However, an increase in the production of secondary BA modulates the intestinal microbiota due to the bactericidal effects and promotes cancer risk in the liver and colon. The ingestion of Bacillus coagulans improves constipation via the activation of bowel movement to promote defaecation in humans, which may alter BA metabolism in the intestinal contents. BA secretion is promoted with high-fat diet consumption, and the ratio of cholic acid (CA):chenodeoxycholic acid in primary BA increases with ageing. The dietary supplementation of CA mimics the BA environment in diet-induced obesity and ageing. We investigated whether B. coagulans lilac-01 and soya pulp influence both BA metabolism and the maintenance of host health in CA-supplemented diet-fed rats. In CA-fed rats, soya pulp significantly increased the production of secondary BA such as deoxycholic acid and ω-muricholic acids, and soya pulp ingestion alleviated problems related to plasma adiponectin and gut permeability in rats fed the CA diet. The combination of B. coagulans and soya pulp successfully suppressed the increased production of secondary BA in CA-fed rats compared with soya pulp itself, without impairing the beneficial effects of soya pulp ingestion. In conclusion, it is possible that a combination of prebiotics and probiotics can be used to avoid an unnecessary increase in the production of secondary BA in the large intestine without impairing the beneficial functions of prebiotics.

Music-Based Cognitive Remediation Therapy for Patients with Traumatic Brain Injury

PubMed Central

Hegde, Shantala

2014-01-01

Traumatic brain injury (TBI) is one of the common causes of disability in physical, psychological, and social domains of functioning leading to poor quality of life. TBI leads to impairment in sensory, motor, language, and emotional processing, and also in cognitive functions such as attention, information processing, executive functions, and memory. Cognitive impairment plays a central role in functional recovery in TBI. Innovative methods such as music therapy to alleviate cognitive impairments have been investigated recently. The role of music in cognitive rehabilitation is evolving, based on newer findings emerging from the fields of neuromusicology and music cognition. Research findings from these fields have contributed significantly to our understanding of music perception and cognition, and its neural underpinnings. From a neuroscientific perspective, indulging in music is considered as one of the best cognitive exercises. With “plasticity” as its veritable nature, brain engages in producing music indulging an array of cognitive functions and the product, the music, in turn permits restoration and alters brain functions. With scientific findings as its basis, “neurologic music therapy” (NMT) has been developed as a systematic treatment method to improve sensorimotor, language, and cognitive domains of functioning via music. A preliminary study examining the effect of NMT in cognitive rehabilitation has reported promising results in improving executive functions along with improvement in emotional adjustment and decreasing depression and anxiety following TBI. The potential usage of music-based cognitive rehabilitation therapy in various clinical conditions including TBI is yet to be fully explored. There is a need for systematic research studies to bridge the gap between increasing theoretical understanding of usage of music in cognitive rehabilitation and application of the same in a heterogeneous condition such as TBI. PMID:24715887

Does visual impairment lead to additional disability in adults with intellectual disabilities?

PubMed

Evenhuis, H M; Sjoukes, L; Koot, H M; Kooijman, A C

2009-01-01

This study addresses the question to what extent visual impairment leads to additional disability in adults with intellectual disabilities (ID). In a multi-centre cross-sectional study of 269 adults with mild to profound ID, social and behavioural functioning was assessed with observant-based questionnaires, prior to expert assessment of visual function. With linear regression analysis the percentage of variance, explained by levels of visual function, was calculated for the total population and per ID level. A total of 107/269 participants were visually impaired or blind (WHO criteria). On top of the decrease by ID visual impairment significantly decreased daily living skills, communication & language, recognition/communication. Visual impairment did not cause more self-absorbed and withdrawn behaviour or anxiety. Peculiar looking habits correlated with visual impairment and not with ID. In the groups with moderate and severe ID this effect seems stronger than in the group with profound ID. Although ID alone impairs daily functioning, visual impairment diminishes the daily functioning even more. Timely detection and treatment or rehabilitation of visual impairment may positively influence daily functioning, language development, initiative and persistence, social skills, communication skills and insecure movement.

Inappropriate Prescription and Renal Function Among Older Patients with Cognitive Impairment.

PubMed

Sönnerstam, Eva; Sjölander, Maria; Gustafsson, Maria

2016-12-01

Older people are more sensitive to drugs and adverse drug reactions than younger people because of age-related physiological changes such as impaired renal function. As people with dementia are particularly vulnerable to the effects of drugs, it is especially important to evaluate the dosages of renally cleared medications in this group. The aim of this study was to estimate the prevalence of impaired renal function and inappropriate prescriptions on the basis of renal function among older patients with dementia or cognitive impairment. The medical records of 428 patients aged ≥65 years who were admitted to two hospitals in northern Sweden were reviewed and renally cleared medications were identified. The Cockcroft-Gault equation was used to evaluate renal function. Doses were evaluated according to the Geriatric Dosage Handbook. Renal function was impaired (estimated glomerular filtration rate <60 ml/min) in 65.4 % of the study population. Impaired renal function was associated with increasing age. Among 547 prescriptions identified as renally cleared medications, 9.1 % were inappropriate based on the patient's renal function; 13.5 % of the 326 patients prescribed renally cleared medications had inappropriate prescriptions. Inappropriate prescriptions were more common among patients living in nursing homes. Impaired renal function is common and inappropriate prescription is prevalent among old people with cognitive impairment in northern Sweden. Continuous consideration of renal function is important when prescribing medications to this group.

Alzheimer's disease and age-related memory decline (preclinical).

PubMed

Terry, Alvin V; Callahan, Patrick M; Hall, Brandon; Webster, Scott J

2011-08-01

An unfortunate result of the rapid rise in geriatric populations worldwide is the increasing prevalence of age-related cognitive disorders such as Alzheimer's disease (AD). AD is a devastating neurodegenerative illness that is characterized by a profound impairment of cognitive function, marked physical disability, and an enormous economic burden on the afflicted individual, caregivers, and society in general. The rise in elderly populations is also resulting in an increase in individuals with related (potentially treatable) conditions such as "Mild Cognitive Impairment" (MCI) which is characterized by a less severe (but abnormal) level of cognitive impairment and a high-risk for developing dementia. Even in the absence of a diagnosable disorder of cognition (e.g., AD and MCI), the perception of increased forgetfulness and declining mental function is a clear source of apprehension in the elderly. This is a valid concern given that even a modest impairment of cognitive function is likely to be associated with significant disability in a rapidly evolving, technology-based society. Unfortunately, the currently available therapies designed to improve cognition (i.e., for AD and other forms of dementia) are limited by modest efficacy and adverse side effects, and their effects on cognitive function are not sustained over time. Accordingly, it is incumbent on the scientific community to develop safer and more effective therapies that improve and/or sustain cognitive function in the elderly allowing them to remain mentally active and productive for as long as possible. As diagnostic criteria for memory disorders evolve, the demand for pro-cognitive therapeutic agents is likely to surpass AD and dementia to include MCI and potentially even less severe forms of memory decline. The purpose of this review is to provide an overview of the contemporary therapeutic targets and preclinical pharmacologic approaches (with representative drug examples) designed to enhance memory function. Copyright © 2011 Elsevier Inc. All rights reserved.

Validation of DSM-5 age-of-onset criterion of attention deficit/hyperactivity disorder (ADHD) in adults: Comparison of life quality, functional impairment, and family function.

PubMed

Lin, Yu-Ju; Lo, Kuan-Wu; Yang, Li-Kuang; Gau, Susan Shur-Fen

2015-12-01

The newly published Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) elevates the threshold of the ADHD age-of-onset criterion from 7 to 12 years. This study evaluated the quality of life and functional impairment of adults with ADHD who had symptoms onset by or after 7 years and examined the mediation effect of family function and anxiety/depression symptoms between ADHD diagnosis and quality of life and functional impairment. We assessed 189 adults with ADHD and 153 non-ADHD controls by psychiatric interview and self-administered reports on the Adult ADHD Quality of Life Scale, Weiss Functional Impairment Rating Scale, Family APGAR, and Adult Self Report Inventory-4. The ADHD group was divided into early-onset ADHD (onset <7 years, n=147) and late-onset ADHD (onset between 7 and 12 years, n=42). The mediation analysis was conducted to verify the mediating factors from ADHD to functional impairment and quality of life. The late-onset ADHD had more severe functional impairment at work and poorer family support than early-onset ADHD while they had comparable impairment at other domains. Less perceived family support and current anxiety/depressive symptoms partially mediated the link between ADHD diagnosis and quality of life/functional impairment both in early- and late-onset ADHD. Our data support decreased quality of life and increased functional impairment in adult ADHD, regardless of age of onset, and these adverse outcomes may be mediated by family support and anxiety/depression at adulthood. Our findings also imply that the new DSM-5 ADHD criteria do not over-include individuals without impairment. Copyright © 2015 Elsevier Ltd. All rights reserved.

Quantifying the Clinical Significance of Cannabis Withdrawal

PubMed Central

Allsop, David J.; Copeland, Jan; Norberg, Melissa M.; Fu, Shanlin; Molnar, Anna; Lewis, John; Budney, Alan J.

2012-01-01

Background and Aims Questions over the clinical significance of cannabis withdrawal have hindered its inclusion as a discrete cannabis induced psychiatric condition in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV). This study aims to quantify functional impairment to normal daily activities from cannabis withdrawal, and looks at the factors predicting functional impairment. In addition the study tests the influence of functional impairment from cannabis withdrawal on cannabis use during and after an abstinence attempt. Methods and Results A volunteer sample of 49 non-treatment seeking cannabis users who met DSM-IV criteria for dependence provided daily withdrawal-related functional impairment scores during a one-week baseline phase and two weeks of monitored abstinence from cannabis with a one month follow up. Functional impairment from withdrawal symptoms was strongly associated with symptom severity (p = 0.0001). Participants with more severe cannabis dependence before the abstinence attempt reported greater functional impairment from cannabis withdrawal (p = 0.03). Relapse to cannabis use during the abstinence period was associated with greater functional impairment from a subset of withdrawal symptoms in high dependence users. Higher levels of functional impairment during the abstinence attempt predicted higher levels of cannabis use at one month follow up (p = 0.001). Conclusions Cannabis withdrawal is clinically significant because it is associated with functional impairment to normal daily activities, as well as relapse to cannabis use. Sample size in the relapse group was small and the use of a non-treatment seeking population requires findings to be replicated in clinical samples. Tailoring treatments to target withdrawal symptoms contributing to functional impairment during a quit attempt may improve treatment outcomes. PMID:23049760

Behavioral Impairment and Oxidative Damage Induced by Chronic Application of Nonylphenol

PubMed Central

Mao, Zhen; Zheng, Yuan-Lin; Zhang, Yan-Qiu

2011-01-01

Nonylphenol (NP) is a degradation product of nonylphenol polyethoxylates, which are widely used in the production of industrial and consumer surfactants. The aim of the present study was to evaluate the effect of NP on the antioxidant capacity and cognitive ability of mice. NP was given orally by gavages at doses of 0, 50, 100, and 200 mg kg−1 d−1 for 90 days. The results showed that NP significantly decreased the activity of superoxide dismutases (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR) and at the same time increased malondialdehyde (MDA) levels in mice brains. Exploration, memory function and ability to learn a novel task were significantly decreased in NP fed mice. These results indicate that chronic high dose of NP exposure has the potential to generate oxidative stress and induce the cognitive impairment in male mice. PMID:21339980

High-fat diet induces cardiac remodelling and dysfunction: assessment of the role played by SIRT3 loss.

PubMed

Zeng, Heng; Vaka, Venkata Ramana; He, Xiaochen; Booz, George W; Chen, Jian-Xiong

2015-08-01

Mitochondrial dysfunction plays an important role in obesity-induced cardiac impairment. SIRT3 is a mitochondrial protein associated with increased human life span and metabolism. This study investigated the functional role of SIRT3 in obesity-induced cardiac dysfunction. Wild-type (WT) and SIRT3 knockout (KO) mice were fed a normal diet (ND) or high-fat diet (HFD) for 16 weeks. Body weight, fasting glucose levels, reactive oxygen species (ROS) levels, myocardial capillary density, cardiac function and expression of hypoxia-inducible factor (HIF)-1α/-2α were assessed. HFD resulted in a significant reduction in SIRT3 expression in the heart. Both HFD and SIRT3 KO mice showed increased ROS formation, impaired HIF signalling and reduced capillary density in the heart. HFD induced cardiac hypertrophy and impaired cardiac function. SIRT3 KO mice fed HFD showed greater ROS production and a further reduction in cardiac function compared to SIRT3 KO mice on ND. Thus, the adverse effects of HFD on cardiac function were not attributable to SIRT3 loss alone. However, HFD did not further reduce capillary density in SIRT3 KO hearts, implicating SIRT3 loss in HFD-induced capillary rarefaction. Our study demonstrates the importance of SIRT3 in preserving heart function and capillary density in the setting of obesity. Thus, SIRT3 may be a potential therapeutic target for obesity-induced heart failure. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Protective effects of physical exercise on MDMA-induced cognitive and mitochondrial impairment.

PubMed

Taghizadeh, Ghorban; Pourahmad, Jalal; Mehdizadeh, Hajar; Foroumadi, Alireza; Torkaman-Boutorabi, Anahita; Hassani, Shokoufeh; Naserzadeh, Parvaneh; Shariatmadari, Reyhaneh; Gholami, Mahdi; Rouini, Mohammad Reza; Sharifzadeh, Mohammad

2016-10-01

Debate continues about the effect of 3, 4-methylenedioxymethamphetamine (MDMA) on cognitive and mitochondrial function through the CNS. It has been shown that physical exercise has an important protective effect on cellular damage and death. Therefore, we investigated the effect of physical exercise on MDMA-induced impairments of spatial learning and memory as well as MDMA effects on brain mitochondrial function in rats. Male wistar rats underwent short-term (2 weeks) or long-term (4 weeks) treadmill exercise. After completion of exercise duration, acquisition and retention of spatial memory were evaluated by Morris water maze (MWM) test. Rats were intraperitoneally (I.P) injected with MDMA (5, 10, and 15mg/kg) 30min before the first training trial in 4 training days of MWM. Different parameters of brain mitochondrial function were measured including the level of ROS production, mitochondrial membrane potential (MMP), mitochondrial swelling, mitochondrial outermembrane damage, the amount of cytochrome c release from the mitochondria, and ADP/ATP ratio. MDMA damaged the spatial learning and memory in a dose-dependent manner. Brain mitochondria isolated from the rats treated with MDMA showed significant increase in ROS formation, collapse of MMP, mitochondrial swelling, and outer membrane damage, cytochrome c release from the mitochondria, and finally increased ADP/ATP ratio. This study also found that physical exercise significantly decreased the MDMA-induced impairments of spatial learning and memory and also mitochondrial dysfunction. The results indicated that MDMA-induced neurotoxicity leads to brain mitochondrial dysfunction and subsequent oxidative stress is followed by cognitive impairments. However, physical exercise could reduce these deleterious effects of MDMA through protective effects on brain mitochondrial function. Copyright © 2016 Elsevier Inc. All rights reserved.

Levomilnacipran Extended-Release Treatment in Patients With Major Depressive Disorder: Improvements in Functional Impairment Categories

PubMed Central

Gommoll, Carl P.; Chen, Changzheng; Greenberg, William M.; Ruth, Adam

2015-01-01

Objective: In this post hoc analysis, improvement in functional impairment in patients with major depressive disorder (MDD) treated with levomilnacipran extended release (ER) was evaluated by assessing shifts from more severe to less severe functional impairment categories on individual Sheehan Disability Scale (SDS) subscales. Method: SDS data were pooled from 5 phase II/III studies conducted between December 2006 and March 2012 of levomilnacipran ER versus placebo in adult patients with MDD (DSM-IV-TR criteria). Proportions of patients shifting from moderate-extreme baseline impairment (score ≥ 4) to mild-no impairment (score ≤ 3) at end of treatment were assessed for each SDS subscale. Proportions of patients shifting from marked-extreme (score ≥ 7) baseline impairment to moderate-no (score ≤ 6) or mild-no impairment (score ≤ 3) at end of treatment, and shifts in which patients worsened from moderate-no to marked-extreme impairment, were also evaluated. Results: A significantly higher proportion of patients treated with levomilnacipran ER than placebo-treated patients improved from more severe categories of functional impairment at baseline to less severe impairment categories across all SDS subscales: work/school, social life, and family life/home responsibilities (P < .01). Depending on the SDS subscale, 48%–55% of levomilnacipran ER–treated patients with moderate-extreme impairment at baseline improved to mild or no impairment, compared with no more than 40% of placebo patients on any subscale. Almost half (42%–47%) of levomilnacipran ER–treated patients versus only about one-third (29%–34%) of placebo patients improved from marked-extreme to mild or no impairment across functional domains. Conclusions: These results suggest that functional improvement was observed across the SDS functional domains. To our knowledge, this is the first such categorical analysis of functional improvement, as measured by the SDS, for an antidepressant. Trial Registration: ClinicalTrials.gov identifiers: NCT00969709, NCT01377194, NCT00969150, and NCT01034462 and EudraCT identifier: 2006–002404-34 PMID:26644957

Functional impairment and mental health functioning among Vietnamese children.

PubMed

Dang, Hoang-Minh; Weiss, Bahr; Trung, Lam T

2016-01-01

Functional impairment is a key indicator of need for mental health services among children and adolescents, often a stronger predictor of service usage than mental health symptoms themselves. Functional impairment may be of particular importance in low- and middle-income countries (LMIC) because of its potential to focus policy on treatment of child mental health problems which is generally given low priority in LMIC. However, few studies have assessed functional impairment in LMIC. The present study assessed rates of functional impairment among children in Vietnam, as a case example of an LMIC, as well as effects of other risk/protective factors of particular relevance to LMIC (e.g., whether the family lived in an urban or rural area; family structure variables such as grandparents living with the family). 1314 parents of children 6-16 years old from 10 Vietnamese provinces were interviewed. The overall rate of functional impairment among Vietnamese children was 20 %, similar to rates in high-income countries such as Germany and the United States, suggesting that LMIC status may not be associated with dramatic increases in functional impairment in children. Functional impairment was significantly greater among mental health cases than non-cases, with increases of over 550 % associated with mental health caseness. A number of other risk factors (e.g., marital status) had smaller but significant effects. Mental health problems are a major but not the sole contributor to functional impairment among Vietnamese children. The pragmatic significance of this research lies in its potential to affect public awareness and policy related to child mental health in LMIC.

Functional impairment and mental health functioning among Vietnamese children

PubMed Central

Dang, Hoang-Minh; Weiss, Bahr; Trung, Lam T.

2015-01-01

Purpose Functional impairment is a key indicator of need for mental health services among children and adolescents, often a stronger predictor of service usage than mental health symptoms themselves. Functional impairment may be of particular importance in low and middle income countries (LMIC) because of its potential to focus policy on treatment of child mental health problems which is generally given low priority in LMIC. However, few studies have assessed functional impairment in LMIC. The present study assessed rates of functional impairment among children in Vietnam, as a case example of an LMIC, as well as effects of other risk/protective factors of particular relevance to LMIC (e.g., whether the family lived in an urban or rural area; family structure variables such as grandparents living with the family). Methods 1,314 parents of children 6–16 years old from 10 Vietnamese provinces were interviewed. Results The overall rate of functional impairment among Vietnamese children was 20%, similar to rates in high income countries such as Germany and the United States, suggesting that LMIC status may not be associated with dramatic increases in functional impairment in children. Functional impairment was significantly greater among mental health cases than non-cases, with increases of over 550% associated with mental health caseness. A number of other risk factors (e.g., marital status) had smaller but significant effects. Conclusions Mental health problems are a major but not the sole contributor to functional impairment among Vietnamese children. The pragmatic significance of this research lies in its potential to affect public awareness and policy related to child mental health in LMIC. PMID:26315942

Functional Impairment and Hospital Readmission in Medicare Seniors

PubMed Central

Greysen, S. Ryan; Cenzer, Irena Stijacic; Auerbach, Andrew D.; Covinsky, Kenneth E.

2015-01-01

Importance Medicare currently penalizes hospitals for high rates of readmission for seniors but does not account for common age-related syndromes such as functional impairment. Objectives Given the high prevalence of functional impairments in community-dwelling seniors, we assessed effects of functional impairment on Medicare hospital readmissions. Study Design, Participants, and Setting We created a nationally-representative cohort of 7,854 community-dwelling seniors in the Health and Retirement Study (HRS) with 22,289 Medicare hospitalizations from 2000–2010. Main Outcome and Measurements Outcome was 30-day readmission, assessed by Medicare claims. Main predictor was functional impairment determined from HRS interview preceding hospitalization, stratified into 5 levels: no functional impairments, difficulty with ≥1 instrumental activity of daily living (IADL), difficulty with ≥1 activity of daily living (ADL), dependency (need for help) in 1–2 ADLs, and dependency in ≥3 ADLs. Adjustment variables included age, race, gender, income, and net worth and comorbid conditions (Elixhauser score from Medicare claims), and prior admission. We performed multivariable logistic regression adjusted for clustering at patient level to characterize the association of functional impairments and readmission. Results Mean age 79 (±8; 65–105), 58% female, 85% White, 90% reported ≥3 comorbidities, 86% had ≥1 hospitalization in previous year. Overall, 48% had some level of functional impairment prior to admission and 15% experienced a 30-day readmission. We found a progressive increase in adjusted risk of readmission as the degree of functional impairment increased: 13.5% with no functional impairment, 14.3% with ≥ 1 IADL difficulty (OR 1.06; 95% CI 0.94–1.20), 14.4% with ≥1 ADL difficulty (OR 1.08; 0.96–1.21), 16.5% with dependency in 1–2 ADLs (OR 1.26; 1.11–1.44), and 18.2% with dependency in ≥3 ADLs (1.42; 1.20–1.69). Sub-analysis restricted to patients admitted with conditions targeted by Medicare (heart failure, myocardial infarction, and pneumonia) revealed a parallel trend with larger effects for the most-impaired (16.9% readmission rate for no impairment vs. 25.7% for dependency in ≥3 ADLs, OR 1.70; 1.04–2.78). Conclusions Functional impairment is associated with increased risk of 30-day, all-cause hospital readmission in Medicare seniors, especially those admitted for heart failure, myocardial infarction or pneumonia. Functional impairment on admission may be an overlooked but highly suitable target for interventions to reduce Medicare hospital readmissions. Relevance Functional impairment may be an important but under-addressed factor in preventing readmissions for Medicare seniors. PMID:25642907

The Reliability of the CVI Range: A Functional Vision Assessment for Children with Cortical Visual Impairment

ERIC Educational Resources Information Center

Newcomb, Sandra

2010-01-01

Children who are identified as visually impaired frequently have a functional vision assessment as one way to determine how their visual impairment affects their educational performance. The CVI Range is a functional vision assessment for children with cortical visual impairment. The purpose of the study presented here was to examine the…

Population pharmacokinetics of pomalidomide in patients with relapsed or refractory multiple myeloma with various degrees of impaired renal function.

PubMed

Li, Yan; Wang, Xiaomin; O'Mara, Edward; Dimopoulos, Meletios A; Sonneveld, Pieter; Weisel, Katja C; Matous, Jeffrey; Siegel, David S; Shah, Jatin J; Kueenburg, Elisabeth; Sternas, Lars; Cavanaugh, Chloe; Zaki, Mohamed; Palmisano, Maria; Zhou, Simon

2017-01-01

Pomalidomide is an immunomodulatory drug for treatment of relapsed or refractory multiple myeloma (rrMM) in patients who often have comorbid renal conditions. To assess the impact of renal impairment on pomalidomide exposure, a population pharmacokinetics (PPK) model of pomalidomide in rrMM patients with various degrees of impaired renal function was developed. Intensive and sparse pomalidomide concentration data collected from two clinical studies in rrMM patients with normal renal function, moderately impaired renal function, severely impaired renal function not requiring dialysis, and with severely impaired renal function requiring dialysis were pooled over the dose range of 2 to 4 mg, to assess specifically the influence of the impaired renal function as a categorical variable and a continuous variable on pomalidomide clearance and plasma exposure. In addition, pomalidomide concentration data collected on dialysis days from both the withdrawal (arterial) side and from the returning (venous) side of the dialyzer, from rrMM patients with severely impaired renal function requiring dialysis, were used to assess the extent to which dialysis contributes to the removal of pomalidomide from blood circulation. PPK analyses demonstrated that moderate to severe renal impairment not requiring dialysis has no influence on pomalidomide clearance or plasma exposure, as compared to those patients with normal renal function, while pomalidomide exposure increased approximately 35% in patients with severe renal impairment requiring dialysis on nondialysis days. In addition, dialysis increased total body pomalidomide clearance from 5 L/h to 12 L/h, indicating that dialysis will significantly remove pomalidomide from the blood circulation. Thus, pomalidomide should be administered post-dialysis on the days of dialysis.

Telephone-administered cognitive-behavioral therapy for clients with depressive symptoms in an employee assistance program: a pilot study.

PubMed

Lam, Raymond W; Lutz, Kevin; Preece, Melady; Cayley, Paula M; Bowen Walker, Anne

2011-02-01

To assess the clinical and work productivity effects of a brief intervention using telephone-administered cognitive-behavioral therapy (CBT) for clients with depressive symptoms attending an employee assistance program (EAP). Self-referred clients attending the PPC Canada EAP with clinically relevant depressive symptoms at initial assessment were offered an 8-session telephone-administered CBT program. Outcomes before and after intervention were assessed with the 9-item Personal Health Questionnaire (PHQ-9), Global Assessment of Functioning (GAF), and clinician ratings of work absence and performance impairment. Fifty clients were referred to the pilot program; 39 participated and 31 completed the telephone CBT program. Among program participants, there was significant improvement in PHQ-9 and GAF scores. There was also a significant reduction in performance impairment but not work absence. Anecdotal reports indicated high satisfaction ratings among participants. The results of this pilot study, although limited by the absence of a comparison or control group, suggest that a brief telephone-administered CBT program can improve depressive symptomatology, work productivity, and general function in depressed clients attending an EAP. Further controlled studies are needed to confirm these preliminary findings.

The Association Between Higher Social Support and Lower Depressive Symptoms Among Aging Services Clients is Attenuated at Higher Levels of Functional Impairment

PubMed Central

Van Orden, Kimberly A.; Yan, Li; Podgorski, Carol A.; Conwell, Yeates

2015-01-01

Objective Adults seeking services from the Aging Services Provider Network (ASPN) are at risk for depression. ASPN clients also have high prevalence of both functional impairments and social morbidities. Study of the relationships between these factors may inform the development of interventions for depression in this service setting. Methods We interviewed 373 older adults accessing ASPN services and assessed depression symptom severity, functional impairment (instrumental activities of daily living and activities of daily living), and social support. Results Lower social support and greater functional impairment were associated with greater depressive symptoms. At a high level of functional impairment, the inverse associations between indices of social support and depressive symptoms were attenuated. Conclusions Results suggest that older adults with more severe functional impairment may benefit somewhat less from increased social support with respect to depression symptom severity. PMID:25663607

Prevalence and Functional Consequences of Severe Insomnia Symptoms in Mood and Anxiety Disorders: Results from a Nationally Representative Sample

PubMed Central

Soehner, Adriane M.; Harvey, Allison G.

2012-01-01

Study Objectives: To evaluate the prevalence of severe insomnia symptoms and the extent to which they are associated with daytime impairments in comorbid mood and anxiety disorders. Design: Nationally representative cross-sectional survey. Setting: National Comorbidity Survey-Replication (NCS-R). Participants: There were 5,692 NCS-R respondents with no mood or anxiety disorder (n = 3,711), mood disorders only (n = 327), anxiety disorders only (n = 1,137), and coexisting mood and anxiety disorders (n = 517). Interventions: N/A. Measurements and Results: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition disorders and severe insomnia symptoms in the past year were assessed using the World Health Organization (WHO) Composite International Diagnostic Interview. The World Health Organization Disability Assessment Schedule (WHO-DAS) indexed eight domains of daytime impairment in the past 30 days, which included self-care, mobility, cognition, social functioning, time out of role, and four components of productive role functioning. Respondents with comorbid mood and anxiety disorders had significantly higher rates of severe insomnia complaints (42.1-62.8%) relative to the three other groups. Severe insomnia complaints were also significantly more prevalent in individuals with mood (25.2-45.6%) or anxiety disorders only (24.9-45.5%) relative to those with no disorder (12.4-24.3%). Moreover, endorsing a severe insomnia complaint in the past year was associated with increased days of impairment across all past-month WHO-DAS domains for respondents with mood-anxiety comorbidity. For the remaining groups, severe insomnia complaints were related to increased days of impairment across all domains except self-care, and additionally mobility for the group with mood disorders only. Conclusions: Comorbid mood and anxiety disorders are associated with high rates of severe insomnia complaints, which were independently associated with substantial functional impairment. Citation: Soehner AM; Harvey AG. Prevalence and functional consequences of severe insomnia symptoms in mood and anxiety disorders: results from a nationally representative sample. SLEEP 2012;35(10):1367–1375. PMID:23024435

Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations*

PubMed Central

Halwani, Rabih; Ma, Cindy S.; Wong, Natalie; Soudais, Claire; Henderson, Lauren A.; Marzouqa, Hiyam; Shamma, Jamal; Gonzalez, Marcela; Martinez-Barricarte, Rubén; Okada, Chizuru; Avery, Danielle T.; Latorre, Daniela; Deswarte, Caroline; Jabot-Hanin, Fabienne; Torrado, Egidio; Fountain, Jeffrey; Belkadi, Aziz; Itan, Yuval; Boisson, Bertrand; Migaud, Mélanie; Arlehamn, Cecilia S. Lindestam; Sette, Alessandro; Breton, Sylvain; McCluskey, James; Rossjohn, Jamie; de Villartay, Jean-Pierre; Moshous, Despina; Hambleton, Sophie; Latour, Sylvain; Arkwright, Peter D.; Picard, Capucine; Lantz, Olivier; Engelhard, Dan; Kobayashi, Masao; Abel, Laurent; Casanova, Jean-Laurent

2015-01-01

Human inborn errors of immunity mediated by the cytokines interleukin (IL)-17A/F underlie mucocutaneous candidiasis, whereas inborn errors of interferon (IFN)-γ immunity underlie mycobacterial disease. We report the discovery of bi-allelic RORC loss-of-function mutations in seven individuals from three kindreds of different ethnic origins with both candidiasis and mycobacteriosis. The lack of functional RORγ and RORγT isoforms resulted in the absence of IL-17A/F-producing T cells in these individuals, probably accounting for their chronic candidiasis. Unexpectedly, leukocytes from RORγ- and RORγT-deficient individuals also displayed an impaired IFN-γ response to Mycobacterium. This principally reflected profoundly defective IFN-γ production by circulating γδ T cells and CD4+CCR6+ CXCR3+ αβ T cells. In humans, both mucocutaneous immunity to Candida and systemic immunity to Mycobacterium require RORγ, or RORγT, or both. PMID:26160376

Impaired NLRP3 Inflammasome Function in Elderly Mice during Influenza Infection is Rescued by Treatment with Nigericin1

PubMed Central

Stout-Delgado, Heather W.; Vaughan, Sarah E.; Shirali, Anushree C.; Jaramillo, Richard J.; Harrod, Kevin S.

2012-01-01

The NLRP3 inflammasome is activated in the lung during influenza viral infection; however the impact of aging on inflammasome function during influenza infection has not been examined. Here, we show that elderly mice infected with a mouse adapted strain of influenza produced lower levels of IL-1β during in vitro and in vivo infection. Dendritic cells from elderly mice exhibited decreased expression of ASC, NLRP3, and capase-1, but increased expression of pro-IL-1β, pro-IL-18, and pro-IL-33 when compared to young infected mice. Treatment with nigericin during influenza infection augmented IL-1β production, increased caspase-1 activity, and decreased morbidity and mortality in elderly mice. Our study demonstrates for the first time that during influenza viral infection, elderly mice have impaired NLRP3 inflammasome activity and that treatment with nigericin rescues NLRP3 activation in elderly hosts. PMID:22327078

Consumption of meat in relation to physical functioning in the Seniors-ENRICA cohort.

PubMed

Struijk, Ellen A; Banegas, José R; Rodríguez-Artalejo, Fernando; Lopez-Garcia, Esther

2018-04-05

Meat is an important source of high-quality protein and vitamin B but also has a relatively high content of saturated and trans fatty acids. Although protein and vitamin B intake seems to protect people from functional limitations, little is known about the effect of habitual meat consumption on physical function. The objective of this study was to examine the prospective association between the intake of meat (processed meat, red meat, and poultry) and physical function impairment in older adults. Data were collected for 2982 participants in the Seniors-ENRICA cohort, who were aged ≥60 years and free of physical function impairment. In 2008-2010, their habitual diet was assessed through a validated computer-assisted face-to-face diet history. Study participants were followed up through 2015 to assess self-reported incident impairment in agility, mobility, and performance-based lower-extremity function. Over a median follow-up of 5.2 years, we identified 625 participants with impaired agility, 455 with impaired mobility, and 446 with impaired lower-extremity function. After adjustment for potential confounders, processed meat intake was associated with a higher risk of impaired agility (hazard ratio [HR] for highest vs. lowest tertile: 1.33; 95% confidence interval [CI]: 1.08-1.64; p trend = 0.01) and of impaired lower-extremity function (HR for highest vs. lowest tertile: 1.31; 95% CI: 1.02-1.68; p trend = 0.04). No significant associations were found for red meat and poultry. Replacing one serving per day of processed meat with one serving per day of red meat, poultry, or with other important protein sources (fish, legumes, dairy, and nuts) was associated with lower risk of impaired agility and lower-extremity function. A higher consumption of processed meat was associated with a higher risk of impairment in agility and lower-extremity function. Replacing processed meat by other protein sources may slow the decline in physical functioning in older adults.

Hypothalamic Nitric Oxide in Hypoglycemia Detection and Counterregulation: A Two-Edged Sword

PubMed Central

Song, Zhentao; Vazirani, Reema P.; Beuve, Annie; Routh, Vanessa H.

2011-01-01

Abstract Hypoglycemia is the main complication for patients with type 1 diabetes mellitus receiving intensive insulin therapy. In addition to the obvious deleterious effects of acute hypoglycemia on brain function, recurrent episodes of hypoglycemia (RH) have an even more insidious effect. RH impairs the ability of the brain to detect and initiate an appropriate counterregulatory response (CRR) to restore euglycemia in response to subsequent hypoglycemia. Knowledge of mechanisms involved in hypoglycemia detection and counterregulation has significantly improved over the past 20 years. Glucose sensitive neurons (GSNs) in the ventromedial hypothalamus (VMH) may play a key role in the CRR. VMH nitric oxide (NO) production has recently been shown to be critical for both the CRR and glucose sensing by glucose-inhibited neurons. Interestingly, downstream effects of NO may also contribute to the impaired CRR after RH. In this review, we will discuss current literature regarding the molecular mechanisms by which VMH GSNs sense glucose. Putative roles of GSNs in the detection and initiation of the CRR will then be described. Finally, hypothetical mechanisms by which VMH NO production may both facilitate and subsequently impair the CRR will be discussed. Antioxid. Redox Signal. 14, 505–517. PMID:20518706

Deficiency of PHB complex impairs respiratory supercomplex formation and activates mitochondrial flashes.

PubMed

Jian, Chongshu; Xu, Fengli; Hou, Tingting; Sun, Tao; Li, Jinghang; Cheng, Heping; Wang, Xianhua

2017-08-01

Prohibitins (PHBs; prohibitin 1, PHB1 or PHB, and prohibitin 2, PHB2) are evolutionarily conserved and ubiquitously expressed mitochondrial proteins. PHBs form multimeric ring complexes acting as scaffolds in the inner mitochondrial membrane. Mitochondrial flashes (mitoflashes) are newly discovered mitochondrial signaling events that reflect electrical and chemical excitations of the organelle. Here, we investigate the possible roles of PHBs in the regulation of mitoflash signaling. Downregulation of PHBs increases mitoflash frequency by up to 5.4-fold due to elevated basal reactive oxygen species (ROS) production in the mitochondria. Mechanistically, PHB deficiency impairs the formation of mitochondrial respiratory supercomplexes (RSCs) without altering the abundance of individual respiratory complex subunits. These impairments induced by PHB deficiency are effectively rescued by co-expression of PHB1 and PHB2, indicating that the multimeric PHB complex acts as the functional unit. Furthermore, downregulating other RSC assembly factors, including SCAFI (also known as COX7A2L), RCF1a (HIGD1A), RCF1b (HIGD2A), UQCC3 and SLP2 (STOML2), all activate mitoflashes through elevating mitochondrial ROS production. Our findings identify the PHB complex as a new regulator of RSC formation and mitoflash signaling, and delineate a general relationship among RSC formation, basal ROS production and mitoflash biogenesis. © 2017. Published by The Company of Biologists Ltd.

Evidence for compromised metabolic function and limited glucose uptake in spermatozoa from the teratospermic domestic cat (Felis catus) and cheetah (Acinonyx jubatus).

PubMed

Terrell, Kimberly A; Wildt, David E; Anthony, Nicola M; Bavister, Barry D; Leibo, Stanley P; Penfold, Linda M; Marker, Laurie L; Crosier, Adrienne E

2010-11-01

Cheetahs and certain other felids consistently ejaculate high proportions (≥ 60%) of malformed spermatozoa, a condition known as teratospermia, which is prevalent in humans. Even seemingly normal spermatozoa from domestic cat teratospermic ejaculates have reduced fertilizing capacity. To understand the role of sperm metabolism in this phenomenon, we conducted a comparative study in the normospermic domestic cat versus the teratospermic cat and cheetah with the general hypothesis that sperm metabolic function is impaired in males producing predominantly pleiomorphic spermatozoa. Washed ejaculates were incubated in chemically defined medium containing glucose and pyruvate. Uptake of glucose and pyruvate and production of lactate were assessed using enzyme-linked fluorescence assays. Spermatozoa from domestic cats and cheetahs exhibited similar metabolic profiles, with minimal glucose metabolism and approximately equimolar rates of pyruvate uptake and lactate production. Compared to normospermic counterparts, pyruvate and lactate metabolism were reduced in teratospermic cat and cheetah ejaculates, even when controlling for sperm motility. Rates of pyruvate and lactate (but not glucose) metabolism were correlated positively with sperm motility, acrosomal integrity, and normal morphology. Collectively, our findings reveal that pyruvate uptake and lactate production are reliable, quantitative indicators of sperm quality in these two felid species and that metabolic function is impaired in teratospermic ejaculates. Furthermore, patterns of substrate utilization are conserved between these species, including the unexpected lack of exogenous glucose metabolism. Because glycolysis is required to support sperm motility and capacitation in certain other mammals (including dogs), the activity of this pathway in felid spermatozoa is a target for future investigation.

Participation of reactive oxygen species in diabetes-induced endothelial dysfunction.

PubMed

Zúrová-Nedelcevová, Jana; Navarová, Jana; Drábiková, Katarína; Jancinová, Viera; Petríková, Margita; Bernátová, Iveta; Kristová, Viera; Snirc, Vladimír; Nosál'ová, Viera; Sotníková, Ruzena

2006-12-01

In the present study, the relationship between diabetes-induced hyperglycemia, reactive oxygen species production and endothelium-mediated arterial function was examined. The effect of antioxidant on the reactive oxygen species induced damage was tested. Diabetes was induced by streptozotocin (STZ), 3 x 30 mg/kg i.p., administered on three consecutive days. After 10 weeks of diabetes, the functional state of the endothelium of the aorta was tested, endothelemia evaluation was performed and systolic blood pressure was measured. Reactive oxygen species (ROS) formation in blood and the aorta was measured using luminol-enhanced chemiluminescence (CL). Levels of reduced glutathione (GSH) were determined in the aorta, kidney, and plasma. To study the involvement of hyperglycemia in functional impairment of the endothelium, aortal rings incubated in solution with high glucose concentration were tested in in vitro experiments. After 10 weeks of diabetes, endothelial injury was observed, exhibited by diminished endothelium-dependent relaxation of the aorta, increased endothelemia and by elevated systolic blood pressure. Using luminol-enhanced CL, a significant increase of ROS production was found in arterial tissue and blood. GSH levels were significantly increased in the kidney, while there were no GSH changes in plasma and the aorta. Incubation of aortic rings in solution with high glucose concentration led to impairment of endothelium-dependent relaxation. The synthetic antioxidant SMe1EC2 was able to restore reduced endothelium-mediated relaxation. Our results suggest an important role of hyperglycemia-induced ROS production in mediating endothelial dysfunction in experimental diabetes, confirmed by CL and the protective effect of the antioxidant SMe1EC2.

Impact of higher-order heme degradation products on hepatic function and hemodynamics.

PubMed

Seidel, Raphael A; Claudel, Thierry; Schleser, Franziska A; Ojha, Navin K; Westerhausen, Matthias; Nietzsche, Sandor; Sponholz, Christoph; Cuperus, Frans; Coldewey, Sina M; Heinemann, Stefan H; Pohnert, Georg; Trauner, Michael; Bauer, Michael

2017-08-01

Biliverdin and bilirubin were previously considered end products of heme catabolism; now, however, there is evidence for further degradation to diverse bioactive products. Z-BOX A and Z-BOX B arise upon oxidation with unknown implications for hepatocellular function and integrity. We studied the impact of Z-BOX A and B on hepatic functions and explored their alterations in health and cholestatic conditions. Functional implications and mechanisms were investigated in rats, hepatocytic HepG2 and HepaRG cells, human immortalized hepatocytes, and isolated perfused livers. Z-BOX A and B were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in acute and acute-on-chronic liver failure and hereditary unconjugated hyperbilirubinemia. Z-BOX A and B are found in similar amounts in humans and rodents under physiological conditions. Serum concentrations increased ∼20-fold during cholestatic liver failure in humans (p<0.001) and in hereditary deficiency of bilirubin glucuronidation in rats (p<0.001). Pharmacokinetic studies revealed shorter serum half-life of Z-BOX A compared to its regio-isomer Z-BOX B (p=0.035). While both compounds were taken up by hepatocytes, Z-BOX A was enriched ∼100-fold and excreted in bile. Despite their reported vasoconstrictive properties in the brain vasculature, BOXes did not affect portal hemodynamics. Both Z-BOX A and B showed dose-dependent cytotoxicity, affected the glutathione redox state, and differentially modulated activity of Rev-erbα and Rev-erbβ. Moreover, BOXes-triggered remodeling of the hepatocellular cytoskeleton. Our data provide evidence that higher-order heme degradation products, namely Z-BOX A and B, impair hepatocellular integrity and might mediate intra- and extrahepatic cytotoxic effects previously attributed to hyperbilirubinemia. Degradation of the blood pigment heme yields the bile pigment bilirubin and the oxidation products Z-BOX A and Z-BOX B. Serum concentrations of these bioactive molecules increase in jaundice and can impair liver function and integrity. Amounts of Z-BOX A and Z-BOX B that are observed during liver failure in humans have profound effects on hepatic function when added to cultured liver cells or infused into healthy rats. Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Functional Literacy for Students with Visual Impairments and Significant Cognitive Disabilities: The Perspective of Teachers of Students with Visual Impairments

ERIC Educational Resources Information Center

Zebehazy, Kim T.

2014-01-01

This study reports opinions and practices of teachers of students with visual impairments (TSVIs) in 34 states regarding functional literacy for students with visual impairments (VIs) and significant cognitive disabilities (SCDs). The survey asked TSVIs to select a definition of functional literacy, indicate agreement with a series of literacy…

Prevalence and correlates of hearing and visual impairments in European nursing homes: results from the SHELTER study.

PubMed

Yamada, Yukari; Vlachova, Martina; Richter, Tomas; Finne-Soveri, Harriet; Gindin, Jacob; van der Roest, Henriëtte; Denkinger, Michael D; Bernabei, Roberto; Onder, Graziano; Topinkova, Eva

2014-10-01

Visual and hearing impairments are known to be related to functional disability, cognitive impairment, and depression in community-dwelling older people. The aim of this study was to examine the prevalence of sensory impairment in nursing home residents, and whether sensory impairment is related to other common clinical problems in nursing homes, mediated by functional disability, cognitive impairment, and depressive symptoms. Cross-sectional data of 4007 nursing home residents in 59 facilities in 8 countries from the SHELTER study were analyzed. Visual and hearing impairments were assessed by trained staff using the interRAI instrument for Long-Term Care Facilities. Generalized linear mixed models adjusted for functional disability, cognitive impairment, and depressive symptoms were used to analyze associations of sensory impairments with prevalence of clinical problems, including behavioral symptoms, incontinence, fatigue, falls, problems with balance, sleep, nutrition, and communication. Of the participants, 32% had vision or hearing impairment (single impairment) and another 32% had both vision and hearing impairments (dual impairment). Residents with single impairment had significantly higher rates of communication problems, fatigue, balance problems, and sleep problems, as compared with residents without any sensory impairment. Those with dual impairment had significantly higher rates of all clinical problems assessed in this study as compared with those without sensory impairment. For each clinical problem, the magnitude of the odds ratio for specific clinical problems was higher for dual impairment than for single impairment. Visual and hearing impairments are associated with higher rates of common clinical problems among nursing home residents, independent of functional disability, cognitive impairment, and depressive symptoms. Copyright © 2014 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.

Cognitive Impairment Precedes and Predicts Functional Impairment in Mild Alzheimer's Disease.

PubMed

Liu-Seifert, Hong; Siemers, Eric; Price, Karen; Han, Baoguang; Selzler, Katherine J; Henley, David; Sundell, Karen; Aisen, Paul; Cummings, Jeffrey; Raskin, Joel; Mohs, Richard

2015-01-01

The temporal relationship of cognitive deficit and functional impairment in Alzheimer's disease (AD) is not well characterized. Recent analyses suggest cognitive decline predicts subsequent functional decline throughout AD progression. To better understand the relationship between cognitive and functional decline in mild AD using autoregressive cross-lagged (ARCL) panel analyses in several clinical trials. Data included placebo patients with mild AD pooled from two multicenter, double-blind, Phase 3 solanezumab (EXPEDITION/2) or semagacestat (IDENTITY/2) studies, and from AD patients participating in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cognitive and functional outcomes were assessed using AD Assessment Scale-Cognitive subscale (ADAS-Cog), AD Cooperative Study-Activities of Daily Living instrumental subscale (ADCS-iADL), or Functional Activities Questionnaire (FAQ), respectively. ARCL panel analyses evaluated relationships between cognitive and functional impairment over time. In EXPEDITION, ARCL panel analyses demonstrated cognitive scores significantly predicted future functional impairment at 5 of 6 time points, while functional scores predicted subsequent cognitive scores in only 1 of 6 time points. Data from IDENTITY and ADNI programs yielded consistent results whereby cognition predicted subsequent function, but not vice-versa. Analyses from three databases indicated cognitive decline precedes and predicts subsequent functional decline in mild AD dementia, consistent with previously proposed hypotheses, and corroborate recent publications using similar methodologies. Cognitive impairment may be used as a predictor of future functional impairment in mild AD dementia and can be considered a critical target for prevention strategies to limit future functional decline in the dementia process.

Electromagnetic articulography assessment of articulatory function in adults with dysarthria following traumatic brain injury.

PubMed

Kuruvilla, Mili; Murdoch, Bruce; Goozèe, Justine

2007-06-01

To explore articulatory kinematic differences between normal and dysarthric speakers post-traumatic brain injury (TBI) during syllable and sentence productions. A comparison between the control, mild (MTBI) and severe TBI groups for all measured kinematic parameters was carried out using the Kruskal Wallis test. Ten participants with a severe TBI and six post-MTBI formed the experimental group. The control group consisted of 14 age and sex matched non-neurologically impaired speakers. Articulatory kinematic profiles for the three groups were obtained using the Electromagnetic Articulograph (EMA) while repeating sentence and syllable embedded /t/ and /k/ productions at a habitual rate and loudness level. Significant differences between the severe TBI and control group were identified only for the release phase of the /t/ sentence productions wherein an increase in mean maximum acceleration was observed for the severe TBI group. While a simple syllable repetition task at a moderate rate was unable to differentiate the three groups, a complex sentence production task precipitated an increase in mean maximum acceleration which may be indicative of increased articulatory effort and impaired speech motor control even at a convenient rate for the severe group.

Cognitive and motor function of neurologically impaired extremely low birth weight children.

PubMed

Bernardo, Janine; Friedman, Harriet; Minich, Nori; Taylor, H Gerry; Wilson-Costello, Deanne; Hack, Maureen

2015-01-01

Rates of neurological impairment among extremely low birth weight children (ELBW [<1 kg]) have decreased since 2000; however, their functioning is unexamined. To compare motor and cognitive functioning of ELBW children with neurological impairment, including cerebral palsy and severe hypotonia/hypertonia, between two periods: 1990 to 1999 (n=83) and 2000 to 2005 (n=34). Measures of function at 20 months corrected age included the Mental and Psychomotor Developmental Indexes of the Bayley Scales of Infant Development and the Gross Motor Functional Classification System as primary outcomes and individual motor function items as secondary outcomes. Analysis failed to reveal significant differences for the primary outcomes, although during 2000 to 2005, sitting significantly improved in children with neurological impairment (P=0.003). Decreases in rates of neurological impairment among ELBW children have been accompanied by a suggestion of improved motor function, although cognitive function has not changed.

Impact of Sensory Impairments on Functional Disability in Adults With Arthritis

PubMed Central

Fisher, Diana E.; Ward, Michael M.; Hoffman, Howard J.; Li, Chuan-Ming; Cotch, Mary Frances

2015-01-01

Introduction Mobility is reduced in people with sensory impairments and those with arthritis. The joint impact of these conditions may be underappreciated. This study examines the associations between impairments in vision, hearing, and balance and functional ability in adults with versus without arthritis. Methods Using National Health and Nutrition Examination Survey data from 1999–2004, arthritis status, functional ability, and sensory impairments (vision, hearing, and balance) were assessed from self-reported responses by 6,654 individuals aged ≥50 years (mean age, 63.4 years; 46.3% male). Multivariable regression analyses, conducted in 2014, assessed the associations between sensory impairment and arthritis on functional ability and mobility. Results Among study participants, 41.8% reported having arthritis; of these, 27.1%, 44.9%, and 35.1% reported impaired vision, hearing, or balance, respectively. Having multiple sensory impairments was significantly associated with reduced functional ability in people with arthritis; individuals with three sensory impairments reported the highest levels of disability for all functional domains (compared with no impairment; lower extremity mobility, 80.2% vs 39.1%; general physical activities, 94.7% vs 75.9%; activities of daily living, 69.7% vs 27.2%; instrumental activities of daily living, 77.2% vs 37.4%; leisure and social activities, 66.3% vs 30.6%; impaired gait speed, 48.1% vs 16.3%; all p<0.001). Importantly, visual deficits, in combination with arthritis, had the greatest impact on mobility, with odds of impaired mobility at least twice as high as for individuals without arthritis. Conclusions Addressing sensory deficits, especially difficulties with vision, may improve functional ability, which may be particularly helpful for adults with arthritis. PMID:26410186

Progressively Disrupted Brain Functional Connectivity Network in Subcortical Ischemic Vascular Cognitive Impairment Patients.

PubMed

Sang, Linqiong; Chen, Lin; Wang, Li; Zhang, Jingna; Zhang, Ye; Li, Pengyue; Li, Chuanming; Qiu, Mingguo

2018-01-01

Cognitive impairment caused by subcortical ischemic vascular disease (SIVD) has been elucidated by many neuroimaging studies. However, little is known regarding the changes in brain functional connectivity networks in relation to the severity of cognitive impairment in SIVD. In the present study, 20 subcortical ischemic vascular cognitive impairment no dementia patients (SIVCIND) and 20 dementia patients (SIVaD) were enrolled; additionally, 19 normal controls were recruited. Each participant underwent a resting-state functional MRI scan. Whole-brain functional networks were analyzed with graph theory and network-based statistics (NBS) to study the functional organization of networks and find alterations in functional connectivity among brain regions. After adjustments for age, gender, and duration of formal education, there were significant group differences for two network functional organization indices, global efficiency and local efficiency, which decreased (NC > SIVCIND > SIVaD) as cognitive impairment worsened. Between-group differences in functional connectivity (NBS corrected, p  < 0.01) mainly involved the orbitofrontal, parietal, and temporal cortices, as well as the basal ganglia. The brain connectivity network was progressively disrupted as cognitive impairment worsened, with an increased number of decreased connections between brain regions. We also observed more reductions in nodal efficiency in the prefrontal and temporal cortices for SIVaD than for SIVCIND. These findings indicated a progressively disrupted pattern of the brain functional connectivity network with increased cognitive impairment and showed promise for the development of reliable biomarkers of network metric changes related to cognitive impairment caused by SIVD.

Immunomodulation of phloretin by impairing dendritic cell activation and function.

PubMed

Lin, Chi-Chen; Chu, Ching-Liang; Ng, Chin-Sheng; Lin, Ching-Yen; Chen, Der-Yuan; Pan, I-Hong; Huang, Kao-Jean

2014-05-01

Dietary compounds in fruits and vegetables have been shown to exert many biological activities. In addition to antioxidant effects, a number of flavonoids are able to modulate inflammatory responses. Here, we demonstrated that phloretin (PT), a natural dihydrochalcone found in many fruits, suppressed the activation and function of mouse dendritic cells (DCs). Phloretin disturbed the multiple intracellular signaling pathways in DCs induced by the Toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS), including ROS, MAPKs (ERK, JNK, p38 MAPK), and NF-κB, and thereby reducing the production of inflammatory cytokines and chemokines. Phloretin also effectively suppressed the activation of DCs treated with different dosages of LPS or various TLR agonists. The LPS-induced DC maturation was attenuated by phloretin because the expression levels of the MHC class II and the co-stimulatory molecules were down-regulated, which then inhibited the LPS-stimulating DCs and the subsequent naïve T cell activation in a mixed lymphocyte reaction. Moreover, in vivo administration of phloretin suppressed the phenotypic maturation of the LPS-challenged splenic DCs and decreased the IFN-γ production from the activated CD4 T cells. Thus, we suggest that phloretin may potentially be an immunomodulator by impairing the activation and function of DCs and phloretin-contained fruits may be helpful in the improvement of inflammation and autoimmune diseases.

Genes determining the severity of cerebral palsy: the role of single nucleotide polymorphisms on the amount and structure of apolipoprotein E

PubMed Central

Lien, Espen; Andersen, Guro; Bao, Yongde; Gordish-Dressman, Heather; Skranes, Jon S.; Blackman, James A.; Vik, Torstein

2015-01-01

Aim ApolipoproteinE (apoE) influences repair and other processes in the brain and the apoE4 variant is a risk factor for Alzheimer's disease and for prolonged recovery following traumatic brain injury. We previously reported that specific single nucleotide polymorphisms in the APOE or TOMM40 genes affecting the structure and production of apoE were associated with epilepsy, more impaired hand function and gastrostomy tube feeding in children with cerebral palsy (CP). This study explored how various combinations of the same polymorphisms may affect these clinical manifestations. Methods Successful DNA analyses of APOE and TOMM40 were carried out on 227 children. The CP Register of Norway provided details of gross and fine motor function, epilepsy and gastrostomy tube feeding. Possible associations between these clinical manifestations and various combinations of the APOEε2, ε3 or ε4 alleles and of the rs59007384 polymorphism in the TOMM40 gene were explored. Results Epilepsy, impaired fine motor function and gastrostomy tube feeding were less common in children carrying the combination of rs59007384 GG and APOEε2 or ε3 than in children with other combinations. Conclusion Our findings suggest that specific combinations of genes influence the structure and production of apoE differently and affect the clinical manifestations of CP. PMID:25703783

The aftermath of terrorism: posttraumatic stress and functional impairment after the 2011 Oslo bombing

PubMed Central

Solberg, Øivind; Blix, Ines; Heir, Trond

2015-01-01

Objective: In the present study we wanted to investigate the link between exposure, posttraumatic stress symptomatology, and functional impairment in the aftermath of terrorism. Method: Posttraumatic stress symptomatology and functional impairment related to the Oslo bombing 22nd of July, 2011, in directly and indirectly exposed individuals (N = 1927) were assessed together with demographics, exposure, peri-traumatic reactions, and event centrality approximately 1 year after the attack. Results: Directly and indirectly exposed individuals qualifying for posttraumatic stress disorder (PTSD) reported similar peri-traumatic reactions, event centrality, and functional impairment. However, clusters within the PTSD symptomatology were differentially associated with impairment as a function of their exposure. In the directly exposed group, all clusters within the PTSD symptomatology were associated with impairment in function, while only emotional numbing was associated with impairment within the indirectly exposed group. Conclusion: Considering that terror attacks frequently involve directly exposed individuals and a larger population of indirectly exposed individuals, this finding is of importance, especially in the design of intervention programs and the development of treatment policies. PMID:26300833

Early developmental bisphenol-A exposure sex-independently impairs spatial memory by remodeling hippocampal dendritic architecture and synaptic transmission in rats

NASA Astrophysics Data System (ADS)

Liu, Zhi-Hua; Ding, Jin-Jun; Yang, Qian-Qian; Song, Hua-Zeng; Chen, Xiang-Tao; Xu, Yi; Xiao, Gui-Ran; Wang, Hui-Li

2016-08-01

Bisphenol-A (BPA, 4, 4‧-isopropylidene-2-diphenol), a synthetic xenoestrogen that widely used in the production of polycarbonate plastics, has been reported to impair hippocampal development and function. Our previous study has shown that BPA exposure impairs Sprague-Dawley (SD) male hippocampal dendritic spine outgrowth. In this study, the sex-effect of chronic BPA exposure on spatial memory in SD male and female rats and the related synaptic mechanism were further investigated. We found that chronic BPA exposure impaired spatial memory in both SD male and female rats, suggesting a dysfunction of hippocampus without gender-specific effect. Further investigation indicated that BPA exposure causes significant impairment of dendrite and spine structure, manifested as decreased dendritic complexity, dendritic spine density and percentage of mushroom shaped spines in hippocampal CA1 and dentate gyrus (DG) neurons. Furthermore, a significant reduction in Arc expression was detected upon BPA exposure. Strikingly, BPA exposure significantly increased the mIPSC amplitude without altering the mEPSC amplitude or frequency, accompanied by increased GABAARβ2/3 on postsynaptic membrane in cultured CA1 neurons. In summary, our study indicated that Arc, together with the increased surface GABAARβ2/3, contributed to BPA induced spatial memory deficits, providing a novel molecular basis for BPA achieved brain impairment.

Functional Impairment: An Unmeasured Marker of Medicare Costs for Postacute Care of Older Adults.

PubMed

Greysen, S Ryan; Stijacic Cenzer, Irena; Boscardin, W John; Covinsky, Kenneth E

2017-09-01

To assess the effects of preadmission functional impairment on Medicare costs of postacute care up to 365 days after hospital discharge. Longitudinal cohort study. Health and Retirement Study (HRS). Nationally representative sample of 16,673 Medicare hospitalizations of 8,559 community-dwelling older adults from 2000 to 2012. The main outcome was total Medicare costs in the year after hospital discharge, assessed according to Medicare claims data. The main predictor was functional impairment (level of difficulty or dependence in activities of daily living (ADLs)), determined from HRS interview preceding hospitalization. Multivariable linear regression was performed, adjusted for age, race, sex, income, net worth, and comorbidities, with clustering at the individual level to characterize the association between functional impairment and costs of postacute care. Unadjusted mean Medicare costs for 1 year after discharge increased with severity of impairment in a dose-response fashion (P < .001 for trend); 68% had no functional impairment ($25,931), 17% had difficulty with one ADL ($32,501), 7% had dependency in one ADL ($39,928), and 8% had dependency in two or more ADLs ($45,895). The most severely impaired participants cost 77% more than those with no impairment; adjusted analyses showed attenuated effect size (33% more) but no change in trend. Considering costs attributable to comorbidities, only three conditions were more expensive than severe functional impairment (lymphoma, metastatic cancer, paralysis). Functional impairment is associated with greater Medicare costs for postacute care and may be an unmeasured but important marker of long-term costs that cuts across conditions. © 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.

Ten-Year Review of Rating Scales, VII: Scales Assessing Functional Impairment

ERIC Educational Resources Information Center

Winters, Nancy C.; Collett, Brent R.; Myers, Kathleen M.

2005-01-01

Objective: This is the seventh in a series of 10-year reviews of rating scales. Here the authors present scales measuring functional impairment, a sequela of mental illness. The measurement of functional impairment has assumed importance with the recognition that symptom resolution does not necessarily correlate with functional improvement.…

Elevated 20-HETE impairs coronary collateral growth in metabolic syndrome via endothelial dysfunction.

PubMed

Joseph, Gregory; Soler, Amanda; Hutcheson, Rebecca; Hunter, Ian; Bradford, Chastity; Hutcheson, Brenda; Gotlinger, Katherine H; Jiang, Houli; Falck, John R; Proctor, Spencer; Schwartzman, Michal Laniado; Rocic, Petra

2017-03-01

Coronary collateral growth (CCG) is impaired in metabolic syndrome (MetS). microRNA-145 (miR-145-Adv) delivery to our rat model of MetS (JCR) completely restored and neutrophil depletion significantly improved CCG. We determined whether low endogenous levels of miR-145 in MetS allowed for elevated production of 20-hydroxyeicosatetraenoic acid (20-HETE), which, in turn, resulted in excessive neutrophil accumulation and endothelial dysfunction leading to impaired CCG. Rats underwent 0-9 days of repetitive ischemia (RI). RI-induced cardiac CYP4F (neutrophil-specific 20-HETE synthase) expression and 20-HETE levels were increased (4-fold) in JCR vs. normal rats. miR-145-Adv and 20-HETE antagonists abolished and neutrophil depletion (blocking antibodies) reduced (~60%) RI-induced increases in CYP4F expression and 20-HETE production in JCR rats. Impaired CCG in JCR rats (collateral-dependent blood flow using microspheres) was completely restored by 20-HETE antagonists [collateral-dependent zone (CZ)/normal zone (NZ) flow ratio was 0.76 ± 0.07 in JCR + 20-SOLA, 0.84 ± 0.05 in JCR + 20-HEDGE vs. 0.11 ± 0.02 in JCR vs. 0.84 ± 0.03 in normal rats]. In JCR rats, elevated 20-HETE was associated with excessive expression of endothelial adhesion molecules and neutrophil infiltration, which were reversed by miR-145-Adv. Endothelium-dependent vasodilation of coronary arteries, endothelial nitric oxide synthase (eNOS) Ser1179 phosphorylation, eNOS-dependent NO ·- production and endothelial cell survival were compromised in JCR rats. These parameters of endothelial dysfunction were completely reversed by 20-HETE antagonism or miR-145-Adv delivery, whereas neutrophil depletion resulted in partial reversal (~70%). We conclude that low miR-145 in MetS allows for increased 20-HETE, mainly from neutrophils, which compromises endothelial cell survival and function leading to impaired CCG. 20-HETE antagonists could provide viable therapy for restoration of CCG in MetS. NEW & NOTEWORTHY Elevated 20-hydroxyeicosatetraenoic acid (20-HETE) impairs coronary collateral growth (CCG) in metabolic syndrome by eliciting endothelial dysfunction and apoptosis via excessive neutrophil infiltration. 20-HETE antagonists completely restore coronary collateral growth in metabolic syndrome. microRNA-145 (miR-145) is an upstream regulator of 20-HETE production in metabolic syndrome; low expression of miR-145 in metabolic syndrome promotes elevated production of 20-HETE. Copyright © 2017 the American Physiological Society.

Dissociative symptoms mediate the relation between PTSD symptoms and functional impairment in a sample of military members, veterans, and first responders with PTSD.

PubMed

Boyd, Jenna E; Protopopescu, Alina; O'Connor, Charlene; Neufeld, Richard W J; Jetly, Rakesh; Hood, Heather K; Lanius, Ruth A; McKinnon, Margaret C

2018-01-01

Background : Posttraumatic Stress Disorder (PTSD) is associated with significant functional impairment in important areas, including interpersonal relationships and occupational or educational roles. Preliminary evidence suggests that the dissociative subtype of PTSD (PTSD+DS), characterized by marked symptoms of depersonalization and derealization, is associated with increased functional impairment and disease severity, including among military members and veterans diagnosed with PTSD. Similarly, first responders (e.g. police, fire, paramedics) have also been found to experience dissociative symptoms. Despite these findings, little work has investigated whether dissociative symptoms are related to heightened functional impairment among these populations. Objective : We examined the relation between functional impairment and symptom level variables, including dissociative symptoms of depersonalization and derealization among military members, veterans, and first responders with probable PTSD. We further investigated the hypothesis that dissociative symptoms mediate the relation between PTSD symptomatology and functional impairment. Method : Eighty-one medical charts of inpatients at a residential PTSD treatment programme were accessed via retrospective review. Sixty-two were included in the present analyses. Comparison of means on symptom measures between first responders and military members/veterans were conducted, followed by correlational and mediation analyses. Results : Compared with first responders, military members and veterans showed higher levels of derealization, functional impairment, alexithymia, anxiety, and depression. Within the total sample, dissociative symptoms emerged as the strongest correlate of functional impairment and, among the dissociative symptom clusters, derealization symptoms demonstrated the strongest relation with impairment. Mediation analyses revealed that total dissociative symptoms and derealization symptoms significantly mediated the relation between PTSD symptoms and functional impairment. Conclusions : These findings highlight the importance of assessing and treating dissociative symptoms, consistent with the dissociative subtype of PTSD, among military members, veterans, and first responders with PTSD. Successful recovery on a functional and symptomatic level may necessitate treatment of dissociative symptoms, particularly derealization.

Dissociative symptoms mediate the relation between PTSD symptoms and functional impairment in a sample of military members, veterans, and first responders with PTSD

PubMed Central

Protopopescu, Alina; O’Connor, Charlene; Neufeld, Richard W. J.; Jetly, Rakesh; Hood, Heather K.; Lanius, Ruth A.; McKinnon, Margaret C.

2018-01-01

ABSTRACT Background: Posttraumatic Stress Disorder (PTSD) is associated with significant functional impairment in important areas, including interpersonal relationships and occupational or educational roles. Preliminary evidence suggests that the dissociative subtype of PTSD (PTSD+DS), characterized by marked symptoms of depersonalization and derealization, is associated with increased functional impairment and disease severity, including among military members and veterans diagnosed with PTSD. Similarly, first responders (e.g. police, fire, paramedics) have also been found to experience dissociative symptoms. Despite these findings, little work has investigated whether dissociative symptoms are related to heightened functional impairment among these populations. Objective: We examined the relation between functional impairment and symptom level variables, including dissociative symptoms of depersonalization and derealization among military members, veterans, and first responders with probable PTSD. We further investigated the hypothesis that dissociative symptoms mediate the relation between PTSD symptomatology and functional impairment. Method: Eighty-one medical charts of inpatients at a residential PTSD treatment programme were accessed via retrospective review. Sixty-two were included in the present analyses. Comparison of means on symptom measures between first responders and military members/veterans were conducted, followed by correlational and mediation analyses. Results: Compared with first responders, military members and veterans showed higher levels of derealization, functional impairment, alexithymia, anxiety, and depression. Within the total sample, dissociative symptoms emerged as the strongest correlate of functional impairment and, among the dissociative symptom clusters, derealization symptoms demonstrated the strongest relation with impairment. Mediation analyses revealed that total dissociative symptoms and derealization symptoms significantly mediated the relation between PTSD symptoms and functional impairment. Conclusions: These findings highlight the importance of assessing and treating dissociative symptoms, consistent with the dissociative subtype of PTSD, among military members, veterans, and first responders with PTSD. Successful recovery on a functional and symptomatic level may necessitate treatment of dissociative symptoms, particularly derealization. PMID:29805778

Hemozoin Differentially Regulates Proinflammatory Cytokine Production in Human Immunodeficiency Virus-Seropositive and -Seronegative Women with Placental Malaria

PubMed Central

Moore, Julie M.; Chaisavaneeyakorn, Sujittra; Perkins, Douglas J.; Othoro, Caroline; Otieno, Juliana; Nahlen, Bernard L.; Shi, Ya Ping; Udhayakumar, Venkatachalam

2004-01-01

Pregnant women are at an increased risk for malarial infection. Plasmodium falciparum accumulates in the placenta and is associated with dysregulated immune function and poor birth outcomes. Malarial pigment (hemozoin) also accumulates in the placenta and may modulate local immune function. In this study, the impact of hemozoin on cytokine production by intervillous blood mononuclear cells from malaria-infected placentas was investigated. There was a dose-dependent, suppressive effect of hemozoin on production of gamma interferon (IFN-γ), with less of an effect on tumor necrosis factor alpha (TNF-α) and interleukin-10, in human immunodeficiency virus-seronegative (HIV−) women. In contrast, IFN-γ and TNF-α production tended to increase in HIV-seropositive women with increasing hemozoin levels. Production patterns of cytokines, especially IFN-γ in HIV− women, followed different trends as a function of parasite density and hemozoin level. The findings suggest that the influences of hemozoin accumulation and high-density parasitemia on placental cytokine production are not equivalent and may involve different mechanisms, all of which may operate differently in the context of HIV infection. Cytokine production dysregulated by accumulation of hemozoin or high-density parasitemia may induce pathology and impair protective immunity in HIV-infected and -uninfected women. PMID:15557625

Effects of Mycotoxins on Mucosal Microbial Infection and Related Pathogenesis

PubMed Central

Park, Seong-Hwan; Kim, Dongwook; Kim, Juil; Moon, Yuseok

2015-01-01

Mycotoxins are fungal secondary metabolites detected in many agricultural commodities and water-damaged indoor environments. Susceptibility to mucosal infectious diseases is closely associated with immune dysfunction caused by mycotoxin exposure in humans and other animals. Many mycotoxins suppress immune function by decreasing the proliferation of activated lymphocytes, impairing phagocytic function of macrophages, and suppressing cytokine production, but some induce hypersensitive responses in different dose regimes. The present review describes various mycotoxin responses to infectious pathogens that trigger mucosa-associated diseases in the gastrointestinal and respiratory tracts of humans and other animals. In particular, it focuses on the effects of mycotoxin exposure on invasion, pathogen clearance, the production of cytokines and immunoglobulins, and the prognostic implications of interactions between infectious pathogens and mycotoxin exposure. PMID:26529017

South Africa: the new world of disability.

PubMed

Coetzer, Pieter

2008-01-01

Over the past 10 years, unique business imperatives in South Africa have led to innovative risk product design, some of which are still unfamiliar to the rest of the world. The main drivers are: the unique mix of first- and third-world societies in our country, and an energetic marketing force operating in an already highly saturated insurance market. As a result, new product design has become one of the most effective ways to grow new business volumes in this competitive environment. This article reviews some of the unique products available and their advantages, target markets and disadvantages. The products that are discussed include lump sum total and permanent disability benefits, extended critical illness products, cover for impairment of function as well as risk products for people living with HIV/AIDS.

Hepatitis B virus surface antigen impairs myeloid dendritic cell function: a possible immune escape mechanism of hepatitis B virus

PubMed Central

Op den Brouw, Marjoleine L; Binda, Rekha S; van Roosmalen, Mark H; Protzer, Ulrike; Janssen, Harry L A; van der Molen, Renate G; Woltman, Andrea M

2009-01-01

Chronic hepatitis B virus (HBV) infection is the result of an inadequate immune response towards the virus. Myeloid dendritic cells (mDC) of patients with chronic HBV are impaired in their maturation and function, resulting in more tolerogenic rather than immunogenic responses, which may contribute to viral persistence. The mechanism responsible for altered mDC function remains unclear. The HBV-infected patients display large amounts of HBV particles and viral proteins in their circulation, especially the surface antigen HBsAg, which allows multiple interactions between the virus, its viral proteins and DC. To assess whether HBV directly influences mDC function, the effects of HBV and HBsAg on human mDC maturation and function were investigated in vitro. As already described for internalization of HBV by DC, the present study shows that peripheral blood-derived mDC of healthy controls also actively take up HBsAg in a time-dependent manner. Cytokine-induced maturation in the presence of HBV or HBsAg resulted in a significantly more tolerogenic mDC phenotype as demonstrated by a diminished up-regulation of costimulatory molecules and a decreased T-cell stimulatory capacity, as assessed by T-cell proliferation and interferon-γ production. In addition, the presence of HBV significantly reduced interleukin-12 production by mDC. These results show that both HBV particles and purified HBsAg have an immune modulatory capacity and may directly contribute to the dysfunction of mDC in patients with chronic HBV. The direct immune regulatory effect of HBV and circulating HBsAg particles on the function of DC can be considered as part of the mechanism by which HBV escapes immunity. PMID:18624732

The receptor for advanced glycation end products impairs collateral formation in both diabetic and non-diabetic mice.

PubMed

Hansen, Laura M; Gupta, Divya; Joseph, Giji; Weiss, Daiana; Taylor, W Robert

2017-01-01

Diabetics often have poor perfusion in their limbs as a result of peripheral artery disease and an impaired ability to generate collateral vessels. The receptor for advanced glycation end products (RAGE) is one protein that is thought to play a detrimental role in collateral development in diabetics due to increased levels of advanced glycation end products (AGE), one of its ligands, in diabetes. Thus, the aim of this study was to investigate the role of RAGE in both diabetic and non-diabetic settings in a model of collateral formation in mice. Streptozotocin was used to induce diabetes in both wild type and RAGE knockout mice. Increased levels of the AGE, N ɛ -(carboxymethyl) lysine (CML), were confirmed via an ELISA. A hindlimb ischemia model, in which the femoral artery is ligated, was used to drive collateral growth and reperfusion was assessed using laser Doppler perfusion imaging and histological analysis of vessels in the muscle. Both of these measurements showed impaired collateral growth in diabetic compared with wild-type mice as well as improved collateral growth in both diabetic and non-diabetic RAGE knockout mice when compared their wild-type counterparts. Distance on a freely accessed running wheel, used as a measure of perfusion recovery, showed that wild-type diabetic mice had functionally impaired recovery compared with their wild-type counterparts. Immunohistochemistry and immunoblotting showed that HMGB-1 (high-mobility group box 1), another RAGE ligand, was increased in the ischemic leg compared with the non-ischemic leg in all mice. This increase in HMGB-1 may explain improvement in animals lacking RAGE and its subsequent signaling. In conclusion, this study shows that RAGE impairs collateral growth in a diabetic setting and also in a non-diabetic setting. This demonstrates the importance of RAGE and alternate RAGE ligands in the setting of collateral vessel growth.

Visual Search Performance in Patients with Vision Impairment: A Systematic Review.

PubMed

Senger, Cassia; Margarido, Maria Rita Rodrigues Alves; De Moraes, Carlos Gustavo; De Fendi, Ligia Issa; Messias, André; Paula, Jayter Silva

2017-11-01

Patients with visual impairment are constantly facing challenges to achieve an independent and productive life, which depends upon both a good visual discrimination and search capacities. Given that visual search is a critical skill for several daily tasks and could be used as an index of the overall visual function, we investigated the relationship between vision impairment and visual search performance. A comprehensive search was undertaken using electronic PubMed, EMBASE, LILACS, and Cochrane databases from January 1980 to December 2016, applying the following terms: "visual search", "visual search performance", "visual impairment", "visual exploration", "visual field", "hemianopia", "search time", "vision lost", "visual loss", and "low vision". Two hundred seventy six studies from 12,059 electronic database files were selected, and 40 of them were included in this review. Studies included participants of all ages, both sexes, and the sample sizes ranged from 5 to 199 participants. Visual impairment was associated with worse visual search performance in several ophthalmologic conditions, which were either artificially induced, or related to specific eye and neurological diseases. This systematic review details all the described circumstances interfering with visual search tasks, highlights the need for developing technical standards, and outlines patterns for diagnosis and therapy using visual search capabilities.

Neuro-mechanics of muscle coordination during recumbent pedaling in post-acute stroke patients.

PubMed

De Marchis, C; Ambrosini, E; Schmid, M; Monticone, M; Pedrocchi, A; Ferrigno, G; D'Alessio, T; Conforto, S; Ferrante, S

2015-01-01

Motor impairment after stroke has been hypothesized to be related, among others, to impairments in the modular control of movement. In this study we analyzed muscle coordination and pedal forces during a recumbent pedaling exercise from a sample of post-acute stroke patients (n=5) and a population of age-matched healthy individuals (n=4). Healthy subjects and the less impaired patients showed a shared modular organization of pedaling based on 4 similar muscle synergies. The most impaired patient, characterized by a Motricity Index of 52/100, showed a reduced complexity (only 2 muscle synergies for the affected side). Differences between healthy subjects and post-stroke patients in the execution of the task were identified in terms of unbalance in mechanical work production, which well corresponded to the level of impairment. This pedaling unbalance could be traced back to different activation strategies of the 4 identified modules. Investigation on a more representative sample will provide a full characterization of the neuro-mechanics of pedaling after stroke, helping our understandings of the disruption of motor coordination at central level after stroke and of the most effective solutions for functional recovery.

A new approach for evaluating flexible working hours.

PubMed

Giebel, Ole; Janssen, Daniela; Schomann, Carsten; Nachreiner, Friedhelm

2004-01-01

Recent studies on flexible working hours show at least some of these working time arrangements seem to be associated with impairing effects of health and well-being. According to available evidence, variability of working hours seems to play an important role. The question, however, is how this variability can be assessed and used to explain or predict impairments. Based on earlier methods used to assess shift-work effects, a time series analysis approach was applied to the matter of flexible working hours. Data on the working hours of 4 week's length of 137 respondents derived from a survey on flexible work hours involving 15 companies of different production and service sectors in Germany were converted to time series and analyzed by spectral analysis. A cluster analysis of the resulting power spectra yielded 5 clusters of flexible work hours. Analyzing these clusters for differences in reported impairments showed that workers who showed suppression of circadian and weekly rhythms experienced severest impairments, especially in circadian controlled functions like sleep and digestion. The results thus indicate that analyzing the periodicity of flexible working hours seems to be a promising approach for predicting impairments which should be investigated further in the future.

Visual impairment at baseline is associated with future poor physical functioning among middle-aged women: The Study of Women's Health Across the Nation, Michigan Site.

PubMed

Chandrasekaran, Navasuja; Harlow, Sioban; Moroi, Sayoko; Musch, David; Peng, Qing; Karvonen-Gutierrez, Carrie

2017-02-01

Emerging evidence suggests that the prevalence rates of poor functioning and of disability are increasing among middle-aged individuals. Visual impairment is associated with poor functioning among older adults but little is known about the impact of vision on functioning during midlife. The objective of this study was to assess the impact of visual impairment on future physical functioning among middle-aged women. In this longitudinal study, the sample consisted of 483 women aged 42 to 56 years, from the Michigan site of the Study of Women's Health Across the Nation. At baseline, distance and near vision were measured using a Titmus vision screener. Visual impairment was defined as visual acuity worse than 20/40. Physical functioning was measured up to 10 years later using performance-based measures, including a 40-foot timed walk, timed stair climb and forward reach. Women with impaired distance vision at baseline had 2.81 centimeters less forward reach distance (95% confidence interval (CI): -4.19, -1.42) and 4.26s longer stair climb time (95% CI: 2.73, 5.79) at follow-up than women without impaired distance vision. Women with impaired near vision also had less forward reach distance (2.26 centimeters, 95% CI: -3.30, -1.21) than those without impaired near vision. Among middle-aged women, visual impairment is a marker of poor physical functioning. Routine eye testing and vision correction may help improve physical functioning among midlife individuals. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Visual Impairment at Baseline is Associated with Future Poor Physical Functioning Among Middle-Aged Women: The Study of Women's Health Across the Nation, Michigan site

PubMed Central

Chandrasekaran, Navasuja; Harlow, Sioban; Moroi, Sayoko; Musch, David; Peng, Qing; Karvonen-Gutierrez, Carrie

2016-01-01

Objectives Emerging evidence suggests that the prevalence rates of poor functioning and of disability are increasing among middle-aged individuals. Visual impairment is associated with poor functioning among older adults but little is known about the impact of vision on functioning during midlife. The objective of this study was to assess the impact of visual impairment on future physical functioning among middle-aged women. Study design In this longitudinal study, the sample consisted of 483 women aged 42 to 56 years, from the Michigan site of the Study of Women's Health Across the Nation. Main Outcome Measures At baseline, distance and near vision were measured using a Titmus vision screener. Visual impairment was defined as visual acuity worse than 20/40. Physical functioning was measured up to 10 years later using performance-based measures, including a 40-foot timed walk, timed stair climb and forward reach. Results Women with impaired distance vision at baseline had 2.81 centimeters less forward reach distance (95% confidence interval (CI): −4.19,−1.42) and 4.26 seconds longer stair climb time (95% CI: 2.73, 5.79) at follow-up than women without impaired distance vision. Women with impaired near vision also had less forward reach distance (2.26 centimeters, 95% CI: −3.30,−1.21) than those without impaired near vision. Conclusion Among middle-aged women, visual impairment is a marker of poor physical functioning. Routine eye testing and vision correction may help improve physical functioning among midlife individuals. PMID:28041592

Iron Balance and the Role of Hepcidin in Chronic Kidney Disease

PubMed Central

Ganz, Tomas; Nemeth, Elizabeta

2016-01-01

Summary The hepatic iron-regulatory hormone hepcidin and its receptor, the cellular iron exporter ferroportin, constitute a feedback-regulated mechanism that maintains adequate plasma concentrations of iron-transferrin for erythropoiesis and other functions, ensures sufficient iron stores, and avoids iron toxicity and iron-dependent microbial pathogenesis. In chronic kidney disease, inflammation and impaired renal clearance increase plasma hepcidin, inhibiting duodenal iron absorption and sequestering iron in macrophages. These effects of hepcidin can cause systemic iron deficiency, decreased availability of iron for erythropoiesis, and resistance to endogenous and exogenous erythropoietin. Together with impaired renal production of erythropoietin, hepcidin-mediated iron restriction contributes to anemia of chronic kidney disease. PMID:27236128

Functional impairment and hospital readmission in Medicare seniors.

PubMed

Greysen, S Ryan; Stijacic Cenzer, Irena; Auerbach, Andrew D; Covinsky, Kenneth E

2015-04-01

Medicare currently penalizes hospitals for high readmission rates for seniors but does not account for common age-related syndromes, such as functional impairment. To assess the effects of functional impairment on Medicare hospital readmissions given the high prevalence of functional impairments in community-dwelling seniors. We created a nationally representative cohort of 7854 community-dwelling seniors in the Health and Retirement Study, with 22,289 Medicare hospitalizations from January 1, 2000, through December 31, 2010. Outcome was 30-day readmission assessed by Medicare claims. The main predictor was functional impairment determined from the Health and Retirement Study interview preceding hospitalization, stratified into the following 5 levels: no functional impairments, difficulty with 1 or more instrumental activities of daily living, difficulty with 1 or more activities of daily living (ADL), dependency (need for help) in 1 to 2 ADLs, and dependency in 3 or more ADLs. Adjustment variables included age, race/ethnicity, sex, annual income, net worth, comorbid conditions (Elixhauser score from Medicare claims), and prior admission. We performed multivariable logistic regression to adjust for clustering at the patient level to characterize the association of functional impairments and readmission. Patients had a mean (SD) age of 78.5 (7.7) years (range, 65-105 years); 58.4% were female, 84.9% were white, 89.6% reported 3 or more comorbidities, and 86.0% had 1 or more hospitalizations in the previous year. Overall, 48.3% had some level of functional impairment before admission, and 15.5% of hospitalizations were followed by readmission within 30 days. We found a progressive increase in the adjusted risk of readmission as the degree of functional impairment increased: 13.5% with no functional impairment, 14.3% with difficulty with 1 or more instrumental activities of daily living (odds ratio [OR], 1.06; 95% CI, 0.94-1.20), 14.4% with difficulty with 1 or more ADL (OR, 1.08; 95% CI, 0.96-1.21), 16.5% with dependency in 1 to 2 ADLs (OR, 1.26; 95% CI, 1.11-1.44), and 18.2% with dependency in 3 or more ADLs (OR, 1.42; 95% CI, 1.20-1.69). Subanalysis restricted to patients admitted with conditions targeted by Medicare (ie, heart failure, myocardial infarction, and pneumonia) revealed a parallel trend with larger effects for the most impaired (16.9% readmission rate for no impairment vs 25.7% for dependency in 3 or more ADLs [OR, 1.70; 95% CI, 1.04-2.78]). Functional impairment is associated with increased risk of 30-day all-cause hospital readmission in Medicare seniors, especially those admitted for heart failure, myocardial infarction, or pneumonia. Functional impairment may be an important but underaddressed factor in preventing readmissions for Medicare seniors.

Trainable Mentally Impaired/Severely Multiply Impaired/Autistic Impaired/Severely Mentally Impaired. Product Evaluation Report 1989-1990.

ERIC Educational Resources Information Center

Claus, Richard N.; And Others

The evaluation report describes special education services provided to trainable mentally impaired (TMI), autistic impaired (AI), severely multiply impaired (SXI), and severely mentally impaired (SMI) students at and through the Melvin G. Millet Learning Center (Bridgeport, Michigan). The eight program components are described individually and…

Cantonese tone production performance of mainstream school children with hearing impairment.

PubMed

Cheung, Karen K L; Lau, Ada H Y; Lam, Joffee H S; Lee, Kathy Y S

2014-12-01

This study investigated the Cantonese tone production ability of children with hearing impairment studying in mainstream schools. The participants were 87 Cantonese-speaking children with mild-to-profound degrees of hearing loss aged 5.92-13.58 in Hong Kong. Most of the children were fitted with hearing aids (n = 65); 17 of them had profound hearing impairment, one who had severe hearing loss had cochlear implantation, and four who had mild hearing loss were without any hearing device. The Hong Kong Cantonese Articulation Test was administered, and the tones produced were rated by two of the authors and a speech-language pathologist. Group effects of tones, hearing loss level, and also an interaction of the two were found to be significant. The children with profound hearing impairment performed significantly worse than most of the other children. Tone 1 was produced most accurately, whereas tone 6 productions were the poorest. No relationship was found between the number of years of mainstreaming and tone production ability. Tone production error pattern revealed that confusion patterns in tone perception coincided with those in production. Tones having a similar fundamental frequency (F0) at the onset also posed difficulty in tone production for children with hearing impairment.

Derangement of calcium metabolism in diabetes mellitus: negative outcome from the synergy between impaired bone turnover and intestinal calcium absorption.

PubMed

Wongdee, Kannikar; Krishnamra, Nateetip; Charoenphandhu, Narattaphol

2017-01-01

Both types 1 and 2 diabetes mellitus (T1DM and T2DM) are associated with profound deterioration of calcium and bone metabolism, partly from impaired intestinal calcium absorption, leading to a reduction in calcium uptake into the body. T1DM is associated with low bone mineral density (BMD) and osteoporosis, whereas the skeletal changes in T2DM are variable, ranging from normal to increased and to decreased BMD. However, both types of DM eventually compromise bone quality through production of advanced glycation end products and misalignment of collagen fibrils (so-called matrix failure), thereby culminating in a reduction of bone strength. The underlying cellular mechanisms (cellular failure) are related to suppression of osteoblast-induced bone formation and bone calcium accretion, as well as to enhancement of osteoclast-induced bone resorption. Several other T2DM-related pathophysiological changes, e.g., osteoblast insulin resistance, impaired productions of osteogenic growth factors (particularly insulin-like growth factor 1 and bone morphogenetic proteins), overproduction of pro-inflammatory cytokines, hyperglycemia, and dyslipidemia, also aggravate diabetic osteopathy. In the kidney, DM and the resultant hyperglycemia lead to calciuresis and hypercalciuria in both humans and rodents. Furthermore, DM causes deranged functions of endocrine factors related to mineral metabolism, e.g., parathyroid hormone, 1,25-dihydroxyvitamin D 3 , and fibroblast growth factor-23. Despite the wealth of information regarding impaired bone remodeling in DM, the long-lasting effects of DM on calcium metabolism in young growing individuals, pregnant women, and neonates born to women with gestational DM have received scant attention, and their underlying mechanisms are almost unknown and worth exploring.

Phonological and Motor Errors in Individuals with Acquired Sound Production Impairment

ERIC Educational Resources Information Center

Buchwald, Adam; Miozzo, Michele

2012-01-01

Purpose: This study aimed to compare sound production errors arising due to phonological processing impairment with errors arising due to motor speech impairment. Method: Two speakers with similar clinical profiles who produced similar consonant cluster simplification errors were examined using a repetition task. We compared both overall accuracy…

Decreased Cerebellar-Orbitofrontal Connectivity Correlates with Stuttering Severity: Whole-Brain Functional and Structural Connectivity Associations with Persistent Developmental Stuttering

PubMed Central

Sitek, Kevin R.; Cai, Shanqing; Beal, Deryk S.; Perkell, Joseph S.; Guenther, Frank H.; Ghosh, Satrajit S.

2016-01-01

Persistent developmental stuttering is characterized by speech production disfluency and affects 1% of adults. The degree of impairment varies widely across individuals and the neural mechanisms underlying the disorder and this variability remain poorly understood. Here we elucidate compensatory mechanisms related to this variability in impairment using whole-brain functional and white matter connectivity analyses in persistent developmental stuttering. We found that people who stutter had stronger functional connectivity between cerebellum and thalamus than people with fluent speech, while stutterers with the least severe symptoms had greater functional connectivity between left cerebellum and left orbitofrontal cortex (OFC). Additionally, people who stutter had decreased functional and white matter connectivity among the perisylvian auditory, motor, and speech planning regions compared to typical speakers, but greater functional connectivity between the right basal ganglia and bilateral temporal auditory regions. Structurally, disfluency ratings were negatively correlated with white matter connections to left perisylvian regions and to the brain stem. Overall, we found increased connectivity among subcortical and reward network structures in people who stutter compared to controls. These connections were negatively correlated with stuttering severity, suggesting the involvement of cerebellum and OFC may underlie successful compensatory mechanisms by more fluent stutterers. PMID:27199712

[A new strategy for preventive and functional therapeutic methods for dementia--approach using natural products].

PubMed

Ohizumi, Yasushi

2015-01-01

Alzheimer's disease (AD) has become a serious social problem in Japan. However, effective preventive and fundamental therapeutic methods for AD have not yet been developed. Using a new strategy in the course of our survey of numerous natural resouces having neurotrophic activity, we isolated a variety of active constituents and proved their pharmacological properties. As a result, we successfully found nobiletin, a compound with anti-dementia activity that comes from citrus peels. Also, we have demonstrated that nobiletin ameliorates cognitive impairment in several dementia model animals such as chronically amyloid β(Aβ) infused rats, amyloid precursor protein transgenic (APPTg) mice, olfactory-bulbectomized (OBX) mice, N-methyl-D-aspartate (NMDA) receptor antagonist (MK-801)-treated mice, senescence-accelated mice and bilaterial common carotid arteries occlusion mice. In a APPTg mouse of AD, nobiletin greatly improved memory impairment, and this was accompanied by a marked decrease in Aβ deposition. Also, in OBX mice memory impairment was markedly recoverd by nobiletin, accompanied by improvement of a decrease indensity of cholinergic neurons. Interestingly, nobiletin improves age-related congnitive impairment and decreased hyperphosphorylation of tau as well as oxidative stress in senescence-accelerated mice. In cultured cells, nobiletin reversed the Aβ-induced inhibition of glutamate-induced increases in cAMP response element binding protein (CREB) phosphorylation and modulated gen expression of thioredoxin-interacting protein and NMDA resceptor subunits. These results suggest that nobiletin prevents memory impairment and exhibits a protecting action against neurodgeneration in AD model animals. Nobiletin and citrus peels thus have potential as functional foods for prevention of dementia.

COGNITIVE-HD study: protocol of an observational study of neurocognitive functioning and association with clinical outcomes in adults with end-stage kidney disease treated with haemodialysis.

PubMed

Palmer, Suetonia C; Ruospo, Marinella; Barulli, Maria Rosaria; Iurillo, Annalisa; Saglimbene, Valeria; Natale, Patrizia; Gargano, Letizia; Murgo, Angelo M; Loy, Clement; van Zwieten, Anita; Wong, Germaine; Tortelli, Rosanna; Craig, Jonathan C; Johnson, David W; Tonelli, Marcello; Hegbrant, Jörgen; Wollheim, Charlotta; Logroscino, Giancarlo; Strippoli, G F M

2015-12-09

The prevalence of cognitive impairment may be increased in adults with end-stage kidney disease compared with the general population. However, the specific patterns of cognitive impairment and association of cognitive dysfunction with activities of daily living and clinical outcomes (including withdrawal from treatment) among haemodialysis patients remain incompletely understood. The COGNITIVE impairment in adults with end-stage kidney disease treated with HemoDialysis (COGNITIVE-HD) study aims to characterise the age-adjusted and education-adjusted patterns of cognitive impairment (using comprehensive testing for executive function, perceptual-motor function, language, learning and memory, and complex attention) in patients on haemodialysis and association with clinical outcomes. A prospective, longitudinal, cohort study of 750 adults with end-stage kidney disease treated with long-term haemodialysis has been recruited within haemodialysis centres in Italy (July 2013 to April 2014). Testing for neurocognitive function was carried out by a trained psychologist at baseline to assess cognitive functioning. The primary study factor is cognitive impairment and secondary study factors will be specific domains of cognitive function. The primary outcome will be total mortality. Secondary outcomes will be cause-specific mortality, major cardiovascular events, fatal and non-fatal myocardial infarction and stroke, institutionalisation, and withdrawal from treatment at 12 months. This protocol was approved before study conduct by the following responsible ethics committees: Catania (approval reference 186/BE; 26/09/2013), Agrigento (protocol numbers 61-62; 28/6/2013), USL Roma C (CE 39217; 24/6/2013), USL Roma F (protocol number 0041708; 23/7/2013), USL Latina (protocol number 20090/A001/2011; 12/7/2013), Trapani (protocol number 3413; 16/7/2013) and Brindisi (protocol number 40259; 6/6/2013). All participants have provided written and informed consent and can withdraw from the study at any time. The findings of the study will be disseminated through peer-reviewed journals and national and international conference presentations and to the participants through communication within the dialysis network in which this study is conducted. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

[Evaluation of mental and communication functions in mapuche and non mapuche elderly subjects in rural communities in Southern Chile].

PubMed

Mella, Rebeca; Alvear, María; Carrillo, Berta; Caire, Victor

2003-11-01

The main predictors of functional impairment in the elderly are alterations in mental or communication functions. To study mental and communication functions in rural elderly subjects of Mapuche and non Mapuche origin. Elderly subjects coming from a rural Mapuche community and a non Mapuche community were studied. Subjects were interviewed at their homes. The communication and mental function assessments of the Functional Autonomy Measurement System were applied. Fifty one Mapuche and 49 non Mapuche subjects with a mean age of 71 +/- 7 and 74 +/- 8 years respectively, were studied. Fifty four percent were female and 31% were illiterate. Twenty six percent had impairment in mental functions. The item with the highest difficulty was memory. The visual function was the most severely impaired among communication items. Mapuche elderly subjects had significantly higher degrees of impairment in mental and communication functions. There is a higher degree of mental and communication impairment among rural Mapuche elderly subjects than in their non Mapuche counterparts.

Testicular gonadotropin-releasing hormone II receptor (GnRHR-II) knockdown constitutively impairs diurnal testosterone secretion in the boar

USDA-ARS?s Scientific Manuscript database

The second mammalian GnRH isoform (GnRH-II) and its specific receptor (GnRHR-II) are highly expressed in the testis, suggesting an important role in testis biology. Gene coding errors prevent the production of GnRH-II and GnRHR-II in many species, but both genes are functional in swine. We have demo...

Salivary function impairment in type 2 Diabetes patients associated with concentration and genetic polymorphisms of chromogranin A.

PubMed

Kogawa, Evelyn Mikaela; Grisi, Daniela Corrêa; Falcão, Denise Pinheiro; Amorim, Ingrid Aquino; Rezende, Taia Maria Berto; da Silva, Izabel Cristina Rodrigues; Silva, Osmar Nascimento; Franco, Octávio Luiz; de Amorim, Rivadávio Fernandes Batista

2016-11-01

The purpose of this study was to evaluate the effect of type 2 diabetes mellitus (T2DM) on salivary function impairments according to glycemic control status and subsequently compare the concentration of chromogranin A (CHGA) with its genetic profile. Thirty-six patients with controlled T2DM, 36 with poorly controlled T2DM, and 38 nondiabetic subjects underwent salivary flow rate measurements by means of unstimulated labial (ULS), unstimulated whole (UWS), and stimulated whole saliva (SWS) collections. CHGA concentrations were determined in saliva and plasma with ELISA, and two CHGA polymorphisms (T-415C and Glu264Asp) were analyzed by polymerase chain reaction-restriction fragment length polymorphism. T2DM patients presented significantly lower ULS and UWS flow rates regardless of glycemic control status compared to controls (P = 0.002 and P = 0.027, respectively). The SWS flow rate in the poorly controlled T2DM was the lowest among the groups (P = 0.026). Significantly higher plasma and salivary CHGA levels were found in T2DM groups (P = 0.019 and P < 0.001, respectively). CHGA gene variants (T-415C and Glu264Asp) revealed significant differences between diabetics and control subjects when associated with lower salivary flow and higher salivary CHGA production (P < 0.05). T2DM causes abnormalities in the function of salivary glands. However, poorly controlled T2DM has the most influence on SWS flow rates. Our findings indicate an association between plasma and salivary CHGA levels and T2DM patients. Furthermore, the results suggest that CGHA polymorphisms might be associated with salivary gland hypofunction and higher salivary CHGA production in T2DM patients. Nevertheless, further epidemiological studies are required to elucidate this clinical implication. Salivary impairments and high levels of CHGA are associated with T2DM patients. In addition, CGHA polymorphisms might be associated with salivary gland hypofunction and higher salivary CHGA production in T2DM patients. This could be a significant insight to establish a role for salivary CHGA as a potential clinical biomarker to T2DM.

Development of the NBT assay as a marker of sperm oxidative stress.

PubMed

Tunc, Ozlem; Thompson, Jeremy; Tremellen, Kelton

2010-02-01

Oxidative stress is a well-established cause of male infertility, with reactive oxygen species (ROS) causing infertility principally by impairing sperm motility and DNA integrity. Currently, most clinics do not test their infertile patients for the presence of oxidative stress because the available tests are expensive or difficult to perform. As antioxidant therapy may improve sperm DNA integrity and pregnancy outcomes, it has become apparent that there is an unmet clinical need for an inexpensive and easy-to-perform assay to identify sperm oxidative stress. The aim of this study was to develop a standardized protocol for performing a photometric nitro blue tetrazolium (NBT) assay for the measurement of seminal ROS production via production of coloured formazan, whilst correlating these results with impaired sperm function (motility and DNA integrity). Semen samples from 21 fertile and 36 male aetiology infertile men were assessed for ROS production (NBT assay), sperm DNA integrity (TUNEL), apoptosis (Annexin V) and sperm motility. Infertile men's semen contained on average fourfold higher levels of ROS than fertile men. The production of ROS by sperm was positively correlated with sperm DNA fragmentation and apoptosis, whilst being negatively correlated with sperm motility. Receiver-operating characteristic plot analysis established a cut-off point of 24 microg formazan/10(7) sperm having a sensitivity of 91.7% and a specificity of 81% for determining the fertility status of an individual. This study has been successful in establishing a standardized protocol for performing a photometric seminal NBT assay that has significant clinical utility in identifying men with impaired fertility because of oxidative stress.

Contrasting Olfaction, Vision, and Audition as Predictors of Cognitive Change and Impairment in Non-Demented Older Adults

PubMed Central

MacDonald, Stuart W.S.; Keller, Connor J.C.; Brewster, Paul W.H.; Dixon, Roger A.

2017-01-01

Objective This study examines the relative utility of a particular class of non-invasive functional biomarkers -- sensory functions -- for detecting those at risk of cognitive decline and impairment. Three central research objectives were examined including whether: (1) olfactory function, vision, and audition exhibited significant longitudinal declines in non-demented older adults, (2) multi-wave change for these sensory function indicators predicted risk of mild cognitive impairment, and (3) change within persons for each sensory measure shared dynamic time-varying associations with within-person change in cognitive functioning. Method A longitudinal sample (n=408) from the Victoria Longitudinal Study was assembled. Three cognitive status subgroups were identified: not impaired cognitively (NIC), single assessment mild cognitive impairment (SA-MCI), and multiple assessment mild cognitive impairment (MA-MCI). Results We tested independent predictive associations, contrasting change in sensory function as predictors of cognitive decline and impairment, utilizing both linear mixed models and logistic regression analysis. Olfaction and, to a lesser extent, vision were identified as the most robust predictors of cognitive status and decline; audition showed little predictive influence. Conclusions These findings underscore the potential utility of deficits in olfactory function, in particular, as an early marker of age- and pathology-related cognitive decline. Functional biomarkers may represent potential candidates for use in the early stages of a multi-step screening approach for detecting those at risk of cognitive impairment, as well as for targeted intervention. PMID:29809033

Nucleolus-derived mediators in oncogenic stress response and activation of p53-dependent pathways.

PubMed

Stępiński, Dariusz

2016-08-01

Rapid growth and division of cells, including tumor ones, is correlated with intensive protein biosynthesis. The output of nucleoli, organelles where translational machineries are formed, depends on a rate of particular stages of ribosome production and on accessibility of elements crucial for their effective functioning, including substrates, enzymes as well as energy resources. Different factors that induce cellular stress also often lead to nucleolar dysfunction which results in ribosome biogenesis impairment. Such nucleolar disorders, called nucleolar or ribosomal stress, usually affect cellular functioning which in fact is a result of p53-dependent pathway activation, elicited as a response to stress. These pathways direct cells to new destinations such as cell cycle arrest, damage repair, differentiation, autophagy, programmed cell death or aging. In the case of impaired nucleolar functioning, nucleolar and ribosomal proteins mediate activation of the p53 pathways. They are also triggered as a response to oncogenic factor overexpression to protect tissues and organs against extensive proliferation of abnormal cells. Intentional impairment of any step of ribosome biosynthesis which would direct the cells to these destinations could be a strategy used in anticancer therapy. This review presents current knowledge on a nucleolus, mainly in relation to cancer biology, which is an important and extremely sensitive element of the mechanism participating in cellular stress reaction mediating activation of the p53 pathways in order to counteract stress effects, especially cancer development.

Dietary fibre-based SCFA mixtures promote both protection and repair of intestinal epithelial barrier function in a Caco-2 cell model.

PubMed

Chen, Tingting; Kim, Choon Young; Kaur, Amandeep; Lamothe, Lisa; Shaikh, Maliha; Keshavarzian, Ali; Hamaker, Bruce R

2017-03-22

Impaired gut barrier function plays an important role in the development of many diseases such as obesity, inflammatory bowel disease, and in HIV infection. Dietary fibres have been shown to improve intestinal barrier function through their fermentation products, short chain fatty acids (SCFAs), and the effects of individual SCFAs have been studied. Here, different SCFA mixtures representing possible compositions from fibre fermentation products were studied for protective and reparative effects on intestinal barrier function. The effect of fermentation products from four dietary fibres, i.e. resistant starch, fructooligosaccharides, and sorghum and corn arabinoxylan (varying in their branched structure) on barrier function was positively correlated with their SCFA concentration. Pure SCFA mixtures of various concentrations and compositions were tested using a Caco-2 cell model. SCFAs at a moderate concentration (40-80 mM) improved barrier function without causing damage to the monolayer. In a 40 mM SCFA mixture, the butyrate proportion at 20% and 50% showed both a protective and a reparative effect on the monolayer to disrupting agents (LPS/TNF-α) applied simultaneously or prior to the SCFA mixtures. Relating this result to dietary fibre selection, slow fermenting fibres that deliver appropriate concentrations of SCFAs to the epithelium with a high proportion of butyrate may improve barrier function.

Functional relevance of intestinal epithelial cells in inflammatory bowel disease.

PubMed

Okamoto, Ryuichi; Watanabe, Mamoru

2016-01-01

The intestinal epithelium constitutes a physical barrier between inner and outer side of our body. It also functions as a "hub" which connects factors that determine the development of inflammatory bowel disease, such as microbiota, susceptibility genes, and host immune response. Accordingly, recent studies have implicated and further featured the role of intestinal epithelial cell dysfunction in the pathophysiology of inflammatory bowel disease. For example, mucin producing goblet cells are usually "depleted" in ulcerative colitis patients. Studies have shown that those goblet cells exhibit various immune-regulatory functions in addition to mucin production, such as antigen presentation or cytokine production. Paneth cells are another key cell lineage that has been deeply implicated in the pathophysiology of Crohn's disease. Several susceptibility genes for Crohn's disease may lead to impairment of anti-bacterial peptide production and secretion by Paneth cells. Also, other susceptibility genes may determine the survival of Paneth cells, which leads to reduced Paneth cell function in the patient small intestinal mucosa. Further studies may reveal other unexpected roles of the intestinal epithelium in the pathophysiology of inflammatory bowel disease, and may help to develop alternative therapies targeted to intestinal epithelial cell functions.

Immunomodulatory effects of Bacteroides products on in vitro human lymphocyte functions.

PubMed

Shenker, B J; Slots, J

1989-03-01

Bacteroides spp. have been implicated in the pathogenesis of several diseases, including periodontal diseases. In this study sonic extracts of 6 Bacteroides spp. were examined for their abilities to alter human lymphocyte function. We found that soluble extracts from Bacteroides intermedius, Bacteroides endodontalis, Bacteroides asaccharolyticus, Bacteroides melaninogenicus, and to a lesser degree Bacteroides loescheii, caused dose-dependent inhibition of human lymphocyte responsiveness to both mitogens and antigens. Suppression involved altered DNA, RNA and protein synthesis as well as immunoglobulin production. In contrast, Bacteroides gingivalis did not suppress these responses; instead, it stimulated lymphocyte proliferation and enhanced immunoglobulin production. It has been proposed that impaired host defense may play a pivotal role in the pathogenesis of many infections. The data presented in this paper suggest that microbial mediated immunosuppression may conceivably alter the nature and consequences of host-parasite interactions in periodontal disease.

Heme oxygenase: the key to renal function regulation

PubMed Central

Cao, Jian; Sacerdoti, David; Li, Xiaoying; Drummond, George

2009-01-01

Heme oxygenase (HO) plays a critical role in attenuating the production of reactive oxygen species through its ability to degrade heme in an enzymatic process that leads to the production of equimolar amounts of carbon monoxide and biliverdin/bilirubin and the release of free iron. The present review examines the beneficial role of HO-1 (inducible form of HO) that is achieved by increased expression of this enzyme in renal tissue. The influence of the HO system on renal physiology, obesity, vascular dysfunction, and blood pressure regulation is reviewed, and the clinical potential of increased levels of HO-1 protein, HO activity, and HO-derived end products of heme degradation is discussed relative to renal disease. The use of pharmacological and genetic approaches to investigate the role of the HO system in the kidney is key to the development of therapeutic approaches to prevent the adverse effects that accrue due to an impairment in renal function. PMID:19570878

Flavorings in Tobacco Products Induce Endothelial Cell Dysfunction.

PubMed

Fetterman, Jessica L; Weisbrod, Robert M; Feng, Bihua; Bastin, Reena; Tuttle, Shawn T; Holbrook, Monica; Baker, Gregory; Robertson, Rose Marie; Conklin, Daniel J; Bhatnagar, Aruni; Hamburg, Naomi M

2018-06-14

Use of alternative tobacco products including electronic cigarettes is rapidly rising. The wide variety of flavored tobacco products available is of great appeal to smokers and youth. The flavorings added to tobacco products have been deemed safe for ingestion, but the cardiovascular health effects are unknown. The purpose of this study was to examine the effect of 9 flavors on vascular endothelial cell function. Freshly isolated endothelial cells from participants who use nonmenthol- or menthol-flavored tobacco cigarettes showed impaired A23187-stimulated nitric oxide production compared with endothelial cells from nonsmoking participants. Treatment of endothelial cells isolated from nonsmoking participants with either menthol (0.01 mmol/L) or eugenol (0.01 mmol/L) decreased A23187-stimulated nitric oxide production. To further evaluate the effects of flavoring compounds on endothelial cell phenotype, commercially available human aortic endothelial cells were incubated with vanillin, menthol, cinnamaldehyde, eugenol, dimethylpyrazine, diacetyl, isoamyl acetate, eucalyptol, and acetylpyrazine (0.1-100 mmol/L) for 90 minutes. Cell death, reactive oxygen species production, expression of the proinflammatory marker IL-6 (interleukin-6), and nitric oxide production were measured. Cell death and reactive oxygen species production were induced only at high concentrations unlikely to be achieved in vivo. Lower concentrations of selected flavors (vanillin, menthol, cinnamaldehyde, eugenol, and acetylpyridine) induced both inflammation and impaired A23187-stimulated nitric oxide production consistent with endothelial dysfunction. Our data suggest that short-term exposure of endothelial cells to flavoring compounds used in tobacco products have adverse effects on endothelial cell phenotype that may have relevance to cardiovascular toxicity. © 2018 American Heart Association, Inc.

Impact of neurocognition on social and role functioning in individuals at clinical high risk for psychosis.

PubMed

Carrión, Ricardo E; Goldberg, Terry E; McLaughlin, Danielle; Auther, Andrea M; Correll, Christoph U; Cornblatt, Barbara A

2011-08-01

Cognitive deficits have been well documented in schizophrenia and have been shown to impair quality of life and to compromise everyday functioning. Recent studies of adolescents and young adults at high risk for developing psychosis show that neurocognitive impairments are detectable before the onset of psychotic symptoms. However, it remains unclear how cognitive impairments affect functioning before the onset of psychosis. The authors assessed cognitive impairment in adolescents at clinical high risk for psychosis and examined its impact on social and role functioning. A sample of 127 treatment-seeking patients at clinical high risk for psychosis and a group of 80 healthy comparison subjects were identified and recruited for research in the Recognition and Prevention Program. At baseline, participants were assessed with a comprehensive neurocognitive battery as well as measures of social and role functioning. Relative to healthy comparison subjects, clinical high-risk patients showed significant impairments in the domains of processing speed, verbal memory, executive function, working memory, visuospatial processing, motor speed, sustained attention, and language. Clinical high-risk patients also displayed impaired social and role functioning at baseline. Among patients with attenuated positive symptoms, processing speed was related to social and role functioning at baseline. These findings demonstrate that cognitive and functional impairments are detectable in patients at clinical high risk for psychosis before the onset of psychotic illness and that processing speed appears to be an important cognitive predictor of poor functioning.

Impact of Neurocognition on Social and Role Functioning in Individuals at Clinical High Risk for Psychosis

PubMed Central

Carrión, Ricardo E.; Goldberg, Terry E.; McLaughlin, Danielle; Auther, Andrea M.; Correll, Christoph U.; Cornblatt, Barbara A.

2011-01-01

Objective Cognitive deficits have been well documented in schizophrenia and have been shown to impair quality of life and to compromise everyday functioning. Recent studies of adolescents and young adults at high risk for developing psychosis show that neurocognitive impairments are detectable before the onset of psychotic symptoms. However, it remains unclear how cognitive impairments affect functioning before the onset of psychosis. The authors assessed cognitive impairment in adolescents at clinical high risk for psychosis and examined its impact on social and role functioning. Method A sample of 127 treatment-seeking patients at clinical high risk for psychosis and a group of 80 healthy comparison subjects were identified and recruited for research in the Recognition and Prevention Program. At baseline, participants were assessed with a comprehensive neurocognitive battery as well as measures of social and role functioning. Results Relative to healthy comparison subjects, clinical high-risk patients showed significant impairments in the domains of processing speed, verbal memory, executive function, working memory, visuospatial processing, motor speed, sustained attention, and language. Clinical high-risk patients also displayed impaired social and role functioning at baseline. Among patients with attenuated positive symptoms, processing speed was related to social and role functioning at baseline. Conclusions These findings demonstrate that cognitive and functional impairments are detectable in patients at clinical high risk for psychosis before the onset of psychotic illness and that processing speed appears to be an important cognitive predictor of poor functioning. PMID:21536691

EEG correlates of the alcohol-induced organic brain syndrome in man.

PubMed

Zilm, D H; Huszar, L; Carlen, P L; Kaplan, H L; Wilkinson, D A

1980-05-01

Fourteen chronic alcoholics were studied within 1 to 3 weeks of beginning abstinence for a duration of 6 to 10 weeks. Patients were drug-free during the study. Electroencephalograms were recorded on admission, and twice at 2- to 3-week intervals. Neurologic examinations were performed during the same week as EEGs, and patients received a psychologic examination and CT scan within 3 weeks. Two groups could be identified. One group had high neurologic impairment scores, low alpha production, high 20 to 30 Hz power, impaired gait, and mental performance, while the other had low scores, normal alpha rhythm, and reduced degree of mental dysfunction. The impaired group showed marked improvement in neurologic scores, alpha rhythm, and 20 to 30 Hz power within 4 to 6 weeks, in contrast to no change for the unimpaired group. There was no evidence that age, duration of drinking, time from last drink, or cortical atrophy were involved in predisposing alcoholics to demonstrate the observed changes. It is submitted that spontaneous recovery in brain function of neurologically impaired alcoholics accompanies abstinence from chronic alcohol consumption.

Measuring Disability in Population Based Surveys: The Interrelationship between Clinical Impairments and Reported Functional Limitations in Cameroon and India

PubMed Central

2016-01-01

Purpose To investigate the relationship between two distinct measures of disability: self-reported functional limitations and objectively-screened clinical impairments. Methods We undertook an all age population-based survey of disability in two areas: North-West Cameroon (August/October 2013) and Telangana State, India (Feb/April 2014). Participants were selected for inclusion via two-stage cluster randomised sampling (probability proportionate to size cluster selection and compact segment sampling within clusters). Disability was defined as the presence of self-reported functional limitations across eight domains, or presence of moderate or greater clinical impairments. Clinical impairment screening comprised of visual acuity testing for vision impairment, pure tone audiometry for hearing impairment, musculoskeletal functioning assessment for musculoskeletal impairment, reported seizure history for epilepsy and reported symptoms of clinical depression (depression adults only). Information was collected using structured questionnaires, observations and examinations. Results Self-reported disability prevalence was 5.9% (95% CI 4.7–7.4) and 7.5% (5.9–9.4) in Cameroon and India respectively. The prevalence of moderate or greater clinical impairments in the same populations were 8.4% (7.5–9.4) in Cameroon and 10.5% (9.4–11.7) in India. Overall disability prevalence (self-report and/or screened positive to a moderate or greater clinical impairment) was 10.5% in Cameroon and 12.2% in India, with limited overlap between the sub-populations identified using the two types of tools. 33% of participants in Cameroon identified to have a disability, and 45% in India, both reported functional limitations and screened positive to objectively-screened impairments, whilst the remainder were identified via one or other tool only. A large proportion of people with moderate or severe clinical impairments did not self-report functional difficulties despite reporting participation restrictions. Conclusion Tools to assess reported functional limitation alone are insufficient to identify all persons with participation restrictions and moderate or severe clinical impairments. A self-reported functional limitation tool followed by clinical screening of all those who report any level of difficulty would identify 94% of people with disabilities in Cameroon and 95% in India, meeting the study criteria. PMID:27741320

Measuring Disability in Population Based Surveys: The Interrelationship between Clinical Impairments and Reported Functional Limitations in Cameroon and India.

PubMed

Mactaggart, Islay; Kuper, Hannah; Murthy, G V S; Oye, Joseph; Polack, Sarah

2016-01-01

To investigate the relationship between two distinct measures of disability: self-reported functional limitations and objectively-screened clinical impairments. We undertook an all age population-based survey of disability in two areas: North-West Cameroon (August/October 2013) and Telangana State, India (Feb/April 2014). Participants were selected for inclusion via two-stage cluster randomised sampling (probability proportionate to size cluster selection and compact segment sampling within clusters). Disability was defined as the presence of self-reported functional limitations across eight domains, or presence of moderate or greater clinical impairments. Clinical impairment screening comprised of visual acuity testing for vision impairment, pure tone audiometry for hearing impairment, musculoskeletal functioning assessment for musculoskeletal impairment, reported seizure history for epilepsy and reported symptoms of clinical depression (depression adults only). Information was collected using structured questionnaires, observations and examinations. Self-reported disability prevalence was 5.9% (95% CI 4.7-7.4) and 7.5% (5.9-9.4) in Cameroon and India respectively. The prevalence of moderate or greater clinical impairments in the same populations were 8.4% (7.5-9.4) in Cameroon and 10.5% (9.4-11.7) in India. Overall disability prevalence (self-report and/or screened positive to a moderate or greater clinical impairment) was 10.5% in Cameroon and 12.2% in India, with limited overlap between the sub-populations identified using the two types of tools. 33% of participants in Cameroon identified to have a disability, and 45% in India, both reported functional limitations and screened positive to objectively-screened impairments, whilst the remainder were identified via one or other tool only. A large proportion of people with moderate or severe clinical impairments did not self-report functional difficulties despite reporting participation restrictions. Tools to assess reported functional limitation alone are insufficient to identify all persons with participation restrictions and moderate or severe clinical impairments. A self-reported functional limitation tool followed by clinical screening of all those who report any level of difficulty would identify 94% of people with disabilities in Cameroon and 95% in India, meeting the study criteria.

Pharmacokinetics and Tolerability of Lorcaserin in Special Populations: Elderly Patients and Patients with Renal or Hepatic Impairment.

PubMed

Christopher, Ronald J; Morgan, Michael E; Tang, Yong; Anderson, Christen; Sanchez, Matilde; Shanahan, William

2017-04-01

To determine whether dosage adjustment is likely to be necessary for effective and well-tolerated use of a pharmaceutical agent, guidance documents from the US Food and Drug Administration recommend pharmacokinetics studies in patients with impaired renal or impaired hepatic function and in the elderly population. Three studies were conducted to evaluate the pharmacokinetic properties and tolerability of lorcaserin in these populations. Lorcaserin was evaluated in single-dose pharmacokinetics studies of 3 overweight/obese populations: (1) elderly (aged >65 years) patients; (2) patients with impaired renal function; and (3) those with impaired hepatic function. In elderly patients, C max was lower (geometric mean ratio [GMR], 0.83; 90% CI, 0.71-0.97), but AUC was unchanged versus adult patients. In patients with renal impairment, C max was reduced versus that in patients with normal renal function (GMR: mild impairment, 0.99 [90% CI, 0.76-1.29]; moderate, 0.70 [90% CI, 0.54-0.90]; and severe, 0.69 [90% CI, 0.53-0.89]); no trend in AUC was observed in this group versus renal impairment. In patients with hepatic impairment, C max was decreased (GMR: mild impairment, 0.92 [90% CI, 0.76-1.11]; moderate, 0.86 [90% CI, 0.71-1.04]), and AUC was increased versus patients with normal hepatic function. Based on these findings, no lorcaserin dose adjustments are necessary in elderly patients with normal renal function or in patients with mild/moderate renal or hepatic impairment. ClinicalTrials.gov identifiers: NCT00828581, NCT00828438, and NCT00828932. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

38 CFR 4.75 - General considerations for evaluating visual impairment.

Code of Federal Regulations, 2012 CFR

2012-07-01

... refraction), visual field, and muscle function. (b) Examination for visual impairment. The examination must.... Examinations of visual fields or muscle function will be conducted only when there is a medical indication of disease or injury that may be associated with visual field defect or impaired muscle function. Unless...

38 CFR 4.75 - General considerations for evaluating visual impairment.

Code of Federal Regulations, 2013 CFR

2013-07-01

... refraction), visual field, and muscle function. (b) Examination for visual impairment. The examination must.... Examinations of visual fields or muscle function will be conducted only when there is a medical indication of disease or injury that may be associated with visual field defect or impaired muscle function. Unless...

38 CFR 4.75 - General considerations for evaluating visual impairment.

Code of Federal Regulations, 2014 CFR

2014-07-01

... refraction), visual field, and muscle function. (b) Examination for visual impairment. The examination must.... Examinations of visual fields or muscle function will be conducted only when there is a medical indication of disease or injury that may be associated with visual field defect or impaired muscle function. Unless...

Marital Conflict, Depressive Symptoms, and Functional Impairment

ERIC Educational Resources Information Center

Choi, Heejeong; Marks, Nadine F

2008-01-01

Guided by a stress process perspective, we investigated (a) whether marital conflict might directly lead to changes in depression and functional impairment, (b) whether marital conflict might indirectly lead to changes in functional impairment via depression, and (c) whether marital conflict might indirectly lead to changes in depression via…

Effect of Visual Impairment on Physical and Cognitive Function in Old Age: Findings of a Population-Based Prospective Cohort Study in Germany.

PubMed

Hajek, André; Brettschneider, Christian; Lühmann, Dagmar; Eisele, Marion; Mamone, Silke; Wiese, Birgitt; Weyerer, Siegfried; Werle, Jochen; Pentzek, Michael; Fuchs, Angela; Riedel-Heller, Steffi G; Luck, Tobias; Bickel, Horst; Weeg, Dagmar; Koppara, Alexander; Wagner, Michael; Scherer, Martin; Maier, Wolfgang; König, Hans-Helmut

2016-11-01

To examine how visual impairment affects physical and cognitive function in old age. A longitudinal population-based prospective cohort study. General practitioner offices at six study centers in Germany. They were observed every 1.5 years over four waves. Individuals aged 77-101 at follow-up Wave 2 (N = 2,394). Physical and cognitive function were assessed using an adapted scale that had been previously developed, and visual impairment was rated on a Likert scale (none, mild, severe or profound). Adjusting for sociodemographic factors and comorbidity, linear fixed-effects regression showed that the onset of severe visual impairment was associated with a decline in physical function score in the total sample (β = -0.15, P = .01) and in women (β = -.15, P = .03). Moreover, the onset of severe visual impairment was associated with decline in cognitive function score in the total sample (β = -0.38, P < .001) and in women (β = -0.38, P < .001) and men (β = -0.37, P = .001). Visual impairment affects physical and cognitive function in old age. Interventional strategies to postpone visual impairment may contribute to maintaining physical and cognitive function. © 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.

The Compensatory ADHD Behaviors Scale (CABS): Development and Initial Validation.

PubMed

Castagna, Peter J; Roye, Scott; Calamia, Matthew

2018-05-01

Several measures are available that assess inattention, hyperactivity/impulsivity, and executive functioning deficits. Treatments for adults with attention-deficit/hyperactivity disorder (ADHD) and skill-based academic interventions focus on improving compensatory strategies to ameliorate functional impairment; however, no measure exists that examines the compensatory behaviors adults utilize to compensate for the functional deficits associated with inattention and hyperactivity/impulsivity. The current study aimed to determine the psychometric properties of the Compensatory ADHD Behaviors Scale (CABS). Five-hundred participants ( M age = 36.83, SD = 11.57) completed measures of ADHD symptomatology, executive functioning, functional impairment, mood disorder symptoms, and the CABS. Analyses revealed that scales assessing both use and effectiveness of compensatory behaviors subscales had similar factor structures, reflecting present- and future-oriented behaviors. The present-, but not future-oriented, behaviors significantly related to ADHD symptomatology, executive dysfunction, and functional impairment; effectiveness of present-oriented compensatory behaviors demonstrated incremental validity in predicting impairment. Compensatory strategies may be a useful variable to measure when examining functional impairment associated with inattention and hyperactivity/impulsivity. The current study provides preliminary evidence of the ability of CABS to validly measure various strategies associated with (clinical and subclinical) ADHD symptomatology, executive functioning, and overall impairment.

20 CFR 404.1527 - Evaluating opinion evidence.

Code of Federal Regulations, 2011 CFR

2011-04-01

... impairment(s) in the Listing of Impairments in appendix 1 to this subpart, your residual functional capacity... your residual functional capacity. These administrative findings of fact are based on the evidence in...

Body Dysmorphic Symptoms, Functional Impairment, and Depression: The Role of Appearance-Based Teasing.

PubMed

Weingarden, Hilary; Renshaw, Keith D

2016-01-01

Body dysmorphic disorder is associated with elevated social and occupational impairment and comorbid depression, but research on risk factors for body dysmorphic symptoms and associated outcomes is limited. Appearance-based teasing may be a potential risk factor. To examine the specificity of this factor, the authors assessed self-reported appearance-based teasing, body dysmorphic, and obsessive-compulsive symptom severity, functional impairment (i.e., social, occupational, family impairment), and depression in a nonclinical sample of undergraduates. As hypothesized, appearance-based teasing was positively correlated with body dysmorphic symptoms. The correlation between teasing and body dysmorphic symptoms was stronger than that between teasing and obsessive-compulsive symptom severity. Last, body dysmorphic symptom severity and appearance-based teasing interacted in predicting functional impairment and depression. Specifically, appearance-based teasing was positively associated with depression and functional impairment only in those with elevated body dysmorphic symptoms. When a similar moderation was tested with obsessive-compulsive, in place of body dysmorphic, symptom severity, the interaction was nonsignificant. Findings support theory that appearance-based teasing is a specific risk factor for body dysmorphic symptoms and associated functional impairment.

Functional impairment and the economic consequences of female breast cancer.

PubMed

Chirikos, Thomas N; Russell-Jacobs, Anita; Jacobsen, Paul B

2002-01-01

Recent trends in breast cancer diagnosis and mortality suggest that long-term survivors are now more likely to be functionally impaired and, hence, more likely to experience adverse economic outcomes. This study tests whether women who have survived breast cancer for at least five years exhibit more, or more severe, functional impairments than otherwise similar women without breast cancer. It also tests whether women with more severe impairments experience poorer economic outcomes attributable to their functional status. A group of 105 breast cancer survivors was interviewed to obtain data on health and economic changes in the five-year period since diagnosis and initial treatment. An age- and work-matched group of 105 women without cancer was also interviewed to obtain the same data over the same time period. Key changes in the functional status of the subjects as well as economic outcomes such as changes in market earnings, household income, and insurance coverage were measured. Whether impairment is more severe in the breast cancer group than the comparison group was then tested statistically; whether economic outcomes are more adverse in more impaired than less impaired women regardless of their breast cancer status was also tested. The analysis turned up statistically significant evidence in regard to each of these relationships. Breast cancer survivors were more likely than controls to be functionally impaired at the five-year benchmark. Impaired women, in turn, were more likely to reduce work effort and experience downturns in market earnings, among other things. Policy and research implications are discussed.

Parallel functional category deficits in clauses and nominal phrases: The case of English agrammatism

PubMed Central

Wang, Honglei; Yoshida, Masaya; Thompson, Cynthia K.

2015-01-01

Individuals with agrammatic aphasia exhibit restricted patterns of impairment of functional morphemes, however, syntactic characterization of the impairment is controversial. Previous studies have focused on functional morphology in clauses only. This study extends the empirical domain by testing functional morphemes in English nominal phrases in aphasia and comparing patients’ impairment to their impairment of functional morphemes in English clauses. In the linguistics literature, it is assumed that clauses and nominal phrases are structurally parallel but exhibit inflectional differences. The results of the present study indicated that aphasic speakers evinced similar impairment patterns in clauses and nominal phrases. These findings are consistent with the Distributed Morphology Hypothesis (DMH), suggesting that the source of functional morphology deficits among agrammatics relates to difficulty implementing rules that convert inflectional features into morphemes. Our findings, however, are inconsistent with the Tree Pruning Hypothesis (TPH), which suggests that patients have difficulty building complex hierarchical structures. PMID:26379370

The Association of Domestic Violence and Social Resources With Functioning in an Adult Trauma-Affected Sample Living in Kurdistan, Northern Iraq.

PubMed

Kane, Jeremy C; Hall, Brian J; Bolton, Paul; Murray, Laura K; Mohammed Amin Ahmed, Ahmed; Bass, Judith K

2016-03-27

Domestic violence (DV) and other experienced trauma types increase the risk for impaired functioning. Access to social resources may provide a buffer to existing risks and allow individuals to continue and build functioning. This cross-sectional study investigated the direct effects of DV and access to social resources (perceived social support, social integration, and frequency of social contact), as well as their potential interactive effects, on daily functioning among 894 male and female trauma survivors who attended primary care clinics in Kurdistan, Iraq in 2009 and 2010. Experiencing DV was not associated with functioning for males (p=.15) or females (p=.60), suggesting that in the context of a trauma-affected sample, the experience of DV may not significantly increase the risk for functional impairment. Greater amounts of social integration were associated with less functional impairment among males (p<.01) and females (p<.05); social integration was associated with less functional impairment among males only (p<.01); and frequency of social contact was associated with less functional impairment among females only (p<.05), indicating that the association between social resource type and functioning differed by gender. Social resources had a stronger effect on functioning among men compared to women. Among males who experienced DV, social integration was the only social resource associated with less functional impairment (p<.01); among male trauma survivors who did not experience DV, social support was the only resource associated with less functional impairment (p<.01). Further investigation into these associations is warranted to inform intervention strategies for survivors of DV and other traumas in post-conflict settings. © The Author(s) 2016.

What explains health in persons with visual impairment?

PubMed Central

2014-01-01

Background Visual impairment is associated with important limitations in functioning. The International Classification of Functioning, Disability and Health (ICF) adopted by the World Health Organisation (WHO) relies on a globally accepted framework for classifying problems in functioning and the influence of contextual factors. Its comprehensive perspective, including biological, individual and social aspects of health, enables the ICF to describe the whole health experience of persons with visual impairment. The objectives of this study are (1) to analyze whether the ICF can be used to comprehensively describe the problems in functioning of persons with visual impairment and the environmental factors that influence their lives and (2) to select the ICF categories that best capture self-perceived health of persons with visual impairment. Methods Data from 105 persons with visual impairment were collected, including socio-demographic data, vision-related data, the Extended ICF Checklist and the visual analogue scale of the EuroQoL-5D, to assess self-perceived health. Descriptive statistics and a Group Lasso regression were performed. The main outcome measures were functioning defined as impairments in Body functions and Body structures, limitations in Activities and restrictions in Participation, influencing Environmental factors and self-perceived health. Results In total, 120 ICF categories covering a broad range of Body functions, Body structures, aspects of Activities and Participation and Environmental factors were identified. Thirteen ICF categories that best capture self-perceived health were selected based on the Group Lasso regression. While Activities-and-Participation categories were selected most frequently, the greatest impact on self-perceived health was found in Body-functions categories. The ICF can be used as a framework to comprehensively describe the problems of persons with visual impairment and the Environmental factors which influence their lives. Conclusions There are plenty of ICF categories, Environmental-factors categories in particular, which are relevant to persons with visual impairment, but have hardly ever been taken into consideration in literature and visual impairment-specific patient-reported outcome measures. PMID:24886326

Comparison of Spontaneously Elicited Language Patterns in Specific Language Impairment and High-Functioning Autism.

PubMed

Craig, Megan; Trauner, Doris

2018-02-01

We aimed to characterize differences in the use of language in children with specific language impairment and high-functioning autism by analyzing verbal responses on standardized tests. The overall goal was to provide clinicians with additional tools with which to aid in distinguishing the two neurodevelopmental disorders. This study included 16 children with specific language impairment, 28 children with high-functioning autism, and 52 typically developing participants between the ages of six and 14. Groups were matched for age, and specific language impairment and high-functioning autism groups were matched on verbal and performance IQ. Responses from standardized tests were examined for response length, grammatical errors, filler words, perseverations, revisions (repeated attempts to begin or continue a sentence), off-topic attention shifts (lapses in attention to the task), and rambling. Data were analyzed using parametric and nonparametric methods. Specific language impairment responses were longer and contained more filler words than did those of the other two groups, whereas high-functioning autism responses exhibited more grammatical errors, off-topic attention shifts, and rambling. Specific language impairment and high-functioning autism responses showed higher rates of perseveration compared with controls. There were no significant differences in revisions among the three groups. Differences in language patterns of participants with specific language impairment and high-functioning autism may be useful to the clinician in helping to differentiate isolated language impairment from high-functioning autism. The results also support the conclusion that the two conditions are separable, and each exhibits a different pattern of language dysfunction. Copyright © 2017 Elsevier Inc. All rights reserved.

Annual Research Review: Conceptualising Functional Impairment in Children and Adolescents

ERIC Educational Resources Information Center

Rapee, Ronald M.; Bogels, Susan M.; van der Sluis, Cathy M.; Craske, Michelle G.; Ollendick, Thomas

2012-01-01

Functional impairment is a key factor in the clinical importance of mental health problems in children. Yet, the nature of impairment and criteria for defining and assessing impairment in childhood disorders has been surprisingly overlooked in much of the literature. The current article examines the extant literature on the conceptualisation,…

Executive Functions in Children with Communication Impairments, in Relation to Autistic Symptomatology. 2: Response Inhibition

ERIC Educational Resources Information Center

Bishop, Dorothy V. M.; Norbury, Courtenay Frazier

2005-01-01

Although impairment in executive functions has been described in autism, there has been debate as to whether response inhibition is specifically affected. We compared four groups: highfunctioning autism; pragmatic language impairment; specific language impairment; and control. Inhibition was assessed using two subtests from the Test of Everyday…

Angiogenic function of prostacyclin biosynthesis in human endothelial progenitor cells

PubMed Central

He, Tongrong; Lu, Tong; d’Uscio, Livius V.; Lam, Chen-Fuh; Lee, Hon-Chi; Katusic, Zvonimir S.

2009-01-01

The role of prostaglandins production in the control of regenerative function of endothelial progenitor cells (EPCs) has not been studied. We hypothesized that activation of cyclooxygenase (COX) enzymatic activity and the subsequent production of prostacyclin (PGI2) is an important mechanism responsible for the regenerative function of EPCs. In the present study, we detected high levels of COX-1 protein expression and PGI2 biosynthesis in human EPCs outgrown from blood mononuclear cells. Expression of COX-2 protein was almost undetectable under basal conditions but significantly elevated after treatment with tumor necrosis factor-α. Condition medium derived from EPCs hyperpolarized human coronary artery smooth muscle cells, similar to the effect of the PGI2 analogue iloprost. The proliferation and in vitro tube formation by EPCs were inhibited by the COX inhibitor indomethacin, or by genetic inactivation of COX-1 or PGI2 synthase (PGIS) with small interfering RNA (siRNA). Impaired tube formation and cell proliferation induced by inactivation of COX-1 were rescued by the treatment with iloprost or selective peroxisome-proliferator activated receptor-δ (PPARδ) agonist, GW501516, but not by the selective PGI2 receptor agonist, cicaprost. Down regulation of PPARδ by siRNA also reduced angiogenic capacity of EPCs. Iloprost failed to reverse PPARδ-siRNA-induced impairment of angiogenesis. Furthermore, transfection of PGIS-siRNA, COX-1-siRNA, or PPARδ-siRNA into EPCs decreased the capillary formation in vivo after transplantation of human EPCs into the nude mice. These results suggest that activation of COX-1-PGI2-PPARδ pathway is an important mechanism underlying pro-angiogenic function of EPCs. PMID:18511850

Potential involvement of dietary advanced glycation end products in impairment of skeletal muscle growth and muscle contractile function in mice.

PubMed

Egawa, Tatsuro; Tsuda, Satoshi; Goto, Ayumi; Ohno, Yoshitaka; Yokoyama, Shingo; Goto, Katsumasa; Hayashi, Tatsuya

2017-01-01

Diets enriched with advanced glycation end products (AGE) have recently been related to muscle dysfunction processes. However, it remains unclear whether long-term exposure to an AGE-enriched diet impacts physiological characteristics of skeletal muscles. Therefore, we explored the differences in skeletal muscle mass, contractile function and molecular responses between mice receiving a diet high in AGE (H-AGE) and low in AGE (L-AGE) for 16 weeks. There were no significant differences between L-AGE and H-AGE mice with regard to body weight, food intake or epididymal fat pad weight. However, extensor digitorum longus (EDL) and plantaris (PLA) muscle weights in H-AGE mice were lower compared with L-AGE mice. Higher levels of N ε -(carboxymethyl)-l-lysine, a marker for AGE, in EDL muscles of H-AGE mice were observed compared with L-AGE mice. H-AGE mice showed lower muscle strength and endurance in vivo and lower muscle force production of PLA muscle in vitro. mRNA expression levels of myogenic factors including myogenic factor 5 and myogenic differentiation in EDL muscle were lower in H-AGE mice compared with L-AGE mice. The phosphorylation status of 70-kDa ribosomal protein S6 kinase Thr389, an indicator of protein synthesis signalling, was lower in EDL muscle of H-AGE mice than that of L-AGE mice. These findings suggest that long-term exposure to an AGE-enriched diet impairs skeletal muscle growth and muscle contractile function, and that these muscle dysfunctions may be attributed to the inhibition of myogenic potential and protein synthesis.

Mitochondrial Cardiomyopathy Caused by Elevated Reactive Oxygen Species and Impaired Cardiomyocyte Proliferation.

PubMed

Zhang, Donghui; Li, Yifei; Heims-Waldron, Danielle; Bezzerides, Vassilios; Guatimosim, Silvia; Guo, Yuxuan; Gu, Fei; Zhou, Pingzhu; Lin, Zhiqiang; Ma, Qing; Liu, Jianming; Wang, Da-Zhi; Pu, William T

2018-01-05

Although mitochondrial diseases often cause abnormal myocardial development, the mechanisms by which mitochondria influence heart growth and function are poorly understood. To investigate these disease mechanisms, we studied a genetic model of mitochondrial dysfunction caused by inactivation of Tfam (transcription factor A, mitochondrial), a nuclear-encoded gene that is essential for mitochondrial gene transcription and mitochondrial DNA replication. Tfam inactivation by Nkx2.5 Cre caused mitochondrial dysfunction and embryonic lethal myocardial hypoplasia. Tfam inactivation was accompanied by elevated production of reactive oxygen species (ROS) and reduced cardiomyocyte proliferation. Mosaic embryonic Tfam inactivation confirmed that the block to cardiomyocyte proliferation was cell autonomous. Transcriptional profiling by RNA-seq demonstrated the activation of the DNA damage pathway. Pharmacological inhibition of ROS or the DNA damage response pathway restored cardiomyocyte proliferation in cultured fetal cardiomyocytes. Neonatal Tfam inactivation by AAV9-cTnT-Cre caused progressive, lethal dilated cardiomyopathy. Remarkably, postnatal Tfam inactivation and disruption of mitochondrial function did not impair cardiomyocyte maturation. Rather, it elevated ROS production, activated the DNA damage response pathway, and decreased cardiomyocyte proliferation. We identified a transient window during the first postnatal week when inhibition of ROS or the DNA damage response pathway ameliorated the detrimental effect of Tfam inactivation. Mitochondrial dysfunction caused by Tfam inactivation induced ROS production, activated the DNA damage response, and caused cardiomyocyte cell cycle arrest, ultimately resulting in lethal cardiomyopathy. Normal mitochondrial function was not required for cardiomyocyte maturation. Pharmacological inhibition of ROS or DNA damage response pathways is a potential strategy to prevent cardiac dysfunction caused by some forms of mitochondrial dysfunction. © 2017 American Heart Association, Inc.

CD155T/TIGIT Signaling Regulates CD8+ T-cell Metabolism and Promotes Tumor Progression in Human Gastric Cancer.

PubMed

He, Weiling; Zhang, Hui; Han, Fei; Chen, Xinlin; Lin, Run; Wang, Wei; Qiu, Haibo; Zhuang, Zhenhong; Liao, Qi; Zhang, Weijing; Cai, Qinbo; Cui, Yongmei; Jiang, Wenting; Wang, Han; Ke, Zunfu

2017-11-15

The T-cell surface molecule TIGIT is an immune checkpoint molecule that inhibits T-cell responses, but its roles in cancer are little understood. In this study, we evaluated the role TIGIT checkpoint plays in the development and progression of gastric cancer. We show that the percentage of CD8 T cells that are TIGIT + was increased in gastric cancer patients compared with healthy individuals. These cells showed functional exhaustion with impaired activation, proliferation, cytokine production, and metabolism, all of which were rescued by glucose. In addition, gastric cancer tissue and cell lines expressed CD155, which bound TIGIT receptors and inactivated CD8 T cells. In a T cell-gastric cancer cell coculture system, gastric cancer cells deprived CD8 T cells of glucose and impaired CD8 T-cell effector functions; these effects were neutralized by the additional glucose or by TIGIT blockade. In gastric cancer tumor cells, CD155 silencing increased T-cell metabolism and IFNγ production, whereas CD155 overexpression inhibited T-cell metabolism and IFNγ production; this inhibition was neutralized by TIGIT blockade. Targeting CD155/TIGIT enhanced CD8 T-cell reaction and improved survival in tumor-bearing mice. Combined targeting of TIGIT and PD-1 further enhanced CD8 T-cell activation and improved survival in tumor-bearing mice. Our results suggest that gastric cancer cells inhibit CD8 T-cell metabolism through CD155/TIGIT signaling, which inhibits CD8 T-cell effector functions, resulting in hyporesponsive antitumor immunity. These findings support the candidacy of CD155/TIGIT as a potential therapeutic target in gastric cancer. Cancer Res; 77(22); 6375-88. ©2017 AACR . ©2017 American Association for Cancer Research.

Invariant Natural Killer T Cell Deficiency and Functional Impairment in Sleep Apnea: Links to Cancer Comorbidity.

PubMed

Gaoatswe, Gadintshware; Kent, Brian D; Corrigan, Michelle A; Nolan, Geraldine; Hogan, Andrew E; McNicholas, Walter T; O'Shea, Donal

2015-10-01

Emerging evidence links obstructive sleep apnea (OSA) with increased cancer incidence and mortality. Invariant natural killer T (iNKT) cells play an important role in cancer immunity. We hypothesized that patients with OSA have low number of circulating invariant natural killer T (iNKT) cells, which may also be functionally impaired. This study aims to evaluate the frequency of circulating iNKT cells in OSA. We evaluated the frequency of circulating iNKT cells by flow cytometry in 33 snorers being assessed for possible OSA. Using iNKT cell lines, we also evaluated the effect of exposure to hypoxia over 24 hours on apoptosis, cytotoxicity, and cytokine production. Teaching hospital based sleep unit and research laboratory. Thirty-three snorers were evaluated: 9 with no OSA (apnea-hypopnea frequency [AHI] < 5/h), 12 with mild-moderate OSA (AHI 5-30) and 12 with severe OSA (AHI > 30). Patients with severe OSA had considerably fewer iNKT cells (0.18%) compared to patients with mild-moderate (0.24%) or no OSA (0.35%), P = 0.0026. The frequency of iNKT cells correlated negatively with apnea-hypopnea index (r = -0.58, P = 0.001), oxygen desaturation index (r = -0.58, P = 0.0003), and SpO2% < 90% (r = -0.5407, P = 0.005). The frequency of iNKT cells increased following 12 months of nCPAP therapy (P = 0.015). Hypoxia resulted in increased apoptosis (P = 0.016) and impaired cytotoxicity (P = 0.035). Patients with obstructive sleep apnea (OSA) have significantly reduced levels of circulating invariant natural killer T (iNKT) cells and hypoxia leads to impaired iNKT cell function. These observations may partly explain the increased cancer risk reported in patients with OSA. © 2015 Associated Professional Sleep Societies, LLC.

Characteristics, burden of illness, and physical functioning of patients with relapsing-remitting and secondary progressive multiple sclerosis: a cross-sectional US survey.

PubMed

Gross, Hillary J; Watson, Crystal

2017-01-01

Although most patients with relapsing-remitting multiple sclerosis (RRMS) will develop secondary progressive multiple sclerosis (SPMS), little is known about the burden of multiple sclerosis by disease subtype. This study describes the burden of disease in terms of demographics, disease severity, symptoms, health care resource and disease-modifying therapy (DMT) utilization, work and activity impairment, and physical functioning of SPMS and RRMS patients. SPMS and RRMS patient responses from the 2012 and 2013 waves of the US National Health and Wellness Survey were evaluated to detect differences in demographics, disease severity, symptoms, and health care resource and DMT utilization. In addition, data from the Work Productivity and Activity Impairment and Short Form-36 questionnaires were analyzed. SPMS patients were older than RRMS patients (mean age 55.7 vs 48.9 years; P <0.001); a lower proportion were female (56.2% with SPMS vs 71.6% with RRMS; P =0.002), and fewer SPMS than RRMS patients were employed (20.0% vs 39.7%; P <0.001). SPMS patients described their disease as more severe, reporting several neurological symptoms more frequently and higher hospitalization rates than RRMS patients. A lower percentage of SPMS than RRMS patients reported DMT use. SPMS patients had greater overall work and activity impairment than RRMS patients. After controlling for baseline characteristics, impairment in physical functioning was greater in SPMS patients. Overall, SPMS patients had a higher burden of illness than RRMS patients, underscoring the need to treat RRMS patients early to delay disability progressing using therapies that are effective in real-world settings.

Cardiac Metabolism in Heart Failure - Implications beyond ATP production

PubMed Central

Doenst, Torsten; Nguyen, T. Dung; Abel, E. Dale

2013-01-01

The heart has a high rate of ATP production and turnover which is required to maintain its continuous mechanical work. Perturbations in ATP generating processes may therefore affect contractile function directly. Characterizing cardiac metabolism in heart failure revealed several metabolic alterations termed metabolic remodeling, ranging from changes in substrate utilization to mitochondrial dysfunction, ultimately resulting in ATP deficiency and impaired contractility. However, ATP depletion is not the only relevant consequence of metabolic remodeling during heart failure. By providing cellular building blocks and signaling molecules, metabolic pathways control essential processes such as cell growth and regeneration. Thus, alterations in cardiac metabolism may also affect the progression to heart failure by mechanisms beyond ATP supply. Our aim is therefore to highlight that metabolic remodeling in heart failure not only results in impaired cardiac energetics, but also induces other processes implicated in the development of heart failure such as structural remodeling and oxidative stress. Accordingly, modulating cardiac metabolism in heart failure may have significant therapeutic relevance that goes beyond the energetic aspect. PMID:23989714

Explorative evaluation of the impact of severe premenstrual disorders on work absenteeism and productivity.

PubMed

Heinemann, Lothar A J; Minh, Thai Do; Filonenko, Anna; Uhl-Hochgräber, Kerstin

2010-01-01

To assess the effects of premenstrual disorders on work productivity and absenteeism in the multinational Impact study. Women aged 15-45 years were screened for suspected premenstrual dysphoric disorders (PMDD) and premenstrual syndrome (PMS) and invited to participate in this web-based study. Based on the Daily Record of Severity of Problems (DRSP) questionnaire, symptoms were assessed prospectively over 2 months. Participants were categorized as having no perceived symptoms/mild PMS or moderate-to-severe PMS/PMDD based on a validated algorithm. Work productivity impairment and absenteeism were assessed retrospectively using the Premenstrual Symptoms Screening Tool (PSST) and a modified version of the Work Productivity and Activity Impairment (WPAI) questionnaire. Work productivity impairment was also assessed prospectively over 2 months using the DRSP questionnaire. Overall 1,477 women started the study-of these, 822 (56%) completed the study as planned and represent the full analysis set. Employed women with moderate-to-severe PMS/PMDD had higher rate of productivity impairment on the modified version of the WPAI questionnaire (values >/=7) relative to those with no perceived symptoms/mild PMS (adjusted odds ratio, 3.12; 95% confidence interval, 1.75-5.57). Similar outcomes were obtained for impairment of working productivity or efficiency using the PSST scale (value 4). The mean number of days on the DRSP with at least moderate reduction in productivity or efficiency in daily routine was higher for women with moderate-to-severe PMS/PMDD (5.6 vs. 1.1). Women with moderate-to-severe PMS/PMDD had a higher rate of absenteeism (>8hours per cycle; 14.2% vs. 6.0%). Moderate-to-severe PMS/PMDD seems to be associated with work productivity impairment and increased absenteeism, and thus poses a potential economic burden. Copyright 2010 Jacobs Institute of Women

Differential impairments underlying decision making in anorexia nervosa and bulimia nervosa: a cognitive modeling analysis.

PubMed

Chan, Trista Wai Sze; Ahn, Woo-Young; Bates, John E; Busemeyer, Jerome R; Guillaume, Sebastien; Redgrave, Graham W; Danner, Unna N; Courtet, Philippe

2014-03-01

This study examined the underlying processes of decision-making impairments in individuals with anorexia nervosa (AN) and bulimia nervosa (BN). We deconstructed their performance on the widely used decision task, the Iowa Gambling Task (IGT) into cognitive, motivational, and response processes using cognitive modeling analysis. We hypothesized that IGT performance would be characterized by impaired memory functions and heightened punishment sensitivity in AN, and by elevated sensitivity to reward as opposed to punishment in BN. We analyzed trial-by-trial data of IGT obtained from 224 individuals: 94 individuals with AN, 63 with BN, and 67 healthy comparison individuals (HC). The prospect valence learning model was used to assess cognitive, motivational, and response processes underlying IGT performance. Individuals with AN showed marginally impaired IGT performance compared to HC. Their performance was characterized by impairments in memory functions. Individuals with BN showed significantly impaired IGT performance compared to HC. They showed greater relative sensitivity to gains as opposed to losses than HC. Memory functions in AN were positively correlated with body mass index. This study identified differential impairments underlying IGT performance in AN and BN. Findings suggest that impaired decision making in AN might involve impaired memory functions. Impaired decision making in BN might involve altered reward and punishment sensitivity. Copyright © 2013 Wiley Periodicals, Inc.

The 20-Year Longitudinal Trajectories of Social Functioning in Individuals With Psychotic Disorders.

PubMed

Velthorst, Eva; Fett, Anne-Kathrin J; Reichenberg, Avraham; Perlman, Greg; van Os, Jim; Bromet, Evelyn J; Kotov, Roman

2017-11-01

Social impairment is a long-recognized core feature of schizophrenia and is common in other psychotic disorders. Still, to date the long-term trajectories of social impairment in psychotic disorders have rarely been studied systematically. Data came from the Suffolk County Mental Health Project, a 20-year prospective study of first-admission patients with psychotic disorders. A never-psychotic comparison group was also assessed. Latent class growth analysis was applied to longitudinal data on social functioning from 485 respondents with schizophrenia spectrum disorders and psychotic mood disorders, and associations of the empirically derived trajectories with premorbid social adjustment, diagnosis, and 20-year outcomes were examined. Four mostly stable trajectories of preserved (N=82; 59th percentile of comparison group sample distribution), moderately impaired (N=148; 17th percentile), severely impaired (N=181; 3rd percentile), and profoundly impaired (N=74; 1st percentile) functioning best described the 20-year course of social functioning across diagnoses. The outcome in the group with preserved functioning did not differ from that of never-psychotic individuals at 20 years, but the other groups functioned significantly worse. Differences among trajectories were already evident in childhood. The two most impaired trajectories started to diverge in early adolescence. Poorer social functioning trajectories were strongly associated with other real-world outcomes at 20 years. Multiple trajectories were represented within each disorder. However, more participants with schizophrenia spectrum disorders had impaired trajectories, and more with mood disorders had better functioning trajectories. The results highlight substantial variability of social outcomes within diagnoses-albeit overall worse social outcomes in schizophrenia spectrum disorders-and show remarkably stable long-term impairments in social functioning after illness onset across all diagnoses.

Visual impairment, visual functioning, and quality of life assessments in patients with glaucoma.

PubMed Central

Parrish, R K

1996-01-01

BACKGROUND/PURPOSE: To determine the relation between visual impairment, visual functioning, and the global quality of life in patients with glaucoma. METHODS: Visual impairment, defined with the American Medical Association Guides to the Evaluation of Permanent Impairment; visual functioning, measured with the VF-14 and the Field Test Version of the National Eye Institute-Visual Functioning Questionnaire (NEI-VFQ); and the global quality of life, assessed with the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), were determined in 147 consecutive patients with glaucoma. RESULTS: None of the SF-36 domains demonstrated more than a weak correlation with visual impairment. The VF-14 scores were moderately correlated with visual impairment. Of the twelve NEI-VFQ scales, distance activities and vision specific dependency were moderately correlated with visual impairment. Of the twelve NEI-VFQ scales, distance activities and vision specific dependency were moderately correlated with visual field impairment; vision specific social functioning, near activities, vision specific role difficulties, general vision, vision specific mental health, color vision, and driving were modestly correlated; visual pain was weakly correlated; and two were not significantly correlated. Correcting for visual actuity weakened the strength of the correlation coefficients. CONCLUSIONS: The SF-36 is unlikely to be useful in determining visual impairment in patients with glaucoma. Based on the moderate correlation between visual field impairment and the VF-14 score, this questionnaire may be generalizable to patients with glaucoma. Several of the NEI-VFQ scales correlate with visual field impairment scores in patients with a wide range of glaucomatous damage. PMID:8981717

Functional Impairment in Latino Children with ADHD: Implications for Culturally Appropriate Conceptualization and Measurement

ERIC Educational Resources Information Center

Haack, Lauren Marie; Gerdes, Alyson C.

2011-01-01

Conceptualizing and measuring functional impairment related to childhood ADHD, particularly within the rapidly growing, yet underserved, Latino population, is an important area of research that is in its infancy in the field of psychology. The functional impairments related to academic achievement, social competence, and familial relations…

Displacement as a predictor of functional impairment in tsunami-exposed children.

PubMed

Lee, Christopher; Du, Ye Beverly; Christina, Desy; Palfrey, Judith; O'Rourke, Edward; Belfer, Myron

2015-01-01

Thirty months after the Indian Ocean tsunami of 26 December 2004, thousands of families in Aceh Province, Indonesia, remained in temporary barracks while sanitation conditions and non-governmental organisation support deteriorated. This study sought to determine the factors associated with functional impairment in a sample of 138 displaced and non-displaced Acehnese children. Using multivariate linear regression models, it was found that displacement distance was a consistent predictor of impairment using the Brief Impairment Scale. Exposure to tsunami-related trauma markers was not significantly linked with impairment in the model. Paternal employment was a consistent protective factor for child functioning. These findings suggest that post-disaster displacement and the subsequent familial economic disruption are significant predictors of impaired functioning in children's daily activities. Post-disaster interventions should consider the disruption of familiar environments for families and children when relocating vulnerable populations to avoid deleterious impacts on children's functioning. © 2014 The Author(s). Disasters © Overseas Development Institute, 2014.

High Prolactin Excretion in Patients with Diabetes Mellitus and Impaired Renal Function.

PubMed

Triebel, Jakob; Moreno-Vega, Aura Ileana; Vázquez-Membrillo, Miguel; Nava, Gabriel; García-Franco, Renata; López-Star, Ellery; Baldivieso-Hurtado, Olivia; Ochoa, Daniel; Macotela, Yazmín; Bertsch, Thomas; Martinez de la Escalera, Gonzalo; Clapp, Carmen

2015-01-01

The metabolic clearance of prolactin (PRL) is partially executed by the kidney. Here, we investigate the urine excretion of PRL in patients with Diabetes Mellitus and renal impairment. Serum and urine samples were collected from male, mestizo patients in central Mexico employing a cross-sectional study design. Ninety-eight individuals had either no diabetes and normal renal function (control), diabetes and normal renal function, or diabetes with impaired renal function. PRL was determined by a chemiluminescent immunometric assay; protein, albumin, and creatinine were evaluated using quantitative colorimetric assays. The results were analyzed using ANOVA-testing. Patients with Diabetes Mellitus and renal impairment had significantly higher urine PRL levels than patients with Diabetes Mellitus and normal renal function and control patients. Higher urine PRL levels were associated with lower glomerular filtration rates, higher serum creatinine, and higher urinary albumin-to-creatinine ratios (UACR). Urine PRL levels correlated positively with UACR. Serum PRL levels were similar among groups. Patients with Diabetes Mellitus and impaired renal function demonstrate a high urinary PRL excretion. Urinary PRL excretion in the context of proteinuria could contribute to PRL dysregulation in renal impairment.

Reducing Liver Fat by Low Carbohydrate Caloric Restriction Targets Hepatic Glucose Production in Non-Diabetic Obese Adults with Non-Alcoholic Fatty Liver Disease.

PubMed

Yu, Haoyong; Jia, Weiping; Guo, ZengKui

2014-09-01

Non-alcoholic fatty liver disease (NAFLD) impairs liver functions, the organ responsible for the regulation of endogenous glucose production and thus plays a key role in glycemic homeostasis. Therefore, interventions designed to normalize liver fat content are needed to improve glucose metabolism in patients affected by NAFLD such as obesity. this investigation is designed to determine the effects of caloric restriction on hepatic and peripheral glucose metabolism in obese humans with NAFLD. eight non-diabetic obese adults were restricted for daily energy intake (800 kcal) and low carbohydrate (<10%) for 8 weeks. Body compositions, liver fat and hepatic glucose production (HGP) and peripheral glucose disposal before and after the intervention were determined. the caloric restriction reduced liver fat content by 2/3 (p = 0.004). Abdominal subcutaneous and visceral fat, body weight, BMI, waist circumference and fasting plasma triglyceride and free fatty acid concentrations all significantly decreased (p < 0.05). The suppression of post-load HGP was improved by 22% (p = 0.002) whereas glucose disposal was not affected (p = 0.3). Fasting glucose remained unchanged and the changes in the 2-hour plasma glucose and insulin concentration were modest and statistically insignificant (p > 0.05). Liver fat is the only independent variable highly correlated to HGP after the removal of confounders. NAFLD impairs HGP but not peripheral glucose disposal; low carbohydrate caloric restriction effectively lowers liver fat which appears to directly correct the HGP impairment.

Cognitive functioning in dyskinetic cerebral palsy: Its relation to motor function, communication and epilepsy.

PubMed

Ballester-Plané, Júlia; Laporta-Hoyos, Olga; Macaya, Alfons; Póo, Pilar; Meléndez-Plumed, Mar; Toro-Tamargo, Esther; Gimeno, Francisca; Narberhaus, Ana; Segarra, Dolors; Pueyo, Roser

2018-01-01

Cerebral palsy (CP) is a disorder of motor function often accompanied by cognitive impairment. There is a paucity of research focused on cognition in dyskinetic CP and on the potential effect of related factors. To describe the cognitive profile in dyskinetic CP and to assess its relationship with motor function and associated impairments. Fifty-two subjects with dyskinetic CP (28 males, mean age 24 y 10 mo, SD 13 y) and 52 typically-developing controls (age- and gender-matched) completed a comprehensive neuropsychological assessment. Gross Motor Function Classification System (GMFCS), Communication Function Classification System (CFCS) and epilepsy were recorded. Cognitive performance was compared between control and CP groups, also according different levels of GMFCS. The relationship between cognition, CFCS and epilepsy was examined through partial correlation coefficients, controlling for GMFCS. Dyskinetic CP participants performed worse than controls on all cognitive functions except for verbal memory. Milder cases (GMFCS I) only showed impairment in attention, visuoperception and visual memory. Participants with GMFCS II-III also showed impairment in language-related functions. Severe cases (GMFCS IV-V) showed impairment in intelligence and all specific cognitive functions but verbal memory. CFCS was associated with performance in receptive language functions. Epilepsy was related to performance in intelligence, visuospatial abilities, visual memory, grammar comprehension and learning. Cognitive performance in dyskinetic CP varies with the different levels of motor impairment, with more cognitive functions impaired as motor severity increases. This study also demonstrates the relationship between communication and epilepsy and cognitive functioning, even controlling for the effect of motor severity. Copyright © 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Opposite effects of statins on mitochondria of cardiac and skeletal muscles: a ‘mitohormesis’ mechanism involving reactive oxygen species and PGC-1

PubMed Central

Bouitbir, Jamal; Charles, Anne-Laure; Echaniz-Laguna, Andoni; Kindo, Michel; Daussin, Frédéric; Auwerx, Johan; Piquard, François; Geny, Bernard; Zoll, Joffrey

2012-01-01

Aims Statins protect against cardiovascular-related mortality but induce skeletal muscle toxicity. To investigate mechanisms of statins, we tested the hypothesis that statins optimized cardiac mitochondrial function but impaired vulnerable skeletal muscle by inducing different level of reactive oxygen species (ROS). Methods and results In atrium of patients treated with statins, ROS production was decreased and oxidative capacities were enhanced together with an extensive augmentation of mRNAs expression of peroxisome proliferator-activated receptor gamma co-activator (PGC-1) family. However, in deltoid biopsies from patients with statin-induced muscular myopathy, oxidative capacities were decreased together with ROS increase and a collapse of PGC-1 mRNA expression. Several animal and cell culture experiments were conducted and showed by using ROS scavengers that ROS production was the triggering factor responsible of atorvastatin-induced activation of mitochondrial biogenesis pathway and improvement of antioxidant capacities in heart. Conversely, in skeletal muscle, the large augmentation of ROS production following treatment induced mitochondrial impairments, and reduced mitochondrial biogenesis mechanisms. Quercetin, an antioxidant molecule, was able to counteract skeletal muscle deleterious effects of atorvastatin in rat. Conclusion Our findings identify statins as a new activating factor of cardiac mitochondrial biogenesis and antioxidant capacities, and suggest the importance of ROS/PGC-1 signalling pathway as a key element in regulation of mitochondrial function in cardiac as well as skeletal muscles. PMID:21775390

Local Burn Injury Promotes Defects in the Epidermal Lipid and Antimicrobial Peptide Barriers in Human Autograft Skin and Burn Margin: Implications for Burn Wound Healing and Graft Survival

PubMed Central

Plichta, Jennifer K.; Holmes, Casey J.; Gamelli, Richard L.; Radek, Katherine A.

2016-01-01

Burn injury increases the risk of morbidity and mortality by promoting severe hemodynamic shock and risk for local or systemic infection. Graft failure due to poor wound healing or infection remains a significant problem for burn subjects. The mechanisms by which local burn injury compromises the epithelial antimicrobial barrier function in the burn margin, containing the elements necessary for healing of the burn site, and in distal unburned skin, which serves as potential donor tissue, are largely unknown. The objective of this study was to establish defects in epidermal barrier function in human donor skin and burn margin, in order to identify potential mechanisms that may lead to graft failure and/or impaired burn wound healing. In the present study, we established that epidermal lipids and respective lipid synthesis enzymes were significantly reduced in both donor skin and burn margin. We further identified diverse changes in the gene expression and protein production of several candidate skin antimicrobial peptides (AMPs) in both donor skin and burn margin. These results also parallel changes in cutaneous AMP activity against common burn wound pathogens, aberrant production of epidermal proteases known to regulate barrier permeability and AMP activity, and greater production of pro-inflammatory cytokines known to be induced by AMPs. These findings suggest that impaired epidermal lipid and AMP regulation could contribute to graft failure and infectious complications in subjects with burn or other traumatic injury. PMID:27183442

Functional assessment of the elderly. A comparison of standard instruments with clinical judgment.

PubMed

Pinholt, E M; Kroenke, K; Hanley, J F; Kussman, M J; Twyman, P L; Carpenter, J L

1987-03-01

Using specific instruments and scales to measure mental status, nutritional state, visual acuity, gait, and activities of daily living, we studied 79 medical inpatients aged 70 years or older. We then interviewed the patients' primary physicians and nurses and asked them to rate their patients. The prevalence of functional impairment was high: 25 (32%) of the 79 patients were mentally impaired, 31 (39%) were malnourished, 18 (23%) were visually impaired, 31 (39%) had impaired gait, and 23 (29%) had problems with continence. Although clinicians recognized severe impairments, the sensitivity of their clinical judgment was poor in detecting moderate impairment in four categories: mental status sensitivity was 28% (5/18); nutrition, 54% (14/26); vision, 27% (4/15); and continence, 42% (5/12). With clinical judgment alone, physicians and nurses correctly identify severe impairment, but the more prevalent moderate impairments in mental status, nutrition, vision, and continence are poorly recognized. Comprehensive functional assessment instruments can detect these moderate impairments, which may be remediable through early intervention.

JP-8 jet fuel can promote auditory impairment resulting from subsequent noise exposure in rats.

PubMed

Fechter, Laurence D; Gearhart, Caroline; Fulton, Sherry; Campbell, Jerry; Fisher, Jeffrey; Na, Kwangsam; Cocker, David; Nelson-Miller, Alisa; Moon, Patrick; Pouyatos, Benoit

2007-08-01

We report on the transient and persistent effects of JP-8 jet fuel exposure on auditory function in rats. JP-8 has become the standard jet fuel utilized in the United States and North Atlantic Treaty Organization countries for military use and it is closely related to Jet A fuel, which is used in U.S. domestic aviation. Rats received JP-8 fuel (1000 mg/m(3)) by nose-only inhalation for 4 h and half of them were immediately subjected to an octave band of noise ranging between 97 and 105 dB in different experiments. The noise by itself produces a small, but permanent auditory impairment. The current permissible exposure level for JP-8 is 350 mg/m(3). Additionally, a positive control group received only noise exposure, and a fourth group consisted of untreated control subjects. Exposures occurred either on 1 day or repeatedly on 5 successive days. Impairments in auditory function were assessed using distortion product otoacoustic emissions and compound action potential testing. In other rats, tissues were harvested following JP-8 exposure for assessment of hydrocarbon levels or glutathione (GSH) levels. A single JP-8 exposure by itself at 1000 mg/m(3) did not disrupt auditory function. However, exposure to JP-8 and noise produced an additive disruption in outer hair cell function. Repeated 5-day JP-8 exposure at 1000 mg/m(3) for 4 h produced impairment of outer hair cell function that was most evident at the first postexposure assessment time. Partial though not complete recovery was observed over a 4-week postexposure period. The adverse effects of repeated JP-8 exposures on auditory function were inconsistent, but combined treatment with JP-8 + noise yielded greater impairment of auditory function, and hair cell loss than did noise by itself. Qualitative comparison of outer hair cell loss suggests an increase in outer hair cell death among rats treated with JP-8 + noise for 5 days as compared to noise alone. In most instances, hydrocarbon constituents of the fuel were largely eliminated in all tissues by 1-h postexposure with the exception of fat. Finally, JP-8 exposure did result in a significant depletion of total GSH that was observable in liver with a nonsignificant trend toward depletion in the brain and lung raising the possibility that the promotion of noise-induced hearing loss by JP-8 might have resulted from oxidative stress.

Timing, sequencing, and executive control in repetitive movement production.

PubMed

Krampe, Ralf Th; Mayr, Ulrich; Kliegl, Reinhold

2005-06-01

The authors demonstrate that the timing and sequencing of target durations require low-level timing and executive control. Sixteen young (M-sub(age) = 19 years) and 16 older (M-sub(age) = 70 years) adults participated in 2 experiments. In Experiment 1, individual mean-variance functions for low-level timing (isochronous tapping) and the sequencing of multiple targets (rhythm production) revealed (a) a dissociation of low-level timing and sequencing in both age groups, (b) negligible age differences for low-level timing, and (c) large age differences for sequencing. Experiment 2 supported the distinction between low-level timing and executive functions: Selection against a dominant rhythm and switching between rhythms impaired performances in both age groups and induced pronounced perseveration of the dominant pattern in older adults. ((c) 2005 APA, all rights reserved).

Impairment of Natural Killer Cytotoxic Activity and Interferon γ Production in Ccaat/Enhancer Binding Protein γ–Deficient Mice

PubMed Central

Kaisho, Tsuneyasu; Tsutsui, Hiroko; Tanaka, Takashi; Tsujimura, Tohru; Takeda, Kiyoshi; Kawai, Taro; Yoshida, Nobuaki; Nakanishi, Kenji; Akira, Shizuo

1999-01-01

We have investigated in vivo roles of CCAAT/enhancer binding protein γ (C/EBPγ) by gene targeting. C/EBPγ-deficient (C/EBPγ2/−) mice showed a high mortality rate within 48 h after birth. To analyze the roles of C/EBPγ in lymphoid lineage cells, bone marrow chimeras were established. C/EBPγ2/− chimeras showed normal T and B cell development. However, cytolytic functions of their splenic natural killer (NK) cells after stimulation with cytokines such as interleukin (IL)-12, IL-18, and IL-2 were significantly reduced as compared with those of control chimera NK cells. In addition, the ability of C/EBPγ−/− chimera splenocytes to produce interferon (IFN)-γ in response to IL-12 and/or IL-18 was markedly impaired. NK cells could be generated in vitro with normal surface marker expression in the presence of IL-15 from C/EBPγ2/− newborn spleen cells. However, they also showed lower cytotoxic activity and IFN-γ production when stimulated with IL-12 plus IL-18 than control NK cells, as observed in C/EBPγ2/− chimera splenocytes. In conclusion, our study reveals that C/EBPγ is a critical transcription factor involved in the functional maturation of NK cells. PMID:10587348

Impaired Adaptability of in Vivo Mitochondrial Energetics to Acute Oxidative Insult in Aged Skeletal Muscle

PubMed Central

Siegel, Michael P.; Wilbur, Tim; Mathis, Mark; Shankland, Eric; Trieu, Atlas; Harper, Mary-Ellen; Marcinek, David J.

2012-01-01

Periods of elevated reactive oxygen species (ROS) production are a normal part of mitochondrial physiology. However, little is known about age-related changes in the mitochondrial response to elevated ROS in vivo. Significantly, ROS-induced uncoupling of oxidative phosphorylation has received attention as a negative feedback mechanism to reduce mitochondrial superoxide production. Here we use a novel in vivo spectroscopy system to test the hypothesis that ROS-induced uncoupling is diminished in aged mitochondria. This system simultaneously acquires 31P magnetic resonance and near-infrared optical spectra to non-invasively measure phosphometabolite and O2 concentrations in mouse skeletal muscle. Using low dose paraquat to elevate intracellular ROS we assess in vivo mitochondrial function in young, middle aged, and old mice. Oxidative phosphorylation was uncoupled to the same degree in response to ROS at each age, but this uncoupling was associated with loss of phosphorylation capacity and total ATP in old mice only. Using mice lacking UCP3 we demonstrate that this in vivo uncoupling is independent of this putative uncoupler of skeletal muscle mitochondria. These data indicate that ROS-induced uncoupling persists throughout life, but that oxidative stress leads to mitochondrial deficits and loss of ATP in aged organisms that may contribute to impaired function and degeneration. PMID:22935551

The neuropsychological function of children with achondroplasia.

PubMed

Wigg, Kimberley; Tofts, Louise; Benson, Suzanne; Porter, Melanie

2016-11-01

The current observational study had three specific objectives: (i) to document any neuropsychological impairment in a sample of children with achondroplasia; (ii) to explore individual variability; and (iii) to determine the functional impact of any impairments. Fourteen children aged between 6 and 15 years with a medically confirmed diagnosis of achondroplasia (FGFR 3 mutation positive) underwent a comprehensive standardized neuropsychological evaluation. On average, while generally still within normal limits, significantly lower scores compared to standardized means were identified on: Full-scale IQ, verbal IQ, working memory, arithmetic, attention, executive functioning and aspects of day-to-day emotional, social, and behavioral functioning. Clinically significant levels of impairment at a group level were identified on measures of: arithmetic, attention, and executive functioning. There was variability among the group and for most measures scores ranged from impaired to within normal limits. A high percentage of children were impaired on measures of: verbal IQ, attention and executive functioning. Results of this study suggest a need for individual neuropsychological evaluation and monitoring of children with achondroplasia and suggest verbal IQ, arithmetic, attention, and executive functioning are particularly common areas of impairment. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

20 CFR 220.120 - The claimant's residual functional capacity.

Code of Federal Regulations, 2011 CFR

2011-04-01

... medically determinable impairment(s), such as skin impairment(s), epilepsy, impairment(s) of vision, hearing... with a low back disorder may be fully capable of the physical demands consistent with those of...

20 CFR 220.120 - The claimant's residual functional capacity.

Code of Federal Regulations, 2012 CFR

2012-04-01

... medically determinable impairment(s), such as skin impairment(s), epilepsy, impairment(s) of vision, hearing... with a low back disorder may be fully capable of the physical demands consistent with those of...

20 CFR 220.120 - The claimant's residual functional capacity.

Code of Federal Regulations, 2013 CFR

2013-04-01

... medically determinable impairment(s), such as skin impairment(s), epilepsy, impairment(s) of vision, hearing... with a low back disorder may be fully capable of the physical demands consistent with those of...

20 CFR 220.120 - The claimant's residual functional capacity.

Code of Federal Regulations, 2014 CFR

2014-04-01

... medically determinable impairment(s), such as skin impairment(s), epilepsy, impairment(s) of vision, hearing... with a low back disorder may be fully capable of the physical demands consistent with those of...

Nephrotic range proteinuria as a strong risk factor for rapid renal function decline during pre-dialysis phase in type 2 diabetic patients with severely impaired renal function.

PubMed

Kitai, Yuichiro; Doi, Yohei; Osaki, Keisuke; Sugioka, Sayaka; Koshikawa, Masao; Sugawara, Akira

2015-12-01

Proteinuria is an established risk factor for progression of renal disease, including diabetic nephropathy. The predictive power of proteinuria, especially nephrotic range proteinuria, for progressive renal deterioration has been well demonstrated in diabetic patients with normal to relatively preserved renal function. However, little is known about the relationship between severity of proteinuria and renal outcome in pre-dialysis diabetic patients with severely impaired renal function. 125 incident dialysis patients with type 2 diabetes were identified. This study was aimed at retrospectively evaluating the impact of nephrotic range proteinuria (urinary protein-creatinine ratio above 3.5 g/gCr) on renal function decline during the 3 months just prior to dialysis initiation. In total, 103 patients (82.4 %) had nephrotic range proteinuria. The median rate of decline in estimated glomerular filtration rate (eGFR) in this study population was 0.98 (interquartile range 0.51-1.46) ml/min/1.73 m(2) per month. Compared to patients without nephrotic range proteinuria, patients with nephrotic range proteinuria showed significantly faster renal function decline (0.46 [0.24-1.25] versus 1.07 [0.64-1.54] ml/min/1.73 m(2) per month; p = 0.007). After adjusting for gender, age, systolic blood pressure, serum albumin, calcium-phosphorus product, hemoglobin A1c, and use of an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker, patients with nephrotic range proteinuria showed a 3.89-fold (95 % CI 1.08-14.5) increased risk for rapid renal function decline defined as a decline in eGFR ≥0.5 ml/min/1.73 m(2) per month. Nephrotic range proteinuria is the predominant renal risk factor in type 2 diabetic patients with severely impaired renal function receiving pre-dialysis care.

Potential mechanisms for chemotherapy-induced impairments in cognitive function.

PubMed

Jansen, Catherine; Miaskowski, Christine; Dodd, Marilyn; Dowling, Glenna; Kramer, Joel

2005-11-03

To review the domains of cognitive function and their corresponding neuroanatomic structures as well as present current evidence for neurotoxicity associated with specific chemotherapeutic agents and potential mechanisms for chemotherapy-induced cognitive impairments. Published research articles, review articles, and textbooks. Chemotherapy does not appear to cross the blood-brain barrier when given in standard doses; however, many chemotherapy drugs have the potential to cause cognitive impairments through more than one mechanism. In addition, patient factors may be protective or place individuals at higher risk for cognitive impairments. Although evidence of chemotherapy-induced impairments in cognitive function exists, no clinical studies have attempted to elucidate the mechanisms for chemotherapy-induced impairments in cognitive function. In addition, further studies are needed to determine predictive factors, potential biomarkers, and relevant assessment parameters. The ability to identify high-risk patients has important implications for practice in regard to informed consent, patient education about the effects of treatment, and preventive strategies.

Concurrent Hypoparathyroidism Is Associated With Impaired Physical Function and Quality of Life in Hypothyroidism.

PubMed

Sikjaer, Tanja; Moser, Emil; Rolighed, Lars; Underbjerg, Line; Bislev, Lise Sofie; Mosekilde, Leif; Rejnmark, Lars

2016-07-01

Total thyroidectomy causes postsurgical hypothyroidism (HypoT). Besides HypoT, as a complication patients may also develop hypoparathyroidism (HypoPT). The aim of this study was to assess quality of life (QoL), muscle function, and postural stability in patients with postsurgical hypothyroidism and hypoparathyroidism (HypoT+PT) as compared to patients with postsurgical HypoT and healthy controls. Age- and gender-matched patients on treatment for HypoT+PT and HypoT were recruited from our outpatient clinic. Matched healthy controls were recruited from the general background population. Compared with controls, HypoT was associated with a significantly lower mental summary score, whereas patients with HypoT+PT had a significantly lower physical summary score (Short Form 36 Health Survey questionnaire version 2). Moreover, the physical component score was significantly lower in patients with HypoT+PT compared with HypoT. WHO-5 well-being index was significantly lower in both groups of patients compared with controls, but did not differ between groups of patients. Compared with controls, muscle strength and maximal force production was significantly reduced in HypoT+PT, but not in HypoT. In HypoT+PT, the time spent on the Timed Up & Go test and the Repeated Chair Stands test were significantly longer than in the HypoT group and the control group. Postsurgical HypoT+PT is associated with a more severe impairment of QoL, in particular regarding physical functioning, than HypoT. HypoT+PT patients are also hampered by impaired muscle function. Studies on how to improve well-being and muscle function in HypoT+PT patients are warranted. © 2016 American Society for Bone and Mineral Research. © 2016 American Society for Bone and Mineral Research.

Natural Killer (NK) Cell Functionality after human Spinal Cord Injury (SCI): protocol of a prospective, longitudinal study.

PubMed

Laginha, Inês; Kopp, Marcel A; Druschel, Claudia; Schaser, Klaus-Dieter; Brommer, Benedikt; Hellmann, Rick C; Watzlawick, Ralf; Ossami-Saidi, Ramin-Raul; Prüss, Harald; Failli, Vieri; Meisel, Christian; Liebscher, Thomas; Prilipp, Erik; Niedeggen, Andreas; Ekkernkamp, Axel; Grittner, Ulrike; Piper, Sophie K; Dirnagl, Ulrich; Killig, Monica; Romagnani, Chiara; Schwab, Jan M

2016-09-13

Natural killer (NK) cells comprise the main components of lymphocyte-mediated nonspecific immunity. Through their effector function they play a crucial role combating bacterial and viral challenges. They are also thought to be key contributors to the systemic spinal cord injury-induced immune-deficiency syndrome (SCI-IDS). SCI-IDS increases susceptibility to infection and extends to the post-acute and chronic phases after SCI. The prospective study of NK cell function after traumatic SCI was carried out in two centers in Berlin, Germany. SCI patients and control patients with neurologically silent vertebral fracture also undergoing surgical stabilization were enrolled. Furthermore healthy controls were included to provide reference data. The NK cell function was assessed at 7 (5-9) days, 14 days (11-28) days, and 10 (8-12) weeks post-trauma. Clinical documentation included the American Spinal Injury Association (ASIA) impairment scale (AIS), neurological level of injury, infection status, concomitant injury, and medications. The primary endpoint of the study is CD107a expression by NK cells (cytotoxicity marker) 8-12 weeks following SCI. Secondary endpoints are the NK cell's TNF-α and IFN-γ production by the NK cells 8-12 weeks following SCI. The protocol of this study was developed to investigate the hypotheses whether i) SCI impairs NK cell function throughout the post-acute and sub-acute phases after SCI and ii) the degree of impairment relates to lesion height and severity. A deeper understanding of the SCI-IDS is crucial to enable strategies for prevention of infections, which are associated with poor neurological outcome and elevated mortality. DRKS00009855 .

[Qualifying language disorders of schizophrenia through the speech therapists' assessment].

PubMed

Boucard, C; Laffy-Beaufils, B

2008-06-01

This study investigates a comprehensive assessment of language disorders in order to identify impaired and unaffected language abilities of individuals with schizophrenia. Furthermore, the purpose of this study was to demonstrate the importance of the role of speech therapists in the treatment of schizophrenia. Speech therapy is especially thought to treat language disorders. However, to date, speech therapists have not been solicited in the treatment of schizophrenia, despite growing evidence supporting that schizophrenia is characterized by cognitive disorders such as impairments in memory, attention, executive functioning and language. In this article, we discuss the fact that elements of language and cognition are interactively affected and that cognition influences language. We then demonstrate that language impairments can be treated in the same way as neurological language impairments (cerebrovascular disease, brain injury), in order to reduce their functional outcome. Schizophrenia affects the pragmatic component of language with a major negative outcome in daily living skills [Champagne M, Stip E, Joanette Y. Social cognition deficit in schizophrenia: accounting for pragmatic deficits in communication abilities? Curr Psychiatry Rev:2006;(2):309-315]. The results of our comprehensive assessment also provide a basis for the design of a care plan. For this, subjects with schizophrenia were examined for language comprehension and language production with a focus on pragmatic abilities. In neurology, standardized tests are available that have been designed specifically to assess language functions. However, no such tests are available in psychiatry, so we gathered assessments widely used in neurology and examined the more relevant skills. In this article, each test we chose is described and particular attention is paid to the information they provided on impaired language abilities in schizophrenia. In this manner, we provide an accurate characterization of schizophrenia-associated language impairments and offer a solid foundation for rehabilitation. Current research makes connections between schizophrenia and other neurological disorders concerning language. Nevertheless, further studies are needed to explore these connections to complete our investigations. The strategies we designed are aimed at enabling a subject with schizophrenia to improve his/her language skills. We support the idea that such improvement could be reached by speech therapy. We conclude that speech therapists can play an important role in the non pharmacological treatment of schizophrenia, by selecting appropriate interventions that capitalize on spared abilities to compensate for impaired abilities.

Epigenetic oxidative redox shift (EORS) theory of aging unifies the free radical and insulin signaling theories.

PubMed

Brewer, Gregory J

2010-03-01

Harman's free radical theory of aging posits that oxidized macromolecules accumulate with age to decrease function and shorten life-span. However, nutritional and genetic interventions to boost anti-oxidants have generally failed to increase life-span. Furthermore, the free radical theory fails to explain why exercise causes higher levels of oxyradical damage, but generally promotes healthy aging. The separate anti-aging paradigms of genetic or caloric reductions in the insulin signaling pathway is thought to slow the rate of living to reduce metabolism, but recent evidence from Westbrook and Bartke suggests metabolism actually increases in long-lived mice. To unify these disparate theories and data, here, we propose the epigenetic oxidative redox shift (EORS) theory of aging. According to EORS, sedentary behavior associated with age triggers an oxidized redox shift and impaired mitochondrial function. In order to maintain resting energy levels, aerobic glycolysis is upregulated by redox-sensitive transcription factors. As emphasized by DeGrey, the need to supply NAD(+) for glucose oxidation and maintain redox balance with impaired mitochondrial NADH oxidoreductase requires the upregulation of other oxidoreductases. In contrast to the 2% inefficiency of mitochondrial reduction of oxygen to the oxyradical, these other oxidoreductases enable glycolytic energy production with a deleterious 100% efficiency in generating oxyradicals. To avoid this catastrophic cycle, lactate dehydrogenase is upregulated at the expense of lactic acid acidosis. This metabolic shift is epigenetically enforced, as is insulin resistance to reduce mitochondrial turnover. The low mitochondrial capacity for efficient production of energy reinforces a downward spiral of more sedentary behavior leading to accelerated aging, increased organ failure with stress, impaired immune and vascular functions and brain aging. Several steps in the pathway are amenable to reversal for exit from the vicious cycle of EORS. Examples from our work in the aging rodent brain as well as other aging models are provided. Copyright 2010 Elsevier Inc. All rights reserved.

Neuroprotectin/protectin D1: endogenous biosynthesis and actions on diabetic macrophages in promoting wound healing and innervation impaired by diabetes

PubMed Central

Tian, Haibin; Lu, Yan; Laborde, James Monroe; Muhale, Filipe A.; Wang, Quansheng; Alapure, Bhagwat V.; Serhan, Charles N.; Bazan, Nicolas G.

2014-01-01

Dysfunction of macrophages (MΦs) in diabetic wounds impairs the healing. MΦs produce anti-inflammatory and pro-resolving neuroprotectin/protectin D1 (NPD1/PD1, 10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid); however, little is known about endogenous NPD1 biosynthesis by MΦs and the actions of NPD1 on diabetic MΦ functions in diabetic wound healing. We used an excisional skin wound model of diabetic mice, MΦ depletion, MΦs isolated from diabetic mice, and mass spectrometry-based targeted lipidomics to study the time course progression of NPD1 levels in wounds, the roles of MΦs in NPD1 biosynthesis, and NPD1 action on diabetic MΦ inflammatory activities. We also investigated the healing, innervation, chronic inflammation, and oxidative stress in diabetic wounds treated with NPD1 or NPD1-modulated MΦs from diabetic mice. Injury induced endogenous NPD1 biosynthesis in wounds, but diabetes impeded NPD1 formation. NPD1 was mainly produced by MΦs. NPD1 enhanced wound healing and innervation in diabetic mice and promoted MΦs functions that accelerated these processes. The underlying mechanisms for these actions of NPD1 or NPD1-modulated MΦs involved 1) attenuating MΦ inflammatory activities and chronic inflammation and oxidative stress after acute inflammation in diabetic wound, and 2) increasing MΦ production of IL10 and hepatocyte growth factor. Taken together, NPD1 appears to be a MΦs-produced factor that accelerates diabetic wound healing and promotes MΦ pro-healing functions in diabetic wounds. Decreased NPD1 production in diabetic wound is associated with impaired healing. This study identifies a new molecular target that might be useful in development of more effective therapeutics based on NPD1 and syngeneic diabetic MΦs for treatment of diabetic wounds. PMID:25273880

Neuroprotectin/protectin D1: endogenous biosynthesis and actions on diabetic macrophages in promoting wound healing and innervation impaired by diabetes.

PubMed

Hong, Song; Tian, Haibin; Lu, Yan; Laborde, James Monroe; Muhale, Filipe A; Wang, Quansheng; Alapure, Bhagwat V; Serhan, Charles N; Bazan, Nicolas G

2014-12-01

Dysfunction of macrophages (MΦs) in diabetic wounds impairs the healing. MΦs produce anti-inflammatory and pro-resolving neuroprotectin/protectin D1 (NPD1/PD1, 10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid); however, little is known about endogenous NPD1 biosynthesis by MΦs and the actions of NPD1 on diabetic MΦ functions in diabetic wound healing. We used an excisional skin wound model of diabetic mice, MΦ depletion, MΦs isolated from diabetic mice, and mass spectrometry-based targeted lipidomics to study the time course progression of NPD1 levels in wounds, the roles of MΦs in NPD1 biosynthesis, and NPD1 action on diabetic MΦ inflammatory activities. We also investigated the healing, innervation, chronic inflammation, and oxidative stress in diabetic wounds treated with NPD1 or NPD1-modulated MΦs from diabetic mice. Injury induced endogenous NPD1 biosynthesis in wounds, but diabetes impeded NPD1 formation. NPD1 was mainly produced by MΦs. NPD1 enhanced wound healing and innervation in diabetic mice and promoted MΦs functions that accelerated these processes. The underlying mechanisms for these actions of NPD1 or NPD1-modulated MΦs involved 1) attenuating MΦ inflammatory activities and chronic inflammation and oxidative stress after acute inflammation in diabetic wound, and 2) increasing MΦ production of IL10 and hepatocyte growth factor. Taken together, NPD1 appears to be a MΦs-produced factor that accelerates diabetic wound healing and promotes MΦ pro-healing functions in diabetic wounds. Decreased NPD1 production in diabetic wound is associated with impaired healing. This study identifies a new molecular target that might be useful in development of more effective therapeutics based on NPD1 and syngeneic diabetic MΦs for treatment of diabetic wounds. Copyright © 2014 the American Physiological Society.

Usefulness of the University of California San Diego Performance-Based Skills Assessment for the evaluation of cognitive function and activities of daily living function in patients with cognitive impairment.

PubMed

Jeon, Dong-Wook; Ju, Hyun-Bin; Jung, Do-Un; Kim, Sung-Jin; Shim, Joo-Cheol; Moon, Jung-Joon; Kim, You-Na

2017-10-25

To assess the usefulness of the University of California San Diego Performance-Based Skills Assessment (UPSA) as a new diagnostic method and tool for the assessment of cognitive function and activities of daily living function in patients with cognitive impairment. In total, 35 patients with cognitive impairment and 35 healthy controls were recruited for this study. The Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), and Global Deterioration Scale (GDS) were used for the evaluation of cognitive function, while the Barthel Activities of Daily Living Index (BADL), Instrumental Activities of Daily Living Index (IADL), and UPSA were used for the evaluation of activities of daily living function. UPSA scores were significantly lower in patients with cognitive impairment than in controls. The UPSA total score was significantly correlated with MMSE, CDR, GDS, and IADL scores. With regard to the detection of cognitive impairment, UPSA exhibited a greater determination power (R 2 = 0.593) compared with BADL (R 2 = 0.149) and IADL (R 2 = 0.423) and higher sensitivity and specificity compared with IADL. Our results suggest that UPSA is a useful tool for the evaluation of cognitive function and activities of daily living function in patients with cognitive impairment.

Impaired renal function modifies the risk of severe hypoglycaemia among users of insulin but not glyburide: a population-based nested case-control study.

PubMed

Weir, Matthew A; Gomes, Tara; Mamdani, Muhammad; Juurlink, David N; Hackam, Daniel G; Mahon, Jeffrey L; Jain, Arsh K; Garg, Amit X

2011-06-01

Little evidence justifies the avoidance of glyburide in patients with impaired renal function. We aimed to determine if renal function modifies the risk of hypoglycaemia among patients using glyburide. We conducted a nested case-control study using administrative records and laboratory data from Ontario, Canada. We included outpatients 66 years of age and older with diabetes mellitus and prescriptions for glyburide, insulin or metformin. We ascertained hypoglycaemic events using administrative records and estimated glomerular filtration rates (eGFR) using serum creatinine concentrations. From a cohort of 19,620 patients, we identified 204 cases whose eGFR was ≥ 60 mL/min/1.73 m(2) (normal renal function) and 354 cases whose eGFR was < 60 mL/min/1.73 m(2) (impaired renal function). Compared to metformin, glyburide is associated with a greater risk of hypoglycaemia in patients with both normal [adjusted odds ratio (OR) 9.0, 95% confidence interval (95% CI) 4.9-16.4] and impaired renal function (adjusted OR 6.0, 95% CI 3.8-9.5). We observed a similar relationship when comparing insulin to metformin; the risk was greater in patients with normal renal function (adjusted OR 18.7, 95% CI 10.5-33.5) compared to those with impaired renal function (adjusted OR 7.9, 95% CI 5.0-12.4). Tests of interaction showed that among glyburide users, renal function did not significantly modify the risk of hypoglycaemia, but among insulin users, impaired renal function is associated with a lower risk. In this population-based study, impaired renal function did not augment the risk of hypoglycaemia associated with glyburide use.

Frontal lobe connectivity and cognitive impairment in pediatric frontal lobe epilepsy.

PubMed

Braakman, Hilde M H; Vaessen, Maarten J; Jansen, Jacobus F A; Debeij-van Hall, Mariette H J A; de Louw, Anton; Hofman, Paul A M; Vles, Johan S H; Aldenkamp, Albert P; Backes, Walter H

2013-03-01

Cognitive impairment is frequent in children with frontal lobe epilepsy (FLE), but its etiology is unknown. With functional magnetic resonance imaging (fMRI), we have explored the relationship between brain activation, functional connectivity, and cognitive functioning in a cohort of pediatric patients with FLE and healthy controls. Thirty-two children aged 8-13 years with FLE of unknown cause and 41 healthy age-matched controls underwent neuropsychological assessment and structural and functional brain MRI. We investigated to which extent brain regions activated in response to a working memory task and assessed functional connectivity between distant brain regions. Data of patients were compared to controls, and patients were grouped as cognitively impaired or unimpaired. Children with FLE showed a global decrease in functional brain connectivity compared to healthy controls, whereas brain activation patterns in children with FLE remained relatively intact. Children with FLE complicated by cognitive impairment typically showed a decrease in frontal lobe connectivity. This decreased frontal lobe connectivity comprised both connections within the frontal lobe as well as connections from the frontal lobe to the parietal lobe, temporal lobe, cerebellum, and basal ganglia. Decreased functional frontal lobe connectivity is associated with cognitive impairment in pediatric FLE. The importance of impairment of functional integrity within the frontal lobe network, as well as its connections to distant areas, provides new insights in the etiology of the broad-range cognitive impairments in children with FLE. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

Osteogenesis imperfecta in childhood: impairment and disability--a follow-up study.

PubMed

Engelbert, R H; Beemer, F A; van der Graaf, Y; Helders, P J

1999-08-01

To evaluate differences over time (mean follow-up, 14 months) on impairment parameters (range of joint motion and muscle strength), functional limitation parameters (functional ability), and disability parameters (caregiver assistance in achieving functional skills) in osteogenesis imperfecta (OI), related to the different types of the disease. A prospective, descriptive study. Fifty-four children with OI and their parents participated at the start of the study. At the end, 44 children participated in the assessment of functional skills and 42 of them participated in clinical assessment (OI type I, n = 19; OI type III, n = 13; OI type IV, n = 10). Range of joint motion was measured by means of goniometry. Generalized hypermobility was scored according to Bulbena. Manual muscle strength was scored by means of the MRC grading system. The level of ambulation was scored according to Bleck, and functional skills and caregiver assistance were scored with the Pediatric Evaluation of Disability Inventory. The different types of OI have impact on impairment, functional limitation, and disability. Almost all impairment parameters did not change significantly over time, whereas some disability parameters seemed to improve significantly. Impairment parameters in OI are presumably not always preconditions for functional limitation and disability. A 1-year follow-up revealed no significant changes in impairment parameters, whereas some disability parameters improved. Treatment strategies in OI should, therefore, focus primarily on improving functional ability, with respect to the natural course of the disease, and not only on impairment parameters.

Sarm1 deficiency impairs synaptic function and leads to behavioral deficits, which can be ameliorated by an mGluR allosteric modulator.

PubMed

Lin, Chia-Wen; Chen, Chiung-Ya; Cheng, Sin-Jhong; Hu, Hsiao-Tang; Hsueh, Yi-Ping

2014-01-01

Innate immune responses have been shown to influence brain development and function. Dysregulation of innate immunity is significantly associated with psychiatric disorders such as autism spectrum disorders and schizophrenia, which are well-known neurodevelopmental disorders. Recent studies have revealed that critical players of the innate immune response are expressed in neuronal tissues and regulate neuronal function and activity. For example, Sarm1, a negative regulator that acts downstream of Toll-like receptor (TLR) 3 and 4, is predominantly expressed in neurons. We have previously shown that Sarm1 regulates neuronal morphogenesis and the expression of inflammatory cytokines in the brain, which then affects learning ability, cognitive flexibility, and social interaction. Because impaired neuronal morphogenesis and dysregulation of cytokine expression may disrupt neuronal activity, we investigated whether Sarm1 knockdown affects the synaptic responses of neurons. We here show that reduced Sarm1 expression impairs metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) formation but enhances N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation production in hippocampal CA1 neurons. The expression levels of post-synaptic proteins, including NR2a, NR1, Shank1 and Shank3, are also altered in Sarm1 knockdown mice, suggesting a role for Sarm1 in the maintenance of synaptic homeostasis. The addition of a positive allosteric modulator of mGluR5, CDPPB, ameliorates the LTD defects in slice recording and the behavioral deficits in social interaction and associative memory. These results suggest an important role for mGluR5 signaling in the function of Sarm1. In conclusion, our study demonstrates a role for Sarm1 in the regulation of synaptic plasticity. Through these mechanisms, Sarm1 knockdown results in the impairment of associative memory and social interactions in mice.

Obesity's Effects on the Onset of Functional Impairment among Older Adults

ERIC Educational Resources Information Center

Jenkins, Kristi Rahrig

2004-01-01

Purpose: This study has two purposes. First, it determines if there is a relationship between body weight and the onset of functional impairment across time among this sample of older adults. More specifically, it examines if obese older adults are more likely to experience the onset of functional impairment. Second, it explores how health…

The Brief Impairment Scale (Bis): A Multidimensional Scale of Functional Impairment for Children and Adolescents.

ERIC Educational Resources Information Center

Bird, Hector R.; Canino, Glorisa J.; Davies, Mark; Ramirez, Rafael; Chavez, Ligia; Duarte, Cristiane; Shen, Sa

2005-01-01

Objective: This article provides the results of the psychometric testing of the Brief Impairment Scale (BIS). The BIS is a 23-item instrument that evaluates three domains of functioning: interpersonal relations, school/work functioning, and self-care/self-fulfilment. It capitalizes on the strengths of existing global measures while addressing some…

Executive Function and Behavioral Problems in Students with Visual Impairments at Mainstream and Special Schools

ERIC Educational Resources Information Center

Heyl, Vera; Hintermair, Manfred

2015-01-01

Introduction: In this study, executive function of school-aged children with visual impairments (that is, those who are blind or have low vision) is examined in the context of behavioral problems and communicative competence. Methods: Teachers assessed the executive function of a sample of 226 visually impaired students from mainstream schools and…

Immunotherapy of Mild Cognitive Impairment by ω-3 Supplementation: Why Are Amyloid-β Antibodies and ω-3 Not Working in Clinical Trials?

PubMed

Fiala, Milan; Restrepo, Lucas; Pellegrini, Matteo

2018-01-01

This article reviews the basic tenets of a clinical approach to effective immunotherapy of Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI). Although one randomized controlled study in early MCI patients by fish-derived omega-3 fatty acids (ω-3) showed slowing of disease progression, large clinical trials with different products have failed to show cognitive effects. Macrophages of healthy subjects phagocytize and degrade amyloid-β1 - 42 (Aβ) in the brain tissues, whereas macrophages of patients with AD and MCI are functionally defective. ω-3 and ω-3-derived specialized proresolving mediators (SPMs), such as resolvin D1, have powerful biochemical and immunological effects, which may repair the functions of MCI patients' macrophages in the brain's clearance of Aβ. Unfortunately, ω-3 products on the market have a variable quality. Nutritional supplementation with a combination drink called Smartfish with an emulsion of ω-3 and other fatty acids, antioxidants, 1,25-dihydroxy vitamin D3, and resveratrol improved the innate immune system of MCI patients by modulation of macrophage type to the pro-phagocytic M1-M2 type with an effective unfolded protein response against endoplasmic reticulum stress. Some MCI patients maintained their initial cognitive status for three years on Smartfish supplementation. Future randomized clinical trials should investigate the immune effects of ω-3, 1,25-dihydroxy vitamin D3, and SPMs on macrophage type, function, and biochemistry in parallel with cognitive effects.

Impairment of liver synthetic function and the production of plasma proteins in primary breast cancer patients on doxorubicincyclophosphamide (AC) protocol.

PubMed

Saleem, Zikria; Ahmad, Mobasher; Hashmi, Furqan Khurshid; Saeed, Hamid; Aziz, Muhammad Tahir

2016-09-01

Doxorubicin and Cyclophosphamide (AC protocol) combination is usually considered as a first line therapy in newly diagnosed breast cancer patients. Thus, a retrospective observational study was conducted to monitor the effect of AC protocol on liver synthetic functions and production of plasma proteins in breast cancer patients, reporting to specialized cancer care hospital of Lahore, Pakistan. A total of 75 patients (n=75) on AC protocol with breast cancer were observed in this study. The patient data including age, gender, body surface area, dosage, disease status and laboratory biochemical values were recorded by reviewing historical treatment records. Pre-treatment values were taken as baseline values for albumin, globulin, blood urea nitrogen (BUN), albumin/globulin (A/G) ratio and total proteins. The baseline values were compared after each cycle of by applying ANOVA using statistical tool SPSS® version 21. The plasma levels of blood urea nitrogen (BUN), total protein and globulin dropped significantly (p<0.05) in patients of all age groups. However, the albumin levels were not significantly changed (p>0.05). The A/G ratio level increased (p<0.05) as a result of reduction in globulin levels. Significant changes in plasma protein levels were observed in the elderly patients (50 to 65 years) than patients between 20 to 50 years of age. AC protocol impairs liver synthetic functions as observed by decreased blood urea nitrogen (BUN) and plasma protein levels.

Examining the Disability Model From the International Classification of Functioning, Disability, and Health Using a Large Data Set of Community-Dwelling Malaysian Older Adults

PubMed Central

Loke, Seng Cheong; Lim, Wee Shiong; Someya, Yoshiko; Hamid, Tengku A.; Nudin, Siti S. H.

2015-01-01

Objective: This study examines the International Classification of Functioning, Disability, and Health model (ICF) using a data set of 2,563 community-dwelling elderly with disease-independent measures of mobility, physical activity, and social networking, to represent ICF constructs. Method: The relationship between chronic disease and disability (independent and dependent variables) was examined using logistic regression. To demonstrate variability in activity performance with functional impairment, graphing was used. The relationship between functional impairment, activity performance, and social participation was examined graphically and using ANOVA. The impact of cognitive deficits was quantified through stratifying by dementia. Results: Disability is strongly related to chronic disease (Wald 25.5, p < .001), functional impairment with activity performance (F = 34.2, p < .001), and social participation (F= 43.6, p < .001). With good function, there is considerable variability in activity performance (inter-quartile range [IQR] = 2.00), but diminishes with high impairment (IQR = 0.00) especially with cognitive deficits. Discussion: Environment modification benefits those with moderate functional impairment, but not with higher grades of functional loss. PMID:26472747

Cholesterol overload impairing cerebellar function: the promise of natural products.

PubMed

El-Sayyad, Hassan I H

2015-05-01

The cerebellum is the part of the brain most involved in controlling motor and cognitive function. The surface becomes convoluted, forming folia that have a characteristic internal structure of three layers including molecular, Purkinje cell, and granular layer. This complex neural network gives rise to a massive signal-processing capability. Cholesterol is a major constituent, derived by de novo synthesis and the blood-brain barrier. Cholesterol is tightly regulated between neurons and glia-that is, astrocytes, microglia, and oligodendrocytes-and is essential for normal brain development. The axon is wrapped by myelin (cholesterol, phospholipids, and glycosphingolipids) and made up of membranes of oligodendrocytes, separated by periodic gaps in the myelin sheath, called nodes of Ranvier. Hypercholesterolemia is associated with increased oxidative stress and the development of neurotoxicity and Alzheimer's disease. Treatment with natural products has been found to support improved brain function and reduce low-density-lipoprotein cholesterol level. Fish oil is one such product; among the many plant products are: Morus alba leaves, fruit, and bark; pomegranate fruit and peel; Barley β - glucans; date palm; and Allium sativum. The therapeutic potential was discussed in relation with the antilipidemic drugs, statins (HMG-CoA reductase inhibitors). Copyright © 2015 Elsevier Inc. All rights reserved.

Cytokinin production by Pseudomonas fluorescens G20-18 determines biocontrol activity against Pseudomonas syringae in Arabidopsis

PubMed Central

Großkinsky, Dominik K.; Tafner, Richard; Moreno, María V.; Stenglein, Sebastian A.; García de Salamone, Inés E.; Nelson, Louise M.; Novák, Ondřej; Strnad, Miroslav; van der Graaff, Eric; Roitsch, Thomas

2016-01-01

Plant beneficial microbes mediate biocontrol of diseases by interfering with pathogens or via strengthening the host. Although phytohormones, including cytokinins, are known to regulate plant development and physiology as well as plant immunity, their production by microorganisms has not been considered as a biocontrol mechanism. Here we identify the ability of Pseudomonas fluorescens G20-18 to efficiently control P. syringae infection in Arabidopsis, allowing maintenance of tissue integrity and ultimately biomass yield. Microbial cytokinin production was identified as a key determinant for this biocontrol effect on the hemibiotrophic bacterial pathogen. While cytokinin-deficient loss-of-function mutants of G20-18 exhibit impaired biocontrol, functional complementation with cytokinin biosynthetic genes restores cytokinin-mediated biocontrol, which is correlated with differential cytokinin levels in planta. Arabidopsis mutant analyses revealed the necessity of functional plant cytokinin perception and salicylic acid-dependent defence signalling for this biocontrol mechanism. These results demonstrate microbial cytokinin production as a novel microbe-based, hormone-mediated concept of biocontrol. This mechanism provides a basis to potentially develop novel, integrated plant protection strategies combining promotion of growth, a favourable physiological status and activation of fine-tuned direct defence and abiotic stress resilience. PMID:26984671

Cytokinin production by Pseudomonas fluorescens G20-18 determines biocontrol activity against Pseudomonas syringae in Arabidopsis.

PubMed

Großkinsky, Dominik K; Tafner, Richard; Moreno, María V; Stenglein, Sebastian A; García de Salamone, Inés E; Nelson, Louise M; Novák, Ondřej; Strnad, Miroslav; van der Graaff, Eric; Roitsch, Thomas

2016-03-17

Plant beneficial microbes mediate biocontrol of diseases by interfering with pathogens or via strengthening the host. Although phytohormones, including cytokinins, are known to regulate plant development and physiology as well as plant immunity, their production by microorganisms has not been considered as a biocontrol mechanism. Here we identify the ability of Pseudomonas fluorescens G20-18 to efficiently control P. syringae infection in Arabidopsis, allowing maintenance of tissue integrity and ultimately biomass yield. Microbial cytokinin production was identified as a key determinant for this biocontrol effect on the hemibiotrophic bacterial pathogen. While cytokinin-deficient loss-of-function mutants of G20-18 exhibit impaired biocontrol, functional complementation with cytokinin biosynthetic genes restores cytokinin-mediated biocontrol, which is correlated with differential cytokinin levels in planta. Arabidopsis mutant analyses revealed the necessity of functional plant cytokinin perception and salicylic acid-dependent defence signalling for this biocontrol mechanism. These results demonstrate microbial cytokinin production as a novel microbe-based, hormone-mediated concept of biocontrol. This mechanism provides a basis to potentially develop novel, integrated plant protection strategies combining promotion of growth, a favourable physiological status and activation of fine-tuned direct defence and abiotic stress resilience.

The association of domestic violence and social resources with functioning in an adult trauma-affected sample living in Kurdistan, Northern Iraq

PubMed Central

Kane, Jeremy C.; Hall, Brian J.; Bolton, Paul; Murray, Laura K.; Ahmed, Ahmed Mohammed Amin; Bass, Judith K.

2016-01-01

Ability to function in tasks and activities is an important aspect of daily living. There are factors that increase the risk for impaired functioning, such as experiences of domestic violence (DV) and other trauma types, and factors that provide a buffer to existing risks and allow the individual to continue and build functioning, such as access to social resources. This cross-sectional study investigated the direct effects of DV and access to social resources (perceived social support, social integration, and frequency of social contact), as well as their potential interactive effects, on daily functioning among 894 male and female trauma survivors who attended primary care clinics in Kurdistan, Iraq in 2009 and 2010. Experiencing DV was not associated with functioning for males (p=.15) or females (p=.60), suggesting that in the context of a trauma-affected sample, the experience of DV may not significantly increase the risk for functional impairment. Greater amounts of social integration were associated with less functional impairment among males (p<.01) and females (p<.05); social integration was associated with less functional impairment among males only (p<.01); and frequency of social contact was associated with less functional impairment among females only (p<.05), indicating that the association between social resource type and functioning differed by gender. Standardized beta coefficients indicated that social resources had a stronger effect on functioning among men compared to women. Among males who experienced DV, social integration was the only social resource associated with less functional impairment (p<.01); among male trauma survivors who did not experience DV, social support was the only resource associated with less functional impairment (p<.01). Further investigation into the association of social resources with functioning and how these differ by gender and DV exposure is warranted to inform intervention strategies for survivors of DV and other traumas in post-conflict settings. PMID:27021741

IMMUNODEFICIENCIES. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations.

PubMed

Okada, Satoshi; Markle, Janet G; Deenick, Elissa K; Mele, Federico; Averbuch, Dina; Lagos, Macarena; Alzahrani, Mohammed; Al-Muhsen, Saleh; Halwani, Rabih; Ma, Cindy S; Wong, Natalie; Soudais, Claire; Henderson, Lauren A; Marzouqa, Hiyam; Shamma, Jamal; Gonzalez, Marcela; Martinez-Barricarte, Rubén; Okada, Chizuru; Avery, Danielle T; Latorre, Daniela; Deswarte, Caroline; Jabot-Hanin, Fabienne; Torrado, Egidio; Fountain, Jeffrey; Belkadi, Aziz; Itan, Yuval; Boisson, Bertrand; Migaud, Mélanie; Arlehamn, Cecilia S Lindestam; Sette, Alessandro; Breton, Sylvain; McCluskey, James; Rossjohn, Jamie; de Villartay, Jean-Pierre; Moshous, Despina; Hambleton, Sophie; Latour, Sylvain; Arkwright, Peter D; Picard, Capucine; Lantz, Olivier; Engelhard, Dan; Kobayashi, Masao; Abel, Laurent; Cooper, Andrea M; Notarangelo, Luigi D; Boisson-Dupuis, Stéphanie; Puel, Anne; Sallusto, Federica; Bustamante, Jacinta; Tangye, Stuart G; Casanova, Jean-Laurent

2015-08-07

Human inborn errors of immunity mediated by the cytokines interleukin-17A and interleukin-17F (IL-17A/F) underlie mucocutaneous candidiasis, whereas inborn errors of interferon-γ (IFN-γ) immunity underlie mycobacterial disease. We report the discovery of bi-allelic RORC loss-of-function mutations in seven individuals from three kindreds of different ethnic origins with both candidiasis and mycobacteriosis. The lack of functional RORγ and RORγT isoforms resulted in the absence of IL-17A/F-producing T cells in these individuals, probably accounting for their chronic candidiasis. Unexpectedly, leukocytes from RORγ- and RORγT-deficient individuals also displayed an impaired IFN-γ response to Mycobacterium. This principally reflected profoundly defective IFN-γ production by circulating γδ T cells and CD4(+)CCR6(+)CXCR3(+) αβ T cells. In humans, both mucocutaneous immunity to Candida and systemic immunity to Mycobacterium require RORγ, RORγT, or both. Copyright © 2015, American Association for the Advancement of Science.

Desnutrin/ATGL Activates PPARδ to Promote Mitochondrial Function for Insulin Secretion in Islet β cells

PubMed Central

Tang, Tianyi; Abbott, Marcia J.; Ahmadian, Maryam; Lopes, Andressa B.; Wang, Yuhui; Sul, Hei Sook

2013-01-01

Excessive caloric intake leading to obesity is associated with insulin resistance and dysfuntion of islet β cells. High fat feeding decreases desnutrin (also called ATGL/PNPLA2) levels in islets. Here we show that desnutrin ablation via RIP-Cre (βKO) or RIP-CreER results in hyperglycemia with impaired glucose-stimulated insulin secretion (GSIS). Due to decreased lipolysis, islets have higher TAG content but lower free FA levels. βKO islets exhibit impaired mitochondrial respiration and lower production of ATP required for GSIS, along with decreased expression of PPARδ target genes involved in mitochondrial oxidation. Furthermore, synthetic PPARδ, but not PPARα, agonist restores GSIS and expression of mitochondrial oxidative genes in βKO mice, revealing desnutrin-catalyzed lipolysis generates PPARδ ligands. Finally, adenoviral expression of desnutrin in βKO islets restores all defects of βKO islet phenotype and function including GSIS and mitochondrial defects, demonstrating the critical role of the desnutrin-PPARδ-mitochondrial oxidation axis in regulating islet β cell GSIS. PMID:24268737

Connecting Malfunctioning Glial Cells and Brain Degenerative Disorders.

PubMed

Kaminsky, Natalie; Bihari, Ofer; Kanner, Sivan; Barzilai, Ari

2016-06-01

The DNA damage response (DDR) is a complex biological system activated by different types of DNA damage. Mutations in certain components of the DDR machinery can lead to genomic instability disorders that culminate in tissue degeneration, premature aging, and various types of cancers. Intriguingly, malfunctioning DDR plays a role in the etiology of late onset brain degenerative disorders such as Parkinson's, Alzheimer's, and Huntington's diseases. For many years, brain degenerative disorders were thought to result from aberrant neural death. Here we discuss the evidence that supports our novel hypothesis that brain degenerative diseases involve dysfunction of glial cells (astrocytes, microglia, and oligodendrocytes). Impairment in the functionality of glial cells results in pathological neuro-glial interactions that, in turn, generate a "hostile" environment that impairs the functionality of neuronal cells. These events can lead to systematic neural demise on a scale that appears to be proportional to the severity of the neurological deficit. Copyright © 2016 The Authors. Production and hosting by Elsevier Ltd.. All rights reserved.

Perception of premenstrual syndrome and attitude of evaluations of work performance among incoming university female students.

PubMed

Cheng, Shu Hui; Sun, Zih-Jie; Lee, I Hui; Shih, Chi-Chen; Chen, Kao Chin; Lin, Shih-Hsien; Lu, Feng-Hwa; Yang, Yi-Ching; Yang, Yen Kuang

2015-01-01

Premenstrual syndrome (PMS) is a common condition, and for 5% of women, the influence is so severe as to interfere with their mental health, interpersonal relationships, or studies. Severe PMS may result in decreased occupational productivity. The aim of this study was to investigate the influence of perception of PMS on evaluation of work performance. A total of 1971 incoming female university students were recruited in September 2009. A simulated clinical scenario was used, with a test battery including measurement of psychological symptoms and the Chinese Premenstrual Symptom Questionnaire. When evaluating employee performance in the simulated scenario, 1565 (79.4%) students neglected the impact of PMS, while 136 (6.9%) students considered it. Multivariate logistic regression showed that perception of daily function impairment due to PMS and frequency of measuring body weight were significantly associated with consideration of the influence of PMS on evaluation of work performance. It is important to increase the awareness of functional impairments related to severe PMS.

Symptoms of problematic cellular phone use, functional impairment and its association with depression among adolescents in Southern Taiwan.

PubMed

Yen, Cheng-Fang; Tang, Tze-Chun; Yen, Ju-Yu; Lin, Huang-Chi; Huang, Chi-Fen; Liu, Shu-Chun; Ko, Chih-Hung

2009-08-01

The aims of this study were: (1) to examine the prevalence of symptoms of problematic cellular phone use (CPU); (2) to examine the associations between the symptoms of problematic CPU, functional impairment caused by CPU and the characteristics of CPU; (3) to establish the optimal cut-off point of the number of symptoms for functional impairment caused by CPU; and (4) to examine the association between problematic CPU and depression in adolescents. A total of 10,191 adolescent students in Southern Taiwan were recruited into this study. Participants' self-reported symptoms of problematic CPU and functional impairments caused by CPU were collected. The associations of symptoms of problematic CPU with functional impairments and with the characteristics of CPU were examined. The cut-off point of the number of symptoms for functional impairment was also determined. The association between problematic CPU and depression was examined by logistic regression analysis. The results indicated that the symptoms of problematic CPU were prevalent in adolescents. The adolescents who had any one of the symptoms of problematic CPU were more likely to report at least one dimension of functional impairment caused by CPU, called more on cellular phones, sent more text messages, or spent more time and higher fees on CPU. Having four or more symptoms of problematic CPU had the highest potential to differentiate between the adolescents with and without functional impairment caused by CPU. Adolescents who had significant depression were more likely to have four or more symptoms of problematic CPU. The results of this study may provide a basis for detecting symptoms of problematic CPU in adolescents.

Selective Insulin Resistance in the Kidney

PubMed Central

Horita, Shoko; Nakamura, Motonobu; Suzuki, Masashi; Satoh, Nobuhiko; Suzuki, Atsushi; Seki, George

2016-01-01

Insulin resistance has been characterized as attenuation of insulin sensitivity at target organs and tissues, such as muscle and fat tissues and the liver. The insulin signaling cascade is divided into major pathways such as the PI3K/Akt pathway and the MAPK/MEK pathway. In insulin resistance, however, these pathways are not equally impaired. For example, in the liver, inhibition of gluconeogenesis by the insulin receptor substrate (IRS) 2 pathway is impaired, while lipogenesis by the IRS1 pathway is preserved, thus causing hyperglycemia and hyperlipidemia. It has been recently suggested that selective impairment of insulin signaling cascades in insulin resistance also occurs in the kidney. In the renal proximal tubule, insulin signaling via IRS1 is inhibited, while insulin signaling via IRS2 is preserved. Insulin signaling via IRS2 continues to stimulate sodium reabsorption in the proximal tubule and causes sodium retention, edema, and hypertension. IRS1 signaling deficiency in the proximal tubule may impair IRS1-mediated inhibition of gluconeogenesis, which could induce hyperglycemia by preserving glucose production. In the glomerulus, the impairment of IRS1 signaling deteriorates the structure and function of podocyte and endothelial cells, possibly causing diabetic nephropathy. This paper mainly describes selective insulin resistance in the kidney, focusing on the proximal tubule. PMID:27247938

Effects of renal function on pharmacokinetics and pharmacodynamics of lesinurad in adult volunteers.

PubMed

Gillen, Michael; Valdez, Shakti; Zhou, Dongmei; Kerr, Bradley; Lee, Caroline A; Shen, Zancong

2016-01-01

Lesinurad is a selective uric acid reabsorption inhibitor approved for the treatment of gout in combination with a xanthine oxidase inhibitor (XOI) in patients who have not achieved target serum uric acid (sUA) levels with an XOI alone. Most people with gout have chronic kidney disease. The pharmacokinetics, pharmacodynamics, and safety of lesinurad were assessed in subjects with impaired renal function. Two Phase I, multicenter, open-label, single-dose studies enrolled subjects with normal renal function (estimated creatinine clearance [eCrCl] >90 mL/min; N=12) or mild (eCrCl 60-89 mL/min; N=8), moderate (eCrCl 30-59 mL/min; N=16), or severe (eCrCl <30 mL/min; N=6) renal impairment. Subjects were given a single oral lesinurad dose of 200 mg (N=24) or 400 mg (N=18). Blood and urine samples were analyzed for plasma lesinurad concentrations and serum and urine uric acid concentrations. Safety was assessed by adverse events and laboratory data. Mild, moderate, and severe renal impairment increased lesinurad plasma area under the plasma concentration-time curve by 34%, 54%-65%, and 102%, respectively. Lesinurad plasma C max was unaffected by renal function status. Lower renal clearance and urinary excretion of lesinurad were associated with the degree of renal impairment. The sUA-lowering effect of a single dose of lesinurad was similar between mild renal impairment and normal function, reduced in moderate impairment, and greatly diminished in severe impairment. Lesinurad increased urinary urate excretion in normal function and mild renal impairment; the increase was less with moderate or severe renal impairment. Lesinurad was well tolerated by all subjects. Lesinurad exposure increased with decreasing renal function; however, the effects of lesinurad on sUA were attenuated in moderate to severe renal impairment.

Elicited Production of Relative Clauses in German: Evidence from Typically Developing Children and Children with Specific Language Impairment

ERIC Educational Resources Information Center

Adani, Flavia; Stegenwallner-Schütz, Maja; Haendler, Yair; Zukowski, Andrea

2016-01-01

We elicited the production of various types of relative clauses in a group of German-speaking children with specific language impairment (SLI) and typically developing controls in order to test the movement optionality account of grammatical difficulty in SLI. The results show that German-speaking children with SLI are impaired in relative clause…

Chemosensory interaction: acquired olfactory impairment is associated with decreased taste function.

PubMed

Landis, Basile N; Scheibe, Mandy; Weber, Cornelia; Berger, Robert; Brämerson, Annika; Bende, Mats; Nordin, Steven; Hummel, Thomas

2010-08-01

Olfaction, taste and trigeminal function are three distinct modalities. However, in daily life they are often activated concomitantly. In health and disease, it has been shown that in two of these senses, the trigeminal and olfactory senses, modification of one sense leads to changes in the other sense and vice versa. The objective of the study was to investigate whether and (if so) how, the third modality, taste, is influenced by olfactory impairment. We tested 210 subjects with normal (n = 107) or impaired (n = 103) olfactory function for their taste identification capacities. Validated tests were used for olfactory and gustatory testing (Sniffin' Sticks, Taste Strips). In an additional experiment, healthy volunteers underwent reversible olfactory cleft obstruction to investigate short-time changes of gustatory function after olfactory alteration. Mean gustatory identification (taste strip score) for the subjects with impaired olfaction was 19.4 +/- 0.6 points and 22.9 +/- 0.5 points for those with normal olfactory function (t = 4.6, p < 0.001). The frequencies of both, smell and taste impairments interacted significantly (Chi(2), F = 16.4, p < 0.001), and olfactory and gustatory function correlated (r (210) = 0.30, p < 0.001). Neither age nor olfactory impairment cause effects interfered with this olfactory-gustatory interaction. In contrast, after short-lasting induced olfactory decrease, gustatory function remained unchanged. The present study suggests that longstanding impaired olfactory function is associated with decreased gustatory function. These findings seem to extend previously described mutual chemosensory interactions also to smell and taste. It further raises the question whether chemical senses in general decrease mutually after acquired damage.

Grammatical Planning Units During Real-Time Sentence Production in Speakers With Agrammatic Aphasia and Healthy Speakers.

PubMed

Lee, Jiyeon; Yoshida, Masaya; Thompson, Cynthia K

2015-08-01

Grammatical encoding (GE) is impaired in agrammatic aphasia; however, the nature of such deficits remains unclear. We examined grammatical planning units during real-time sentence production in speakers with agrammatic aphasia and control speakers, testing two competing models of GE. We queried whether speakers with agrammatic aphasia produce sentences word by word without advanced planning or whether hierarchical syntactic structure (i.e., verb argument structure; VAS) is encoded as part of the advanced planning unit. Experiment 1 examined production of sentences with a predefined structure (i.e., "The A and the B are above the C") using eye tracking. Experiment 2 tested production of transitive and unaccusative sentences without a predefined sentence structure in a verb-priming study. In Experiment 1, both speakers with agrammatic aphasia and young and age-matched control speakers used word-by-word strategies, selecting the first lemma (noun A) only prior to speech onset. However, in Experiment 2, unlike controls, speakers with agrammatic aphasia preplanned transitive and unaccusative sentences, encoding VAS before speech onset. Speakers with agrammatic aphasia show incremental, word-by-word production for structurally simple sentences, requiring retrieval of multiple noun lemmas. However, when sentences involve functional (thematic to grammatical) structure building, advanced planning strategies (i.e., VAS encoding) are used. This early use of hierarchical syntactic information may provide a scaffold for impaired GE in agrammatism.

Heterogeneity in ADHD: Neurocognitive predictors of peer, family, and academic functioning.

PubMed

Kofler, Michael J; Sarver, Dustin E; Spiegel, Jamie A; Day, Taylor N; Harmon, Sherelle L; Wells, Erica L

2017-08-01

Childhood attention-deficit/hyperactivity disorder (ADHD) is associated with impairments in peer, family, and academic functioning. Although impairment is required for diagnosis, children with ADHD vary significantly in the areas in which they demonstrate clinically significant impairment. However, relatively little is known about the mechanisms and processes underlying these individual differences. The current study examined neurocognitive predictors of heterogeneity in peer, family, and academic functioning in a well-defined sample of 44 children with ADHD aged 8-13 years (M = 10.31, SD = 1.42; 31 boys, 13 girls; 81% Caucasian). Reliable change analysis indicated that 98% of the sample demonstrated objectively-defined impairment on at least one assessed outcome measure; 65% were impaired in two or all three areas of functioning. ADHD children with quantifiable deficits in academic success and family functioning performed worse on tests of working memory (d = 0.68 to 1.09), whereas children with impaired parent-reported social functioning demonstrated slower processing speed (d = 0.53). Dimensional analyses identified additional predictors of peer, family, and academic functioning. Working memory abilities were associated with individual differences in all three functional domains, processing speed predicted social functioning, and inhibitory control predicted family functioning. These results add to a growing literature implicating neurocognitive abilities not only in explaining behavioral differences between ADHD and non-ADHD groups, but also in the substantial heterogeneity in ecologically-valid functional outcomes associated with the disorder.

Airway somatosensory deficits and dysphagia in Parkinson's disease.

PubMed

Hammer, Michael J; Murphy, Caitlin A; Abrams, Trisha M

2013-01-01

Individuals with Parkinson's disease (PD) often experience substantial impairment of swallow control, and are typically unaware of the presence or severity of their impairments suggesting that these individuals may also experience airway sensory deficits. However, the degree to which impaired swallow function in PD may relate to airway sensory deficits has yet to be formally tested. The purpose of this study was to examine whether airway sensory function is associated with swallow impairment in PD. Eighteen PD participants and 18 healthy controls participated in this study and underwent endoscopic assessment of airway somatosensory function, endoscopic assessment of swallow function, and clinical ratings of swallow and disease severity. PD participants exhibited abnormal airway somatosensory function and greater swallow impairment compared with healthy controls. Swallow and sensory deficits in PD were correlated with disease severity. Moreover, PD participants reported similar self-rated swallow function as healthy controls, and swallow deficits were correlated with sensory function suggesting an association between impaired sensory function and poor self-awareness of swallow deficits in PD. These results suggest that control of swallow is influenced by airway somatosensory function, that swallow-related deficits in PD are related to abnormal somatosensation, and that swallow and airway sensory function may degrade as a function of disease severity. Therefore, the basal ganglia and related neural networks may play an important role to integrate airway sensory input for swallow-related motor control. Furthermore, the airway deficits observed in PD suggest a disintegration of swallow-related sensory and motor control.

Depression and academic impairment in college students.

PubMed

Heiligenstein, E; Guenther, G; Hsu, K; Herman, K

1996-09-01

Impairment from depression and its impact on productivity are of profound societal importance. We report the results of an evaluation of depression and academic impairment in university students, using standardized measures. Sixty-three students completed the Beck Depression Inventory and the work role section from the Social Adjustment Scale-Self Report. Academic impairment, manifested as missed time from class, decreased academic productivity, and significant interpersonal problems at school, was seen in 92% of the students. More severe depression was related to a higher level of impairment. At all levels of depression, affective impairment-inadequacy, distress, and disinterest in school-was more prevalent than was academic impairment. The risk of academic impairment became likely at only moderate-to-severe levels of depression. Discussing the implications of depression with students and aggressively pursuing both medication and nonmedication therapies are essential in preventing the high morbidity associated with untreated depression.

Alterations in NO- and PGI2- dependent function in aorta in the orthotopic murine model of metastatic 4T1 breast cancer: relationship with pulmonary endothelial dysfunction and systemic inflammation.

PubMed

Buczek, E; Denslow, A; Mateuszuk, L; Proniewski, B; Wojcik, T; Sitek, B; Fedorowicz, A; Jasztal, A; Kus, E; Chmura-Skirlinska, A; Gurbiel, R; Wietrzyk, J; Chlopicki, S

2018-05-22

Patients with cancer develop endothelial dysfunction and subsequently display a higher risk of cardiovascular events. The aim of the present work was to examine changes in nitric oxide (NO)- and prostacyclin (PGI 2 )-dependent endothelial function in the systemic conduit artery (aorta), in relation to the formation of lung metastases and to local and systemic inflammation in a murine orthotopic model of metastatic breast cancer. BALB/c female mice were orthotopically inoculated with 4T1 breast cancer cells. Development of lung metastases, lung inflammation, changes in blood count, systemic inflammatory response (e.g. SAA, SAP and IL-6), as well as changes in NO- and PGI 2 -dependent endothelial function in the aorta, were examined 2, 4, 5 and 6 weeks following cancer cell transplantation. As early as 2 weeks following transplantation of breast cancer cells, in the early metastatic stage, lungs displayed histopathological signs of inflammation, NO production was impaired and nitrosylhemoglobin concentration in plasma was decreased. After 4 to 6 weeks, along with metastatic development, progressive leukocytosis and systemic inflammation (as seen through increased SAA, SAP, haptoglobin and IL-6 plasma concentrations) were observed. Six weeks following cancer cell inoculation, but not earlier, endothelial dysfunction in aorta was detected; this involved a decrease in basal NO production and a decrease in NO-dependent vasodilatation, that was associated with a compensatory increase in cyclooxygenase-2 (COX-2)- derived PGI 2 production. In 4 T1 metastatic breast cancer in mice early pulmonary metastasis was correlated with lung inflammation, with an early decrease in pulmonary as well as systemic NO availability. Late metastasis was associated with robust, cancer-related, systemic inflammation and impairment of NO-dependent endothelial function in the aorta that was associated with compensatory upregulation of the COX-2-derived PGI 2 pathway.

The secreted form of the p40 subunit of interleukin (IL)-12 inhibits IL-23 functions and abrogates IL-23-mediated antitumour effects

PubMed Central

Shimozato, Osamu; Ugai, Shin-ichi; Chiyo, Masako; Takenobu, Hisanori; Nagakawa, Hiroyasu; Wada, Akihiko; Kawamura, Kiyoko; Yamamoto, Hiroshi; Tagawa, Masatoshi

2006-01-01

Interleukin (IL)-23 is a heterodimeric cytokine consisting of a novel p19 molecule and the p40 subunit of IL-12. Since secreted p40 can act as an antagonist for IL-12, we investigated whether p40 also inhibited IL-23-mediated immunological functions. p40 did not induce interferon (IFN)-γ or IL-17 production from splenocytes but impaired IL-23-induced cytokine production by competitive binding to the IL-23 receptors. Furthermore, a mixed population of murine colon carcinoma Colon 26 cells transduced with the p40 gene and those transduced with the IL-23 gene developed tumours in syngenic mice, whereas the IL-23-expressing Colon 26 cells were completely rejected. p40 also suppressed IFN-γ production of antigen-stimulated splenocytes and IL-23-mediated cytotoxic T-lymphocyte activities in the mice that rejected Colon 26 cells expressing IL-23. p40 can thereby antagonize IL-23 and is a possible therapeutic agent for suppression of IL-23 functions. PMID:16423037

Psychosocial functioning in offspring of parents with bipolar disorder.

PubMed

Bella, Tolulope; Goldstein, Tina; Axelson, David; Obreja, Mihaela; Monk, Kelly; Hickey, Mary Beth; Goldstein, Benjamin; Brent, David; Diler, Rasim Somer; Kupfer, David; Sakolsky, Dara; Birmaher, Boris

2011-09-01

Offspring of parents with bipolar disorder are at increased risk for a range of psychopathology, including bipolar disorder. It is not clear if they also have impairments in their psychosocial functioning. We compared the psychosocial functioning of three groups of children enrolled in the Pittsburgh Bipolar Offspring Study (BIOS): offspring of probands with bipolar disorder (n=388), offspring of probands with other types of psychopathology (n=132), and offspring of healthy probands (n=118). Psychosocial functioning was assessed at study intake using the schedule of the Adolescent Longitudinal Interval Follow-Up Evaluation (A-LIFE), the Child Behavior Check List (CBCL) and the Children's Global Assessment Scale (CGAS). Offspring of probands with bipolar disorder exhibited impairments in various aspects of psychosocial functioning. On all measures, they had worse functioning in comparison with offspring of healthy probands. Offspring of probands with bipolar disorder generally exhibited more impairment than offspring of probands with nonbipolar psychopathology. After adjusting for proband parent functioning and the child's Axis I psychopathology, functioning of offspring of probands with bipolar disorder was similar to that of offspring of healthy probands. Data are cross-sectional and therefore do not allow for causal conclusions about the association between parental psychopathology, child psychopathology and offspring psychosocial functioning. Offspring of parents with bipolar disorder exhibit impairments in psychosocial functioning which appear largely attributable to proband parent functional impairment and the child's own psychopathology. As such, interventions to improve parental functioning, as well as early interventions to treat the child's psychopathology may help reduce the risk for long-term functional impairment in offspring. Copyright © 2011 Elsevier B.V. All rights reserved.

Mycobacterium avium subspecies impair dendritic cell maturation.

PubMed

Basler, Tina; Brumshagen, Christina; Beineke, Andreas; Goethe, Ralph; Bäumer, Wolfgang

2013-10-01

Mycobacterium avium ssp. paratuberculosis (MAP) causes Johne's disease, a chronic, granulomatous enteritis of ruminants. Dendritic cells (DC) of the gut are ideally placed to combat invading mycobacteria; however, little is known about their interaction with MAP. Here, we investigated the interaction of MAP and the closely related M. avium ssp. avium (MAA) with murine DC and the effect of infected macrophages on DC maturation. The infection of DC with MAP or MAA induced DC maturation, which differed to that of LPS as maturation was accompanied by higher production of IL-10 and lower production of IL-12. Treatment of maturing DC with supernatants from mycobacteria-infected macrophages resulted in impaired DC maturation, leading to a semi-mature, tolerogenic DC phenotype expressing low levels of MHCII, CD86 and TNF-α after LPS stimulation. Though the cells were not completely differentiated they responded with an increased IL-10 and a decreased IL-12 production. Using recombinant cytokines we provide evidence that the semi-mature DC phenotype results from a combination of secreted cytokines and released antigenic mycobacterial components of the infected macrophage. Our results indicate that MAP and MAA are able to subvert DC function directly by infecting and indirectly via the milieu created by infected macrophages.

The Ways of the Hand: A Study of Hand Function among Blind, Visually Impaired and Visually Impaired Multi-Handicapped Children and Adolescents.

ERIC Educational Resources Information Center

Rogow, Sally M.

1987-01-01

The manual development of 148 blind, visually impaired, and visually impaired multi-handicapped students, aged 3-19, was studied. Results indicated a significant relationship between object manipulation and speech, and an inverse relationship between object manipulation and stereotypic hand mannerisms. Optimal development of manual functions and…

Major Depressive Disorder Is Associated with Broad Impairments on Neuropsychological Measures of Executive Function: A Meta-Analysis and Review

ERIC Educational Resources Information Center

Snyder, Hannah R.

2013-01-01

Cognitive impairments are now widely acknowledged as an important aspect of major depressive disorder (MDD), and it has been proposed that executive function (EF) may be particularly impaired in patients with MDD. However, the existence and nature of EF impairments associated with depression remain strongly debated. Although many studies have…

Differential Item Functioning Comparisons on a Performance-Based Alternate Assessment for Students with Severe Cognitive Impairments, Autism and Orthopedic Impairments

ERIC Educational Resources Information Center

Laitusis, Cara Cahalan; Maneckshana, Behroz; Monfils, Lora; Ahlgrim-Delzell, Lynn

2009-01-01

The purpose of this study was to examine Differential Item Functioning (DIF) by disability groups on an on-demand performance assessment for students with severe cognitive impairments. Researchers examined the presence of DIF for two comparisons. One comparison involved students with severe cognitive impairments who served as the reference group…

Functional IRF3 deficiency in a patient with herpes simplex encephalitis.

PubMed

Andersen, Line Lykke; Mørk, Nanna; Reinert, Line S; Kofod-Olsen, Emil; Narita, Ryo; Jørgensen, Sofie E; Skipper, Kristian A; Höning, Klara; Gad, Hans Henrik; Østergaard, Lars; Ørntoft, Torben F; Hornung, Veit; Paludan, Søren R; Mikkelsen, Jacob Giehm; Fujita, Takashi; Christiansen, Mette; Hartmann, Rune; Mogensen, Trine H

2015-08-24

Herpes simplex encephalitis (HSE) in children has previously been linked to defects in type I interferon (IFN) production downstream of Toll-like receptor 3. Here, we describe a novel genetic etiology of HSE by identifying a heterozygous loss-of-function mutation in the IFN regulatory factor 3 (IRF3) gene, leading to autosomal dominant (AD) IRF3 deficiency by haploinsufficiency, in an adolescent female patient with HSE. IRF3 is activated by most pattern recognition receptors recognizing viral infections and plays an essential role in induction of type I IFN. The identified IRF3 R285Q amino acid substitution results in impaired IFN responses to HSV-1 infection and particularly impairs signaling through the TLR3-TRIF pathway. In addition, the R285Q mutant of IRF3 fails to become phosphorylated at S386 and undergo dimerization, and thus has impaired ability to activate transcription. Finally, transduction with WT IRF3 rescues the ability of patient fibroblasts to express IFN in response to HSV-1 infection. The identification of IRF3 deficiency in HSE provides the first description of a defect in an IFN-regulating transcription factor conferring increased susceptibility to a viral infection in the CNS in humans. © 2015 Andersen et al.

Diagnosing cardiovascular disease from the perspective of the brain and inflammation.

PubMed

Hall, Nicholas R S

2013-01-01

Numerous lifestyle, emotional, and biological factors have been identified as risk factors for heart disease. These include socioeconomic status, early childhood and intimate partner abuse, disruption of sleep patterns, lack of exercise, and unhealthy food choices. Genetic and epigenetic factors are also critical components of the equation. A common denominator that links directly or indirectly all of these factors is inflammation. In some instances, the production of inflammatory molecules may precipitate the illness, while in others they may be produced in response to the underlying cause. Regardless of whether through direct or indirect means, inflammation contributes to the gradual loss of cellular energy substrates, which culminates in impaired diastolic performance. For that reason, to refer to a failure of the cardiovascular system as heart or cardiovascular disease lessens the potentially important contribution of a myriad of other factors. This article begins with the premise that impaired cardiac functioning is more than a heart disorder. An argument will be made that impaired cardiac functioning can also be an economic, behavioral, and/or emotional disorder, which subsequently gives rise to a metabolic failure. Therefore, a multi-systems approach should be taken to identify prior to the onset of damage biological and non-biological predictors of impending heart disease.

Assessing physical function and physical activity in patients with CKD.

PubMed

Painter, Patricia; Marcus, Robin L

2013-05-01

Patients with CKD are characterized by low levels of physical functioning, which, along with low physical activity, predict poor outcomes in those treated with dialysis. The hallmark of clinical care in geriatric practice and geriatric research is the orientation to and assessment of physical function and functional limitations. Although there is increasing interest in physical function and physical activity in patients with CKD, the nephrology field has not focused on this aspect of care. This paper provides an in-depth review of the measurement of physical function and physical activity. It focuses on physiologic impairments and physical performance limitations (impaired mobility and functional limitations). The review is based on established frameworks of physical impairment and functional limitations that have guided research in physical function in the aging population. Definitions and measures for physiologic impairments, physical performance limitations, self-reported function, and physical activity are presented. On the basis of the information presented, recommendations for incorporating routine assessment of physical function and encouragement for physical activity in clinical care are provided.

Mitochondrial function at extreme high altitude.

PubMed

Murray, Andrew J; Horscroft, James A

2016-03-01

At high altitude, barometric pressure falls and with it inspired P(O2), potentially compromising O2 delivery to the tissues. With sufficient acclimatisation, the erythropoietic response increases red cell mass such that arterial O2 content (C(aO2)) is restored; however arterial P(O2)(P(aO2)) remains low, and the diffusion of O2 from capillary to mitochondrion is impaired. Mitochondrial respiration and aerobic capacity are thus limited, whilst reactive oxygen species (ROS) production increases. Restoration of P(aO2) with supplementary O2 does not fully restore aerobic capacity in acclimatised individuals, possibly indicating a peripheral impairment. With prolonged exposure to extreme high altitude (>5500 m), muscle mitochondrial volume density falls, with a particular loss of the subsarcolemmal population. It is not clear whether this represents acclimatisation or deterioration, but it does appear to be regulated, with levels of the mitochondrial biogenesis factor PGC-1α falling, and shows similarities to adapted Tibetan highlanders. Qualitative changes in mitochondrial function also occur, and do so at more moderate high altitudes with shorter periods of exposure. Electron transport chain complexes are downregulated, possibly mitigating the increase in ROS production. Fatty acid oxidation capacity is decreased and there may be improvements in biochemical coupling at the mitochondrial inner membrane that enhance O2 efficiency. Creatine kinase expression falls, possibly impairing high-energy phosphate transfer from the mitochondria to myofibrils. In climbers returning from the summit of Everest, cardiac energetic reserve (phosphocreatine/ATP) falls, but skeletal muscle energetics are well preserved, possibly supporting the notion that mitochondrial remodelling is a core feature of acclimatisation to extreme high altitude. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

Cognitive Ability as a Resource for Everyday Functioning among Older Adults Who Are Visually Impaired

ERIC Educational Resources Information Center

Heyl, Vera; Wahl, Hans-Werner

2010-01-01

This article reports on a study that investigated the role of cognitive resources in the everyday functioning of 121 older adults who were visually impaired and 150 sighted older adults, with a mean age of 82 years. Cognitive performance and everyday functioning were most strongly related in the group who were visually impaired. The authors…

Improvement of mitochondrial function and dynamics by the metabolic enhancer piracetam.

PubMed

Stockburger, Carola; Kurz, Christopher; Koch, Konrad A; Eckert, Schamim H; Leuner, Kristina; Müller, Walter E

2013-10-01

The metabolic enhancer piracetam is used in many countries to treat cognitive impairment in aging, brain injuries, as well as dementia such as AD (Alzheimer's disease). As a specific feature of piracetam, beneficial effects are usually associated with mitochondrial dysfunction. In previous studies we were able to show that piracetam enhanced ATP production, mitochondrial membrane potential as well as neurite outgrowth in cell and animal models for aging and AD. To investigate further the effects of piracetam on mitochondrial function, especially mitochondrial fission and fusion events, we decided to assess mitochondrial morphology. Human neuroblastoma cells were treated with the drug under normal conditions and under conditions imitating aging and the occurrence of ROS (reactive oxygen species) as well as in stably transfected cells with the human wild-type APP (amyloid precursor protein) gene. This AD model is characterized by expressing only 2-fold more human Aβ (amyloid β-peptide) compared with control cells and therefore representing very early stages of AD when Aβ levels gradually increase over decades. Interestingly, these cells exhibit an impaired mitochondrial function and morphology under baseline conditions. Piracetam is able to restore this impairment and shifts mitochondrial morphology back to elongated forms, whereas there is no effect in control cells. After addition of a complex I inhibitor, mitochondrial morphology is distinctly shifted to punctate forms in both cell lines. Under these conditions piracetam is able to ameliorate morphology in cells suffering from the mild Aβ load, as well as mitochondrial dynamics in control cells.

Reduced global brain metabolism but maintained vascular function in amnestic mild cognitive impairment.

PubMed

Thomas, Binu P; Sheng, Min; Tseng, Benjamin Y; Tarumi, Takashi; Martin-Cook, Kristen; Womack, Kyle B; Cullum, Munro C; Levine, Benjamin D; Zhang, Rong; Lu, Hanzhang

2017-04-01

Amnestic mild cognitive impairment represents an early stage of Alzheimer's disease, and characterization of physiological alterations in mild cognitive impairment is an important step toward accurate diagnosis and intervention of this condition. To investigate the extent of neurodegeneration in patients with mild cognitive impairment, whole-brain cerebral metabolic rate of oxygen in absolute units of µmol O 2 /min/100 g was quantified in 44 amnestic mild cognitive impairment and 28 elderly controls using a novel, non-invasive magnetic resonance imaging method. We found a 12.9% reduction ( p = 0.004) in cerebral metabolic rate of oxygen in mild cognitive impairment, which was primarily attributed to a reduction in the oxygen extraction fraction, by 10% ( p = 0.016). Global cerebral blood flow was not found to be different between groups. Another aspect of vascular function, cerebrovascular reactivity, was measured by CO 2 -inhalation magnetic resonance imaging and was found to be equivalent between groups. Therefore, there seems to be a global, diffuse diminishment in neural function in mild cognitive impairment, while their vascular function did not show a significant reduction.

HZE ⁵⁶Fe-ion irradiation induces endothelial dysfunction in rat aorta: role of xanthine oxidase.

PubMed

Soucy, Kevin G; Lim, Hyun Kyo; Kim, Jae Hyung; Oh, Young; Attarzadeh, David O; Sevinc, Baris; Kuo, Maggie M; Shoukas, Artin A; Vazquez, Marcelo E; Berkowitz, Dan E

2011-10-01

Ionizing radiation has been implicated in the development of significant cardiovascular complications. Since radiation exposure is associated with space exploration, astronauts are potentially at increased risk of accelerated cardiovascular disease. This study investigated the effect of high atomic number, high-energy (HZE) iron-ion radiation on vascular and endothelial function as a model of space radiation. Rats were exposed to a single whole-body dose of iron-ion radiation at doses of 0, 0.5 or 1 Gy. In vivo aortic stiffness and ex vivo aortic tension responses were measured 6 and 8 months after exposure as indicators of chronic vascular injury. Rats exposed to 1 Gy iron ions demonstrated significantly increased aortic stiffness, as measured by pulse wave velocity. Aortic rings from irradiated rats exhibited impaired endothelial-dependent relaxation consistent with endothelial dysfunction. Acute xanthine oxidase (XO) inhibition or reactive oxygen species (ROS) scavenging restored endothelial-dependent responses to normal. In addition, XO activity was significantly elevated in rat aorta 4 months after whole-body irradiation. Furthermore, XO inhibition, initiated immediately after radiation exposure and continued until euthanasia, completely inhibited radiation-dependent XO activation. ROS production was elevated after 1 Gy irradiation while production of nitric oxide (NO) was significantly impaired. XO inhibition restored NO and ROS production. Finally, dietary XO inhibition preserved normal endothelial function and vascular stiffness after radiation exposure. These results demonstrate that radiation induced XO-dependent ROS production and nitroso-redox imbalance, leading to chronic vascular dysfunction. As a result, XO is a potential target for radioprotection. Enhancing the understanding of vascular radiation injury could lead to the development of effective methods to ameliorate radiation-induced vascular damage.

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced cytotoxicity accompanied by oxidative stress in rat Sertoli cells: Possible role of mitochondrial fractions of Sertoli cells

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

Aly, Hamdy A.A., E-mail: hamdyaali@yahoo.com; Khafagy, Rasha M.

2011-05-01

TCDD, as an endocrine disruptor, is known to impair testicular functions and fertility. To elucidate the mechanism(s) underlying the testicular effects of TCDD, the potential toxicity of TCDD on Sertoli cells was investigated. Furthermore, the study aims to delineate whether mitochondrial fractions of Sertoli cells are involved in mediating the testicular effects of TCDD. Adult rat Sertoli cells were incubated with (5, 10 or 15 nM) of TCDD for 6, 12 or 24 h. Cell viability, lactate and LDH leakage into media along with lipid peroxidation, ROS generation, SOD, CAT, GPx, GR, {gamma}-GT and {beta}-glucuronidase activities, GSH content and {Delta}{psi}{submore » m} were measured. Superoxide anion production, COX and cardiolipin content were measured in mitochondrial fractions. Cell viability was significantly decreased while lactate and LDH leakage into media were increased. ROS generation along with lipid peroxidation was also increased. SOD, CAT, GPx, GR activities and GSH content were significantly decreased. {gamma}-GT and {beta}-glucuronidase activities were also decreased. Superoxide anion production was increased while COX activity and cardiolipin content were decreased in mitochondrial fractions. Moreover, the {Delta}{psi}{sub m} was significantly decreased as measured in Sertoli cells. In conclusion, TCDD impairs Sertoli cell functions and this effect is, at least in part, attributed to oxidative stress. We have also found that TCDD increases mitochondrial superoxide anion production and decreases {Delta}{psi}{sub m}, COX activity and mitochondrial cardiolipin content. Our findings suggest that mitochondria may play an important role in ROS production, leading to the TCDD-induced oxidative stress response and resulting toxicological consequences in rat Sertoli cells.« less

Predicting neuropsychological test performance on the basis of temporal orientation.

PubMed

Ryan, Joseph J; Glass, Laura A; Bartels, Jared M; Bergner, CariAnn M; Paolo, Anthony M

2009-05-01

Temporal orientation is often disrupted in the context of psychiatric or neurological disease; tests assessing this function are included in most mental status examinations. The present study examined the relationship between scores on the Temporal Orientation Scale (TOS) and performance on a battery of tests that assess memory, language, and cognitive functioning in a sample of patients with Alzheimer's disease (N = 55). Pearson-product moment correlations showed that, in all but two instances, the TOS was significantly correlated with each neuropsychological measure, p values < or = .05. Also, severely disoriented (i.e., TOS score < or = -8) patients were consistently 'impaired' on memory tests but not on tests of language and general cognitive functioning.

Individual and Area Level Socioeconomic Status and Its Association with Cognitive Function and Cognitive Impairment (Low MMSE) among Community-Dwelling Elderly in Singapore.

PubMed

Wee, Liang En; Yeo, Wei Xin; Yang, Gui Rong; Hannan, Nazirul; Lim, Kenny; Chua, Christopher; Tan, Mae Yue; Fong, Nikki; Yeap, Amelia; Chen, Lionel; Koh, Gerald Choon-Huat; Shen, Han Ming

2012-01-01

Neighborhood socioeconomic status (SES) can affect cognitive function. We assessed cognitive function and cognitive impairment among community-dwelling elderly in a multi-ethnic urban low-SES Asian neighborhood and compared them with a higher-SES neighborhood. The study population involved all residents aged ≥60 years in two housing estates comprising owner-occupied housing (higher SES) and rental flats (low SES) in Singapore in 2012. Cognitive impairment was defined as <24 on the Mini Mental State Examination. Demographic/clinical details were collected via questionnaire. Multilevel linear regression was used to evaluate factors associated with cognitive function, while multilevel logistic regression determined predictors of cognitive impairment. Participation was 61.4% (558/909). Cognitive impairment was found in 26.2% (104/397) of residents in the low-SES community and in 16.1% (26/161) of residents in the higher-SES community. After adjusting for other sociodemographic variables, living in a low-SES community was independently associated with poorer cognitive function (β = -1.41, SD = 0.58, p < 0.01) and cognitive impairment (adjusted odds ratio 5.13, 95% CI 1.98-13.34). Among cognitively impaired elderly in the low-SES community, 96.2% (100/104) were newly detected. Living in a low-SES community is independently associated with cognitive impairment in an urban Asian society.

Subjective daytime functioning assessment in people with insomnia.

PubMed

Grabowski, Karol; Nowicka-Sauer, Katarzyna; Zdrojewski, Tomasz; Rutkowski, Marcin; Bandosz, Piotr; Nowicki, Zbigniew

2017-10-29

The aim of this study was to assess the prevalence and severity of subjective daytime functioning impairment among people with insomnia complaints. Another goal was to establish its relationships with age, gender, type and duration of subjective insomnia. Study group consisted of NATPOL study participants - 2,413 people (1,245 women and 1,168 men) aged 18-79. We extracted group with declared insomnia complaints, consisting of 1,221 people (736 women and 485 men) aged 18-79. Data on insomnia symptoms characteristics, their duration and subjective functioning impairment were further analyzed. Functioning impairment was declared by 825 people (67.7% of those who declared subjective insomnia) and it was more common in women. It was most common among people with insomnia complaints lasting over two weeks - 72.4%. In people with symptoms lasting less than two weeks or for a few days it was 70.7% and 64.9% respectively. People with insomnia symptoms lasting over two weeks accounted for 20% of group with severe functioning impairment. For shorter duration of symptoms it was 8.6% and 6.9% respectively. Among people with mild functioning impairment, persons with symptoms lasting for a few days and less than two weeks were predominant - 32.5% and 35.3% respectively. In people aged 18-24 years mild functioning impairment was predominant (66.66%). Subjective daytime functioning impairment is common in people declaring insomnia symptoms. It is more common in women and its prevalence and intensity are greater in people with longer duration of sleep problems. Its prevalence is not correlated with age and it is the mildest in people aged 18-24.

Changes in Neuropsychological Status during the Initial Phase of Abstinence in Alcohol Use Disorder: Neurocognitive Impairment and Implications for Clinical Care.

PubMed

Mulhauser, Kyler; Weinstock, Jeremiah; Ruppert, Phillip; Benware, Jeffrey

2018-05-12

Neuropsychological deficits are common in individuals with alcohol use disorder (AUD) and impact daily functioning and AUD treatment outcomes. Longitudinal studies demonstrate that extended abstinence improves neuropsychological functioning. The effects of short-term abstinence are less clear. This study examined changes in neuropsychological functioning after acute detoxification over a 10-day period at the beginning of residential AUD treatment. Notably, this study evaluated cognitive functioning according to diagnostic classifications for neurocognitive disorder according to DSM-5. Using a within-subjects design, neuropsychological functioning of participants (N = 28) undergoing a 14-day residential AUD treatment program was assessed at two time points over 10 days (i.e., treatment entry, prior to treatment discharge). Tests of immediate memory, visuospatial abilities, attention, language abilities, delayed memory, and executive functioning were administered. After completing acute detoxification, almost all participants (93%) were clinically impaired in at least one of the five cognitive domains at residential treatment entry, with one third of the sample impaired on ≥3 domains. Ten days later, 71% remained clinically impaired in at least one of five cognitive domains, with 29% of the sample impaired on ≥3 domains. Significant improvement over the 10-day period was observed for immediate memory, visuospatial abilities, and overall cognitive functioning. Clinical significance of these changes is also reported. Conclusions/Importance: The results from this study help to characterize cognitive functioning in terms of neurocognitive impairment. A brief period of abstinence begins to ameliorate neuropsychological deficits, but many individuals remain cognitively impaired throughout treatment. Implications for treatment are discussed.

Increase in work productivity of depressed individuals with improvement in depressive symptom severity.

PubMed

Trivedi, Madhukar H; Morris, David W; Wisniewski, Stephen R; Lesser, Ira; Nierenberg, Andrew A; Daly, Ella; Kurian, Benji T; Gaynes, Bradley N; Balasubramani, G K; Rush, A John

2013-06-01

The authors sought to identify baseline clinical and sociodemographic characteristics associated with work productivity in depressed outpatients and to assess the effect of treatment on work productivity. Employed depressed outpatients 18-75 years old who completed the Work Productivity and Activity Impairment scale (N=1,928) were treated with citalopram (20-40 mg/day) in the Sequenced Treatment Alternatives to Relieve Depression study. For patients who did not remit after an initial adequate antidepressant trial (level 1), either a switch to sertraline, sustained-release bupropion, or extended-release venlafaxine or an augmentation with sustained-release bupropion or buspirone was provided (level 2). Participants' clinical and demographic characteristics and treatment outcomes were analyzed for associations with baseline work productivity and change in productivity over time. Education, baseline depression severity, and melancholic, atypical, and recurrent depression subtypes were all independently associated with lower benefit to work productivity domains. During level 1 treatment, work productivity in several domains improved with reductions in depressive symptom severity. However, these findings did not hold true for level 2 outcomes; there was no significant association between treatment response and reduction in work impairment. Results were largely confirmed when multiple imputations were employed to address missing data. During this additional analysis, an association was also observed between greater impairment in work productivity and higher levels of anxious depression. Patients with clinically significant reductions in symptom severity during initial treatment were more likely than nonresponders to experience significant improvements in work productivity. In contrast, patients who achieved symptom remission in second-step treatment continued to have impairment at work. Patients who have demonstrated some degree of treatment resistance are more prone to persistent impairment in occupational productivity, implying a need for additional, possibly novel, treatments.

Contrasting olfaction, vision, and audition as predictors of cognitive change and impairment in non-demented older adults.

PubMed

MacDonald, Stuart W S; Keller, Connor J C; Brewster, Paul W H; Dixon, Roger A

2018-05-01

This study examines the relative utility of a particular class of noninvasive functional biomarkers-sensory functions-for detecting those at risk of cognitive decline and impairment. Three central research objectives were examined including whether (a) olfactory function, vision, and audition exhibited significant longitudinal declines in nondemented older adults; (b) multiwave change for these sensory function indicators predicted risk of mild cognitive impairment (MCI); and (c) change within persons for each sensory measure shared dynamic time-varying associations with within-person change in cognitive functioning. A longitudinal sample (n = 408) from the Victoria Longitudinal Study was assembled. Three cognitive status subgroups were identified: not impaired cognitively, single-assessment MCI, and multiple-assessment MCI. We tested independent predictive associations, contrasting change in sensory function as predictors of cognitive decline and impairment, utilizing both linear mixed models and logistic regression analysis. Olfaction and, to a lesser extent, vision were identified as the most robust predictors of cognitive status and decline; audition showed little predictive influence. These findings underscore the potential utility of deficits in olfactory function, in particular, as an early marker of age- and pathology-related cognitive decline. Functional biomarkers may represent potential candidates for use in the early stages of a multistep screening approach for detecting those at risk of cognitive impairment, as well as for targeted intervention. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Managing daily life with age-related sensory loss: cognitive resources gain in importance.

PubMed

Heyl, Vera; Wahl, Hans-Werner

2012-06-01

This paper investigates the role of cognitive resources in everyday functioning, comparing visually impaired, hearing impaired, and sensory unimpaired older adults. According to arguments that cognitive resources are of increased importance and a greater awareness of cognitive restrictions exists among sensory impaired individuals, in particular among visually impaired individuals, we hypothesized differential relationships between resources and outcomes when comparing sensory impaired and sensory unimpaired older adults. Findings are based on samples of 121 visually impaired, 116 hearing impaired, and 150 sensory unimpaired older adults (M = 82 years). Results from a sample of 43 dual sensory impaired older adults are reported for comparison. Assessment relied on established instruments (e.g., WAIS-R, ADL/IADL). Structural equation modeling showed that cognitive resources and behavior-related everyday functioning were more strongly related in the sensory impaired groups as compared to the sensory unimpaired group. Cognitive resources and evaluation of everyday functioning were significantly linked only among the sensory impaired groups. When medical condition was controlled for, these effects persisted. It is concluded that both cognitive training as well as psychosocial support may serve as important additions to classic vision and hearing loss rehabilitation. PsycINFO Database Record (c) 2012 APA, all rights reserved

Regulation of Vascular Tone, Angiogenesis and Cellular Bioenergetics by the 3-Mercaptopyruvate Sulfurtransferase/H2S Pathway: Functional Impairment by Hyperglycemia and Restoration by DL-α-Lipoic Acid.

PubMed

Coletta, Ciro; Módis, Katalin; Szczesny, Bartosz; Brunyánszki, Attila; Oláh, Gábor; Rios, Ester C S; Yanagi, Kazunori; Ahmad, Akbar; Papapetropoulos, Andreas; Szabo, Csaba

2015-02-18

Hydrogen sulfide (H2S), as a reducing agent and an antioxidant molecule, exerts protective effects against hyperglycemic stress in the vascular endothelium. The mitochondrial enzyme 3-mercaptopyruvate sulfurtransferase (3-MST) is an important biological source of H2S. We have recently demonstrated that 3-MST activity is inhibited by oxidative stress in vitro and speculated that this may have an adverse effect on cellular homeostasis. In the current study, given the importance of H2S as a vasorelaxant, angiogenesis stimulator and cellular bioenergetic mediator, we first determined whether the 3-MST/H2S system plays a physiological regulatory role in endothelial cells. Next, we tested whether a dysfunction of this pathway develops during the development of hyperglycemia and μmol/L to diabetes-associated vascular complications. Intraperitoneal (IP) 3-MP (1 mg/kg) raised plasma H2S levels in rats. 3-MP (10 1 mmol/L) promoted angiogenesis in vitro in bEnd3 microvascular endothelial cells and in vivo in a Matrigel assay in mice (0.3-1 mg/kg). In vitro studies with bEnd3 cell homogenates demonstrated that the 3-MP-induced increases in H2S production depended on enzymatic activity, although at higher concentrations (1-3 mmol/L) there was also evidence for an additional nonenzymatic H2S production by 3-MP. In vivo, 3-MP facilitated wound healing in rats, induced the relaxation of dermal microvessels and increased mitochondrial bioenergetic function. In vitro hyperglycemia or in vivo streptozotocin diabetes impaired angiogenesis, attenuated mitochondrial function and delayed wound healing; all of these responses were associated with an impairment of the proangiogenic and bioenergetic effects of 3-MP. The antioxidants DL-α-lipoic acid (LA) in vivo, or dihydrolipoic acid (DHLA) in vitro restored the ability of 3-MP to stimulate angiogenesis, cellular bioenergetics and wound healing in hyperglycemia and diabetes. We conclude that diabetes leads to an impairment of the 3-MST/H2S pathway, and speculate that this may contribute to the pathogenesis of hyperglycemic endothelial cell dysfunction. We also suggest that therapy with H2S donors, or treatment with the combination of 3-MP and lipoic acid may be beneficial in improving angiogenesis and bioenergetics in hyperglycemia.

Regulation of Vascular Tone, Angiogenesis and Cellular Bioenergetics by the 3-Mercaptopyruvate Sulfurtransferase/H2S Pathway: Functional Impairment by Hyperglycemia and Restoration by dl-α-Lipoic Acid

PubMed Central

Coletta, Ciro; Módis, Katalin; Szczesny, Bartosz; Brunyánszki, Attila; Oláh, Gábor; Rios, Ester CS; Yanagi, Kazunori; Ahmad, Akbar; Papapetropoulos, Andreas; Szabo, Csaba

2015-01-01

Hydrogen sulfide (H2S), as a reducing agent and an antioxidant molecule, exerts protective effects against hyperglycemic stress in the vascular endothelium. The mitochondrial enzyme 3-mercaptopyruvate sulfurtransferase (3-MST) is an important biological source of H2S. We have recently demonstrated that 3-MST activity is inhibited by oxidative stress in vitro and speculated that this may have an adverse effect on cellular homeostasis. In the current study, given the importance of H2S as a vasorelaxant, angiogenesis stimulator and cellular bioenergetic mediator, we first determined whether the 3-MST/H2S system plays a physiological regulatory role in endothelial cells. Next, we tested whether a dysfunction of this pathway develops during the development of hyperglycemia and μmol/L to diabetes-associated vascular complications. Intraperitoneal (IP) 3-MP (1 mg/kg) raised plasma H2S levels in rats. 3-MP (10 1 mmol/L) promoted angiogenesis in vitro in bEnd3 microvascular endothelial cells and in vivo in a Matrigel assay in mice (0.3–1 mg/kg). In vitro studies with bEnd3 cell homogenates demonstrated that the 3-MP-induced increases in H2S production depended on enzymatic activity, although at higher concentrations (1–3 mmol/L) there was also evidence for an additional nonenzymatic H2S production by 3-MP. In vivo, 3-MP facilitated wound healing in rats, induced the relaxation of dermal microvessels and increased mitochondrial bioenergetic function. In vitro hyperglycemia or in vivo streptozotocin diabetes impaired angiogenesis, attenuated mitochondrial function and delayed wound healing; all of these responses were associated with an impairment of the proangiogenic and bioenergetic effects of 3-MP. The antioxidants dl-α-lipoic acid (LA) in vivo, or dihydrolipoic acid (DHLA) in vitro restored the ability of 3-MP to stimulate angiogenesis, cellular bioenergetics and wound healing in hyperglycemia and diabetes. We conclude that diabetes leads to an impairment of the 3-MST/H2S pathway, and speculate that this may contribute to the pathogenesis of hyperglycemic endothelial cell dysfunction. We also suggest that therapy with H2S donors, or treatment with the combination of 3-MP and lipoic acid may be beneficial in improving angiogenesis and bioenergetics in hyperglycemia. PMID:25715337

The representation of lexical-syntactic information: evidence from syntactic and lexical retrieval impairments in aphasia.

PubMed

Biran, Michal; Friedmann, Naama

2012-10-01

This study explored lexical-syntactic information - syntactic information that is stored in the lexicon - and its relation to syntactic and lexical impairments in aphasia. We focused on two types of lexical-syntactic information: predicate argument structure (PAS) of verbs (the number and types of arguments the verb selects) and grammatical gender of nouns. The participants were 17 Hebrew-speaking individuals with aphasia who had a syntactic deficit (agrammatism) or a lexical retrieval deficit (anomia) located at the semantic lexicon, the phonological output lexicon, or the phonological output buffer. After testing the participants' syntactic and lexical retrieval abilities and establishing the functional loci of their deficits, we assessed their PAS and grammatical gender knowledge. This assessment included sentence completion, sentence production, sentence repetition, and grammaticality judgment tasks. The participants' performance on these tests yielded several important dissociations. Three agrammatic participants had impaired syntax but unimpaired PAS knowledge. Three agrammatic participants had impaired syntax but unimpaired grammatical gender knowledge. This indicates that lexical-syntactic information is represented separately from syntax, and can be spared even when syntax at the sentence level, such as embedding and movement are impaired. All 5 individuals with phonological output buffer impairment and all 3 individuals with phonological output lexicon impairment had preserved lexical-syntactic knowledge. These selective impairments indicate that lexical-syntactic information is represented at a lexical stage prior to the phonological lexicon and the phonological buffer. Three participants with impaired PAS (aPASia) and impaired grammatical gender who showed intact lexical-semantic knowledge indicate that the lexical-syntactic information is represented separately from the semantic lexicon. This led us to conclude that lexical-syntactic information is stored in a separate syntactic lexicon. A double dissociation between PAS and grammatical gender impairments indicated that different types of lexical-syntactic information are represented separately in this syntactic lexicon. Copyright © 2011 Elsevier Srl. All rights reserved.

Executive Functioning Heterogeneity in Pediatric ADHD.

PubMed

Kofler, Michael J; Irwin, Lauren N; Soto, Elia F; Groves, Nicole B; Harmon, Sherelle L; Sarver, Dustin E

2018-04-28

Neurocognitive heterogeneity is increasingly recognized as a valid phenomenon in ADHD, with most estimates suggesting that executive dysfunction is present in only about 33%-50% of these children. However, recent critiques question the veracity of these estimates because our understanding of executive functioning in ADHD is based, in large part, on data from single tasks developed to detect gross neurological impairment rather than the specific executive processes hypothesized to underlie the ADHD phenotype. The current study is the first to comprehensively assess heterogeneity in all three primary executive functions in ADHD using a criterion battery that includes multiple tests per construct (working memory, inhibitory control, set shifting). Children ages 8-13 (M = 10.37, SD = 1.39) with and without ADHD (N = 136; 64 girls; 62% Caucasian/Non-Hispanic) completed a counterbalanced series of executive function tests. Accounting for task unreliability, results indicated significantly improved sensitivity and specificity relative to prior estimates, with 89% of children with ADHD demonstrating objectively-defined impairment on at least one executive function (62% impaired working memory, 27% impaired inhibitory control, 38% impaired set shifting; 54% impaired on one executive function, 35% impaired on two or all three executive functions). Children with working memory deficits showed higher parent- and teacher-reported ADHD inattentive and hyperactive/impulsive symptoms (BF 10  = 5.23 × 10 4 ), and were slightly younger (BF 10  = 11.35) than children without working memory deficits. Children with vs. without set shifting or inhibitory control deficits did not differ on ADHD symptoms, age, gender, IQ, SES, or medication status. Taken together, these findings confirm that ADHD is characterized by neurocognitive heterogeneity, while suggesting that contemporary, cognitively-informed criteria may provide improved precision for identifying a smaller number of neuropsychologically-impaired subtypes than previously described.

Post-tuberculous lung function impairment in a tuberculosis reference clinic in Cameroon.

PubMed

Mbatchou Ngahane, Bertrand Hugo; Nouyep, Junior; Nganda Motto, Malea; Mapoure Njankouo, Yacouba; Wandji, Adeline; Endale, Mireille; Afane Ze, Emmanuel

2016-05-01

After completion of treatment, a proportion of pulmonary TB (pTB) patients experience lung function impairment which can influence their quality of life. This study aimed to determine the prevalence of lung function impairment in patients treated for pTB and investigate its associated factors. A cross-sectional study was conducted in TB clinic of the Douala Laquintinie Hospital in Cameroon. Patients aged 15 and above who were treated for pTB between 2008 and 2012 were included in the study. Demographic data, respiratory symptoms prior TB diagnosis, comorbidities and chest radiography findings prior to TB treatment were collected. All participants underwent spirometric measurements. Airflow obstruction was defined as a post-bronchodilation FEV1/FVC <70% with FVC >80%, restrictive defects as an FEV1/FVC ratio of ≥70% with an FVC <80% predicted, and mixed defects as FVC of <80% predicted and an FEV1/FVC ratio of <70%. Lung function impairment was defined by the presence of at least one of these three abnormalities. Logistic regression analysis was employed to investigate risk factors of lung function impairment. Of a total of 269 participants included in the study, 146 (54.3%) were male. The median age of participants was 33 years. The median duration of symptoms before diagnosis of TB was 4 weeks [interquartile range (IQR) 3-8]. The prevalence of lung function impairment was 45.4% (95% CI 39-51). The multivariate analysis identified duration of symptoms [OR 1.08; 95% CI (1.01-1.15)] and fibrotic pattern [OR 3.54; 95% CI (1.40-8.95)] as independent risk factors for lung function impairment. Post-tuberculous pulmonary function impairment is frequent in Douala. Sensitization of patient with symptoms of pulmonary TB for an earlier visit to healthcare facilities could reduce the impact of pTB on lung function of patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

ASSESSMENT OF UPPER EXTREMITY IMPAIRMENT, FUNCTION, AND ACTIVITY FOLLOWING STROKE: FOUNDATIONS FOR CLINICAL DECISION MAKING

PubMed Central

Lang, Catherine E.; Bland, Marghuretta D.; Bailey, Ryan R.; Schaefer, Sydney Y.; Birkenmeier, Rebecca L.

2012-01-01

The purpose of this review is to provide a comprehensive approach for assessing the upper extremity (UE) after stroke. First, common upper extremity impairments and how to assess them are briefly discussed. While multiple UE impairments are typically present after stroke, the severity of one impairment, paresis, is the primary determinant of UE functional loss. Second, UE function is operationally defined and a number of clinical measures are discussed. It is important to consider how impairment and loss of function affect UE activity outside of the clinical environment. Thus, this review also identifies accelerometry as an objective method for assessing UE activity in daily life. Finally, the role that each of these levels of assessment should play in clinical decision making is discussed in order to optimize the provision of stroke rehabilitation services. PMID:22975740

Psychosocial outcomes at three and nine months after good neurological recovery from aneurysmal subarachnoid haemorrhage: predictors and prognosis

PubMed Central

Powell, J; Kitchen, N; Heslin, J; Greenwood, R

2002-01-01

Objectives: To investigate (1) the prevalence of various aspects of cognitive and psychosocial dysfunction, including post-traumatic stress symptoms, over nine months after subarachnoid haemorrhage (SAH); (2) whether SAH is preceded by increased life stress; (3) to what extent adverse outcomes may be predicted from preillness life stress, early neurological impairment, age, and sex; and (4) relations between emotional and functional outcomes. Methods: 52 patients with good neurological recovery after surgery for SAH were each matched for age, sex, and occupation with a healthy control participant. SAH patients were assessed three and nine months postdischarge on measures of cognitive functioning, mood, and social functioning. Objective stressors and subjective life change during the preceding year were rated retrospectively. Controls completed measures of mood and social functioning once only. Results: Compared with controls, SAH patients showed increased mood disturbance, subtle cognitive impairment, and abnormally low independence and participation on measures of social functioning. 60% showed clinically significant post-traumatic stress symptomatology (intrusive thoughts or avoidance of reminders) at three months and 30% at nine months. Independence in activities of daily living was greatly reduced in half to a third of the sample at both three and nine months. Productive employment was below the 10th percentile of the control group for 75% of patients at three months and for 56% at nine months; this outcome could not be predicted from selected demographic, premorbid, or clinical variables but dependence on others for organisational activities was predicted by impaired prose recall. Mood at nine months was strongly predicted by prior mental health problems, poor physical health, dysphasia, and impaired prose recall at three months. There was no evidence of an abnormally high level of stressful life events in the year before SAH, although patients rated their subjective level of stress in this period slightly more highly than did the control participants. Conclusions: These findings highlight the need for structured support and treatment after surgery for SAH to reduce persisting mood disturbance and increase independence and participation. PMID:12023423

A genetic reduction in antioxidant function causes elevated aggression in mice.

PubMed

Garratt, Michael; Brooks, Robert C

2015-01-15

Male-male aggression can have a large influence on access to mates, particularly in highly territorial animals such as mice. It has been suggested that males with impaired antioxidant defence and a consequential increased susceptibility to oxidative stress may have a reduced ability to invest in aggressive behaviours, which could limit their mating opportunities and reproductive success. Oxidative stress occurs as a result of an uncontrolled over-production of reactive oxygen species (ROS) in relation to defence mechanisms (such as antioxidants), and can cause damage to a variety of different cellular components. Impairments in specific aspects of antioxidant defence, leading to oxidative stress, can limit investment in some reproductive traits in males, such as sperm quality and the production of sexual signals to attract mates. However, a direct effect of impaired antioxidant defence on aggressive behaviour has not, to our knowledge, been reported. In this study, we demonstrate that mice with experimentally elevated sensitivity to oxidative stress (through inhibition of copper-zinc superoxide dismutase, Sod1) actually show the opposite response to previous predictions. Males completely deficient in SOD1 are more aggressive than both wild-type males and males that express 50% of this antioxidant enzyme. They are also faster to attack another male. The cause of this increased aggression is unknown, but this result highlights that aggressive behaviour in mice is not highly constrained by inhibited Sod1 expression, in contrast to other reproductive traits known to be impaired in this mouse model. © 2015. Published by The Company of Biologists Ltd.

Pathophysiology and molecular basis of selected metabolic abnormalities in Huntington's disease.

PubMed

Krzysztoń-Russjan, Jolanta

2016-12-30

Huntington's disease (HD) is an incurable, devastating neurodegenerative disease with a known genetic background and autosomally dominant inheritance pattern. HTT gene mutation (mHTT) is associated with polymorphic fragment elongation above 35 repeats of the CAG triplet. The mHTT product is an altered protein with a poly-Q elongated fragment, with the highest expression determined in the central nervous system (CNS) and with differentiated expression outside the CNS. A drastic loss of striatal and deeper layers of the cerebral cortex neurons was determined in the CNS, but muscle and body weight mass loss with dysfunction of many organs was also observed. HD symptoms include neurological disturbances, such as choreal movements with dystonia, speech and swallowing impairments, and additionally a variety of psychiatric and behavioral symptoms with cognitive decline have been described. They are the result of disturbances of several cellular pathways related to signal transmission, mitochondrial dysfunction and energy metabolism impairment shown by gene and protein expression and alteration of their functions. Impairment of energy processes demonstrated by a decrease of ATP production and increase of oxidative stress markers was determined in- and outside of the CNS in glycolysis, the Krebs cycle and the electron transport chain. A correlation between the increase of energy metabolism impairment level and the increase in number of CAG repeats in HTT has often been described. The energy metabolism study is an initial stage of sensitive biomarkers and a new therapeutic investigative option for early application in order to inhibit pathological processes in HD. Identification of pathological changes outside the CNS requires a reevaluation of diagnostic and therapeutic rules in HD.

Cognitive profile in Duchenne muscular dystrophy boys without intellectual disability: The role of executive functions.

PubMed

Battini, R; Chieffo, D; Bulgheroni, S; Piccini, G; Pecini, C; Lucibello, S; Lenzi, S; Moriconi, F; Pane, M; Astrea, G; Baranello, G; Alfieri, P; Vicari, S; Riva, D; Cioni, G; Mercuri, E

2018-02-01

The aim of our prospective observational study was to assess profiles of cognitive function and a possible impairment of executive functions in a cohort of boys with Duchenne muscular dystrophy without intellectual and behavior disability. Forty Duchenne boys (range of age: 6 years to 11 years and 6 months) were assessed by Wechsler Intelligence scale and battery of tests including tasks assessing working memory and executive functions (inhibition and switching, problem solving and planning). In our cohort some aspects of cognitive function were often impaired. These included multitasking, problem solving, inhibition and working memory necessary to plan and direct goal oriented behavior. Our results support the suggestion that aspects of cognitive function could be impaired even in boys without intellectual disability and support the hypothesis that executive functions may play an important role in specific aspects of cognitive impairment in Duchenne muscular dystrophy. Copyright © 2017 Elsevier B.V. All rights reserved.

A network analysis of DSM-5 posttraumatic stress disorder and functional impairment in UK treatment-seeking veterans.

PubMed

Ross, Jana; Murphy, Dominic; Armour, Cherie

2018-05-28

Network analysis is a relatively new methodology for studying psychological disorders. It focuses on the associations between individual symptoms which are hypothesized to mutually interact with each other. The current study represents the first network analysis conducted with treatment-seeking military veterans in UK. The study aimed to examine the network structure of posttraumatic stress disorder (PTSD) symptoms and four domains of functional impairment by identifying the most central (i.e., important) symptoms of PTSD and by identifying those symptoms of PTSD that are related to functional impairment. Participants were 331 military veterans with probable PTSD. In the first step, a network of PTSD symptoms based on the PTSD Checklist for DSM-5 was estimated. In the second step, functional impairment items were added to the network. The most central symptoms of PTSD were recurrent thoughts, nightmares, negative emotional state, detachment and exaggerated startle response. Functional impairment was related to a number of different PTSD symptoms. Impairments in close relationships were associated primarily with the negative alterations in cognitions and mood symptoms and impairments in home management were associated primarily with the reexperiencing symptoms. The results are discussed in relation to previous PTSD network studies and include implications for clinical practice. Copyright © 2018 Elsevier Ltd. All rights reserved.

Does natural selection organize ecosystems for the maintenance of high productivity and diversity?

PubMed Central

Leigh, Egbert Giles; Vermeij, Geerat Jacobus

2002-01-01

Three types of evidence suggest that natural ecosystems are organized for high productivity and diversity: (i) changes not previously experienced by a natural ecosystem, such as novel human disturbances, tend to diminish its productivity and/or diversity, just as 'random' changes in a machine designed for a function usually impair its execution of that function; (ii) humans strive to recreate properties of natural ecosystems to enhance productivity of artificial ones, as farmers try to recreate properties of natural soils in their fields; and (iii) productivity and diversity have increased during the Earth's history as a whole, and after every major biotic crisis. Natural selection results in ecosystems organized to maintain high productivity of organic matter and diversity of species, just as competition among individuals in Adam Smith's ideal economy favours high production of wealth and diversity of occupations. In nature, poorly exploited energy attracts more efficient users. This circumstance favours the opening of new ways of life and more efficient recycling of resources, and eliminates most productivity-reducing 'ecological monopolies'. Ecological dominants tend to be replaced by successors with higher metabolism, which respond to more stimuli and engage in more varied interactions. Finally, increasingly efficient predators and herbivores favour faster turnover of resources. PMID:12079531

Polycystin-1 Cleavage and the Regulation of Transcriptional Pathways

PubMed Central

Merrick, David; Bertuccio, Claudia A.; Chapin, Hannah C.; Lal, Mark; Chauvet, Veronique; Caplan, Michael J.

2013-01-01

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of end stage renal disease, affecting ~1 in 1,000 people. The disease is characterized by the development of numerous large fluid filled renal cysts over the course of decades. These cysts compress the surrounding renal parenchyma and impair its function. Mutations in two genes are responsible for ADPKD. The protein products of both of these genes, polycystin-1 and polycystin-2, localize to the primary cilium and participate in a wide variety of signaling pathways. Polycystin-1 undergoes several proteolytic cleavages that produce fragments that manifest biological activities. Recent results suggest that the production of polycystin-1 cleavage fragments is necessary and sufficient to account for at least some, although certainly not all, of the physiological functions of the parent protein. PMID:23824180

Association of Dynapenia, Sarcopenia, and Cognitive Impairment Among Community-Dwelling Older Taiwanese.

PubMed

Huang, Chung-Yu; Hwang, An-Chun; Liu, Li-Kuo; Lee, Wei-Ju; Chen, Liang-Yu; Peng, Li-Ning; Lin, Ming-Hsien; Chen, Liang-Kung

2016-02-01

A decline in physical and/or cognitive function is a common feature of aging, and frailty has been shown to be associated with cognitive impairment and dementia. This study aimed to evaluate the association between dynapenia, sarcopenia, and cognitive impairment among community-dwelling older people in Taiwan. Data from the I-Lan Longitudinal Aging Study (ILAS) were retrieved for study. Global cognitive function was assessed by Mini-Mental State Examination (MMSE), whereas the Chinese Version Verbal Learning Test, Boston Naming Test, Verbal Fluency Test, Taylor Complex Figure Test, Digits Backward Test, and Clock Drawing Test were used to assess different domains of cognitive function. Association between sarcopenia and global cognitive function as well as all different dimensions of cognitive function were evaluated. Data from 731 elderly participants (mean age 73.4 ± 5.4 years, 53.8% males) were used for study analysis. The overall prevalence of sarcopenia was 6.8%, which was significantly higher in men (9.3% versus 4.1%, p < 0.05). The mean MMSE score was 23.4 ± 4.4 for all participants, and 10.3% of the study participants were cognitively impaired. Sarcopenia was not significantly associated with global cognitive function (odds ratio [OR] = 1.55, p = 0.317), but global cognitive impairment was significantly associated with low physical performance (OR = 2.31, p = 0.003) and low muscle strength (OR = 2.59, p = 0.011). Nonetheless, sarcopenia was significantly associated with impairment in the verbal fluency test (OR = 3.96, p = 0.006) after adjustment for potential confounders. Dynapenia was significantly associated with cognitive impairment in multiple dimensions and global cognitive function, but sarcopenia was only associated with an impaired verbal fluency test. Reduced muscle strength and/or physical performance related to non-muscle etiology were strongly associated with cognitive impairment. More longitudinal studies are needed.

Safety, Tolerability, and Pharmacokinetics of Ribavirin in Hepatitis C Virus-Infected Patients with Various Degrees of Renal Impairment

PubMed Central

Wang, K.; Blotner, S.; Magnusson, M. O.; Wilkins, J. J.; Martin, P.; Solsky, J.; Nieforth, K.; Wat, C.; Grippo, J. F.

2013-01-01

Ribavirin (RBV) is an integral part of standard-of-care hepatitis C virus (HCV) treatments and many future regimens under investigation. The pharmacokinetics (PK), safety, and tolerability of RBV in chronically HCV-infected patients with renal impairment are not well defined and were the focus of an open-label PK study in HCV-infected patients receiving RBV plus pegylated interferon. Serial RBV plasma samples were collected over 12 h on day 1 of weeks 1 and 12 from patients with moderate renal impairment (creatinine clearance [CLCR], 30 to 50 ml/min; RBV, 600 mg daily), severe renal impairment (CLCR, <30 ml/min; RBV, 400 mg daily), end-stage renal disease (ESRD) (RBV, 200 mg daily), or normal renal function (CLCR, >80 ml/min; RBV, 800 to 1,200 mg daily). Of the 44 patients, 9 had moderately impaired renal function, 10 had severely impaired renal function, 13 had ESRD, and 12 had normal renal function. The RBV dose was reduced because of adverse events (AEs) in 71% and 53% of severe and moderate renal impairment groups, respectively. Despite this modification, patients with moderate and severe impairment had 12-hour (area under the concentration-time curve from 0 to 12 h [AUC0–12]) values 36% (38,452 ng · h/ml) and 25% (35,101 ng · h/ml) higher, respectively, than those with normal renal function (28,192 ng · h/ml). Patients with ESRD tolerated a 200-mg daily dose, and AUC0–12 was 20% lower (22,629 ng · h/ml) than in patients with normal renal function. PK modeling and simulation (M&S) indicated that doses of 200 mg or 400 mg alternating daily for patients with moderate renal impairment and 200 mg daily for patients with severe renal impairment were the most appropriate dose regimens in these patients. PMID:24080649

Latent class analysis reveals clinically relevant atopy phenotypes in 2 birth cohorts.

PubMed

Hose, Alexander J; Depner, Martin; Illi, Sabina; Lau, Susanne; Keil, Thomas; Wahn, Ulrich; Fuchs, Oliver; Pfefferle, Petra Ina; Schmaußer-Hechfellner, Elisabeth; Genuneit, Jon; Lauener, Roger; Karvonen, Anne M; Roduit, Caroline; Dalphin, Jean-Charles; Riedler, Josef; Pekkanen, Juha; von Mutius, Erika; Ege, Markus J

2017-06-01

Phenotypes of childhood-onset asthma are characterized by distinct trajectories and functional features. For atopy, definition of phenotypes during childhood is less clear. We sought to define phenotypes of atopic sensitization over the first 6 years of life using a latent class analysis (LCA) integrating 3 dimensions of atopy: allergen specificity, time course, and levels of specific IgE (sIgE). Phenotypes were defined by means of LCA in 680 children of the Multizentrische Allergiestudie (MAS) and 766 children of the Protection against allergy: Study in Rural Environments (PASTURE) birth cohorts and compared with classical nondisjunctive definitions of seasonal, perennial, and food sensitization with respect to atopic diseases and lung function. Cytokine levels were measured in the PASTURE cohort. The LCA classified predominantly by type and multiplicity of sensitization (food vs inhalant), allergen combinations, and sIgE levels. Latent classes were related to atopic disease manifestations with higher sensitivity and specificity than the classical definitions. LCA detected consistently in both cohorts a distinct group of children with severe atopy characterized by high seasonal sIgE levels and a strong propensity for asthma; hay fever; eczema; and impaired lung function, also in children without an established asthma diagnosis. Severe atopy was associated with an increased IL-5/IFN-γ ratio. A path analysis among sensitized children revealed that among all features of severe atopy, only excessive sIgE production early in life affected asthma risk. LCA revealed a set of benign, symptomatic, and severe atopy phenotypes. The severe phenotype emerged as a latent condition with signs of a dysbalanced immune response. It determined high asthma risk through excessive sIgE production and directly affected impaired lung function. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

The effects of self-instruction training on a deaf child's semantic and pragmatic production.

PubMed

Swanson, H L

1987-10-01

Effects of self-instruction training on the communication skills of a profoundly hearing-impaired child were studied. Self-instruction training included modeling a series of problem-solving steps in order to direct communication production. Communication production was operationalized as signed semantic and pragmatic functions. A multiple baseline was used to assess treatment and generalization (treatment variations of person and setting) effects. There was evidence to suggest that self-instruction was immediately effective on pragmatic behaviors but such behaviors were reduced when another person administered treatment. In contrast, self-instruction training had a gradual influence on semantic behaviors and those effects were maintained when treatment included a different person and setting. Implications of the clinical study were discussed.

Oral intake of beet extract provides protection against skin barrier impairment in hairless mice.

PubMed

Kawano, Ken-Ichi; Umemura, Kazuo

2013-05-01

The epidermis acts as a functional barrier against the external environment. Disturbances in the function of this barrier cause water loss and increase the chances of penetration by various irritable stimuli, leading to skin diseases such as dry skin, atopic dermatitis, and psoriasis. Ceramides are a critical natural element of the protective epidermal barrier. The aim of this study was to evaluate whether the oral intake of beet (Beta vulgaris) extract, a natural product rich in glucosylceramide (GlcCer), may prevent disturbance in skin barrier function. When HR-1 hairless mice were fed a special diet (HR-AD), transepidermal water loss (TEWL) from the dorsal skin increased, with a compensatory increase in water intake after 5 weeks. Mice fed with HR-AD had dry skin with erythema and showed increased scratching behaviour. Histological examinations revealed a remarkable increase in the thickness of the skin at 8 weeks. Supplemental addition of beet extract, which contained GlcCer at a final concentration of 0.1%, significantly prevented an increase TEWL, water intake, cumulative scratching time, and epidermal thickness at 8 weeks. These results indicate that oral intake of beet extract shows potential for preventing skin diseases associated with impaired skin barrier function. Copyright © 2012 John Wiley & Sons, Ltd.

The effects of synthetic cannabinoids on executive function.

PubMed

Cohen, K; Kapitány-Fövény, M; Mama, Y; Arieli, M; Rosca, P; Demetrovics, Z; Weinstein, A

2017-04-01

There is a growing use of novel psychoactive substances (NPSs) including synthetic cannabinoids. Synthetic cannabinoid products have effects similar to those of natural cannabis but the new synthetic cannabinoids are more potent and dangerous and their use has resulted in various adverse effects. The purpose of the study was to assess whether persistent use of synthetic cannabinoids is associating with impairments of executive function in chronic users. A total of 38 synthetic cannabinoids users, 43 recreational cannabis users, and 41 non-user subjects were studied in two centers in Hungary and Israel. Computerized cognitive function tests, the classical Stroop word-color task, n-back task, and a free-recall memory task were used. Synthetic cannabinoid users performed significantly worse than both recreational and non-cannabis users on the n-back task (less accuracy), the Stroop task (overall slow responses and less accuracy), and the long-term memory task (less word recall). Additionally, they have also shown higher ratings of depression and anxiety compared with both recreational and non-users groups. This study showed impairment of executive function in synthetic cannabinoid users compared with recreational users of cannabis and non-users. This may have major implications for our understanding of the long-term consequences of synthetic cannabinoid based drugs.

Impact of Rhinitis on Work Productivity: A Systematic Review.

PubMed

Vandenplas, Olivier; Vinnikov, Denis; Blanc, Paul D; Agache, Ioana; Bachert, Claus; Bewick, Michael; Cardell, Lars-Olaf; Cullinan, Paul; Demoly, Pascal; Descatha, Alexis; Fonseca, Joao; Haahtela, Tari; Hellings, Peter W; Jamart, Jacques; Jantunen, Juha; Kalayci, Ömer; Price, David; Samolinski, Boleslaw; Sastre, Joaquin; Tian, Longxiu; Valero, Antonio L; Zhang, Xinyi; Bousquet, Jean

2017-10-07

Allergic rhinitis (AR) is increasingly acknowledged as having a substantial socioeconomic impact associated with impaired work productivity, although available information remains fragmented. This systematic review summarizes recently available information to provide a quantitative estimate of the burden of AR on work productivity including lost work time (ie, absenteeism) and reduced performance while working (ie, presenteeism). A Medline search retrieved original studies from 2005 to 2015 pertaining to the impact of AR on work productivity. A pooled analysis of results was carried out with studies reporting data collected through the validated Work Productivity and Activity Impairment (WPAI) questionnaire. The search identified 19 observational surveys and 9 interventional studies. Six studies reported economic evaluations. Pooled analysis of WPAI-based studies found an estimated 3.6% (95% confidence interval [CI], 2.4; 4.8%) missed work time and 35.9% (95% CI, 29.7; 42.1%) had impairment in at-work performance due to AR. Economic evaluations indicated that indirect costs associated with lost work productivity are the principal contributor to the total AR costs and result mainly from impaired presenteeism. The severity of AR symptoms was the most consistent disease-related factor associated with a greater impact of AR on work productivity, although ocular symptoms and sleep disturbances may independently affect work productivity. Overall, the pharmacologic treatment of AR showed a beneficial effect on work productivity. This systematic review provides summary estimates of the magnitude of work productivity impairment due to AR and identifies its main determinant factors. This information may help guide both clinicians and health policy makers. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Body representation disorders predict left right orientation impairments after stroke: A voxel-based lesion symptom mapping study.

PubMed

van Stralen, Haike E; Dijkerman, H Chris; Biesbroek, J Matthijs; Kuijf, Hugo J; van Gemert, H Maarten A; Sluiter, David; Kappelle, L Jaap; van Zandvoort, Martine J E

2017-06-07

Deficits in the ability to distinguish between the left and right side of the body can severely impair daily life functioning. The current study examined the relation between left right orientation (LRO) impairments and somatosensory related deficits, ranging from primary somatosensory impairments to body representation impairments, in patients who suffered a recent stroke. We also examined which areas in the brain are associated with LRO impairments using a Voxel-based Lesion Symptom Mapping (VLSM) analysis. We tested 47 first-ever stroke patients and 48 age-matched healthy controls. LRO was assessed with the Bergen Right Left Discrimination Test (BRLD). Impairments on primary somatosensory function (touch perception, proprioception), higher order somatosensory function (finger gnosis, subjective sense of body ownership) and other cognitive functions (language, attention & working memory, visuospatial neglect) were entered as predictors in a logistic regression analyses. Outcome measures consisted of the BRLD-total performance which was further subdivided in performance for 1) first person perspective stimuli, 2) third person perspective stimuli, 3) alternating between first- and third person perspective. Impairments on BRLD-total performance was predicted by impairments in finger gnosis and visuospatial neglect. For items placed in third person perspective, performance was predicted by body representation impairments; finger agnosia and the subjective sense of body ownership. VLSM analysis showed a significant association between LRO impairments and damage to the right insula. The current study suggests that the somatosensory system is important for LRO. Furthermore, the results indicate that an affected body representation may hinder adopting a third person perspective that may subsequently also lead to LRO impairments. The right insular cortex appeared crucially involved in these processes. Copyright © 2017 Elsevier Ltd. All rights reserved.

A Paleolithic Diet with and without Combined Aerobic and Resistance Exercise Increases Functional Brain Responses and Hippocampal Volume in Subjects with Type 2 Diabetes

PubMed Central

Stomby, Andreas; Otten, Julia; Ryberg, Mats; Nyberg, Lars; Olsson, Tommy; Boraxbekk, Carl-Johan

2017-01-01

Type 2 diabetes is associated with impaired episodic memory functions and increased risk of different dementing disorders. Diet and exercise may potentially reverse these impairments. In this study, sedentary individuals with type 2 diabetes treated by lifestyle ± metformin were randomized to a Paleolithic diet (PD, n = 12) with and without high intensity exercise (PDEX, n = 12) for 12 weeks. Episodic memory function, associated functional brain responses and hippocampal gray matter volume was measured by magnetic resonance imaging. A matched, but not randomized, non-interventional group was included as a reference (n = 6). The PD included a high intake of unsaturated fatty acids and protein, and excluded the intake of dairy products, grains, refined sugar and salt. The exercise intervention consisted of 180 min of supervised aerobic and resistance exercise per week. Both interventions induced a significant weight loss, improved insulin sensitivity and increased peak oxygen uptake without any significant group differences. Furthermore, both interventions were associated with increased functional brain responses within the right anterior hippocampus, right inferior occipital gyrus and increased volume of the right posterior hippocampus. There were no changes in memory performance. We conclude that life-style modification may improve neuronal plasticity in brain areas linked to cognitive function in type 2 diabetes. Putative long-term effects on cognitive functions including decreased risk of dementing disorders await further studies. Clinical trials registration number: Clinicaltrials. gov NCT01513798. PMID:29255413

A Paleolithic Diet with and without Combined Aerobic and Resistance Exercise Increases Functional Brain Responses and Hippocampal Volume in Subjects with Type 2 Diabetes.

PubMed

Stomby, Andreas; Otten, Julia; Ryberg, Mats; Nyberg, Lars; Olsson, Tommy; Boraxbekk, Carl-Johan

2017-01-01

Type 2 diabetes is associated with impaired episodic memory functions and increased risk of different dementing disorders. Diet and exercise may potentially reverse these impairments. In this study, sedentary individuals with type 2 diabetes treated by lifestyle ± metformin were randomized to a Paleolithic diet (PD, n = 12) with and without high intensity exercise (PDEX, n = 12) for 12 weeks. Episodic memory function, associated functional brain responses and hippocampal gray matter volume was measured by magnetic resonance imaging. A matched, but not randomized, non-interventional group was included as a reference ( n = 6). The PD included a high intake of unsaturated fatty acids and protein, and excluded the intake of dairy products, grains, refined sugar and salt. The exercise intervention consisted of 180 min of supervised aerobic and resistance exercise per week. Both interventions induced a significant weight loss, improved insulin sensitivity and increased peak oxygen uptake without any significant group differences. Furthermore, both interventions were associated with increased functional brain responses within the right anterior hippocampus, right inferior occipital gyrus and increased volume of the right posterior hippocampus. There were no changes in memory performance. We conclude that life-style modification may improve neuronal plasticity in brain areas linked to cognitive function in type 2 diabetes. Putative long-term effects on cognitive functions including decreased risk of dementing disorders await further studies. Clinical trials registration number: Clinicaltrials. gov NCT01513798.

A continuum of executive function deficits in early subcortical vascular cognitive impairment: A systematic review and meta-analysis.

PubMed

Sudo, Felipe Kenji; Amado, Patricia; Alves, Gilberto Sousa; Laks, Jerson; Engelhardt, Eliasz

2017-01-01

Subcortical Vascular Cognitive Impairment (SVCI) is a clinical continuum of vascular-related cognitive impairment, including Vascular Mild Cognitive Impairment (VaMCI) and Vascular Dementia. Deficits in Executive Function (EF) are hallmarks of the disorder, but the best methods to assess this function have yet to be determined. The insidious and almost predictable course of SVCI and the multidimensional concept of EF suggest that a temporal dissociation of impairments in EF domains exists early in the disorder. This study aims to review and analyze data from the literature about performance of VaMCI patients on the most used EF tests through a meta-analytic approach. Medline, Web of Knowledge and PsycINFO were searched, using the terms: "vascular mild cognitive impairment" OR "vascular cognitive impairment no dementia" OR "vascular mild neurocognitive disorder" AND "dysexecutive" OR "executive function". Meta-analyses were conducted for each of the selected tests, using random-effect models. Systematic review showed major discrepancies among the results of the studies included. Meta-analyses evidenced poorer performance on the Trail-Making Test part B and the Stroop color test by VaMCI patients compared to controls. A continuum of EF impairments has been proposed in SVCI. Early deficits appear to occur in cognitive flexibility and inhibitory control.

Aberrant in Vivo T Helper Type 2 Cell Response and Impaired Eosinophil Recruitment in Cc Chemokine Receptor 8 Knockout Mice

PubMed Central

Chensue, Stephen W.; Lukacs, Nicholas W.; Yang, Tong-Yuan; Shang, Xiaozhou; Frait, Kirsten A.; Kunkel, Steven L.; Kung, Ted; Wiekowski, Maria T.; Hedrick, Joseph A.; Cook, Donald N.; Zingoni, Alessandra; Narula, Satwant K.; Zlotnik, Albert; Barrat, Franck J.; O'Garra, Anne; Napolitano, Monica; Lira, Sergio A.

2001-01-01

Chemokine receptors transduce signals important for the function and trafficking of leukocytes. Recently, it has been shown that CC chemokine receptor (CCR)8 is selectively expressed by Th2 subsets, but its functional relevance is unclear. To address the biological role of CCR8, we generated CCR8 deficient (−/−) mice. Here we report defective T helper type 2 (Th2) immune responses in vivo in CCR8−/− mice in models of Schistosoma mansoni soluble egg antigen (SEA)-induced granuloma formation as well as ovalbumin (OVA)- and cockroach antigen (CRA)-induced allergic airway inflammation. In these mice, the response to SEA, OVA, and CRA showed impaired Th2 cytokine production that was associated with aberrant type 2 inflammation displaying a 50 to 80% reduction in eosinophils. In contrast, a prototypical Th1 immune response, elicited by Mycobacteria bovis purified protein derivative (PPD) was unaffected by CCR8 deficiency. Mechanistic analyses indicated that Th2 cells developed normally and that the reduction in eosinophil recruitment was likely due to systemic reduction in interleukin 5. These results indicate an important role for CCR8 in Th2 functional responses in vivo. PMID:11238588

Age-related changes in endothelial function and blood flow regulation.

PubMed

Toda, Noboru

2012-02-01

Vascular endothelial dysfunction is regarded as a primary phenotypic expression of normal human aging. This senescence-induced disorder is the likely culprit underlying the increased cardiovascular and metabolic disease risks associated with aging. The rate of this age-dependent deterioration is largely influenced by the poor-quality lifestyle choice, such as smoking, sedentary daily life, chronic alcohol ingestion, high salt intake, unbalanced diet, and mental stress; and it is accelerated by cardiovascular and metabolic diseases. Although minimizing these detrimental factors is the best course of action, nonetheless chronological age steadily impairs endothelial function through reduced endothelial nitric oxide synthase (eNOS) expression/action, accelerated nitric oxide (NO) degradation, increased phosphodiesterase activity, inhibition of NOS activity by endogenous NOS inhibitors, increased production of reactive oxygen species, inflammatory reactions, decreased endothelial progenitor cell number and function, and impaired telomerase activity or telomere shortening. Endothelial dysfunction in regional vasculatures results in cerebral hypoperfusion triggering cognitive dysfunction and Alzheimer's disease, coronary artery insufficiency, penile erectile dysfunction, and circulatory failures in other organs and tissues. Possible prophylactic measures to minimize age-related endothelial dysfunction are also summarized in this review. Copyright © 2011 Elsevier Inc. All rights reserved.

Pharmacokinetic Properties of Fostamatinib in Patients With Renal or Hepatic Impairment: Results From 2 Phase I Clinical Studies.

PubMed

Martin, Paul; Oliver, Stuart; Gillen, Michael; Marbury, Thomas; Millson, David

2015-12-01

Phase III trials of fostamatinib, an oral spleen tyrosine kinase inhibitor, in the treatment of rheumatoid arthritis have been completed. Herein, we report the effects of renal and hepatic impairment on the pharmacokinetic (PK) properties of the active metabolite of fostamatinib, R406, in plasma, and on the urinary excretion of R406 and its metabolite N-glucuronide. Two Phase I, single-center, open-label clinical trials determined the PK properties and tolerability of fostamatinib in subjects with normal or impaired renal or hepatic function. Twenty-four subjects in the study in renal impairment (8 per group: normal renal function, moderate renal dysfunction, or end-stage renal disease [ESRD]), and 32 subjects in the study in hepatic impairment (8 per group: normal hepatic function or mild, moderate, or severe hepatic impairment) received a single 150-mg dose of fostamatinib. Patients with ESRD in the study in renal impairment participated in 2 treatment periods separated by a ≥1-week washout. In these patients, fostamatinib was administered after dialysis or 2 hours before dialysis. Geometric mean R406 Cmax and AUC values were less in the combined renally impaired group than in the group with normal renal function; Tmax was similar across groups. However, renal impairment had no apparent effect considered clinically relevant on unbound R406. In patients with ESRD, R406 exposure was less when fostamatinib was administered after compared with before dialysis. Urinary excretion of R406 N-glucuronide was decreased with increasing severity of renal impairment. Renal elimination of R406 was negligible in all groups. Varying degrees of hepatic impairment had no consistent effects on the PK properties of R406. R406 Cmax values were 10% to 15% less in all hepatically impaired groups than in the group with normal hepatic function. AUC and Tmax values were similar between the groups with normal and severely impaired hepatic function; in the groups with mild or moderate hepatic impairment, AUC was less and Tmax was greater. The geometric mean percentage of unbound R406 ranged from 0.64% to 1.95% and was greatest in the group with severe hepatic impairment. The urinary excretion of R406 was minimal. The amount of R406 N-glucuronide excreted in urine was greater in severely hepatically impaired patients. Fostamatinib 150 mg was generally well tolerated. In these patients, renal or hepatic impairment did not affect exposure to the active metabolite of fostamatinib, R406, to a clinically relevant extent. ClinicalTrials.gov identifiers: NCT01245790 (renal) and NCT01222455 (hepatic). Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.

Pain, Bullying Involvement, and Mental Health Problems Among Children and Adolescents With ADHD in Taiwan.

PubMed

Yeh, Yi-Chun; Huang, Mei-Feng; Wu, Yu-Yu; Hu, Huei-Fan; Yen, Cheng-Fang

2017-08-01

The aim of this study was to examine the relationships of pain and pain-induced functional impairment with bullying involvement, as well as the relationships between pain and mental health problems among 474 children and adolescents with ADHD. The levels of pain, pain-induced functional impairment, involvement in bullying, depression, anxiety, ADHD symptoms, and sleep quality were assessed. Both victims of verbal and relational bullying and victims of physical bullying were more likely to have pain and pain-induced functional impairment than nonvictims. The perpetrators of verbal and relational bullying were more likely to have pain than the nonperpetrators. Participants with pain and pain-induced functional impairment experienced more severe depression and anxiety and worse sleep quality than did those without pain or pain-induced functional impairment. Clinical and educational professionals should consider the possibility of involvement in bullying and comorbid depression, anxiety, and poor sleep quality among ADHD children and adolescents with pain problems.

Different Functional and Microstructural Changes Depending on Duration of Mild Cognitive Impairment in Parkinson Disease.

PubMed

Shin, N-Y; Shin, Y S; Lee, P H; Yoon, U; Han, S; Kim, D J; Lee, S-K

2016-05-01

The higher cortical burden of Lewy body and Alzheimer disease-type pathology has been reported to be associated with a faster onset of cognitive impairment of Parkinson disease. So far, there has been a few studies only about the changes of gray matter volume depending on duration of cognitive impairment in Parkinson disease. Therefore, our aim was to evaluate the different patterns of structural and functional changes in Parkinson disease with mild cognitive impairment according to the duration of parkinsonism before mild cognitive impairment. Fifty-nine patients with Parkinson disease with mild cognitive impairment were classified into 2 groups on the basis of shorter (<1 year, n = 16) and longer (≥1 year, n = 43) durations of parkinsonism before mild cognitive impairment. Fifteen drug-naïve patients with de novo Parkinson disease with intact cognition were included for comparison. Cortical thickness, Tract-Based Spatial Statistics, and seed-based resting-state functional connectivity analyses were performed. Age, sex, years of education, age at onset of parkinsonism, and levodopa-equivalent dose were included as covariates. The group with shorter duration of parkinsonism before mild cognitive impairment showed decreased fractional anisotropy and increased mean and radial diffusivity values in the frontal areas compared with the group with longer duration of parkinsonism before mild cognitive impairment (corrected P < .05). The group with shorter duration of parkinsonism before mild cognitive impairment showed decreased resting-state functional connectivity in the default mode network area when the left or right posterior cingulate was used as a seed, and in the dorsolateral prefrontal areas when the left or right caudate was used as a seed (corrected P < .05). The group with longer duration of parkinsonism before mild cognitive impairment showed decreased resting-state functional connectivity mainly in the medial prefrontal cortex when the left or right posterior cingulate was used as a seed, and in the parieto-occipital areas when the left or right caudate was used as a seed (corrected P < .05). No differences in cortical thickness were found in all group contrasts. Resting-state functional connectivity and WM alterations might be useful imaging biomarkers for identifying changes in patients with Parkinson disease with mild cognitive impairment according to the duration of parkinsonism before mild cognitive impairment. The functional and microstructural substrates may topographically differ depending on the rate of cognitive decline in these patients. © 2016 by American Journal of Neuroradiology.

Reproductive hormones and menstrual changes with exercise in female athletes.

PubMed

Arena, B; Maffulli, N; Maffulli, F; Morleo, M A

1995-04-01

The endocrine equilibrium which regulates reproductive function in women can be affected by physical and psychological factors. Blood levels of hormones depend on a balance between production, metabolism and clearance rates. Intensive physical exercise may affect this balance via different mechanisms, such as stress associated with competition, dieting, reduction of body fat and body weight, production of heat or hypoxia. Women who engage in regular high intensity exercise may be at risk, as a consequence of these hormonal changes, of developing menstrual disturbances such as oligomenorrhoea, delayed menarche and amenorrhoea. Impaired production of gonadotrophins, which leads to luteal phase deficiency and anovulation, is a common hormonal finding with exercise-induced menstrual disturbances, but several other hormones may show significant alterations. In this article we have reviewed the recent literature on the effects of intensive physical exercise on the menstrual cycle, on some important physical parameters such as bone mineral density and bodyweight, and on those hormones (gonadotrophins, prolactin, melatonin, opioid peptides and steroids) which regulate, directly or indirectly, the reproductive function in women.

Requirement of argininosuccinate lyase for systemic nitric oxide production.

PubMed

Erez, Ayelet; Nagamani, Sandesh C S; Shchelochkov, Oleg A; Premkumar, Muralidhar H; Campeau, Philippe M; Chen, Yuqing; Garg, Harsha K; Li, Li; Mian, Asad; Bertin, Terry K; Black, Jennifer O; Zeng, Heng; Tang, Yaoping; Reddy, Anilkumar K; Summar, Marshall; O'Brien, William E; Harrison, David G; Mitch, William E; Marini, Juan C; Aschner, Judy L; Bryan, Nathan S; Lee, Brendan

2011-11-13

Nitric oxide (NO) is crucial in diverse physiological and pathological processes. We show that a hypomorphic mouse model of argininosuccinate lyase (encoded by Asl) deficiency has a distinct phenotype of multiorgan dysfunction and NO deficiency. Loss of Asl in both humans and mice leads to reduced NO synthesis, owing to both decreased endogenous arginine synthesis and an impaired ability to use extracellular arginine for NO production. Administration of nitrite, which can be converted into NO in vivo, rescued the manifestations of NO deficiency in hypomorphic Asl mice, and a nitric oxide synthase (NOS)-independent NO donor restored NO-dependent vascular reactivity in humans with ASL deficiency. Mechanistic studies showed that ASL has a structural function in addition to its catalytic activity, by which it contributes to the formation of a multiprotein complex required for NO production. Our data demonstrate a previously unappreciated role for ASL in NOS function and NO homeostasis. Hence, ASL may serve as a target for manipulating NO production in experimental models, as well as for the treatment of NO-related diseases.

Inhibiting Microbial Toxins Using Plant-Derived Compounds and Plant Extracts

PubMed Central

Upadhyay, Abhinav; Mooyottu, Shankumar; Yin, Hsinbai; Surendran Nair, Meera; Bhattaram, Varunkumar; Venkitanarayanan, Kumar

2015-01-01

Many pathogenic bacteria and fungi produce potentially lethal toxins that cause cytotoxicity or impaired cellular function either at the site of colonization or other locations in the body through receptor-mediated interactions. Various factors, including biotic and abiotic environments, competing microbes, and chemical cues affect toxin expression in these pathogens. Recent work suggests that several natural compounds can modulate toxin production in pathogenic microbes. However, studies explaining the mechanistic basis for their effect are scanty. This review discusses the potential of various plant-derived compounds for reducing toxin production in foodborne and other microbes. In addition, studies highlighting their anti-toxigenic mechanism(s) are discussed. PMID:28930207

The direct and indirect costs of Dravet Syndrome.

PubMed

Whittington, Melanie D; Knupp, Kelly G; Vanderveen, Gina; Kim, Chong; Gammaitoni, Arnold; Campbell, Jonathan D

2018-03-01

The objective of this study was to estimate the annual direct and indirect costs associated with Dravet Syndrome (DS). A survey was electronically administered to the caregivers of patients with DS treated at Children's Hospital Colorado. Survey domains included healthcare utilization of the patient with DS and DS caregiver work productivity and activity impairment. Patient healthcare utilization was measured using modified questions from the National Health Interview Survey; caregiver work productivity and activity impairment were measured using modified questions from the Work Productivity and Activity Impairment questionnaire. Direct costs were calculated by multiplying the caregiver-reported healthcare utilization rates by the mean unit cost for each healthcare utilization category. Indirect costs included lost productivity, income loss, and lost leisure time. The indirect costs were a function of caregiver-reported hours spent caregiving and an hourly unit cost. The survey was emailed to 60 DS caregivers, of which 34 (57% response rate) responded. Direct costs on average were $27,276 (95% interval: $15,757, $41,904) per patient with DS. Hospitalizations ($11,565 a year) and in-home medical care visits ($9894 a year) were substantial cost drivers. Additionally, caregivers reported extensive time spent providing care to an individual with DS. This caregiver time resulted in average annual indirect costs of $81,582 (95% interval: $57,253, $110,151), resulting in an average total annual financial burden of $106,378 (95% interval: $78,894, $137,906). Dravet Syndrome results in substantial healthcare utilization, financial burden, and time commitment. Establishing evidence on the financial burden of DS is essential to understanding the overall impact of DS, identifying potential areas for support needs, and assessing the impact of novel treatments as they become available. Based on the study findings, in-home visits, hospitalizations, and lost productivity and leisure time of caregivers are key domains for DS economic evaluations. Future research should extend these estimates to include the potential additional healthcare utilization of the DS caregiver. Copyright © 2018 Elsevier Inc. All rights reserved.

Understanding Pervasive Language Impairment in Young Children: Exploring Patterns in Narrative Language and Functional Communication

ERIC Educational Resources Information Center

Waters, Anna Jeddeloh

2013-01-01

Research has identified language impairment as a pervasive disability (Bishop & Edmundson, 1987; Greenhalgh & Strong, 2001). Classroom communication behaviors have a role in the maintenance of special education eligibility and functional communication difficulties for young children with language impairment. This paper reviews the…

Israeli adolescents with ongoing exposure to terrorism: suicidal ideation, posttraumatic stress disorder, and functional impairment.

PubMed

Chemtob, Claude M; Pat-Horenczyk, Ruth; Madan, Anita; Pitman, Seth R; Wang, Yanping; Doppelt, Osnat; Burns, Kelly Dugan; Abramovitz, Robert; Brom, Daniel

2011-12-01

In this study, we examined the relationships among terrorism exposure, functional impairment, suicidal ideation, and probable partial or full posttraumatic stress disorder (PTSD) from exposure to terrorism in adolescents continuously exposed to this threat in Israel. A convenience sample of 2,094 students, aged 12 to 18, was drawn from 10 Israeli secondary schools. In terms of demographic factors, older age was associated with increased risk for suicidal ideation, OR = 1.33, 95% CI [1.09, 1.62], p < .01, but was protective against probable partial or full PTSD, OR = 0.72, 95% CI [0.54, 0.95], p < .05; female gender was associated with greater likelihood of probable partial or full PTSD, OR = 1.57, 95% CI [1.02, 2.40], p < .05. Exposure to trauma due to terrorism was associated with increased risk for each of the measured outcomes including probable partial or full PTSD, functional impairment, and suicidal ideation. When age, gender, level of exposure to terrorism, probable partial or full PTSD, and functional impairment were examined together, only terrorism exposure and functional impairment were associated with suicidal ideation. This study underscores the importance and feasibility of examining exposure to terrorism and functional impairment as risk factors for suicidal ideation. Copyright © 2011 International Society for Traumatic Stress Studies.

Impairment in Occupational Functioning and Adult ADHD: The Predictive Utility of Executive Function (EF) Ratings Versus EF Tests

PubMed Central

Barkley, Russell A.; Murphy, Kevin R.

2010-01-01

Attention deficit hyperactivity disorder (ADHD) is associated with deficits in executive functioning (EF). ADHD in adults is also associated with impairments in major life activities, particularly occupational functioning. We investigated the extent to which EF deficits assessed by both tests and self-ratings contributed to the degree of impairment in 11 measures involving self-reported occupational problems, employer reported workplace adjustment, and clinician rated occupational adjustment. Three groups of adults were recruited as a function of their severity of ADHD: ADHD diagnosis (n = 146), clinical controls self-referring for ADHD but not diagnosed with it (n = 97), and community controls (n = 109). Groups were combined and regression analyses revealed that self-ratings of EF were significantly predictive of impairments in all 11 measures of occupational adjustment. Although several tests of EF also did so, they contributed substantially less than did the EF ratings, particularly when analyzed jointly with the ratings. We conclude that EF deficits contribute to the impairments in occupational functioning that occur in conjunction with adult ADHD. Ratings of EF in daily life contribute more to such impairments than do EF tests, perhaps because, as we hypothesize, each assesses a different level in the hierarchical organization of EF as a meta-construct. PMID:20197297

Depression, anxiety and somatization in primary care: syndrome overlap and functional impairment.

PubMed

Löwe, Bernd; Spitzer, Robert L; Williams, Janet B W; Mussell, Monika; Schellberg, Dieter; Kroenke, Kurt

2008-01-01

To determine diagnostic overlap of depression, anxiety and somatization as well as their unique and overlapping contribution to functional impairment. Two thousand ninety-one consecutive primary care clinic patients participated in a multicenter cross-sectional survey in 15 primary care clinics in the United States (participation rate, 92%). Depression, anxiety, somatization and functional impairment were assessed using validated scales from the Patient Health Questionnaire (PHQ) (PHQ-8, eight-item depression module; GAD-7, seven-item Generalized Anxiety Disorder Scale; and PHQ-15, 15-item somatic symptom scale) and the Short-Form General Health Survey (SF-20). Multiple linear regression analyses were used to investigate unique and overlapping associations of depression, anxiety and somatization with functional impairment. In over 50% of cases, comorbidities existed between depression, anxiety and somatization. The contribution of the commonalities of depression, anxiety and somatization to functional impairment substantially exceeded the contribution of their independent parts. Nevertheless, depression, anxiety and somatization did have important and individual effects (i.e., separate from their overlap effect) on certain areas of functional impairment. Given the large syndrome overlap, a potential consideration for future diagnostic classification would be to describe basic diagnostic criteria for a single overarching disorder and to optionally code additional diagnostic features that allow a more detailed classification into specific depressive, anxiety and somatoform subtypes.

Verb and sentence production and comprehension in aphasia: Northwestern Assessment of Verbs and Sentences (NAVS)

PubMed Central

Cho-Reyes, Soojin; Thompson, Cynthia K.

2015-01-01

Background Verbs and sentences are often impaired in individuals with aphasia, and differential impairment patterns are associated with different types of aphasia. With currently available test batteries, however, it is challenging to provide a comprehensive profile of aphasic language impairments because they do not examine syntactically important properties of verbs and sentences. Aims This study presents data derived from the Northwestern Assessment of Verbs and Sentences (NAVS; Thompson, 2011), a new test battery designed to examine syntactic deficits in aphasia. The NAVS includes tests for verb naming and comprehension, and production of verb argument structure in simple active sentences, with each examining the effects of the number and optionality of arguments. The NAVS also tests production and comprehension of canonical and non-canonical sentences. Methods & Procedures A total of 59 aphasic participants (35 agrammatic and 24 anomic) were tested using a set of action pictures. Participants produced verbs or sentences for the production subtests and identified pictures corresponding to auditorily provided verbs or sentences for the comprehension subtests. Outcomes & Results The agrammatic group, compared to the anomic group, performed significantly more poorly on all subtests except verb comprehension, and for both groups comprehension was less impaired than production. On verb naming and argument structure production tests both groups exhibited difficulty with three-argument verbs, affected by the number and optionality of arguments. However, production of sentences using three-argument verbs was more impaired in the agrammatic, compared to the anomic, group. On sentence production and comprehension tests, the agrammatic group showed impairments in all types of non-canonical sentences, whereas the anomic group exhibited difficulty primarily with the most difficult, object relative, structures. Conclusions Results show that verb and sentence deficits seen in individuals with agrammatic aphasia are largely influenced by syntactic complexity; however, individuals with anomic aphasia appear to exhibit these impairments only for the most complex forms of verbs and sentences. The present data indicate that the NAVS is useful for characterising verb and sentence deficits in people with aphasia. PMID:26379358

The Relationship between the Perception and the Production of Intonation by Hearing-Impaired Children.

ERIC Educational Resources Information Center

Most, Tova; Frank, Yael

1991-01-01

Twenty-two hearing-impaired children (ages 9 to 13) with a hearing loss of 80 dB or greater completed 3 tasks of intonation perception and production. Acoustic analysis suggested a relationship between imitation and discrimination of intonation contours and a relationship between imitation and production of orally read sentences when a rising…

Oral status, cognitive function and dependency among New Zealand nursing home residents.

PubMed

Thomson, William M; Smith, Moira B; Ferguson, Catherine Anna; Kerse, Ngaire M; Peri, Kathryn; Gribben, Barry

2018-04-23

To investigate clinical oral disease and its association with cognitive function and dependency among older New Zealanders in residential aged care. National survey of oral health in aged residential care throughout New Zealand. We classified residents into 1 of 3 levels of care: "low dependency care (or assisted living)"; "high dependency care"; or "specialist dementia care/psychogeriatric care." The Abbreviated Mental Test characterised cognitive function as "unimpaired" (scores of 7-10), "moderately impaired" (4-6) or "severely impaired" (0-3). Intra-oral examinations were conducted, along with a computer-assisted personal interview. Most of the 987 clinically examined participants were either at low or high dependency care level, with another 1 in 6 in psychogeriatric care. Almost half overall had severely impaired cognitive function. Just under half of the sample had 1 or more natural teeth remaining. Negative binomial regression modelling showed that the number of carious teeth was lower among women and higher among those who were older, those with more teeth and in those with severely impaired cognitive function. Oral debris scores (representing plaque biofilm and other soft deposits on teeth) were higher in men, those with more teeth, and in those with severely impaired cognitive function. Impaired cognitive function is a risk indicator for both dental caries and oral debris in aged residential care. © 2018 John Wiley & Sons A/S and The Gerodontology Association. Published by John Wiley & Sons Ltd.

Invited review: heat stress effects during late gestation on dry cows and their calves.

PubMed

Tao, S; Dahl, G E

2013-07-01

In dairy cattle, late gestation is a critical period for fetal growth and physiological transition into the next lactation. Environmental factors, such as temperature and light, exert dramatic effects on the production, health, and well-being of animals during this period and after parturition. The aim of this review was to introduce effects of heat stress during late gestation on dairy cattle, and discuss the biological mechanisms that underlie the observed production and health responses in the dam and her fetus. Relative to cooled cows, cows that are heat stressed during late gestation have impaired mammary growth before parturition and decreased milk production in the subsequent lactation. In response to higher milk yield, cows cooled prepartum undergo a series of homeorhetic adaptations in early lactation to meet higher demand for milk synthesis compared with heat-stressed cows, but no direct effect of environmental heat stress on metabolism exists during the dry period. Prepartum cooling improves immune status of transition cows and evidence suggests that altered prolactin signaling in immune cells mediates the effects of heat stress on immune function. Late-gestation heat stress compromises placental development, which results in fetal hypoxia, malnutrition, and eventually fetal growth retardation. Maternal heat stress may also have carryover effects on the postnatal growth of offspring, but direct evidence is still lacking. Emerging evidence suggests that offspring from prepartum heat-stressed cows have compromised passive immunity and impaired cell-mediated immune function compared with those from cooled cows. Copyright © 2013 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Cohesive and coherent connected speech deficits in mild stroke.

PubMed

Barker, Megan S; Young, Breanne; Robinson, Gail A

2017-05-01

Spoken language production theories and lesion studies highlight several important prelinguistic conceptual preparation processes involved in the production of cohesive and coherent connected speech. Cohesion and coherence broadly connect sentences with preceding ideas and the overall topic. Broader cognitive mechanisms may mediate these processes. This study aims to investigate (1) whether stroke patients without aphasia exhibit impairments in cohesion and coherence in connected speech, and (2) the role of attention and executive functions in the production of connected speech. Eighteen stroke patients (8 right hemisphere stroke [RHS]; 6 left [LHS]) and 21 healthy controls completed two self-generated narrative tasks to elicit connected speech. A multi-level analysis of within and between-sentence processing ability was conducted. Cohesion and coherence impairments were found in the stroke group, particularly RHS patients, relative to controls. In the whole stroke group, better performance on the Hayling Test of executive function, which taps verbal initiation/suppression, was related to fewer propositional repetitions and global coherence errors. Better performance on attention tasks was related to fewer propositional repetitions, and decreased global coherence errors. In the RHS group, aspects of cohesive and coherent speech were associated with better performance on attention tasks. Better Hayling Test scores were related to more cohesive and coherent speech in RHS patients, and more coherent speech in LHS patients. Thus, we documented connected speech deficits in a heterogeneous stroke group without prominent aphasia. Our results suggest that broader cognitive processes may play a role in producing connected speech at the early conceptual preparation stage. Copyright © 2017 Elsevier Inc. All rights reserved.

Restoring function in major depressive disorder: A systematic review.

PubMed

Sheehan, David V; Nakagome, Kazuyuki; Asami, Yuko; Pappadopulos, Elizabeth A; Boucher, Matthieu

2017-06-01

Functional impairment contributes to significant disability and economic burden in major depressive disorder (MDD). Treatment response is measured by improvement in depressive symptoms, but functional improvement often lags behind symptomatic improvement. Residual deficits are associated with relapse of depressive symptoms. A literature search was conducted using the following terms: "major depressive disorder," "functional impairment," "functional outcomes," "recovery of function," "treatment outcome," "outcome assessment," "social functioning," "presenteeism," "absenteeism," "psychiatric status rating scales," and "quality of life." Search limits included publication date (January 1, 1995 to August 31, 2016), English language, and human clinical trials. Controlled, acute-phase, nonrecurrent MDD treatment studies in adults were included if a functional outcome was measured at baseline and endpoint. The qualitative analysis included 35 controlled studies. The Sheehan Disability Scale was the most commonly used functional assessment. Antidepressant treatments significantly improved functional outcomes. Early treatment response predicted functional improvement, while baseline disease severity did not. Clinical studies utilized various methodologies and assessments for functional impairment, and were not standardized or adequately powered. The lack of synchronicity between symptomatic and functional improvement highlights an unmet need for MDD. Treatment guided by routine monitoring of symptoms and functionality may minimize residual functional impairments. Copyright © 2017. Published by Elsevier B.V.

Impairment of extramitochondrial oxidative phosphorylation in mouse rod outer segments by blue light irradiation.

PubMed

Calzia, Daniela; Panfoli, Isabella; Heinig, Nora; Schumann, Ulrike; Ader, Marius; Traverso, Carlo Enrico; Funk, Richard H W; Roehlecke, Cora

2016-06-01

Exposure to short wavelength light causes increased reactive oxygen intermediates production in the outer retina, particularly in the rod Outer Segments (OS). Consistently, the OS were shown to conduct aerobic ATP production through the ectopic expression of the electron transfer chain complexes I-IV and F1Fo-ATP synthase. These facts prompted us to verify if the oxidative phosphorylation in the OS is implied in the oxidative damage of the blue-light (BL) treated OS, in an organotypic model of mouse retina. Whole mouse eyeball cultures were treated with short wavelength BL (peak at 405 nm, output power 1 mW/cm(2)) for 6 h. Immunogold transmission electron microscopy confirmed the expression of Complex I and F1Fo-ATP synthase in the OS. In situ histochemical assays on unfixed sections showed impairment of respiratory Complexes I and II after BL exposure, both in the OS and IS, utilized as a control. Basal O2 consumption and ATP synthesis were impaired in the OS purified from blue-light irradiated eyeball cultures. Electron transfer capacity between Complex I and II as well as activity of Complexes I and II was decreased in blue-light irradiated purified OS. The severe malfunctioning of the OS aerobic respiratory capacity after 6 h BL treatment may be the consequence of a self-induced damage. BL exposure would cause an initial over-functioning of both the phototransduction and respiratory chain, with reactive oxygen species production. In a self-renewal vicious cycle, membrane and protein oxidative damage, proton leakage and uncoupling, would impair redox chains, perpetuating the damage and causing hypo-metabolism with eventual apoptosis of the rod. Data may shed new light on the rod-driven retinopathies such as Age Related Macular Degeneration, of which blue-light irradiated retina represents a model. Copyright © 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Impaired Growth and Force Production in Skeletal Muscles of Young Partially Pancreatectomized Rats: A Model of Adolescent Type 1 Diabetic Myopathy?

PubMed Central

Gordon, Carly S.; Serino, Antonio S.; Krause, Matthew P.; Campbell, Jonathan E.; Cafarelli, Enzo; Adegoke, Olasunkanmi A. J.; Hawke, Thomas J.; Riddell, Michael C.

2010-01-01

This present study investigated the temporal effects of type 1 diabetes mellitus (T1DM) on adolescent skeletal muscle growth, morphology and contractile properties using a 90% partial pancreatecomy (Px) model of the disease. Four week-old male Sprague-Dawley rats were randomly assigned to Px (n = 25) or Sham (n = 24) surgery groups and euthanized at 4 or 8 weeks following an in situ assessment of muscle force production. Compared to Shams, Px were hyperglycemic (>15 mM) and displayed attenuated body mass gains by days 2 and 4, respectively (both P<0.05). Absolute maximal force production of the gastrocnemius plantaris soleus complex (GPS) was 30% and 50% lower in Px vs. Shams at 4 and 8 weeks, respectively (P<0.01). GP mass was 35% lower in Px vs Shams at 4 weeks (1.24±0.06 g vs. 1.93±0.03 g, P<0.05) and 45% lower at 8 weeks (1.57±0.12 vs. 2.80±0.06, P<0.05). GP fiber area was 15–20% lower in Px vs. Shams at 4 weeks in all fiber types. At 8 weeks, GP type I and II fiber areas were ∼25% and 40% less, respectively, in Px vs. Shams (group by fiber type interactions, P<0.05). Phosphorylation states of 4E-BP1 and S6K1 following leucine gavage increased 2.0- and 3.5-fold, respectively, in Shams but not in Px. Px rats also had impaired rates of muscle protein synthesis in the basal state and in response to gavage. Taken together, these data indicate that exposure of growing skeletal muscle to uncontrolled T1DM significantly impairs muscle growth and function largely as a result of impaired protein synthesis in type II fibers. PMID:21103335

[Functional impairment associated with cognitive impairment in hospitalised elderly].

PubMed

Ocampo-Chaparro, José Mauricio; Mosquera-Jiménez, José Ignacio; Davis, Annabelle S; Reyes-Ortiz, Carlos A

The aim of this study was to analyse the effect of cognitive impairment on functional decline in hospitalised patients aged ≥60 years. Measurements at admission included demographic data, Charlson's comorbidity index, and cognitive impairment (according to education level). Data were also collected on hospital length of stay, depression, and delirium developed during hospitalisation. The outcome, Barthel Index (BI), was measured at admission, discharge, and 1-month post-discharge. Patients with BI≤75 at admission (n=54) or with a missing BI value were excluded (n=1). Multivariate logistic regression analyses were conducted to explore predictive factors with functional decline (BI≤75) from admission to discharge, and 1-month later. Of the 133 patients included, 24.8% and 19.6% had a BI≤75 at discharge and at 1-month, respectively. Compared with men, women had more than double risk for functional decline at discharge and 1-month (P<.05). Compared with those without delirium and without cognitive impairment, those with delirium and cognitive impairment had an increased risk for functional decline (BI≤75) at discharge (OR 5.15, 95% CI; 1.94-13.67), and at 1-month (OR 6.26, 95% CI; 2.30-17.03). Similarly, those with comorbidity (≥2) had increased functional decline at discharge (OR 2.36, 95% CI; 1.14-4.87), and at 1-month after discharge (OR 2.71, 95% CI; 1.25-5.89). Delirium during hospitalisation, together with cognitive impairment on admission, was a strong predictor of functional decline. Copyright © 2017 SEGG. Publicado por Elsevier España, S.L.U. All rights reserved.

Neural underpinnings for model-oriented therapy of aphasic word production.

PubMed

Abel, Stefanie; Weiller, Cornelius; Huber, Walter; Willmes, Klaus

2014-05-01

Model-oriented therapies of aphasic word production have been shown to be effective, with item-specific therapy effects being larger than generalisation effects for untrained items. However, it remains unclear whether semantic versus phonological therapy lead to differential effects, depending on type of lexical impairment. Functional imaging studies revealed that mainly left-hemisphere, perisylvian brain areas were involved in successful therapy-induced recovery of aphasic word production. However, the neural underpinnings for model-oriented therapy effects have not received much attention yet. We aimed at identifying brain areas indicating (1) general therapy effects using a naming task measured by functional magnetic resonance imaging (fMRI) in 14 patients before and after a 4-week naming therapy, which comprised increasing semantic and phonological cueing-hierarchies. We also intended to reveal differential effects (2) of training versus generalisation, (3) of therapy methods, and (4) of type of impairment as assessed by the connectionist Dell model. Training effects were stronger than generalisation effects, even though both were significant. Furthermore, significant impairment-specific therapy effects were observed for patients with phonological disorders (P-patients). (1) Left inferior frontal gyrus, pars opercularis (IFGoper), was a positive predictor of therapy gains while the right caudate was a negative predictor. Moreover, less activation decrease due to therapy in left-hemisphere temporo-parietal language areas was positively correlated with therapy gains. (2) Naming of trained compared to untrained words yielded less activation decrease in left superior temporal gyrus (STG) and precuneus, bilateral thalamus, and right caudate due to therapy. (3) Differential therapy effects could be detected in the right superior parietal lobule for the semantic method, and in regions involving bilateral anterior and mid cingulate, right precuneus, and left middle/superior frontal gyrus for the phonological method. (4) Impairment-specific changes of activation were found for P-patients in left IFGoper. Patients with semantic disorders (S-patients) relied on right frontal areas involving IFG, pars triangularis. After therapy, they revealed less activation decrease in areas involving left STG, caudate, paracentral lobule, and right rolandic operculum. Regarding naming performance, the present study corroborates previous findings on training and generalisation effects and reveals differential therapy effects for P-patients. Moreover, brain imaging results confirm a predominance of (1) general effects in the left brain hemisphere. (2) Brain regions related to visual strategy, monitoring/feedback, and articulatory patterns were characteristic for the familiar trained items. (3) Distinct regions associated with strategies, monitoring capacities, and linguistic information indicate the specific therapeutic influence on word retrieval. (4) While P-patients relied more on preserved phonological functions in the left hemisphere, S-patients revealed right-sided compensation of semantic processing as well as increased strategic efforts in both hemispheres. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Symptom-limited exercise testing causes sustained diastolic dysfunction in patients with coronary disease and low effort tolerance.

PubMed

Fragasso, G; Benti, R; Sciammarella, M; Rossetti, E; Savi, A; Gerundini, P; Chierchia, S L

1991-05-01

Exercise stress testing is routinely used for the noninvasive assessment of coronary artery disease and is considered a safe procedure. However, the provocation of severe ischemia might potentially cause delayed recovery of myocardial function. To investigate the possibility that maximal exercise testing could induce prolonged impairment of left ventricular function, 15 patients with angiographically proved coronary disease and 9 age-matched control subjects with atypical chest pain and normal coronary arteries were studied. Radionuclide ventriculography was performed at rest, at peak exercise, during recovery and 2 and 7 days after exercise. Ejection fraction, peak filling and peak emptying rates and left ventricular wall motion were analyzed. All control subjects had a normal exercise test at maximal work loads and improved left ventricular function on exercise. Patients developed 1 mm ST depression at 217 +/- 161 s at a work load of 70 +/- 30 W and a rate-pressure product of 18,530 +/- 4,465 mm Hg x beats/min. Although exercise was discontinued when angina or equivalent symptoms occurred, in all patients diagnostic ST depression (greater than or equal to 1 mm) developed much earlier than symptoms. Predictably, at peak exercise patients showed a decrease in ejection fraction and peak emptying and filling rates. Ejection fraction and peak emptying rate normalized within the recovery period, whereas peak filling rate remained depressed throughout recovery (p less than 0.002) and was still reduced 2 days after exercise (p less than 0.02). In conclusion, in patients with severe impairement of coronary flow reserve, maximal exercise may cause sustained impairement of diastolic function.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol hangover: type and time-extension of motor function impairments.

PubMed

Karadayian, Analía G; Cutrera, Rodolfo A

2013-06-15

Alcohol hangover is defined as the unpleasant next-day state following an evening of excessive alcohol consumption. Hangover begins when ethanol is absent in plasma and is characterized by physical and psychological symptoms. During hangover cognitive functions and subjective capacities are affected along with inefficiency, reduced productivity, absenteeism, driving impairments, poor academic achievement and reductions in motor coordination. The aim of this work was to study the type and length of motor and exploratory functions from the beginning to the end of the alcohol hangover. Male Swiss mice were injected i.p. either with saline (control group) or with ethanol (3.8 g/kg BW) (hangover group). Motor performance, walking deficiency, motor strength, locomotion and exploratory activity were evaluated at a basal point (ZT0) and every 2 h up to 20 h after blood alcohol levels were close to zero (hangover onset). Motor performance was 80% decreased at the onset of hangover (p<0.001). Hangover mice exhibited a reduced motor performance during the next 16 h (p<0.01). Motor function was recovered 20 h after hangover onset. Hangover mice displayed walking deficiencies from the beginning to 16 h after hangover onset (p<0.05). Moreover, mice suffering from a hangover, exhibited a significant decrease in neuromuscular strength during 16 h (p<0.001). Averaged speed and total distance traveled in the open field test and the exploratory activity on T-maze and hole board tests were reduced during 16 h after hangover onset (p<0.05). Our findings demonstrate a time-extension between 16 to 20 h for hangover motor and exploratory impairments. As a whole, this study shows the long lasting effects of alcohol hangover. Copyright © 2013 Elsevier B.V. All rights reserved.

Altered Memory Circulating T Follicular Helper-B Cell Interaction in Early Acute HIV Infection

PubMed Central

Muir, Roshell; Metcalf, Talibah; Tardif, Virginie; Takata, Hiroshi; Phanuphak, Nittaya; Kroon, Eugene; Colby, Donn J.; Trichavaroj, Rapee; Valcour, Victor; Robb, Merlin L.; Michael, Nelson L.; Ananworanich, Jintanat; Trautmann, Lydie; Haddad, Elias K.

2016-01-01

The RV254 cohort of HIV-infected very early acute (4thG stage 1 and 2) (stage 1/2) and late acute (4thG stage 3) (stage 3) individuals was used to study T helper- B cell responses in acute HIV infection and the impact of early antiretroviral treatment (ART) on T and B cell function. To investigate this, the function of circulating T follicular helper cells (cTfh) from this cohort was examined, and cTfh and memory B cell populations were phenotyped. Impaired cTfh cell function was observed in individuals treated in stage 3 when compared to stage 1/2. The cTfh/B cell cocultures showed lower B cell survival and IgG secretion at stage 3 compared to stage 1/2. This coincided with lower IL-10 and increased RANTES and TNF-α suggesting a role for inflammation in altering cTfh and B cell responses. Elevated plasma viral load in stage 3 was found to correlate with decreased cTfh-mediated B cell IgG production indicating a role for increased viremia in cTfh impairment and dysfunctional humoral response. Phenotypic perturbations were also evident in the mature B cell compartment, most notably a decrease in resting memory B cells in stage 3 compared to stage 1/2, coinciding with higher viremia. Our coculture assay also suggested that intrinsic memory B cell defects could contribute to the impaired response despite at a lower level. Overall, cTfh-mediated B cell responses are significantly altered in stage 3 compared to stage 1/2, coinciding with increased inflammation and a reduction in memory B cells. These data suggest that early ART for acutely HIV infected individuals could prevent immune dysregulation while preserving cTfh function and B cell memory. PMID:27463374

Mirror therapy in chronic stroke survivors with severely impaired upper limb function: a randomized controlled trial.

PubMed

Colomer, Carolina; NOé, Enrique; Llorens, Roberto

2016-06-01

Mirror therapy (MT) has been proposed to improve the motor function of chronic individuals with stroke with mild to moderate impairment. With regards to severe upper limb paresis, MT has shown to provide limited motor improvement in the acute or sub-acute phase. However, no previous research has described the effects of MT in chronic individuals with stroke with severely impaired upper limb function. The aim of this study was to determine the effectiveness of MT on chronic stroke survivors with severe upper-limb impairment in comparison with passive mobilization. A randomized controlled trial. Rehabilitative outpatient unit. A total of 31 chronic subjects poststroke with severely impaired upper limb function were randomly assigned to either an experimental group (N.=15), or a control group (N.=16). Twenty-four intervention sessions were performed for both groups. Each session included 45-minute period of MT (experimental group) or passive mobilization (control group), administered three days a week. Participants were assessed before and after the intervention with the Wolf Motor Function Test, the Fugl-Meyer Assessment, and the Nottingham Sensory Assessment. Improvement in motor function was observed in both groups on the time (P=0.002) and ability (P=0.001) subscales of the Wolf Motor Function Test. No differences were detected in kinesthesis or stereognosis. However, the experimental group showed a significant improvement in tactile sensation that was mainly observed as an increased sensitivity to light touches. In comparison with passive mobilization, MT in chronic stroke survivors with severely impaired upper-limb function may provide a limited but positive effect on light touch sensitivity while providing similar motor improvement. MT is a therapeutic approach that can be used in the rehabilitation of severely impaired upper limb in chronic stroke survivors, specifically to address light touch sensitivity deficits.

Alzheimer’s Disease and Age-Related Memory Decline (Preclinical)

PubMed Central

Terry, Alvin V.; Callahan, Patrick M.; Hall, Brandon; Webster, Scott J.

2011-01-01

An unfortunate result of the rapid rise in geriatric populations worldwide is the increasing prevalence of age-related cognitive disorders such as Alzheimer’s disease (AD). AD is a devastating neurodegenerative illness that is characterized by a profound impairment of cognitive function, marked physical disability, and an enormous economic burden on the afflicted individual, caregivers, and society in general. The rise in elderly populations is also resulting in an increase in individuals with related (potentially treatable) conditions such as “Mild Cognitive Impairment” (MCI) which is characterized by a less severe (but abnormal) level of cognitive impairment and a high-risk for developing dementia. Even in the absence of a diagnosable disorder of cognition (e.g., AD, MCI), the perception of increased forgetfulness and declining mental function is a clear source of apprehension in the elderly. This is a valid concern given that even a modest impairment of cognitive function is likely to be associated with significant disability in a rapidly evolving, technology-based society. Unfortunately, the currently available therapies designed to improve cognition (i.e., for AD and other forms of dementia) are limited by modest efficacy, adverse side effects, and their effects on cognitive function are not sustained over time. Accordingly, it is incumbent on the scientific community to develop safer and more effective therapies that improve and/or sustain cognitive function in the elderly allowing them to remain mentally active and productive for as long as possible. As diagnostic criteria for memory disorders evolve, the demand for pro-cognitive therapeutic agents is likely to surpass AD and dementia to include MCI and potentially even less severe forms of memory decline. The purpose of this review is to provide an overview of the contemporary therapeutic targets and preclinical pharmacologic approaches (with representative drug examples) designed to enhance memory function. PMID:21315756

The Impaired Function of Macrophages Induced by Strenuous Exercise Could Not Be Ameliorated by BCAA Supplementation

PubMed Central

Xiao, Weihua; Chen, Peijie; Liu, Xiaoguang; Zhao, Linlin

2015-01-01

The aim of this study was to evaluate the effect of strenuous exercise on the functions of peritoneal macrophages in rats and to test the hypothesis that branched-chain amino acid (BCAA) supplementation will be beneficial to the macrophages of rats from strenuous exercise. Forty male Wistar rats were randomly divided into five groups: (C) Control, E) Exercise, (E1) Exercise with one week to recover, (ES) Exercise + Supplementation and (ES1) Exercise + Supplementation with 1 week to recover. All rats except those of the sedentary control were subjected to four weeks of strenuous exercise. Blood hemoglobin, serum testosterone and BCAA levels were tested. Peritoneal macrophages functions were also determined at the same time. The data showed that hemoglobin, testosterone, BCAA levels, and body weight in group E decreased significantly as compared with that of group C. Meanwhile, phagocytosis capacity (decreased by 17.07%, p = 0.031), reactive oxygen species (ROS) production (decreased by 26%, p = 0.003) and MHC II mRNA (decreased by 22%, p = 0.041) of macrophages decreased in the strenuous exercise group as compared with group C. However, the chemotaxis of macrophages did not change significantly. In addition, BCAA supplementation could slightly increase the serum BCAA levels of rats from strenuous exercise (increased by 6.70%, p > 0.05). Moreover, the body weight, the blood hemoglobin, the serum testosterone and the function of peritoneal macrophages in group ES did not change significantly as compared with group E. These results suggest that long-term intensive exercise impairs the function of macrophages, which is essential for microbicidal capability. This may represent a novel mechanism of immunosuppression induced by strenuous exercise. Moreover, the impaired function of macrophage induced by strenuous exercise could not be ameliorated by BCAA supplementation in the dosing and timing used for this study. PMID:26506374

The Impaired Function of Macrophages Induced by Strenuous Exercise Could Not Be Ameliorated by BCAA Supplementation.

PubMed

Xiao, Weihua; Chen, Peijie; Liu, Xiaoguang; Zhao, Linlin

2015-10-21

The aim of this study was to evaluate the effect of strenuous exercise on the functions of peritoneal macrophages in rats and to test the hypothesis that branched-chain amino acid (BCAA) supplementation will be beneficial to the macrophages of rats from strenuous exercise. Forty male Wistar rats were randomly divided into five groups: (C) Control, E) Exercise, (E1) Exercise with one week to recover, (ES) Exercise + Supplementation and (ES1) Exercise + Supplementation with 1 week to recover. All rats except those of the sedentary control were subjected to four weeks of strenuous exercise. Blood hemoglobin, serum testosterone and BCAA levels were tested. Peritoneal macrophages functions were also determined at the same time. The data showed that hemoglobin, testosterone, BCAA levels, and body weight in group E decreased significantly as compared with that of group C. Meanwhile, phagocytosis capacity (decreased by 17.07%, p = 0.031), reactive oxygen species (ROS) production (decreased by 26%, p = 0.003) and MHC II mRNA (decreased by 22%, p = 0.041) of macrophages decreased in the strenuous exercise group as compared with group C. However, the chemotaxis of macrophages did not change significantly. In addition, BCAA supplementation could slightly increase the serum BCAA levels of rats from strenuous exercise (increased by 6.70%, p > 0.05). Moreover, the body weight, the blood hemoglobin, the serum testosterone and the function of peritoneal macrophages in group ES did not change significantly as compared with group E. These results suggest that long-term intensive exercise impairs the function of macrophages, which is essential for microbicidal capability. This may represent a novel mechanism of immunosuppression induced by strenuous exercise. Moreover, the impaired function of macrophage induced by strenuous exercise could not be ameliorated by BCAA supplementation in the dosing and timing used for this study.

Validation of Self-Report Impairment Measures for Section III Obsessive-Compulsive and Avoidant Personality Disorders.

PubMed

Liggett, Jacqueline; Carmichael, Kieran L C; Smith, Alexander; Sellbom, Martin

2017-01-01

This study examined the validity of newly developed disorder-specific impairment scales (IS), modeled on the Level of Personality Functioning Scale, for obsessive-compulsive (OCPD) and avoidant (AvPD) personality disorders. The IS focused on content validity (items directly reflected the disorder-specific impairments listed in DSM-5 Section III) and severity of impairment. A community sample of 313 adults completed personality inventories indexing the DSM-5 Sections II and III diagnostic criteria for OCPD and AvPD, as well as measures of impairment in the domains of self- and interpersonal functioning. Results indicated that both impairment measures (for AvPD in particular) showed promise in their ability to measure disorder-specific impairment, demonstrating convergent validity with their respective Section II counterparts and discriminant validity with their noncorresponding Section II disorder and with each other. The pattern of relationships between scores on the IS and scores on external measures of personality functioning, however, did not indicate that it is useful to maintain a distinction between impairment in the self- and interpersonal domains, at least for AvPD and OCPD.

Vocal function after transoral videolaryngoscopic surgery (TOVS) for hypopharyngeal and supraglottic cancer.

PubMed

Tanaka, Shingo; Tomifuji, Masayuki; Araki, Koji; Uno, Kosuke; Tanaka, Yuya; Mizokami, Daisuke; Suzuki, Hiroshi; Miyagawa, Yoshihiro; Taniai, Shinichi; Shiotani, Akihiro

2017-04-01

The resection of the medial and lateral pyriform sinus was associated with post-operative voice impairment after TOVS. Scar contracture around the cricoarytenoid joint lead to arytenoid fixation toward lateral position, and this wound healing process caused insufficient glottis closure. Although oncological and functional outcomes of TOVS was satisfactory, surgeons should mention the risk of post-operative voice impairment in pre-operative counseling. Transoral surgery is a minimally invasive treatment option for hypopharyngeal and supraglottic cancer. Post-operative vocal function was satisfactory in most cases, but in some cases vocal cord was fixed and occasionally voice impairment persists. Vocal function of 55 patients who underwent transoral videolaryngoscopic surgery (TOVS) for hypopharyngeal and supraglottic cancers was evaluated by the GRBAS perceptive scale, aerodynamic tests and acoustic analyses, and the Voice Handicap Index questionnaire. The risk factors for voice impairment were identified. Voice impairment (G score ≧2) was found in 16 cases (29.1%). Univariate analysis revealed that the resection of medial and lateral pyriform sinus (p = .0018) and neck dissection (p = .0421) were associated with post-operative voice impairment. Multivariate analysis revealed that the resection of medial and lateral pyriform sinus (p = .0021) was associated with post-operative voice impairment.

Impaired Voluntary Movement Control and Its Rehabilitation in Cerebral Palsy.

PubMed

Gordon, Andrew M

2016-01-01

Cerebral palsy is caused by early damage to the developing brain, as the most common pediatric neurological disorder. Hemiplegia (unilateral spastic cerebral palsy) is the most common subtype, and the resulting impairments, lateralized to one body side, especially affect the upper extremity, limiting daily function. This chapter first describes the pathophysiology and mechanisms underlying impaired upper extremity control of cerebral palsy. It will be shown that the severity of impaired hand function closely relates to the integrity of the corticospinal tract innervating the affected hand. It will also shown that the developing corticospinal tract can reorganize its connectivity depending on the timing and location of CNS injury, which also has implications for the severity of hand impairments and rehabilitation. The mechanisms underlying impaired motor function will be highlighted, including deficits in movement execution and planning and sensorimotor integration. It will be shown that despite having unimanual hand impairments, bimanual movement control deficits and mirror movements also impact function. Evidence for motor learning-based therapies including Constraint-Induced Movement Therapy and Bimanual Training, and the possible pathophysiological predictors of treatment outcome and plasticity will be described. Finally, future directions for rehabilitations will be presented.

Executive functions deficit in mild cognitive impairment.

PubMed

Traykov, Latchezar; Raoux, Nadine; Latour, Florence; Gallo, Livia; Hanon, Olivier; Baudic, Sophie; Bayle, Catherine; Wenisch, Emilie; Remy, Philippe; Rigaud, Anne-Sophie

2007-12-01

To investigate whether patients diagnosed with amnestic mild cognitive impairment (MCI) have also impairment in attention/executive functions, and therefore to clarify whether all subcomponents of executive control are equally affected in MCI. MCI refers to the transitional state between normal aging and dementia. Amnestic MCI is characterized by impaired episodic memory, although subtle impairment of executive functions has been noted on neuropsychologic tests. We investigated 20 MCI patients and 20 normal controls using episodic memory, attention/executive functions, language, and praxis tests. MCI patients had significantly lower scores on all measures of the Free and Cued Selective Reminding Test (P<0.05 to 0.01) than controls. Furthermore, MCI had a greater number of perseverations (P<0.01) on Modified Card Sorting Test and the lowest performance on the Stroop Test (P<0.02). Our findings showed impairment in episodic memory performance in MCI as compared with that of controls. In addition, MCI patients had problems with response inhibition, switching, and cognitive flexibility, which encompass various aspects of executive functions. This suggests that MCI may be identified by using a more detailed procedure for the assessment of cognitive decline than the evaluation of memory alone.

Testing a Model of Functional Impairment in Telephone Crisis Support Workers.

PubMed

Kitchingman, Taneile A; Wilson, Coralie J; Caputi, Peter; Wilson, Ian; Woodward, Alan

2017-11-01

It is well known that helping professionals experience functional impairment related to elevated symptoms of psychological distress as a result of frequent empathic engagement with distressed others. Whether telephone crisis support workers are impacted in a similar way is not currently reported in the literature. The purpose of this study was to test a hypothesized model of factors contributing to functional impairment in telephone crisis support workers. A national sample of 210 telephone crisis support workers completed an online survey including measures of emotion regulation, symptoms of general psychological distress and suicidal ideation, intentions to seek help for symptoms, and functional impairment. Structural equation modeling was used to test the fit of the data to the hypothesized model. Goodness-of-fit indices were adequate and supported the interactive effects of emotion regulation, general psychological distress, suicidal ideation, and intentions to seek help for ideation on functional impairment. These results warrant the deliberate management of telephone crisis support workers' impairment through service selection, training, supervision, and professional development strategies. Future research replicating and extending this model will further inform the modification and/or development of strategies to optimize telephone crisis support workers' well-being and delivery of support to callers.

Solvent exposure and cognitive function in automotive technicians.

PubMed

Bates, Michael N; Reed, Bruce R; Liu, Sa; Eisen, Ellen A; Hammond, S Katharine

2016-12-01

Automotive technicians are commonly exposed to organic and chlorinated solvents, particularly through use of cleaning products. Occupational solvent exposures have been associated with deficits in cognitive function but, to our knowledge, no previous studies have investigated automotive technicians. The purpose of the present study was to investigate whether previous exposures to n-hexane, in particular, or general solvents posed a persistent neurotoxic hazard to automotive workers. Enrolled in the study were 830 San Francisco Bay Area automotive repair workers. Each participant underwent a battery of cognitive function tests to investigate central nervous system impairment, with a primary focus on the domains of psychomotor speed, fine motor function, memory and mood. Cognitive test results regressed against estimated hexane and total solvent exposures showed little evidence of associations. Exposures to both solvents and hexane were well below the occupational exposure limits. Our results provide some reassurance about persistent neuropsychological effects in automotive workers who use solvent-based products and those who previously used hexane-containing automotive cleaning products, since this solvent is believed no longer to be used in automotive cleaning products. The lack of observed effect in this study may be attributable to low exposures, or it may reflect improved cognitive function since hexane use in automotive cleaning products was discontinued. However, impacts on results of exposure misclassification and/or the healthy worker survivor effect cannot be discounted. Irrespective of the outcome of this study, the main known neurologic effect of n-hexane is peripheral neuropathy, and such an association in automotive technicians is not excluded by these results. Copyright © 2016 Elsevier B.V. All rights reserved.

Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in Japanese patients with type 2 diabetes mellitus.

PubMed

Sarashina, Akiko; Ueki, Kohjiro; Sasaki, Tomohiro; Tanaka, Yuko; Koiwai, Kazuki; Sakamoto, Wataru; Woerle, Hans J; Salsali, Afshin; Broedl, Uli C; Macha, Sreeraj

2014-11-01

The purpose of this study was to assess the effect of renal impairment on the pharmacokinetic, pharmacodynamic, and safety profiles of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in Japanese patients with type 2 diabetes mellitus (T2DM). In an open-label, parallel-group study, 32 Japanese patients with T2DM and different degrees of renal function (n = 8 per renal function category: normal renal function, estimated glomerular filtration rate [eGFR; Japanese equation] ≥90 mL/min/1.73 m(2); mild renal impairment, eGFR of 60-<90 mL/min/1.73 m(2); moderate renal impairment, eGFR of 30-<60 mL/min/1.73 m(2); and severe renal impairment, eGFR of 15-<30 mL/min/1.73 m(2)) received a single 25 mg dose of empagliflozin. Empagliflozin exposure increased with increasing renal impairment. Maximum empagliflozin plasma concentrations were similar among all renal function groups. Adjusted geometric mean ratios for extent of exposure (AUC0-∞) to empagliflozin versus normal renal function were 128.8% (95% CI, 106.0-156.6%), 143.8% (95% CI, 118.3-174.8%), and 152.3% (95% CI, 125.3-185.2%) for patients with mild, moderate, and severe renal impairment, respectively. Decreases in renal clearance of empagliflozin correlated with eGFR. Urinary glucose excretion decreased with increasing renal impairment and correlated with eGFR (adjusted mean [SE] change from baseline: 75.0 [4.84] g, 62.6 [5.75] g, 57.9 [4.86] g, and 23.7 [5.24] g for patients with normal renal function and mild, moderate, and severe renal impairment, respectively). Only 2 patients (6%) had adverse events; both were mild. Pharmacokinetic data suggest that no dose adjustment of empagliflozin is necessary in Japanese patients with T2DM and renal impairment because increases in exposure were <2-fold. Urinary glucose excretion decreased with increasing renal impairment. ClinicalTrials.gov identifier: NCT01581658. Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.

Does impaired socioemotional functioning account for behavioral dysexecutive disorders? Evidence from a transnosological study.

PubMed

Narme, Pauline; Roussel, Martine; Mouras, Harold; Krystkowiak, Pierre; Godefroy, Olivier

2017-01-01

Behavioral dysexecutive disorders are highly prevalent in patients with neurological diseases but cannot be explained by cognitive dysexecutive impairments. In fact, the underlying mechanisms are poorly understood. Given that socioemotional functioning underlies appropriate behavior, socioemotional impairments may contribute to the appearance of behavioral disorders. To investigate this issue, we performed a transnosological study. Seventy-five patients suffering from various neurological diseases (Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal lobar degeneration, and stroke) were included in the study. The patients were comprehensively assessed in terms of cognitive and behavioral dysexecutive disorders and socioemotional processes (facial emotion recognition and theory of mind). As was seen for cognitive and behavioral dysexecutive impairments, the prevalence of socioemotional impairments varied according to the diagnosis. Stepwise logistic regressions showed that (i) only cognitive executive indices predicted hypoactivity with apathy/abulia, (ii) theory of mind impairments predicted hyperactivity-distractibility-impulsivity and stereotyped/perseverative behaviors, and (iii) impaired facial emotion recognition predicted social behavior disorders. Several dysexecutive behavioral disorders are associated with an underlying impairment in socioemotional processes but not with cognitive indices of executive functioning (except for apathy). These results strongly suggest that some dysexecutive behavioral disorders are the outward signs of an underlying impairment in socioemotional processes.

Deficits of anticipatory grip force control after damage to peripheral and central sensorimotor systems.

PubMed

Hermsdörfer, Joachim; Hagl, Elke; Nowak, Dennis A

2004-11-01

Healthy subjects adjust their grip force economically to the weight of a hand-held object. In addition, inertial loads, which arise from arm movements with the grasped object, are anticipated by parallel grip force modulations. Internal forward models have been proposed to predict the consequences of voluntary movements. Anesthesia of the fingers impairs grip force economy but the feedforward character of the grip force/load coupling is preserved. To further analyze the role of sensory input for internal forward models and to characterize the consequences of central nervous system damage for anticipatory grip force control, we measured grip force behavior in neurological patients. We tested a group of stroke patients with varying degrees of impaired fine motor control and sensory loss, a single patient with complete and permanent differentation from all tactile and proprioceptive input, and a group of patients with amyotrophic lateral sclerosis (ALS) that exclusively impairs the motor system without affecting sensory modalities. Increased grip forces were a common finding in all patients. Sensory deficits were a strong but not the only predictor of impaired grip force economy. The feedforward mode of grip force control was typically preserved in the stroke patients despite their central sensory deficits, but was severely disturbed in the patient with peripheral sensory deafferentation and in a minority of stroke patients. Moderate deficits of feedforward control were also obvious in ALS patients. Thus, the function of the internal forward model and the precision of grip force production may depend on a complex anatomical and functional network of sensory and motor structures and their interaction in time and space.

Intrinsic motivation as a mediator between metacognition deficits and impaired functioning in psychosis.

PubMed

Luther, Lauren; Firmin, Ruth L; Vohs, Jenifer L; Buck, Kelly D; Rand, Kevin L; Lysaker, Paul H

2016-09-01

Poor functioning has long been observed in individuals with psychosis. Recent studies have identified metacognition - one's ability to form complex ideas about oneself and others and to use that information to respond to psychological and social challenges-as being an important determinant of functioning. However, the exact process by which deficits in metacognition lead to impaired functioning remains unclear. This study first examined whether low intrinsic motivation, or the tendency to pursue novel experiences and to engage in self-improvement, mediates the relationship between deficits in metacognition and impaired functioning. We then examined whether intrinsic motivation significantly mediated the relationship when controlling for age, education, symptoms, executive functioning, and social cognition. Mediation models were examined in a cross-sectional data set. One hundred and seventy-five individuals with a psychotic disorder completed interview-based measures of metacognition, intrinsic motivation, symptoms, and functioning and performance-based measures of executive functioning and social cognition. Analyses revealed that intrinsic motivation mediated the relationship between metacognition deficits and impaired functioning (95% CI of indirect effect [0.12-0.43]), even after controlling for the aforesaid variables (95% CI of indirect effect [0.04-0.29]). Results suggest that intrinsic motivation may be a mechanism that underlies the link between deficits in metacognition and impaired functioning and indicate that metacognition and intrinsic motivation may be important treatment targets to improve functioning in individuals with psychosis. The findings of this study suggest that deficits in metacognition may indirectly lead to impaired functioning through their effect on intrinsic motivation in individuals with psychosis. Psychological treatments that target deficits in both metacognition and intrinsic motivation may help to alleviate impaired functioning in individuals with psychosis. The cross-sectional design of this study is a limitation, and additional longitudinal studies are needed to confirm the direction of the findings and rule out rival hypotheses. Generalization of the findings may be limited by the sample composition. It may be that different relationships exist between metacognition, intrinsic motivation, and functioning in those with early psychosis or among those in an acute phase or who decline treatment. © 2016 The British Psychological Society.

An experimental evaluation of a new designed apparatus (NDA) for the rapid measurement of impaired motor function in rats.

PubMed

Jarrahi, M; Sedighi Moghadam, B; Torkmandi, H

2015-08-15

Assessment of the ability of rat to balance by rotarod apparatus (ROTA) is frequently used as a measure of impaired motor system function. Most of these methods have some disadvantages, such as failing to sense motor coordination rather than endurance and as the sensitivity of the method is low, more animals are needed to obtain statistically significant results. We have designed and tested a new designed apparatus (NDA) to measure motor system function in rats. Our system consists of a glass box containing 4 beams which placed with 1cm distance between them, two electrical motors for rotating the beams, and a camera to record the movements of the rats. The RPM of the beams is adjustable digitally between 0 and 50 rounds per minute. We evaluated experimentally the capability of the NDA for the rapid measurement of impaired motor function in rats. Also we demonstrated that the sensitivity of the NDA increases by faster rotation speeds and may be more sensitive than ROTA for evaluating of impaired motor system function. Compared to a previous version of this task, our NDA provides a more efficient method to test rodents for studies of motor system function after impaired motor nervous system. In summary, our NDA will allow high efficient monitoring of rat motor system function and may be more sensitive than ROTA for evaluating of impaired motor system function in rats. Copyright © 2015 Elsevier B.V. All rights reserved.

Defective TFH Cell Function and Increased TFR Cells Contribute to Defective Antibody Production in Aging.

PubMed

Sage, Peter T; Tan, Catherine L; Freeman, Gordon J; Haigis, Marcia; Sharpe, Arlene H

2015-07-14

Defective antibody production in aging is broadly attributed to immunosenescence. However, the precise immunological mechanisms remain unclear. Here, we demonstrate an increase in the ratio of inhibitory T follicular regulatory (TFR) cells to stimulatory T follicular helper (TFH) cells in aged mice. Aged TFH and TFR cells are phenotypically distinct from those in young mice, exhibiting increased programmed cell death protein-1 expression but decreased ICOS expression. Aged TFH cells exhibit defective antigen-specific responses, and programmed cell death protein-ligand 1 blockade can partially rescue TFH cell function. In contrast, young and aged TFR cells have similar suppressive capacity on a per-cell basis in vitro and in vivo. Together, these studies reveal mechanisms contributing to defective humoral immunity in aging: an increase in suppressive TFR cells combined with impaired function of aged TFH cells results in reduced T-cell-dependent antibody responses in aged mice. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Starring role of toll-like receptor-4 activation in the gut-liver axis

PubMed Central

Carotti, Simone; Guarino, Michele Pier Luca; Vespasiani-Gentilucci, Umberto; Morini, Sergio

2015-01-01

Since the introduction of the term “gut-liver axis”, many studies have focused on the functional links of intestinal microbiota, barrier function and immune responses to liver physiology. Intestinal and extra-intestinal diseases alter microbiota composition and lead to dysbiosis, which aggravates impaired intestinal barrier function via increased lipopolysaccharide translocation. The subsequent increased passage of gut-derived product from the intestinal lumen to the organ wall and bloodstream affects gut motility and liver biology. The activation of the toll-like receptor 4 (TLR-4) likely plays a key role in both cases. This review analyzed the most recent literature on the gut-liver axis, with a particular focus on the role of TLR-4 activation. Findings that linked liver disease with dysbiosis are evaluated, and links between dysbiosis and alterations of intestinal permeability and motility are discussed. We also examine the mechanisms of translocated gut bacteria and/or the bacterial product activation of liver inflammation and fibrogenesis via activity on different hepatic cell types. PMID:26600967

Language processing and executive functions in early treated adults with phenylketonuria (PKU).

PubMed

De Felice, Sara; Romani, Cristina; Geberhiwot, Tarekegn; MacDonald, Anita; Palermo, Liana

We provide an in-depth analysis of language functions in early-treated adults with phenylketonuria (AwPKUs, N = 15-33), as compared to age- and education-matched controls (N = 24-32; N varying across tasks), through: a. narrative production (the Cinderella story), b. language pragmatics comprehension (humour, metaphors, inferred meaning), c. prosody discrimination d. lexical inhibitory control and planning (Blocked Cyclic Naming; Hayling Sentence Completion Test, Burgess & Shallice, 1997). AwPKUs exhibited intact basic language processing (lexical retrieval, phonology/articulation, sentence construction). Instead, deficits emerged in planning and reasoning abilities. Compared to controls, AwPKUs were: less informative in narrative production (lower rate of Correct Information Units); slower in metaphorical understanding and inferred meaning; less accurate in focused lexical-search (Hayling test). These results suggest that i) executive deficits in PKU cannot be explained by an accumulation of lower-order deficits and/or general speed impairments, ii) executive functions engage dedicated neurophysiological resources, rather than simply being an emergent property of lower-level systems.

Control of the synthesis and subcellular targeting of the two GDH genes products in leaves and stems of Nicotiana plumbaginifolia and Arabidopsis thaliana.

PubMed

Fontaine, Jean-Xavier; Saladino, Francesca; Agrimonti, Caterina; Bedu, Magali; Tercé-Laforgue, Thérèse; Tétu, Thierry; Hirel, Bertrand; Restivo, Francesco M; Dubois, Frédéric

2006-03-01

Although the physiological role of the enzyme glutamate dehydrogenase which catalyses in vitro the reversible amination of 2-oxoglutarate to glutamate remains to be elucidated, it is now well established that in higher plants the enzyme preferentially occurs in the mitochondria of phloem companion cells. The Nicotiana plumbaginifolia and Arabidopis thaliana enzyme is encoded by two distinct genes encoding either an alpha- or a beta-subunit. Using antisense plants and mutants impaired in the expression of either of the two genes, we showed that in leaves and stems both the alpha- and beta-subunits are targeted to the mitochondria of the companion cells. In addition, we found in both species that there is a compensatory mechanism up-regulating the expression of the alpha-subunit in the stems when the expression of the beta-subunit is impaired in the leaves, and of the beta-subunit in the leaves when the expression of the alpha-subunit is impaired in the stems. When one of the two genes encoding glutamate dehydrogenase is ectopically expressed, the corresponding protein is targeted to the mitochondria of both leaf and stem parenchyma cells and its production is increased in the companion cells. These results are discussed in relation to the possible signalling and/or physiological function of the enzyme which appears to be coordinated in leaves and stems.

Role of eNOS in water exchange index maintenance-MRI studies

NASA Astrophysics Data System (ADS)

Atochin, D.; Litvak, M.; Huang, S.; Kim, Y. R.; Huang, P.

2017-08-01

Stroke studies employ experimental models of cerebral ischemic and reperfusion injury in rodents. MRI provides valuable supravital data of cerebral blood flow and brain tissue damage. This paper presents MRI applications for cerebral blood flow research in mice lines with impaired nitric oxide production by endothelial nitric oxide synthase. Our data demonstrates that specific modifications of MRI methodology in transgenic mouse models help to evaluate the role of eNOS in the brain-blood barrier function.

[The participation of ethanol in induction of carbohydrates metabolism disturbances].

PubMed

Orywal, Karolina; Jelski, Wojciech; Szmitkowski, Maciej

2009-07-01

Alcohol and products of its metabolism lead to impairment of many organs functions, what cause systemic and local carbohydrates metabolism disturbances. Abusing of alcohol induces changes in pancreatic digestive enzymes secretion, what contributes to development of chronic alcoholic pancreatitis. Alcohol can cause secondary diabetes, what is result of pancreatic beta-cells damage and is a risk factor for type 2 diabetes. Alcohol cause liver cells degeneration and induction of many metabolic disturbances especially carbohydrates.

Impaired adaptability of in vivo mitochondrial energetics to acute oxidative insult in aged skeletal muscle.

PubMed

Siegel, Michael P; Wilbur, Tim; Mathis, Mark; Shankland, Eric G; Trieu, Atlas; Harper, Mary-Ellen; Marcinek, David J

2012-01-01

Periods of elevated reactive oxygen species (ROS) production are a normal part of mitochondrial physiology. However, little is known about age-related changes in the mitochondrial response to elevated ROS in vivo. Significantly, ROS-induced uncoupling of oxidative phosphorylation has received attention as a negative feedback mechanism to reduce mitochondrial superoxide production. Here we use a novel in vivo spectroscopy system to test the hypothesis that ROS-induced uncoupling is diminished in aged mitochondria. This system simultaneously acquires (31)P magnetic resonance and near-infrared optical spectra to non-invasively measure phosphometabolite and O(2) concentrations in mouse skeletal muscle. Using low dose paraquat to elevate intracellular ROS we assess in vivo mitochondrial function in young, middle aged, and old mice. Oxidative phosphorylation was uncoupled to the same degree in response to ROS at each age, but this uncoupling was associated with loss of phosphorylation capacity and total ATP in old mice only. Using mice lacking UCP3 we demonstrate that this in vivo uncoupling is independent of this putative uncoupler of skeletal muscle mitochondria. These data indicate that ROS-induced uncoupling persists throughout life, but that oxidative stress leads to mitochondrial deficits and loss of ATP in aged organisms that may contribute to impaired function and degeneration. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Working memory and social functioning in children.

PubMed

McQuade, Julia D; Murray-Close, Dianna; Shoulberg, Erin K; Hoza, Betsy

2013-07-01

This study extends previous research and examines whether working memory (WM) is associated with multiple measures of concurrent social functioning (peer rejection, overall social competence, relational aggression, physical aggression, and conflict resolutions skills) in typically developing fourth- and fifth-grade children (N=116). Poor central executive WM was associated with both broad social impairments (peer rejection and poor overall social competence) and specific social impairments (physical aggression, relational aggression, and impaired conflict resolution skills); poor verbal storage was associated only with greater peer rejection, and spatial storage was not associated with any measures of social impairment. Analyses also examined whether specific impairments in aggressive behavior and conflict resolution skills mediated the association between central executive and broad measures of social functioning. Greater physical aggression and impaired conflict resolution skills were both significant mediators; relational aggression was not. Implications for theory and future research are discussed. Copyright © 2013 Elsevier Inc. All rights reserved.

Semi-spontaneous oral text production: measurements in clinical practice.

PubMed

Lind, Marianne; Kristoffersen, Kristian Emil; Moen, Inger; Simonsen, Hanne Gram

2009-12-01

Functionally relevant assessment of the language production of speakers with aphasia should include assessment of connected speech production. Despite the ecological validity of everyday conversations, more controlled and monological types of texts may be easier to obtain and analyse in clinical practice. This article discusses some simple measurements for the analysis of semi-spontaneous oral text production by speakers with aphasia. Specifically, the measurements are related to the production of verbs and nouns, and the realization of different sentence types. The proposed measurements should be clinically relevant, easily applicable, and linguistically meaningful. The measurements have been applied to oral descriptions of the 'Cookie Theft' picture by eight monolingual Norwegian speakers, four with an anomic type of aphasia and four without any type of language impairment. Despite individual differences in both the clinical and the non-clinical group, most of the measurements seem to distinguish between speakers with and without aphasia.

Impaired Kidney Function and Associated Factors Among Rural Adults With Disabilities in Taiwan.

PubMed

Chen, Chu-Yeh; Chiu, Wen-Nan; Lin, Yu-Chen; Jane, Sui-Hwi; Chiang, Hsin-Hung; Chen, Mei-Yen

2017-04-01

The results of numerous studies indicate that people with disabilities seek more healthcare than those who are not disabled, particularly for conditions such as chronic kidney disease, cardiovascular disease, and obesity. However, little is known about the incidence of impaired kidney function and its associated factors among adults with disabilities in Taiwan. The aim of this study was to explore the prevalence and factors associated with impaired kidney function among adults with disabilities. This descriptive study was nurse led and was conducted as part of a health promotion program for disadvantaged rural adults with disabilities in Chiayi County, Taiwan. Health screening and a health needs survey were conducted between July and December 2013. Kidney function, physiological biomarkers, health-related behaviors, and demographic characteristics were examined. Eight hundred ten rural adults with disabilities were enrolled. The most common disabilities included physical-related disability (33.1%), intellectual-related disability (26.7%), and hearing and vision impairment (18.6%). The prevalence of impaired kidney function in this population was 85%. According to classification for chronic kidney disease, 68.6% were in Stages 1-2, and 16.8% were in Stages 3-4. Univariate analysis showed that impaired kidney function was significantly associated with lower educational level (p < .001), hearing or vision impairment (p < .001), being overweight or obese (p < .05), high systolic blood pressure (p < .01), fasting blood glucose (p < .001), total cholesterol (p < .001), total triglyceride (p < .05), older age (p < .001), smoking (p < .05), chewing betel nuts (p = .001), and low levels of participation in social activities (p < .05). The final logistic regression model showed that residents with disabilities who were older or had less education, high fasting blood glucose, and high total cholesterol tended to have impaired kidney function after adjustment for other potential confounding variables. Most participants showed impaired kidney function. The factors that were found to relate significantly to this impairment include being overweight, having hyperlipidemia, having hypertension, having high fasting blood glucose, and having an unhealthy lifestyle. Because of the lack of symptoms during the early stages of chronic kidney disease, a community-based health promotion program for these factors is an important element in health advocacy for this vulnerable population.

20 CFR 220.13 - Establishment of permanent disability for work in regular railroad occupation.

Code of Federal Regulations, 2011 CFR

2011-04-01

... functional capacity test or other consultative examinations; (B) Step 2. If the employee's impairment(s) has... differences in opinions concerning the residual functional capacity evaluations among treating physicians, or significant differences between the results of functional capacity evaluations and residual functional...

20 CFR 220.120 - The claimant's residual functional capacity.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 20 Employees' Benefits 1 2010-04-01 2010-04-01 false The claimant's residual functional capacity... RETIREMENT ACT DETERMINING DISABILITY Residual Functional Capacity § 220.120 The claimant's residual functional capacity. (a) General. The claimant's impairment(s), and any related symptoms, such as pain, may...

Mitochondrion-Derived Reactive Oxygen Species Lead to Enhanced Amyloid Beta Formation

PubMed Central

Schütt, Tanja; Kurz, Christopher; Eckert, Schamim H.; Schiller, Carola; Occhipinti, Angelo; Mai, Sören; Jendrach, Marina; Eckert, Gunter P.; Kruse, Shane E.; Palmiter, Richard D.; Brandt, Ulrich; Dröse, Stephan; Wittig, Ilka; Willem, Michael; Haass, Christian; Reichert, Andreas S.; Müller, Walter E.

2012-01-01

Abstract Aims: Intracellular amyloid beta (Aβ) oligomers and extracellular Aβ plaques are key players in the progression of sporadic Alzheimer's disease (AD). Still, the molecular signals triggering Aβ production are largely unclear. We asked whether mitochondrion-derived reactive oxygen species (ROS) are sufficient to increase Aβ generation and thereby initiate a vicious cycle further impairing mitochondrial function. Results: Complex I and III dysfunction was induced in a cell model using the respiratory inhibitors rotenone and antimycin, resulting in mitochondrial dysfunction and enhanced ROS levels. Both treatments lead to elevated levels of Aβ. Presence of an antioxidant rescued mitochondrial function and reduced formation of Aβ, demonstrating that the observed effects depended on ROS. Conversely, cells overproducing Aβ showed impairment of mitochondrial function such as comprised mitochondrial respiration, strongly altered morphology, and reduced intracellular mobility of mitochondria. Again, the capability of these cells to generate Aβ was partly reduced by an antioxidant, indicating that Aβ formation was also ROS dependent. Moreover, mice with a genetic defect in complex I, or AD mice treated with a complex I inhibitor, showed enhanced Aβ levels in vivo. Innovation: We show for the first time that mitochondrion-derived ROS are sufficient to trigger Aβ production in vitro and in vivo. Conclusion: Several lines of evidence show that mitochondrion-derived ROS result in enhanced amyloidogenic amyloid precursor protein processing, and that Aβ itself leads to mitochondrial dysfunction and increased ROS levels. We propose that starting from mitochondrial dysfunction a vicious cycle is triggered that contributes to the pathogenesis of sporadic AD. Antioxid. Redox Signal. 16, 1421–1433. PMID:22229260

The Objective Assessment of Cough Frequency in Bronchiectasis.

PubMed

Spinou, Arietta; Lee, Kai K; Sinha, Aish; Elston, Caroline; Loebinger, Michael R; Wilson, Robert; Chung, Kian Fan; Yousaf, Nadia; Pavord, Ian D; Matos, Sergio; Garrod, Rachel; Birring, Surinder S

2017-10-01

Cough in bronchiectasis is associated with significant impairment in health status. This study aimed to quantify cough frequency objectively with a cough monitor and investigate its relationship with health status. A secondary aim was to identify clinical predictors of cough frequency. Fifty-four patients with bronchiectasis were compared with thirty-five healthy controls. Objective 24-h cough, health status (cough-specific: Leicester Cough Questionnaire LCQ and bronchiectasis specific: Bronchiectasis Health Questionnaire BHQ), cough severity and lung function were measured. The clinical predictors of cough frequency in bronchiectasis were determined in a multivariate analysis. Objective cough frequency was significantly raised in patients with bronchiectasis compared to healthy controls [geometric mean (standard deviation)] 184.5 (4.0) vs. 20.6 (3.2) coughs/24-h; mean fold-difference (95% confidence interval) 8.9 (5.2, 15.2); p < 0.001 and they had impaired health status. There was a significant correlation between objective cough frequency and subjective measures; LCQ r = -0.52 and BHQ r = -0.62, both p < 0.001. Sputum production, exacerbations (between past 2 weeks to 12 months) and age were significantly associated with objective cough frequency in multivariate analysis, explaining 52% of the variance (p < 0.001). There was no statistically significant association between cough frequency and lung function. Cough is a common and significant symptom in patients with bronchiectasis. Sputum production, exacerbations and age, but not lung function, were independent predictors of cough frequency. Ambulatory objective cough monitoring provides novel insights and should be further investigated as an outcome measure in bronchiectasis.

Role of Acinetobactin-Mediated Iron Acquisition Functions in the Interaction of Acinetobacter baumannii Strain ATCC 19606T with Human Lung Epithelial Cells, Galleria mellonella Caterpillars, and Mice

PubMed Central

Gaddy, Jennifer A.; Arivett, Brock A.; McConnell, Michael J.; López-Rojas, Rafael; Pachón, Jerónimo

2012-01-01

Acinetobacter baumannii, which causes serious infections in immunocompromised patients, expresses high-affinity iron acquisition functions needed for growth under iron-limiting laboratory conditions. In this study, we determined that the initial interaction of the ATCC 19606T type strain with A549 human alveolar epithelial cells is independent of the production of BasD and BauA, proteins needed for acinetobactin biosynthesis and transport, respectively. In contrast, these proteins are required for this strain to persist within epithelial cells and cause their apoptotic death. Infection assays using Galleria mellonella larvae showed that impairment of acinetobactin biosynthesis and transport functions significantly reduces the ability of ATCC 19606T cells to persist and kill this host, a defect that was corrected by adding inorganic iron to the inocula. The results obtained with these ex vivo and in vivo approaches were validated using a mouse sepsis model, which showed that expression of the acinetobactin-mediated iron acquisition system is critical for ATCC 19606T to establish an infection and kill this vertebrate host. These observations demonstrate that the virulence of the ATCC 19606T strain depends on the expression of a fully active acinetobactin-mediated system. Interestingly, the three models also showed that impairment of BasD production results in an intermediate virulence phenotype compared to those of the parental strain and the BauA mutant. This observation suggests that acinetobactin intermediates or precursors play a virulence role, although their contribution to iron acquisition is less relevant than that of mature acinetobactin. PMID:22232188

Acute hypoglycemia impairs executive cognitive function in adults with and without type 1 diabetes.

PubMed

Graveling, Alex J; Deary, Ian J; Frier, Brian M

2013-10-01

Acute hypoglycemia impairs cognitive function in several domains. Executive cognitive function governs organization of thoughts, prioritization of tasks, and time management. This study examined the effect of acute hypoglycemia on executive function in adults with and without diabetes. Thirty-two adults with and without type 1 diabetes with no vascular complications or impaired awareness of hypoglycemia were studied. Two hyperinsulinemic glucose clamps were performed at least 2 weeks apart in a single-blind, counterbalanced order, maintaining blood glucose at 4.5 mmol/L (euglycemia) or 2.5 mmol/L (hypoglycemia). Executive functions were assessed with a validated test suite (Delis-Kaplan Executive Function). A general linear model (repeated-measures ANOVA) was used. Glycemic condition (euglycemia or hypoglycemia) was the within-participant factor. Between-participant factors were order of session (euglycemia-hypoglycemia or hypoglycemia-euglycemia), test battery used, and diabetes status (with or without diabetes). Compared with euglycemia, executive functions (with one exception) were significantly impaired during hypoglycemia; lower test scores were recorded with more time required for completion. Large Cohen d values (>0.8) suggest that hypoglycemia induces decrements in aspects of executive function with large effect sizes. In some tests, the performance of participants with diabetes was more impaired than those without diabetes. Executive cognitive function, which is necessary to carry out many everyday activities, is impaired during hypoglycemia in adults with and without type 1 diabetes. This important aspect of cognition has not received previous systematic study with respect to hypoglycemia. The effect size is large in terms of both accuracy and speed.

Quality of life and functional impairment in obsessive-compulsive disorder: a comparison of patients with and without comorbidity, patients in remission, and healthy controls.

PubMed

Huppert, Jonathan D; Simpson, H Blair; Nissenson, Kore J; Liebowitz, Michael R; Foa, Edna B

2009-01-01

Several studies have demonstrated that obsessive-compulsive disorder (OCD) is associated with interference in quality of life (QOL) and functional impairment. However, these studies did not compare individuals in remission to individuals who continue to have the disorder, predominantly used comparisons with norms and not with a matched normal sample, and did not always consider the impact of comorbidity. We administered multiple measures that assess QOL and functional impairment to 66 OCD patients who had previously consented for a clinical trial and to 36 age and sex matched individuals who denied any psychiatric history. Results confirm that OCD was associated with significantly lower QOL and functional impairment compared to healthy controls (HCs) in areas of work, social life, and family life. Individuals with OCD and other comorbid psychiatric diagnoses showed the poorest QOL and functioning, with comorbid depression accounting for much of the variance. The levels of QOL and functioning in individuals in remission tended to lie in between HCs and individuals with current OCD: their QOL or functioning did not differ significantly from HCs nor did they consistently differ significantly from those who had current OCD. These results suggest that individuals who are in remission have improved levels of QOL and functioning, whereas individuals with OCD are significantly impaired, and individuals with OCD and comorbid disorders are the most impaired. Treatment strategies should be focused on achieving remission of all symptoms to have the greatest impact on functioning and QOL. Published 2008 Wiley-Liss, Inc.

Cognitive Rehabilitation for Bipolar Disorder: An Open Trial for Employed Patients with Residual Depressive Symptoms

PubMed Central

Deckersbach, Thilo; Nierenberg, Andrew A.; Kessler, Ronald; Lund, Hannah G.; Ametrano, Rebecca M.; Sachs, Gary; Rauch, Scott L.; Dougherty, Darin

2009-01-01

Introduction Bipolar Disorder is characterized by recurrent episodes of depression and/or mania along with interepisodic mood symptoms that interfere with psychosocial functioning. Despite periods of symptomatic recovery, individuals with bipolar disorder often continue to experience impairments in psychosocial functioning, particularly occupational functioning. Two determinants of psychosocial functioning of euthymic (neither fully depressed nor manic) individuals with bipolar disorder are residual depressive symptoms and cognitive impairment (i.e. difficulties with executive functioning, attention and memory). Aims The present study explored whether a new cognitive remediation (CR) treatment designed to treat residual depressive symptoms and, for the first time to the best of our knowledge, address cognitive impairment would be associated with improvement in psychosocial functioning in individuals with bipolar disorder. Following a neuropsychological and clinical assessment 18 individuals with DSM-IV bipolar disorder were treated with 14 individual sessions of CR. Results Results indicated that at the end of treatment, as well as at the 3-months follow-up, patients showed lower residual depressive symptoms, and increased occupational, as well as overall psychosocial functioning. Pre-treatment neuropsychological impairment predicted treatment response. Improvements in executive functioning were associated with improvements in occupational functioning. Conclusions These findings suggest that treating residual depressive symptoms and cognitive impairment may be an avenue to improving occupational and overall functioning in individuals with bipolar disorder. PMID:19895584

Muscle growth and poultry meat quality issues.

PubMed

Petracci, Massimiliano; Cavani, Claudio

2012-01-01

Over the past 50 years the worldwide growing demand of poultry meat has resulted in pressure on breeders, nutritionists and growers to increase the growth rate of birds, feed efficiency, size of breast muscle and reduction in abdominal fatness. Moreover, the shift toward further processed products has emphasized the necessity for higher standards in poultry meat to improve sensory characteristics and functional properties. It is believed that genetic progress has put more stress on the growing bird and it has resulted in histological and biochemical modifications of the muscle tissue by impairing some meat quality traits. The most current poultry meat quality concerns are associated with deep pectoral muscle disease and white striping which impair product appearance, and increased occurrence of problems related with the meat's poor ability to hold water during processing and storage (PSE-like condition) as well as poor toughness and cohesiveness related to immaturity of intramuscular connective tissue. This paper is aimed at making a general statement of recent studies focusing on the relationship between muscle growth and meat quality issues in poultry.

Muscle Growth and Poultry Meat Quality Issues

PubMed Central

Petracci, Massimiliano; Cavani, Claudio

2011-01-01

Over the past 50 years the worldwide growing demand of poultry meat has resulted in pressure on breeders, nutritionists and growers to increase the growth rate of birds, feed efficiency, size of breast muscle and reduction in abdominal fatness. Moreover, the shift toward further processed products has emphasized the necessity for higher standards in poultry meat to improve sensory characteristics and functional properties. It is believed that genetic progress has put more stress on the growing bird and it has resulted in histological and biochemical modifications of the muscle tissue by impairing some meat quality traits. The most current poultry meat quality concerns are associated with deep pectoral muscle disease and white striping which impair product appearance, and increased occurrence of problems related with the meat’s poor ability to hold water during processing and storage (PSE-like condition) as well as poor toughness and cohesiveness related to immaturity of intramuscular connective tissue. This paper is aimed at making a general statement of recent studies focusing on the relationship between muscle growth and meat quality issues in poultry. PMID:22347614

PTENα, a PTEN isoform translated through alternative initiation, regulates mitochondrial function and energy metabolism.

PubMed

Liang, Hui; He, Shiming; Yang, Jingyi; Jia, Xinying; Wang, Pan; Chen, Xi; Zhang, Zhong; Zou, Xiajuan; McNutt, Michael A; Shen, Wen Hong; Yin, Yuxin

2014-05-06

PTEN is one of the most frequently mutated genes in human cancer. It is known that PTEN has a wide range of biological functions beyond tumor suppression. Here, we report that PTENα, an N-terminally extended form of PTEN, functions in mitochondrial metabolism. Translation of PTENα is initiated from a CUG codon upstream of and in-frame with the coding region of canonical PTEN. Eukaryotic translation initiation factor 2A (eIF2A) controls PTENα translation, which requires a CUG-centered palindromic motif. We show that PTENα induces cytochrome c oxidase activity and ATP production in mitochondria. TALEN-mediated somatic deletion of PTENα impairs mitochondrial respiratory chain function. PTENα interacts with canonical PTEN to increase PINK1 protein levels and promote energy production. Our studies demonstrate the importance of eIF2A-mediated alternative translation for generation of protein diversity in eukaryotic systems and provide insights into the mechanism by which the PTEN family is involved in multiple cellular processes. Copyright © 2014 Elsevier Inc. All rights reserved.

Functional neuroanatomy of human voluntary cough and sniff production

PubMed Central

Simonyan, Kristina; Saad, Ziad S.; Loucks, Torrey M.J.; Poletto, Christopher J.; Ludlow, Christy L.

2007-01-01

Cough and sniff are both spontaneous respiratory behaviors that can be initiated voluntarily in humans. Disturbances of cough may be life threatening, while inability to sniff impairs the sense of smell in neurological patients. Cortical mechanisms of voluntary cough and sniff production have been predicted to exist; however, the localization and function of supramedullary areas responsible for these behaviors are poorly understood. We used functional magnetic resonance imaging to identify the central control of voluntary cough and sniff compared with breathing. We determined that both voluntary cough and sniff require a widespread pattern of sensorimotor activation along the Sylvian fissure convergent with voluntary breathing. Task-specific activation occurred in a ponto-mesencephalic region during voluntary coughing and in the hippocampus and piriform cortex during voluntary sniffing. Identification of the localization of cortical activation for cough control in humans may help potential drug development to target these regions in patients with chronic cough. Understanding the sensorimotor sniff control mechanisms may provide a new view on the cerebral functional reorganization of olfactory control in patients with neurological disorders. PMID:17574873

Sleep and its associations with perceived and objective cognitive impairment in individuals with multiple sclerosis.

PubMed

Hughes, Abbey J; Parmenter, Brett A; Haselkorn, Jodie K; Lovera, Jesus F; Bourdette, Dennis; Boudreau, Eilis; Cameron, Michelle H; Turner, Aaron P

2017-08-01

Problems with sleep and cognitive impairment are common among people with multiple sclerosis (MS). The present study examined the relationship between self-reported sleep and both objective and perceived cognitive impairment in MS. Data were obtained from the baseline assessment of a multi-centre intervention trial (NCT00841321). Participants were 121 individuals with MS. Nearly half (49%) of participants met the criteria for objective cognitive impairment; however, cognitively impaired and unimpaired participants did not differ on any self-reported sleep measures. Nearly two-thirds (65%) of participants met the criteria for 'poor' sleep, and poorer sleep was significantly associated with greater levels of perceived cognitive impairment. Moreover, the relationships between self-reported sleep and perceived cognitive impairment were significant beyond the influence of clinical and demographic factors known to influence sleep and cognitive functioning (e.g. age, sex, education level, disability severity, type of MS, disease duration, depression and fatigue). However, self-reported sleep was not associated with any measures of objective cognitive impairment. Among different types of perceived cognitive impairment, poor self-reported sleep was most commonly related to worse perceived executive function (e.g. planning/organization) and prospective memory. Results from the present study emphasize that self-reported sleep is significantly and independently related to perceived cognitive impairment in MS. In terms of clinical implications, interventions focused on improving sleep may help improve perceived cognitive function and quality of life in this population; however, the impact of improved sleep on objective cognitive function requires further investigation. © 2017 European Sleep Research Society.

Delineating the trajectories of social and occupational functioning of young people attending early intervention mental health services in Australia: a longitudinal study.

PubMed

Iorfino, Frank; Hermens, Daniel F; Cross, Shane Pm; Zmicerevska, Natalia; Nichles, Alissa; Badcock, Caro-Anne; Groot, Josine; Scott, Elizabeth M; Hickie, Ian B

2018-03-27

Mental disorders typically emerge during adolescence and young adulthood and put young people at risk for prolonged socioeconomic difficulties. This study describes the longitudinal course of social and occupational functioning of young people attending primary care-based, early intervention services. A longitudinal study of young people receiving mental healthcare. Data were collected between January 2005 and August 2017 from a designated primary care-based mental health service. 554 young people (54% women) aged 12-32 years. A systematic medical file audit collected clinical and functional information at predetermined time intervals (ie, 3 months to 5+ years) using a clinical pro forma. Group-based trajectory modelling (GBTM) was used to identify distinct trajectories of social and occupational functioning over time (median number of observations per person=4; median follow-up time=23 months). Between first clinical contact and time last seen, 15% of young people had reliably deteriorated, 23% improved and 62% did not demonstrate substantive change in function. Of the whole cohort, 69% had functional scores less than 70 at time last seen, indicative of ongoing and substantive impairment. GBTM identified six distinct functional trajectories whereby over 60% had moderate-to-serious functional impairment at entry and remained chronically impaired over time; 7% entered with serious impairment and deteriorated further; a quarter were mildly impaired at entry and functionally recovered and only a small minority (4%) presented with serious impairments and functionally improved over time. Not being in education, employment or training, previous hospitalisation and a younger age at baseline emerged as significant predictors of these functional trajectories. Young people with emerging mental disorders have significant functional impairment at presentation for care, and for the majority, it persists over the course of clinical care. In addition to providing clinical care earlier in the course of illness, these data suggest that more sophisticated and more intensive individual-level and organisational strategies may be required to achieve significant and sustained functional improvements. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Parent and Self-Ratings of Executive Function in Adolescents with Specific Language Impairment

ERIC Educational Resources Information Center

Hughes, Deanna M.; Turkstra, Lyn S.; Wulfeck, Beverly B.

2009-01-01

Background: There is accumulating evidence that adolescents with specific language impairment (SLI) have impairments in domains beyond formal language that may affect academic and social outcomes. The findings of previous studies as well as parent reports of behavioural concerns suggest that they lag behind peers in functions such as…

Effects of Multisensory Speech Training and Visual Phonics on Speech Production of a Hearing-Impaired Child.

ERIC Educational Resources Information Center

Zaccagnini, Cindy M.; Antia, Shirin D.

1993-01-01

This study of the effects of intensive multisensory speech training on the speech production of a profoundly hearing-impaired child (age nine) found that the addition of Visual Phonics hand cues did not result in speech production gains. All six target phonemes were generalized to new words and maintained after the intervention was discontinued.…

Impact of psoriasis on patients' work and productivity: a retrospective, matched case-control analysis.

PubMed

Wu, Ying; Mills, Douglas; Bala, Mohan

2009-01-01

Psoriasis negatively impacts patient quality of life; however, the impact on work and productivity is not well known. To determine the impact of psoriasis on work and productivity using data from the National Health and Wellness Survey (NHWS). Data collected from 40 730 adults who completed the NHWS between 1 May and 30 June 2004, of whom 1127 had psoriasis, were analyzed. Psoriasis patients and a matched cohort of non-psoriasis patients were identified to assess the impact of psoriasis on work and productivity. Psoriasis patients were more likely to have missed work for health-related reasons (p < 0.05), had significantly more health-related work productivity impairment (p < 0.001), more overall work impairment (p < 0.001), and more impairment in activity other than work (p < 0.001) than non-psoriasis patients. The results of this large-scale national survey suggest that psoriasis has a significant negative impact on overall work productivity.

Abnormal Functional Lateralization and Activity of Language Brain Areas in Typical Specific Language Impairment (Developmental Dysphasia)

ERIC Educational Resources Information Center

de Guibert, Clement; Maumet, Camille; Jannin, Pierre; Ferre, Jean-Christophe; Treguier, Catherine; Barillot, Christian; Le Rumeur, Elisabeth; Allaire, Catherine; Biraben, Arnaud

2011-01-01

Atypical functional lateralization and specialization for language have been proposed to account for developmental language disorders, yet results from functional neuroimaging studies are sparse and inconsistent. This functional magnetic resonance imaging study compared children with a specific subtype of specific language impairment affecting…

Disagreement between Parent and Adolescent Reports of Functional Impairment

ERIC Educational Resources Information Center

Kramer, Teresa L.; Phillips, Susan D.; Hargis, Michael B.; Miller, Terri L.; Burns, Barbara J.; Robbins, James M.

2004-01-01

Objective: Adolescents' functional impairment has become increasingly important as a criterion for diagnosis and service eligibility as well as a target of therapeutic intervention in mental health settings. This study examines three critical issues in measuring functioning: 1) agreement between parent and adolescent reports of functioning, 2)…

Visual impairment in children and adolescents in Norway.

PubMed

Haugen, Olav H; Bredrup, Cecilie; Rødahl, Eyvind

2016-06-01

BACKGROUND Due to failures in reporting and poor data security, the Norwegian Registry of Blindness was closed down in 1995. Since that time, no registration of visual impairment has taken place in Norway. All the other Nordic countries have registries for children and adolescents with visual impairment. The purpose of this study was to survey visual impairments and their causes in children and adolescents, and to assess the need for an ophthalmic registry.MATERIAL AND METHOD Data were collected via the county teaching centres for the visually impaired in the period from 2005 - 2010 on children and adolescents aged less than 20 years with impaired vision (n = 628). This was conducted as a point prevalence study as of 1 January 2004. Visual function, ophthalmological diagnosis, systemic diagnosis and additional functional impairments were recorded.RESULTS Approximately two-thirds of children and adolescents with visual impairment had reduced vision, while one-third were blind. The three largest diagnostic groups were neuro-ophthalmic diseases (37 %), retinal diseases (19 %) and conditions affecting the eyeball in general (14 %). The prevalence of additional functional impairments was high, at 53 %, most often in the form of motor problems or cognitive impairments.INTERPRETATION The results of the study correspond well with similar investigations in the other Nordic countries. Our study shows that the registries associated with teaching for the visually impaired are inadequate in terms of medical data, and this underlines the need for an ophthalmic registry of children and adolescents with visual impairment.