Sample records for subsequent disease development
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Li, Xin; Lees, Jason R
2013-03-01
In region-specific forms of experimental autoimmune encephalomyelitis (EAE), lesion initiation is regulated by T-cell-produced interferon-γ (IFN-γ) resulting in spinal cord disease in the presence of IFN-γ and cerebellar disease in the absence of IFN-γ. Although this role for IFN-γ in regional disease initiation is well defined, little is known about the consequences of previous tissue inflammation on subsequent regional disease, information vital to the development of therapeutics in established disease states. This study addressed the hypothesis that previous establishment of regional EAE would determine subsequent tissue localization of new T-cell invasion and associated symptoms regardless of the presence or absence of IFN-γ production. Serial transfer of optimal or suboptimal doses of encephalitogenic IFN-γ-sufficient or -deficient T-cell lines was used to examine the development of new clinical responses associated with the spinal cord and cerebellum at various times after EAE initiation. Previous inflammation within either cerebellum or spinal cord allowed subsequent T-cell driven inflammation within that tissue regardless of IFN-γ presence. Further, T-cell IFN-γ production after initial lesion formation exacerbated disease within the cerebellum, suggesting that IFN-γ plays different roles at different stages of cerebellar disease. For the spinal cord, IFN-γ-deficient cells (that are ordinarily cerebellum disease initiators) were capable of driving new spinal-cord-associated clinical symptoms more than 60 days after the initial acute EAE resolution. These data suggest that previous inflammation modulates the molecular requirements for new neuroinflammation development. © 2012 Blackwell Publishing Ltd.
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Samuels, David C; Wonnapinij, Passorn; Chinnery, Patrick F
2013-03-01
Mitochondrial medicine is one of the few areas of genetic disease where germ-line transfer is being actively pursued as a treatment option. All of the germ-line transfer methods currently under development involve some carry-over of the maternal mitochondrial DNA (mtDNA) heteroplasmy, potentially delivering the pathogenic mutation to the offspring. Rapid changes in mtDNA heteroplasmy have been observed within a single generation, and so any 'leakage' of mutant mtDNA could lead to mtDNA disease in future generations, compromising the reproductive health of the first generation, and leading to repeated interventions in subsequent generations. To determine whether this is a real concern, we developed a model of mtDNA heteroplasmy inheritance by studying 87 mother-child pairs, and predicted the likely outcome of different levels of 'mutant mtDNA leakage' on subsequent maternal generations. This showed that, for a clinical threshold of 60%, reducing the proportion of mutant mtDNA to <5% dramatically reduces the chance of disease recurrence in subsequent generations, but transmitting >5% mutant mtDNA was associated with a significant chance of disease recurrence. Mutations with a lower clinical threshold were associated with a higher risk of recurrence. Our findings provide reassurance that, at least from an mtDNA perspective, methods currently under development have the potential to effectively eradicate pathogenic mtDNA mutations from subsequent generations.
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Kwun, Sunna; Tucci, Joseph R
2013-01-01
To present a case of Paget's disease of bone that was unmasked after vascular reperfusion. In this case study, we review the presentation, evaluation, diagnosis, and management of a patient with Paget's disease and peripheral vascular disease. A 79-year-old-woman with a history of coronary artery heart disease and recent finding of a T5 compression fracture was hospitalized for evaluation of right lower extremity claudication. Angiography demonstrated a focal complete occlusion of the distal right femoral and popliteal arteries. A self-expanding stent was placed in the distal femoral and popliteal arteries. Approximately 48 hours after the procedure, the patient developed severe, right lower leg pain. On endocrine evaluation, the patient was found to have clinical signs suggesting Paget's disease of bone, which was subsequently confirmed by imaging. This patient's development of severe pain following reperfusion of distal femoral and popliteal arteries is in keeping with the known and aforementioned hypervascularity of pagetic bone. The finding of increased warmth over an area of skeletal deformation should always raise the possibility of Paget's disease of bone.
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Samuels, David C.; Wonnapinij, Passorn; Chinnery, Patrick F.
2013-01-01
Mitochondrial medicine is one of the few areas of genetic disease where germ-line transfer is being actively pursued as a treatment option. All of the germ-line transfer methods currently under development involve some carry-over of the maternal mitochondrial DNA (mtDNA) heteroplasmy, potentially delivering the pathogenic mutation to the offspring. Rapid changes in mtDNA heteroplasmy have been observed within a single generation, and so any ‘leakage’ of mutant mtDNA could lead to mtDNA disease in future generations, compromising the reproductive health of the first generation, and leading to repeated interventions in subsequent generations. To determine whether this is a real concern, we developed a model of mtDNA heteroplasmy inheritance by studying 87 mother–child pairs, and predicted the likely outcome of different levels of ‘mutant mtDNA leakage’ on subsequent maternal generations. This showed that, for a clinical threshold of 60%, reducing the proportion of mutant mtDNA to <5% dramatically reduces the chance of disease recurrence in subsequent generations, but transmitting >5% mutant mtDNA was associated with a significant chance of disease recurrence. Mutations with a lower clinical threshold were associated with a higher risk of recurrence. Our findings provide reassurance that, at least from an mtDNA perspective, methods currently under development have the potential to effectively eradicate pathogenic mtDNA mutations from subsequent generations. PMID:23297368
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Virulence, transmission, and heterologous protection of four isolates of Haemophilus parasuis.
Brockmeier, Susan L; Loving, Crystal L; Mullins, Michael A; Register, Karen B; Nicholson, Tracy L; Wiseman, Barry S; Baker, Rodney B; Kehrli, Marcus E
2013-09-01
Haemophilus parasuis causes Glässer's disease, a syndrome of polyserositis, meningitis, and arthritis in swine. Previous studies with H. parasuis have revealed virulence disparity among isolates and inconsistent heterologous protection. In this study, virulence, direct transmission, and heterologous protection of 4 isolates of H. parasuis (SW114, 12939, MN-H, and 29755) were evaluated using a highly susceptible pig model. In an initial experiment, isolates 12939, MN-H, and 29755 caused Glässer's disease, while strain SW114 failed to cause any clinical signs of disease. One pig from each group challenged with MN-H or 29755 failed to develop clinical disease but was able to transmit H. parasuis to noninfected pigs, which subsequently developed Glässer's disease. Pigs colonized with SW114, 29755, or MN-H that were free of clinical disease were protected from a subsequent challenge with isolate 12939. In a following experiment, pigs vaccinated with strain SW114 given as either a bacterin intramuscularly or a live intranasal vaccine were protected from subsequent challenge with isolate 12939; however, some pigs given live SW114 developed arthritis. Overall these studies demonstrated that pigs infected with virulent isolates of H. parasuis can remain healthy and serve as reservoirs for transmission to naive pigs and that heterologous protection among H. parasuis isolates is possible. In addition, further attenuation of strain SW114 is necessary if it is to be used as a live vaccine.
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Eilber, Fritz C; Rosen, Gerald; Nelson, Scott D; Selch, Michael; Dorey, Frederick; Eckardt, Jeffery; Eilber, Frederick R
2003-02-01
To identify patient characteristics associated with the development of local recurrence and the effect of local recurrence on subsequent morbidity and mortality in patients with intermediate- to high-grade extremity soft tissue sarcomas. Numerous studies on extremity soft tissue sarcomas have consistently shown that presentation with locally recurrent disease is associated with the development of subsequent local recurrences and that large tumor size and high histologic grade are significant factors associated with decreased survival. However, the effect of local recurrence on patient survival remains unclear. From 1975 to 1997, 753 patients with intermediate- to high-grade extremity soft tissue sarcomas were treated at UCLA. Treatment outcomes and patient characteristics were analyzed to identify factors associated with both local recurrence and survival. Patients with locally recurrent disease were at a significantly increased risk of developing a subsequent local recurrence. Local recurrence was a morbid event requiring amputation in 38% of the cases. The development of a local recurrence was the most significant factor associated with decreased survival. Once a patient developed a local recurrence, he or she was about three times more likely to die of disease compared to similar patients who had not developed a local recurrence. Local recurrence in patients with intermediate- to high-grade extremity soft tissue sarcomas is associated with the development of subsequent local recurrences, a morbid event decreasing functional outcomes and the most significant factor associated with decreased survival. Although 85% to 90% of patients with high-grade extremity soft tissue sarcomas are treatable with a limb salvage approach, patients who develop a local recurrence need aggressive treatment and should be considered for trials of adjuvant systemic therapy.
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Kohelet, D; Arbel, E; Ballin, A; Goldberg, M
2000-01-01
Neutrophil counts were studied in 62 preterm infants receiving mechanical ventilation for neonatal respiratory distress syndrome (NRDS). Exploratory analysis indicated that the severity of NRDS, as demonstrated by fractional inspired oxygen (FiO2), mean airway pressure (MAP), arterial-alveolar PO2 ratio (a/APO2) and oxygenation index (OI), was correlated with percentage change of neutrophil counts during the first 5 days of life. Further analysis demonstrated that infants with NRDS who subsequently developed chronic lung disease (CLD) (n = 21) had statistically significant differences in variation of neutrophil counts when compared with the remainder (n = 41) without CLD (-35.0% +/- 4.3 vs. -16.9% +/- 5.8, p < 0.02). It is concluded that significant variations in neutrophil counts during the first 5 days of life may be found in infants with NRDS who subsequently develop CLD and that these changes may have predictive value regarding the development of CLD.
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Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals.
Wang, Raymond Y; Bodamer, Olaf A; Watson, Michael S; Wilcox, William R
2011-05-01
To develop educational guidelines for the diagnostic confirmation and management of individuals identified by newborn screening, family-based testing after proband identification, or carrier testing in at-risk populations, and subsequent prenatal or postnatal testing of those who are presymptomatic for a lysosomal storage disease. Review of English language literature and discussions in a consensus development panel comprised an international group of experts in the clinical and laboratory diagnosis, treatment and management, newborn screening, and genetic aspects of lysosomal storage diseases. Although clinical trial and longitudinal data were used when available, the evidence in the literature is limited and consequently the recommendations must be considered as expert opinion. Guidelines were developed for Fabry, Gaucher, and Niemann-Pick A/B diseases, glycogen storage type II (Pompe disease), globoid cell leukodystrophy (Krabbe disease), metachromatic leukodystrophy, and mucopolysaccharidoses types I, II, and VI. These guidelines serve as an educational resource for confirmatory testing and subsequent clinical management of presymptomatic individuals suspected to have a lysosomal storage disease; they also help to define a research agenda for longitudinal studies such as the American College of Medical Genetics/National Institutes of Health Newborn Screening Translational Research Network.
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Wolf, Michael S.; Chadha, Ashley D.; Carroll, Clinton M.; Borinstein, Scott C.
2014-01-01
Radiation-induced lung disease is a known complication of therapeutic lung irradiation, but the features have not been well described in children. We report the clinical, radiologic and histologic features of interstitial lung disease (ILD) in a 4-year-old child who had previously received lung irradiation as part of successful treatment for metastatic Wilms tumor. Her radiologic abnormalities and clinical symptoms developed in an indolent manner. Clinical improvement gradually occurred with corticosteroid therapy. However, the observed radiologic progression from interstitial and reticulonodular opacities to diffuse cystic lung disease, with subsequent improvement, is striking and has not been previously described in children. PMID:25434733
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CASE REPORT : GRAVE'S DISEASE PRESENTING AS PARANOID SCHIZOPHRENIA
Singh, S.K.; Hatwal, A.; Agarwal, J.K.; Bajpai, H.S.; Sharma, I.
1989-01-01
SUMMARY The case of a 37 year old male is described who initially presented as paranoid schizophrenia unresponsive to anti-psychotic drug treatment and subsequently developed features of Grave's disease. Treatment with carbimazole alone improved his psychiatric symptoms. PMID:21927380
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Epigenetic Transgenerational Actions of Vinclozolin on the Development of Disease and Cancer
Skinner, Michael K.; Anway, Matthew D.
2018-01-01
Exposure to an environmental endocrine disruptor (e.g., vinclozolin) during embryonic gonadal sex determination appears to alter the male germ line epigenome and subsequently promotes transgenerational adult onset disease. The epigenetic mechanism involves the induction of new imprinted-like genes/DNA sequences in the germ line that appear to transmit disease phenotypes. The disease phenotypes include testis abnormalities, prostate disease, kidney disease, immune abnormalities, and tumor development. This epigenetic transgenerational disease mechanism provides a unique perspective from which to view inheritable adult onset disease states, such as cancer, and ultimately offers new insights into novel diagnostic and therapeutic strategies. PMID:17956218
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Subsequent pancreatitis and haemothorax in a patient of expanded dengue syndrome.
Anam, Ahmad Mursel; Rabbani, Raihan; Shumy, Farzana; Polash, M Mufizul Islam
2016-01-01
We report a case of expanded dengue syndrome, where two different presentations occurred subsequently. A patient of dengue haemorrhagic fever initially was admitted with acute pancreatitis, complicated with left pancreatic effusion, but later on, during resolution of pancreatitis and effusion, developed spontaneous right haemothorax. Such presentations, besides being rare themselves, have not been reported to occur subsequently, in the same patient, during the same disease process. © The Author(s) 2015.
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Hodge, Shekema; de Rosayro, Juliette; Glenn, Amanda; Ojukwu, Ifeoma C.; Dewhurst, Stephen; McClure, Harold M.; Bischofberger, Norbert; Anderson, Daniel C.; Klumpp, Sherry A.; Novembre, Francis J.
1999-01-01
The fatal disease induced by SIVsmmPBj4 clinically resembles endotoxic shock, with the development of severe gastrointestinal disease. While the exact mechanism of disease induction has not been fully elucidated, aspects of virus biology suggest that immune activation contributes to pathogenesis. These biological characteristics include induction of peripheral blood mononuclear cell (PBMC) proliferation, upregulation of activation markers and Fas ligand expression, and increased levels of apoptosis. To investigate the role of immune activation and viral replication on disease induction, animals infected with SIVsmmPBj14 were treated with one of two drugs: FK-506, a potent immunosuppressive agent, or PMPA, a potent antiretroviral agent. While PBMC proliferation was blocked in vitro with FK-506, pig-tailed macaques treated preinoculation with FK-506 were not protected from acutely lethal disease. However, these animals did show some evidence of modulation of immune activation, including reduced levels of CD25 antigen and FasL expression, as well as lower tissue viral loads. In contrast, macaques treated postinoculation with PMPA were completely protected from the development of acutely lethal disease. Treatment with PMPA beginning as late as 5 days postinfection was able to prevent the PBj syndrome. Plasma and cellular viral loads in PMPA-treated animals were significantly lower than those in untreated controls. Although PMPA-treated animals showed acute lymphopenia due to SIVsmmPBj14 infection, cell subset levels subsequently recovered and returned to normal. Based upon subsequent CD4+ cell counts, the results suggest that very early treatment following retroviral infection can have a significant effect on modifying the subsequent course of disease. These results also suggest that viral replication is an important factor involved in PBJ-induced disease. These studies reinforce the idea that the SIVsmmPBj model system is useful for therapy and vaccine testing. PMID:10482616
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Guerrero-Bosagna, Carlos; Savenkova, Marina; Haque, Md. Muksitul; Nilsson, Eric; Skinner, Michael K.
2013-01-01
Environmental toxicants have been shown to induce the epigenetic transgenerational inheritance of adult onset disease, including testis disease and male infertility. The current study was designed to determine the impact of an altered sperm epigenome on the subsequent development of an adult somatic cell (Sertoli cell) that influences the onset of a specific disease (male infertility). A gestating female rat (F0 generation) was exposed to the agriculture fungicide vinclozolin during gonadal sex determination and then the subsequent F3 generation progeny used for the isolation of Sertoli cells and assessment of testis disease. As previously observed, enhanced spermatogenic cell apoptosis was observed. The Sertoli cells provide the physical and nutritional support for the spermatogenic cells. Over 400 genes were differentially expressed in the F3 generation control versus vinclozolin lineage Sertoli cells. A number of specific cellular pathways were identified to be transgenerationally altered. One of the key metabolic processes affected was pyruvate/lactate production that is directly linked to spermatogenic cell viability. The Sertoli cell epigenome was also altered with over 100 promoter differential DNA methylation regions (DMR) modified. The genomic features and overlap with the sperm DMR were investigated. Observations demonstrate that the transgenerational sperm epigenetic alterations subsequently alters the development of a specific somatic cell (Sertoli cell) epigenome and transcriptome that correlates with adult onset disease (male infertility). The environmentally induced epigenetic transgenerational inheritance of testis disease appears to be a component of the molecular etiology of male infertility. PMID:23555832
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Somatic mutations in benign breast disease tissue and risk of subsequent invasive breast cancer.
Rohan, Thomas E; Miller, Christopher A; Li, Tiandao; Wang, Yihong; Loudig, Olivier; Ginsberg, Mindy; Glass, Andrew; Mardis, Elaine
2018-06-06
Insights into the molecular pathogenesis of breast cancer might come from molecular analysis of tissue from early stages of the disease. We conducted a case-control study nested in a cohort of women who had biopsy-confirmed benign breast disease (BBD) diagnosed between 1971 and 2006 at Kaiser Permanente Northwest and who were followed to mid-2015 to ascertain subsequent invasive breast cancer (IBC); cases (n = 218) were women with BBD who developed subsequent IBC and controls, individually matched (1:1) to cases, were women with BBD who did not develop IBC in the same follow-up interval as that for the corresponding case. Targeted sequence capture and sequencing were performed for 83 genes of importance in breast cancer. There were no significant case-control differences in mutation burden overall, for non-silent mutations, for individual genes, or with respect either to the nature of the gene mutations or to mutational enrichment at the pathway level. For seven subjects with DNA from the BBD and ipsilateral IBC, virtually no mutations were shared. This study, the first to use a targeted multi-gene sequencing approach on early breast cancer precursor lesions to investigate the genomic basis of the disease, showed that somatic mutations detected in BBD tissue were not associated with breast cancer risk.
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Benign Breast Disease: Toward Molecular Prediction of Breast Cancer Risk
2008-06-01
of benign histology in predicting risk of future breast cancer, examining in detail the role of proliferative disease, atypia , papillomas, radial...who had proliferative disease with atypia , especially those of younger age. • We identified a marked increased risk of breast cancer in women with...imparts an increased risk of developing a subsequent carcinoma similar to other forms of proliferative breast disease without atypia . Atypical
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Crusted scabies in a patient with chronic graft-versus-host disease.
Magee, K L; Hebert, A A; Rapini, R P
1991-11-01
We describe a 20-year-old man with chronic graft-versus-host disease and progressive cutaneous changes. His skin became more lichenified despite therapy with azathioprine, prednisone, and cyclosporine. Although it was initially thought that lichenoid graft-versus-host disease had developed, it was subsequently discovered that the patient had crusted (Norwegian) scabies.
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Effects of antibiotics on human microbiota and subsequent disease.
Keeney, Kristie M; Yurist-Doutsch, Sophie; Arrieta, Marie-Claire; Finlay, B Brett
2014-01-01
Although antibiotics have significantly improved human health and life expectancy, their disruption of the existing microbiota has been linked to significant side effects such as antibiotic-associated diarrhea, pseudomembranous colitis, and increased susceptibility to subsequent disease. By using antibiotics to break colonization resistance against Clostridium, Salmonella, and Citrobacter species, researchers are now exploring mechanisms for microbiota-mediated modulation against pathogenic infection, revealing potential roles for different phyla and family members as well as microbiota-liberated sugars, hormones, and short-chain fatty acids in regulating pathogenicity. Furthermore, connections are now being made between microbiota dysbiosis and a variety of different diseases such as rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, atopy, and obesity. Future advances in the rapidly developing field of microbial bioinformatics will enable researchers to further characterize the mechanisms of microbiota modulation of disease and potentially identify novel therapeutics against disease.
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Diffuse Lewy body disease: clinical features in 15 cases.
Byrne, E J; Lennox, G; Lowe, J; Godwin-Austen, R B
1989-01-01
Fifteen cases of diffuse Lewy body disease were diagnosed on pathological grounds during a single year in one health district. The range and frequency of clinical features contrast strikingly with previous reports. The majority of cases presented with classical levodopa-responsive Parkinson's disease either alone (6 cases) or with mild cognitive impairment (3 cases); the remaining 6 cases presented with cognitive impairment alone. In time almost all patients developed both dementia and Parkinsonism. The dementia was cortical in type, but unusual in that most (12 cases) showed day-to-day fluctuation in severity at some point in their illness. These findings suggest that diffuse Lewy body disease is not rare, and that it presents in a range of ways from dementia with subsequent Parkinsonism to Parkinson's disease with subsequent dementia. The latter mode of presentation suggests that it should be considered as a significant pathological substrate of dementia in Parkinson's disease. Images PMID:2545827
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Different methods of treatment related to the bilateral occurrence of Perthes' disease.
Futami, T; Suzuki, S
1997-11-01
We treated 98 consecutive patients with Perthes' disease by a unilateral brace in external rotation, flexion and abduction and a further consecutive 110 by a bilateral cast with the hips in internal rotation and abduction. During treatment in the unilateral brace, six (6.1%) hips on the opposite side developed evidence of Perthes' disease and one developed this after the brace had been removed. In children managed in bilateral casts, no contralateral Perthes' disease was seen. Adequate containment of the femoral head may prevent subsequent changes in the opposite hip.
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NASA Astrophysics Data System (ADS)
Shimokawa, Hiroaki
Cardiovascular diseases, such as coronary artery disease and peripheral artery disease, are the major causes of death in developed countries, and the number of elderly patients has been rapidly increasing worldwide. Thus, it is crucial to develop new non-invasive therapeutic strategies for these patients. We found that a low-energy shock wave (SW) (about 10% of the energy density that is used for urolithiasis) effectively increases the expression of vascular endothelial growth factor (VEGF) in cultured endothelial cells. Subsequently, we demonstrated that extracorporeal cardiac SW therapy with low-energy SW up-regulates the expression of VEGF, enhances angiogenesis, and improves myocardial ischemia in a pig model of chronic myocardial ischemia without any adverse effects in vivo. Based on these promising results in animal studies, we have subsequently developed a new, non-invasive angiogenic therapy with low-energy SW for cardiovascular diseases. Our extracorporeal cardiac SW therapy improved symptoms and myocardial perfusion evaluated with stress-scintigraphy in patients with severe coronary artery disease without indication of percutaneous coronary intervention or coronary artery bypass surgery. Importantly, no procedural complications or adverse effects were noted. The SW therapy was also effective in ameliorating left ventricular remodeling after acute myocardial infarction in pigs and in enhancing angiogenesis in hindlimb ischemia in animals and patients with coronary artery disease. Furthermore, our recent experimental studies suggest that the SW therapy is also effective for indications other than cardiovascular diseases. Thus, our extracorporeal cardiac SW therapy is an effective, safe, and non-invasive angiogenic strategy for cardiovascular medicine.
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A 5-Year Follow-up Study on the Relationship between Obstructive Sleep Apnea and Parkinson Disease.
Sheu, Jau-Jiuan; Lee, Hsin-Chien; Lin, Herng-Ching; Kao, Li-Ting; Chung, Shiu-Dong
2015-12-15
Sleep disturbances are among the most common nonmotor symptoms of Parkinson disease. However, no large epidemiological data regarding the association between obstructive sleep apnea (OSA) and Parkinson disease have been reported. The goal of this study was to investigate the risk for Parkinson disease during a 5-y follow-up period after a diagnosis of OSA using a population-based dataset. The data for this retrospective longitudinal cohort study were retrieved from the Taiwan Longitudinal Health Insurance Database 2000. We identified 1,532 patients with OSA as the study cohort and randomly selected 7,660 patients as the comparison cohort. Each subject was individually followed up for a 5-y period to identify those in whom Parkinson disease subsequently developed. Stratified Cox proportional hazard regressions were performed as a means of comparing the 5-y risk of subsequent Parkinson disease between the study cohort and comparison cohort. Of the 9,192 total patients, Parkinson disease developed in 0.73% during the 5-y follow-up period: 1.24% and 0.63% in the OSA and control cohorts, respectively. After censoring patients who died during the follow-up period and adjusting for socio-demographic characteristics, the hazard ratio (HR) of Parkinson disease during the 5-y follow-up period for patients with OSA was 2.26 (95% confidence interval [CI] = 1.32-3.88) compared with comparison patients. In addition, among females, the adjusted HR of Parkinson disease was 3.54 (95% CI = 1.50-8.34) for patients with OSA compared to patients without OSA. However, among males, there was no significantly increased hazard of Parkinson disease for patients with OSA compared to those without OSA. Female patients with OSA were found to be at a significant risk of subsequent Parkinson disease during a 5-y follow-up period. © 2015 American Academy of Sleep Medicine.
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Huscher, Dörte; Saketkoo, Lesley Ann; Pittrow, David; Khanna, Dinesh
2010-05-01
This review article discusses the proposed methodology that will be utilized to develop core set items for connective tissue disease-associated interstitial lung disease (CTD-ILD). CTD-ILD remain an important enigma in clinical medicine. No consensus exists on measurement of disease activity or what constitutes a significant response to therapeutic interventions. Lack of appropriate measures inhibit effective drug development and hamper regulatory evaluation of candidate therapies.An interdisciplinary and international Steering Committee (SC) will oversee the execution of a 3-tier Delphi exercise involving experts in CTD and ILD. In parallel to the Delphi, qualitative information will be gathered from patients with ILD using focus groups. These data will subsequently be used to construct surveys to collect quantitative response from patients with ILD. The final Delphi and Patient Perspective results are to be scrutinized by SC and specialty sub-groups (including patient advocates) for truth, discrimination and feasibility - the OMERACT filters. Through application of Nominal Group technique, a core set of outcome measures will be proposed. Subsequent exercises will evaluate the applicability of a proposed core set to the unique issues posed by individual CTDs in addition to guidelines on screening, prognostication and damage scoring.
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Developmental Programming of Hypertension and Kidney Disease
Chong, Euming; Yosypiv, Ihor V.
2012-01-01
A growing body of evidence supports the concept that changes in the intrauterine milieu during “sensitive” periods of embryonic development or in infant diet after birth affect the developing individual, resulting in general health alterations later in life. This phenomenon is referred to as “developmental programming” or “developmental origins of health and disease.” The risk of developing late-onset diseases such as hypertension, chronic kidney disease (CKD), obesity or type 2 diabetes is increased in infants born prematurely at <37 weeks of gestation or in low birth weight (LBW) infants weighing <2,500 g at birth. Both genetic and environmental events contribute to the programming of subsequent risks of CKD and hypertension in premature or LBW individuals. A number of observations suggest that susceptibility to subsequent CKD and hypertension in premature or LBW infants is mediated, at least in part, by reduced nephron endowment. The major factors influencing in utero environment that are associated with a low final nephron number include uteroplacental insufficiency, maternal low-protein diet, hyperglycemia, vitamin A deficiency, exposure to or interruption of endogenous glucocorticoids, and ethanol exposure. This paper discusses the effect of premature birth, LBW, intrauterine milieu, and infant feeding on the development of hypertension and renal disease in later life as well as examines the role of the kidney in developmental programming of hypertension and CKD. PMID:23251800
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Mast cell hyperactivity underpins the development of oxygen-induced retinopathy
Matsuda, Kenshiro; Okamoto, Noriko; Kondo, Masatoshi; Arkwright, Peter D.; Karasawa, Kaoru; Ishizaka, Saori; Yokota, Shinichi; Matsuda, Akira; Jung, Kyungsook; Oida, Kumiko; Jang, Hyosun; Noda, Eiichiro; Kakinuma, Ryota; Yasui, Koujirou; Kaku, Uiko; Mori, Yasuo; Onai, Nobuyuki; Ohteki, Toshiaki; Tanaka, Akane
2017-01-01
Mast cells are classically thought to play an important role in protection against helminth infections and in the induction of allergic diseases; however, recent studies indicate that these cells also contribute to neovascularization, which is critical for tissue remodeling, chronic inflammation, and carcinogenesis. Here, we demonstrate that mast cells are essential for sprouting angiogenesis in a murine model of oxygen-induced retinopathy (OIR). Although mouse strains lacking mast cells did not exhibit retinal neovascularization following hypoxia, these mice developed OIR following infusion of mast cells or after injection of mast cell tryptase (MCT). Relative hypoxia stimulated mast cell degranulation via transient receptor potential ankyrin 1. Subsequent surges in MCT stimulated retinal endothelial cells to produce monocyte chemotactic protein-1 (MCP1) and angiogenic factors, leading to sprouting angiogenesis. Mast cell stabilizers as well as specific tryptase and MCP1 inhibitors prevented the development of OIR in WT mice. Preterm infants with early retinopathy of prematurity had markedly higher plasma MCT levels than age-matched infants without disease, suggesting mast cells contribute to human disease. Together, these results suggest therapies that suppress mast cell activity should be further explored as a potential option for preventing eye diseases and subsequent blindness induced by neovascularization. PMID:28990934
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Alten, Julia; Klapper, Wolfram; Leuschner, Ivo; Eckert, Cornelia; Beier, Rita; Vallo, Elisabeth; Krause, Martin; Claviez, Alexander; Vieth, Simon; Bleckmann, Kirsten; Möricke, Anja; Schrappe, Martin; Cario, Gunnar
2015-09-01
Histiocytic sarcoma (HS) is a rare disease with poor prognosis which may develop subsequent to acute lymphoblastic leukemia (ALL). Here we report two children treated within the AIEOP-BFM ALL 2009 trial: one patient succumbed to fulminant hemophagocytic lymphohistiocytosis triggered by HS during ALL maintenance therapy, the other patient had a smoldering course of HS for over 2 years, and subsequently died after allogeneic stem cell transplantation. In both cases, HS and ALL were clonally related and apparent return of minimal residual disease (MRD) was detected by qPCR in bone marrow. Thus, HS should be considered in ALL when MRD appears to persist or reappear. © 2015 Wiley Periodicals, Inc.
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Vaccination against Alzheimer disease: an update on future strategies.
Fettelschoss, Antonia; Zabel, Franziska; Bachmann, Martin F
2014-01-01
Alzheimer disease is a devastating chronic disease without adequate therapy. More than 10 years ago, it was demonstrated in transgenic mouse models that vaccination may be a novel, disease-modifying therapy for Alzheimer. Subsequent clinical development has been a roller-coaster with some positive and many negative news. Here, we would like to summarize evidence that next generation vaccines optimized for old people and focusing on patients with mild disease stand a good chance to proof efficacious for the treatment of Alzheimer.
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Vaccination against Alzheimer disease
Fettelschoss, Antonia; Zabel, Franziska; Bachmann, Martin F
2014-01-01
Alzheimer disease is a devastating chronic disease without adequate therapy. More than 10 years ago, it was demonstrated in transgenic mouse models that vaccination may be a novel, disease-modifying therapy for Alzheimer. Subsequent clinical development has been a roller-coaster with some positive and many negative news. Here, we would like to summarize evidence that next generation vaccines optimized for old people and focusing on patients with mild disease stand a good chance to proof efficacious for the treatment of Alzheimer. PMID:24535580
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Yong, J B; Sivarajan, S; Abbott, P V
2018-05-19
To assess whether the timing of pulp disease after tooth restoration was associated with type of restorative dental material used, extent of the restoration, or tooth type. A comprehensive search and analysis of data using the Titanium Oral Health Management software program at The Oral Health Centre of Western Australia was performed to correlate procedural codes for teeth that had restorations placed and subsequently developed pulp disease requiring endodontic treatment or extraction from 1 st January 2009 to 31 st December 2013. Manual analysis of paper and/or electronic patient record cards was also performed. Data collected included restoration type, restored tooth surfaces, tooth type, and the dates of restoration and subsequent endodontic intervention or extraction. Of 330 teeth that met the inclusion criteria, 84 (26%) had composite resin restorations, 80 (24%) had amalgams, 119 (36%) had GICs and 47 (14%) had crowns. The average time between restoration and further intervention was 330 days with a range from 3 days to 1,775 days (approx. 5 years). Teeth restored with crowns or five-surface restorations were significantly more likely to require earlier intervention than other restorations. Premolar and anterior teeth were also more likely to require earlier intervention. Teeth that developed pulp disease requiring further intervention that were restored with crowns and five-surface GIC developed the disease sooner than teeth that were restored with amalgam or composite. In teeth with five surface restorations that developed pulp disease requiring further intervention, premolar and anterior teeth developed the pulp disease sooner than molars. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
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Dunphy, Cherie H; Galambos, Csaba; Polski, Jacek M; Evans, H Lance; Gardner, Laura J; Grosso, Leonard E; Montone, Kathleen T
2002-03-01
Posttransplant lymphoproliferative disorders (PTLDs) represent a morphologic, immunophenotypic, and genotypic spectrum of disease. Most recently, Knowles et al divided PTLDs into 3 distinct categories: (1) plasmacytic hyperplasia, (2) polymorphic B-cell hyperplasia and polymorphic B-cell lymphoma, and (3) immunoblastic lymphoma and multiple myeloma. Although one form of PTLD may progress to another form, only 1 previous case has been reported in which multiple myeloma developed 14 months after an original diagnosis of plasmacytic hyperplasia. The type of solid organ transplant was not specified in that case. We report a post--cardiac transplant plasmacytic hyperplasia developing 7 years posttransplant. Six years subsequent to the plasmacytic hyperplasia, the patient developed a posttransplant plasmacytic malignancy, supported by morphology, flow cytometric immunophenotyping, and genotypic studies. Since we have no data to support disseminated bony disease or an abnormal serum protein, we have not used the term "multiple myeloma" for this case.
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78 FR 8152 - Proposed Collection; Comment Request: Women's Health Initiative Observational Study
Federal Register 2010, 2011, 2012, 2013, 2014
2013-02-05
... of Management and Budget (OMB) for review and approval. Proposed Collection: Title: The Women's... women and relating subsequent disease development to baseline assessments of historical, physical...
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Multimodality and nanoparticles in medical imaging
Huang, Wen-Yen; Davis, Jason J.
2015-01-01
A number of medical imaging techniques are used heavily in the provision of spatially resolved information on disease and physiological status and accordingly play a critical role in clinical diagnostics and subsequent treatment. Though, for most imaging modes, contrast is potentially enhanced through the use of contrast agents or improved hardware or imaging protocols, no single methodology provides, in isolation, a detailed mapping of anatomy, disease markers or physiological status. In recent years, the concept of complementing the strengths of one imaging modality with those of another has come to the fore and been further bolstered by the development of fused instruments such as PET/CT and PET/MRI stations. Coupled with the continual development in imaging hardware has been a surge in reports of contrast agents bearing multiple functionality, potentially providing not only a powerful and highly sensitised means of co-localising physiological/disease status and anatomy, but also the tracking and delineation of multiple markers and indeed subsequent or simultaneous highly localized therapy (“theragnostics”). PMID:21409202
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Retrospective Analysis of Long-Term Outcomes After Combat Injury: A Hidden Cost of War.
Stewart, Ian J; Sosnov, Jonathan A; Howard, Jeffrey T; Orman, Jean A; Fang, Raymond; Morrow, Benjamin D; Zonies, David H; Bollinger, Mary; Tuman, Caroline; Freedman, Brett A; Chung, Kevin K
2015-12-01
During the conflicts in Iraq and Afghanistan, 52,087 service members have been wounded in combat. The long-term sequelae of these injuries have not been carefully examined. We sought to determine the relation between markers of injury severity and the subsequent development of hypertension, coronary artery disease, diabetes mellitus, and chronic kidney disease. Retrospective cohort study of critically injured US military personnel wounded in Iraq or Afghanistan from February 1, 2002 to February 1, 2011. Patients were then followed until January 18, 2013. Chronic disease outcomes were assessed by International Classification of Diseases, 9th edition codes and causes of death were confirmed by autopsy. From 6011 admissions, records were excluded because of missing data or if they were for an individual's second admission. Patients with a disease diagnosis of interest before the injury date were also excluded, yielding a cohort of 3846 subjects for analysis. After adjustment for other factors, each 5-point increment in the injury severity score was associated with a 6%, 13%, 13%, and 15% increase in incidence rates of hypertension, coronary artery disease, diabetes mellitus, and chronic kidney disease, respectively. Acute kidney injury was associated with a 66% increase in rates of hypertension and nearly 5-fold increase in rates of chronic kidney disease. In Iraq and Afghanistan veterans, the severity of combat injury was associated with the subsequent development of hypertension, coronary artery disease, diabetes mellitus, and chronic kidney disease. © 2015 American Heart Association, Inc.
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Squamous cell carcinoma arising in Hailey-Hailey disease of the vulva.
Cockayne, S E; Rassl, D M; Thomas, S E
2000-03-01
A 61-year-old woman, who was known to have Hailey-Hailey disease, presented with increasing vulval soreness. Biopsy showed vulval intraepithelial neoplasia (VIN) 3 and subsequent histology from a vulvectomy specimen showed extensive VIN with early invasive squamous cell carcinoma. This may be another example of chronic inflammation of the vulval area leading to the development of squamous cell carcinoma. However, in this case, chronic human papillomavirus may also have played a part, leading to VIN and reactivation of the Hailey-Hailey disease. We can find no previous reports of squamous cell carcinoma developing in the setting of Hailey-Hailey disease.
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Wei, Han-Ting; Lan, Wen-Hsuan; Hsu, Ju-Wei; Huang, Kai-Lin; Su, Tung-Ping; Li, Cheng-Ta; Lin, Wei-Chen; Chen, Tzeng-Ji; Bai, Ya-Mei; Chen, Mu-Hong
2016-10-01
Previous studies have found an increased prevalence of atopic diseases among patients with major depression and bipolar disorder. But the temporal association between atopic diseases in adolescence and the subsequent risk of developing mood disorders has been rarely investigated. Using the Taiwan National Health Insurance Research Databases, 5075 adolescents with atopic diseases (atopic cohort) and 44,729 without (non-atopic cohort) aged between 10 and 17 in 2000 were enrolled into our study and followed to the end of 2010. Subjects who developed major depression or bipolar disorder during the follow-up were identified. The atopic cohort had an increased risk of developing major depression (HR: 2.45, 95% CI: 1.93~3.11) and bipolar disorder (HR: 2.51, 95% CI: 1.71~3.67) compared to the non-atopic cohort, with a dose-dependent relationship between having a greater number of atopic comorbidities and a greater likelihood of major depression (1 atopic disease: HR: 1.80, 95% CI: 1.29~2.50; 2 atopic comorbidities: HR: 2.42, 95% CI: 1.93~3.04;≥3 atopic comorbidities: HR: 3.79, 95% CI: 3.05~4.72) and bipolar disorder (HR: 1.40, 95% CI: 0.57~3.44; HR: 2.81, 95% CI: 1.68~4.68; HR: 3.02, 95% CI: 1.69~5.38). Having atopic diseases in adolescence increased the risk of developing major depression and bipolar disorder in later life. Further studies may be required to clarify the underlying mechanism between atopy and mood disorders, and to investigate whether prompt intervention may decrease the risk of subsequent mood disorders. Copyright © 2016 Elsevier B.V. All rights reserved.
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Fifty years of Australian pediatric gastroenterology.
Cameron, Don
2009-10-01
When the Gastroenterological Society of Australia (GESA) began 50 years ago there were very few pediatric gastroenterologists in the world. The 'Mother' of Paediatric Gastroenterology was Australian Charlotte ('Charlo') Anderson who established one of the world's first pediatric gastroenterology units in Melbourne in the early 1960s. Her earlier work in Birmingham had identified gluten as the component of wheat responsible for celiac disease and helped separate maldigestion (cystic fibrosis) and mucosal malabsorption. The first comprehensive textbook of Paediatric Gastroenterology was edited by Charlotte Anderson and Valerie Burke in 1975. Rudge Townley succeeded Charlotte Anderson in Melbourne and went on to further develop small bowel biopsy techniques making it a safe, simple, and quick procedure that led to much greater understanding of small bowel disease and ultimately the discovery of Rotavirus by Ruth Bishop et al. and subsequently to Rotavirus immunization. Australian Paediatric Gastroenterology subsequently developed rapidly with units being established in all mainland capital cities by the end of the 1970s. The Australian Society of Paediatric Gastroenterology Hepatology and Nutrition (AuSPGHAN) was established in the 1980s. Australians have contributed significantly in many areas of gastroenterology in infants, children, and adolescents including celiac disease, cystic fibrosis, liver disease, transplantation, gastrointestinal infection, allergy, indigenous health, inflammatory bowel disease, gastrointestinal motility, and the development of novel tests of gastrointestinal function and basic science. There have also been major contributions to nutrition in cystic fibrosis, end-stage liver disease, and intestinal failure. The future of Australian Paediatric Gastroenterology is in good hands.
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Mackiewicz-Wysocka, Małgorzata; Krokowicz, Lukasz; Kocur, Jacek; Mackiewicz, Jacek
2014-12-01
About 40% to 60% of melanomas present BRAF mutation. Selective BRAF inhibitors such as vemurafenib and dabrafenib are currently approved for the treatment of advanced melanoma patients with BRAF mutation. The treatment-induced tumor regression occurs in the majority of patients; however, acquired resistance to BRAF inhibitors is observed in most of the patients after 6 to 7 months. After progression of the disease, the patient might be offered treatment with ipilimumab followed by chemotherapy. Subsequent lines of systemic treatment of metastatic melanoma patients do not exist.Here we report a case of a 59-year-old woman with a diagnosis of BRAF-mutant metastatic melanoma that responded to initial treatment with vemurafenib. Subsequently, after disease progression, the patient received chemotherapy. Since no clinical response to dacarbazine was observed, carboplatin with paclitaxel were applied. Transient partial response was obtained, which was followed by further disease progression. Then retreatment with vemurafenib was applied. The patient developed very short-term tumor regression and significant biochemical response (serum lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase) to the treatment. However, following 5 weeks of retreatment, the patient developed progression of the disease. Our clinical observation indicates that in melanoma patients who developed resistance to selective BRAF inhibitors, rechallenge after treatment interruption might be beneficial.
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Resistance to Vemurafenib Can Be Reversible After Treatment Interruption
Mackiewicz-Wysocka, Małgorzata; Krokowicz, Łukasz; Kocur, Jacek; Mackiewicz, Jacek
2014-01-01
Abstract About 40% to 60% of melanomas present BRAF mutation. Selective BRAF inhibitors such as vemurafenib and dabrafenib are currently approved for the treatment of advanced melanoma patients with BRAF mutation. The treatment-induced tumor regression occurs in the majority of patients; however, acquired resistance to BRAF inhibitors is observed in most of the patients after 6 to 7 months. After progression of the disease, the patient might be offered treatment with ipilimumab followed by chemotherapy. Subsequent lines of systemic treatment of metastatic melanoma patients do not exist. Here we report a case of a 59-year-old woman with a diagnosis of BRAF-mutant metastatic melanoma that responded to initial treatment with vemurafenib. Subsequently, after disease progression, the patient received chemotherapy. Since no clinical response to dacarbazine was observed, carboplatin with paclitaxel were applied. Transient partial response was obtained, which was followed by further disease progression. Then retreatment with vemurafenib was applied. The patient developed very short-term tumor regression and significant biochemical response (serum lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase) to the treatment. However, following 5 weeks of retreatment, the patient developed progression of the disease. Our clinical observation indicates that in melanoma patients who developed resistance to selective BRAF inhibitors, rechallenge after treatment interruption might be beneficial. PMID:25501056
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Acute Pancreatitis in a Patient with Maple Syrup Urine Disease: A Management Paradox.
Gold, Nina B; Blumenthal, Jennifer A; Wessel, Ann E; Stein, Deborah R; Scott, Adam; Fox, Victor L; Turner, Amy; Kritzer, Amy; Rajabi, Farrah; Peeler, Katherine; Tan, Wen-Hann
2018-04-19
Maple syrup urine disease (MSUD) is an inborn error of metabolism that causes elevated leucine in the setting of acute illnesses. We describe an 8-year-old boy with MSUD who developed acute pancreatitis and subsequent leucinosis. This case highlights the complexities of fluid management in patients with MSUD. Copyright © 2018 Elsevier Inc. All rights reserved.
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Derikx, Lauranne A A P; de Jong, Michiel E; Hoentjen, Frank
2018-05-17
Approximately 30% of patients with ulcerative colitis require a colectomy during their disease course. This substantially reduces colorectal cancer risk, although it is still possible to develop colorectal neoplasia in the remaining rectum. Although clear and well-accepted surveillance guidelines exist for patients with inflammatory bowel disease with an intact colon, specific surveillance recommendations following colectomy are less clear. Here, we aim to summarize the prevalence, incidence, and risk factors for developing colorectal cancer in patients with inflammatory bowel disease who underwent subtotal colectomy with a permanent end ileostomy and rectal stump, or with ileorectal anastomosis. Subsequently, gained insights are integrated into a proposed endoscopic surveillance strategy of the residual rectum.
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Antiphospholipid antibody syndrome complicated by Grave's disease.
Takahashi, Ayumi; Tamura, Atsushi; Ishikawa, Osamu
2002-12-01
The report describes a woman with primary antiphospholipid antibody syndrome complicated with Grave's disease. Developing symptoms included a small cutaneous nodule on her finger and subsequently ecchymotic purpura on the cheeks, ears, buttocks and lower legs. Histological examinations showed thrombosed vessels in the dermis without or with hemorrhage, respectively. Laboratory investigation revealed positive lupus anticoagulant and immunogenic hyperthyroidism due to Grave's disease. There is a close relationship between the cutaneous manifestation of antiphospholipid antibody syndrome and the activities of Grave's disease and a possible link of antiphospholipid antibody syndrome with Grave's disease was suggested both by the etiology of the disease as well as the disease activity.
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Kuo, Chiu-Huang; Hsieh, Tsung-Cheng; Wang, Chih-Hsien; Chou, Chu-Lin; Lai, Yu-Hsien; Chen, Yi-Ya; Lin, Yu-Li; Wu, Sheng-Teng; Fang, Te-Chao
2015-01-01
Hemodialysis (HD) patients with bone fractures have an increased risk for death. However, the risks for mortality and atherosclerotic complications in incident HD patients subsequently with bone fractures are unknown. Data derived from the Taiwan National Health Institute Research Database between January 1997 and December 2008 was analyzed. The enrolled patients included 3,008 incident HD patients subsequently with a single long bone fracture (LB Fx) and 2,070 incident HD patients subsequently with a single non-long bone fracture (NLB Fx). These patients were matched (1:5 ratio) for age, sex, and same duration of HD with incident HD patients who had no fractures and outcomes were measured over a 3-year follow-up. After demographic and co-morbidity adjustment, LB Fx increased the risk for overall mortality (HR = 1.59, p < 0.001) and stroke (HR = 1.09, p = 0.028) in incident HD patients. NLB Fx increased the risk for overall mortality (HR = 1.52, p < 0.001), stroke (HR = 1.19, p < 0.001), coronary artery disease (CAD), (HR = 1.13, p = 0.003), and peripheral arterial occlusive disease (PAOD), (HR = 1.41, p < 0.001) in incident HD patients. Moreover, incident patients subsequently with NLB Fx had significantly higher risks of CAD and PAOD than those subsequently with LB Fx. The rates of mortality and stroke were significantly higher in incident HD patients subsequently with bone fractures than in matched patients without bone fractures. Incident HD patients subsequently with NLB Fx had significantly higher risks of CAD and PAOD than those subsequently with LB Fx and without bone fractures. Thus, incident HD patients subsequently with bone fractures should be closely followed for a higher mortality and possible development of atherosclerotic complications.
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Protein aggregation, cardiovascular diseases, and exercise training: Where do we stand?
Gouveia, Marisol; Xia, Ke; Colón, Wilfredo; Vieira, Sandra I; Ribeiro, Fernando
2017-11-01
Cells ensure their protein quality control through the proteostasis network. Aging and age-related diseases, such as neurodegenerative and cardiovascular diseases, have been associated to the reduction of proteostasis network efficiency and, consequently, to the accumulation of protein misfolded aggregates. The decline in protein homeostasis has been associated with the development and progression of atherosclerotic cardiovascular disease, cardiac hypertrophy, cardiomyopathies, and heart failure. Exercise training is a key component of the management of patients with cardiovascular disease, consistently improving quality of life and prognosis. In this review, we give an overview on age-related protein aggregation, the role of the increase of misfolded protein aggregates on cardiovascular pathophysiology, and describe the beneficial or deleterious effects of the proteostasis network on the development of cardiovascular disease. We subsequently discuss how exercise training, a key lifestyle intervention in those with cardiovascular disease, could restore proteostasis and improve disease status. Copyright © 2017 Elsevier B.V. All rights reserved.
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Perthes disease in a 2-year-old child.
Dhas, Daphne; Viswanath, Aparna; Latimer, Mark David
2015-03-02
Perthes disease represents a transient interruption of the blood supply to the femoral head followed by collapse and subsequent remodelling. The majority of cases present between the ages of 4 and 10 years. We report the case of a child who developed a painful right-sided limp some days after his second birthday. The limp was initially interpreted as a transient synovitis of the hip. However, when the limp persisted, further investigations revealed that he had Perthes disease. 2015 BMJ Publishing Group Ltd.
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Perthes disease in a 2-year-old child
Dhas, Daphne; Viswanath, Aparna
2015-01-01
Perthes disease represents a transient interruption of the blood supply to the femoral head followed by collapse and subsequent remodelling. The majority of cases present between the ages of 4 and 10 years. We report the case of a child who developed a painful right-sided limp some days after his second birthday. The limp was initially interpreted as a transient synovitis of the hip. However, when the limp persisted, further investigations revealed that he had Perthes disease. PMID:25733084
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Measuring public health practice and outcomes in chronic disease: a call for coordination.
Porterfield, Deborah S; Rogers, Todd; Glasgow, LaShawn M; Beitsch, Leslie M
2015-04-01
A strategic opportunity exists to coordinate public health systems and services researchers' efforts to develop local health department service delivery measures and the efforts of divisions within the Centers for Disease Control and Prevention's National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP) to establish outcome indicators for public health practice in chronic disease. Several sets of outcome indicators developed by divisions within NCCDPHP and intended for use by state programs can be tailored to assess outcomes of interventions within smaller geographic areas or intervention settings. Coordination of measurement efforts could potentially allow information to flow from the local to the state to the federal level, enhancing program planning, accountability, and even subsequent funding for public health practice.
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Molecular diagnostics of neurodegenerative disorders.
Agrawal, Megha; Biswas, Abhijit
2015-01-01
Molecular diagnostics provide a powerful method to detect and diagnose various neurological diseases such as Alzheimer's and Parkinson's disease. The confirmation of such diagnosis allows early detection and subsequent medical counseling that help specific patients to undergo clinically important drug trials. This provides a medical pathway to have better insight of neurogenesis and eventual cure of the neurodegenerative diseases. In this short review, we present recent advances in molecular diagnostics especially biomarkers and imaging spectroscopy for neurological diseases. We describe advances made in Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), and finally present a perspective on the future directions to provide a framework for further developments and refinements of molecular diagnostics to combat neurodegenerative disorders.
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Brown, Traci Ann; Holian, Andrij; Pinkerton, Kent E; Lee, Joong Won; Cho, Yoon Hee
2016-07-01
Asbestos in combination with tobacco smoke exposure reportedly leads to more severe physiological consequences than asbestos alone; limited data also show an increased disease risk due to environmental tobacco smoke (ETS) exposure. Environmental influences during gestation and early lung development can result in physiological changes that alter risk for disease development throughout an individual's lifetime. Therefore, maternal lifestyle may impact the ability of offspring to subsequently respond to environmental insults and alter overall disease susceptibility. In this study, we examined the effects of exposure to ETS in utero and during early postnatal development on asbestos-related inflammation and disease in adulthood. ETS exposure in utero appeared to shift inflammation towards a Th2 phenotype, via suppression of Th1 inflammatory cytokine production. This effect was further pronounced in mice exposed to ETS in utero and during early postnatal development. In utero ETS exposure led to increased collagen deposition, a marker of fibrotic disease, when the offspring was later exposed to asbestos, which was further increased with additional ETS exposure during early postnatal development. These data suggest that ETS exposure in utero alters the immune responses and leads to greater disease development after asbestos exposure, which is further exacerbated when exposure to ETS continues during early postnatal development.
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The Epidemiology of Liver Diseases Unique to Pregnancy in a US Community: A Population-Based Study.
Allen, Alina M; Kim, W Ray; Larson, Joseph J; Rosedahl, Jordan K; Yawn, Barbara P; McKeon, Kimberly; Hay, J Eileen
2016-02-01
Little is known in the United States about the epidemiology of liver diseases that develop only during (are unique to) pregnancy. We investigated the incidence of liver diseases unique to pregnancy in Olmsted County, Minnesota, and long-term maternal and fetal outcomes. We identified 247 women with liver diseases unique to pregnancy from 1996 through 2010 using the Rochester Epidemiology Project database. The crude incidence rate was calculated by the number of liver disease cases divided by 35,101 pregnancies. Of pregnant women with liver diseases, 134 had preeclampsia with liver dysfunction, 72 had hemolysis-associated increased levels of liver enzymes and low-platelet (HELLP) syndrome, 26 had intrahepatic cholestasis of pregnancy, 14 had hyperemesis gravidarum with abnormal liver enzymes, and 1 had acute fatty liver of pregnancy. The crude incidence of liver diseases unique to pregnancy was 0.77%. Outcomes were worse among women with HELLP or preeclampsia than the other disorders--of women with HELLP, 70% had a premature delivery, 4% had abruptio placentae, 3% had acute kidney injury, and 3% had infant death. Of women with preeclampsia, 56.0% had a premature delivery, 4% had abruptio placentae, 3% had acute kidney injury, and 0.7% had infant death. After 7 median years of follow-up (range, 0-18 years), 14% of the women developed recurrent liver disease unique to pregnancy; the proportions were highest in women with initial hyperemesis gravidarum (36%) or intrahepatic cholestasis of pregnancy (35%). Women with preeclampsia were more likely to develop subsequent hepatobiliary diseases. We found the incidence of liver disease unique to pregnancy in Olmsted County, Minnesota, to be lower than that reported from Europe or US tertiary referral centers. Maternal and fetal outcomes in Olmsted County were better than those reported from other studies, but fetal mortality was still high (0.7%-3.0%). Women with preeclampsia or HELLP are at higher risk for peripartum complications and subsequent development of comorbidities. Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.
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Second primary cancers following borderline ovarian tumors.
Sanci, Muzaffer; Gultekin, Emre; Cingillioglu, Basak; Gultekin, Ozge Elmastas; Ozvural, Seyfettin; Emirdar, Volkan; Yildirim, Yusuf
2011-06-01
Several studies have reported an increased risk of second primary cancers subsequent to invasive epithelial ovarian cancer. However, there is no adequate data regarding such risk in borderline ovarian tumors (BOTs). The aim of this study was to evaluate the risk of subsequent second primary cancers among women with BOTs. BOT patients treated in our center between December 1985 and April 2009 were retrospectively screened for developing second primary cancer during follow-up period. There were 96 women diagnosed with BOT. Mean age at the time of diagnosis was 47 ± 14.3, ranging from 19 to 79. Eighty-eight (91.6%) patients had stage I disease, two patients (2.1%) had stage II and six (6.2%) had stage III. Twenty-five (26.0%) patients received platinum-based adjuvant chemotherapy. Mean follow-up time was 96.5 ± 442 months (range: 9-280 months). There were ten (10.4%) recurrences. Only one patient developed second primary cancer. Second primary cancer observed in this case was basal cell carsinoma of the eyelid, which was diagnosed 2 years after primary disease. There were no patients with common women's cancers such as breast and colorectal cancers. These findings do not suggest increased risk of subsequent cancers in patients with BOT. However, population-based studies are needed for evaluating exact risk of developing second primary malignancies in women with BOTs.
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21 CFR 520.1451 - Moxidectin tablets.
Code of Federal Regulations, 2013 CFR
2013-04-01
... and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL... (1.36 micrograms per pound) of body weight. (2) Indications for use. To prevent infection by the canine heartworm Dirofilaria immitis and the subsequent development of canine heartworm disease. (3...
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21 CFR 520.1451 - Moxidectin tablets.
Code of Federal Regulations, 2011 CFR
2011-04-01
... and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL... (1.36 micrograms per pound) of body weight. (2) Indications for use. To prevent infection by the canine heartworm Dirofilaria immitis and the subsequent development of canine heartworm disease. (3...
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21 CFR 520.1451 - Moxidectin tablets.
Code of Federal Regulations, 2012 CFR
2012-04-01
... and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL... (1.36 micrograms per pound) of body weight. (2) Indications for use. To prevent infection by the canine heartworm Dirofilaria immitis and the subsequent development of canine heartworm disease. (3...
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21 CFR 520.1451 - Moxidectin tablets.
Code of Federal Regulations, 2014 CFR
2014-04-01
... and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL... (1.36 micrograms per pound) of body weight. (2) Indications for use. To prevent infection by the canine heartworm Dirofilaria immitis and the subsequent development of canine heartworm disease. (3...
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Cell phenotypic variation in normal and damaged tendons
Clegg, Peter D; Strassburg, Sandra; Smith, Roger K
2007-01-01
Injuries to tendons are common in both human athletes as well as in animals, such as the horse, which are used for competitive purposes. Furthermore, such injuries are also increasing in prevalence in the ageing, sedentary population. Tendon diseases often respond poorly to treatment and require lengthy periods of rehabilitation. The tendon has a unique extracellular matrix, which has developed to withstand the mechanical demands of such tensile-load bearing structures. Following injury, any repair process is inadequate and results in tissue that is distinct from original tendon tissue. There is growing evidence for the key role of the tendon cell (tenocyte) in both the normal physiological homeostasis and regulation of the tendon matrix and the pathological derangements that occur in disease. In particular, the tenocyte is considered to have a major role in effecting the subclinical matrix degeneration that is thought to occur prior to clinical disease, as well as in the severe degradative events that occur in the tendon at the onset of clinical disease. Furthermore, the tenocyte is likely to have a central role in the production of the biologically inadequate fibrocartilaginous repair tissue that develops subsequent to tendinopathy. Understanding the biology of the tenocyte is central to the development of appropriate interventions and drug therapies that will either prevent the onset of disease, or lead to more rapid and appropriate repair of injured tendon. Central to this is a full understanding of the proteolytic response in the tendon in disease by such enzymes as metalloproteinases, as well as the control of the inappropriate fibrocartilaginous differentiation. Finally, it is important that we understand the role of both intrinsic and extrinsic cellular elements in the repair process in the tendon subsequent to injury. PMID:17696903
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Spinal aspergillus abscess in a patient with bronchocentric granulomatosis.
Collier, J; Wolfe, R; Lerner, R; Nathan, S; Mohsenifar, Z
1995-01-01
Aspergillus fumigatus hyphae is often found in the lung tissue of patients with bronchocentric granulomatosis (BCG). This organism is believed to be one agent responsible for inciting the hypersensitivity response and subsequent development of the characteristic pathology that defines BCG. The definitive etiology of this disease, however, remains conjectural. Corticosteroids represent the mainstay of therapy. The fungi recovered from patients with BCG are considered noninvasive; thus, the risk of fungal invasion secondary to steroid-induced immunosuppression is believed to be negligible. However, we report a case of spinal aspergillus abscess that developed in a patient with BCG subsequent to steroid therapy. This case also highlights the necessity for aggressive medical and neurosurgical intervention to avert the development of neurological sequelae.
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Preterm Birth and its Impact on Renal Health.
Luyckx, Valerie A
2017-07-01
Preterm birth occurs in approximately 10% of all births worldwide. Preterm infants have reduced nephron numbers at birth in proportion to gestational age, and are at increased risk of neonatal acute kidney injury as well as higher blood pressure, proteinuria, and chronic kidney disease later in life. Rapid catch-up growth in preterm infants, especially if resulting in obesity, is a risk factor for end-stage kidney disease among children with proteinuric renal disease. Preterm birth, however, is a risk factor not only for the infant because mothers who deliver preterm have an increased risk of having subsequent preterm deliveries as well as hypertension, cardiovascular disease, and renal disease later in life. Preterm birth in a female infant is also a risk factor for her future risk of having a preterm delivery, gestational hypertension, and gestational diabetes, which in turn may impact the development of fetal kidneys and the offspring's risk of hypertension and renal disease. This intergenerational programming cycle, therefore, perpetuates the risks and consequences of prematurity. Interruption of this cycle may be possible through optimization of maternal nutrition and health as well as careful antenatal care, which may in turn reduce the global burden of hypertension and renal disease in subsequent generations. Copyright © 2017 Elsevier Inc. All rights reserved.
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Targeting Super-Enhancers for Disease Treatment and Diagnosis.
Shin, Ha Youn
2018-05-10
The transcriptional regulation of genes determines the fate of animal cell differentiation and subsequent organ development. With the recent progress in genome-wide technologies, the genomic landscapes of enhancers have been broadly explored in mammalian genomes, which led to the discovery of novel specific subsets of enhancers, termed superenhancers. Super-enhancers are large clusters of enhancers covering the long region of regulatory DNA and are densely occupied by transcription factors, active histone marks, and co-activators. Accumulating evidence points to the critical role that super-enhancers play in cell type-specific development and differentiation, as well as in the development of various diseases. Here, I provide a comprehensive description of the optimal approach for identifying functional units of superenhancers and their unique chromatin features in normal development and in diseases, including cancers. I also review the recent updated knowledge on novel approaches of targeting super-enhancers for the treatment of specific diseases, such as small-molecule inhibitors and potential gene therapy. This review will provide perspectives on using superenhancers as biomarkers to develop novel disease diagnostic tools and establish new directions in clinical therapeutic strategies.
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Khan, Kamran; Wozniak, Susan E.; Mehrabi, Erfan; Giannone, Anna Lucia; Dave, Mitul
2015-01-01
Patient: Male, 62 Final Diagnosis: Sternoclavicular osteomyelitis Symptoms: — Medication: — Clinical Procedure: Debridement Specialty: Infectious Diseases Objective: Rare disease Background: Sternoclavicular osteomyelitis is a rare disease, with less than 250 cases identified in the past 50 years. We present a rare case of sternoclavicular osteomyelitis in an immunosuppressed patient that developed from a conservatively treated dislocation. Case Report: A 62-year-old white man with a history of metastatic renal cell carcinoma presented to the emergency department (ED) with a dislocated left sternoclavicular joint. He was managed conservatively and subsequently discharged. However, over subsequent days he began to experience pain, fever, chills, and night sweats. He presented to the ED again and imaging revealed osteomyelitis. In the operating room, the wound was aggressively debrided and a wound vac (vacuum-assisted closure) was placed. He was diagnosed with sternoclavicular osteomyelitis and placed on a 6-week course of intravenous Nafcillin. Conclusions: Chemotherapy patients who sustain joint trauma normally associated with a low risk of infection should be monitored thoroughly, and the option to discontinue immunosuppressive therapy should be considered if signs of infection develop. PMID:26708708
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Muir, Peter; Schwartz, Zeev; Malek, Sarah; Kreines, Abigail; Cabrera, Sady Y.; Buote, Nicole J.; Bleedorn, Jason A.; Schaefer, Susan L.; Holzman, Gerianne; Hao, Zhengling
2011-01-01
Background Non-contact cranial cruciate ligament rupture (CrCLR) is an important cause of lameness in client-owned dogs and typically occurs without obvious injury. There is a high incidence of bilateral rupture at presentation or subsequent contralateral rupture in affected dogs. Although stifle synovitis increases risk of contralateral CrCLR, relatively little is known about risk factors for subsequent contralateral rupture, or whether therapeutic intervention may modify this risk. Methodology/Principal Findings We conducted a longitudinal study examining survival of the contralateral CrCL in client-owned dogs with unilateral CrCLR in a large baseline control population (n = 380), and a group of dogs that received disease-modifying therapy with arthroscopic lavage, intra-articular hyaluronic acid and oral doxycycline (n = 16), and were followed for one year. Follow-up in treated dogs included analysis of mobility, radiographic evaluation of stifle effusion and arthritis, and quantification of biomarkers of synovial inflammation. We found that median survival of the contralateral CrCL was 947 days. Increasing tibial plateau angle decreased contralateral ligament survival, whereas increasing age at diagnosis increased survival. Contralateral ligament survival was reduced in neutered dogs. Our disease-modifying therapy did not significantly influence contralateral ligament survival. Correlative analysis of clinical and biomarker variables with development of subsequent contralateral rupture revealed few significant results. However, increased expression of T lymphocyte-associated genes in the index unstable stifle at diagnosis was significantly related to development of subsequent non-contact contralateral CrCLR. Conclusion Subsequent contralateral CrCLR is common in client-owned dogs, with a median ligament survival time of 947 days. In this naturally occurring model of non-contact cruciate ligament rupture, cranial tibial translation is preceded by development of synovial inflammation. However, treatment with arthroscopic lavage, intra-articular hyaluronic acid and oral doxycycline does not significantly influence contralateral CrCL survival. PMID:21998650
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An infectious way to teach students about outbreaks.
Cremin, Íde; Watson, Oliver; Heffernan, Alastair; Imai, Natsuko; Ahmed, Norin; Bivegete, Sandra; Kimani, Teresia; Kyriacou, Demetris; Mahadevan, Preveina; Mustafa, Rima; Pagoni, Panagiota; Sophiea, Marisa; Whittaker, Charlie; Beacroft, Leo; Riley, Steven; Fisher, Matthew C
2018-06-01
The study of infectious disease outbreaks is required to train today's epidemiologists. A typical way to introduce and explain key epidemiological concepts is through the analysis of a historical outbreak. There are, however, few training options that explicitly utilise real-time simulated stochastic outbreaks where the participants themselves comprise the dataset they subsequently analyse. In this paper, we present a teaching exercise in which an infectious disease outbreak is simulated over a five-day period and subsequently analysed. We iteratively developed the teaching exercise to offer additional insight into analysing an outbreak. An R package for visualisation, analysis and simulation of the outbreak data was developed to accompany the practical to reinforce learning outcomes. Computer simulations of the outbreak revealed deviations from observed dynamics, highlighting how simplifying assumptions conventionally made in mathematical models often differ from reality. Here we provide a pedagogical tool for others to use and adapt in their own settings. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.
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Sundram, Shamala; Meon, Sariah; Seman, Idris Abu; Othman, Radziah
2015-07-01
The effect of arbuscular mycorrhizal fungi (AMF) in combination with endophytic bacteria (EB) in reducing development of basal stem rot (BSR) disease in oil palm (Elaeis guineensis) was investigated. BSR caused by Ganoderma boninense leads to devastating economic loss and the oil palm industry is struggling to control the disease. The application of two AMF with two EB as biocontrol agents was assessed in the nursery and subsequently, repeated in the field using bait seedlings. Seedlings pre-inoculated with a combination of Glomus intraradices UT126, Glomus clarum BR152B and Pseudomonas aeruginosa UPMP3 significantly reduced disease development measured as the area under disease progression curve (AUDPC) and the epidemic rate (R L) of disease in the nursery. A 20-month field trial using similar treatments evaluated disease development in bait seedlings based on the rotting area/advancement assessed in cross-sections of the seedling base. Data show that application of Glomus intraradices UT126 singly reduced disease development of BSR, but that combination of the two AMF with P. aeruginosa UPMP3 significantly improved biocontrol efficacy in both nursery and fields reducing BSR disease to 57 and 80%, respectively. The successful use of bait seedlings in the natural environment to study BSR development represents a promising alternative to nursery trial testing in the field with shorter temporal assessment.
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Cell Death and Cell Death Responses in Liver Disease: Mechanisms and Clinical Relevance
Luedde, Tom; Kaplowitz, Neil; Schwabe, Robert F.
2015-01-01
Summary Hepatocellular death is present in almost all types of human liver disease and is used as a sensitive parameter for the detection of acute and chronic liver disease of viral, toxic, metabolic, or autoimmune origin. Clinical data and animal models suggest that hepatocyte death is the key trigger of liver disease progression, manifested by the subsequent development of inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. Modes of hepatocellular death differ substantially between liver diseases. Different modes of cell death such as apoptosis, necrosis, and necroptosis trigger specific cell death responses and promote progression of liver disease through distinct mechanisms. In this review, we first discuss molecular mechanisms by which different modes of cell death, damage-associated molecular patterns, and specific cell death responses contribute to the development of liver disease. We then review the clinical relevance of cell death, focusing on biomarkers; the contribution of cell death to drug-induced, viral, and fatty liver disease and liver cancer; and evidence for cell death pathways as therapeutic targets. PMID:25046161
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Gupta, Yashdeep; Singh, Sandeep; Ammini, Ariachery C
2012-08-01
Thyroid hyperfunction in a patient with long-standing hypothyroidism is uncommon. Here, we describe and discuss the unusual scenario of development of severe skin rash to carbimazole, with subsequent acute toxicity to lithium in clinically indicated doses, in a patient who manifested hyperthyroidism after being on treatment for hypothyroidism for 7 years.
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Periodontal disease with treatment reduces subsequent cancer risks.
Hwang, Ing-Ming; Sun, Li-Min; Lin, Cheng-Li; Lee, Chun-Feng; Kao, Chia-Hung
2014-10-01
The aim of our study was to evaluate the relationship between routine treatment of periodontal disease (PD) and the subsequent risks for cancers in Taiwan. Study participants were selected from the Taiwan National Health Insurance (NHI) system database. The PD with a routine treatment cohort contained 38 902 patients. For each treatment cohort participant, two age- and sex-matched comparison (control) cohort participants were randomly selected. Cox's proportional hazards regression analysis was used to estimate the effects of PD with treatment on the subsequent risk of cancer. The overall risk of developing cancer was significantly lower in the treatment cohort than in the patients without treatment (adjusted Hazard ratio = 0.72, 95% confidence interval = 0.68-0.76). The risks of developing most gastrointestinal tract, lung, gynecological and brain malignancies were significantly lower in the treatment cohort than in the comparison cohort. In contrast, the risks of prostate and thyroid cancers were significantly higher in the treatment cohort than in the comparison cohort. Our findings suggest that PD with treatment is associated with a significantly reduced overall risk of cancer and reduced risks of certain types of cancers. © The Author 2014. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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Kuo, Chiu-Huang; Hsieh, Tsung-Cheng; Wang, Chih-Hsien; Chou, Chu-Lin; Lai, Yu-Hsien; Chen, Yi-Ya; Lin, Yu-Li; Wu, Sheng-Teng; Fang, Te-Chao
2015-01-01
Background Hemodialysis (HD) patients with bone fractures have an increased risk for death. However, the risks for mortality and atherosclerotic complications in incident HD patients subsequently with bone fractures are unknown. Methods Data derived from the Taiwan National Health Institute Research Database between January 1997 and December 2008 was analyzed. The enrolled patients included 3,008 incident HD patients subsequently with a single long bone fracture (LB Fx) and 2,070 incident HD patients subsequently with a single non-long bone fracture (NLB Fx). These patients were matched (1:5 ratio) for age, sex, and same duration of HD with incident HD patients who had no fractures and outcomes were measured over a 3-year follow-up. Results After demographic and co-morbidity adjustment, LB Fx increased the risk for overall mortality (HR = 1.59, p < 0.001) and stroke (HR = 1.09, p = 0.028) in incident HD patients. NLB Fx increased the risk for overall mortality (HR = 1.52, p < 0.001), stroke (HR = 1.19, p < 0.001), coronary artery disease (CAD), (HR = 1.13, p = 0.003), and peripheral arterial occlusive disease (PAOD), (HR = 1.41, p < 0.001) in incident HD patients. Moreover, incident patients subsequently with NLB Fx had significantly higher risks of CAD and PAOD than those subsequently with LB Fx. Conclusions The rates of mortality and stroke were significantly higher in incident HD patients subsequently with bone fractures than in matched patients without bone fractures. Incident HD patients subsequently with NLB Fx had significantly higher risks of CAD and PAOD than those subsequently with LB Fx and without bone fractures. Thus, incident HD patients subsequently with bone fractures should be closely followed for a higher mortality and possible development of atherosclerotic complications. PMID:25874794
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Brown, Traci A.; Holian, Andrij; Pinkerton, Kent E.; Lee, Joong Won; Cho, Yoon Hee
2016-01-01
Asbestos in combination with tobacco smoke exposure reportedly leads to more severe physiological consequences than asbestos alone; limited data also show an increased disease risk due to environmental tobacco smoke (ETS) exposure. Environmental influences during gestation and early lung development can result in physiological changes that alter risk for disease development throughout an individual’s lifetime. Therefore, maternal lifestyle may impact the ability of offspring to subsequently respond to environmental insults and alter overall disease susceptibility. In this study, we examined the effects of exposure to ETS in utero and during early postnatal development on asbestos-related inflammation and disease in adulthood. ETS exposure in utero appeared to shift inflammation towards a Th2 phenotype, via suppression of Th1 inflammatory cytokine production. This effect was further pronounced in mice exposed to ETS in utero and during early postnatal development. In utero ETS exposure led to increased collagen deposition, a marker of fibrotic disease, when the offspring was later exposed to asbestos, which was further increased with additional ETS exposure during early postnatal development. These data suggest that ETS exposure in utero alters the immune responses and leads to greater disease development after asbestos exposure, which is further exacerbated when exposure to ETS continues during early postnatal development. PMID:27138493
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Spontaneous Achilles tendon rupture in alkaptonuria
Alajoulin, Omar A.; Alsbou, Mohammed S.; Ja’afreh, Somayya O.; Kalbouneh, Heba M.
2015-01-01
Alkaptonuria (AKU) is a rare inborn metabolic disease characterized by accumulation of homogentisic acid (HGA). Excretion of HGA in urine causes darkening of urine and its deposition in connective tissues causes dark pigmentation (ochronosis), early degeneration of articular cartilage, weakening of the tendons, and subsequent rupture. In this case report, we present a rare case of a patient presented with unilateral spontaneous rupture of Achilles tendon due to AKU. The patient developed most of the orthopedic manifestations of the disease earlier than typical presentations. Alkaptonuria patients should avoid strenuous exercises and foot straining especially in patients developing early orthopedic manifestations. PMID:26620992
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Spontaneous Achilles tendon rupture in alkaptonuria.
Alajoulin, Omar A; Alsbou, Mohammed S; Ja'afreh, Somayya O; Kalbouneh, Heba M
2015-12-01
Alkaptonuria (AKU) is a rare inborn metabolic disease characterized by accumulation of homogentisic acid (HGA). Excretion of HGA in urine causes darkening of urine and its deposition in connective tissues causes dark pigmentation (ochronosis), early degeneration of articular cartilage, weakening of the tendons, and subsequent rupture. In this case report, we present a rare case of a patient presented with unilateral spontaneous rupture of Achilles tendon due to AKU. The patient developed most of the orthopedic manifestations of the disease earlier than typical presentations. Alkaptonuria patients should avoid strenuous exercises and foot straining especially in patients developing early orthopedic manifestations.
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Endocrine Disruptor Vinclozolin Induced Epigenetic Transgenerational Adult-Onset Disease
Anway, Matthew D.; Leathers, Charles; Skinner, Michael K.
2018-01-01
The fetal basis of adult disease is poorly understood on a molecular level and cannot be solely attributed to genetic mutations or a single etiology. Embryonic exposure to environmental compounds has been shown to promote various disease states or lesions in the first generation (F1). The current study used the endocrine disruptor vinclozolin (antiandrogenic compound) in a transient embryonic exposure at the time of gonadal sex determination in rats. Adult animals from the F1 generation and all subsequent generations examined (F1–F4) developed a number of disease states or tissue abnormalities including prostate disease, kidney disease, immune system abnormalities, testis abnormalities, and tumor development (e.g. breast). In addition, a number of blood abnormalities developed including hypercholesterolemia. The incidence or prevalence of these transgenerational disease states was high and consistent across all generations (F1–F4) and, based on data from a previous study, appears to be due in part to epigenetic alterations in the male germ line. The observations demonstrate that an environmental compound, endocrine disruptor, can induce transgenerational disease states or abnormalities, and this suggests a potential epigenetic etiology and molecular basis of adult onset disease. PMID:16973726
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Onset of recent exertional dyspnoea in a firefighter with left bundle-branch block
De Rosa, Roberto; Ratti, Gennaro; Lamberti, Monica
2014-01-01
Background The presence of a left bundle-branch block (LBBB) among firefighters raises questions about stratifying risk of subsequent cardiovascular events as this conduction disorder may mask underlying coronary artery disease. This report describes the case of a firefighter with a history LBBB with exertional dyspnoea of recent onset after work activity. Case report A 39-year-old male firefighter with LBBB developed exertional dyspnoea after a prolonged session of work. ECG and treadmill test only showed a permanent LBBB; echocardiography and myocardial scintigraphy did not add to this. However, multislice CT (MSCT) showed a significant stenosis in the mid-left anterior descending artery (LAD). Coronary angiography confirmed the stenosis with subsequent placement of a coronary stent. Conclusions An occupational physician should take into account that factors such as age and low cardiovascular risk do not always exclude heart disease, especially when there are conduction system abnormalities that can mask possible coronary artery disease. PMID:25352387
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Onset of recent exertional dyspnoea in a firefighter with left bundle-branch block.
De Rosa, Roberto; Ratti, Gennaro; Lamberti, Monica
2014-10-28
The presence of a left bundle-branch block (LBBB) among firefighters raises questions about stratifying risk of subsequent cardiovascular events as this conduction disorder may mask underlying coronary artery disease. This report describes the case of a firefighter with a history LBBB with exertional dyspnoea of recent onset after work activity. A 39-year-old male firefighter with LBBB developed exertional dyspnoea after a prolonged session of work. ECG and treadmill test only showed a permanent LBBB; echocardiography and myocardial scintigraphy did not add to this. However, multislice CT (MSCT) showed a significant stenosis in the mid-left anterior descending artery (LAD). Coronary angiography confirmed the stenosis with subsequent placement of a coronary stent. An occupational physician should take into account that factors such as age and low cardiovascular risk do not always exclude heart disease, especially when there are conduction system abnormalities that can mask possible coronary artery disease. 2014 BMJ Publishing Group Ltd.
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Garseth, Å H; Fritsvold, C; Svendsen, J C; Bang Jensen, B; Mikalsen, A B
2018-01-01
Cardiomyopathy syndrome (CMS) is a severe cardiac disease affecting Atlantic salmon Salmo salar L. The disease was first recognized in farmed Atlantic salmon in Norway in 1985 and subsequently in farmed salmon in the Faroe Islands, Scotland and Ireland. CMS has also been described in wild Atlantic salmon in Norway. The demonstration of CMS as a transmissible disease in 2009, and the subsequent detection and initial characterization of piscine myocarditis virus (PMCV) in 2010 and 2011 were significant discoveries that gave new impetus to the CMS research. In Norway, CMS usually causes mortality in large salmon in ongrowing and broodfish farms, resulting in reduced fish welfare, significant management-related challenges and substantial economic losses. The disease thus has a significant impact on the Atlantic salmon farming industry. There is a need to gain further basic knowledge about the virus, the disease and its epidemiology, but also applied knowledge from the industry to enable the generation and implementation of effective prevention and control measures. This review summarizes the currently available, scientific information on CMS and PMCV with special focus on epidemiology and factors influencing the development of CMS. © 2017 The Authors. Journal of Fish Diseases Published by John Wiley & Sons Ltd.
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Tseng, William W; Madewell, John E; Wei, Wei; Somaiah, Neeta; Lazar, Alexander J; Ghadimi, Markus P; Hoffman, Aviad; Pisters, Peter W T; Lev, Dina C; Pollock, Raphael E
2014-07-01
Well-differentiated (WD)/dedifferentiated (DD) liposarcoma is the most common soft tissue sarcoma of the retroperitoneum. The frequency of distant metastasis is low and the major burden of disease is locoregional. We sought to define the patterns of locoregional disease to help guide surgical decision making. Data were collected from 247 patients with de novo or recurrent tumors treated at our institution from 1993 to early 2012. The number and location of tumors at both initial presentation and subsequent locoregional recurrence were determined by combined analysis of operative dictations and radiologic imaging. Thirty-four percent of patients had multifocal locoregional disease (two or more tumors) at initial presentation to our institution, including 9 % who had tumors at synchronous remote retroperitoneal sites. The impact of multifocal disease on overall survival was dependent on histologic subtype (WD vs. DD) and disease presentation (de novo vs. recurrence) at the time of resection. Among patients with initial unifocal disease, 57 % progressed to multifocal locoregional disease with subsequent recurrence, including 11 % with new tumors outside of the original resection field. No clinicopathologic or treatment-related variable, including the type or extent of resection, was predictive of either multifocal or 'outside field' progression. Multifocal disease is common in patients with WD/DD retroperitoneal liposarcoma, and tumors can also develop at remote, locoregional sites. Surgical resection remains the primary method of locoregional control in this disease; however, the aggressiveness of resection should be individualized, with consideration of both tumor and patient-related factors.
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Programming of endocrine mechanisms of cardiovascular control and growth.
Green, L R
2001-01-01
Several epidemiologic studies have linked size at birth to health in adult life. One school of thought centers on the part that periconceptual or intrauterine events play in this relationship. The idea is that an event, or several events, during critical periods of development can program, or permanently alter, fetal physiology resulting in altered size at birth and subsequent adult disease, including that of the cardiovascular system. Maternal diet or body composition at the time of conception can influence placental development and subsequent transfer of nutrients and substrates to the fetus. Alterations to the maternal diet or body composition throughout gestation are then seen as challenges that are superimposed on this backdrop of periconceptual events. One task is to find an animal model that replicates the major features of the epidemiologic data: for adult cardiovascular disease this would be altered fetal size and the development of postnatal hypertension. In addition, a critical issue is to investigate the mechanisms underlying this Fetal Origins of Adult Disease hypothesis. The multiple mechanisms that constitute fetal cardiovascular responses to hypoxia in late gestation at neuronal, endocrine, and local tissue levels have been studied extensively, and there is evidence from several different experimental paradigms that these control mechanisms can be programmed by intrauterine challenges. This review synthesizes the current knowledge in this area and considers how the programming of cardiovascular control relates to fetal growth.
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Herman, Christine; Karolak, Wojtek; Yip, Alexandra M; Buth, Karen J; Hassan, Ansar; Légaré, Jean-Francois
2009-10-01
We sought to develop a predictive model based exclusively on preoperative factors to identify patients at risk for PrlICULOS following coronary artery bypass grafting (CABG). Retrospective analysis was performed on patients undergoing isolated CABG at a single center between June 1998 and December 2002. PrlICULOS was defined as initial admission to ICU exceeding 72 h. A parsimonious risk-predictive model was constructed on the basis of preoperative factors, with subsequent internal validation. Of 3483 patients undergoing isolated CABG between June 1998 and December 2002, 411 (11.8%) experienced PrlICULOS. Overall in-hospital mortality was higher among these patients (14.4% vs. 1.2%, P
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Ancient Dietary Wisdom for Tomorrow's Children.
ERIC Educational Resources Information Center
Fallon, Sally
1997-01-01
A review of Dr. Weston Price's work on the nutritional practices of "primitive" peoples and their subsequent levels of physical development shows that animal fats and cholesterol are not villains but vital factors in the diet, necessary for normal growth, proper functioning of the brain and nervous system, protection from disease, and…
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Exercise echocardiography for structural heart disease.
Izumo, Masaki; Akashi, Yoshihiro J
2016-03-01
Since the introduction of transcatheter structural heart intervention, the term "structural heart disease" has been widely used in the field of cardiology. Structural heart disease refers to congenital heart disease, valvular heart disease, and cardiomyopathy. In structural heart disease, valvular heart disease is frequently identified in the elderly. Of note, the number of patients who suffer from aortic stenosis (AS) and mitral regurgitation (MR) is increasing in developed countries because of the aging of the populations. Transcatheter aortic valve replacement and percutaneous mitral valve repair has been widely used for AS and MR, individually. Echocardiography is the gold standard modality for initial diagnosis and subsequent evaluation of AS and MR, although the difficulties in assessing patients with these diseases still remain. Here, we review the clinical usefulness and prognostic impact of exercise echocardiography on structural heart disease, particularly on AS and MR.
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Winkler, Dirk; Beconi, Maria; Toledo-Sherman, Leticia M; Prime, Michael; Ebneth, Andreas; Dominguez, Celia; Muñoz-Sanjuan, Ignacio
2013-09-01
Kynurenine monooxygenase (KMO) catalyzes the conversion of kynurenine to 3-hydroxykynurenine. Modulation of KMO activity has been implicated in several neurodegenerative diseases, including Huntington disease. Our goal is to develop potent and selective small-molecule KMO inhibitors with suitable pharmacokinetic characteristics for in vivo proof-of-concept studies and subsequent clinical development. We developed a comprehensive panel of biochemical and cell-based assays that use liquid chromatography/tandem mass spectrometry to quantify unlabeled kynurenine and 3-hydroxykynurenine. We describe assays to measure KMO inhibition in cell and tissue extracts, as well as cellular assays including heterologous cell lines and primary rat microglia and human peripheral blood mononuclear cells.
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Cancer in heart disease patients: what are the limitations in the treatment strategy?
Mistiaen, Wilhelm P
2013-07-01
Cardiovascular disease and cancer are leading causes of morbidity and mortality, and can both be present in one patient. In patients with simultaneous disease, the most threatening disease should be treated first. This is usually heart disease, but this can pose specific problems. If percutaneous coronary intervention is preferred, bleeding and thrombotic tendencies have to be taken into account in the subsequent treatment of the malignancy. With coronary artery bypass grafting, the advantages and disadvantages of one- or two-stage procedures, and the use of extracorporeal circulation have to be balanced. Development of heart disease after treatment of malignancy could be due to radiotherapy and chemotherapy. The effects of these cancer treatments have to be taken into account for the treatment options of the heart disease and the postoperative prognosis.
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Szodoray, Peter; Nakken, Britt; Barath, Sandor; Csipo, Istvan; Nagy, Gabor; El-Hage, Fadi; Osnes, Liv T; Szegedi, Gyula; Bodolay, Edit
2013-12-01
A shift in the balance between Th17-cells and regulatory T-cells (Treg) is an important feature of systemic autoimmune diseases (SAID), and may also contribute to their development. Hereby, we assessed the distribution of peripheral Th17 and Treg-cells in patients with undifferentiated connective tissue disease (UCTD), the forerunner of SAIDs and followed these parameters during the development towards definitive SAIDs. Fifty-one UCTD patients were investigated and followed-up for 3 years. Flow cytometry was used to identify and follow three cell-populations: Th17-cells (CD4+IL-17+ T-cells), natural regulatory T-cells (CD4(+)CD25(bright)FoxP3(+); nTregs) and IL-10 producing Type-1 regulatory T-cells (CD4+IL-10+ T-cells; Tr1). Altogether 37.3% of these patients progressed into SAIDs. Th17-cells were increased in UCTD vs. controls, which further increased in those, whom developed SAIDs eventually. The Th17/nTreg ratio gradually increased from controls through UCTD patients, reaching the highest values in SAID-progressed patients. Regarding the Th17/Tr1 ratios, a similar tendency was observed moreover Th17/Tr1 could distinguish between UCTD patients with, or without subsequent SAID progression in a very early UCTD stage. Various immunoserological markers showed association with Th17 and Th17/nTreg at baseline, indicating the consecutive development of a distinct SAID. The derailed Th17/Treg balance may contribute to disease progression therefore could function as a prognostic marker. Copyright © 2013 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.
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Early pulmonary vascular disease in preterm infants at risk for bronchopulmonary dysplasia.
Mourani, Peter M; Sontag, Marci K; Younoszai, Adel; Miller, Joshua I; Kinsella, John P; Baker, Christopher D; Poindexter, Brenda B; Ingram, David A; Abman, Steven H
2015-01-01
Pulmonary hypertension (PH) is associated with poor outcomes among preterm infants with bronchopulmonary dysplasia (BPD), but whether early signs of pulmonary vascular disease are associated with the subsequent development of BPD or PH at 36 weeks post-menstrual age (PMA) is unknown. To prospectively evaluate the relationship of early echocardiogram signs of pulmonary vascular disease in preterm infants to the subsequent development of BPD and late PH (at 36 wk PMA). Prospectively enrolled preterm infants with birthweights 500-1,250 g underwent echocardiogram evaluations at 7 days of age (early) and 36 weeks PMA (late). Clinical and echocardiographic data were analyzed to identify early risk factors for BPD and late PH. A total of 277 preterm infants completed echocardiogram and BPD assessments at 36 weeks PMA. The median gestational age at birth and birthweight of the infants were 27 weeks and 909 g, respectively. Early PH was identified in 42% of infants, and 14% were diagnosed with late PH. Early PH was a risk factor for increased BPD severity (relative risk, 1.12; 95% confidence interval, 1.03-1.23) and late PH (relative risk, 2.85; 95% confidence interval, 1.28-6.33). Infants with late PH had greater duration of oxygen therapy and increased mortality in the first year of life (P < 0.05). Early pulmonary vascular disease is associated with the development of BPD and with late PH in preterm infants. Echocardiograms at 7 days of age may be a useful tool to identify infants at high risk for BPD and PH.
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Growth and development of a new subspecialty: pediatric hepatology.
Balistreri, William F
2013-08-01
Several major forces converged to catalyze the formal emergence of a body of knowledge and an organized focus on disorders of the liver in early life. Attendant to the development of a focused clinical subspecialty the pace of patient- and laboratory-based research in the field quickened in parallel to decipher the consequences of genetic or metabolic aberrations on immature liver structure and function. The key research observations that catalyzed the emergence and subsequent rapid growth of Pediatric Hepatology include: (1) an understanding of the dynamic events occurring during hepatobiliary development and the importance of these physiologic variables that occur during liver maturation; (2) the recognition of the unique nature of inherited and acquired liver diseases that affect infants and children-such as biliary atresia and Reye's syndrome; and (3) redefinition of the once obscure inherited intrahepatic cholestatic diseases of the liver, which, in turn, provided insight into normal and abnormal hepatobiliary physiology. The clinical advances were highlighted by the development of specific approaches to the diagnosis and management of liver disease in infants and children, including both liver transplantation and nontransplant treatment options. These seminal events led to the expansion of the workforce, creating a critical mass consisting of individuals with focused, specialized skills and techniques. In-depth expertise allowed more accurate diagnosis and highly effective treatment strategies for advanced hepatobiliary disease in children. The demand for pediatric clinicians with experience in advanced hepatology allowed sub-sub-specialization to flourish. Continued maturation of the field led to definition of hepatology-focused curricular elements and educational content for Pediatric Gastroenterology training programs, and subsequently the development of program requirements for those who wished to acquire additional training in Pediatric Hepatology. A significant rite of passage was marked by the election of pediatric hepatologists to leadership positions in the American Association for the Study of Liver Diseases (AASLD). Further validation of the field occurred with approval of the petition for establishing a Certificate of Added Qualification in Transplant Hepatology by the American Board of Pediatrics. Here I relate my perspective on the history of the advances in our field and the contributions of many of the clinicians and scientists whose efforts led to the development of focused clinical, research, and training programs that improved the care of children with diseases of the liver. Copyright © 2013 by the American Association for the Study of Liver Diseases.
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Genetics and Genomics of Coronary Artery Disease.
Pjanic, Milos; Miller, Clint L; Wirka, Robert; Kim, Juyong B; DiRenzo, Daniel M; Quertermous, Thomas
2016-10-01
Coronary artery disease (or coronary heart disease), is the leading cause of mortality in many of the developing as well as the developed countries of the world. Cholesterol-enriched plaques in the heart's blood vessels combined with inflammation lead to the lesion expansion, narrowing of blood vessels, reduced blood flow, and may subsequently cause lesion rupture and a heart attack. Even though several environmental risk factors have been established, such as high LDL-cholesterol, diabetes, and high blood pressure, the underlying genetic composition may substantially modify the disease risk; hence, genome composition and gene-environment interactions may be critical for disease progression. Ongoing scientific efforts have seen substantial advancements related to the fields of genetics and genomics, with the major breakthroughs yet to come. As genomics is the most rapidly advancing field in the life sciences, it is important to present a comprehensive overview of current efforts. Here, we present a summary of various genetic and genomics assays and approaches applied to coronary artery disease research.
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Biological pathways involved in the development of inflammatory bowel disease.
Zemljic, Mateja; Pejkovic, Bozena; Krajnc, Ivan; Lipovsek, Saska
2014-10-01
Apoptosis, autophagy and necrosis are three distinct functional types of the mammalian cell death network. All of them are characterized by a number of cell's morphological changes. The inappropriate induction of cell death is involved in the pathogenesis of a number of diseases.Pathogenesis of inflammatory bowel diseases (ulcerative colitis, Crohn's disease) includes an abnormal immunological response to disturbed intestinal microflora. One of the most important reason in pathogenesis of chronic inflammatory disease and subsequent multiple organ pathology is a barrier function of the gut, regulating cellular viability. Recent findings have begun to explain the mechanisms by which intestinal epithelial cells are able to survive in such an environment and how loss of normal regulatory processes may lead to inflammatory bowel disease (IBD).This review focuses on the regulation of biological pathways in development and homeostasis in IBD. Better understanding of the physiological functions of biological pathways and their influence on inflammation, immunity, and barrier function will simplify our expertice of homeostasis in the gastrointestinal tract and in upgrading diagnosis and treatment.
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Black, G C; Perveen, R; Bonshek, R; Cahill, M; Clayton-Smith, J; Lloyd, I C; McLeod, D
1999-10-01
Coats' disease is characterized by abnormal retinal vascular development (so-called 'retinal telangiectasis') which results in massive intraretinal and subretinal lipid accumulation (exudative retinal detachment). The classical form of Coats' disease is almost invariably isolated, unilateral and seen in males. A female with a unilateral variant of Coats' disease gave birth to a son affected by Norrie disease. Both carried a missense mutation within the NDP gene on chromosome Xp11.2. Subsequently analysis of the retinas of nine enucleated eyes from males with Coats' disease demonstrated in one a somatic mutation in the NDP gene which was not present within non-retinal tissue. We suggest that Coats' telangiectasis is secondary to somatic mutation in the NDP gene which results in a deficiency of norrin (the protein product of the NDP gene) within the developing retina. This supports recent observations that the protein is critical for normal retinal vasculogenesis.
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Management of pneumothorax in cattle by continuous-flow evacuation.
Peek, Simon E; Slack, J A; McGuirk, Sheila M
2003-01-01
Pneumothorax in cattle can develop subsequent to acute or chronic pulmonary disease, and if unresolved may lead to respiratory distress and death due to hypoxia and compression and collapse of cardiac and thoracic great vessels. Therapeutic evacuation of free air within the pleural space can provide acute relief and improve chances of survival. This article descibes the adaptation and use of a continuous flow evacuation device to resolve pneumothorax in 3 cattle with pneumothorax associated with infectious lower airway disease.
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Spirochetal Lipoproteins and Immune Evasion
Christodoulides, Alexei; Boyadjian, Ani; Kelesidis, Theodoros
2017-01-01
Spirochetes are a major threat to public health. However, the exact pathogenesis of spirochetal diseases remains unclear. Spirochetes express lipoproteins that often determine the cross talk between the host and spirochetes. Lipoproteins are pro-inflammatory, modulatory of immune responses, and enable the spirochetes to evade the immune system. In this article, we review the modulatory effects of spirochetal lipoproteins related to immune evasion. Understanding lipoprotein-induced immunomodulation will aid in elucidating innate pathogenesis processes and subsequent adaptive mechanisms potentially relevant to spirochetal disease vaccine development and treatment. PMID:28424696
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BATMAN-TCM: a Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine.
Liu, Zhongyang; Guo, Feifei; Wang, Yong; Li, Chun; Zhang, Xinlei; Li, Honglei; Diao, Lihong; Gu, Jiangyong; Wang, Wei; Li, Dong; He, Fuchu
2016-02-16
Traditional Chinese Medicine (TCM), with a history of thousands of years of clinical practice, is gaining more and more attention and application worldwide. And TCM-based new drug development, especially for the treatment of complex diseases is promising. However, owing to the TCM's diverse ingredients and their complex interaction with human body, it is still quite difficult to uncover its molecular mechanism, which greatly hinders the TCM modernization and internationalization. Here we developed the first online Bioinformatics Analysis Tool for Molecular mechANism of TCM (BATMAN-TCM). Its main functions include 1) TCM ingredients' target prediction; 2) functional analyses of targets including biological pathway, Gene Ontology functional term and disease enrichment analyses; 3) the visualization of ingredient-target-pathway/disease association network and KEGG biological pathway with highlighted targets; 4) comparison analysis of multiple TCMs. Finally, we applied BATMAN-TCM to Qishen Yiqi dripping Pill (QSYQ) and combined with subsequent experimental validation to reveal the functions of renin-angiotensin system responsible for QSYQ's cardioprotective effects for the first time. BATMAN-TCM will contribute to the understanding of the "multi-component, multi-target and multi-pathway" combinational therapeutic mechanism of TCM, and provide valuable clues for subsequent experimental validation, accelerating the elucidation of TCM's molecular mechanism. BATMAN-TCM is available at http://bionet.ncpsb.org/batman-tcm.
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Elhasid, R; Rowe, J M; Berkowitz, D; Ben-Arush, M; Bar-Shalom, R; Brik, R
2004-06-01
A 12-year-old girl presented with arthritis, myalgia, anemia and positive ANA. Subsequently, she developed recurrent episodes of pulmonary hemorrhage, thrombocytopenia, CNS abnormalities, skin ulcers and diffuse calcinosis. This was followed by secondary antiphospholipid syndrome. Despite vigorous immunosuppression, the patient became bedridden. A peripheral blood stem cell autograft was offered when she developed pulmonary hypertension and digital ischemia at the age of 16 years. The post-transplantation course was uneventful. Liquefaction of calcinosis nodules with improvement of mobility occurred gradually. She is now 24 months post-transplant with no sign of disease activity and total disappearance of calcinosis nodules.
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Status of adolescent pelvic inflammatory disease management in the United States.
Trent, Maria
2013-10-01
Pelvic inflammatory disease (PID) is a common and serious reproductive health disorder and disease rates remain unacceptably high among adolescent girls and young adult women in the United States. Despite data demonstrating that women experience major adverse health outcomes after PID, national recommendations for management of adolescents have become increasingly less cautious in an era of cost-containment. In this review, we take an alternative look at published data on adolescents with PID to frame the next steps for optimizing management for this vulnerable population. Several findings emerge from review of the literature. First, there is limited evidence to guide the best practice strategies for adolescents with PID due to low enrolment of early and middle adolescents in national trials. Second, adolescents and adult women in the United States receive suboptimal treatment regimens per Centers for Disease Control and Prevention (CDC) standards. Third, available evidence suggests that adolescents are at an increased risk for poor adherence to CDC recommendations for self-care, reacquisition of sexually transmitted infections (STIs) and PID, and subsequent adverse reproductive health outcomes. Efforts to develop and integrate adolescent-focused, evidence-based strategies for PID management and prevention of subsequent STIs and recurrent PID are warranted.
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Kuo, Ho-Chang; Yang, Ya-Ling; Ho, Shu-Chen; Guo, Mindy Ming-Huey; Jiang, Jyun-Hong; Huang, Ying-Hsien
2016-07-01
General anesthesia (GA) has been used for second line treatment strategy for status asthmaticus in pediatric patients. The association between GA in children and risk of followed-up allergic diseases is unclear. This study aims to assess the risk of allergic diseases after GA in children.We did a nationwide retrospective cohort study by analyzing data from the National Health Insurance Research Database (NHIRD) in Taiwan. The subsequent risks for allergic diseases, including asthma (ICD-9: 493.X), allergic rhinitis (AR; ICD-9 CM code 477.X), and atopic dermatitis (AD; ICD-9-CM code 691.X), were compared between exposure to GA and none before 1 year of age throughout the follow-up period using the Cox proportional hazards model.Insurance claims data for 32,742 children younger than 1 year old from all insured children in the NHIRD. Of those, 2358 subjects were exposed to GA; 414 and 1944 children exposed to mask and intubation ventilation, respectively, served as the study cohort, whereas the remaining 30,384 children made up the comparison cohort. Children in the GA group were at a lower risk of developing asthma, AR and AD, with adjusted hazard ratios of 0.67 (0.62-0.72, 95%CI), 0.72 (0.68-0.77, 95%CI), 0.60 (0.56-0.64, 95%CI), respectively.Children who were exposed to GA in early life before 1 year of age had reduced risk of subsequently developing allergic diseases such as asthma, AD, and AR, when compared with general population.
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Endotoxin, Toll-like Receptor-4, and Atherosclerotic Heart Disease
Horseman, Michael A.; Surani, Salim; Bowman, John D.
2017-01-01
Background: Endotoxin is a lipopolysaccharide (LPS) constituent of the outer membrane of most gram negative bacteria. Ubiquitous in the environment, it has been implicated as a cause or con-tributing factor in several disparate disorders from sepsis to heatstroke and Type II diabetes mellitus. Starting at birth, the innate immune system develops cellular defense mechanisms against environmen-tal microbes that are in part modulated through a series of receptors known as toll-like receptors. Endo-toxin, often referred to as LPS, binds to toll-like receptor 4 (TLR4)/ myeloid differentiation protein 2 (MD2) complexes on various tissues including cells of the innate immune system, smooth muscle and endothelial cells of blood vessels including coronary arteries, and adipose tissue. Entry of LPS into the systemic circulation ultimately leads to intracellular transcription of several inflammatory mediators. The subsequent inflammation has been implicated in the development and progression atherosclerosis and subsequent coronary artery disease and heart failure. Objective: The potential roles of endotoxin and TLR4 are reviewed regarding their role in the pathogen-esis of atherosclerotic heart disease. Conclusion: Atherosclerosis is initiated by inflammation in arterial endothelial and subendothelial cells, and inflammatory processes are implicated in its progression to clinical heart disease. Endotoxin and TLR4 play a central role in the inflammatory process, and represent potential targets for therapeutic intervention. Therapy with HMG-CoA inhibitors may reduce the expression of TLR4 on monocytes. Other therapeutic interventions targeting TLR4 expression or function may prove beneficial in athero-sclerotic disease prevention and treatment.
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Borrelia infection and risk of celiac disease.
Alaedini, Armin; Lebwohl, Benjamin; Wormser, Gary P; Green, Peter H; Ludvigsson, Jonas F
2017-09-15
Environmental factors, including infectious agents, are speculated to play a role in the rising prevalence and the geographic distribution of celiac disease, an autoimmune disorder. In the USA and Sweden where the regional variation in the frequency of celiac disease has been studied, a similarity with the geographic distribution of Lyme disease, an emerging multisystemic infection caused by Borrelia burgdorferi spirochetes, has been found, thus raising the possibility of a link. We aimed to determine if infection with Borrelia contributes to an increased risk of celiac disease. Biopsy reports from all of Sweden's pathology departments were used to identify 15,769 individuals with celiac disease. Through linkage to the nationwide Patient Register, we compared the rate of earlier occurrence of Lyme disease in the patients with celiac disease to that in 78,331 matched controls. To further assess the temporal relationship between Borrelia infection and celiac disease, we also examined the risk of subsequent Lyme disease in patients with a diagnosis of celiac disease. Twenty-five individuals (0.16%) with celiac disease had a prior diagnosis of Lyme disease, whereas 79 (0.5%) had a subsequent diagnosis of Lyme disease. A modest association between Lyme disease and celiac disease was seen both before (odds ratio, 1.61; 95% confidence interval (CI), 1.06-2.47) and after the diagnosis of celiac disease (hazard ratio, 1.82; 95% CI, 1.40-2.35), with the risk of disease being highest in the first year of follow-up. Only a minor fraction of the celiac disease patient population had a prior diagnosis of Lyme disease. The similar association between Lyme disease and celiac disease both before and after the diagnosis of celiac disease is strongly suggestive of surveillance bias as a likely contributor. Taken together, the data indicate that Borrelia infection is not a substantive risk factor in the development of celiac disease.
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Novis, B. H.; Marks, I. N.; Bank, S.; Sloan, A. W.
1973-01-01
One hundred and seventy-six students free of gastrointestinal disease were studied to establish normal acid secretion values for healthy male and female students by the augmented histamine test and to re-examine the relationship between gastric acid secretion and ABO blood groups, body weight, fat-free body mass, height, degree of ectomorphy and mesomorphy, the number of cigarettes smoked per day, and serum cholesterol. A prospective study was then carried out on gastric acid secretion and the subsequent development after 10 years of duodenal ulcers or dyspepsia. Young, healthy medical students have a fairly high mean basal and maximal acid output. There was very little difference in the mean acid outputs of the various ABO blood groups. A significant correlation was shown between acid output and body weight and fat-free body mass, but not with the other measurements of body build. Basal acid output was also related to the number of cigarettes smoked per day. Three students who subsequently developed duodenal ulcers all had a preexistent high level of acid secretion. The acid output was, however, similar in the groups who developed significant or minor dyspepsia or who remained asymptomatic. PMID:4696532
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D'Mello, Charlotte; Ronaghan, Natalie; Zaheer, Raza; Dicay, Michael; Le, Tai; MacNaughton, Wallace K; Surrette, Michael G; Swain, Mark G
2015-07-29
Patients with systemic inflammatory diseases (e.g., rheumatoid arthritis, inflammatory bowel disease, chronic liver disease) commonly develop debilitating symptoms (i.e., sickness behaviors) that arise from changes in brain function. The microbiota-gut-brain axis alters brain function and probiotic ingestion can influence behavior. However, how probiotics do this remains unclear. We have previously described a novel periphery-to-brain communication pathway in the setting of peripheral organ inflammation whereby monocytes are recruited to the brain in response to systemic TNF-α signaling, leading to microglial activation and subsequently driving sickness behavior development. Therefore, we investigated whether probiotic ingestion (i.e., probiotic mixture VSL#3) alters this periphery-to-brain communication pathway, thereby reducing subsequent sickness behavior development. Using a well characterized mouse model of liver inflammation, we now show that probiotic (VSL#3) treatment attenuates sickness behavior development in mice with liver inflammation without affecting disease severity, gut microbiota composition, or gut permeability. Attenuation of sickness behavior development was associated with reductions in microglial activation and cerebral monocyte infiltration. These events were paralleled by changes in markers of systemic immune activation, including decreased circulating TNF-α levels. Our observations highlight a novel pathway through which probiotics mediate cerebral changes and alter behavior. These findings allow for the potential development of novel therapeutic interventions targeted at the gut microbiome to treat inflammation-associated sickness behaviors in patients with systemic inflammatory diseases. This research shows that probiotics, when eaten, can improve the abnormal behaviors (including social withdrawal and immobility) that are commonly associated with inflammation. Probiotics are able to cause this effect within the body by changing how the immune system signals the brain to alter brain function. These findings broaden our understanding of how probiotics may beneficially affect brain function in the context of inflammation occurring within the body and may open potential new therapeutic alternatives for the treatment of these alterations in behavior that can greatly affect patient quality of life. Copyright © 2015 the authors 0270-6474/15/3510822-10$15.00/0.
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Zinckernagel, Line; Schneekloth, Nanna; Zwisler, Ann-Dorthe Olsen; Ersbøll, Annette Kjær; Rod, Morten Hulvej; Jensen, Poul Dengsøe; Timm, Helle; Holmberg, Teresa
2017-10-30
Measuring the quality of care as experienced by patients is increasingly recognised as a way of improving healthcare services. However, disease-specific measures that take the patient journey into account are needed. This paper presents the development of such a measure for patients with heart disease and details the psychometric evaluation. The questionnaire was developed based on a literature review, qualitative interviews and a pilot-test. The psychometric evaluation of the measure was assessed using exploratory factor analysis (EFA) and confirmatory factor analysis (CFA), Cronbach's alpha coefficient and differential item functioning analysis with data from a population-based survey. Denmark in 2013-2014. Nineteen heart patients, four relatives and eight health professionals participated in qualitative interviews in the development phase, and 15 patients participated in the pilot-test. The questionnaire was subsequently sent to a random sample of 5000 heart patients who were diagnosed in 2013. The comprehensive development phase and pilot-testing contributed to high content validity of the questionnaire. Eligible questionnaire responses were received from 2496 patients. EFA indicated a nine-factor model: communication at the hospital, communication with the general practitioner, information on disease and treatment, information on psychosocial aspects, rehabilitation/support, organisation, medication, involvement of relatives and consideration of comorbidity. CFA confirmed the proposed factor structure (eg, goodness-of-fit index=0.88, adjusted goodness-of-fit index=0.86, root mean square error of approximation=0.05), and Cronbach's alpha coefficient revealed good internal consistency of the factors (range: 0.69-0.93). The results suggest that this disease-specific patient-reported experience measure is of good quality when measuring the quality of care among heart patients. The inclusion of patients in the development phase contributed to high content validity, and subsequent psychometric evaluation found high construct validity and internal consistency. This measure may be especially relevant when seeking information about which aspects of care require improvement and the impact on health outcomes. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
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Bawankar, Pritam; Das, Dipankar; Tayab, Shahinur; Kuri, Ganesh Chandra; Medhi, Jnanankar; Barman, Manabjyoti; Soibam, Ronel; Bhattacharjee, Harsha; Deka, Panna; Misra, Diva Kant; Dhar, Shriya
2017-01-01
We describe a case of a 13-year-old male patient of Coats' disease who developed sympathetic ophthalmia (SO) following contact diode laser cyclophotocoagulation. There was no history of invasive surgery or any perforating injuries preceding cyclodestructive therapy. The eye had neovascular glaucoma secondary to Coats' disease, which was treated once with contact cyclophotocoagulation. Subsequently, the intraocular pressure slowly decreased, and the eye became phthisical. Intraocular inflammation developed in the fellow eye and SO was suspected, which was confirmed by characteristic findings seen on fluorescein angiography. The case was successfully managed with the help of topical and systemic immunosuppression. Enucleation with silicone ball implantation was performed in the right phthisical eye and specimen was sent for histopathological examination. Histopathology and immunostaining supported the diagnosis of SO. PMID:28820164
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Linking acute kidney injury to chronic kidney disease: the missing links.
Kaballo, Mohammed A; Elsayed, Mohamed E; Stack, Austin G
2017-08-01
Acute kidney injury (AKI) is considered to be a major public health problem around the globe, and it is associated with major adverse clinical outcomes and significant health care costs. There is growing evidence suggesting that AKI is associated with the subsequent development of chronic kidney disease (CKD). While recovery of kidney function occurs in the majority of patients surviving an AKI episode, a large number of patients do not recover completely. Similarly, CKD is a well-known risk factor for the development of AKI. Recent studies suggest that both AKI and CKD are not separate disease entities but are in fact components of a far more closely interconnected disease continuum. However, the true nature of this relationship is complex and poorly understood. This review explores potential relationships between AKI and CKD, and seeks to uncover a number of "missing links" in this tentative emerging relationship.
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Curing genetic disease with gene therapy.
Williams, David A
2014-01-01
Development of viral vectors that allow high efficiency gene transfer into mammalian cells in the early 1980s foresaw the treatment of severe monogenic diseases in humans. The application of gene transfer using viral vectors has been successful in diseases of the blood and immune systems, albeit with several curative studies also showing serious adverse events (SAEs). In children with X-linked severe combined immunodeficiency (SCID-X1), chronic granulomatous disease, and Wiskott-Aldrich syndrome, these SAEs were caused by inappropriate activation of oncogenes. Subsequent studies have defined the vector sequences responsible for these transforming events. Members of the Transatlantic Gene Therapy Consortium [TAGTC] have collaboratively developed new vectors that have proven safer in preclinical studies and used these vectors in new clinical trials in SCID-X1. These trials have shown evidence of early efficacy and preliminary integration analysis data from the SCID-X1 trial suggest an improved safety profile.
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Ethical aspects on rare diseases.
Barrera, Luis A; Galindo, Gilberto Cely
2010-01-01
In this chapter we discuss several of the most relevant subjects related to ethics on Rare Diseases. Some general aspects are discussed such as the socio-psychological problems that confront the patients and their families that finally lead to marginalization and exclusion of patients affected by these diseases from the health programs, even in wealthy countries. Then we address problems related to diagnosis and some ethical aspects of newborn screening, prenatal, pre-implantation diagnosis and reference centers, as well as some conditions that should be met by the persons and institutions performing such tasks. Alternatives of solutions for the most critical situations are proposed. Subsequently the orphan drugs subject is discussed not only from the availability point of view, prizes, industrial practices, and purchasing power in developed and developing societies. The research related to rare disease in children and other especially vulnerable conditions, the need for informed consent, review boards or ethics comities, confidentiality of the information, biobanks and pharmacogenetics are discussed.
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Curing Genetic Disease with Gene Therapy
Williams, David A.
2014-01-01
Development of viral vectors that allow high efficiency gene transfer into mammalian cells in the early 1980s foresaw the treatment of severe monogenic diseases in humans. The application of gene transfer using viral vectors has been successful in diseases of the blood and immune systems, albeit with several curative studies also showing serious adverse events (SAEs). In children with X-linked severe combined immunodeficiency (SCID-X1), chronic granulomatous disease, and Wiskott-Aldrich syndrome, these SAEs were caused by inappropriate activation of oncogenes. Subsequent studies have defined the vector sequences responsible for these transforming events. Members of the Transatlantic Gene Therapy Consortium [TAGTC] have collaboratively developed new vectors that have proven safer in preclinical studies and used these vectors in new clinical trials in SCID-X1. These trials have shown evidence of early efficacy and preliminary integration analysis data from the SCID-X1 trial suggest an improved safety profile. PMID:25125725
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Transmission of human infection with Nipah Virus
Luby, Stephen P.; Gurley, Emily S.; Hossain, M. Jahangir
2009-01-01
Nipah virus (NiV) is a paramyxovirus whose reservoir host is fruit bats of the genus Pteropus. Occasionally the virus is introduced into human populations and causes severe illness characterized by encephalitis or respiratory disease. The first outbreak of NiV was recognized in Malaysia, but since 2001 eight outbreaks have been reported from Bangladesh. The primary pathways of transmission from bats to people in Bangladesh are through contamination of raw date palm sap by bats with subsequent consumption by humans and through infection of domestic animals (cattle, pigs, and goats), presumably from consumption of food contaminated with bat saliva or urine with subsequent transmission to people. Approximately half of recognized Nipah cases in Bangladesh developed their disease following person to person transmission of the virus. Efforts to prevent transmission should focus on decreasing bat access to date palm sap and reducing family members' and friends' exposure to infected patients' saliva. PMID:19886791
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Airborne spread of foot-and-mouth disease - model intercomparison
DOE Office of Scientific and Technical Information (OSTI.GOV)
Gloster, J; Jones, A; Redington, A
2008-09-04
Foot-and-mouth disease is a highly infectious vesicular disease of cloven-hoofed animals caused by foot-and-mouth disease virus. It spreads by direct contact between animals, by animal products (milk, meat and semen), by mechanical transfer on people or fomites and by the airborne route - with the relative importance of each mechanism depending on the particular outbreak characteristics. Over the years a number of workers have developed or adapted atmospheric dispersion models to assess the risk of foot-and-mouth disease virus spread through the air. Six of these models were compared at a workshop hosted by the Institute for Animal Health/Met Office duringmore » 2008. A number of key issues emerged from the workshop and subsequent modelling work: (1) in general all of the models predicted similar directions for 'at risk' livestock with much of the remaining differences strongly related to differences in the meteorological data used; (2) determination of an accurate sequence of events is highly important, especially if the meteorological conditions vary substantially during the virus emission period; and (3) differences in assumptions made about virus release, environmental fate, and subsequent infection can substantially modify the size and location of the downwind risk area. Close relationships have now been established between participants, which in the event of an outbreak of disease could be readily activated to supply advice or modelling support.« less
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Hatakeyama, Hiroto
2017-01-01
Significant progress has been achieved in the development of stimuli-responsive nanocarriers for drug delivery, diagnosis, and therapy. Various types of triggers are utilized in the development of nanocarrier delivery. Endogenous factors such as changes in pH, redox, gradient, and enzyme concentration which are linked to disease progression have been utilized for controlling biodistribution and releasing drugs from nanocarriers, as well as increasing subsequent pharmacological activity at the disease site. Nanocarriers which respond to artificially-induced exogenous factors (such as temperature, light, magnetic field, and ultrasound) have also been developed. This review aims to discuss recent advances in the design of stimuli-responsive nanocarriers which appear to have a promising future in medicine.
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2013-01-01
Background Previous studies have suggested that there may be an association between vitamin D deficiency and the risk of developing immune-mediated diseases. Methods We analyzed a database of linked statistical records of hospital admissions and death registrations for the whole of England (from 1999 to 2011). Rate ratios for immune-mediated disease were determined, comparing vitamin D deficient cohorts (individuals admitted for vitamin D deficiency or markers of vitamin D deficiency) with comparison cohorts. Results After hospital admission for either vitamin D deficiency, osteomalacia or rickets, there were significantly elevated rates of Addison’s disease, ankylosing spondylitis, autoimmune hemolytic anemia, chronic active hepatitis, celiac disease, Crohn’s disease, diabetes mellitus, pemphigoid, pernicious anemia, primary biliary cirrhosis, rheumatoid arthritis, Sjogren’s syndrome, systemic lupus erythematosus, thyrotoxicosis, and significantly reduced risks for asthma and myxoedema. Conclusions This study shows that patients with vitamin D deficiency may have an increased risk of developing some immune-mediated diseases, although we cannot rule out reverse causality or confounding. Further study of these associations is warranted and these data may aid further public health studies. PMID:23885887
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Protective and immunological behavior of chimeric yellow fever dengue vaccine.
Halstead, Scott B; Russell, Philip K
2016-03-29
Clinical observations from the third year of the Sanofi Pasteur chimeric yellow fever dengue tetravalent vaccine (CYD) trials document both protection and vaccination-enhanced dengue disease among vaccine recipients. Children who were 5 years-old or younger when vaccinated experienced a DENV disease resulting in hospitalization at 5 times the rate of controls. On closer inspection, hospitalized cases among vaccinated seropositives, those at highest risk to hospitalized disease accompanying a dengue virus (DENV) infection, were greatly reduced by vaccination. But, seronegative individuals of all ages after being vaccinated were only modestly protected from mild to moderate disease throughout the entire observation period despite developing neutralizing antibodies at high rates. Applying a simple epidemiological model to the data, vaccinated seronegative individuals of all ages were at increased risk of developing hospitalized disease during a subsequent wild type DENV infection. The etiology of disease in placebo and vaccinated children resulting in hospitalization during a DENV infection, while clinically similar are of different origin. The implications of the observed mixture of DENV protection and enhanced disease in CYD vaccinees are discussed. Copyright © 2016 Elsevier Ltd. All rights reserved.
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Heijnen, Willemijn T C J; Pluijms, Esther M; Birkenhager, Tom K
2013-06-01
This report describes a 55-year-old woman who had 1 previous episode of major depression that responded favorably to treatment with tricyclic antidepressants. After the development of Addison disease, she experienced a new episode of major depression that failed to respond to adequate treatment with imipramine and was subsequently successfully treated with electroconvulsive therapy (ECT) with steroid cover. The patient did not experience adrenal crisis or adverse effects. After 9 ECT sessions, she attained full remission. These findings support the suggestion that ECT treatment is safe in patients with Addison disease when using 100 mg intravenous hydrocortisone as prophylaxis.
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Foundas, Maria; Donaldson, Mark D; McAllister, Ian L; Bridges, Leslie R
2008-03-01
Creutzfeldt-Jakob disease (CJD) is a degenerative disease of the brain associated with a rapidly progressive spongiform encephalopathy. Visual symptoms and neuro-ophthalmological signs are not infrequent, and presentation to an ophthalmologist may result. A case is reported of an 89-years-old gentleman who presented with a short history of isolated deterioration in vision. He underwent ocular intervention but subsequently developed progressive dementia, asterixis, myoclonus, cerebellar and extrapyramidal signs, and cortical blindness. An electroencephalogram was consistent with CJD. The patient progressively deteriorated and died 9 weeks after symptom onset. Limited post-mortem examination confirmed CJD.
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Sleeman, Jonathan M; Manning, Elizabeth J B; Rohm, John H; Sims, Jerry P; Sanchez, Susan; Gerhold, Richard W; Keel, M Kevin
2009-01-01
Johne's disease (paratuberculosis) was diagnosed in a 2-yr-old, male, free-ranging white-tailed deer (Odocoileus virginianus) from Fauquier County, Virginia, USA, based on histopathology and culture for Mycobacterium avium subspecies paratuberculosis. Clinical and pathologic findings included emaciation; loss of body fat; chronic diarrhea; severe, chronic, diffuse granulomatous colitis with intrahistiocytic acid-fast bacilli; moderate, chronic granulomatous lymphadenitis with intrahistiocytic acid-fast bacilli; as well as moderate chronic, multifocal, lymphoplasmacytic hepatitis. These findings are consistent with previous reports of Johne's disease in cervids. Subsequent targeted surveillance of 10 emaciated deer with diarrhea, as well as sampling of 72 asymptomatic deer for M. avium subsp. paratuberculosis using culture of multiple tissue types, as well as serology using an enzyme-linked immunosorbent assay (ELISA) optimized for cervid antibody detection, did not reveal any additional cases of infection in this geographic region. To date, this appears to be an isolated case of Johne's disease in a free-ranging white-tailed deer, and infection with the causative agent for Johne's disease appears to be an infrequent occurrence in deer from this region. The origin of infection was most likely domestic ruminants. This is the first report of clinical Johne's disease in a free-ranging white-tailed deer outside of the Florida Keys, USA. Stressors, such as high deer population density and low selenium levels, may have contributed to the development of clinical disease in this case and warrant further investigation.
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The development and implementation of the Chronic Care Management Programme in Counties Manukau.
Wellingham, John; Tracey, Jocelyn; Rea, Harold; Gribben, Barry
2003-02-21
To develop an effective and efficient process for the seamless delivery of care for targeted patients with specific chronic diseases. To reduce inexplicable variation and maximise use of available resources by implementing evidence-based care processes. To develop a programme that is acceptable and applicable to the Counties Manukau region. A model for the management of people with chronic diseases was developed. Model components and potential interventions were piloted. For each disease project, a return on investment was calculated and external evaluation was undertaken. The initial model was subsequently modified and individual disease projects aligned to it. The final Chronic Care Management model, agreed in September 2001, described a single common process. Key components were the targeting of high risk patients, organisation of cost effective interventions into a system of care, and an integrated care server acting as a data warehouse with a rules engine, providing flags and reminders. Return on investment analysis suggested potential savings for each disease component from $277 to $980 per person per annum. For selected chronic diseases, introduction of an integrated chronic care management programme, based on internationally accepted best practice processes and interventions can make significant savings, reducing morbidity and improving the efficiency of health delivery in the Counties Manukau region.
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Toptas, Tayfun; Karalok, Alper; Ureyen, Isin; Tasci, Tolga; Erol, Onur; Bozkurt, Selen; Tulunay, Gokhan; Simsek, Tayup; Turan, Taner
2016-10-01
Predictive factors for survival following liver metastasis in endometrial cancer (EC) have not been studied to date. It is expected that patients who initially presented with liver metastasis or developed liver metastasis as the subsequent metastatic site of progressive disease are likely to have poor outcomes. However, patients developing liver metastasis as the first site of recurrence may have a chance of benefiting from the salvage therapies. Therefore, we aimed to determine factors influencing postrecurrence survival in EC patients who developed liver metastasis as the first site of recurrence. Patients with EC who underwent primary surgery at three centers between 1993 and 2013 were reviewed. Liver recurrence was defined as documentation of parenchymal liver metastasis either by radiologically or biopsy, after a disease-free interval of ≥3 months. Patients with liver metastasis at presentation, or liver metastasis as the subsequent metastatic site of progressive disease were excluded. Forty-six patients were identified. Median time to liver recurrence was 12 months, with 91.3 % of recurrences detected within 3 years. Most patients (73.9 %) had liver recurrence concomitant with extra-hepatic disease. Median survival after the diagnosis of liver recurrence was 9 months. While in univariate analysis, time to liver recurrence (p < 0.001) and presence of concomitant extra-hepatic metastasis (p = 0.048) were potential predictors of survival, multivariate analysis revealed that time to liver recurrence (p < 0.001) was the only independent predictor. This criterion may be used as a marker for stratifying patients into different prognostic risk groups and for selection of patients for salvage therapies.
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Lee, Shyh-Chyang; Hu, Li-Yu; Huang, Min-Wei; Shen, Cheng-Che; Huang, Wei-Lun; Lu, Ti; Hsu, Chiao-Lin; Pan, Chih-Chuan
2017-01-01
OBJECTIVE: Previous studies have reported that depression may play a crucial role in the occurrence of vertebral fractures. However, a clear correlation between depressive disorders and osteoporotic fractures has not been established. We explored the association between depressive disorders and subsequent new-onset vertebral fractures. Additionally, we aimed to identify the potential risk factors for vertebral fracture in patients with a depressive disorder. METHODS: We studied patients listed in the Taiwan National Health Insurance Research Database who were diagnosed with a depressive disorder by a psychiatrist. The comparison cohort consisted of age- and sex-matched patients without a depressive disorder. The incidence rate and hazard ratios of subsequent vertebral fracture were evaluated. We used Cox regression analysis to evaluate the risk of vertebral fracture among patients with a depressive disorder. RESULTS: The total number of patients with and without a depressive disorder was 44,812. The incidence risk ratio (IRR) between these 2 cohorts indicated that depressive disorder patients had a higher risk of developing a subsequent vertebral fracture (IRR=1.41, 95% confidence interval [CI]=1.26–1.57, p<0.001). In the multivariate analysis, the depressive disorder cohort showed a higher risk of vertebral fracture than the comparison cohort (adjusted hazard ratio=1.24, 95% CI=1.11–1.38, p<0.001). Being older than 50 years, having a lower monthly income, and having hypertension, diabetes mellitus, cerebrovascular disease, chronic obstructive pulmonary disease, autoimmune disease, or osteoporosis were considered predictive factors for vertebral fracture in patients with depressive disorders. CONCLUSIONS: Depressive disorders may increase the risk of a subsequent new-onset vertebral fracture. PMID:28226032
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Lee, Shyh-Chyang; Hu, Li-Yu; Huang, Min-Wei; Shen, Cheng-Che; Huang, Wei-Lun; Lu, Ti; Hsu, Chiao-Lin; Pan, Chih-Chuan
2017-01-01
Previous studies have reported that depression may play a crucial role in the occurrence of vertebral fractures. However, a clear correlation between depressive disorders and osteoporotic fractures has not been established. We explored the association between depressive disorders and subsequent new-onset vertebral fractures. Additionally, we aimed to identify the potential risk factors for vertebral fracture in patients with a depressive disorder. We studied patients listed in the Taiwan National Health Insurance Research Database who were diagnosed with a depressive disorder by a psychiatrist. The comparison cohort consisted of age- and sex-matched patients without a depressive disorder. The incidence rate and hazard ratios of subsequent vertebral fracture were evaluated. We used Cox regression analysis to evaluate the risk of vertebral fracture among patients with a depressive disorder. The total number of patients with and without a depressive disorder was 44,812. The incidence risk ratio (IRR) between these 2 cohorts indicated that depressive disorder patients had a higher risk of developing a subsequent vertebral fracture (IRR=1.41, 95% confidence interval [CI]=1.26-1.57, p<0.001). In the multivariate analysis, the depressive disorder cohort showed a higher risk of vertebral fracture than the comparison cohort (adjusted hazard ratio=1.24, 95% CI=1.11-1.38, p<0.001). Being older than 50 years, having a lower monthly income, and having hypertension, diabetes mellitus, cerebrovascular disease, chronic obstructive pulmonary disease, autoimmune disease, or osteoporosis were considered predictive factors for vertebral fracture in patients with depressive disorders. Depressive disorders may increase the risk of a subsequent new-onset vertebral fracture.
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Therapeutic RNA interference for neurodegenerative diseases: From promise to progress.
Gonzalez-Alegre, Pedro
2007-04-01
RNA interference (RNAi) has emerged as a powerful tool to manipulate gene expression in the laboratory. Due to its remarkable discriminating properties, individual genes, or even alleles can be targeted with exquisite specificity in cultured cells or living animals. Among its many potential biomedical applications, silencing of disease-linked genes stands out as a promising therapeutic strategy for many incurable disorders. Neurodegenerative diseases represent one of the more attractive targets for the development of therapeutic RNAi. In this group of diseases, the progressive loss of neurons leads to the gradual appearance of disabling neurological symptoms and premature death. Currently available therapies aim to improve the symptoms but not to halt the process of neurodegeneration. The increasing prevalence and economic burden of some of these diseases, such as Alzheimer's disease (AD) or Parkinson's disease (PD), has boosted the efforts invested in the development of interventions, such as RNAi, aimed at altering their natural course. This review will summarize where we stand in the therapeutic application of RNAi for neurodegenerative diseases. The basic principles of RNAi will be reviewed, focusing on features important for its therapeutic manipulation. Subsequently, a stepwise strategy for the development of therapeutic RNAi will be presented. Finally, the different preclinical trials of therapeutic RNAi completed in disease models will be summarized, stressing the experimental questions that need to be addressed before planning application in human disease.
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Knowledge and Risk Perceptions of Occupational Infections Among Health-care Workers in Malaysia.
Subramanian, Ganesh Chidambar; Arip, Masita; Saraswathy Subramaniam, T S
2017-09-01
Health-care workers are at risk of exposure to occupational infections with subsequent risk of contracting diseases, disability, and even death. A systematic collection of occupational disease data is useful for monitoring current trends in work situations and disease exposures; however, these data are usually limited due to under-reporting. The objective of this study was to review literature related to knowledge, risk perceptions, and practices regarding occupational exposures to infectious diseases in Malaysian health-care settings, in particular regarding blood-borne infections, universal precautions, use of personal protective equipment, and clinical waste management. The data are useful for determining improvements in knowledge and risk perceptions among health-care workers with developments of health policies and essential interventions for prevention and control of occupational diseases.
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Prognosis Research Strategy (PROGRESS) 2: prognostic factor research.
Riley, Richard D; Hayden, Jill A; Steyerberg, Ewout W; Moons, Karel G M; Abrams, Keith; Kyzas, Panayiotis A; Malats, Núria; Briggs, Andrew; Schroter, Sara; Altman, Douglas G; Hemingway, Harry
2013-01-01
Prognostic factor research aims to identify factors associated with subsequent clinical outcome in people with a particular disease or health condition. In this article, the second in the PROGRESS series, the authors discuss the role of prognostic factors in current clinical practice, randomised trials, and developing new interventions, and explain why and how prognostic factor research should be improved.
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Leger, Kasey J; Baker, K Scott; Cushing-Haugen, Kara L; Flowers, Mary E D; Leisenring, Wendy M; Martin, Paul J; Mendoza, Jason A; Reding, Kerryn W; Syrjala, Karen L; Lee, Stephanie J; Chow, Eric J
2018-04-01
The objective of this study was to evaluate whether modifiable cardiovascular risk conditions and lifestyle factors were temporally associated with an increased risk for ischemic heart disease and overall mortality in a cohort of hematopoietic cell transplantation (HCT) survivors. HCT recipients who had survived for ≥1 year, were ≥20 years old, and had undergone transplantation between 1970 and 2010 at a transplant referral center were surveyed in 2010-2011 about cardiovascular health and lifestyle factors (n = 3833). Respondents (n = 2360 [61.6%]) were followed to 2016 for incident ischemic heart disease and overall mortality. Among the 2360 transplant survivors (median age at the baseline survey, 55.9 years; median time since transplantation, 10.8 years), 162 (6.9%) reported ischemic heart disease at the baseline survey. Among those without ischemic heart disease at the baseline survey (n = 2198), the 5-year cumulative incidence of subsequent ischemic heart disease was 4.3%. Obesity, dyslipidemia, diabetes, and physical inactivity at baseline were associated with an increased risk for subsequent ischemic heart disease (hazard ratio [HRs] ≥ 1.8). Greater physical activity and fruit/vegetable intake at baseline were associated with subsequent lower overall mortality (HRs ≤ 0.7). When jointly considered, each additional cardiovascular risk condition and each adverse lifestyle factor were independently associated with subsequent ischemic heart disease (HR for risk conditions, 1.4; 95% confidence interval [CI], 1.0-1.9; HR for lifestyle factors, 1.9; 95% CI, 1.2-2.9), and adverse lifestyle factors remained associated with overall mortality (HR, 1.8; 95% CI, 1.5-2.3). These results support strong efforts to promote healthy lifestyle behaviors and to treat cardiovascular risk factors aggressively in HCT survivors. This may reduce future ischemic heart disease and overall mortality in this high-risk population. Cancer 2018;124:1507-15. © 2018 American Cancer Society. © 2018 American Cancer Society.
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Lucke-Wold, Brandon Peter; Turner, Ryan Coddington; Logsdon, Aric Flint; Bailes, Julian Edwin; Huber, Jason Delwyn; Rosen, Charles Lee
2014-07-01
Significant attention has recently been drawn to the potential link between head trauma and the development of neurodegenerative disease, namely chronic traumatic encephalopathy (CTE). The acute neurotrauma associated with sports-related concussions in athletes and blast-induced traumatic brain injury in soldiers elevates the risk for future development of chronic neurodegenerative diseases such as CTE. CTE is a progressive disease distinguished by characteristic tau neurofibrillary tangles (NFTs) and, occasionally, transactive response DNA binding protein 43 (TDP43) oligomers, both of which have a predilection for perivascular and subcortical areas near reactive astrocytes and microglia. The disease is currently only diagnosed postmortem by neuropathological identification of NFTs. A recent workshop sponsored by National Institute of Neurological Disorders and Stroke emphasized the need for premortem diagnosis, to better understand disease pathophysiology and to develop targeted treatments. In order to accomplish this objective, it is necessary to discover the mechanistic link between acute neurotrauma and the development of chronic neurodegenerative and neuropsychiatric disorders such as CTE. In this review, we briefly summarize what is currently known about CTE development and pathophysiology, and subsequently discuss injury-induced pathways that warrant further investigation. Understanding the mechanistic link between acute brain injury and chronic neurodegeneration will facilitate the development of appropriate diagnostic and therapeutic options for CTE and other related disorders.
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Severely Crusted Cheilitis as an Initial Presentation of Systemic Lupus Erythematosus.
Chan, Wai Man Mandy; Pang, Shiu Ming; Ng, See Ket
2017-01-01
Lupus erythematosus (LE) is an autoimmune disease which may initially present solely with lip lesions. Due to a wide spectrum of presentation, these features may initially be misdiagnosed as other oral diseases such as lichen planus, erythema multiforme (EM), and actinic cheilitis, leading to a delay in diagnosis and treatment. We discuss a case of severely crusted cheilitis which was initially diagnosed as EM, with subsequent development of subacute cutaneous LE, and progression to systemic LE. We will discuss the clinical and histological features of lupus cheilitis.
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Impact of HbA1c Testing at Point of Care on Diabetes Management
Schnell, Oliver; Crocker, J. Benjamin; Weng, Jianping
2016-01-01
Diabetes is a highly prevalent disease also implicated in the development of several other serious complications like cardiovascular or renal disease. HbA1c testing is a vital step for effective diabetes management, however, given the low compliance to testing frequency and, commonly, a subsequent delay in the corresponding treatment modification, HbA1c at the point of care (POC) offers an opportunity for improvement of diabetes care. In this review, based on data from 1999 to 2016, we summarize the evidence supporting a further implementation of HbA1c testing at POC, discuss its limitations and propose recommendations for further development. PMID:27898388
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Using decision analysis to support proactive management of emerging infectious wildlife diseases
Grant, Evan H. Campbell; Muths, Erin L.; Katz, Rachel A.; Canessa, Stefano; Adams, Michael J.; Ballard, Jennifer R.; Berger, Lee; Briggs, Cheryl J.; Coleman, Jeremy; Gray, Matthew J.; Harris, M. Camille; Harris, Reid N.; Hossack, Blake R.; Huyvaert, Kathryn P.; Kolby, Jonathan E.; Lips, Karen R.; Lovich, Robert E.; McCallum, Hamish I.; Mendelson, Joseph R.; Nanjappa, Priya; Olson, Deanna H.; Powers, Jenny G.; Richgels, Katherine L. D.; Russell, Robin E.; Schmidt, Benedikt R.; Spitzen-van der Sluijs, Annemarieke; Watry, Mary Kay; Woodhams, Douglas C.; White, C. LeAnn
2017-01-01
Despite calls for improved responses to emerging infectious diseases in wildlife, management is seldom considered until a disease has been detected in affected populations. Reactive approaches may limit the potential for control and increase total response costs. An alternative, proactive management framework can identify immediate actions that reduce future impacts even before a disease is detected, and plan subsequent actions that are conditional on disease emergence. We identify four main obstacles to developing proactive management strategies for the newly discovered salamander pathogen Batrachochytrium salamandrivorans (Bsal). Given that uncertainty is a hallmark of wildlife disease management and that associated decisions are often complicated by multiple competing objectives, we advocate using decision analysis to create and evaluate trade-offs between proactive (pre-emergence) and reactive (post-emergence) management options. Policy makers and natural resource agency personnel can apply principles from decision analysis to improve strategies for countering emerging infectious diseases.
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Wang, Zhi-Bo; Zhang, Xiaoqing; Li, Xue-Jun
2013-01-01
Establishing human cell models of spinal muscular atrophy (SMA) to mimic motor neuron-specific phenotypes holds the key to understanding the pathogenesis of this devastating disease. Here, we developed a closely representative cell model of SMA by knocking down the disease-determining gene, survival motor neuron (SMN), in human embryonic stem cells (hESCs). Our study with this cell model demonstrated that knocking down of SMN does not interfere with neural induction or the initial specification of spinal motor neurons. Notably, the axonal outgrowth of spinal motor neurons was significantly impaired and these disease-mimicking neurons subsequently degenerated. Furthermore, these disease phenotypes were caused by SMN-full length (SMN-FL) but not SMN-Δ7 (lacking exon 7) knockdown, and were specific to spinal motor neurons. Restoring the expression of SMN-FL completely ameliorated all of the disease phenotypes, including specific axonal defects and motor neuron loss. Finally, knockdown of SMN-FL led to excessive mitochondrial oxidative stress in human motor neuron progenitors. The involvement of oxidative stress in the degeneration of spinal motor neurons in the SMA cell model was further confirmed by the administration of N-acetylcysteine, a potent antioxidant, which prevented disease-related apoptosis and subsequent motor neuron death. Thus, we report here the successful establishment of an hESC-based SMA model, which exhibits disease gene isoform specificity, cell type specificity, and phenotype reversibility. Our model provides a unique paradigm for studying how motor neurons specifically degenerate and highlights the potential importance of antioxidants for the treatment of SMA. PMID:23208423
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Presenilins and γ-Secretase: Structure, Function, and Role in Alzheimer Disease
De Strooper, Bart; Iwatsubo, Takeshi; Wolfe, Michael S.
2012-01-01
Presenilins were first discovered as sites of missense mutations responsible for early-onset Alzheimer disease (AD). The encoded multipass membrane proteins were subsequently found to be the catalytic components of γ-secretases, membrane-embedded aspartyl protease complexes responsible for generating the carboxyl terminus of the amyloid β-protein (Aβ) from the amyloid protein precursor (APP). The protease complex also cleaves a variety of other type I integral membrane proteins, most notably the Notch receptor, signaling from which is involved in many cell differentiation events. Although γ-secretase is a top target for developing disease-modifying AD therapeutics, interference with Notch signaling should be avoided. Compounds that alter Aβ production by γ-secretase without affecting Notch proteolysis and signaling have been identified and are currently at various stages in the drug development pipeline. PMID:22315713
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Tooth loss, dementia and neuropathology in the Nun study.
Stein, Pamela Sparks; Desrosiers, Mark; Donegan, Sara Jean; Yepes, Juan F; Kryscio, Richard J
2007-10-01
Numerous studies have linked dementia to the subsequent deterioration of oral health. Few investigators, however, have examined oral disease as a potential risk factor in the development of dementia. The authors conducted a study to investigate a potential association between a history of oral disease and the development of dementia. Longitudinal dental records supplemented data collected from 10 annual cognitive assessments of 144 Milwaukee participants in the Nun Study, a longitudinal study of aging and Alzheimer disease, who were 75 to 98 years old. Neuropathologic findings at autopsy were available for 118 participants who died. A low number of teeth increased the risk of higher prevalence and incidence of dementia. Participants with the fewest teeth had the highest risk of prevalence and incidence of dementia. Edentulism or very few (one to nine) teeth may be predictors of dementia late in life.
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Radford, Elizabeth J.; Corish, Jennifer A.; Seisenberger, Stefanie; Hore, Timothy A.; Reik, Wolf; Erkek, Serap; Peters, Antoine H. F. M.; Patti, Mary-Elizabeth; Ferguson-Smith, Anne C.
2015-01-01
Adverse prenatal environments can promote metabolic disease in offspring and subsequent generations. Animal models and epidemiological data implicate epigenetic inheritance but mechanisms remain unknown. In an intergenerational developmental programming model affecting F2 metabolism, we demonstrate that the in utero nutritional environment of F1 embryos alters the germline DNA methylome of F1 adult males in a locus-specific manner. Differentially methylated regions are hypomethylated and enriched in nucleosome-retaining regions. A substantial fraction is resistant to early embryo methylation reprogramming, potentially impacting F2 development. Importantly, differential methylation is not maintained in F2 tissues, yet locus-specific expression is perturbed. Thus, in utero nutritional exposures during critical windows of germ cell development can impact the male germline methylome, associated with metabolic disease in offspring. PMID:25011554
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Norris, Edmund J; Coats, Joel R
2017-01-29
Every year, approximately 700,000 people die from complications associated with etiologic disease agents transmitted by mosquitoes. While insecticide-based vector control strategies are important for the management of mosquito-borne diseases, insecticide-resistance and other logistical hurdles may lower the efficacy of this approach, especially in developing countries. Repellent technologies represent another fundamental aspect of preventing mosquito-borne disease transmission. Among these technologies, spatial repellents are promising alternatives to the currently utilized contact repellents and may significantly aid in the prevention of mosquito-borne disease if properly incorporated into integrated pest management approaches. As their deployment would not rely on prohibitively expensive or impractical novel accessory technologies and resources, they have potential utility in developing countries where the burden of mosquito-borne disease is most prevalent. This review aims to describe the history of various repellent technologies, highlight the potential of repellent technologies in preventing the spread of mosquito-borne disease, and discuss currently known mechanisms that confer resistance to current contact and spatial repellents, which may lead to the failures of these repellents. In the subsequent section, current and future research projects aimed at exploring long-lasting non-pyrethroid spatial repellent molecules along with new paradigms and rationale for their development will be discussed.
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Norris, Edmund J.; Coats, Joel R.
2017-01-01
Every year, approximately 700,000 people die from complications associated with etiologic disease agents transmitted by mosquitoes. While insecticide-based vector control strategies are important for the management of mosquito-borne diseases, insecticide-resistance and other logistical hurdles may lower the efficacy of this approach, especially in developing countries. Repellent technologies represent another fundamental aspect of preventing mosquito-borne disease transmission. Among these technologies, spatial repellents are promising alternatives to the currently utilized contact repellents and may significantly aid in the prevention of mosquito-borne disease if properly incorporated into integrated pest management approaches. As their deployment would not rely on prohibitively expensive or impractical novel accessory technologies and resources, they have potential utility in developing countries where the burden of mosquito-borne disease is most prevalent. This review aims to describe the history of various repellent technologies, highlight the potential of repellent technologies in preventing the spread of mosquito-borne disease, and discuss currently known mechanisms that confer resistance to current contact and spatial repellents, which may lead to the failures of these repellents. In the subsequent section, current and future research projects aimed at exploring long-lasting non-pyrethroid spatial repellent molecules along with new paradigms and rationale for their development will be discussed. PMID:28146066
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Experimental Vaccines against Chagas Disease: A Journey through History.
Rodríguez-Morales, Olivia; Monteón-Padilla, Víctor; Carrillo-Sánchez, Silvia C; Rios-Castro, Martha; Martínez-Cruz, Mariana; Carabarin-Lima, Alejandro; Arce-Fonseca, Minerva
2015-01-01
Chagas disease, or American trypanosomiasis, which is caused by the protozoan parasite Trypanosoma cruzi, is primarily a vector disease endemic in 21 Latin American countries, including Mexico. Although many vector control programs have been implemented, T. cruzi has not been eradicated. The development of an anti-T. cruzi vaccine for prophylactic and therapeutic purposes may significantly contribute to the transmission control of Chagas disease. Immune protection against experimental infection with T. cruzi has been studied since the second decade of the last century, and many types of immunogens have been used subsequently, such as killed or attenuated parasites and new DNA vaccines. This primary prevention strategy appears feasible, effective, safe, and inexpensive, although problems remain. The objective of this review is to summarize the research efforts about the development of vaccines against Chagas disease worldwide. A thorough literature review was conducted by searching PubMed with the terms "Chagas disease" and "American trypanosomiasis" together with "vaccines" or "immunization". In addition, reports and journals not cited in PubMed were identified. Publications in English, Spanish, and Portuguese were reviewed.
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Page, W F; Ostfeld, A M
1994-12-01
The harsh treatment of former prisoners of war (POWs) of World War II and the Korean conflict resulted in severe malnutrition. Although rarely linked to specific long-term medical problems, a specific marker of malnutrition, self-reported lower limb edema (presumably due to a vitamin B deficiency) was associated with a three-fold increase in subsequent death attributed to ischemic heart disease (IHD) during the follow-up period from 1967 through 1975. Although there is at present no medical basis for linking edema, which is perhaps a marker for some unmeasured risk factor, to subsequent IHD, this finding may nonetheless have medical implications for the group of former POWs and other populations with severe dietary deficiency. It also suggests there may be a need to reexamine currently held theories on malnutrition and subsequent chronic disease.
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Neonatal Systemic AAV Induces Tolerance to CNS Gene Therapy in MPS I Dogs and Nonhuman Primates
Hinderer, Christian; Bell, Peter; Louboutin, Jean-Pierre; Zhu, Yanqing; Yu, Hongwei; Lin, Gloria; Choa, Ruth; Gurda, Brittney L; Bagel, Jessica; O'Donnell, Patricia; Sikora, Tracey; Ruane, Therese; Wang, Ping; Tarantal, Alice F; Casal, Margret L; Haskins, Mark E; Wilson, James M
2015-01-01
The potential host immune response to a nonself protein poses a fundamental challenge for gene therapies targeting recessive diseases. We demonstrate in both dogs and nonhuman primates that liver-directed gene transfer using an adeno-associated virus (AAV) vector in neonates induces a persistent state of immunological tolerance to the transgene product, substantially improving the efficacy of subsequent vector administration targeting the central nervous system (CNS). We applied this approach to a canine model of mucopolysaccharidosis type I (MPS I), a progressive neuropathic lysosomal storage disease caused by deficient activity of the enzyme α-l-iduronidase (IDUA). MPS I dogs treated systemically in the first week of life with a vector expressing canine IDUA did not develop antibodies against the enzyme and exhibited robust expression in the CNS upon intrathecal AAV delivery at 1 month of age, resulting in complete correction of brain storage lesions. Newborn rhesus monkeys treated systemically with AAV vector expressing human IDUA developed tolerance to the transgene, resulting in high cerebrospinal fluid (CSF) IDUA expression and no antibody induction after subsequent CNS gene therapy. These findings suggest that inducing tolerance to the transgene product during a critical period in immunological development can improve the efficacy and safety of gene therapy. PMID:26022732
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Neonatal Systemic AAV Induces Tolerance to CNS Gene Therapy in MPS I Dogs and Nonhuman Primates.
Hinderer, Christian; Bell, Peter; Louboutin, Jean-Pierre; Zhu, Yanqing; Yu, Hongwei; Lin, Gloria; Choa, Ruth; Gurda, Brittney L; Bagel, Jessica; O'Donnell, Patricia; Sikora, Tracey; Ruane, Therese; Wang, Ping; Tarantal, Alice F; Casal, Margret L; Haskins, Mark E; Wilson, James M
2015-08-01
The potential host immune response to a nonself protein poses a fundamental challenge for gene therapies targeting recessive diseases. We demonstrate in both dogs and nonhuman primates that liver-directed gene transfer using an adeno-associated virus (AAV) vector in neonates induces a persistent state of immunological tolerance to the transgene product, substantially improving the efficacy of subsequent vector administration targeting the central nervous system (CNS). We applied this approach to a canine model of mucopolysaccharidosis type I (MPS I), a progressive neuropathic lysosomal storage disease caused by deficient activity of the enzyme α-l-iduronidase (IDUA). MPS I dogs treated systemically in the first week of life with a vector expressing canine IDUA did not develop antibodies against the enzyme and exhibited robust expression in the CNS upon intrathecal AAV delivery at 1 month of age, resulting in complete correction of brain storage lesions. Newborn rhesus monkeys treated systemically with AAV vector expressing human IDUA developed tolerance to the transgene, resulting in high cerebrospinal fluid (CSF) IDUA expression and no antibody induction after subsequent CNS gene therapy. These findings suggest that inducing tolerance to the transgene product during a critical period in immunological development can improve the efficacy and safety of gene therapy.
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Luhmann, Ulrich F O; Lin, Jihong; Acar, Niyazi; Lammel, Stefanie; Feil, Silke; Grimm, Christian; Seeliger, Mathias W; Hammes, Hans-Peter; Berger, Wolfgang
2005-09-01
To characterize developmental defects and the time course of Norrie disease in retinal and hyaloid vasculature during retinal development and to identify underlying molecular angiogenic pathways that may be affected in Norrie disease, exudative vitreoretinopathy, retinopathy of prematurity, and Coats' disease. Norrie disease pseudoglioma homologue (Ndph)-knockout mice were studied during retinal development at early postnatal (p) stages (p5, p10, p15, and p21). Histologic techniques, quantitative RT-PCR, ELISA, and Western blot analyses provided molecular data, and scanning laser ophthalmoscopy (SLO) angiography and electroretinography (ERG) were used to obtain in vivo data. The data showed that regression of the hyaloid vasculature of Ndph-knockout mice occurred but was drastically delayed. The development of the superficial retinal vasculature was strongly delayed, whereas the deep retinal vasculature did not form because of the blockage of vessel outgrowth into the deep retinal layers. Subsequently, microaneurysm-like lesions formed. Several angiogenic factors were differentially transcribed during retinal development. Increased levels of hypoxia inducible factor-1alpha (HIF1alpha) and VEGFA, as well as a characteristic ERG pattern, confirmed hypoxic conditions in the inner retina of the Ndph-knockout mouse. These data provide evidence for a crucial role of Norrin in hyaloid vessel regression and in sprouting angiogenesis during retinal vascular development, especially in the development of the deep retinal capillary networks. They also suggest an early and a late phase of Norrie disease and may provide an explanation for similar phenotypic features of allelic retinal diseases in mice and patients as secondary consequences of pathologic hypoxia.
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BATMAN-TCM: a Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine
NASA Astrophysics Data System (ADS)
Liu, Zhongyang; Guo, Feifei; Wang, Yong; Li, Chun; Zhang, Xinlei; Li, Honglei; Diao, Lihong; Gu, Jiangyong; Wang, Wei; Li, Dong; He, Fuchu
2016-02-01
Traditional Chinese Medicine (TCM), with a history of thousands of years of clinical practice, is gaining more and more attention and application worldwide. And TCM-based new drug development, especially for the treatment of complex diseases is promising. However, owing to the TCM’s diverse ingredients and their complex interaction with human body, it is still quite difficult to uncover its molecular mechanism, which greatly hinders the TCM modernization and internationalization. Here we developed the first online Bioinformatics Analysis Tool for Molecular mechANism of TCM (BATMAN-TCM). Its main functions include 1) TCM ingredients’ target prediction; 2) functional analyses of targets including biological pathway, Gene Ontology functional term and disease enrichment analyses; 3) the visualization of ingredient-target-pathway/disease association network and KEGG biological pathway with highlighted targets; 4) comparison analysis of multiple TCMs. Finally, we applied BATMAN-TCM to Qishen Yiqi dripping Pill (QSYQ) and combined with subsequent experimental validation to reveal the functions of renin-angiotensin system responsible for QSYQ’s cardioprotective effects for the first time. BATMAN-TCM will contribute to the understanding of the “multi-component, multi-target and multi-pathway” combinational therapeutic mechanism of TCM, and provide valuable clues for subsequent experimental validation, accelerating the elucidation of TCM’s molecular mechanism. BATMAN-TCM is available at http://bionet.ncpsb.org/batman-tcm.
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BATMAN-TCM: a Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine
Liu, Zhongyang; Guo, Feifei; Wang, Yong; Li, Chun; Zhang, Xinlei; Li, Honglei; Diao, Lihong; Gu, Jiangyong; Wang, Wei; Li, Dong; He, Fuchu
2016-01-01
Traditional Chinese Medicine (TCM), with a history of thousands of years of clinical practice, is gaining more and more attention and application worldwide. And TCM-based new drug development, especially for the treatment of complex diseases is promising. However, owing to the TCM’s diverse ingredients and their complex interaction with human body, it is still quite difficult to uncover its molecular mechanism, which greatly hinders the TCM modernization and internationalization. Here we developed the first online Bioinformatics Analysis Tool for Molecular mechANism of TCM (BATMAN-TCM). Its main functions include 1) TCM ingredients’ target prediction; 2) functional analyses of targets including biological pathway, Gene Ontology functional term and disease enrichment analyses; 3) the visualization of ingredient-target-pathway/disease association network and KEGG biological pathway with highlighted targets; 4) comparison analysis of multiple TCMs. Finally, we applied BATMAN-TCM to Qishen Yiqi dripping Pill (QSYQ) and combined with subsequent experimental validation to reveal the functions of renin-angiotensin system responsible for QSYQ’s cardioprotective effects for the first time. BATMAN-TCM will contribute to the understanding of the “multi-component, multi-target and multi-pathway” combinational therapeutic mechanism of TCM, and provide valuable clues for subsequent experimental validation, accelerating the elucidation of TCM’s molecular mechanism. BATMAN-TCM is available at http://bionet.ncpsb.org/batman-tcm. PMID:26879404
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Stenberg, Anna; Macdonald, Clare; Hunter, Paul R
2008-01-01
Background To assess whether domestic kitchen hygiene is an important contributor to the development of diarrhoea in the developed world. Methods Electronic searches were carried out in October 2006 in EMBASE, MEDLINE, Web of Knowledge, Cochrane central register of clinical trials and CINAHL. All publications, irrespective of study design, assessing food hygiene practices with an outcome measure of diarrhoea were included in the review. All included studies underwent data extraction and the data was subsequently analysed. The analysis was conducted by qualitative synthesis of the results. Given the substantial heterogeneity in study design and outcome measures meta-analysis was not done. In addition the existing dataset of the UK IID study was reanalysed to investigate possible associations between self-reported diarrhoea and variables indicative of poor domestic kitchen hygiene Results Some 14 studies were finally included in subsequent analyses. Of the 14 studies included in this systematic review, 11 were case-control studies, 2 cross-sectional surveys, and 1 RCT. Very few studies identified any significant association with good environmental kitchen hygiene. Although some of the variables in the reanalysis of the UK IID study were statistically significant no obvious trend was seen. Conclusion The balance of the available evidence does not support the hypothesis that poor domestic kitchen hygiene practices are important risk factors for diarrhoeal disease in developed countries. PMID:18294383
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Stenberg, Anna; Macdonald, Clare; Hunter, Paul R
2008-02-22
To assess whether domestic kitchen hygiene is an important contributor to the development of diarrhoea in the developed world. Electronic searches were carried out in October 2006 in EMBASE, MEDLINE, Web of Knowledge, Cochrane central register of clinical trials and CINAHL. All publications, irrespective of study design, assessing food hygiene practices with an outcome measure of diarrhoea were included in the review. All included studies underwent data extraction and the data was subsequently analysed. The analysis was conducted by qualitative synthesis of the results. Given the substantial heterogeneity in study design and outcome measures meta-analysis was not done. In addition the existing dataset of the UK IID study was reanalysed to investigate possible associations between self-reported diarrhoea and variables indicative of poor domestic kitchen hygiene Some 14 studies were finally included in subsequent analyses. Of the 14 studies included in this systematic review, 11 were case-control studies, 2 cross-sectional surveys, and 1 RCT. Very few studies identified any significant association with good environmental kitchen hygiene. Although some of the variables in the reanalysis of the UK IID study were statistically significant no obvious trend was seen. The balance of the available evidence does not support the hypothesis that poor domestic kitchen hygiene practices are important risk factors for diarrhoeal disease in developed countries.
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Epidemiology of Viliuisk encephalomyelitis in Eastern Siberia.
Lee, Hee Suk; Zhdanova, Svetlana N; Vladimirtsev, Vsevolod A; Platonov, Fyodor A; Osakovskiy, Vladimir L; Subbotina, Ekaterina L; Broytman, Oleg; Danilova, Al'bina P; Nikitina, Raisa S; Chepurnov, Alexander A; Krivoshapkin, Vadim G; Gajdusek, D Carleton; Savilov, Yevgeniy D; Garruto, Ralph M; Goldfarb, Lev G
2010-01-01
Viliuisk encephalomyelitis is a disorder that starts, in most cases, as an acute meningoencephalitis. Survivors of the acute phase develop a slowly progressing neurologic syndrome characterized by dementia, dysarthria, and spasticity. An epidemic of this disease has been spreading throughout the Yakut Republic of the Russian Federation. Although clinical, neuropathologic, and epidemiologic data suggest infectious etiology, multiple attempts at pathogen isolation have been unsuccessful. Detailed clinical, pathologic, laboratory, and epidemiologic studies have identified 414 patients with definite Viliuisk encephalomyelitis in 15 of 33 administrative regions of the Yakut Republic between 1940 and 1999. All data are documented in a Registry. The average annual Viliuisk encephalomyelitis incidence rate at the height of the epidemic reached 8.8 per 100,000 population and affected predominantly young adults. The initial outbreak occurred in a remote isolated area of the middle reaches of Viliui River; the disease spread to adjacent areas and further in the direction of more densely populated regions. The results suggest that intensified human migration from endemic villages led to the emergence of this disease in new communities. Recent social and demographic changes have presumably contributed to a subsequent decline in disease incidence. Based on the largest known set of diagnostically verified Viliuisk encephalomyelitis cases, we demonstrate how a previously little-known disease that was endemic in a small indigenous population subsequently reached densely populated areas and produced an epidemic involving hundreds of persons.
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Erasmus Syndrome: Association of Silicosis and Systemic Sclerosis.
Sharma, Reena K; Sharma, Anjna K; Sharma, Anuj
2018-01-01
Silicosis is an inflammatory disease of the lung characterized by irreversible lung fibrosis which develops from prolonged pulmonary inhalation and retention of crystalline silica and immune reaction. It mainly appears as an occupational hazard in persons involved in stone-quarrying, mining, and sand blasting. Crystalline silica is not only known to be responsible for silicosis but also for other autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA)-Caplan syndrome, systemic sclerosis (SSc), and antineutrophil cytoplasmic antibody (ANCA)-related vasculitis. Erasmus syndrome is the association of silica exposure and subsequent development of SSc. The limited numbers of cases reported in the literature were miners and only sporadically involved in other professionals. Here, we report a case of a 52 -year-old stone cutter who developed silicosis and SSc after 25 years of exposure.
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[Chronic maternal diseases and pregnancy losses. French guidelines].
Nizard, J; Guettrot-Imbert, G; Plu-Bureau, G; Ciangura, C; Jacqueminet, S; Leenhardt, L; Nedellec, S; Gallot, V; Vialard, F; Quibel, T; Huchon, C; Costedoat-Chalumeau, N
2014-12-01
To review the available data on maternal chronic diseases and pregnancy losses. We searched PubMed and the Cochrane library with pregnancy loss, stillbirth, intrauterine fetal demise, intrauterine fetal death, miscarriage and each maternal diseases of this paper. Antiphospholipid antibodies (anticardiolipin, anti-beta-2-glycoprotein, lupus anticoagulant) should be measured in case of miscarriage after 10WG confirmed by ultrasound (grade B) and an antiphospholipid syndrome should be treated by a combination of aspirin and low-molecular-weight heparin during a subsequent pregnancy (grade A). We do not recommend testing for genetic thrombophilia in case of first trimester miscarriage (grade B) or stillbirth (grade C). Glycemic control should be a goal before pregnancy for women with pregestational diabetes to limit the risks of pregnancy loss (grade A) with a goal of prepregnancy HbA1c<7%. Overt and subclinical hypothyroidisms should be treated by L-thyroxin during pregnancy to reduce the risks of pregnancy loss (grade A). Women who are positive for TPOAb should have TSH concentrations follow-up during pregnancy and subsequently treated by L-thyroxin if they develop subclinical hypothyroidism (grade B). Prepregnancy management of most chronic maternal diseases, ideally through prepregnancy multidisciplinary counseling, reduces the risks of pregnancy loss. Copyright © 2014 Elsevier Masson SAS. All rights reserved.
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Crowder, Lauren A; Schonberger, Lawrence B; Dodd, Roger Y; Steele, Whitney R
2017-08-01
Transfusion transmission of human prion diseases has been observed for variant Creutzfeldt-Jakob disease (vCJD), but not for the classic forms of prion disease (CJD: sporadic, genetic, and iatrogenic). Although the presence of prions or misfolded prion proteins in blood has been documented in some patients with the most common form of CJD, sporadic CJD, no transfusion-transmitted cases of CJD have been recognized. Since 1995, the American Red Cross has conducted a lookback study of the recipients of blood products from donors who develop CJD to assess the risk of blood-borne CJD transmission in the United States. Blood donors subsequently diagnosed with confirmed or probable CJD were enrolled and the consignees were asked to identify the recipients of their blood products. These donors' transfusion recipients are traced annually with the National Death Index to see if they subsequently die of CJD. To date, 65 CJD donors have been enrolled along with 826 of their blood recipients. These recipients have contributed 3934 person-years of follow-up and no transfusion-transmitted cases of CJD have been recognized. From this study, as well as other epidemiologic studies, there is no evidence of CJD transfusion transmission; this risk remains theoretical. © 2017 AABB.
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Distinct First Trimester Cytokine Profiles for Gestational Hypertension and Preeclampsia.
Tangerås, Line H; Austdal, Marie; Skråstad, Ragnhild B; Salvesen, Kjell Å; Austgulen, Rigmor; Bathen, Tone F; Iversen, Ann-Charlotte
2015-11-01
Gestational hypertension and preeclampsia involve dysregulated maternal inflammatory responses to pregnancy, but whether such responses differ between the disorders has not been determined. We aimed to investigate disease-specific early pregnancy serum cytokine profiles of women subsequently developing gestational hypertension or preeclampsia for new insight into the underlying pathogeneses and differences between the disorders. The study cohort consisted of 548 pregnant Norwegian women who were either multiparous with previous gestational hypertension or preeclampsia or were nulliparous. Maternal sera at gestational weeks 11(0)-13(6) were assayed for 27 cytokines, C-reactive protein, total cholesterol, high-density lipoprotein, triglyceride, creatinine, calcium, uric acid, and placental growth factor. Compared with normotensive women, women with both hypertensive conditions presented an atherogenic lipid profile at early gestation, but only those later developing gestational hypertension had significantly higher serum levels of interleukin (IL)-5 and IL-12. Comparing the 2 hypertensive pregnancy disorders, women subsequently developing gestational hypertension had higher serum levels of IL-1β, IL-5, IL-7, IL-8, IL-13, basic fibroblast growth factor, and vascular endothelial growth factor than the women subsequently developing preeclampsia. This study identifies early pregnancy differences in serum cytokine profiles for gestational hypertension and preeclampsia. © 2015 American Heart Association, Inc.
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Liu, Shiming; Su, Zhaobing; Tan, Sainan; Ni, Bin; Pan, Hong; Liu, Beihong; Wang, Jing; Xiao, Jianmin; Chen, Qiuhong
2017-08-01
CITED2 gene is an important cardiac transcription factor that plays a fundamental role in the formation and development of embryonic cardiovascular. Previous studies have showed that knock-out of CITED2 in mice might result in various cardiac malformations. However, the mechanisms of CITED2 mutation on congenital heart disease (CHD) in Chinese Tibetan population are still poorly understood. In the present study, 187 unrelated Tibetan patients with CHD and 200 unrelated Tibetan healthy controls were screened for variants in the CITED2 gene; we subsequently identified one potential disease-causing mutation p.G143A in a 6-year-old girl with PDA and functional analyses of the mutation were carried out. Our study showed that the novel mutation of CITED2 significantly enhanced the expression activity of vascular endothelial growth factor (VEGF) under the role of co-receptor hypoxia inducible factor 1-aipha (HIF-1A), which is closely related with embryonic cardiac development. As a result, CITED2 gene mutation may play a significant role in the development of pediatric congenital heart disease.
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Røe, Kathrine; Bratland, Åse; Vlatkovic, Ljiljana; Ragnum, Harald Bull; Saelen, Marie Grøn; Olsen, Dag Rune; Marignol, Laure; Ree, Anne Hansen
2013-01-01
In this study, we hypothesized that androgen-deprivation therapy (ADT) in prostate cancer, although initially efficient, induces changes in the tumor kinome, which subsequently promote development of castration-resistant (CR) disease. Recognizing the correlation between tumor hypoxia and poor prognosis in prostate cancer, we further hypothesized that such changes might be influenced by hypoxia. Microarrays with 144 kinase peptide substrates were applied to analyze CWR22 prostate carcinoma xenograft samples from ADT-naïve, androgen-deprived (AD), long-term AD (ADL), and CR disease stages. The impact of hypoxia was assessed by matching the xenograft kinase activity profiles with those acquired from hypoxic and normoxic prostate carcinoma cell cultures, whereas the clinical relevance was evaluated by analyzing prostatectomy tumor samples from patients with locally advanced disease, either in ADT-naïve or early CR disease stages. By using this novel peptide substrate microarray method we revealed high kinase activity mediated by signal transducer and activator of transcription 5A (STAT5A) in CR prostate cancer. Additionally, we uncovered high STAT5A kinase activity already in regressing ADL xenografts, before renewed CR growth was evidenced. Finally, since increased STAT5A kinase activity also was detected after exposing prostate carcinoma cells to hypoxia, we propose long-term ADT to induce tumor hypoxia and stimulate STAT5A kinase activity, subsequently leading to renewed CR tumor growth. Hence, the study detected STAT5A as a candidate to be further investigated for its potential as marker of advanced prostate cancer and as possible therapeutic target protein. PMID:23675504
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Fawzy, Mohamed S; Mohamed, Randa H; Elfayoumi, Abdel-Rahman R
2015-03-01
The aim of this study was to determine whether detection of prostate stem cell antigen (PSCA) expression in BPH might be associated with the subsequent presence of Prostate cancer (PCa) and also to determine whether detection of PSCA expression has potential for prognosis in PCa. This study was comprised of 112 PCa patients, 111 BPH patients and 120 control subjects. We employed reverse-transcriptase polymerase chain reaction (RT-PCR) to detect PSCA mRNA-bearing cells in peripheral blood. PSCA mRNA was detected in the peripheral blood of 71.4% PCa patients and in 13.5% of patients with BPH by RT-PCR. PSCA was positive in 80% of high-grade diseases compared with 20% of low-grade diseases (P = 0.01). Whereas only 38.8% of prostate-confined diseases were PSCA positive, 61.2% of extraprostatic diseases were PSCA positive (P < 0.001). Patients with a lymphovascular invasion of tumor emboli tended to be PSCA positive (P = 0.02). BPH patients with RT-PCR PSCA positive were significantly more likely to develop prostate cancer (OR = 16, 95% CI = 8.1-31.6, P < 0.001). In conclusion, RT-PCR PSCA positivity is significantly associated with the Gleason score, LV tumor emboli and whether or not the tumor was organ confined. In this study, RT-PCR PSCA detection may be a promising tumor marker of diagnostic and metastasis detection for patients with prostate cancer. Also, it may be an important test for predicting BPH patients who are at high risk of subsequent cancer development.
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Szomjak, E; Der, H; Kerekes, G; Veres, K; Csiba, L; Toth, J; Peter, M; Soltesz, P; Szodoray, P
2010-04-01
The most commonly occurring atherosclerotic manifestations are peripheral artery diseases (PAD). Immune-mediated processes contribute to the development of atherosclerosis, and affect the diseases outcome. The aim of the present study was to assess various immune-competent cells, cytokines and chemokines in patients with PAD and to evaluate whether the base immunological values reflect the subsequent development of cardio/cerebrovascular symptoms. One hundred sixty patients with PAD were followed-up for 42 months. At the time of enrolment, we determined blood lymphocyte subpopulations, both T-helper (Th)1/Th2-type intracytoplasmic cytokines and soluble cytokines, chemokines. Intracellular cytokines were measured on phorbol-myristate-acetate- and ionomycine- stimulated cells. Lymphocyte subgroups were quantified by flow cytometry, soluble cytokines by ELISA and intracellular cytokine levels were measured by flow cytometry. The ankle-brachial index (ABI), indicator of atherosclerosis, was also evaluated. The clinical results were correlated with the immune-parameters to assess the input of immune-inflammatory events in the propagation of vascular manifestation. CD4(+) T-cell proportions in patients with PAD with cerebro- cardio-vascular manifestations were decreased, which further reduced in patients with fatal outcome. Of circulating chemokines, IL-8 (CXCL-8) was increased in patients with subsequent cerebro- cardio-vascular manifestations, compared to those without the symptoms, and further raised in patients with fatal outcome. The percentage of interferon (IFN)-gamma positive cells showed clear negative correlation with ABI. We conclude that altered peripheral lymphocyte subsets and cytokine/chemokine imbalance play important roles in the proinflammatory cascade and reflect disease severity in patients with PAD.
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Karalexi, M A; Skalkidou, A; Thomopoulos, T P; Belechri, M; Biniaris-Georgallis, S-I; Bouka, E; Baka, M; Hatzipantelis, E; Kourti, M; Polychronopoulou, S; Sidi, V; Stiakaki, E; Moschovi, M; Dessypris, N; Petridou, E Th
2015-09-01
Despite the putative intrauterine origins of childhood (0-14 years) leukaemia, it is complex to assess the impact of perinatal factors on disease onset. Results on the association of maternal history of fetal loss (miscarriage/stillbirth) with specific disease subtypes in the subsequent offspring are in conflict. We sought to investigate whether miscarriage and stillbirth may have different impacts on the risk of acute lymphoblastic leukaemia (ALL) and of its main immunophenotypes (B-cell and T-cell ALL), as contrasted to acute myeloid leukaemia (AML). One thousand ninety-nine ALL incidents (957 B-ALL) and 131 AML cases along with 1:1 age and gender-matched controls derived from the Nationwide Registry for Childhood Hematological Malignancies and Brain Tumors (1996-2013) were studied. Multivariable regression models were used to assess the roles of previous miscarriage(s) and stillbirth(s) on ALL (overall, B-, T-ALL) and AML, controlling for potential confounders. Statistically significant exposure and disease subtype-specific associations of previous miscarriage(s) exclusively with AML [odds ratio (OR) 1.67, 95% confidence interval (CI) 1.00, 2.81] and stillbirth(s) with ALL [OR 4.82, 95% CI 1.63, 14.24] and B-ALL particularly, emerged. Differential pathophysiological pathways pertaining to genetic polymorphisms or cytogenetic aberrations are likely to create hostile environments leading either to fetal loss or the development of specific leukaemia subtypes in subsequent offspring, notably distinct associations of maternal miscarriage history confined to AML and stillbirth history confined to ALL (specifically B-ALL). If confirmed and further supported by studies revealing underlying mechanisms, these results may shed light on the divergent leukemogenesis processes. © 2015 John Wiley & Sons Ltd.
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Yende, Sachin; D'Angelo, Gina; Mayr, Florian; Kellum, John A.; Weissfeld, Lisa; Kaynar, A. Murat; Young, Tammy; Irani, Kaikobad; Angus, Derek C.
2011-01-01
Background Acceleration of chronic diseases, particularly cardiovascular disease, may increase long-term mortality after community-acquired pneumonia (CAP), but underlying mechanisms are unknown. Persistence of the prothrombotic state that occurs during an acute infection may increase risk of subsequent atherothrombosis in patients with pre-existing cardiovascular disease and increase subsequent risk of death. We hypothesized that circulating hemostasis markers activated during CAP persist at hospital discharge, when patients appear to have recovered clinically, and are associated with higher mortality, particularly due to cardiovascular causes. Methods In a cohort of survivors of CAP hospitalization from 28 US sites, we measured D-Dimer, thrombin-antithrombin complexes [TAT], Factor IX, antithrombin, and plasminogen activator inhibitor-1 at hospital discharge, and determined 1-year all-cause and cardiovascular mortality. Results Of 893 subjects, most did not have severe pneumonia (70.6% never developed severe sepsis) and only 13.4% required intensive care unit admission. At discharge, 88.4% of subjects had normal vital signs and appeared to have clinically recovered. D-dimer and TAT levels were elevated at discharge in 78.8% and 30.1% of all subjects, and in 51.3% and 25.3% of those without severe sepsis. Higher D-dimer and TAT levels were associated with higher risk of all-cause mortality (range of hazard ratios were 1.66-1.17, p = 0.0001 and 1.46-1.04, p = 0.001 after adjusting for demographics and comorbid illnesses) and cardiovascular mortality (p = 0.009 and 0.003 in competing risk analyses). Conclusions Elevations of TAT and D-dimer levels are common at hospital discharge in patients who appeared to have recovered clinically from pneumonia and are associated with higher risk of subsequent deaths, particularly due to cardiovascular disease. PMID:21853050
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Yende, Sachin; D'Angelo, Gina; Mayr, Florian; Kellum, John A; Weissfeld, Lisa; Kaynar, A Murat; Young, Tammy; Irani, Kaikobad; Angus, Derek C
2011-01-01
Acceleration of chronic diseases, particularly cardiovascular disease, may increase long-term mortality after community-acquired pneumonia (CAP), but underlying mechanisms are unknown. Persistence of the prothrombotic state that occurs during an acute infection may increase risk of subsequent atherothrombosis in patients with pre-existing cardiovascular disease and increase subsequent risk of death. We hypothesized that circulating hemostasis markers activated during CAP persist at hospital discharge, when patients appear to have recovered clinically, and are associated with higher mortality, particularly due to cardiovascular causes. In a cohort of survivors of CAP hospitalization from 28 US sites, we measured D-Dimer, thrombin-antithrombin complexes [TAT], Factor IX, antithrombin, and plasminogen activator inhibitor-1 at hospital discharge, and determined 1-year all-cause and cardiovascular mortality. Of 893 subjects, most did not have severe pneumonia (70.6% never developed severe sepsis) and only 13.4% required intensive care unit admission. At discharge, 88.4% of subjects had normal vital signs and appeared to have clinically recovered. D-dimer and TAT levels were elevated at discharge in 78.8% and 30.1% of all subjects, and in 51.3% and 25.3% of those without severe sepsis. Higher D-dimer and TAT levels were associated with higher risk of all-cause mortality (range of hazard ratios were 1.66-1.17, p = 0.0001 and 1.46-1.04, p = 0.001 after adjusting for demographics and comorbid illnesses) and cardiovascular mortality (p = 0.009 and 0.003 in competing risk analyses). Elevations of TAT and D-dimer levels are common at hospital discharge in patients who appeared to have recovered clinically from pneumonia and are associated with higher risk of subsequent deaths, particularly due to cardiovascular disease.
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Scabies increased the risk of chronic kidney disease: a 5-year follow-up study.
Chung, S-D; Wang, K-H; Huang, C-C; Lin, H-C
2014-03-01
The most documented complication of scabies has been reported to be infection by group A streptococci, which has in turn been suggested to contribute to the development of glomerulonephritis. This study aimed to investigate the risk of chronic kidney disease (CKD) subsequent to scabies utilizing a population-based dataset in Taiwan. This retrospective matched-cohort study included 5071 subjects with scabies and 25 355 randomly selected comparison subjects. We individually tracked each subject for a 5-year period to identify those who subsequently received a diagnosis of CKD during the follow-up period. Stratified Cox proportional hazards regressions were performed to compute the hazard ratio (HR) of CKD during the 5-year follow-up period. The incidence rate of CKD during the 5-year follow-up period was 9.66 (8.51-10.93) per 1,000 person-years and 6.24 (5.82-6.69) per 1000 person-years for subjects with and without scabies respectively. The HR for CKD during the 5-year follow-up period for subjects with scabies was 1.34 (95% CI = 1.15-1.56) that of comparison subjects after adjusting for monthly income, hypertension, diabetes, obesity, stroke, coronary heart disease, chronic obstructive pulmonary disease, tobacco use disorder, hyperlipidemia and alcohol abuse during the 5-year follow-up period. Male subjects with scabies were 1.40 (95% CI = 1.14-1.71) times more likely than comparison subjects to suffer from subsequent CKD, and female study subjects were 1.27 (95% CI = 1.05-1.61) times more likely. We concluded that there was an increased risk for CKD among patients suffering from scabies. © 2013 The Authors Journal of the European Academy of Dermatology and Venereology © 2013 European Academy of Dermatology and Venereology.
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Madriago, Erin J; Punn, Rajesh; Geeter, Natalie; Silverman, Norman H
2016-02-01
Trans-oesophageal echocardiographic imaging is valuable in the pre- and post-operative evaluation of children and adults with CHD; however, the frequency by which trans-oesophageal echocardiography guides the intra-operative course of patients is unknown. We retrospectively reviewed 1748 intra-operative trans-oesophageal echocardiograms performed between 1 October, 2005 and 31 December, 2010, and found 99 cases (5.7%) that required return to bypass, based in part upon the intra-operative echocardiographic findings. The diagnoses most commonly requiring further repair and subsequent imaging were mitral valve disease (20.9%), tricuspid valve disease (16.0%), atrioventricular canal defects (12.0%), and pulmonary valve disease (14.1%). The vast majority of those requiring immediate return to bypass benefited by avoiding subsequent operations and longer lengths of hospital stay. A total of 14 patients (0.8%) who received routine imaging required further surgical repair within 1 week, usually due to disease that developed over ensuing days. Patients who had second post-operative trans-oesophageal echocardiograms in the operating room rarely required re-operations, confirming the benefit of routine intra-operative imaging. This study represents a large single institutional review of intra-operative trans-oesophageal echocardiography, and confirms its applicability in the surgical repair of patients with CHD. Routine imaging accurately identifies patients requiring further intervention, does not confer additional risk of mortality or prolonged length of hospital stay, and prevents subsequent operations and associated sequelae in a substantial subset of patients. This study demonstrates the utility of echocardiography in intra-operative monitoring of surgical repair and highlights patients who are most likely to require return to bypass, as well as the co-morbidities of such manipulations.
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USDA-ARS?s Scientific Manuscript database
Mating of compatible haploid cells of Ustilago maydis is essential for infection and disease development in the host. For mating and subsequent filamentous growth and pathogenicity, the transcription factor, prf1 is necessary. Prf1 is in turn regulated by the cAMP and MAPK pathways and other regul...
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West Europe Report, Science and Technology
1986-03-06
organizations. New Vaccines The development of biotechnologies has enabled design and subsequent production of new vaccines which are important for...have included vaccines in their research progrmms. It is essential that research into new vaccines conducted by large European centers be...quality; -effective vaccines against major endemic tropical diseases will be Europe’s best ambassadors in Third World countries; -market potentials are
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2014-10-01
SUPPLEMENTARY NOTES 14. ABSTRACT Traumatic Brain Injury (TBI) is a risk factor for subsequent development of Alzheimer’s disease (AD). Abnormal tau...Special Reporting Requirements……………………………………10 9. Appendices……………………………………………………………10 1. INTRODUCTION Traumatic Brain Injury (TBI) is a risk factor for... risk factor for Alzheimer’s disease, Neurosci. Biobehav. Rev. 36(5), 1376-81. Teague SJ, Davis AM, Leeson PD, Oprea T (1999) The Design of Leadlike
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[Human bartonellosis: before and after Daniel Alcides Carrion].
Takano Morón, Juan
2014-04-01
This is a review of bibliographic aspects associated to the knowledge about human bartonelosis before and after the death of Daniel Alcides Carrion. Emphasis is placed on stimulus in the development of medical research in Peru by the self-inoculation and subsequent death of Carrion especially in relation to human bartonellosis, conducted by Peruvian researchers and others around the world. The review includes the basic area of knowledge about the bacteria that causes the illness, the host response to infection as well as the biphasic behavior of the disease. The revised bibliography includes contributions to the knowledge of the disease in the last 100 years, now known with the eponym "Carrion's disease".
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“Noncognitive” symptoms of early Alzheimer disease
Masters, Mary Clare; Morris, John C.
2015-01-01
Objectives: To observe the natural time course of noncognitive symptoms before the onset of symptomatic Alzheimer disease dementia. Methods: Using the National Alzheimer's Coordinating Center Uniform Data Set from September 2005 to March 2013, data from cognitively normal individuals who were aged 50 years or older at first visit and had subsequent follow-up were analyzed. Survival analyses were used to examine the development of particular symptoms relative to each other on the Neuropsychiatric Inventory Questionnaire (NPI-Q), Functional Activities Questionnaire, and Geriatric Depression Scale, and to compare the development of individual symptoms for persons who did and did not receive a Clinical Dementia Rating (CDR) >0 (indicating abnormal cognition) during the follow-up period. Results: The order of symptom occurrence on the NPI-Q was similar for participants who remained at CDR 0 and for those who received a CDR >0 over the follow-up period, although the time to most NPI-Q symptoms was faster for participants who received a CDR >0 (p < 0.001). With the exception of memory, Geriatric Depression Scale symptoms reported by both CDR groups were similar. Conclusions: We found a significantly earlier presence of positive symptoms on the NPI-Q in cognitively normal patients who subsequently developed CDR >0. Among participants with no depression symptoms at baseline, results suggest that depressive symptoms may increase with aging regardless of incipient dementia. Such findings begin to delineate the noncognitive course of Alzheimer disease dementia in the preclinical stages. Future research must further elucidate the correlation between noncognitive changes and distinct dementia subtypes. PMID:25589671
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Pathophysiological role of host microbiota in the development of obesity.
Kobyliak, Nazarii; Virchenko, Oleksandr; Falalyeyeva, Tetyana
2016-04-23
Overweight and obesity increase the risk for a number of diseases, namely, cardiovascular diseases, type 2 diabetes, dyslipidemia, premature death, non-alcoholic fatty liver disease as well as different types of cancer. Approximately 1.7 billion people in the world suffer from being overweight, most notably in developed countries. Current research efforts have focused on host and environmental factors that may affect energy balance. It was hypothesized that a microbiota profile specific to an obese host with increased energy-yielding behavior may exist. Consequently, the gut microbiota is becoming of significant research interest in relation to obesity in an attempt to better understand the aetiology of obesity and to develop new methods of its prevention and treatment. Alteration of microbiota composition may stimulate development of obesity and other metabolic diseases via several mechanisms: increasing gut permeability with subsequent metabolic inflammation; increasing energy harvest from the diet; impairing short-chain fatty acids synthesis; and altering bile acids metabolism and FXR/TGR5 signaling. Prebiotics and probiotics have physiologic functions that contribute to the health of gut microbiota, maintenance of a healthy body weight and control of factors associated with obesity through their effects on mechanisms that control food intake, body weight, gut microbiota and inflammatory processes.
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Automatic Detection of Diseased Tomato Plants Using Thermal and Stereo Visible Light Images
Raza, Shan-e-Ahmed; Prince, Gillian; Clarkson, John P.; Rajpoot, Nasir M.
2015-01-01
Accurate and timely detection of plant diseases can help mitigate the worldwide losses experienced by the horticulture and agriculture industries each year. Thermal imaging provides a fast and non-destructive way of scanning plants for diseased regions and has been used by various researchers to study the effect of disease on the thermal profile of a plant. However, thermal image of a plant affected by disease has been known to be affected by environmental conditions which include leaf angles and depth of the canopy areas accessible to the thermal imaging camera. In this paper, we combine thermal and visible light image data with depth information and develop a machine learning system to remotely detect plants infected with the tomato powdery mildew fungus Oidium neolycopersici. We extract a novel feature set from the image data using local and global statistics and show that by combining these with the depth information, we can considerably improve the accuracy of detection of the diseased plants. In addition, we show that our novel feature set is capable of identifying plants which were not originally inoculated with the fungus at the start of the experiment but which subsequently developed disease through natural transmission. PMID:25861025
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Lakatos, Peter L; Sipeki, Nora; Kovacs, Gyorgy; Palyu, Eszter; Norman, Gary L; Shums, Zakera; Golovics, Petra A; Lovasz, Barbara D; Antal-Szalmas, Peter; Papp, Maria
2015-10-01
Early identification of patients with Crohn's disease (CD) at risk of subsequent complications is essential for adapting the treatment strategy. We aimed to develop a prediction model including clinical and serological markers for assessing the probability of developing advanced disease in a prospective referral CD cohort. Two hundred and seventy-one consecutive CD patients (42.4% males, median follow-up 108 months) were included and followed up prospectively. Anti-Saccharomyces cerevisiae antibodies (ASCA IgA/IgG) were determined by enzyme-linked immunosorbent assay. The final analysis was limited to patients with inflammatory disease behaviour at diagnosis. The final definition of advanced disease outcome was having intestinal resection or disease behaviour progression. Antibody (ASCA IgA and/or IgG) status, disease location and need for early azathioprine were included in a 3-, 5- and 7-year prediction matrix. The probability of advanced disease after 5 years varied from 6.2 to 55% depending on the combination of predictors. Similar findings were obtained in Kaplan-Meier analysis; the combination of ASCA, location and early use of azathioprine was associated with the probability of developing advanced disease (p < 0.001, log rank test). Our prediction models identified substantial differences in the probability of developing advanced disease in the early disease course of CD. Markers identified in this referral cohort were different from those previously published in a population-based cohort, suggesting that different prediction models should be used in the referral setting. Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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Duong-Ly, Krisna C.; Devarajan, Karthik; Liang, Shuguang; Horiuchi, Kurumi Y.; Wang, Yuren; Ma, Haiching; Peterson, Jeffrey R.
2016-01-01
Summary Small-molecule kinase inhibitors have typically been designed to inhibit wild-type kinases rather than the mutant forms that frequently arise in diseases such as cancer. Mutations can have serious clinical implications by increasing kinase catalytic activity or conferring therapeutic resistance. To identify opportunities to repurpose inhibitors against disease-associated mutant kinases, we conducted a large-scale functional screen of 183 known kinase inhibitors against 76 recombinant, mutant kinases. The results revealed lead compounds with activity against clinically important mutant kinases including ALK, LRRK2, RET, and EGFR as well as unexpected opportunities for repurposing FDA-approved kinase inhibitors as leads for additional indications. Furthermore, using T674I PDGFRα as an example, we show how single-dose screening data can provide predictive structure-activity data to guide subsequent inhibitor optimization. This study provides a resource for the development of inhibitors against numerous disease-associated mutant kinases and illustrates the potential of unbiased profiling as an approach to compound-centric inhibitor development. PMID:26776524
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[Imaging assessment of bone and cartilage destruction in rheumatoid arthritis].
Hirata, Shintaro; Tanaka, Yoshiya
2015-12-01
Rheumatoid arthritis (RA) is characterized by synovitis and subsequent joint destruction involving bone and cartilage. Recent therapeutic development have improved outcomes including disease activity and structural progression in RA, and standardized procedures of imaging assessment including modified total Sharp score (mTSS) have contributed largely for the development of therapeutic strategy. In addition, ultrasonography and MRI of joints have been recently emerging as novel imaging methods for RA. Here, we review current imaging assessments of bone and cartilage destruction in RA.
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Fragment-based approaches to TB drugs.
Marchetti, Chiara; Chan, Daniel S H; Coyne, Anthony G; Abell, Chris
2018-02-01
Tuberculosis is an infectious disease associated with significant mortality and morbidity worldwide, particularly in developing countries. The rise of antibiotic resistance in Mycobacterium tuberculosis (Mtb) urgently demands the development of new drug leads to tackle resistant strains. Fragment-based methods have recently emerged at the forefront of pharmaceutical development as a means to generate more effective lead structures, via the identification of fragment molecules that form weak but high quality interactions with the target biomolecule and subsequent fragment optimization. This review highlights a number of novel inhibitors of Mtb targets that have been developed through fragment-based approaches in recent years.
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Utility of Leflunomide in the Treatment of Drug Resistant Cytomegalovirus Retinitis.
Rifkin, Lana M; Minkus, Caroline L; Pursell, Kenneth; Jumroendararasame, Chaisiri; Goldstein, Debra A
2017-02-01
To describe leflunomide use in the treatment of drug resistant cytomegalovirus retinitis. Leflunomide has been shown to be effective in the treatment of systemic CMV viremia. Retrospective chart review of patients with CMV retinitis treated with leflunomide. Two HIV-negative organ transplant recipients with UL 97 mutation resistant-genotype CMV were identified. Patient 1 developed CMV viremia post-kidney transplant and subsequently bilateral CMV retinitis. Retinitis progressed, despite intravitreal injection of ganciclovir and foscarnet, and IV foscarnet and oral valganciclovir. Retinitis control was achieved with the addition of oral leflunomide. Disease remained inactive for 22 months. Patient 2 developed CMV retinitis after lung transplant. Disease progressed despite intravitreal foscarnet injections and oral valganciclovir. Control of retinitis was achieved with addition of oral leflunomide, allowing cessation of intravitreal therapy. Disease remained inactive until his death. Leflunomide may be considered as a treatment option for resistant CMV retinitis.
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Developmental programming of the metabolic syndrome - critical windows for intervention
Vickers, Mark H
2011-01-01
Metabolic disease results from a complex interaction of many factors, including genetic, physiological, behavioral and environmental influences. The recent rate at which these diseases have increased suggests that environmental and behavioral influences, rather than genetic causes, are fuelling the present epidemic. In this context, the developmental origins of health and disease hypothesis has highlighted the link between the periconceptual, fetal and early infant phases of life and the subsequent development of adult obesity and the metabolic syndrome. Although the mechanisms are yet to be fully elucidated, this programming was generally considered an irreversible change in developmental trajectory. Recent work in animal models suggests that developmental programming of metabolic disorders is potentially reversible by nutritional or targeted therapeutic interventions during the period of developmental plasticity. This review will discuss critical windows of developmental plasticity and possible avenues to ameliorate the development of postnatal metabolic disorders following an adverse early life environment. PMID:21954418
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[Postpartum thyroiditis. A review].
Hurtado-Hernández, Z; Segura-Domínguez, A
2013-01-01
Postpartum thyroiditis (PPT) is a transient thyroid dysfunction of autoimmune origin that can occur in the first year postpartum in women who have not been previously diagnosed with thyroid disease. It may start with clinical thyrotoxicosis followed by hypothyroidism and the subsequent recovery of thyroid function, or may just appear as isolated thyrotoxicosis or hypothyroidism. PPT recurs in high percentage of patients after subsequent pregnancies. Many women develop permanent hypothyroidism sometime during the 3 to 10 year period after an episode of PPT. It is important for family physicians to be familiar with this disease, due to its high prevalence in order to make a correct diagnosis and therapeutic intervention. Family doctors also play a crucial role in the monitoring of these patients, given the negative implications of established hypothyroidism on reproduction in the female population during their reproductive years. This article reviews the principle characteristics of PPT along with its diagnosis and treatment. Copyright © 2012 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España. All rights reserved.
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The interaction between stress and exercise, and its impact on brain function.
Russell, Vivienne A; Zigmond, Michael J; Dimatelis, Jacqueline J; Daniels, William M U; Mabandla, Musa V
2014-06-01
In response to acute adversity, emotional signals shift the body into a state that permits rapid detection, identification, and appropriate response to a potential threat. The stress response involves the release of a variety of substances, including neurotransmitters, neurotrophic factors, hormones, and cytokines, that enable the body to deal with the challenges of daily life. The subsequent activation of various physiological systems can be both protective and damaging to the individual, depending on timing, intensity, and duration of the stressor. Successful recovery from stressful challenges during early life leads to strengthening of synaptic connections in health-promoting neural networks and reduced vulnerability to subsequent stressors that can be protective in later life. In contrast, chronic intense uncontrollable stress can be pathogenic and lead to disorders such as depression, anxiety, hypertension, Alzheimer's disease, Parkinson's disease, and an increased toxic response to additional stressors such as traumatic brain injury and stroke. This review briefly explores the interaction between stress experienced at different stages of development and exercise later in life.
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Juvenile rheumatoid arthritis in velo-cardio-facial syndrome: Coincidence of unusual complication?
DOE Office of Scientific and Technical Information (OSTI.GOV)
Rasmussen, S.A.; Williams, C.A.; Gray, B.A.
We report on two patients with velo-cardio-facial syndrome (VCFS) and juvenile rheumatoid arthritis (JRA). The first, a 9-year-old girl, presented with microcephaly, characteristic face, congenital heart disease, and velopharyngeal insufficiency. Fluorescence in situ hybridization (FISH) study showed deletion of D22S75 (N25), confirming the diagnosis of VCFS. At age 7, she developed joint pain, and polyarticular JRA was diagnosed. Awareness of this case led to the subsequent diagnosis of VCFS (also confirmed by FISH) in another, unrelated 12-year-old girl with characteristic face, hypernasal speech, and obesity. JRA was first diagnosed in this case at age 5 years, and she subsequently developedmore » severe polyarticular disease. Neither patient had clinical or laboratory evidence of immunodeficiency. This observation represents the first report of the association of JRA with VCFS and raises the question of whether this is a coincidental association or a rare complication of this condition. 33 refs., 4 figs., 1 tab.« less
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Margolis, Kara Gross
2017-10-01
Many disease conditions considered CNS-predominant harbor significant intestinal comorbidities. Serotonin (5-HT) and the serotonin reuptake transporter (SERT) have increasingly been shown to play important roles in both brain and intestinal development and long-term function. 5-HT and SERT may thus modulate critical functions in the development and perpetuation of brain-gut axis disease. We discuss the potential roles of 5-HT and SERT in the brain and intestinal manifestations of autism spectrum disorders and developmental antidepressant exposure. The potential therapeutic value of 5-HT 4 modulation in the subsequent treatment of these conditions is also addressed. Copyright © 2017 Elsevier B.V. All rights reserved.
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Hazenberg, M P; Pennock-Schröder, A M; van de Merwe, J P
1986-01-01
Agglutinating antibodies to Coprococcus comes and three other obligately anaerobic coccoid rods from the intestinal flora are used in the diagnosis of Crohn's disease. Further studies on the pathogenetic role as well as the development of more sensitive and specific methods for detecting antibodies require extraction of the antigen fractions. Culturing methods to obtain C. comes with optimal antigen presentation and isolation of soluble antigen fractions were therefore developed. Hot water extraction of whole cells and subsequent removal of proteins with trichloroacetic acid provided a fraction that absorbed serum agglutinins, was useful for an enzyme-linked immunosorbent assay and induced agglutinating antibodies in rats.
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Adult celiac disease with acetylcholine receptor antibody positive myasthenia gravis
Freeman, Hugh J; Gillett, Helen R; Gillett, Peter M; Oger, Joel
2009-01-01
Celiac disease has been associated with some autoimmune disorders. A 40-year-old competitive strongman with celiac disease responded to a gluten-free diet, but developed profound and generalized motor weakness with acetylcholine receptor antibody positive myasthenia gravis, a disorder reported to occur in about 1 in 5000. This possible relationship between myasthenia gravis and celiac disease was further explored in serological studies. Frozen stored serum samples from 23 acetylcholine receptor antibody positive myasthenia gravis patients with no intestinal symptoms were used to screen for celiac disease. Both endomysial and tissue transglutaminase antibodies were examined. One of 23 (or, about 4.3%) was positive for both IgA-endomysial and IgA tissue transglutaminase antibodies. Endoscopic studies subsequently showed duodenal mucosal scalloping and biopsies confirmed the histopathological changes of celiac disease. Celiac disease and myasthenia gravis may occur together more often than is currently appreciated. The presence of motor weakness in celiac disease may be a clue to occult myasthenia gravis, even in the absence of intestinal symptoms. PMID:19824105
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Viral myocarditis: potential defense mechanisms within the cardiomyocyte against virus infection.
Yajima, Toshitaka
2011-05-01
Virus infection can inflict significant damage on cardiomyocytes through direct injury and secondary immune reactions, leading to myocarditis and dilated cardiomyopathy. While viral myocarditis or cardiomyopathy is a complication of systemic infection of cardiotropic viruses, most individuals infected with the viruses do not develop significant cardiac disease. However, some individuals proceed to develop severe virus-mediated heart disease. Recent studies have shown that viral infection of cardiomyocytes is required for the development of myocarditis and subsequent cardiomyopathy. This suggests that viral infection of cardiomyocytes can be an important step that determines the pathogenesis of viral myocarditis during systemic infection. Accordingly, this article focuses on potential defense mechanisms within the cardiomyocyte against virus infection. Understanding of the cardiomyocyte defense against invading viruses may give us novel insights into the pathophysiology of viral myocarditis, and enable us to develop innovative strategies of diagnosis and treatment for this challenging clinical entity.
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How to Make a Heart Valve: From Embryonic Development to Bioengineering of Living Valve Substitutes
MacGrogan, Donal; Luxán, Guillermo; Driessen-Mol, Anita; Bouten, Carlijn; Baaijens, Frank; de la Pompa, José Luis
2014-01-01
Cardiac valve disease is a significant cause of ill health and death worldwide, and valve replacement remains one of the most common cardiac interventions in high-income economies. Despite major advances in surgical treatment, long-term therapy remains inadequate because none of the current valve substitutes have the potential for remodeling, regeneration, and growth of native structures. Valve development is coordinated by a complex interplay of signaling pathways and environmental cues that cause disease when perturbed. Cardiac valves develop from endocardial cushions that become populated by valve precursor mesenchyme formed by an epithelial–mesenchymal transition (EMT). The mesenchymal precursors, subsequently, undergo directed growth, characterized by cellular compartmentalization and layering of a structured extracellular matrix (ECM). Knowledge gained from research into the development of cardiac valves is driving exploration into valve biomechanics and tissue engineering directed at creating novel valve substitutes endowed with native form and function. PMID:25368013
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Liu, Feng-Cheng; Huang, Wen-Yen; Lin, Te-Yu; Shen, Chih-Hao; Chou, Yu-Ching; Lin, Cheng-Li; Lin, Kuen-Tze; Kao, Chia-Hung
2015-11-01
The effects of the inflammatory mediators involved in systemic lupus erythematous (SLE) on subsequent Parkinson disease have been reported, but no relevant studies have focused on the association between the 2 diseases. This nationwide population-based study evaluated the risk of Parkinson disease in patients with SLE.We identified 12,817 patients in the Taiwan National Health Insurance database diagnosed with SLE between 2000 and 2010 and compared the incidence rate of Parkinson disease among these patients with that among 51,268 randomly selected age and sex-matched non-SLE patients. A Cox multivariable proportional-hazards model was used to evaluate the risk factors of Parkinson disease in the SLE cohort.We observed an inverse association between a diagnosis of SLE and the risk of subsequent Parkinson disease, with the crude hazard ratio (HR) being 0.60 (95% confidence interval 0.45-0.79) and adjusted HR being 0.68 (95% confidence interval 0.51-0.90). The cumulative incidence of Parkinson disease was 0.83% lower in the SLE cohort than in the non-SLE cohort. The adjusted HR of Parkinson disease decreased as the follow-up duration increased and was decreased among older lupus patients with comorbidity.We determined that patients with SLE had a decreased risk of subsequent Parkinson disease. Further research is required to elucidate the underlying mechanism.
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Portable Video/Digital Retinal Funduscope
NASA Technical Reports Server (NTRS)
Taylor, Gerald R.; Meehan, Richard; Hunter, Norwood; Caputo, Michael; Gibson, C. Robert
1991-01-01
Lightweight, inexpensive electronic and photographic instrument developed for detection, monitoring, and objective quantification of ocular/systemic disease or physiological alterations of retina, blood vessels, or other structures in anterior and posterior chambers of eye. Operated with little training. Functions with human or animal subject seated, recumbent, inverted, or in almost any other orientation; and in hospital, laboratory, field, or other environment. Produces video images viewed directly and/or digitized for simultaneous or subsequent analysis. Also equipped to produce photographs and/or fitted with adaptors to produce stereoscopic or magnified images of skin, nose, ear, throat, or mouth to detect lesions or diseases.
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Williams-Beuren syndrome: pitfalls for diagnosis in limited resources setting.
Lumaka, Aimé; Lukoo, Rita; Mubungu, Gerrye; Lumbala, Paul; Mbayabo, Gloire; Mupuala, Aimée; Tshilobo, Prosper Lukusa; Devriendt, Koenraad
2016-03-01
Patients with Williams-Beuren Syndrome can be recognized clinically, given the characteristic dysmorphism, intellectual disability, and behavior. We report on a Congolese boy with typical WBS facial characteristics. He suffered meningitis and coma at the age of 2 years then subsequently presented with profound intellectual disability and atypical behavior. The WBS was only made at age 8.2 years and confirmed with FISH testing and microarray-CGH. The present report aims to warn clinicians that infections may associate and/or modify a genetic disease as this may be observed in developing countries given the prevalence of infectious diseases.
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The development of a simulation model of the treatment of coronary heart disease.
Cooper, Keith; Davies, Ruth; Roderick, Paul; Chase, Debbie; Raftery, James
2002-11-01
A discrete event simulation models the progress of patients who have had a coronary event, through their treatment pathways and subsequent coronary events. The main risk factors in the model are age, sex, history of previous events and the extent of the coronary vessel disease. The model parameters are based on data collected from epidemiological studies of incidence and prognosis, efficacy studies. national surveys and treatment audits. The simulation results were validated against different sources of data. The initial results show that increasing revascularisation has considerable implications for resource use but has little impact on patient mortality.
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Potential biomarkers of ageing.
Simm, Andreas; Nass, Norbert; Bartling, Babett; Hofmann, Britt; Silber, Rolf-Edgar; Navarrete Santos, Alexander
2008-03-01
Life span in individual humans is very heterogeneous.Thus, the ageing rate, measured as the decline of functional capacity and stress resistance, is different in every individual. There have been attempts made to analyse this individual age, the so-called biological age, in comparison to chronological age. Biomarkers of ageing should help to characterise this biological age and, as age is a major risk factor in many degenerative diseases,could be subsequently used to identify individuals at high risk of developing age-associated diseases or disabilities. Markers based on oxidative stress, protein glycation,inflammation, cellular senescence and hormonal deregulation are discussed.
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Evidence-Based mHealth Chronic Disease Mobile App Intervention Design: Development of a Framework.
Wilhide Iii, Calvin C; Peeples, Malinda M; Anthony Kouyaté, Robin C
2016-02-16
Mobile technology offers new capabilities that can help to drive important aspects of chronic disease management at both an individual and population level, including the ability to deliver real-time interventions that can be connected to a health care team. A framework that supports both development and evaluation is needed to understand the aspects of mHealth that work for specific diseases, populations, and in the achievement of specific outcomes in real-world settings. This framework should incorporate design structure and process, which are important to translate clinical and behavioral evidence, user interface, experience design and technical capabilities into scalable, replicable, and evidence-based mobile health (mHealth) solutions to drive outcomes. The purpose of this paper is to discuss the identification and development of an app intervention design framework, and its subsequent refinement through development of various types of mHealth apps for chronic disease. The process of developing the framework was conducted between June 2012 and June 2014. Informed by clinical guidelines, standards of care, clinical practice recommendations, evidence-based research, best practices, and translated by subject matter experts, a framework for mobile app design was developed and the refinement of the framework across seven chronic disease states and three different product types is described. The result was the development of the Chronic Disease mHealth App Intervention Design Framework. This framework allowed for the integration of clinical and behavioral evidence for intervention and feature design. The application to different diseases and implementation models guided the design of mHealth solutions for varying levels of chronic disease management. The framework and its design elements enable replicable product development for mHealth apps and may provide a foundation for the digital health industry to systematically expand mobile health interventions and validate their effectiveness across multiple implementation settings and chronic diseases.
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Evidence-Based mHealth Chronic Disease Mobile App Intervention Design: Development of a Framework
Peeples, Malinda M; Anthony Kouyaté, Robin C
2016-01-01
Background Mobile technology offers new capabilities that can help to drive important aspects of chronic disease management at both an individual and population level, including the ability to deliver real-time interventions that can be connected to a health care team. A framework that supports both development and evaluation is needed to understand the aspects of mHealth that work for specific diseases, populations, and in the achievement of specific outcomes in real-world settings. This framework should incorporate design structure and process, which are important to translate clinical and behavioral evidence, user interface, experience design and technical capabilities into scalable, replicable, and evidence-based mobile health (mHealth) solutions to drive outcomes. Objective The purpose of this paper is to discuss the identification and development of an app intervention design framework, and its subsequent refinement through development of various types of mHealth apps for chronic disease. Methods The process of developing the framework was conducted between June 2012 and June 2014. Informed by clinical guidelines, standards of care, clinical practice recommendations, evidence-based research, best practices, and translated by subject matter experts, a framework for mobile app design was developed and the refinement of the framework across seven chronic disease states and three different product types is described. Results The result was the development of the Chronic Disease mHealth App Intervention Design Framework. This framework allowed for the integration of clinical and behavioral evidence for intervention and feature design. The application to different diseases and implementation models guided the design of mHealth solutions for varying levels of chronic disease management. Conclusions The framework and its design elements enable replicable product development for mHealth apps and may provide a foundation for the digital health industry to systematically expand mobile health interventions and validate their effectiveness across multiple implementation settings and chronic diseases. PMID:26883135
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Modeling human neurological disorders with induced pluripotent stem cells.
Imaizumi, Yoichi; Okano, Hideyuki
2014-05-01
Human induced pluripotent stem (iPS) cells obtained by reprogramming technology are a source of great hope, not only in terms of applications in regenerative medicine, such as cell transplantation therapy, but also for modeling human diseases and new drug development. In particular, the production of iPS cells from the somatic cells of patients with intractable diseases and their subsequent differentiation into cells at affected sites (e.g., neurons, cardiomyocytes, hepatocytes, and myocytes) has permitted the in vitro construction of disease models that contain patient-specific genetic information. For example, disease-specific iPS cells have been established from patients with neuropsychiatric disorders, including schizophrenia and autism, as well as from those with neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. A multi-omics analysis of neural cells originating from patient-derived iPS cells may thus enable investigators to elucidate the pathogenic mechanisms of neurological diseases that have heretofore been unknown. In addition, large-scale screening of chemical libraries with disease-specific iPS cells is currently underway and is expected to lead to new drug discovery. Accordingly, this review outlines the progress made via the use of patient-derived iPS cells toward the modeling of neurological disorders, the testing of existing drugs, and the discovery of new drugs. The production of human induced pluripotent stem (iPS) cells from the patients' somatic cells and their subsequent differentiation into specific cells have permitted the in vitro construction of disease models that contain patient-specific genetic information. Furthermore, innovations of gene-editing technologies on iPS cells are enabling new approaches for illuminating the pathogenic mechanisms of human diseases. In this review article, we outlined the current status of neurological diseases-specific iPS cell research and described recently obtained knowledge in the form of actual examples. © 2013 International Society for Neurochemistry.
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Tumour mutation status and melanoma recurrence following a negative sentinel lymph node biopsy.
Adler, Nikki R; Wolfe, Rory; McArthur, Grant A; Kelly, John W; Haydon, Andrew; McLean, Catriona A; Mar, Victoria J
2018-05-14
A proportion of patients develop recurrence following a tumour-negative sentinel lymph node biopsy (SLNB). This study aimed to explore whether melanoma patients with BRAF or NRAS mutant tumours have an increased risk of developing disease recurrence following a negative SLNB compared to patients with wild-type tumours. Prospective cohort study of melanoma patients at three tertiary referral centres in Melbourne, who underwent SLNB. Clinical, pathological and molecular characteristics and recurrence data were prospectively recorded. Multivariate Cox proportional hazards regression models estimated the adjusted hazard ratio (aHR) and corresponding 95% confidence interval (CI) for the association between mutation status and development of recurrence following a negative-SLNB. Overall, 344/477 (72.1%) patients had a negative SLNB. Of these, 54 (15.7%) developed subsequent recurrence. The risk of disease recurrence following a negative SLNB was increased for patients with either a BRAF or NRAS mutant tumour compared to wild-type tumours (aHR 1.92, 95% CI: 1.02-3.60, p = 0.04). Melanoma patients with BRAF or NRAS mutant tumours had an increased risk compared to patients with BRAF/NRAS wild-type tumours of developing disease recurrence following a tumour-negative SLNB. The findings also confirm the importance of continued surveillance to monitor for disease recurrence among SLNB-negative patients.
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Rest tremor in Parkinson's disease: Body distribution and time of appearance.
Gigante, Angelo Fabio; Pellicciari, Roberta; Iliceto, Giovanni; Liuzzi, Daniele; Mancino, Paola Vincenza; Custodero, Giacomo Emanuele; Guido, Marco; Livrea, Paolo; Defazio, Giovanni
2017-04-15
To assess body distribution and timing of appearance of rest tremor in Parkinson's disease. Information was obtained by a computerized database containing historical information collected at the first visit and data collected during the subsequent follow-up visits. Information on rest tremor developed during the follow-up could be therefore obtained by our own observation in a proportion of patients. Among 289 patients, rest tremor was reported at disease onset in 65.4% of cases and detected at last follow-up examination in 74.4% of patients. Analysis of patients who did not report rest tremor at disease onset indicated that 26% of such patients (9% in the overall population) manifested rest tremor over the disease course. Rest tremor spread to new sites in 39% of patients who manifested rest tremor at disease onset. Regardless of tremor presentation at disease onset or during the follow-up, upper limb was the most frequent tremor localization. Over the follow-up, rest tremor developed faster in the upper limb than in other body sites. The risk of developing rest tremor during the follow-up was not affected by sex, side of motor symptom onset and site of tremor presentation. However, age of disease onset >63years was associated with an increased risk of rest tremor spread. This study provides new information about body distribution and timing of rest tremor appearance during the course of early stages of Parkinson's disease that may help clinicians in patients' counselling. Copyright © 2017 Elsevier B.V. All rights reserved.
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Multiple Roles of Pitx2 in Cardiac Development and Disease
2017-01-01
Cardiac development is a complex morphogenetic process initiated as bilateral cardiogenic mesoderm is specified at both sides of the gastrulating embryo. Soon thereafter, these cardiogenic cells fuse at the embryonic midline configuring a symmetrical linear cardiac tube. Left/right bilateral asymmetry is first detected in the forming heart as the cardiac tube bends to the right, and subsequently, atrial and ventricular chambers develop. Molecular signals emanating from the node confer distinct left/right signalling pathways that ultimately lead to activation of the homeobox transcription factor Pitx2 in the left side of distinct embryonic organ anlagen, including the developing heart. Asymmetric expression of Pitx2 has therefore been reported during different cardiac developmental stages, and genetic deletion of Pitx2 provided evidence of key regulatory roles of this transcription factor during cardiogenesis and thus congenital heart diseases. More recently, impaired Pitx2 function has also been linked to arrhythmogenic processes, providing novel roles in the adult heart. In this manuscript, we provide a state-of-the-art review of the fundamental roles of Pitx2 during cardiogenesis, arrhythmogenesis and its contribution to congenital heart diseases. PMID:29367545
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Nycz, Bryan T; Dominguez, Samuel R; Friedman, Deborah; Hilden, Joanne M; Ir, Diana; Robertson, Charles E; Frank, Daniel N
2018-01-01
Bloodstream infections (BSI) and Clostridium difficile infections (CDI) in pediatric oncology/hematology/bone marrow transplant (BMT) populations are associated with significant morbidity and mortality. The objective of this study was to explore possible associations between altered microbiome composition and the occurrence of BSI and CDI in a cohort of pediatric oncology patients. Stool samples were collected from all patients admitted to the pediatric oncology floor from Oct.-Dec. 2012. Bacterial profiles from patient stools were determined by bacterial 16S rRNA gene profiling. Differences in overall microbiome composition were assessed by a permutation-based multivariate analysis of variance test, while differences in the relative abundances of specific taxa were assessed by Kruskal-Wallis tests. At admission, 9 of 42 patients (21%) were colonized with C. difficile, while 6 of 42 (14%) subsequently developed a CDI. Furthermore, 3 patients (7%) previously had a BSI and 6 patients (14%) subsequently developed a BSI. Differences in overall microbiome composition were significantly associated with disease type (p = 0.0086), chemotherapy treatment (p = 0.018), BSI following admission from any cause (p < 0.0001) or suspected gastrointestinal organisms (p = 0.00043). No differences in baseline microbiota were observed between individuals who did or did not subsequently develop C. difficile infection. Additionally, multiple bacterial groups varied significantly between subjects with post-admission BSI compared with no BSI. Our results suggest that differences in gut microbiota not only are associated with type of cancer and chemotherapy, but may also be predictive of subsequent bloodstream infection.
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2013-01-01
aquatic plants and subsequent ecological consequences. The authors of this technical note have linked avian vacuolar myelinopathy (AVM), a disease...additional cyanobacteria sequences to determine designations for probe development, to advance understanding of the species’ phylogeny , and to lay...groundwork for its formal description. Phylogeny data confirm that the species is in section V, order Stigonematales. Phylogeny also infers that the
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van der Lely, Aart J; Gomez, Roy; Pleil, Andreas; Badia, Xavier; Brue, Thierry; Buchfelder, Michael; Burman, Pia; Clemmons, David; Ghigo, Ezio; Jørgensen, Jens Otto Lunde; Luger, Anton; van der Lans-Bussemaker, Joli; Webb, Susan M; Strasburger, Christian J
2017-12-01
Despite availability of multimodal treatment options for acromegaly, achievement of long-term disease control is suboptimal in a significant number of patients. Furthermore, disease control as defined by biochemical normalization may not always show concordance with disease-related symptoms or patient's perceived quality of life. We developed and validated a tool to measure disease activity in acromegaly to support decision-making in clinical practice. An international expert panel (n = 10) convened to define the most critical indicators of disease activity. Patient scenarios were constructed based on these chosen parameters. Subsequently, a panel of 21 renowned endocrinologists at pituitary centers (Europe and Canada) categorized each scenario as stable, mild, or significant disease activity in an online validation study. From expert opinion, five parameters emerged as the best overall indicators to evaluate disease activity: insulin-like growth factor I (IGF-I) level, tumor status, presence of comorbidities (cardiovascular disease, diabetes, sleep apnea), symptoms, and health-related quality of life. In the validation study, IGF-I and tumor status became the predominant parameters selected for classification of patients with moderate or severe disease activity. If IGF-I level was ≤1.2x upper limit of normal and tumor size not significantly increased, the remaining three parameters contributed to the decision in a compensatory manner. The validation study underlined IGF-I and tumor status for routine clinical decision-making, whereas patient-oriented outcome measures received less medical attention. An Acromegaly Disease Activity Tool (ACRODAT) is in development that might assist clinicians towards a more holistic approach to patient management in acromegaly.
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Development of a Metabolic Biosignature for Detection of Early Lyme Disease
Molins, Claudia R.; Ashton, Laura V.; Wormser, Gary P.; Hess, Ann M.; Delorey, Mark J.; Mahapatra, Sebabrata; Schriefer, Martin E.; Belisle, John T.
2015-01-01
Background. Early Lyme disease patients often present to the clinic prior to developing a detectable antibody response to Borrelia burgdorferi, the etiologic agent. Thus, existing 2-tier serology-based assays yield low sensitivities (29%–40%) for early infection. The lack of an accurate laboratory test for early Lyme disease contributes to misconceptions about diagnosis and treatment, and underscores the need for new diagnostic approaches. Methods. Retrospective serum samples from patients with early Lyme disease, other diseases, and healthy controls were analyzed for small molecule metabolites by liquid chromatography-mass spectrometry (LC-MS). A metabolomics data workflow was applied to select a biosignature for classifying early Lyme disease and non-Lyme disease patients. A statistical model of the biosignature was trained using the patients' LC-MS data, and subsequently applied as an experimental diagnostic tool with LC-MS data from additional patient sera. The accuracy of this method was compared with standard 2-tier serology. Results. Metabolic biosignature development selected 95 molecular features that distinguished early Lyme disease patients from healthy controls. Statistical modeling reduced the biosignature to 44 molecular features, and correctly classified early Lyme disease patients and healthy controls with a sensitivity of 88% (84%–95%), and a specificity of 95% (90%–100%). Importantly, the metabolic biosignature correctly classified 77%–95% of the of serology negative Lyme disease patients. Conclusions. The data provide proof-of-concept that metabolic profiling for early Lyme disease can achieve significantly greater (P < .0001) diagnostic sensitivity than current 2-tier serology, while retaining high specificity. PMID:25761869
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Diagnosis of Dengue Infection Using Conventional and Biosensor Based Techniques
Parkash, Om; Hanim Shueb, Rafidah
2015-01-01
Dengue is an arthropod-borne viral disease caused by four antigenically different serotypes of dengue virus. This disease is considered as a major public health concern around the world. Currently, there is no licensed vaccine or antiviral drug available for the prevention and treatment of dengue disease. Moreover, clinical features of dengue are indistinguishable from other infectious diseases such as malaria, chikungunya, rickettsia and leptospira. Therefore, prompt and accurate laboratory diagnostic test is urgently required for disease confirmation and patient triage. The traditional diagnostic techniques for the dengue virus are viral detection in cell culture, serological testing, and RNA amplification using reverse transcriptase PCR. This paper discusses the conventional laboratory methods used for the diagnosis of dengue during the acute and convalescent phase and highlights the advantages and limitations of these routine laboratory tests. Subsequently, the biosensor based assays developed using various transducers for the detection of dengue are also reviewed. PMID:26492265
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Rahim, M; Kazi, B M; Bile, K M; Munir, M; Khan, A R
2010-01-01
The disease early warning system (DEWS) was introduced in the immediate aftermath of the 2005 earthquake in Pakistan, with the objective to undertake prompt investigation and mitigation of disease outbreaks. The DEWS network was replicated successfully during subsequent flood and earthquake disasters as well as during the 2008-09 internally displaced persons' crisis. DEWS-generated alerts, prompt investigations and timely responses had an effective contribution to the control of epidemics. Through DEWS, 1360 reported alerts during 2005-09 averted the risk of disease outbreaks through pre-emptive necessary measures, while the 187 confirmed outbreaks were effectively controlled. In the aftermath of the disasters, DEWS technology also facilitated the development of a disease-surveillance system that became an integral part of the district health system. This study aims to report the DEWS success and substantiate its lead role as a priority emergency health response intervention.
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Emerging Infections: Lessons from the Viral Hemorrhagic Fevers
Peters, C. J
2006-01-01
Two Institute of Medicine reports since 1992 have emphasized the dangerous and continuing threat to the world from emerging infectious diseases. Working with viral hemorrhagic fevers provides a number of lessons related to the processes that control emergence, the pattern of disease after emergence, and how to cope with these incidents. This short paper uses two arenavirus hemorrhagic fevers to illustrate some of these principles. Argentine and Bolivian hemorrhagic fevers first came to medical attention in the 1950’s. The forces that underlie the emergence of disease in Argentina are not understood, but the Bolivian episode has a reasonably understandable train of events behind it. The Argentine disease had serious impact on the large agricultural economy, and the ecology of the rodent reservoir did not lend itself to control; a vaccine was developed by Argentina and the U.S. with the latter motivated largely by biodefense. The Bolivian disease was controlled in large part by eliminating rodents that invaded towns, and the impact was subsequently below the level needed to trigger drug or vaccine development. These two viruses were important in the recognition of a new family of viruses (Arenaviridae), and this finding of new taxons during the investigation of emerging infectious diseases continues. PMID:18528473
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Foster, Charlie; Hutchinson, Lauren; Arambepola, Carukshi
2008-01-01
During and beyond the twentieth century, urbanization has represented a major demographic shift particularly in the developed world. The rapid urbanization experienced in the developing world brings increased mortality from lifestyle diseases such as cancer and cardiovascular disease. We set out to understand how urbanization has been measured in studies which examined chronic disease as an outcome. Following a pilot search of PUBMED, a full search strategy was developed to identify papers reporting the effect of urbanization in relation to chronic disease in the developing world. Full searches were conducted in MEDLINE, EMBASE, CINAHL, and GLOBAL HEALTH. Of the 868 titles identified in the initial search, nine studies met the final inclusion criteria. Five of these studies used demographic measures (such as population density) at an area level to measure urbanization. Four studies used more complicated summary measures of individual and area level data (such as distance from a city, occupation, home and land ownership) to define urbanization. The papers reviewed were limited by using simple area level summary measures (e.g., urban rural dichotomy) or having to rely on preexisting data at the individual level. Further work is needed to develop a measure of urbanization that treats urbanization as a process and which is sensitive enough to track changes in “urbanicity” and subsequent emergence of chronic disease risk factors and mortality. Electronic supplementary material The online version of this article doi:10.1007/s11524-008-9325-4 contains supplementary material, which is available to authorized users. PMID:18931915
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The impact of strain-specific immunity on Lyme disease incidence is spatially heterogeneous.
Khatchikian, Camilo E; Nadelman, Robert B; Nowakowski, John; Schwartz, Ira; Wormser, Gary P; Brisson, Dustin
2017-12-01
Lyme disease, caused by the bacterium Borrelia burgdorferi, is the most common tick-borne infection in the US. Recent studies have demonstrated that the incidence of human Lyme disease would have been even greater were it not for the presence of strain-specific immunity, which protects previously infected patients against subsequent infections by the same B. burgdorferi strain. Here, spatial heterogeneity is incorporated into epidemiological models to accurately estimate the impact of strain-specific immunity on human Lyme disease incidence. The estimated reduction in the number of Lyme disease cases is greater in epidemiologic models that explicitly include the spatial distribution of Lyme disease cases reported at the county level than those that utilize nationwide data. strain-specific immunity has the greatest epidemiologic impact in geographic areas with the highest Lyme disease incidence due to the greater proportion of people that have been previously infected and have developed strain-specific immunity. Copyright © 2017 Elsevier Inc. All rights reserved.
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Seasonality of childhood infectious diseases in Niono, Mali.
Findley, S E; Medina, D C; Sogoba, N; Guindo, B; Doumbia, S
2010-01-01
Common childhood diseases vary seasonally in Mali, much of the Sahel, and other parts of the world, yet patterns for multiple diseases have rarely been simultaneously described for extended periods at single locations. In this retrospective longitudinal (1996-2004) investigation, we studied the seasonality of malaria, acute respiratory infection and diarrhoea time-series in the district of Niono, Sahelian Mali. We extracted and analysed seasonal patterns from each time-series with the Multiplicative Holt-Winters and Wavelet Transform methods. Subsequently, we considered hypothetical scenarios where successful prevention and intervention measures reduced disease seasonality by 25 or 50% to assess the impact of health programmes on annual childhood morbidity. The results showed that all three disease time-series displayed remarkable seasonal stability. Malaria, acute respiratory infection and diarrhoea peaked in December, March (and September) and August, respectively. Finally, the annual childhood morbidity stemming from each disease diminished 7-26% in the considered hypothetical scenarios. We concluded that seasonality may assist with guiding the development of integrated seasonal disease calendars for programmatic child health promotion activities.
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Martin, Paul J.; Storb, Rainer F.; Bhatia, Smita; Maziarz, Richard T.; Pulsipher, Michael A.; Maris, Michael B.; Davis, Christopher; Deeg, H. Joachim; Lee, Stephanie J.; Maloney, David G.; Sandmaier, Brenda M.; Appelbaum, Frederick R.; Gooley, Theodore A.
2014-01-01
Whether the hematopoietic cell transplantation comorbidity index (HCT-CI) can provide prognostic information about development of acute graft-versus-host disease (GVHD) and subsequent mortality is unknown. Five institutions contributed information on 2985 patients given human leukocyte antigen-matched grafts to address this question. Proportional hazards models were used to estimate the hazards of acute GVHD and post-GVHD mortality after adjustment for known risk variables. Higher HCT-CI scores predicted increased risk of grades 3 to 4 acute GVHD (P < .0001 and c-statistic of 0.64), and tests of interaction suggested that this association was consistent among different conditioning intensities, donor types, and stem cell sources. Probabilities of grades 3 to 4 GVHD were 13%, 18%, and 24% for HCT-CI risk groups of 0, 1 to 4, and ≥5. The HCT-CI was statistically significantly associated with mortality rates following diagnosis of grade 2 (hazard ratio [HR] = 1.24; P < .0001) or grades 3 to 4 acute GVHD (HR = 1.19; P < .0001). Patients with HCT-CI scores of ≥3 who developed grades 3 to 4 acute GVHD had a 2.63-fold higher risk of mortality than those with scores of 0 to 2 and did not develop acute GVHD. Thus, pretransplant comorbidities are associated with the development and severity of acute GVHD and with post-GVHD mortality. The HCT-CI could be useful in designing trials for GVHD prevention and could inform expectations for GVHD treatment trials. PMID:24797298
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Chronic obstructive pulmonary disease associated with increased risk of bipolar disorder.
Su, Vincent Yi-Fong; Hu, Li-Yu; Yeh, Chiu-Mei; Chiang, Huey-Ling; Shen, Cheng-Che; Chou, Kun-Ta; Chen, Tzeng-Ji; Lu, Ti; Tzeng, Cheng-Hwai; Liu, Chia-Jen
2017-05-01
Epidemiological studies have identified a trend in the development of depressive and anxiety disorders following a diagnosis of chronic obstructive pulmonary disease (COPD). However, the relationship between COPD and subsequent bipolar disorder remains unclear. From January 1, 2000, we identified adult patients with COPD from the Taiwan National Health Insurance Research Database. A nationwide population-based study was conducted; 46,778 COPD patients and 46,778 age-, sex-, and comorbidity-matched subjects between 2000 and 2011 were enrolled. The two cohorts were followed up till December 31, 2011 and observed for occurrence of bipolar disorder. We observed the COPD and comparison cohorts for 263,020 and 267,895 person-years, respectively, from 2000 to 2011. The incidence rate for bipolar disorder was 1.6/1000 person-years in the COPD cohort and 1.2/1000 person-years in the comparison cohort ( p < 0.001). After multivariate adjustment, the hazard ratio (HR) for subsequent bipolar disorder among the COPD patients was 1.42 (95% confidence interval [CI], 1.22-1.64; p < 0.001). In the COPD patients, short-acting beta-agonists (SABAs) was associated with a significantly increased risk of bipolar disorder development (HR = 1.83, 95% CI = 1.25-2.69, p = 0.002). Other COPD medications were not associated with the risk of bipolar disorder development. The study results indicate that COPD may be an independent risk factor for the development of bipolar disorder. The regular use of SABAs might increase the risk of bipolar disorder in COPD patients.
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Boege, Yannick; Malehmir, Mohsen; Healy, Marc E; Bettermann, Kira; Lorentzen, Anna; Vucur, Mihael; Ahuja, Akshay K; Böhm, Friederike; Mertens, Joachim C; Shimizu, Yutaka; Frick, Lukas; Remouchamps, Caroline; Mutreja, Karun; Kähne, Thilo; Sundaravinayagam, Devakumar; Wolf, Monika J; Rehrauer, Hubert; Koppe, Christiane; Speicher, Tobias; Padrissa-Altés, Susagna; Maire, Renaud; Schattenberg, Jörn M; Jeong, Ju-Seong; Liu, Lei; Zwirner, Stefan; Boger, Regina; Hüser, Norbert; Davis, Roger J; Müllhaupt, Beat; Moch, Holger; Schulze-Bergkamen, Henning; Clavien, Pierre-Alain; Werner, Sabine; Borsig, Lubor; Luther, Sanjiv A; Jost, Philipp J; Weinlich, Ricardo; Unger, Kristian; Behrens, Axel; Hillert, Laura; Dillon, Christopher; Di Virgilio, Michela; Wallach, David; Dejardin, Emmanuel; Zender, Lars; Naumann, Michael; Walczak, Henning; Green, Douglas R; Lopes, Massimo; Lavrik, Inna; Luedde, Tom; Heikenwalder, Mathias; Weber, Achim
2017-09-11
Concomitant hepatocyte apoptosis and regeneration is a hallmark of chronic liver diseases (CLDs) predisposing to hepatocellular carcinoma (HCC). Here, we mechanistically link caspase-8-dependent apoptosis to HCC development via proliferation- and replication-associated DNA damage. Proliferation-associated replication stress, DNA damage, and genetic instability are detectable in CLDs before any neoplastic changes occur. Accumulated levels of hepatocyte apoptosis determine and predict subsequent hepatocarcinogenesis. Proliferation-associated DNA damage is sensed by a complex comprising caspase-8, FADD, c-FLIP, and a kinase-dependent function of RIPK1. This platform requires a non-apoptotic function of caspase-8, but no caspase-3 or caspase-8 cleavage. It may represent a DNA damage-sensing mechanism in hepatocytes that can act via JNK and subsequent phosphorylation of the histone variant H2AX. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
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Fetal growth and risk of childhood asthma and allergic disease
Tedner, S G; Örtqvist, A K; Almqvist, C
2012-01-01
Introduction Early genetic and environmental factors have been discussed as potential causes for the high prevalence of asthma and allergic disease in the western world, and knowledge on fetal growth and its consequence on future health and disease development is emerging. Objective This review article is an attempt to summarize research on fetal growth and risk of asthma and allergic disease. Current knowledge and novel findings will be reviewed and open research questions identified, to give basic scientists, immunologists and clinicians an overview of an emerging research field. Methods PubMed-search on pre-defined terms and cross-references. Results Several studies have shown a correlation between low birth weight and/or gestational age and asthma and high birth weight and/or gestational age and atopy. The exact mechanism is not yet clear but both environmental and genetic factors seem to contribute to fetal growth. Some of these factors are confounders that can be adjusted for, and twin studies have been very helpful in this context. Suggested mechanisms behind fetal growth are often linked to the feto-maternal circulation, including the development of placenta and umbilical cord. However, the causal link between fetal growth restriction and subsequent asthma and allergic disease remains unexplained. New research regarding the catch-up growth following growth restriction has posited an alternative theory that diseases later on in life result from rapid catch-up growth rather than intrauterine growth restriction per se. Several studies have found a correlation between a rapid weight gain after birth and development of asthma or wheezing in childhood. Conclusion and clinical relevance Asthma and allergic disease are multifactorial. Several mechanisms seem to influence their development. Additional studies are needed before we fully understand the causal links between fetal growth and development of asthma and allergic diseases. PMID:22994341
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Nutrition and Nonmotor Symptoms of Parkinson's Disease.
Mischley, Laurie K
2017-01-01
To date, no guidelines exist for the screening, evaluation, and management of nutritional status in PD. Dozens of studies demonstrate an association between diet in adulthood with subsequent risk of developing PD. Individuals with PD are at increased risk of malnutrition due to the increased metabolic demands and disease pathophysiology. Risk of malnutrition is further complicated by anosmia, swallowing difficulties, constipation, and drug-nutrient interactions. An emerging body of evidence suggests that the intestinal tract is affected early in the disease, creating therapeutic opportunities for early intervention. Dietary modification and nutritional supplementation may improve symptoms of constipation, depression, insomnia, dystonia, and help prevent cognitive dysfunction. This review summarizes the state of the science related to nutrition and nonmotor symptoms of PD. © 2017 Elsevier Inc. All rights reserved.
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Jenkins, Jill A.; Tiersch, Terrence R.
2011-01-01
Although cryopreservation of sperm has become an accepted technique for selective breeding and genetic improvement in livestock industries, no systematic approach is available for banking germplasm of aquatic species (i.e. embryos, semen and ova). The intent of this chapter is not to provide recommendations for specific measures to eliminate particular pathogens and subsequent diseases, but rather to develop a general framework and strategies for facing the new and unexpected. This chapter presents microbiological and quality assurance concerns for a cryopreservation program. In particular, the chapter identifies organisms transmittable in semen of animals, microorganisms and diseases of importance to aquatic species, pathogen detection issues, methods for prevention and control and how sperm quality can be assessed.
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A new mutation in MT-ND1 m.3928G>C p.V208L causes Leigh disease with infantile spasms.
Wray, Carter D; Friederich, Marisa W; du Sart, Desiree; Pantaleo, Sarah; Smet, Joél; Kucera, Cathlin; Fenton, Laura; Scharer, Gunter; Van Coster, Rudy; Van Hove, Johan L K
2013-11-01
New mutations in mitochondrial DNA encoded genes of complex I are rarely reported. An infant developed Leigh disease with infantile spasms. Complex I enzyme activity was deficient and response to increasing coenzyme Q concentrations was reduced. Complex I assembly was intact. A new mutation in MT-ND1 m.3928G>C p.V208L, affecting a conserved amino acid in a critical domain, part of the coenzyme Q binding pocket, was present at high heteroplasmy. The unaffected mother did not carry measurable mutant mitochondrial DNA, but concern remained for gonadal mosaicism. Prenatal testing was possible for a subsequent sibling. The ND1 p.V208L mutation causes Leigh disease. © 2013.
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Zhang, Qiu-Li; Brenner, Hermann; Koenig, Wolfgang; Rothenbacher, Dietrich
2010-07-01
Chronic kidney disease (CKD) increases risk of coronary heart disease (CHD), but the impact of using different equations for estimating kidney function on CHD is not clear yet. This study described the prognostic value of CKD as defined by various creatinine- (Cr-eGFR) and cystatin C-based estimating (Cys-eGFR) equations and their combinations on subsequent cardiovascular disease (CVD) events in patients with CHD. Cohort study. Patients with coronary heart disease in in-patient rehabilitation and long-term follow-up (mean 63.4 months). 1050 patients with coronary heart disease aged 30-70 years at baseline. CKD was defined as eGFR<60 mL/min/1.73 m2 (CKD stages 3-5) estimated by three Cr-eGFR equations (Cockroft-Gault equation adjusted for body surface area (CG/BSA), Modification of Diet in Renal Disease Study (MDRD) equation, CKD-EPIcrea) and by two Cys-eGFR equations (Arnal-Dade equation, CKD-EPIcys) and a combination. The primary endpoint of our study was subsequent CVD events. During follow-up 118 patients (11.2%) experienced the outcome of our study. CKD assessed by the CG/BSA, MDRD, and CKD-EPIcrea equations showed no statistically significant association with subsequent CVD events after adjustment for multiple covariates (hazard ratio (HR) 1.45 [95% CI, 0.81-2.59], HR 1.47 [95% CI, 0.84-2.60], and HR 1.31 [95% CI, 0.72-2.83], respectively). By contrast, the Cys-eGFR equations were much stronger associated with subsequent CVD endpoints (Arnal-Dade: HR, 2.01 [95% CI, 1.34-3.04]; CKD-EPIcys HR, 2.22 [95% CI, 1.46-3.37]). The CKD-EPIcys also provided the highest area under the curve value. Our study shows that prevalent CKD is an independent risk factor for subsequent CVD in patients with prevalent CHD and implies that Cys-eGFR equations show a better clinical utility compared to the Cr-eGFR equations. Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.
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Weiden, Michael D.; Kwon, Sophia; Caraher, Erin; Berger, Kenneth I.; Reibman, Joan; Rom, William N.; Prezant, David J.; Nolan, Anna
2016-01-01
Biomarkers can be important predictors of disease severity and progression. The intense exposure to particulates and other toxins from the destruction of the World Trade Center (WTC) overwhelmed the lung’s normal protective barriers. The Fire Department of New York (FDNY) cohort not only had baseline pre-exposure lung function measures but also had serum samples banked soon after their WTC exposure. This well phenotyped group of highly exposed first responders is an ideal cohort for biomarker discovery and eventual validation. Disease progression was heterogeneous in this group in that some individuals subsequently developed abnormal lung function while others recovered. Airflow obstruction predominated in WTC exposed patients who were symptomatic. Multiple independent disease pathways may cause this abnormal FEV1 after irritant exposure. WTC exposure activates one or more of these pathways causing abnormal FEV1 in an individual. Our hypothesis was that serum biomarkers expressed within 6 months after World Trade Center (WTC) exposure reflect active disease pathways and predict subsequent development or protection from abnormal FEV1
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Penicillin: the medicine with the greatest impact on therapeutic outcomes.
Kardos, Nelson; Demain, Arnold L
2011-11-01
The principal point of this paper is that the discovery of penicillin and the development of the supporting technologies in microbiology and chemical engineering leading to its commercial scale production represent it as the medicine with the greatest impact on therapeutic outcomes. Our nomination of penicillin for the top therapeutic molecule rests on two lines of evidence concerning the impact of this event: (1) the magnitude of the therapeutic outcomes resulting from the clinical application of penicillin and the subsequent widespread use of antibiotics and (2) the technologies developed for production of penicillin, including both microbial strain selection and improvement plus chemical engineering methods responsible for successful submerged fermentation production. These became the basis for production of all subsequent antibiotics in use today. These same technologies became the model for the development and production of new types of bioproducts (i.e., anticancer agents, monoclonal antibodies, and industrial enzymes). The clinical impact of penicillin was large and immediate. By ushering in the widespread clinical use of antibiotics, penicillin was responsible for enabling the control of many infectious diseases that had previously burdened mankind, with subsequent impact on global population demographics. Moreover, the large cumulative public effect of the many new antibiotics and new bioproducts that were developed and commercialized on the basis of the science and technology after penicillin demonstrates that penicillin had the greatest therapeutic impact event of all times. © Springer-Verlag 2011
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Voutilainen, Markku; Hutri-Kähönen, Nina; Tossavainen, Päivi; Sipponen, Taina; Pitkänen, Niina; Laitinen, Tomi; Jokinen, Eero; Rönnemaa, Tapani; Viikari, Jorma S A; Raitakari, Olli T; Juonala, Markus
2018-04-01
Several genetic and environmental risk factors have been linked to chronic inflammatory bowel disease (IBD). The incidence of IBD has significantly increased in developed countries during last decades. The aim of the present study was to examine childhood risk factors for subsequent IBD diagnosis in a longitudinal cohort study of children and adolescents. A Finnish study population consisting of 3551 children and adolescents originally evaluated as part of the Cardiovascular Risk in Young Finns study in 1980. At baseline, participant BMI, insulin, lipid, C-reactive protein and blood pressure levels, socioeconomic position, dietary habits, and physical activity, were evaluated. In addition, information was gathered on rural residency, severe infections, breast feeding, parental smoking and birth weight. Subsequent IBD diagnosis status was evaluated based on nationwide registries on hospitalisations and drug imbursement decisions. Altogether, 49 participants (1.4%) had IBD diagnosed during the 34 years of register follow-up, of which 31 had ulcerative colitis, 12 Crohn's disease and 6 undetermined colitis. In univariate analyses, significant correlations were observed between childhood HDL-cholesterol (risk ratio (95% CI) for 1-SD change (0.58 (0.42-0.79)) and CRP concentrations (1.20 (1.01-1.43)) with IBD. The inverse association between HDL-cholesterol and IBD remained significant (0.57 (0.39-0.82)) in a multivariable model including data on age, sex and CRP. In addition, a weighted genetic z-score of 71 single nucleotide polymorphisms associated with elevated HDL-cholesterol levels was significantly lower in IBD patients, P=0.01). Low childhood HDL-cholesterol levels are associated with subsequent IBD diagnosis. In addition, a genetic risk score associated with low HDL-cholesterol levels predict later IBD suggesting that HDL-cholesterol metabolism might have a role in the pathogenesis of IBD. Copyright © 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
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Zika Virus Update: More on an Emerging Arboviral Disease in the Western Hemisphere.
Vest, Kelly G
2017-04-01
Zika virus has captivated the world with its quick spread throughout the Western Hemisphere. Increased emphasis has been placed on the infection of pregnant women and subsequent adverse and severe effects in the developing fetus and newborn. This article supplements a previous article and provides updated information on new and evolving evidence that strengthens the association between Zika virus and unique congenital and neurologic diseases, updates what is known about the epidemiology of the disease, and provides new and updated material for primary care providers as they counsel patients who may be exposed or infected. With the extent of disease spread, it is expected that Zika virus will become endemic to the Western Hemisphere and will change the public health parameters and approach in this area of the world. (Disaster Med Public Health Preparedness. 2017;11:163-167).
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Lyme disease: a rigorous review of diagnostic criteria and treatment.
Borchers, Andrea T; Keen, Carl L; Huntley, Arthur C; Gershwin, M Eric
2015-02-01
Lyme disease was originally identified in Lyme, Connecticut, based upon an unusual cluster of what appeared to be patients with juvenile rheumatoid arthritis. It was subsequently identified as a new clinical entity originally called Lyme arthritis based on the observation that arthritis was a major clinical feature. However, Lyme arthritis is now called Lyme disease based upon the understanding that the clinical features include not only arthritis, but also potential cardiac, dermatologic and neurologic findings. Lyme disease typically begins with an erythematous rash called erythema migrans (EM). Approximately 4-8% of patients develop cardiac, 11% develop neurologic and 45-60% of patients manifest arthritis. The disease is transmitted following exposure to a tick bite containing a spirochete in a genetically susceptible host. There is considerable data on spirochetes, including Borrelia burgdorferi (Bb), the original bacteria identified in this disease. Lyme disease, if an organism had not been identified, would be considered as a classic autoimmune disease and indeed the effector mechanisms are similar to many human diseases manifest as loss of tolerance. The clinical diagnosis is highly likely based upon appropriate serology and clinical manifestations. However, the serologic features are often misinterpreted and may have false positives if confirmatory laboratory testing is not performed. Antibiotics are routinely and typically used to treat patients with Lyme disease, but there is no evidence that prolonged or recurrent treatment with antibiotics change the natural history of Lyme disease. Although there are animal models of Lyme disease, there is no system that faithfully recapitulates the human disease. Further research on the effector mechanisms that lead to pathology in some individuals should be further explored to develop more specific therapy. Copyright © 2014 Elsevier Ltd. All rights reserved.
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Assessment and management of soil microbial community structure for disease suppression.
Mazzola, Mark
2004-01-01
Identification of the biological properties contributing to the function of suppressive soils is a necessary first step to the management of such systems for use in the control of soilborne diseases. The development and application of molecular methods for the characterization and monitoring of soil microbial properties will enable a more rapid and detailed assessment of the biological nature of soil suppressiveness. Although suppressive soils have provided a wealth of microbial resources that have subsequently been applied for the biological control of soilborne plant pathogens, the full functional capabilities of the phenomena have not been realized in production agricultural ecosystems. Cultural practices, such as the application of soil amendments, have the capacity to enhance disease suppression, though the biological modes of action may vary from that initially resident to the soil. Plants have a distinct impact on characteristics and activity of resident soil microbial communities, and therefore play an important role in determining the development of the disease-suppressive state. Likewise, plant genotype will modulate these same biological communities, and should be considered when developing strategies to exploit the potential of such a natural disease control system. Implementation of consistently effective practices to manage this resource in an economically and environmentally feasible manner will require more detailed investigation of these biologically complex systems and refinement of currently available methodologies.
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Tanaka, Aki; Kass, Philip H; Martinez-Lopez, Beatriz; Hayama, Shinichi
2017-01-01
The Great East Japan Earthquakes of March 11, 2011 caused immense harm to the community and subsequent nuclear accident in Fukushima Prefecture extended the damage. Local residents were forced to evacuated without pets and the left behind animals were rescued from the restricted zone one month later. Unplanned animal rescue and unregulated sheltering caused secondary damage to animals such as disease epidemics at impounded animal shelter. The purpose of this study was to retrospectively evaluate the incidence of upper respiratory infection (URI) and diarrhea in cats at the first response animal shelter in Fukushima, and investigate factors affecting the duration of disease and determinants of treatments performed. Eighty percent and 59% of impounded cats developed URI, 71% and 54% of cats developed diarrhea, and 91% and 83% of cats had at least one disease in 2011 and 2012, respectively. Uses of multiple drug administration (more than five drugs) was associated with prolonged URI and diarrhea. Multiple antibiotics, antihistamines, interferon, and steroids were associated with relapse of and prolonged URI. Developing a standardized treatment protocol for commonly observed diseases at Japanese animal shelters to prevent and control diseases, to promote animal welfare, and protect public health in the face of future disasters is overdue.
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Kannan, Venkateshan; Swartz, Fredrik; Kiani, Narsis A.; Silberberg, Gilad; Tsipras, Giorgos; Gomez-Cabrero, David; Alexanderson, Kristina; Tegnèr, Jesper
2016-01-01
Health care data holds great promise to be used in clinical decision support systems. However, frequent near-synonymous diagnoses recorded separately, as well as the sheer magnitude and complexity of the disease data makes it challenging to extract non-trivial conclusions beyond confirmatory associations from such a web of interactions. Here we present a systematic methodology to derive statistically valid conditional development of diseases. To this end we utilize a cohort of 5,512,469 individuals followed over 13 years at inpatient care, including data on disability pension and cause of death. By introducing a causal information fraction measure and taking advantage of the composite structure in the ICD codes, we extract an effective directed lower dimensional network representation (100 nodes and 130 edges) of our cohort. Unpacking composite nodes into bipartite graphs retrieves, for example, that individuals with behavioral disorders are more likely to be followed by prescription drug poisoning episodes, whereas women with leiomyoma were more likely to subsequently experience endometriosis. The conditional disease development represent putative causal relations, indicating possible novel clinical relationships and pathophysiological associations that have not been explored yet. PMID:27211115
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2010-01-01
Flawed clinical practice guidelines may compromise patient care. Commercial conflicts of interest on panels that write treatment guidelines are particularly problematic, because panelists may have conflicting agendas that influence guideline recommendations. Historically, there has been no legal remedy for conflicts of interest on guidelines panels. However, in May 2008, the Attorney General of Connecticut concluded a ground-breaking antitrust investigation into the development of Lyme disease treatment guidelines by one of the largest medical societies in the United States, the Infectious Diseases Society of America (IDSA). Although the investigation found significant flaws in the IDSA guidelines development process, the subsequent review of the guidelines mandated by the settlement was compromised by a lack of impartiality at various stages of the IDSA review process. This article will examine the interplay between the recent calls for guidelines reform, the ethical canons of medicine, and due process considerations under antitrust laws as they apply to the formulation of the IDSA Lyme disease treatment guidelines. The article will also discuss pitfalls in the implementation of the IDSA antitrust settlement that should be avoided in the future. PMID:20529367
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Kannan, Venkateshan; Swartz, Fredrik; Kiani, Narsis A; Silberberg, Gilad; Tsipras, Giorgos; Gomez-Cabrero, David; Alexanderson, Kristina; Tegnèr, Jesper
2016-05-23
Health care data holds great promise to be used in clinical decision support systems. However, frequent near-synonymous diagnoses recorded separately, as well as the sheer magnitude and complexity of the disease data makes it challenging to extract non-trivial conclusions beyond confirmatory associations from such a web of interactions. Here we present a systematic methodology to derive statistically valid conditional development of diseases. To this end we utilize a cohort of 5,512,469 individuals followed over 13 years at inpatient care, including data on disability pension and cause of death. By introducing a causal information fraction measure and taking advantage of the composite structure in the ICD codes, we extract an effective directed lower dimensional network representation (100 nodes and 130 edges) of our cohort. Unpacking composite nodes into bipartite graphs retrieves, for example, that individuals with behavioral disorders are more likely to be followed by prescription drug poisoning episodes, whereas women with leiomyoma were more likely to subsequently experience endometriosis. The conditional disease development represent putative causal relations, indicating possible novel clinical relationships and pathophysiological associations that have not been explored yet.
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Guidelines for the treatment of childhood-onset Graves' disease in Japan, 2016.
Minamitani, Kanshi; Sato, Hirokazu; Ohye, Hidemi; Harada, Shohei; Arisaka, Osamu
2017-01-01
Purpose behind developing these guidelines: Over one decade ago, the "Guidelines for the Treatment of Graves' Disease with Antithyroid Drug, 2006" (Japan Thyroid Association (JTA)) were published as the standard drug therapy protocol for Graves' disease. The "Guidelines for the Treatment of Childhood-Onset Graves' Disease with Antithyroid Drug in Japan, 2008" were published to provide guidance on the treatment of pediatric patients. Based on new evidence, a revised version of the "Guidelines for the Treatment of Graves' Disease with Antithyroid Drug, 2006" (JTA) was published in 2011, combined with the "Handbook of Radioiodine Therapy for Graves' Disease 2007" (JTA). Subsequently, newer findings on pediatric Graves' disease have been reported. Propylthiouracil (PTU)-induced serious hepatopathy is an important problem in pediatric patients. The American Thyroid Association's guidelines suggest that, in principle, physicians must not administer PTU to children. On the other hand, the "Guidelines for the Treatment of Graves' Disease with Antithyroid Drug, 2011" (JTA) state that radioiodine therapy is no longer considered a "fundamental contraindication" in children. Therefore, the "Guidelines for the Treatment of Childhood-Onset Graves' Disease with Antithyroid Drug in Japan, 2008" required revision.
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Hypertensive Disorders in Pregnancy and the Risk of Subsequent Cardiovascular Disease.
Grandi, Sonia M; Vallée-Pouliot, Karine; Reynier, Pauline; Eberg, Maria; Platt, Robert W; Arel, Roxane; Basso, Olga; Filion, Kristian B
2017-09-01
Hypertensive disorders in pregnancy (HDP) have been shown to predict later risk of cardiovascular disease (CVD). However, previous studies have not accounted for subsequent pregnancies and their complications, which are potential confounders and intermediates of this association. A cohort of 146 748 women with a first pregnancy was constructed using the Clinical Practice Research Datalink. HDP was defined using diagnostic codes, elevated blood pressure readings, or new use of an anti-hypertensive drug between 18 weeks' gestation and 6 weeks post-partum. The study outcomes were incident CVD and hypertension. Marginal structural Cox models (MSM) were used to account for time-varying confounders and intermediates. Time-fixed exposure defined at the first pregnancy was used in secondary analyses. A total of 997 women were diagnosed with incident CVD, and 6812 women were diagnosed with hypertension or received a new anti-hypertensive medication during the follow-up period. Compared with women without HDP, those with HDP had a substantially higher rate of CVD (hazard ratio (HR) 2.2, 95% confidence interval (CI) 1.7, 2.7). In women with HDP, the rate of hypertension was five times that of women without a HDP (HR 5.6, 95% CI 5.1, 6.3). With overlapping 95% CIs, the time-fixed analysis and the MSM produced consistent results for both outcomes. Women with HDP are at increased risk of developing subsequent CVD and hypertension. Similar estimates obtained with the MSM and the time-fixed analysis suggests that subsequent pregnancies do not confound a first episode of HDP and later CVD. © 2017 John Wiley & Sons Ltd.
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Roles of ZFAT in haematopoiesis, angiogenesis and cancer development.
Tsunoda, Toshiyuki; Shirasawa, Senji
2013-07-01
A zinc-finger gene in autoimmune thyroid disease susceptibility region (ZFAT) was originally identified as a highly conserved immune-related transcriptional regulator containing one adenosine-thymidine (AT)-hook and 18 C2H2-type zinc-finger domains. Subsequently, roles of ZFAT in development, primitive haematopoiesis, angiogenesis, immune responses and several common diseases, such as multiple sclerosis, hypertension and cancer, have been demonstrated. Previously, we recorded a ZFAT protein expression in MOLT-4 human acute T-lymphoblastic leukaemia cells, while ZFAT knockdown activated caspases and induced apoptosis in these cells. Hence, the precise functions of ZFAT are of particular interest in cancer research. In this article, we have reviewed investigations on the roles of ZFAT in haematopoietic and angiogenesis, and discussed the possible involvement of ZFAT in haematopoietic malignancies.
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Hsu, Emory; Phadke, Varun K; Nguyen, Minh Ly T
2016-06-01
We describe an HIV-infected patient initiated on combined antiretroviral therapy (cART) who subsequently developed immune restoration disease (IRD) hyperthyroidism-this case represents one of five such patients seen at our center within the past year. Similar to previous reports of hyperthyroidism due to IRD, all of our patients experienced a rapid early recovery in total CD4 count, but developed symptoms of hyperthyroidism on average 3 years (38 months) after beginning cART, which represents a longer time frame than previously reported. Awareness and recognition of this potential complication of cART, which may occur years after treatment initiation, will allow patients with immune restorative hyperthyroidism to receive timely therapy and avoid the long-term complications associated with undiagnosed thyroid disease.
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Physical Fitness in Adolescence and Subsequent Inflammatory Bowel Disease Risk.
Melinder, Carren; Hiyoshi, Ayako; Hussein, Oula; Halfvarson, Jonas; Ekbom, Anders; Montgomery, Scott
2015-11-05
Physical fitness may reduce systemic inflammation levels relevant to the risk of symptomatic Crohn's disease (CD) and ulcerative colitis (UC); we assessed if fitness in adolescence is associated with subsequent inflammatory bowel disease (IBD) risk, independent of markers of risk and prodromal disease activity. Swedish registers provided information on a cohort of 240,984 men (after exclusions) who underwent military conscription assessments in late adolescence (1969-1976). Follow-up started at least 4 years after the conscription assessment until 31 December 2009 (up to age 57 years). Cox's regression assessed the association of physical fitness with CD (n=986) and UC (n=1,878) in separate models, with adjustment including: socioeconomic conditions in childhood; physical fitness, height, body mass index, and erythrocyte sedimentation rate (ESR) in adolescence; and subsequent diagnoses of IBD. Low fitness was associated with a raised risk of IBD, with unadjusted hazard ratios (and 95% confidence intervals) of 1.62 (1.31-2.00) for CD and 1.36 (1.17-1.59) for UC. The results were attenuated by adjustment, particularly for markers of prodromal disease activity to 1.32 (1.05-1.66) and 1.25 (1.06-1.48), respectively. Raised ESR in adolescence was associated with increased risks for subsequent CD (5.95 (4.47-7.92)) and UC (1.92 (1.46-2.52)). The inverse association of physical fitness with IBD risk is consistent with a protective role for exercise. However, evidence of disease activity before diagnosis was already present in adolescence, suggesting that some or all of the association between fitness and IBD may be due to prodromal disease activity reducing exercise capacity and therefore fitness.
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RNA Interference in Infectious Tropical Diseases
Hong, Young S.
2008-01-01
Introduction of double-stranded RNA (dsRNA) into some cells or organisms results in degradation of its homologous mRNA, a process called RNA interference (RNAi). The dsRNAs are processed into short interfering RNAs (siRNAs) that subsequently bind to the RNA-induced silencing complex (RISC), causing degradation of target mRNAs. Because of this sequence-specific ability to silence target genes, RNAi has been extensively used to study gene functions and has the potential to control disease pathogens or vectors. With this promise of RNAi to control pathogens and vectors, this paper reviews the current status of RNAi in protozoans, animal parasitic helminths and disease-transmitting vectors, such as insects. Many pathogens and vectors cause severe parasitic diseases in tropical regions and it is difficult to control once the host has been invaded. Intracellularly, RNAi can be highly effective in impeding parasitic development and proliferation within the host. To fully realize its potential as a means to control tropical diseases, appropriate delivery methods for RNAi should be developed, and possible off-target effects should be minimized for specific gene suppression. RNAi can also be utilized to reduce vector competence to interfere with disease transmission, as genes critical for pathogenesis of tropical diseases are knockdowned via RNAi. PMID:18344671
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Köebner phenomenon induced by cupping therapy in a psoriasis patient.
Yu, Rui-Xing; Hui, Yun; Li, Cheng-Rang
2013-06-15
Psoriasis is a chronic, immune-mediated inflammatory and refractory disease. The koebner phenomenon, which can be induced by trauma, is common in psoriasis patients. Herein, we report a patient with psoriasis who was treated by cupping therapy and subsequently developed the koebner phenomenon (KP) at the cupped sites. To our knowledge, it is the first report about cupping therapy leading to KP in a psoriasis patient.
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Cakir, Evrim; Ozbek, Mustafa; Sahin, Mustafa; Cakal, Erman; Gungunes, Askin; Ginis, Zeynep; Demirci, Taner; Delibasi, Tuncay
2012-12-18
Women with polycystic ovary syndrome (PCOS) have higher risk for cardiovascular disease (CVD). Heart type fatty acid binding protein (HFABP) has been found to be predictive for myocardial ischemia.Wet ested whether HFABP is the predictor for CVD in PCOS patients, who have an increased risk of cardiovascular disease. This was a prospective, cross sectional controlled study conducted in a training and research hospital.The study population consisted of 46 reproductive-age PCOS women and 28 control subjects. We evaluated anthropometric and metabolic parameters, carotid intima media thickness and HFABP levels in both PCOS patients and control group. Mean fasting insulin, homeostasis model assessment insulin resistance index (HOMA-IR), triglyceride, total cholesterol, low density lipoprotein cholesterol, free testosterone, total testosterone, carotid intima media thickness (CIMT) levels were significantly higher in PCOS patients. Although HFABP levels were higher in PCOS patients, the difference did not reach statistically significant in early age groups. After adjustment for age and body mass index, HFABP level was positive correlated with hsCRP, free testosterone levels, CIMT and HOMA-IR. Heart type free fatty acid binding protein appeared to have an important role in metabolic response and subsequent development of atherosclerosis in insulin resistant, hyperandrogenemic PCOS patients.
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Association of Periodontitis and Subsequent Depression: A Nationwide Population-Based Study.
Hsu, Chih-Chao; Hsu, Yi-Chao; Chen, Hsuan-Ju; Lin, Che-Chen; Chang, Kuang-Hsi; Lee, Chang-Yin; Chong, Lee-Won; Kao, Chia-Hung
2015-12-01
Periodontitis is a systemic and chronic inflammatory disease associated with multiple physical conditions. Distress and depression are other problems affecting the progression of periodontitis. However, the causal relationship between depression and periodontitis has not been adequately investigated. This aim of this study was to determine the association between periodontitis and the subsequent development of depression.We identified 12,708 patients with newly diagnosed periodontitis from 2000 to 2005 and 50,832 frequency-matched individuals without periodontitis. Both groups were followed until diagnosed with depression, withdrawal from the National Health Insurance program, or the end of 2011. The association between periodontitis and depressio was analyzed using Cox proportional hazard regression models.The incidence density rate of depression was higher in the periodontitis group than in the nonperiodontitis group, with an adjusted hazard ratio of 1.73 (95% confidence interval 1.58-1.89) when adjusting for sex, age, and comorbidity. Cox models revealed that periodontitis was an independent risk factor for depression in patients, except for comorbidities of diabetes mellitus (DM), alcohol abuse, and cancer.Periodontitis may increase the risk of subsequent depression and was suggested an independent risk factor regardless of sex, age, and most comorbidities. However, DM, alcohol abuse, and cancer may prevent the development of subsequent depression because of DM treatment, the paradoxical effect of alcohol, and emotional distress to cancer, respectively. Prospective studies on the relationship between periodontitis and depression are warranted.
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Association of Periodontitis and Subsequent Depression
Hsu, Chih-Chao; Hsu, Yi-Chao; Chen, Hsuan-Ju; Lin, Che-Chen; Chang, Kuang-Hsi; Lee, Chang-Yin; Chong, Lee-Won; Kao, Chia-Hung
2015-01-01
Abstract Periodontitis is a systemic and chronic inflammatory disease associated with multiple physical conditions. Distress and depression are other problems affecting the progression of periodontitis. However, the causal relationship between depression and periodontitis has not been adequately investigated. This aim of this study was to determine the association between periodontitis and the subsequent development of depression. We identified 12,708 patients with newly diagnosed periodontitis from 2000 to 2005 and 50,832 frequency-matched individuals without periodontitis. Both groups were followed until diagnosed with depression, withdrawal from the National Health Insurance program, or the end of 2011. The association between periodontitis and depressio was analyzed using Cox proportional hazard regression models. The incidence density rate of depression was higher in the periodontitis group than in the nonperiodontitis group, with an adjusted hazard ratio of 1.73 (95% confidence interval 1.58–1.89) when adjusting for sex, age, and comorbidity. Cox models revealed that periodontitis was an independent risk factor for depression in patients, except for comorbidities of diabetes mellitus (DM), alcohol abuse, and cancer. Periodontitis may increase the risk of subsequent depression and was suggested an independent risk factor regardless of sex, age, and most comorbidities. However, DM, alcohol abuse, and cancer may prevent the development of subsequent depression because of DM treatment, the paradoxical effect of alcohol, and emotional distress to cancer, respectively. Prospective studies on the relationship between periodontitis and depression are warranted. PMID:26705230
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Nephrectomy in patients with Caroli’s and ADPKD may be associated with increased morbidity
Aguilar, Martin; Meterissian, Sarkis; Levesque, Sebastien; Andonian, Sero
2011-01-01
Autosomal dominant polycystic kidney disease (ADPKD), characterized by multiple bilateral renal cysts, is the most common inherited disorder of the kidney and an important cause of end-stage renal disease (ESRD). Caroli’s disease is a much less frequent condition with ectasia of the intrahepatic biliary system. A clear association between autosomal recessive and Caroli’s disease has been described, but only 4 cases of ADPKD and Caroli’s disease have been reported with 2 postoperative mortalities. The aim of this case is to increase the awareness of intra-operative and postoperative complications. A 66 year-old male was diagnosed with ADPKD and Caroli’s disease with hepatosplenomegaly and 4 episodes of ascending cholangitis. After 3 years of hemodialysis for ESRD, he received a cadaveric renal allograft. Subsequently, he developed paroxysmal atrial fibrillation. Upon anticoagulation, he developed multiple episodes of gross hematuria from the left native kidney. After the anticoagulation therapy was discontinued, he underwent bilateral nephrectomies of his native kidneys. Intra-operatively, a splenic laceration could not be managed conservatively. Therefore, splenectomy was performed. In addition, he developed ascending cholangitis post-operatively that was treated with antibiotics. He was discharged on postoperative day 18. Genetic testing revealed that the patient is heterozygote for a large deletion in PKD1 gene, which encompasses all tested exons (exons 1–44). PMID:21470545
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Development of a metabolic biosignature for detection of early Lyme disease.
Molins, Claudia R; Ashton, Laura V; Wormser, Gary P; Hess, Ann M; Delorey, Mark J; Mahapatra, Sebabrata; Schriefer, Martin E; Belisle, John T
2015-06-15
Early Lyme disease patients often present to the clinic prior to developing a detectable antibody response to Borrelia burgdorferi, the etiologic agent. Thus, existing 2-tier serology-based assays yield low sensitivities (29%-40%) for early infection. The lack of an accurate laboratory test for early Lyme disease contributes to misconceptions about diagnosis and treatment, and underscores the need for new diagnostic approaches. Retrospective serum samples from patients with early Lyme disease, other diseases, and healthy controls were analyzed for small molecule metabolites by liquid chromatography-mass spectrometry (LC-MS). A metabolomics data workflow was applied to select a biosignature for classifying early Lyme disease and non-Lyme disease patients. A statistical model of the biosignature was trained using the patients' LC-MS data, and subsequently applied as an experimental diagnostic tool with LC-MS data from additional patient sera. The accuracy of this method was compared with standard 2-tier serology. Metabolic biosignature development selected 95 molecular features that distinguished early Lyme disease patients from healthy controls. Statistical modeling reduced the biosignature to 44 molecular features, and correctly classified early Lyme disease patients and healthy controls with a sensitivity of 88% (84%-95%), and a specificity of 95% (90%-100%). Importantly, the metabolic biosignature correctly classified 77%-95% of the of serology negative Lyme disease patients. The data provide proof-of-concept that metabolic profiling for early Lyme disease can achieve significantly greater (P < .0001) diagnostic sensitivity than current 2-tier serology, while retaining high specificity. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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Sakamoto, M; Wakabayashi, K; Kakita, A; Hitoshi Takahashi; Adachi, T; Nakano, A
1998-02-16
The neurotoxicity of methylmercury (MeHg) treatment during the postnatal developing phase in rats was studied. Rats on postnatal day 1 were orally administered 5 mg/kg/day methylmercury chloride (MMC) for more than 30 consecutive days. Body weight loss began 26 days after MMC was administered, and severe paralysis of the hind-limbs and unsteadiness appeared subsequently. Histopathologically, the widespread neuronal degeneration was observed in the cerebral neocortex, neostriatum, red nucleus, brainstem, cerebellum and spinal dorsal root ganglia on day 32. The widespread distribution of the lesions was quite similar to that in fetal cases of MeHg intoxication in Minamata, Japan. These findings suggest that MMC treatment during the postnatal development phase in rats produce a good model of fetal-type Minamata disease. Copyright 1998 Elsevier Science B.V.
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Refractory rheumatoid vasculitis
Kumar, Ashok; Goel, Anshul; Lapsiwala, Mehul; Singhal, Suman
2016-01-01
Systemic rheumatoid vasculitis (SRV) can develop in rheumatoid arthritis of long duration and high disease activity. It most commonly manifests as cutaneous vasculitis and mononeuritis multiplex. This can involve any organ of the body and carries very high mortality. We report a case of a young male who had rheumatoid arthritis for the past 15 years and became refractory to standard drugs and anti-TNF agents. He subsequently developed SRV, which started as mononeuritis multiplex. Disease progressed to result in gangrene of hands and feet despite receiving intravenous cyclophosphamide. Intravenous immunoglobulin and rituximab also could not provide any response. Prolonged ICU stay resulted in critical care neuromyopathy. Central nervous system vasculitis developed even after repeated infusions of intravenous immunoglobulins and at last he died of complications. In this case report, we have presented rare and chronic protracted presentation of rheumatoid vasculitis involving skin, nerves, brain and testis, which was refractory to the recommended therapies. PMID:28031844
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Persistent hyperthyroidism and de novo Graves' ophthalmopathy after total thyroidectomy.
Tay, Wei Lin; Loh, Wann Jia; Lee, Lianne Ai Ling; Chng, Chiaw Ling
2017-01-01
We report a patient with Graves' disease who remained persistently hyperthyroid after a total thyroidectomy and also developed de novo Graves' ophthalmopathy 5 months after surgery. She was subsequently found to have a mature cystic teratoma containing struma ovarii after undergoing a total hysterectomy and salpingo-oophorectomy for an incidental ovarian lesion. It is important to investigate for other causes of primary hyperthyroidism when thyrotoxicosis persists after total thyroidectomy.TSH receptor antibody may persist after total thyroidectomy and may potentially contribute to the development of de novo Graves' ophthalmopathy.
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Lee, J C
2017-12-01
Genetic studies in complex diseases have been highly successful, but have also been largely one-dimensional: predominantly focusing on the genetic contribution to disease susceptibility. While this is undoubtedly important-indeed it is a pre-requisite for understanding the mechanisms underlying disease development-there are many other important aspects of disease biology that have received comparatively little attention. In this review, I will discuss how existing genetic data can be leveraged to provide new insights into other aspects of disease biology, why such insights could change the way we think about complex disease, and how this could provide opportunities for better therapies and/or facilitate personalised medicine. To do this, I will use the example of Crohn's disease-a chronic form of inflammatory bowel disease that has been one of the main success stories in complex disease genetics. Indeed, thanks to genetic studies, we now have a much more detailed understanding of the processes involved in Crohn's disease development, but still know relatively little about what determines the subsequent disease course (prognosis) and why this differs so considerably between individuals. I will discuss how we came to realise that genetic variation plays an important role in determining disease prognosis and how this has changed the way we think about Crohn's disease genetics. This will illustrate how phenotypic data can be used to leverage new insights from genetic data and will provide a broadly applicable framework that could yield new insights into the biology of multiple diseases. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa
Smith, Yoland; Wichmann, Thomas; Factor, Stewart A; DeLong, Mahlon R
2012-01-01
The demonstration that dopamine loss is the key pathological feature of Parkinson's disease (PD), and the subsequent introduction of levodopa have revolutionalized the field of PD therapeutics. This review will discuss the significant progress that has been made in the development of new pharmacological and surgical tools to treat PD motor symptoms since this major breakthrough in the 1960s. However, we will also highlight some of the challenges the field of PD therapeutics has been struggling with during the past decades. The lack of neuroprotective therapies and the limited treatment strategies for the nonmotor symptoms of the disease (ie, cognitive impairments, autonomic dysfunctions, psychiatric disorders, etc.) are among the most pressing issues to be addressed in the years to come. It appears that the combination of early PD nonmotor symptoms with imaging of the nigrostriatal dopaminergic system offers a promising path toward the identification of PD biomarkers, which, once characterized, will set the stage for efficient use of neuroprotective agents that could slow down and alter the course of the disease. PMID:21956442
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Genetically engineered livestock for biomedical models.
Rogers, Christopher S
2016-06-01
To commemorate Transgenic Animal Research Conference X, this review summarizes the recent progress in developing genetically engineered livestock species as biomedical models. The first of these conferences was held in 1997, which turned out to be a watershed year for the field, with two significant events occurring. One was the publication of the first transgenic livestock animal disease model, a pig with retinitis pigmentosa. Before that, the use of livestock species in biomedical research had been limited to wild-type animals or disease models that had been induced or were naturally occurring. The second event was the report of Dolly, a cloned sheep produced by somatic cell nuclear transfer. Cloning subsequently became an essential part of the process for most of the models developed in the last 18 years and is stilled used prominently today. This review is intended to highlight the biomedical modeling achievements that followed those key events, many of which were first reported at one of the previous nine Transgenic Animal Research Conferences. Also discussed are the practical challenges of utilizing livestock disease models now that the technical hurdles of model development have been largely overcome.
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Subclinical thyrotoxicosis in an outpatient population - predictors of outcome.
Schouten, Belinda J; Brownlie, Bevan E W; Frampton, Chris M; Turner, John G
2011-02-01
Individuals with endogenous subclinical thyrotoxicosis (SCT) may subsequently require treatment for overt disease. We aimed to evaluate the frequency of progression to hyperthyroidism and factors influencing this outcome. This is a retrospective analysis of outcome in 96 consecutive patients (aged 16-91 years) diagnosed with SCT over a 6-year period. Individuals with secondary causes of TSH suppression were excluded. Mean follow-up was 3·8 years. The significance of age, gender, family history of thyrotoxicosis, symptoms at presentation, thyroid nodule(s) on clinical examination, entry TSH level, antithyroid antibody status and (99m) Tc pertechnetate thyroid imaging results on subsequent development of overt thyrotoxicosis was assessed. Progression to overt thyrotoxicosis was seen in 8% at 1 year, 16% at 2 years, 21% at 3 years and 26% at 5 years. Multivariate analysis determined that diagnosis as determined by scintiscan to be the only independent predictor of outcome (P = 0·003) with the cumulative percentage requiring therapy at 5 years being 9% for subclinical Graves' disease, 21% for multinodular goitre and 61% for the autonomous nodule subgroup. Progression of SCT to overt hyperthyroidism occurred at a rate of 5-8% per year with disease aetiology, as determined by thyroid scintigraphy, significantly influencing risk of progression. © 2011 Blackwell Publishing Ltd.
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Maternal determinants of renal mass and function in the fetus and neonate.
Brophy, Patrick
2017-04-01
The impact of adverse maternal and early gestational issues, ranging from maternal-fetal interactions all the way through to premature birth, are recognized as having influence on the subsequent development of chronic diseases later in life. The development of chronic kidney disease (CKD) as a direct result of early life renal injury or a sequela of diseases such as hypertension or diabetes is a good model example of the potential impact that early life events may have on renal development and lifelong function. The global monetary and human resource cost of CKD is exorbitant. Socio-economic factors, along with other factors (genetic and environmental) may significantly influence the timing and display of phenotypic expression in fetuses and neonates at risk for developing CKD, yet very few of these factors are studied or well understood. In general our focus has been directed at treatment once CKD is established. This strategy has been and remains short-sighted and costly. Earlier understanding of the intrauterine determinants of renal mass development (i.e. environmental "biomes", poor maternal-fetal health, socio-economic factors impacting early life events, diet, access to value based health care and educational opportunities on disease evolution) may allow us an opportunity for earlier intervention. This article aims to provide some foundation for improved understanding of the maternal determinants of renal mass and function in the fetus and neonate. Copyright © 2017 Elsevier Ltd. All rights reserved.
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Progression of pathogenic events in cynomolgus macaques infected with variola virus.
Wahl-Jensen, Victoria; Cann, Jennifer A; Rubins, Kathleen H; Huggins, John W; Fisher, Robert W; Johnson, Anthony J; de Kok-Mercado, Fabian; Larsen, Thomas; Raymond, Jo Lynne; Hensley, Lisa E; Jahrling, Peter B
2011-01-01
Smallpox, caused by variola virus (VARV), is a devastating human disease that affected millions worldwide until the virus was eradicated in the 1970 s. Subsequent cessation of vaccination has resulted in an immunologically naive human population that would be at risk should VARV be used as an agent of bioterrorism. The development of antivirals and improved vaccines to counter this threat would be facilitated by the development of animal models using authentic VARV. Towards this end, cynomolgus macaques were identified as adequate hosts for VARV, developing ordinary or hemorrhagic smallpox in a dose-dependent fashion. To further refine this model, we performed a serial sampling study on macaques exposed to doses of VARV strain Harper calibrated to induce ordinary or hemorrhagic disease. Several key differences were noted between these models. In the ordinary smallpox model, lymphoid and myeloid hyperplasias were consistently found whereas lymphocytolysis and hematopoietic necrosis developed in hemorrhagic smallpox. Viral antigen accumulation, as assessed immunohistochemically, was mild and transient in the ordinary smallpox model. In contrast, in the hemorrhagic model antigen distribution was widespread and included tissues and cells not involved in the ordinary model. Hemorrhagic smallpox developed only in the presence of secondary bacterial infections - an observation also commonly noted in historical reports of human smallpox. Together, our results support the macaque model as an excellent surrogate for human smallpox in terms of disease onset, acute disease course, and gross and histopathological lesions.
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Dissection of Host Susceptibility to Bacterial Infections and Its Toxins.
Nashef, Aysar; Agbaria, Mahmoud; Shusterman, Ariel; Lorè, Nicola Ivan; Bragonzi, Alessandra; Wiess, Ervin; Houri-Haddad, Yael; Iraqi, Fuad A
2017-01-01
Infection is one of the leading causes of human mortality and morbidity. Exposure to microbial agents is obviously required. However, also non-microbial environmental and host factors play a key role in the onset, development and outcome of infectious disease, resulting in large of clinical variability between individuals in a population infected with the same microbe. Controlled and standardized investigations of the genetics of susceptibility to infectious disease are almost impossible to perform in humans whereas mouse models allow application of powerful genomic techniques to identify and validate causative genes underlying human diseases with complex etiologies. Most of current animal models used in complex traits diseases genetic mapping have limited genetic diversity. This limitation impedes the ability to create incorporated network using genetic interactions, epigenetics, environmental factors, microbiota, and other phenotypes. A novel mouse genetic reference population for high-resolution mapping and subsequently identifying genes underlying the QTL, namely the Collaborative Cross (CC) mouse genetic reference population (GRP) was recently developed. In this chapter, we discuss a variety of approaches using CC mice for mapping genes underlying quantitative trait loci (QTL) to dissect the host response to polygenic traits, including infectious disease caused by bacterial agents and its toxins.
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Heneghan, MaryKathleen; Alemzadeh, Ramin
2011-12-01
Growth hormone (GH) therapy in children with small for gestational age (SGA) has been shown to be of significant therapeutic benefit. We report the case of an 11-year-old Caucasian male who developed early adrenarche, hypertension and insulin resistance on GH therapy for SGA and profound short stature (ht -5 SD). This patient demonstrated a poor response to GH therapy and developed physical and biochemical findings of insulin resistance responsive to metformin therapy. He remained hypertensive, however, and continued to have elevated serum dehydroepiandrosterone sulfate levels. Urinary free cortisol excretion was subsequently found to be elevated. The diagnosis of Cushing's disease was confirmed with inferior petrosal sinus sampling and pituitary MRI. The patient underwent partial adenohypophysectomy with resulting normalization of plasma cortisol levels and associated symptoms. Our patient's diagnosis of Cushing's disease was complicated by his past history of poor growth since birth and history of SGA. The signs of Cushing's disease did not overtly appear until GH therapy was initiated to help treat severe short stature. It is possible that the metabolic effects of GH therapy unmasked the presence of underlying Cushing's disease.
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2014-01-01
Background The molecular mechanisms causing pigment dispersion syndrome (PDS) and the pathway(s) by which it progresses to pigmentary glaucoma are not known. Mutations in two melanosomal protein genes (Tyrp1 b and Gpnmb R150X ) are responsible for pigment dispersing iris disease, which progresses to intraocular pressure (IOP) elevation and subsequent glaucoma in DBA/2J mice. Melanosomal defects along with ocular immune abnormalities play a role in the propagation of pigment dispersion and progression to IOP elevation. Here, we tested the role of specific immune components in the progression of the iris disease and high IOP. Results We tested the role of NK cells in disease etiology by genetically modifying the B6.D2-Gpnmb R150X Tyrp1 b strain, which develops the same iris disease as DBA/2J mice. Our findings demonstrate that neither diminishing NK mediated cytotoxic activity (Prf1 mutation) nor NK cell depletion (Il2rg mutation) has any influence on the severity or timing of Gpnmb R150X Tyrp1 b mediated iris disease. Since DBA/2J mice are deficient in CD94, an important immune modulator that often acts as an immune suppressor, we generated DBA/2J mice sufficient in CD94. Sufficiency of CD94 failed to alter either the iris disease or the subsequent IOP elevation. Additionally CD94 status had no detected effect on glaucomatous optic nerve damage. Conclusion Our previous data implicate immune components in the manifestation of pigment dispersion and/or IOP elevation in DBA/2J mice. The current study eliminates important immune components, specifically NK cells and CD94 deficiency, as critical in the progression of iris disease and glaucoma. This narrows the field of possible immune components responsible for disease progression. PMID:24678736
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Takimoto, Eiki; Zhang, Ailan; Weiner, Noah C.; Meuchel, Lucas W.; Berger, Alan E.; Cheadle, Chris; Johns, Roger A.
2014-01-01
Pulmonary hypertension (PH) is characterized by elevated pulmonary artery pressure that leads to progressive right heart failure and ultimately death. Injury to endothelium and consequent wound repair cascades have been suggested to trigger pulmonary vascular remodeling, such as that observed during PH. The relationship between injury to endothelium and disease pathogenesis in this disorder remains poorly understood. We and others have shown that, in mice, hypoxia-induced mitogenic factor (HIMF, also known as FIZZ1 or RELMα) plays a critical role in the pathogenesis of lung inflammation and the development of PH. In this study, we dissected the mechanism by which HIMF and its human homolog resistin (hRETN) induce pulmonary endothelial cell (EC) apoptosis and subsequent lung inflammation-mediated PH, which exhibits many of the hallmarks of the human disease. Systemic administration of HIMF caused increases in EC apoptosis and interleukin (IL)-4-dependent vascular inflammatory marker expression in mouse lung during the early inflammation phase. In vitro, HIMF, hRETN, and IL-4 activated pulmonary microvascular ECs (PMVECs) by increasing angiopoietin-2 expression and induced PMVEC apoptosis. In addition, the conditioned medium from hRETN-treated ECs had elevated levels of endothelin-1 and caused significant increases in pulmonary vascular smooth muscle cell proliferation. Last, HIMF treatment caused development of PH that was characterized by pulmonary vascular remodeling and right heart failure in wild-type mice but not in IL-4 knockout mice. These data suggest that HIMF contributes to activation of vascular inflammation at least in part by inducing EC apoptosis in the lung. These events lead to subsequent PH. PMID:24793164
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Ponjoan, Anna; Blanch, Jordi; Alves-Cabratosa, Lia; Martí-Lluch, Ruth; Comas-Cufí, Marc; Parramon, Dídac; Del Mar Garcia-Gil, María; Ramos, Rafel; Petersen, Irene
2017-04-04
Cold spells and heatwaves increase mortality. However little is known about the effect of heatwaves or cold spells on cardiovascular morbidity. This study aims to assess the effect of cold spells and heatwaves on cardiovascular diseases in a Mediterranean region (Catalonia, Southern Europe). We conducted a population-based retrospective study. Data were obtained from the System for the Development of Research in Primary Care and from the Catalan Meteorological Service. The outcome was first emergency hospitalizations due to coronary heart disease, stroke, or heart failure. Exposures were: cold spells; cold spells and 3 or 7 subsequent days; and heatwaves. Incidence rate ratios (IRR) and 95% confidence intervals were calculated using the self-controlled case series method. We accounted for age, time trends, and air pollutants; results were shown by age groups, gender or cardiovascular event type. There were 22,611 cardiovascular hospitalizations in winter and 17,017 in summer between 2006 and 2013. The overall incidence of cardiovascular hospitalizations significantly increased during cold spells (IRR = 1.120; CI 95%: 1.10-1.30) and the effect was even stronger in the 7 days subsequent to the cold spell (IRR = 1.29; CI 95%: 1.22-1.36). Conversely, cardiovascular hospitalizations did not increase during heatwaves, neither in the overall nor in the stratified analysis. Cold spells but not heatwaves, increased the incidence of emergency cardiovascular hospitalizations in Catalonia. The effect of cold spells was greater when including the 7 subsequent days. Such knowledge might be useful to develop strategies to reduce the impact of extreme temperature episodes on human health.
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Activity of single-agent decitabine in atypical chronic myeloid leukemia.
Hausmann, Heidi; Bhatt, Vijaya R; Yuan, Ji; Maness, Lori J; Ganti, Apar K
2016-12-01
Atypical chronic myeloid leukemia is a rare entity that presents diagnostic and therapeutic challenges. Traditionally utilized therapeutic agents such as hydroxyurea or interferon result in a median survival of approximately two years, thus warranting identification of better options. We report a 49-year-old Caucasian female, who presented with extreme leukocytosis (white blood cells of 148,300/µL) with left shift, severe anemia, and thrombocytopenia. Following a diagnosis of atypical chronic myeloid leukemia, she was started on intravenous decitabine. She subsequently developed paraneoplastic vasculitis of large arteries, which responded to high-dose glucocorticoid. Decitabine therapy resulted in an excellent hematologic response, transfusion independence, and successful transition to an allogeneic peripheral stem cell transplantation. However, the patient subsequently succumbed to the complications of acute graft-versus-host-disease. This case illustrates an association between atypical chronic myeloid leukemia and steroid-responsive paraneoplastic vasculitis and highlights the single-agent disease activity of decitabine in atypical chronic myeloid leukemia, which may be utilized as a bridging therapy to allogeneic stem cell transplantation. © The Author(s) 2015.
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Orsucci, D; Rocchi, A; Caldarazzo Ienco, E; Alì, G; LoGerfo, A; Petrozzi, L; Scarpelli, M; Filosto, M; Carlesi, C; Siciliano, G; Bonuccelli, U; Mancuso, M
2014-01-01
Kennedy disease (spinal and bulbar muscular atrophy, or SBMA) is a motor neuron disease caused by a CAG expansion in the androgen-receptor (AR) gene. Increasing evidence shows that SBMA may have a primary myopathic component and that mitochondrial dysfunction may have some role in the pathogenesis of this disease. In this article, we review the role of mitochondrial dysfunction and of the mitochondrial genome (mtDNA) in SBMA, and we present the illustrative case of a patient who presented with increased CK levels and exercise intolerance. Molecular analysis led to definitive diagnosis of SBMA, whereas muscle biopsy showed a mixed myopathic and neurogenic process with "mitochondrial features" and multiple mtDNA deletions, supporting some role of mitochondria in the pathogenesis of the myopathic component of Kennedy disease. Furthermore, we briefly review the role of mitochondrial dysfunction in two other motor neuron diseases (namely spinal muscular atrophy and amyotrophic lateral sclerosis). Most likely, in most cases mtDNA does not play a primary role and it is involved subsequently. MtDNA deletions may contribute to the neurodegenerative process, but the exact mechanisms are still unclear. It will be important to develop a better understanding of the role of mitochondrial dysfunction in motoneuron diseases, since it may lead to the development of more effective strategies for the treatment of this devastating disorder.
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MAPK Usage in Periodontal Disease Progression
Li, Qiyan; Valerio, Michael S.; Kirkwood, Keith L.
2012-01-01
In periodontal disease, host recognition of bacterial constituents, including lipopolysaccharide (LPS), induces p38 MAPK activation and subsequent inflammatory cytokine expression, favoring osteoclastogenesis and increased net bone resorption in the local periodontal environment. In this paper, we discuss evidence that the p38/MAPK-activated protein kinase-2 (MK2) signaling axis is needed for periodontal disease progression: an orally administered p38α inhibitor reduced the progression of experimental periodontal bone loss by reducing inflammation and cytokine expression. Subsequently, the significance of p38 signaling was confirmed with RNA interference to attenuate MK2-reduced cytokine expression and LPS-induced alveolar bone loss. MAPK phosphatase-1 (MKP-1), a negative regulator of MAPK activation, was also critical for periodontal disease progression. In MPK-1-deficient mice, p38-sustained activation increased osteoclast formation and bone loss, whereas MKP-1 overexpression dampened p38 signaling and subsequent cytokine expression. Finally, overexpression of the p38/MK2 target RNA-binding tristetraprolin (TTP) decreased mRNA stability of key inflammatory cytokines at the posttranscriptional level, thereby protecting against periodontal inflammation. Collectively, these studies highlight the importance of p38 MAPK signaling in immune cytokine production and periodontal disease progression. PMID:22315682
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The Honolulu Liver Disease Cluster at the Medical Center: Its Mysteries and Challenges.
Teschke, Rolf; Eickhoff, Axel
2016-03-31
In 2013, physicians at the Honolulu Queen's Medical Center (QMC) noticed that seven liver disease patients reported the use of OxyELITE Pro (OEP), a widely consumed dietary supplement (DS). Assuming a temporal association between OEP use and disease, they argued that OEP was the cause of this mysterious cluster. Subsequent reexamination, however, has revealed that this QMC cohort is heterogeneous and not a cluster with a single agent causing a single disease. It is heterogeneous because patients used multiple DS's and drugs and because patients appeared to have suffered from multiple liver diseases: liver cirrhosis, liver failure by acetaminophen, hepatotoxicity by non-steroidal antiinflammatory drugs (NSAIDs), resolving acute viral hepatitis by hepatitis B virus (HBV), herpes simplex virus (HSV), and varicella zoster virus (VZV), and suspected hepatitis E virus (HEV). Failing to exclude these confounders and to consider more viable diagnoses, the QMC physicians may have missed specific treatment options in some of their patients. The QMC physicians unjustifiably upgraded their Roussel Uclaf Causality Assessment Method (RUCAM) causality scores so that all patients would appear to be "probable" for OEP. However, subsequent RUCAM reassessments by our group demonstrated a lack of causality for OEP in the evaluated QMC cases. The QMC's questionable approaches explain the extraordinary accumulation of suspected OEP cases at the QMC in Hawaii as single place, whereas similar cohorts were not published by any larger US liver center, substantiating that the problem is with the QMC. In this review article, we present and discuss new case data and critically evaluate upcoming developments of problematic regulatory assessments by the US Centers for Disease Control and Prevention (CDC), the Hawaii Department of Health (HDOH), and the Food and Drug Administration (FDA), as based on invalid QMC conclusions, clarifying now also basic facts and facilitating constructive discussions.
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Spaeder, Michael C; Klugman, Darren; Skurow-Todd, Kami; Glass, Penny; Jonas, Richard A; Donofrio, Mary T
2017-03-01
To evaluate the value of perioperative cerebral near-infrared spectroscopy monitoring using variability analysis in the prediction of neurodevelopmental outcomes in neonates undergoing surgery for congenital heart disease. Retrospective cohort study. Urban, academic, tertiary-care children's hospital. Neonates undergoing surgery with cardiopulmonary bypass for congenital heart disease. Perioperative monitoring of continuous cerebral tissue oxygenation index by near-infrared spectroscopy and subsequent neurodevelopmental testing at 6, 15, and 21 months of age. We developed a new measure, cerebral tissue oxygenation index variability, using the root mean of successive squared differences of averaged 1-minute cerebral tissue oxygenation index values for both the intraoperative and first 24-hours postoperative phases of monitoring. There were 62 neonates who underwent cerebral tissue oxygenation index monitoring during surgery for congenital heart disease and 44 underwent subsequent neurodevelopmental testing (12 did not survive until testing and six were lost to follow-up). Among the 44 monitored patients who underwent neurodevelopmental testing, 20 (45%) had abnormal neurodevelopmental indices. Patients with abnormal neurodevelopmental indices had lower postoperative cerebral tissue oxygenation index variability when compared with patients with normal indices (p = 0.01). Adjusting for class of congenital heart disease and duration of deep hypothermic circulatory arrest, lower postoperative cerebral tissue oxygenation index variability was associated with poor neurodevelopmental outcome (p = 0.02). We found reduced postoperative cerebral tissue oxygenation index variability in neonatal survivors of congenital heart disease surgery with poor neurodevelopmental outcomes. We hypothesize that reduced cerebral tissue oxygenation index variability may be a surrogate for impaired cerebral metabolic autoregulation in the immediate postoperative period. Further research is needed to investigate clinical implications of this finding and opportunities for using this measure to drive therapeutic interventions.
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The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD).
Buzzetti, Elena; Pinzani, Massimo; Tsochatzis, Emmanuel A
2016-08-01
Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and represents a growing challenge in terms of prevention and treatment. Despite its high prevalence, only a small minority of affected patients develops inflammation and subsequently fibrosis and chronic liver disease, while most of them only exhibit simple steatosis. In this context, the full understanding of the mechanisms underlying the development of NAFLD and non-alcoholic steatohepatitis (NASH) is of extreme importance; despite advances in this field, knowledge on the pathogenesis of NAFLD is still incomplete. The 'two-hit' hypothesis is now obsolete, as it is inadequate to explain the several molecular and metabolic changes that take place in NAFLD. The "multiple hit" hypothesis considers multiple insults acting together on genetically predisposed subjects to induce NAFLD and provides a more accurate explanation of NAFLD pathogenesis. Such hits include insulin resistance, hormones secreted from the adipose tissue, nutritional factors, gut microbiota and genetic and epigenetic factors. In this article, we review the factors that form this hypothesis. Copyright © 2016 Elsevier Inc. All rights reserved.
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[Demodicosis of dogs--a factorial disease?].
Gothe, R
1989-09-01
Demodex canis is a normal resident of the intact canine skin, being present in small numbers in virtually every dog. Most animals are only carriers of the mites and do not develop clinical symptoms, therefore, demodectic mange has already to be considered as a factorial disease. The modus operandi of transition of clinically inapparent colonization of the mites into a disease may be explained according to investigations so far published multifactorially and thereby essentially as consequences of primary or secondary immunodepression. A primary immunodepression is initially based most probably on a hereditary defect of T-cells and is subsequently reinforced by substances, which are presumably synthesized and liberated not only by mites but also by secondary bacterial agents. A secondary immunodepression operates as trigger mechanism of a clinical manifestation after corticosteroid or cytostatic therapy or in course of underlying diseases of potentially immunodepressive nature, i.e., malignant neoplasia, hepatopathies, hyperadrenocorticism and lymphosarcoma.
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A Fruitful Endeavor: Modeling ALS in the Fruit Fly
Casci, Ian; Pandey, Udai Bhan
2014-01-01
For over a century Drosophila melanogaster, commonly known as the fruit fly, has been instrumental in genetics research and disease modeling. In more recent years, it has been a powerful tool for modeling and studying neurodegenerative diseases, including the devastating and fatal amyotrophic lateral sclerosis (ALS). The success of this model organism in ALS research comes from the availability of tools to manipulate gene/protein expression in a number of desired cell-types, and the subsequent recapitulation of cellular and molecular phenotypic features of the disease. Several Drosophila models have now been developed for studying the roles of ALS-associated genes in disease pathogenesis that allowed us to understand the molecular pathways that lead to motor neuron degeneration in ALS patients. Our primary goal in this review is to highlight the lessons we have learned using Drosophila models pertaining to ALS research. PMID:25289585
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Shared Risk Factors in Cardiovascular Disease and Cancer.
Koene, Ryan J; Prizment, Anna E; Blaes, Anne; Konety, Suma H
2016-03-15
Cardiovascular disease (CVD) and cancer are the 2 leading causes of death worldwide. Although commonly thought of as 2 separate disease entities, CVD and cancer possess various similarities and possible interactions, including a number of similar risk factors (eg, obesity, diabetes mellitus), suggesting a shared biology for which there is emerging evidence. Although chronic inflammation is an indispensable feature of the pathogenesis and progression of both CVD and cancer, additional mechanisms can be found at their intersection. Therapeutic advances, despite improving longevity, have increased the overlap between these diseases, with millions of cancer survivors now at risk of developing CVD. Cardiac risk factors have a major impact on subsequent treatment-related cardiotoxicity. In this review, we explore the risk factors common to both CVD and cancer, highlighting the major epidemiological studies and potential biological mechanisms that account for them. © 2016 American Heart Association, Inc.
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Moris, Demetrios; Avgerinos, Efthymios; Makris, Marinos; Bakoyiannis, Chris; Pikoulis, Emmanuel; Georgopoulos, Sotirios
2014-01-01
Abdominal aortic aneurysm (AAA) is a prevalent and potentially life-threatening disease. Early detection by screening programs and subsequent surveillance has been shown to be effective at reducing the risk of mortality due to aneurysm rupture. The aim of this review is to summarize the developments in the literature concerning the latest biomarkers (from 2008 to date) and their potential screening and therapeutic values. Our search included human studies in English and found numerous novel biomarkers under research, which were categorized in 6 groups. Most of these studies are either experimental or hampered by their low numbers of patients. We concluded that currently no specific laboratory markers allow screeing for the disease and monitoring its progression or the results of treatment. Further studies and studies in larger patient groups are required in order to validate biomarkers as cost-effective tools in the AAA disease. PMID:24967416
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Cano, I; Alonso, M C; Garcia-Rosado, E; Saint-Jean, S Rodriguez; Castro, D; Borrego, Juan J
2006-03-10
An immunoblot technique for the detection of lymphocystis disease virus (LCDV) in naturally infected gilt-head seabream (Sparus aurata, L.) has been developed. A specific antiserum against a 60 kDa viral protein has been proven to be an appropriate tool for LCDV diagnosis either from inoculated cell cultures or from fish tissues using the immunoblot assay. The sensitivity of this technique varied between 10(-1) and 10(2) TCID50. LCDV has also been detected in fish tissues from both, diseased and asymptomatic gilt-head seabream. For the asymptomatic fish detection, a viral amplification step in cell culture and a subsequent viral concentration using polyethylene glycol (PEG) (600 wt) are required. On the contrary, immunoblot allowed the detection of LCDV antigens directly from tissue homogenates of diseased fish. The method described in this study shows higher sensitivity than classical detection techniques based on cell culture inoculation.
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Altered Immune Regulation in Type 1 Diabetes
Zóka, András; Műzes, Györgyi; Somogyi, Anikó; Varga, Tímea; Szémán, Barbara; Al-Aissa, Zahra; Hadarits, Orsolya; Firneisz, Gábor
2013-01-01
Research in genetics and immunology was going on separate strands for a long time. Type 1 diabetes mellitus might not be characterized with a single pathogenetic factor. It develops when a susceptible individual is exposed to potential triggers in a given sequence and timeframe that eventually disarranges the fine-tuned immune mechanisms that keep autoimmunity under control in health. Genomewide association studies have helped to understand the congenital susceptibility, and hand-in-hand with the immunological research novel paths of immune dysregulation were described in central tolerance, apoptotic pathways, or peripheral tolerance mediated by regulatory T-cells. Epigenetic factors are contributing to the immune dysregulation. The interplay between genetic susceptibility and potential triggers is likely to play a role at a very early age and gradually results in the loss of balanced autotolerance and subsequently in the development of the clinical disease. Genetic susceptibility, the impaired elimination of apoptotic β-cell remnants, altered immune regulatory functions, and environmental factors such as viral infections determine the outcome. Autoreactivity might exist under physiologic conditions and when the integrity of the complex regulatory process is damaged the disease might develop. We summarized the immune regulatory mechanisms that might have a crucial role in disease pathology and development. PMID:24285974
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Fuller, L Claire
2013-04-01
Scabies is a common skin infestation globally, particularly in the developing world. With the launch of the International Alliance for the Control of Scabies (IACS) in 2012, this review aims to present the recent evidence of the current epidemiological situation for scabies across the globe. Mindful of the fact that the downstream complications of scabies infestations, pyoderma, streptococcal glomerulonephritis and subsequent chronic renal impairment and rheumatic fever, have been recognized as being more significant to global health than previously acknowledged, the review focusses also on the epidemiological evidence from developing countries. Scabies occurrence rates vary in the recent literature from 2.71 per 1000 to 46%. Although it is responsible for larger disease burdens and complications such as pyoderma and renal and heart disease in the tropics, scabies outbreaks in the developed world amongst vulnerable communities and health institutions contribute a significant cost to the health services managing them. Scabies remains common across the world, but is such a health issue in the developing world that the suggestion that it be considered a neglected tropical disease is a pertinent one. Standardized diagnostic criteria and even a point-of-care diagnostic test would be a major contribution to the understanding of this epidemic.
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Development and validation of an administrative case definition for inflammatory bowel diseases
Rezaie, Ali; Quan, Hude; Fedorak, Richard N; Panaccione, Remo; Hilsden, Robert J
2012-01-01
BACKGROUND: A population-based database of inflammatory bowel disease (IBD) patients is invaluable to explore and monitor the epidemiology and outcome of the disease. In this context, an accurate and validated population-based case definition for IBD becomes critical for researchers and health care providers. METHODS: IBD and non-IBD individuals were identified through an endoscopy database in a western Canadian health region (Calgary Health Region, Calgary, Alberta). Subsequently, using a novel algorithm, a series of case definitions were developed to capture IBD cases in the administrative databases. In the second stage of the study, the criteria were validated in the Capital Health Region (Edmonton, Alberta). RESULTS: A total of 150 IBD case definitions were developed using 1399 IBD patients and 15,439 controls in the development phase. In the validation phase, 318,382 endoscopic procedures were searched and 5201 IBD patients were identified. After consideration of sensitivity, specificity and temporal stability of each validated case definition, a diagnosis of IBD was assigned to individuals who experienced at least two hospitalizations or had four physician claims, or two medical contacts in the Ambulatory Care Classification System database with an IBD diagnostic code within a two-year period (specificity 99.8%; sensitivity 83.4%; positive predictive value 97.4%; negative predictive value 98.5%). An alternative case definition was developed for regions without access to the Ambulatory Care Classification System database. A novel scoring system was developed that detected Crohn disease and ulcerative colitis patients with a specificity of >99% and a sensitivity of 99.1% and 86.3%, respectively. CONCLUSION: Through a robust methodology, a reproducible set of criteria to capture IBD patients through administrative databases was developed. The methodology may be used to develop similar administrative definitions for chronic diseases. PMID:23061064
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Subacute sclerosing panencephalitis presenting as mania
Aggarwal, Ashish; Khandelwal, Ashish; Jain, Manish; Jiloha, R. C.
2011-01-01
Subacute sclerosing panencephalitis (SSPE) is a rare, invariably fatal degenerative disease of the central nervous system developing after measles infection. Besides neurological symptoms as initial presenting symptoms, rare reports of its presentation with pure psychiatric symptoms have been reported. We here report a case of 14 year old male who initially presented with manic symptoms and then subsequently diagnosed to be suffering from SSPE. Improtance of ruling our organic conditions is emphasized. PMID:21808475
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Immunologic responses to therapeutic biologic agents.
Purcell, R T; Lockey, R F
2008-01-01
Recombinant protein technology and the subsequent development of biologic agents for pharmacotherapy have greatly improved the treatment of a wide variety of diseases in humans. These products are subject to reactions not previously seen in other drug classes. Additionally, subtle alteration in the manufacture or administration of a biologic agent may cause reactions in subjects who previously tolerated it. This review highlights the unique immunologic reactions that are associated with the more commonly used biologic agents.
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Metabolomics and Personalized Medicine.
Koen, Nadia; Du Preez, Ilse; Loots, Du Toit
2016-01-01
Current clinical practice strongly relies on the prognosis, diagnosis, and treatment of diseases using methods determined and averaged for the specific diseased cohort/population. Although this approach complies positively with most patients, misdiagnosis, treatment failure, relapse, and adverse drug effects are common occurrences in many individuals, which subsequently hamper the control and eradication of a number of diseases. These incidences can be explained by individual variation in the genome, transcriptome, proteome, and metabolome of a patient. Various "omics" approaches have investigated the influence of these factors on a molecular level, with the intention of developing personalized approaches to disease diagnosis and treatment. Metabolomics, the newest addition to the "omics" domain and the closest to the observed phenotype, reflects changes occurring at all molecular levels, as well as influences resulting from other internal and external factors. By comparing the metabolite profiles of two or more disease phenotypes, metabolomics can be applied to identify biomarkers related to the perturbation being investigated. These biomarkers can, in turn, be used to develop personalized prognostic, diagnostic, and treatment approaches, and can also be applied to the monitoring of disease progression, treatment efficacy, predisposition to drug-related side effects, and potential relapse. In this review, we discuss the contributions that metabolomics has made, and can potentially still make, towards the field of personalized medicine. © 2016 Elsevier Inc. All rights reserved.
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Diseases in marine invertebrates associated with mariculture and commercial fisheries
NASA Astrophysics Data System (ADS)
Sweet, Michael J.; Bateman, Kelly S.
2015-10-01
Diseases in marine invertebrates are increasing in both frequency and intensity around the globe. Diseases in individuals which offer some commercial value are often well documented and subsequently well studied in comparison to those wild groups offering little commercial gain. This is particularly the case with those associated with mariculture or the commercial fisheries. Specifically, these include many Holothuroidea, and numerous crustacea and mollusca species. Pathogens/parasites consisting of both prokaryotes and eukaryotes from all groups have been associated with diseases from such organisms, including bacteria, viruses, fungi and protozoa. Viral pathogens in particular, appear to be an increasingly important group and research into this group will likely highlight a larger number of diseases and pathogens being described in the near future. Interestingly, although there are countless examples of the spread of disease usually associated with transportation of specific infected hosts for development of aquaculture practices, this process appears to be continuing with no real sign of effective management and mitigation strategies being implicated. Notably, even in well developed countries such as the UK and the US, even though live animal trade may be well managed, the transport of frozen food appears to be less well so and as evidence suggests, even these to have the potential to transmit pathogens when used as a food source for example.
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Reprint of 'Diseases in marine invertebrates associated with mariculture and commercial fisheries'
NASA Astrophysics Data System (ADS)
Sweet, Michael J.; Bateman, Kelly S.
2016-07-01
Diseases in marine invertebrates are increasing in both frequency and intensity around the globe. Diseases in individuals which offer some commercial value are often well documented and subsequently well studied in comparison to those wild groups offering little commercial gain. This is particularly the case with those associated with mariculture or the commercial fisheries. Specifically, these include many Holothuroidea, and numerous crustacea and mollusca species. Pathogens/parasites consisting of both prokaryotes and eukaryotes from all groups have been associated with diseases from such organisms, including bacteria, viruses, fungi and protozoa. Viral pathogens in particular, appear to be an increasingly important group and research into this group will likely highlight a larger number of diseases and pathogens being described in the near future. Interestingly, although there are countless examples of the spread of disease usually associated with transportation of specific infected hosts for development of aquaculture practices, this process appears to be continuing with no real sign of effective management and mitigation strategies being implicated. Notably, even in well developed countries such as the UK and the US, even though live animal trade may be well managed, the transport of frozen food appears to be less well so and as evidence suggests, even these to have the potential to transmit pathogens when used as a food source for example.
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Little, S.; Dean, T.; Bevin, S.; Hall, M.; Ashton, M.; Church, M.; Warner, J.; Shute, J.
1995-01-01
BACKGROUND--Pulmonary neutrophilia characterises both the relatively transient inflammation associated with infant respiratory distress syndrome (IRDS) and the persistent inflammation of chronic lung disease. The possibility that persistently raised markers of inflammation indicate the development of chronic lung disease in low birth weight (< 1730 g) preterm (< 31 weeks) infants was therefore investigated. METHODS--Soluble ICAM-1 (sICAM-1) levels in plasma, and interleukin (IL)-8 and myeloperoxidase (MPO) levels in bronchial lavage fluid (BLF) obtained from 17 infants on days 1, 5, and 14 following birth were measured and correlations with the number of neutrophils in BLF sought. Peripheral neutrophils were isolated on Polymorphoprep and chemotactic responsiveness to IL-8 was assessed using micro Boyden chambers. RESULTS--Sixteen infants developed IRDS and, of these, 10 infants subsequently developed chronic lung disease. Levels of IL-8 in BLF at 14 days of age correlated with the long term requirement for intermittent positive pressure ventilation (IPPV). Interleukin 8 levels in BLF correlated with neutrophil numbers and MPO concentration, suggesting both recruitment and activation in response to this cytokine. Antibody depletion studies showed that approximately 50% of total neutrophil chemotactic activity in BLF was due to IL-8. No difference in peripheral neutrophil chemotactic responsiveness at any age was observed for infants with IRDS or chronic lung disease. Plasma soluble intercellular adhesion molecule (sICAM-1) was higher at 14 days of age in infants who developed chronic lung disease than in those with resolving IRDS, and correlated with severity of disease, as indicated by duration of IPPV. CONCLUSIONS--The results indicate that high levels of plasma sICAM-1 and IL-8 in BLF at day 14 correlate with the development of chronic lung disease and indicate the severity of disease. PMID:7491556
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Fowler, Veronica L; Bankowski, Bartlomiej M; Armson, Bryony; Di Nardo, Antonello; Valdazo-Gonzalez, Begoña; Reid, Scott M; Barnett, Paul V; Wadsworth, Jemma; Ferris, Nigel P; Mioulet, Valérie; King, Donald P
2014-01-01
Foot-and-mouth disease Virus (FMDV) is an economically important, highly contagious picornavirus that affects both wild and domesticated cloven hooved animals. In developing countries, the effective laboratory diagnosis of foot-and-mouth disease (FMD) is often hindered by inadequate sample preservation due to difficulties in the transportation and storage of clinical material. These factors can compromise the ability to detect and characterise FMD virus in countries where the disease is endemic. Furthermore, the high cost of sending infectious virus material and the biosecurity risk it presents emphasises the need for a thermo-stable, non-infectious mode of transporting diagnostic samples. This paper investigates the potential of using FMDV lateral-flow devices (LFDs) for dry transportation of clinical samples for subsequent nucleic acid amplification, sequencing and recovery of infectious virus by electroporation. FMDV positive samples (epithelial suspensions and cell culture isolates) representing four FMDV serotypes were applied to antigen LFDs: after which it was possible to recover viral RNA that could be detected using real-time RT-PCR. Using this nucleic acid, it was also possible to recover VP1 sequences and also successfully utilise protocols for amplification of complete FMD virus genomes. It was not possible to recover infectious FMDV directly from the LFDs, however following electroporation into BHK-21 cells and subsequent cell passage, infectious virus could be recovered. Therefore, these results support the use of the antigen LFD for the dry, non-hazardous transportation of samples from FMD endemic countries to international reference laboratories.
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Recommendations for the use of molecular diagnostics in the diagnosis of allergic dis-eases.
Villalta, D; Tonutti, E; Bizzaro, N; Brusca, I; Sargentini, V; Asero, R; Bilo, M B; Manzotti, G; Murzilli, F; Cecchi, L; Musarra, A
2018-03-01
The Study Group on Allergology of the Italian Society of Clinical Pathology and Laboratory Medicine (SIPMeL) and the Associazione Italiana degli Allergologi e Immunologi Territoriali e Ospedalieri (AAIITO) developed the present recommendations on the diagnosis of allergic diseases based on the use of molecular allergenic components, whose purpose is to provide the pathologists and the clinicians with information and algorithms enabling a proper use of this second-level diagnostics. Molecular diagnostics allows definition of the exact sensitization profile of the allergic patient. The methodology followed to develop these recommendations included an initial phase of discussion between all the components to integrate the knowledge derived from scientific evidence, a revision of the recommendations made by Italian and foreign experts, and the subsequent production of this document to be disseminated to all those who deal with allergy diagnostics.
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The prevention of canine leishmaniasis and its impact on public health.
Otranto, Domenico; Dantas-Torres, Filipe
2013-07-01
Canine leishmaniasis (CanL) caused by Leishmania infantum is a vector-borne disease of great veterinary and medical significance. Prevention of CanL requires a combined approach including measures focused on dogs and the environment where the vectors perpetuate. Over past decades, considerable effort has been put towards developing novel and cost-effective strategies against CanL. Vaccination is considered among the most promising tools for controlling CanL, and synthetic pyrethroids are useful and cost-effective in reducing risk of L. infantum infection in dogs. The effectiveness of the use of vaccines plus repellents in preventing L. infantum infection and subsequent disease development should be assessed by means of large-scale, randomized controlled field trials because this combined strategy may become the next frontier in the control of CanL. Copyright © 2013 Elsevier Ltd. All rights reserved.
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Emerging role of IL-35 in inflammatory autoimmune diseases.
Su, Lin-Chong; Liu, Xiao-Yan; Huang, An-Fang; Xu, Wang-Dong
2018-05-03
Interleukin 35 (IL-35) is the recently identified member of the IL-12 family of cytokines and provides the possibility to be a target for new therapies for autoimmune, inflammatory diseases. It is composed of an α chain (p35) and a β chain (EBI3). IL-35 mediates signaling by binding to its receptors, activates subsequent signaling pathways, and therefore, regulates the differentiation, function of T, B cells, macrophages, dendritic cells. Recent findings have shown abnormal expression of IL-35 in inflammatory autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, type 1 diabetes, psoriasis, multiple sclerosis, autoimmune hepatitis, experimental autoimmune uveitis. In addition, functional analysis suggested that IL-35 is critical in the onset and development of these diseases. Therefore, the present study will systematically review what had been occurred regarding IL-35 in inflammatory autoimmune disease. The information collected will help to understand the biologic role of IL-35 in immune cells, and give information about the therapeutic potential of IL-35 in these diseases. Copyright © 2018. Published by Elsevier B.V.
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Effect of Huanglongbing (HLB) disease on orange juice flavor
USDA-ARS?s Scientific Manuscript database
The disease, Huanglongbing (HLB), also called greening or yellow dragon disease was first discovered in Florida in 2005. This is a serious disease of citrus that can kill the tree in 5-10 years. It has also been rumored that the disease causes off-flavor in the fruit and subsequent juice that has be...
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Secondary Pulmonary Hypertension and Right-Sided Heart Failure at Presentation in Grave's Disease.
Ganeshpure, Swapnil Panjabrao; Vaidya, Gaurang Nandkishor; Gattani, Vipul
2012-01-01
A young female presented with evidence of right-sided heart failure and was subsequently found to have significant pulmonary artery hypertension (PAH). Because of her normal left ventricular function and pulmonary capillary wedge pressure, the most probable site of etiology seemed to be the pulmonary vasculature. All the common possible secondary causes of PAH were ruled out, but during the investigations, she was found to have elevated thyroid function tests compatible with the diagnosis of Grave's disease. The treatment of Grave's disease, initially by medications and subsequently by radioiodine therapy, was associated with a significant reduction in the pulmonary artery systolic pressure. The purpose of this case report is to highlight one of the unusual and underdiagnosed presentations of Grave's disease.
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Modelling indirect interactions during failure spreading in a project activity network.
Ellinas, Christos
2018-03-12
Spreading broadly refers to the notion of an entity propagating throughout a networked system via its interacting components. Evidence of its ubiquity and severity can be seen in a range of phenomena, from disease epidemics to financial systemic risk. In order to understand the dynamics of these critical phenomena, computational models map the probability of propagation as a function of direct exposure, typically in the form of pairwise interactions between components. By doing so, the important role of indirect interactions remains unexplored. In response, we develop a simple model that accounts for the effect of both direct and subsequent exposure, which we deploy in the novel context of failure propagation within a real-world engineering project. We show that subsequent exposure has a significant effect in key aspects, including the: (a) final spreading event size, (b) propagation rate, and (c) spreading event structure. In addition, we demonstrate the existence of 'hidden influentials' in large-scale spreading events, and evaluate the role of direct and subsequent exposure in their emergence. Given the evidence of the importance of subsequent exposure, our findings offer new insight on particular aspects that need to be included when modelling network dynamics in general, and spreading processes specifically.
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Type 3c (pancreatogenic) diabetes mellitus secondary to chronic pancreatitis and pancreatic cancer.
Hart, Phil A; Bellin, Melena D; Andersen, Dana K; Bradley, David; Cruz-Monserrate, Zobeida; Forsmark, Christopher E; Goodarzi, Mark O; Habtezion, Aida; Korc, Murray; Kudva, Yogish C; Pandol, Stephen J; Yadav, Dhiraj; Chari, Suresh T
2016-11-01
Diabetes mellitus is a group of diseases defined by persistent hyperglycaemia. Type 2 diabetes, the most prevalent form, is characterised initially by impaired insulin sensitivity and subsequently by an inadequate compensatory insulin response. Diabetes can also develop as a direct consequence of other diseases, including diseases of the exocrine pancreas. Historically, diabetes due to diseases of the exocrine pancreas was described as pancreatogenic or pancreatogenous diabetes mellitus, but recent literature refers to it as type 3c diabetes. It is important to note that type 3c diabetes is not a single entity; it occurs because of a variety of exocrine pancreatic diseases with varying mechanisms of hyperglycaemia. The most commonly identified causes of type 3c diabetes are chronic pancreatitis, pancreatic ductal adenocarcinoma, haemochromatosis, cystic fibrosis, and previous pancreatic surgery. In this Review, we discuss the epidemiology, pathogenesis, and clinical relevance of type 3c diabetes secondary to chronic pancreatitis and pancreatic ductal adenocarcinoma, and highlight several important knowledge gaps. Copyright © 2016 Elsevier Ltd. All rights reserved.
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Type 3c (pancreatogenic) diabetes mellitus secondary to chronic pancreatitis and pancreatic cancer
Hart, Phil A; Bellin, Melena D; Andersen, Dana K; Bradley, David; Cruz-Monserrate, Zobeida; Forsmark, Christopher E; Goodarzi, Mark O; Habtezion, Aida; Korc, Murray; Kudva, Yogish C; Pandol, Stephen J; Yadav, Dhiraj; Chari, Suresh T
2017-01-01
Diabetes mellitus is a group of diseases defined by persistent hyperglycaemia. Type 2 diabetes, the most prevalent form, is characterised initially by impaired insulin sensitivity and subsequently by an inadequate compensatory insulin response. Diabetes can also develop as a direct consequence of other diseases, including diseases of the exocrine pancreas. Historically, diabetes due to diseases of the exocrine pancreas was described as pancreatogenic or pancreatogenous diabetes mellitus, but recent literature refers to it as type 3c diabetes. It is important to note that type 3c diabetes is not a single entity; it occurs because of a variety of exocrine pancreatic diseases with varying mechanisms of hyperglycaemia. The most commonly identified causes of type 3c diabetes are chronic pancreatitis, pancreatic ductal adenocarcinoma, haemochromatosis, cystic fibrosis, and previous pancreatic surgery. In this Review, we discuss the epidemiology, pathogenesis, and clinical relevance of type 3c diabetes secondary to chronic pancreatitis and pancreatic ductal adenocarcinoma, and highlight several important knowledge gaps. PMID:28404095
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Figueroa, Jonine D; Pfeiffer, Ruth M; Brinton, Louise A; Palakal, Maya M; Degnim, Amy C; Radisky, Derek; Hartmann, Lynn C; Frost, Marlene H; Stallings Mann, Melody L; Papathomas, Daphne; Gierach, Gretchen L; Hewitt, Stephen M; Duggan, Maire A; Visscher, Daniel; Sherman, Mark E
2016-08-01
Lesser degrees of terminal duct-lobular unit (TDLU) involution predict higher breast cancer risk; however, standardized measures to quantitate levels of TDLU involution have only recently been developed. We assessed whether three standardized measures of TDLU involution, with high intra/inter pathologist reproducibility in normal breast tissue, predict subsequent breast cancer risk among women in the Mayo benign breast disease (BBD) cohort. We performed a masked evaluation of biopsies from 99 women with BBD who subsequently developed breast cancer (cases) after a median of 16.9 years and 145 age-matched controls. We assessed three metrics inversely related to TDLU involution: TDLU count/mm(2), median TDLU span (microns, which approximates acini content), and median category of acini counts/TDLU (0-10; 11-20; 21-30; 31-50; >50). Associations with subsequent breast cancer risk for quartiles (or categories of acini counts) of each of these measures were assessed with multivariable conditional logistic regression to estimate odds ratios (ORs) and 95 % confidence intervals (CI). In multivariable models, women in the highest quartile compared to the lowest quartiles of TDLU counts and TDLU span measures were significantly associated with subsequent breast cancer diagnoses; TDLU counts quartile4 versus quartile1, OR = 2.44, 95 %CI 0.96-6.19, p-trend = 0.02; and TDLU spans, quartile4 versus quartile1, OR = 2.83, 95 %CI = 1.13-7.06, p-trend = 0.03. Significant associations with categorical measures of acini counts/TDLU were also observed: compared to women with median category of <10 acini/TDLU, women with >25 acini counts/TDLU were at significantly higher risk, OR = 3.40, 95 %CI 1.03-11.17, p-trend = 0.032. Women with TDLU spans and TDLU count measures above the median were at further increased risk, OR = 3.75 (95 %CI 1.40-10.00, p-trend = 0.008), compared with women below the median for both of these metrics. Similar results were observed for combinatorial metrics of TDLU acini counts/TDLU, and TDLU count. Standardized quantitative measures of TDLU counts and acini counts approximated by TDLU span measures or visually assessed in categories are independently associated with breast cancer risk. Visual assessment of TDLU numbers and acini content, which are highly reproducible between pathologists, could help identify women at high risk for subsequent breast cancer among the million women diagnosed annually with BBD in the US.
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Figueroa, Jonine D.; Pfeiffer, Ruth M.; Brinton, Louise A.; Palakal, Maya M.; Degnim, Amy C.; Radisky, Derek; Hartmann, Lynn C.; Frost, Marlene H.; Mann, Melody L. Stallings; Papathomas, Daphne; Gierach, Gretchen L.; Hewitt, Stephen M.; Duggan, Maire A.; Visscher, Daniel; Sherman, Mark E.
2016-01-01
Lesser degrees of terminal duct-lobular unit (TDLU) involution predict higher breast cancer risk; however, standardized measures to quantitate levels of TDLU involution have only recently been developed. We assessed whether three standardized measures of TDLU involution, with high intra/inter pathologist reproducibility in normal breast tissue, predict subsequent breast cancer risk among women in the Mayo benign breast disease (BBD) cohort. We performed a masked evaluation of biopsies from 99 women with BBD who subsequently developed breast cancer (cases) after a median of 16.9 years and 145 age-matched controls. We assessed three metrics inversely related to TDLU involution: TDLU count/mm2, median TDLU span (microns, which approximates acini content), and median category of acini counts/TDLU (0–10; 11–20; 21–30; 31–50; >50). Associations with subsequent breast cancer risk for quartiles (or categories of acini counts) of each of these measures were assessed with multivariable conditional logistic regression to estimate odds ratios (ORs) and 95 % confidence intervals (CI). In multivariable models, women in the highest quartile compared to the lowest quartiles of TDLU counts and TDLU span measures were significantly associated with subsequent breast cancer diagnoses; TDLU counts quartile4 versus quartile1, OR = 2.44, 95 %CI 0.96–6.19, p-trend = 0.02; and TDLU spans, quartile4 versus quartile1, OR = 2.83, 95 %CI = 1.13–7.06, p-trend = 0.03. Significant associations with categorical measures of acini counts/TDLU were also observed: compared to women with median category of <10 acini/TDLU, women with >25 acini counts/TDLU were at significantly higher risk, OR = 3.40, 95 %CI 1.03–11.17, p-trend = 0.032. Women with TDLU spans and TDLU count measures above the median were at further increased risk, OR = 3.75 (95 %CI 1.40–10.00, p-trend = 0.008), compared with women below the median for both of these metrics. Similar results were observed for combinatorial metrics of TDLU acini counts/TDLU, and TDLU count. Standardized quantitative measures of TDLU counts and acini counts approximated by TDLU span measures or visually assessed in categories are independently associated with breast cancer risk. Visual assessment of TDLU numbers and acini content, which are highly reproducible between pathologists, could help identify women at high risk for subsequent breast cancer among the million women diagnosed annually with BBD in the US. PMID:27488681
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Glynn, Nigel; Bashir, Mohammed; Smith, Diarmuid; Thompson, Christopher J
2014-09-01
Type 1 diabetes mellitus (TIDM) classically presents with symptomatic hyperglycemia and many patients develop diabetic ketoacidosis prior to their diagnosis. However, non-classical presentation or co-presentation with associated diseases may delay diagnosis or lead to challenges in acute, clinical management. An 18-yr-old girl presented to hospital with severe, symptomatic hypoglycemia. Clinical history and serum electrolyte concentrations suggested a diagnosis of adrenal insufficiency. She remained hypoglycemic until glucocorticoid replacement was commenced, at which point she developed persistent hyperglycemia requiring insulin therapy. Subsequent follow up confirmed the diagnosis of Addison's disease (AD), the treatment of which unmasked co-existing type 1 diabetes. Autoimmune diseases often cluster together in affected patients and first-degree relatives. Approximately 1 in 200 patients with T1DM develop AD. However, months or more commonly years usually elapse between the presentation of different autoimmune conditions. The co-diagnosis T1DM and AD in the acute setting is rare. Moreover, the first presentation of T1DM with severe hypoglycemia is even more exceptional. This case highlights the need for vigilance during the acute, emergency management of patients with autoimmune conditions and, in particular, to consider the possibility of concurrent antibody-mediated diseases which may need to be addressed during resuscitation. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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You, Zi-Hong; Perng, Chin-Lin; Hu, Li-Yu; Lu, Ti; Chen, Pan-Ming; Yang, Albert C; Tsai, Shih-Jen; Huang, Yi-Shin; Chen, Hon-Jhe
2015-09-01
Recent studies have shown that the peripheral inflammation may cause the up-regulation of central nervous system inflammation and therefore possibly plays a vital role in the pathophysiology of subsequent psychiatric disorders. We explored the relationship between gastroesophageal reflux disease (GERD) and the subsequent development of psychiatric disorders including schizophrenia as well as bipolar, depressive, anxiety, and sleep disorders. We investigated patients who were diagnosed with GERD according to the data in the Taiwan National Health Insurance Research Database. A comparison cohort comprised patients without GERD who were matched according to age and sex. The incidence rate and the hazard ratios (HRs) of subsequent new-onset psychiatric disorders were calculated for both cohorts, based on the diagnoses of psychiatrists. The GERD cohort consisted of 3813 patients, and the comparison cohort comprised 15,252 matched control patients without GERD. The risks of depressive disorder (HR=3.37, 95% confidence interval [CI]=2.49-4.57), anxiety disorder (HR=2.99, 95% CI=2.12-4.22), and sleep disorder (HR=2.69, 95% CI=1.83-3.94), were higher in the GERD cohort than in the comparison cohort. In addition, the incidence of newly diagnosed depressive, anxiety, and sleep disorders remained significantly increased in all of the stratified follow-up durations (0-1, ≥1year). GERD may increase the risks of subsequent depressive, anxiety, and sleep disorders. These psychiatric disorders have a negative effect on people's quality of life. Clinicians should pay a particular attention to psychiatric comorbidities in GERD patients. Copyright © 2015 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
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Degree of host susceptibility in the initial disease outbreak influences subsequent epidemic spread
Severns, Paul M.; Estep, Laura K.; Sackett, Kathryn E.; Mundt, Christopher C.
2014-01-01
Summary Disease epidemics typically begin as an outbreak of a relatively small, spatially explicit population of infected individuals (focus), in which disease prevalence increases and rapidly spreads into the uninfected, at-risk population. Studies of epidemic spread typically address factors influencing disease spread through the at-risk population, but the initial outbreak may strongly influence spread of the subsequent epidemic.We initiated wheat stripe rust Puccinia striiformis f. sp. tritici epidemics to assess the influence of the focus on final disease prevalence when the degree of disease susceptibility differed between the at-risk and focus populations.When the focus/at-risk plantings consisted of partially genetic resistant and susceptible cultivars, final disease prevalence was statistically indistinguishable from epidemics produced by the focus cultivar in monoculture. In these experimental epidemics, disease prevalence was not influenced by the transition into an at-risk population that differed in disease susceptibility. Instead, the focus appeared to exert a dominant influence on the subsequent epidemic.Final disease prevalence was not consistently attributable to either the focus or the at-risk population when focus/at-risk populations were planted in a factorial set-up with a mixture (~28% susceptible and 72% resistant) and susceptible individuals. In these experimental epidemics, spatial heterogeneity in disease susceptibility within the at-risk population appeared to counter the dominant influence of the focus.Cessation of spore production from the focus (through fungicide/glyphosate application) after 1.3 generations of stripe rust spread did not reduce final disease prevalence, indicating that the focus influence on disease spread is established early in the epidemic.Synthesis and applications. Our experiments indicated that outbreak conditions can be highly influential on epidemic spread, even when disease resistance in the at-risk population is greater than that of the focus. Disease control treatments administered shortly after the initial outbreak within the focus may either prevent an epidemic from occurring or reduce its severity. PMID:25512677
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Intestinal fungi contribute to development of alcoholic liver disease.
Yang, An-Ming; Inamine, Tatsuo; Hochrath, Katrin; Chen, Peng; Wang, Lirui; Llorente, Cristina; Bluemel, Sena; Hartmann, Phillipp; Xu, Jun; Koyama, Yukinori; Kisseleva, Tatiana; Torralba, Manolito G; Moncera, Kelvin; Beeri, Karen; Chen, Chien-Sheng; Freese, Kim; Hellerbrand, Claus; Lee, Serene Ml; Hoffman, Hal M; Mehal, Wajahat Z; Garcia-Tsao, Guadalupe; Mutlu, Ece A; Keshavarzian, Ali; Brown, Gordon D; Ho, Samuel B; Bataller, Ramon; Stärkel, Peter; Fouts, Derrick E; Schnabl, Bernd
2017-06-30
Chronic liver disease with cirrhosis is the 12th leading cause of death in the United States, and alcoholic liver disease accounts for approximately half of all cirrhosis deaths. Chronic alcohol consumption is associated with intestinal bacterial dysbiosis, yet we understand little about the contribution of intestinal fungi, or mycobiota, to alcoholic liver disease. Here we have demonstrated that chronic alcohol administration increases mycobiota populations and translocation of fungal β-glucan into systemic circulation in mice. Treating mice with antifungal agents reduced intestinal fungal overgrowth, decreased β-glucan translocation, and ameliorated ethanol-induced liver disease. Using bone marrow chimeric mice, we found that β-glucan induces liver inflammation via the C-type lectin-like receptor CLEC7A on Kupffer cells and possibly other bone marrow-derived cells. Subsequent increases in IL-1β expression and secretion contributed to hepatocyte damage and promoted development of ethanol-induced liver disease. We observed that alcohol-dependent patients displayed reduced intestinal fungal diversity and Candida overgrowth. Compared with healthy individuals and patients with non-alcohol-related cirrhosis, alcoholic cirrhosis patients had increased systemic exposure and immune response to mycobiota. Moreover, the levels of extraintestinal exposure and immune response correlated with mortality. Thus, chronic alcohol consumption is associated with an altered mycobiota and translocation of fungal products. Manipulating the intestinal mycobiome might be an effective strategy for attenuating alcohol-related liver disease.
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Tzatzalos, Evangeline; Abilez, Oscar J; Shukla, Praveen; Wu, Joseph C
2016-01-15
Engineered heart tissue has emerged as a personalized platform for drug screening. With the advent of induced pluripotent stem cell (iPSC) technology, patient-specific stem cells can be developed and expanded into an indefinite source of cells. Subsequent developments in cardiovascular biology have led to efficient differentiation of cardiomyocytes, the force-producing cells of the heart. iPSC-derived cardiomyocytes (iPSC-CMs) have provided potentially limitless quantities of well-characterized, healthy, and disease-specific CMs, which in turn has enabled and driven the generation and scale-up of human physiological and disease-relevant engineered heart tissues. The combined technologies of engineered heart tissue and iPSC-CMs are being used to study diseases and to test drugs, and in the process, have advanced the field of cardiovascular tissue engineering into the field of precision medicine. In this review, we will discuss current developments in engineered heart tissue, including iPSC-CMs as a novel cell source. We examine new research directions that have improved the function of engineered heart tissue by using mechanical or electrical conditioning or the incorporation of non-cardiomyocyte stromal cells. Finally, we discuss how engineered heart tissue can evolve into a powerful tool for therapeutic drug testing. Copyright © 2015 Elsevier B.V. All rights reserved.
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Job decision latitude, job demands, and cardiovascular disease: a prospective study of Swedish men.
Karasek, R; Baker, D; Marxer, F; Ahlbom, A; Theorell, T
1981-01-01
The association between specific job characteristics and subsequent cardiovascular disease was tested using a large random sample of the male working Swedish population. The prospective development of coronary heart disease (CHD) symptoms and signs was analyzed using a multivariate logistic regression technique. Additionally, a case-controlled study was used to analyze all cardiovascular-cerebrovascular (CHD-CVD) deaths during a six-year follow-up. The indicator of CHD symptoms and signs was validated in a six-year prospective study of CHD deaths (standardized mortality ratio 5.0; p less than or equal to .001). A hectic and psychologically demanding job increases the risk of developing CHD symptoms and signs (standardized odds ratio 1.29, p less than 0.25) and premature CHD-CVD death (relative risk 4.0, p less than .01). Low decision latitude-expressed as low intellectual discretion and low personal schedule freedom-is also associated with increased risk of cardiovascular disease. Low intellectual discretion predicts the development of CHD symptoms and signs (SOR 1.44, p less than .01), while low personal schedule freedom among the majority of workers with the minimum statutory education increases the risk of CHD-CVD death (RR 6.6, p less than .0002). The associations exist after controlling for age, education, smoking, and overweight. PMID:7246835
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Job decision latitude, job demands, and cardiovascular disease: a prospective study of Swedish men.
Karasek, R; Baker, D; Marxer, F; Ahlbom, A; Theorell, T
1981-07-01
The association between specific job characteristics and subsequent cardiovascular disease was tested using a large random sample of the male working Swedish population. The prospective development of coronary heart disease (CHD) symptoms and signs was analyzed using a multivariate logistic regression technique. Additionally, a case-controlled study was used to analyze all cardiovascular-cerebrovascular (CHD-CVD) deaths during a six-year follow-up. The indicator of CHD symptoms and signs was validated in a six-year prospective study of CHD deaths (standardized mortality ratio 5.0; p less than or equal to .001). A hectic and psychologically demanding job increases the risk of developing CHD symptoms and signs (standardized odds ratio 1.29, p less than 0.25) and premature CHD-CVD death (relative risk 4.0, p less than .01). Low decision latitude-expressed as low intellectual discretion and low personal schedule freedom-is also associated with increased risk of cardiovascular disease. Low intellectual discretion predicts the development of CHD symptoms and signs (SOR 1.44, p less than .01), while low personal schedule freedom among the majority of workers with the minimum statutory education increases the risk of CHD-CVD death (RR 6.6, p less than .0002). The associations exist after controlling for age, education, smoking, and overweight.
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Burden and Management of Noncommunicable Diseases After Earthquakes and Tsunamis.
Suneja, Amit; Gakh, Maxim; Rutkow, Lainie
This integrative review examines extant literature assessing the burden and management of noncommunicable diseases 6 months or more after earthquakes and tsunamis. We conducted an integrative review to identify and characterize the strength of published studies about noncommunicable disease-specific outcomes and interventions at least 6 months after an earthquake and/or tsunami. We included disasters that occurred from 2004 to 2016. We focused primarily on the World Health Organization noncommunicable disease designations to define chronic disease, but we also included chronic renal disease, risk factors for noncommunicable diseases, and other chronic diseases or symptoms. After removing duplicates, our search yielded 6,188 articles. Twenty-five articles met our inclusion criteria, some discussing multiple noncommunicable diseases. Results demonstrate that existing medical conditions may worsen and subsequently improve, new diseases may develop, and risk factors, such as weight and cholesterol levels, may increase for several years after an earthquake and/or tsunami. We make 3 recommendations for practitioners and researchers: (1) plan for noncommunicable disease management further into the recovery period of disaster; (2) increase research on the burden of noncommunicable diseases, the treatment modalities employed, resulting population-level outcomes in the postdisaster setting, and existing models to improve stakeholder coordination and action regarding noncommunicable diseases after disasters; and (3) coordinate with preexisting provision networks, especially primary care.
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Cancer linked to Alzheimer disease but not vascular dementia
Roe, C M.; Fitzpatrick, A L.; Xiong, C; Sieh, W; Kuller, L; Miller, J P.; Williams, M M.; Kopan, R; Behrens, M I.; Morris, J C.
2010-01-01
Objective: To investigate whether cancer is associated with Alzheimer disease (AD) and vascular dementia (VaD). Methods: Cox proportional hazards models were used to test associations between prevalent dementia and risk of future cancer hospitalization, and associations between prevalent cancer and risk of subsequent dementia. Participants in the Cardiovascular Health Study–Cognition Substudy, a prospective cohort study, aged 65 years or older (n = 3,020) were followed a mean of 5.4 years for dementia and 8.3 years for cancer. Results: The presence of any AD (pure AD + mixed AD/VaD; hazard ratio [HR] = 0.41, 95% confidence interval [CI] = 0.20–0.84) and pure AD (HR = 0.31, 95% CI = 0.12–0.86) was associated with a reduced risk of future cancer hospitalization, adjusted for demographic factors, smoking, obesity, and physical activity. No significant associations were found between dementia at baseline and rate of cancer hospitalizations for participants with diagnoses of VaD. Prevalent cancer was associated with reduced risk of any AD (HR = 0.72; 95% CI = 0.52–0.997) and pure AD (HR = 0.57; 95% CI = 0.36–0.90) among white subjects after adjustment for demographics, number of APOE ε4 alleles, hypertension, diabetes, and coronary heart disease; the opposite association was found among minorities, but the sample size was too small to provide stable estimates. No significant association was found between cancer and subsequent development of VaD. Conclusions: In white older adults, prevalent Alzheimer disease (AD) was longitudinally associated with a reduced risk of cancer, and a history of cancer was associated with a reduced risk of AD. Together with other work showing associations between cancer and Parkinson disease, these findings suggest the possibility that cancer is linked to neurodegeneration. GLOSSARY 3MSE = modified Mini-Mental State Examination; AD = Alzheimer disease; ADDTC = Alzheimer Disease Diagnostic and Treatment Centers; CHD = coronary heart disease; CHS = Cardiovascular Health Study; CI = confidence interval; HR = hazard ratio; ICD-9 = International Classification of Diseases–Ninth Revision; MCI = mild cognitive impairment; NINCDS-ADRDA = National Institute of Neurological and Communicative Diseases and Stroke–Alzheimer's Disease and Related Disorders Association; PD = Parkinson disease; VaD = vascular dementia. PMID:20032288
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Chronic wasting disease: Bambi vs. the prion
USDA-ARS?s Scientific Manuscript database
Chronic wasting disease (CWD) was first described in Colorado in 1967 and subsequently recognized as a prion disease in 1980. CWD has a long and asymptomatic incubation period (> 1 year) followed by a short disease course that ends in the death of the animal. There is no known treatment or cure for ...
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Fear and distress disorders as predictors of heart disease: a temporal perspective
Roest, AM; de Jonge, P; Lim, C; Stein, DJ; Al-Hamzawi, A; Alonso, J; Benjet, C; Bruffaerts, R; Bunting, B; Caldas-de-Almeida, JM; Ciutan, M; de Girolamo, G; Hu, C; Levinson, D; Nakamura, Y; Navarro-Mateu, F; Piazza, M; Posada-Villa, J; Torres, Y; Wojtyniak, B; Kessler, RC; Scott, KM
2017-01-01
Objective Few studies have been able to contrast associations of anxiety and depression with heart disease. These disorders can be grouped in fear and distress disorders. Aim of this study was to study the association between fear and distress disorders with subsequent heart disease, taking into account the temporal order of disorders. Methods Twenty household surveys were conducted in 18 countries (n=53791; person years=2,212,430). The Composite International Diagnostic Interview assessed lifetime prevalence and age at onset of disorders, and respondents were categorized into categories based on the presence and timing of fear and distress disorders. Heart disease was indicated by self-report of physician-diagnosed heart disease or self-report of heart attack, together with year of onset. Survival analyses estimated associations between disorder categories and heart disease. Results Most respondents with fear or distress disorders had either pure distress or pure fear (8.5% and 7.7% of total sample), while fear preceded distress in the large majority of respondents with comorbid fear and distress (3.8% of total sample). Compared to the “no fear or distress disorder” category, respondents with pure fear disorder had the highest odds of subsequent heart disease (OR:1.8;95%CI:1.5–2.2; p<.001) and compared to respondents with pure distress disorder, these respondents were at a significantly increased risk of heart disease (OR:1.3;95%CI:1.0–1.6; p=0.020). Conclusion This novel analytic approach indicates that the risk of subsequent self-reported heart disease associated with pure fear disorder is significantly larger than the risk associated with distress disorder. These results should be confirmed in prospective studies using objective measures of heart disease. PMID:28545795
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Fear and distress disorders as predictors of heart disease: A temporal perspective.
Roest, A M; de Jonge, P; Lim, C W W; Stein, D J; Al-Hamzawi, A; Alonso, J; Benjet, C; Bruffaerts, R; Bunting, B; Caldas-de-Almeida, J M; Ciutan, M; de Girolamo, G; Hu, C; Levinson, D; Nakamura, Y; Navarro-Mateu, F; Piazza, M; Posada-Villa, J; Torres, Y; Wojtyniak, B; Kessler, R C; Scott, K M
2017-05-01
Few studies have been able to contrast associations of anxiety and depression with heart disease. These disorders can be grouped in fear and distress disorders. Aim of this study was to study the association between fear and distress disorders with subsequent heart disease, taking into account the temporal order of disorders. Twenty household surveys were conducted in 18 countries (n=53791; person years=2,212,430). The Composite International Diagnostic Interview assessed lifetime prevalence and age at onset of disorders, and respondents were categorized into categories based on the presence and timing of fear and distress disorders. Heart disease was indicated by self-report of physician-diagnosed heart disease or self-report of heart attack, together with year of onset. Survival analyses estimated associations between disorder categories and heart disease. Most respondents with fear or distress disorders had either pure distress or pure fear (8.5% and 7.7% of total sample), while fear preceded distress in the large majority of respondents with comorbid fear and distress (3.8% of total sample). Compared to the "no fear or distress disorder" category, respondents with pure fear disorder had the highest odds of subsequent heart disease (OR:1.8; 95%CI:1.5-2.2; p<0.001) and compared to respondents with pure distress disorder, these respondents were at a significantly increased risk of heart disease (OR:1.3; 95%CI:1.0-1.6; p=0.020). This novel analytic approach indicates that the risk of subsequent self-reported heart disease associated with pure fear disorder is significantly larger than the risk associated with distress disorder. These results should be confirmed in prospective studies using objective measures of heart disease. Copyright © 2017. Published by Elsevier Inc.
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Kwan, Jennifer L; Seitz, Amy E; Fried, Michal; Lee, Kun-Lin; Metenou, Simon; Morrison, Robert; Kabyemela, Edward; Nutman, Thomas B; Prevots, D Rebecca; Duffy, Patrick E
2018-03-01
The disease burden of Wuchereria bancrofti and Plasmodium falciparum malaria is high, particularly in Africa, and co-infection is common. However, the effects of filarial infection on the risk of severe malaria are unknown. We used the remaining serum samples from a large cohort study in Muheza, Tanzania to describe vector-borne filarial sero-reactivity among young children and to identify associations between exposure to filarial parasites and subsequent severe malaria infections. We identified positive filarial antibody responses (as well as positive antibody responses to Strongyloides stercoralis) among infants as young as six months. In addition, we found a significant association between filarial seropositivity at six months of age and subsequent severe malaria. Specifically, infants who developed severe malaria by one year of age were 3.9 times more likely (OR = 3.9, 95% CI: 1.2, 13.0) to have been seropositive for filarial antigen at six months of age compared with infants who did not develop severe malaria.
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Khan, Kamran; Wozniak, Susan E; Mehrabi, Erfan; Giannone, Anna Lucia; Dave, Mitul
2015-12-28
BACKGROUND Sternoclavicular osteomyelitis is a rare disease, with less than 250 cases identified in the past 50 years. We present a rare case of sternoclavicular osteomyelitis in an immunosuppressed patient that developed from a conservatively treated dislocation. CASE REPORT A 62-year-old white man with a history of metastatic renal cell carcinoma presented to the emergency department (ED) with a dislocated left sternoclavicular joint. He was managed conservatively and subsequently discharged. However, over subsequent days he began to experience pain, fever, chills, and night sweats. He presented to the ED again and imaging revealed osteomyelitis. In the operating room, the wound was aggressively debrided and a wound vac (vacuum-assisted closure) was placed. He was diagnosed with sternoclavicular osteomyelitis and placed on a 6-week course of intravenous Nafcillin. CONCLUSIONS Chemotherapy patients who sustain joint trauma normally associated with a low risk of infection should be monitored thoroughly, and the option to discontinue immunosuppressive therapy should be considered if signs of infection develop.
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Earhart, Christopher M.; Hughes, Casey E.; Gaster, Richard S.; Ooi, Chin Chun; Wilson, Robert J.; Zhou, Lisa Y.; Humke, Eric W.; Xu, Lingyun; Wong, Dawson J.; Willingham, Stephen B.; Schwartz, Erich J.; Weissman, Irving L.; Jeffrey, Stefanie S.; Neal, Joel W.; Rohatgi, Rajat; Wakelee, Heather A.; Wang, Shan X.
2014-01-01
Detection and characterization of circulating tumor cells (CTCs) may reveal insights into the diagnosis and treatment of malignant disease. Technologies for isolating CTCs developed thus far suffer from one or more limitations, such as low throughput, inability to release captured cells, and reliance on expensive instrumentation for enrichment or subsequent characterization. We report a continuing development of a magnetic separation device, the magnetic sifter, which is a miniature microfluidic chip with a dense array of magnetic pores. It offers high efficiency capture of tumor cells, labeled with magnetic nanoparticles, from whole blood with high throughput and efficient release of captured cells. For subsequent characterization of CTCs, an assay, using a protein chip with giant magnetoresistive nanosensors, has been implemented for mutational analysis of CTCs enriched with the magnetic sifter. The use of these magnetic technologies, which are separate devices, may lead the way to routine preparation and characterization of “liquid biopsies” from cancer patients. PMID:23969419
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Spiliopoulos, Kyriakos; Tsantsaridou, Angeliki; Papamichali, Rodula; Kimpouri, Konstantina; Salemis, Nicolaos S.; Koukoulis, George K.; Tsilimingas, Nicolaos B.
2013-01-01
Lymphangioleiomyomatosis (LAM) is a rare disease that occurs predominantly in females between the ages of 30 and 50 years and is clinically characterized by progressive dyspnoea on exertion, recurrent pneumothoraces, abdominal and thoracic lymphadenopathy, as well tumors-like angiomyolipomas and lymphangiomyomas. We present the case of a 42-year-old woman, who developed recurrent pneumothoraces and was subsequently diagnosed with LAM. Although pneumothorax is a common complication of the disease, its optimal approach to treatment and prevention remains unclear. Chemical or surgical pleurodesis are often performed in order to prevent recurrence, but may predispose to perioperative complications in the event of future lung transplantation. PMID:23390481
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Spiliopoulos, Kyriakos; Tsantsaridou, Angeliki; Papamichali, Rodula; Kimpouri, Konstantina; Salemis, Nicolaos S; Koukoulis, George K; Tsilimingas, Nicolaos B
2013-02-01
Lymphangioleiomyomatosis (LAM) is a rare disease that occurs predominantly in females between the ages of 30 and 50 years and is clinically characterized by progressive dyspnoea on exertion, recurrent pneumothoraces, abdominal and thoracic lymphadenopathy, as well tumors-like angiomyolipomas and lymphangiomyomas. We present the case of a 42-year-old woman, who developed recurrent pneumothoraces and was subsequently diagnosed with LAM. Although pneumothorax is a common complication of the disease, its optimal approach to treatment and prevention remains unclear. Chemical or surgical pleurodesis are often performed in order to prevent recurrence, but may predispose to perioperative complications in the event of future lung transplantation.
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In Vitro Cultivation of Microsporidia of Clinical Importance
Visvesvara, Govinda S.
2002-01-01
Although attempts to develop methods for the in vitro cultivation of microsporidia began as early as 1937, the interest in the culture of these organisms was confined mostly to microsporidia that infect insects. The successful cultivation in 1969 of Encephalitozoon cuniculi, a microsporidium of mammalian origin, and the subsequent identification of these organisms as agents of human disease heightened interest in the cultivation of microsporidia. I describe the methodology as well as the cell lines, the culture media, and culture conditions used in the in vitro culture of microsporidia such as Brachiola (Nosema) algerae, Encephalitozoon cuniculi, E. hellem, E. intestinalis, Enterocytozoon bieneusi, Trachipleistophora hominis, and Vittaforma corneae that cause human disease. PMID:12097248
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Iatrogenic tracheal laceration in the setting of chronic steroids.
Singh, Punit; Wojnar, Margaret; Malhotra, Anita
2017-02-01
We report the case of a 71-year-old woman with end-stage chronic obstructive pulmonary disease who presented with a 10-cm tracheal laceration from a presumed traumatic intubation in the setting of respiratory distress and chronic obstructive pulmonary disease exacerbation and subsequently developed significant subcutaneous emphysema along her neck and mediastinum in addition to her peritoneum and mesentery. We were successfully able to treat this patient conservatively up until the time that tracheostomy was warranted. We discuss and review tracheobronchial injuries with respect to etiology, risk factors, and management and hope to benefit health care providers managing airways in patients at risk for tracheal injury. Copyright © 2016 Elsevier Inc. All rights reserved.
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Physical examination and history-taking skills in a prostate clinic.
Wareing, Mark
The proliferation of nurse-led initiatives arising from nurse specialist/practitioner posts in urology is reflected in areas such as the management of bladder cancer, erectile dysfunction, stoma care, and prostate disease. The establishment of the role of urology specialist nurse in one North Oxfordshire hospital led to the development of a nurse-led prostate assessment clinic for male patients with lower urinary tract symptoms arising from benign prostatic hyperplasia. A description of how training was conducted, and the subsequent reappraisal of competency, is given in relation to physical examination and history-taking skills necessary for the development of this initiative.
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Nosocomial infection of CCHF among health care workers in Rajasthan, India.
Yadav, Pragya D; Patil, Deepak Y; Shete, Anita M; Kokate, Prasad; Goyal, Pulkit; Jadhav, Santosh; Sinha, Sanjeev; Zawar, Divya; Sharma, Surendra K; Kapil, Arti; Sharma, D K; Upadhyay, Kamlesh J; Mourya, Devendra T
2016-11-03
Ever since Crimean-Congo hemorrhagic fever [CCHF] discovered in India, several outbreaks of this disease have been recorded in Gujarat State, India. During the year 2011 to 2015 several districts of Gujarat and Rajasthan state (Sirohi) found to be affected with CCHF including the positivity among ticks and livestock. During these years many infected individuals succumbed to this disease; which subsequently led to nosocomial infections. Herein, we report CCHF cases recorded from Rajasthan state during January 2015. This has affected four individuals apparently associated with one suspected CCHF case admitted in a private hospital in Jodhpur, Rajasthan. A 30-year-old male was hospitalized in a private hospital in Jodhpur, Rajasthan State, who subsequently had developed thrombocytopenia and showed hemorrhagic manifestations and died in the hospital. Later on, four nursing staff from the same hospital also developed the similar symptoms (Index case and Case A, B, C). Index case succumbed to the disease in the hospital at Jodhpur followed by the death of the case A that was shifted to AIIMS hospital, Delhi due to clinical deterioration. Blood samples of the index case and Case A, B, C were referred to the National institute of Virology, Pune, India for CCHF diagnosis from the different hospitals in Rajasthan, Delhi and Gujarat. However, a sample of deceased suspected CCHF case was not referred. Subsequently, blood samples of 5 nursing staff and 37 contacts (Case D was one of them) from Pokhran area, Jaisalmer district were referred to NIV, Pune. It clearly indicated that nursing staff acquired a nosocomial infection while attending the suspected CCHF case in an Intensive Care Unit of a private hospital in Jodhpur. However, one case was confirmed from the Pokhran area where the suspected CCHF case was residing. This case might have got the infection from suspected CCHF case or through other routes. CCHF strain associated with these nosocomial infections shares the highest identity with Afghanistan strain and its recent introduction from Afghanistan cannot be ruled out. However, lack of active surveillance, unawareness among health care workers leads to such nosocomial infections.
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MicroRNA expression in benign breast tissue and risk of subsequent invasive breast cancer.
Rohan, Thomas; Ye, Kenny; Wang, Yihong; Glass, Andrew G; Ginsberg, Mindy; Loudig, Olivier
2018-01-01
MicroRNAs are endogenous, small non-coding RNAs that control gene expression by directing their target mRNAs for degradation and/or posttranscriptional repression. Abnormal expression of microRNAs is thought to contribute to the development and progression of cancer. A history of benign breast disease (BBD) is associated with increased risk of subsequent breast cancer. However, no large-scale study has examined the association between microRNA expression in BBD tissue and risk of subsequent invasive breast cancer (IBC). We conducted discovery and validation case-control studies nested in a cohort of 15,395 women diagnosed with BBD in a large health plan between 1971 and 2006 and followed to mid-2015. Cases were women with BBD who developed subsequent IBC; controls were matched 1:1 to cases on age, age at diagnosis of BBD, and duration of plan membership. The discovery stage (316 case-control pairs) entailed use of the Illumina MicroRNA Expression Profiling Assay (in duplicate) to identify breast cancer-associated microRNAs. MicroRNAs identified at this stage were ranked by the strength of the correlation between Illumina array and quantitative PCR results for 15 case-control pairs. The top ranked 14 microRNAs entered the validation stage (165 case-control pairs) which was conducted using quantitative PCR (in triplicate). In both stages, linear regression was used to evaluate the association between the mean expression level of each microRNA (response variable) and case-control status (independent variable); paired t-tests were also used in the validation stage. None of the 14 validation stage microRNAs was associated with breast cancer risk. The results of this study suggest that microRNA expression in benign breast tissue does not influence the risk of subsequent IBC.
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MicroRNA expression in benign breast tissue and risk of subsequent invasive breast cancer
Ye, Kenny; Wang, Yihong; Ginsberg, Mindy; Loudig, Olivier
2018-01-01
MicroRNAs are endogenous, small non-coding RNAs that control gene expression by directing their target mRNAs for degradation and/or posttranscriptional repression. Abnormal expression of microRNAs is thought to contribute to the development and progression of cancer. A history of benign breast disease (BBD) is associated with increased risk of subsequent breast cancer. However, no large-scale study has examined the association between microRNA expression in BBD tissue and risk of subsequent invasive breast cancer (IBC). We conducted discovery and validation case-control studies nested in a cohort of 15,395 women diagnosed with BBD in a large health plan between 1971 and 2006 and followed to mid-2015. Cases were women with BBD who developed subsequent IBC; controls were matched 1:1 to cases on age, age at diagnosis of BBD, and duration of plan membership. The discovery stage (316 case-control pairs) entailed use of the Illumina MicroRNA Expression Profiling Assay (in duplicate) to identify breast cancer-associated microRNAs. MicroRNAs identified at this stage were ranked by the strength of the correlation between Illumina array and quantitative PCR results for 15 case-control pairs. The top ranked 14 microRNAs entered the validation stage (165 case-control pairs) which was conducted using quantitative PCR (in triplicate). In both stages, linear regression was used to evaluate the association between the mean expression level of each microRNA (response variable) and case-control status (independent variable); paired t-tests were also used in the validation stage. None of the 14 validation stage microRNAs was associated with breast cancer risk. The results of this study suggest that microRNA expression in benign breast tissue does not influence the risk of subsequent IBC. PMID:29432432
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VIM-D salvage chemotherapy in Hodgkin's disease.
Phillips, J K; Spearing, R L; Davies, J M; Hay, C R; Parry, H; Nash, J R; Cawley, J C
1990-01-01
A total of 15 patients with relapsed or resistant Hodgkin's disease were treated with a combination of etoposide (VP16), ifosfamide, mitozantrone and dexamethasone (VIM-D). The regime was well tolerated, the only major toxicity being myelosuppression. Complete remissions (CRs) were obtained in 4 patients and were maintained for 2, 4, 10 and 14 months. 10 subjects subsequently received an autologous bone marrow transplant with high-dose chemotherapy (ABMT). Previous exposure to VIM-D did not appear to predict for or prejudice the response to subsequent ABMT.
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Omer, Omer; Cohen, Patrizia; Neong, Shuet Fong; Smith, Geoffrey V
2016-07-01
We report the case of a 76-year-old man who presented with moderate active Crohn's colitis that was refractory to high-dose corticosteroids, mesalazine and 6-mercaptopurine. He subsequently received a trial of infliximab with poor response and was diagnosed with cytomegalovirus (CMV) colitis, improving on antiviral therapy. Three weeks into treatment he developed acute respiratory distress with hypoxaemia and diffuse pulmonary interstitial infiltrates. This was confirmed as Pneumocystis jirovecii on bronchoalveolar lavage. He responded well to treatment with trimethoprim-sulfamethoxazole (TMP-SMX) and was subsequently discharged home. Despite the favourable outcome, our case raises the question of whether chemoprophylaxis against opportunistic infections in immunosuppressed patients with inflammatory bowel disease (IBD) is appropriate. There are currently no recommendations on providing chemoprophylaxis against CMV colitis and so we focus on pneumocystis pneumonia (PCP) where wide debate surrounds the use of prophylactic TMP-SMX in HIV-negative patients. Contrasting approaches to chemoprophylaxis against PCP in IBD likely relates to a lack of clear parameters for defining risk of PCP among patient groups. This must be addressed in order to develop universal guidelines that take into account patient-dependent risk factors. Awareness of the severity of PCP among HIV-negative individuals and the current consensus on PCP prophylaxis in IBD must be raised in order to minimise the risk of PCP and drive research in this controversial area.
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Omer, Omer; Cohen, Patrizia; Neong, Shuet Fong; Smith, Geoffrey V
2016-01-01
We report the case of a 76-year-old man who presented with moderate active Crohn's colitis that was refractory to high-dose corticosteroids, mesalazine and 6-mercaptopurine. He subsequently received a trial of infliximab with poor response and was diagnosed with cytomegalovirus (CMV) colitis, improving on antiviral therapy. Three weeks into treatment he developed acute respiratory distress with hypoxaemia and diffuse pulmonary interstitial infiltrates. This was confirmed as Pneumocystis jirovecii on bronchoalveolar lavage. He responded well to treatment with trimethoprim-sulfamethoxazole (TMP-SMX) and was subsequently discharged home. Despite the favourable outcome, our case raises the question of whether chemoprophylaxis against opportunistic infections in immunosuppressed patients with inflammatory bowel disease (IBD) is appropriate. There are currently no recommendations on providing chemoprophylaxis against CMV colitis and so we focus on pneumocystis pneumonia (PCP) where wide debate surrounds the use of prophylactic TMP-SMX in HIV-negative patients. Contrasting approaches to chemoprophylaxis against PCP in IBD likely relates to a lack of clear parameters for defining risk of PCP among patient groups. This must be addressed in order to develop universal guidelines that take into account patient-dependent risk factors. Awareness of the severity of PCP among HIV-negative individuals and the current consensus on PCP prophylaxis in IBD must be raised in order to minimise the risk of PCP and drive research in this controversial area. PMID:28839859
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Skinner, Michael K.; Haque, Carlos Guerrero-Bosagna M.; Nilsson, Eric; Bhandari, Ramji; McCarrey, John R.
2013-01-01
A number of environmental factors (e.g. toxicants) have been shown to promote the epigenetic transgenerational inheritance of disease and phenotypic variation. Transgenerational inheritance requires the germline transmission of altered epigenetic information between generations in the absence of direct environmental exposures. The primary periods for epigenetic programming of the germ line are those associated with primordial germ cell development and subsequent fetal germline development. The current study examined the actions of an agricultural fungicide vinclozolin on gestating female (F0 generation) progeny in regards to the primordial germ cell (PGC) epigenetic reprogramming of the F3 generation (i.e. great-grandchildren). The F3 generation germline transcriptome and epigenome (DNA methylation) were altered transgenerationally. Interestingly, disruptions in DNA methylation patterns and altered transcriptomes were distinct between germ cells at the onset of gonadal sex determination at embryonic day 13 (E13) and after cord formation in the testis at embryonic day 16 (E16). A larger number of DNA methylation abnormalities (epimutations) and transcriptional alterations were observed in the E13 germ cells than in the E16 germ cells. These observations indicate that altered transgenerational epigenetic reprogramming and function of the male germline is a component of vinclozolin induced epigenetic transgenerational inheritance of disease. Insights into the molecular control of germline transmitted epigenetic inheritance are provided. PMID:23869203
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If You Build It, They Will Come: How to Establish an Academic Innovation Enterprise.
Srimathveeravalli, Govindarajan; Balesh, Elie; Cheng, Christopher P; Chen, David
2017-06-01
The rapid growth of minimally invasive, image-guided intervention has redefined the procedural management of multiple disease entities. The process of innovation which has characterized the growth of interventional radiology can be best described as "needs-based," whereby practicing interventionalists identify unmet clinical needs and subsequently invent solutions to achieve desired technical and clinical outcomes. Historically, catheters and other percutaneous devices were developed with rudimentary manufacturing techniques and subsequently translated to patients with relatively little regulatory oversight. Since then, the resources required and financial costs of interventional technology development have grown exponentially. Fortunately, advances in software development, new methods of rapid prototyping, and commoditization of hardware components have made in-house engineering feasible once again. This has created an opportunity for academic medical centers to translate their research into testable prototypes in humans sooner and at reduced costs, and academic interventional radiology divisions are now leveraging these developments to create collaborative centers of innovation. This article describes five such organizational formats for collaboration and innovation in the academic setting, describing the structure, opportunities, requirements, and caveats of each model. Copyright © 2017 Elsevier Inc. All rights reserved.
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Rossi, Marcos A.; Tanowitz, Herbert B.; Malvestio, Lygia M.; Celes, Mara R.; Campos, Erica C.; Blefari, Valdecir; Prado, Cibele M.
2010-01-01
This review focuses on the short and bewildered history of Brazilian scientist Carlos Chagas's discovery and subsequent developments, the anatomopathological features of chronic Chagas cardiomyopathy (CCC), an overview on the controversies surrounding theories concerning its pathogenesis, and studies that support the microvascular hypothesis to further explain the pathological features and clinical course of CCC. It is our belief that knowledge of this particular and remarkable cardiomyopathy will shed light not only on the microvascular involvement of its pathogenesis, but also on the pathogenetic processes of other cardiomyopathies, which will hopefully provide a better understanding of the various changes that may lead to an end-stage heart disease with similar features. This review is written to celebrate the 100th anniversary of the discovery of Chagas disease. PMID:20824217
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Aging With Down Syndrome: The Dual Diagnosis: Alzheimer's Disease and Down Syndrome.
Cipriani, Gabriele; Danti, Sabrina; Carlesi, Cecilia; Di Fiorino, Mario
2018-06-01
People with Down syndrome (DS) enjoy a longer life expectancy now than they ever have before and are therefore at greater risk of developing conditions associated with aging, including dementia. To explore the phenomenon of dementia in DS. Medline and Google Scholar searches were conducted for relevant articles, chapters, and books published until 2017. Search terms included Alzheimer's disease, cognitive impairment, dementia, DS, and trisomy 21. Publications found through this indexed search were reviewed for further references. Virtually, all subject aged 35 to 40 show key neuropathologic changes characteristic of Alzheimer's disease, but only a part of them show clinical signs of dementia, usually around the age of 50 years. Early signs of dementia in people with DS may be different from those experienced by the general population. Failure to recognize this can delay diagnosis and subsequent interventions.
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Guidelines for diagnosis and treatment of 21-hydroxylase deficiency (2014 revision)
Ishii, Tomohiro; Anzo, Makoto; Adachi, Masanori; Onigata, Kazumichi; Kusuda, Satoshi; Nagasaki, Keisuke; Harada, Shohei; Horikawa, Reiko; Minagawa, Masanori; Minamitani, Kanshi; Mizuno, Haruo; Yamakami, Yuji; Fukushi, Masaru; Tajima, Toshihiro
2015-01-01
Purpose of developing the guidelines: The first guidelines for diagnosis and treatment of 21-hydroxylase deficiency (21-OHD) were published as a diagnostic handbook in Japan in 1989, with a focus on patients with severe disease. The “Guidelines for Treatment of Congenital Adrenal Hyperplasia (21-Hydroxylase Deficiency) Found in Neonatal Mass Screening (1999 revision)” published in 1999 were revised to include 21-OHD patients with very mild or no clinical symptoms. Accumulation of cases and experience has subsequently improved diagnosis and treatment of the disease. Based on these findings, the Mass Screening Committee of the Japanese Society for Pediatric Endocrinology further revised the guidelines for diagnosis and treatment. Target disease/conditions: 21-hydroxylase deficiency. Users of the guidelines: Physician specialists in pediatric endocrinology, pediatric specialists, referring pediatric practitioners, general physicians; and patients. PMID:26594092
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Whitehead, Elizabeth; Dodds, Linda; Joseph, K S; Gordon, Kevin E; Wood, Ellen; Allen, Alexander C; Camfield, Peter; Dooley, Joseph M
2006-04-01
We examined the effect of pregnancy and neonatal factors on the subsequent development of childhood epilepsy in a population-based cohort study. Children born between January 1986 and December 2000 in Nova Scotia, Canada were followed up to December 2001. Data on pregnancy and neonatal events and on diagnoses of childhood epilepsy were obtained through record linkage of 2 population-based databases: the Nova Scotia Atlee Perinatal Database and the Canadian Epilepsy Database and Registry. Factors analyzed included events during the prenatal, labor and delivery, and neonatal time periods. Cox proportional hazards regression models were used to estimate relative risks and 95% confidence intervals. There were 648 new cases of epilepsy diagnosed among 124,207 live births, for an overall rate of 63 per 100,000 person-years. Incidence rates were highest among children <1 year of age. In adjusted analyses, factors significantly associated with an increased risk of epilepsy included eclampsia, neonatal seizures, central nervous system (CNS) anomalies, placental abruption, major non-CNS anomalies, neonatal metabolic disorders, neonatal CNS diseases, previous low birth weight infant, infection in pregnancy, small for gestational age, unmarried, and not breastfeeding infant at the time of discharge from hospital. Our study supports the concept that prenatal factors contribute to the occurrence of subsequent childhood epilepsy.
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Android and ODK based data collection framework to aid in epidemiological analysis
Raja, A.; Tridane, A.; Gaffar, A.; Lindquist, T.; Pribadi, K.
2014-01-01
Periodic collection of field data, analysis and interpretation of data are key to a good healthcare service. This data is used by the subsequent decision makers to recognize preventive measures, provide timely support to the affected and to help measure the effects of their interventions. While the resources required for good disease surveillance and proactive healthcare are available more readily in developed countries, the lack of these in developing countries may compromise the quality of service provided. This combined with the critical nature of some diseases makes this an essential issue to be addressed. Taking advantage of the rapid growth of cell phone usage and related infrastructure in developed as well as developing countries, several systems have been established to address the gaps in data collection. Android, being an open sourced platform, has gained considerable popularity in this aspect. Open data kit is one such tool developed to aid in data collection. The aim of this paper is to present a prototype framework built using few such existing tools and technologies to address data collection for seasonal influenza, commonly referred to as the flu. PMID:24678381
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Lee, Chih-Ying; Chen, Mu-Hong; Jeng, Mei-Jy; Hsu, Ju-Wei; Tsai, Shih-Jen; Bai, Ya-Mei; Hung, Giun-Yi; Yen, Hsiu-Ju; Chen, Tzeng-Ji; Su, Tung-Ping
2016-09-01
Atopic dermatitis (AD) is one of the common allergic diseases in children. The presence of allergic diseases was found to have association with the risk of developing attention-deficit hyperactivity disorder (ADHD) or autistic spectrum disorder (ASD) in children, but it is still inconclusive. This study was to investigate the longitudinal relationship between AD developed during toddlerhood and subsequent development of ADHD or ASD in later childhood. Toddlers born between 1998 and 2008 and diagnosed with AD at the age younger than 3 years and older than 1 month were retrieved from Taiwan's National Health Insurance Research Database. Age- and gender-matched toddlers with no lifetime AD were enrolled as the control group. All enrolled toddlers were followed until 2011 to identify the development of ADHD or ASD. Multivariate Cox regression analysis was performed to analyze the hazard ratios (HRs). The risks associated with allergic comorbidities were analyzed. A total of 18,473 toddlers were enrolled into the AD group. The presence of AD significantly increased the risk of developing ADHD (HR = 2.92, 95% confidence interval [CI] = 2.48-3.45) or ASD (HR = 8.90, 95% CI = 4.98-15.92) when aged 3 years or older. Children from the AD group with 3 comorbidities together, namely, allergic rhinitis, allergic conjunctivitis, and asthma, had the greatest risk of developing ADHD and ASD (ADHD: HR = 4.67, 95% CI = 3.81-5.43; ASD: HR = 16.65, 95% CI = 8.63-30.60). In conclusion, toddlers who suffer from AD at the age younger than 3 years are at a higher risk of developing ADHD and ASD during later childhood. Pediatricians taking care of toddlers with AD should have knowledge of this increased risk of developing ADHD and ASD later in life, especially when children have certain comorbidities such as allergic rhinitis, allergic conjunctivitis, and asthma.
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Lee, Chih-Ying; Chen, Mu-Hong; Jeng, Mei-Jy; Hsu, Ju-Wei; Tsai, Shih-Jen; Bai, Ya-Mei; Hung, Giun-Yi; Yen, Hsiu-Ju; Chen, Tzeng-Ji; Su, Tung-Ping
2016-01-01
Abstract Atopic dermatitis (AD) is one of the common allergic diseases in children. The presence of allergic diseases was found to have association with the risk of developing attention-deficit hyperactivity disorder (ADHD) or autistic spectrum disorder (ASD) in children, but it is still inconclusive. This study was to investigate the longitudinal relationship between AD developed during toddlerhood and subsequent development of ADHD or ASD in later childhood. Toddlers born between 1998 and 2008 and diagnosed with AD at the age younger than 3 years and older than 1 month were retrieved from Taiwan's National Health Insurance Research Database. Age- and gender-matched toddlers with no lifetime AD were enrolled as the control group. All enrolled toddlers were followed until 2011 to identify the development of ADHD or ASD. Multivariate Cox regression analysis was performed to analyze the hazard ratios (HRs). The risks associated with allergic comorbidities were analyzed. A total of 18,473 toddlers were enrolled into the AD group. The presence of AD significantly increased the risk of developing ADHD (HR = 2.92, 95% confidence interval [CI] = 2.48–3.45) or ASD (HR = 8.90, 95% CI = 4.98–15.92) when aged 3 years or older. Children from the AD group with 3 comorbidities together, namely, allergic rhinitis, allergic conjunctivitis, and asthma, had the greatest risk of developing ADHD and ASD (ADHD: HR = 4.67, 95% CI = 3.81–5.43; ASD: HR = 16.65, 95% CI = 8.63–30.60). In conclusion, toddlers who suffer from AD at the age younger than 3 years are at a higher risk of developing ADHD and ASD during later childhood. Pediatricians taking care of toddlers with AD should have knowledge of this increased risk of developing ADHD and ASD later in life, especially when children have certain comorbidities such as allergic rhinitis, allergic conjunctivitis, and asthma. PMID:27684861
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Progression of Pathogenic Events in Cynomolgus Macaques Infected with Variola Virus
Rubins, Kathleen H.; Huggins, John W.; Fisher, Robert W.; Johnson, Anthony J.; de Kok-Mercado, Fabian; Larsen, Thomas; Raymond, Jo Lynne; Hensley, Lisa E.; Jahrling, Peter B.
2011-01-01
Smallpox, caused by variola virus (VARV), is a devastating human disease that affected millions worldwide until the virus was eradicated in the 1970 s. Subsequent cessation of vaccination has resulted in an immunologically naive human population that would be at risk should VARV be used as an agent of bioterrorism. The development of antivirals and improved vaccines to counter this threat would be facilitated by the development of animal models using authentic VARV. Towards this end, cynomolgus macaques were identified as adequate hosts for VARV, developing ordinary or hemorrhagic smallpox in a dose-dependent fashion. To further refine this model, we performed a serial sampling study on macaques exposed to doses of VARV strain Harper calibrated to induce ordinary or hemorrhagic disease. Several key differences were noted between these models. In the ordinary smallpox model, lymphoid and myeloid hyperplasias were consistently found whereas lymphocytolysis and hematopoietic necrosis developed in hemorrhagic smallpox. Viral antigen accumulation, as assessed immunohistochemically, was mild and transient in the ordinary smallpox model. In contrast, in the hemorrhagic model antigen distribution was widespread and included tissues and cells not involved in the ordinary model. Hemorrhagic smallpox developed only in the presence of secondary bacterial infections – an observation also commonly noted in historical reports of human smallpox. Together, our results support the macaque model as an excellent surrogate for human smallpox in terms of disease onset, acute disease course, and gross and histopathological lesions. PMID:21998632
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Secondary Pulmonary Hypertension and Right-Sided Heart Failure at Presentation in Grave's Disease
Ganeshpure, Swapnil Panjabrao; Vaidya, Gaurang Nandkishor; Gattani, Vipul
2012-01-01
A young female presented with evidence of right-sided heart failure and was subsequently found to have significant pulmonary artery hypertension (PAH). Because of her normal left ventricular function and pulmonary capillary wedge pressure, the most probable site of etiology seemed to be the pulmonary vasculature. All the common possible secondary causes of PAH were ruled out, but during the investigations, she was found to have elevated thyroid function tests compatible with the diagnosis of Grave's disease. The treatment of Grave's disease, initially by medications and subsequently by radioiodine therapy, was associated with a significant reduction in the pulmonary artery systolic pressure. The purpose of this case report is to highlight one of the unusual and underdiagnosed presentations of Grave's disease. PMID:23198182
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Atiim, George A; Elliott, Susan J
2016-04-01
Globally, there has been a shift in the causes of illness and death from infectious diseases to noncommunicable diseases. This changing pattern has been attributed to the effects of an (ongoing) epidemiologic transition. Although researchers have applied epidemiologic transition theory to questions of global health, there have been relatively few studies exploring its relevance especially in the context of emerging allergic disorders in sub-Saharan Africa (SSA). In this article, we address the growing burden of noncommunicable diseases in sub-Saharan Africa through the lens of epidemiologic transition theory. After a brief review of the literature on the evolution of the epidemiologic transition with a particular emphasis on sub-Saharan Africa, we discuss existing frameworks designed to help inform our understanding of changing health trends in the developing world. We subsequently propose a framework that privileges "place" as a key construct informing our understanding. In so doing, we use the example of allergic disease, one of the fastest growing chronic conditions in most parts of the world. © 2015 Society for Public Health Education.
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Hirschsprung disease and hepatoblastoma: case report of a rare association.
Pinto, Raquel Borges; Ramos, Ana Regina Lima; Backes, Ariane Nadia; Santos, Beatriz John Dos; Provenzi, Valentina Oliveira; Carbonera, Mário Rafael; Roenick, Maria Lúcia; Santos, Pedro Paulo Albino Dos; Falhauber, Fabrizia; Souza, Meriene Viquetti de; Bassols, João Vicente; Artigalás, Osvaldo
2016-04-01
Hirschsprung disease is a developmental disorder of the enteric nervous system that is characterized by absence of ganglion cells in the distal intestine, and it occurs in approximately 1 in every 500,000 live births. Hepatoblastoma is a malignant liver neoplasm that usually occurs in children aged 6 months to 3 years, with a prevalence of 0.54 cases per 100,000. A boy diagnosed with intestinal atresia in the first week of life progressed to a diagnosis of comorbid Hirschsprung disease. Congenital cataracts and sensorineural deafness were diagnosed. A liver mass developed and was subsequently confirmed to be a hepatoblastoma, which was treated by means of surgical resection of 70% of the liver volume and neoadjuvant chemotherapy (ifosfamide, cisplatin and doxorubicin). It is known that Hirschsprung disease may be associated with syndromes predisposing towards cancer, and that hepatoblastoma may also be associated with certain congenital syndromes. However, co-occurrence of hepatoblastoma and Hirschsprung disease has not been previously described. We have reported a case of a male patient born with ileal atresia, Hirschsprung disease and bilateral congenital cataract who was later diagnosed with hepatoblastoma.
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Climate change, aeroallergens, and pediatric allergic disease.
Sheffield, Perry E; Weinberger, Kate R; Kinney, Patrick L
2011-01-01
The degree to which aeroallergens are contributing to the global increase in pediatric allergic disease is incompletely understood. We review the evidence that links climate change to changes in aeroallergens such as pollen and outdoor mold concentrations and, subsequently, aeroallergen association with pediatric allergic disease. We specifically explore the evidence on both the exacerbation and the development of allergic disease in children related to outdoor pollen and mold concentrations. Pediatric allergic diseases include atopic dermatitis or eczema, allergic rhinitis or hay fever, and some types of asthma in children, typically defined as < 18 years of age. We discuss how the timing of aeroallergen exposure both in utero and in childhood could be associated with allergies. We conclude that the magnitude and type of health impacts due to climate change will depend on improved understanding of the relationship between climatic variables, multiple allergen factors, and allergic disease. Improved public-health strategies such as adequate humidity control, optimum air filtration and ventilation, and improved anticipatory public-health messaging will be critical to adaptation. © 2011 Mount Sinai School of Medicine.
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Nakano, Makiko; Omae, Kazuyuki; Takeuchi, Koichiro; Chonan, Tatsuya; Xiao, Yong-long; Harley, Russell A.; Roggli, Victor L.; Hebisawa, Akira; Tallaksen, Robert J.; Trapnell, Bruce C.; Day, Gregory A.; Saito, Rena; Stanton, Marcia L.; Suarthana, Eva; Kreiss, Kathleen
2012-01-01
Background: Reports of pulmonary fibrosis, emphysema, and, more recently, pulmonary alveolar proteinosis (PAP) in indium workers suggested that workplace exposure to indium compounds caused several different lung diseases. Methods: To better understand the pathogenesis and natural history of indium lung disease, a detailed, systematic, multidisciplinary analysis of clinical, histopathologic, radiologic, and epidemiologic data for all reported cases and workplaces was undertaken. Results: Ten men (median age, 35 years) who produced, used, or reclaimed indium compounds were diagnosed with interstitial lung disease 4-13 years after first exposure (n = 7) or PAP 1-2 years after first exposure (n = 3). Common pulmonary histopathologic features in these patients included intraalveolar exudate typical of alveolar proteinosis (n = 9), cholesterol clefts and granulomas (n = 10), and fibrosis (n = 9). Two patients with interstitial lung disease had pneumothoraces. Lung disease progressed following cessation of exposure in most patients and was fatal in two. Radiographic data revealed that two patients with PAP subsequently developed fibrosis and one also developed emphysematous changes. Epidemiologic investigations demonstrated the potential for exposure to respirable particles and an excess of lung abnormalities among coworkers. Conclusions: Occupational exposure to indium compounds was associated with PAP, cholesterol ester crystals and granulomas, pulmonary fibrosis, emphysema, and pneumothoraces. The available evidence suggests exposure to indium compounds causes a novel lung disease that may begin with PAP and progress to include fibrosis and emphysema, and, in some cases, premature death. Prospective studies are needed to better define the natural history and prognosis of this emerging lung disease and identify effective prevention strategies. PMID:22207675
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New cardiovascular targets to prevent late onset Alzheimer disease.
Claassen, Jurgen A H R
2015-09-15
The prevalence of dementia rises to between 20% and 40% with advancing age. The dominant cause of dementia in approximately 70% of these patients is Alzheimer disease. There is no effective disease-modifying pharmaceutical treatment for this neurodegenerative disease. A wide range of Alzheimer drugs that appeared effective in animal models have recently failed to show clinical benefit in patients. However, hopeful news has emerged from recent studies that suggest that therapeutic strategies aimed at reducing cardiovascular disease may also reduce the prevalence of dementia due to Alzheimer disease. This review summarizes the evidence for this link between cardiovascular disease and late onset Alzheimer dementia. Only evidence from human research is considered here. Longitudinal studies show an association between high blood pressure and pathological accumulation of the protein amyloid-beta42, and an even stronger association between vascular stiffness and amyloid accumulation, in elderly subjects. Amyloid-beta42 accumulation is considered to be an early marker of Alzheimer disease, and increases the risk of subsequent cognitive decline and development of dementia. These observations could provide an explanation for recent observations of reduced dementia prevalence associated with improved cardiovascular care. Copyright © 2015 Elsevier B.V. All rights reserved.
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A power study of bivariate LOD score analysis of a complex trait and fear/discomfort with strangers
Ji, Fei; Lee, Dayoung; Mendell, Nancy Role
2005-01-01
Complex diseases are often reported along with disease-related traits (DRT). Sometimes investigators consider both disease and DRT phenotypes separately and sometimes they consider individuals as affected if they have either the disease or the DRT, or both. We propose instead to consider the joint distribution of the disease and the DRT and do a linkage analysis assuming a pleiotropic model. We evaluated our results through analysis of the simulated datasets provided by Genetic Analysis Workshop 14. We first conducted univariate linkage analysis of the simulated disease, Kofendrerd Personality Disorder and one of its simulated associated traits, phenotype b (fear/discomfort with strangers). Subsequently, we considered the bivariate phenotype, which combined the information on Kofendrerd Personality Disorder and fear/discomfort with strangers. We developed a program to perform bivariate linkage analysis using an extension to the Elston-Stewart peeling method of likelihood calculation. Using this program we considered the microsatellites within 30 cM of the gene pleiotropic for this simulated disease and DRT. Based on 100 simulations of 300 families we observed excellent power to detect linkage within 10 cM of the disease locus using the DRT and the bivariate trait. PMID:16451570
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A power study of bivariate LOD score analysis of a complex trait and fear/discomfort with strangers.
Ji, Fei; Lee, Dayoung; Mendell, Nancy Role
2005-12-30
Complex diseases are often reported along with disease-related traits (DRT). Sometimes investigators consider both disease and DRT phenotypes separately and sometimes they consider individuals as affected if they have either the disease or the DRT, or both. We propose instead to consider the joint distribution of the disease and the DRT and do a linkage analysis assuming a pleiotropic model. We evaluated our results through analysis of the simulated datasets provided by Genetic Analysis Workshop 14. We first conducted univariate linkage analysis of the simulated disease, Kofendrerd Personality Disorder and one of its simulated associated traits, phenotype b (fear/discomfort with strangers). Subsequently, we considered the bivariate phenotype, which combined the information on Kofendrerd Personality Disorder and fear/discomfort with strangers. We developed a program to perform bivariate linkage analysis using an extension to the Elston-Stewart peeling method of likelihood calculation. Using this program we considered the microsatellites within 30 cM of the gene pleiotropic for this simulated disease and DRT. Based on 100 simulations of 300 families we observed excellent power to detect linkage within 10 cM of the disease locus using the DRT and the bivariate trait.
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Aerobic exercise conditioning: a nonpharmacological antiarrhythmic intervention.
Billman, George E
2002-02-01
Sudden, unexpected cardiac death due to ventricular fibrillation is the leading cause of death in most industrially developed countries. Yet, despite the enormity of this problem, the development of safe and effective antiarrhythmic therapies has proven to be an elusive goal. In fact, many initially promising antiarrhythmic medications were subsequently found to increase rather than to decrease cardiac mortality. It is now known that cardiac disease alters cardiac autonomic balance and that the patients with the greatest changes in this cardiac neural regulation (i.e., decreased parasympathetic coupled with increased sympathetic activity) are also the patients at the greatest risk for sudden death. A growing body of experimental and epidemiological data demonstrates that aerobic exercise conditioning can dramatically reduce cardiac mortality, even in patients with preexisting cardiac disease. Conversely, the lack of exercise is strongly associated with an increased incidence of many chronic debilitating diseases, including coronary heart disease. Because it is well established that aerobic exercise conditioning can alter autonomic balance (increasing parasympathetic tone and decreasing sympathetic activity), a prudently designed exercise program could prove to be an effective and nonpharmacological way to enhance cardiac electrical stability, thereby protecting against sudden cardiac death.
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Dynamic release and clearance of circulating microparticles during cardiac stress.
Augustine, Daniel; Ayers, Lisa V; Lima, Eduardo; Newton, Laura; Lewandowski, Adam J; Davis, Esther F; Ferry, Berne; Leeson, Paul
2014-01-03
Microparticles are cell-derived membrane vesicles, relevant to a range of biological responses and known to be elevated in cardiovascular disease. To investigate microparticle release during cardiac stress and how this response differs in those with vascular disease. We measured a comprehensive panel of circulating cell-derived microparticles by a standardized flow cytometric protocol in 119 patients referred for stress echocardiography. Procoagulant, platelet, erythrocyte, and endothelial but not leukocyte, granulocyte, or monocyte-derived microparticles were elevated immediately after a standardized dobutamine stress echocardiogram and decreased after 1 hour. Twenty-five patients developed stress-induced wall motion abnormalities suggestive of myocardial ischemia. They had similar baseline microparticle levels to those who did not develop ischemia, but, interestingly, their microparticle levels did not change during stress. Furthermore, no stress-induced increase was observed in those without inducible ischemia but with a history of vascular disease. Fourteen patients subsequently underwent coronary angiography. A microparticle rise during stress echocardiography had occurred only in those with normal coronary arteries. Procoagulant, platelet, erythrocyte, and endothelial microparticles are released during cardiac stress and then clear from the circulation during the next hour. This stress-induced rise seems to be a normal physiological response that is diminished in those with vascular disease.
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A Case Report of Recurrent Takotsubo Cardiomyopathy in a Patient during Myasthenia Crisis
Battineni, Anusha; Mullaguri, Naresh; Thanki, Shail; Chockalingam, Anand
2017-01-01
Introduction Patients with myasthenia crisis can develop Takotsubo stress cardiomyopathy (SC) due to emotional or physical stress and high level of circulating catecholamines. We report a patient who developed recurrent Takotsubo cardiomyopathy during myasthenia crisis. Coexisting autoimmune disorders known to precipitate stress cardiomyopathy like Grave's disease need to be evaluated. Case Report A 69-year-old female with seropositive myasthenia gravis (MG), Grave's disease, and coronary artery disease on monthly infusion of intravenous immunoglobulin (IVIG), prednisone, pyridostigmine, and methimazole presented with shortness of breath and chest pain. Electrocardiogram (ECG) showed ST elevation in anterolateral leads with troponemia. Coronary angiogram was unremarkable for occlusive coronary disease with left ventriculogram showing reduced wall motion with apical and mid left ventricle (LV) hypokinesis suggestive of Takotsubo stress cardiomyopathy. Her symptoms were attributed to MG crisis. Her symptoms, ECG, and echocardiographic findings resolved after five cycles of plasma exchange (PLEX). She had another similar episode one year later during myasthenia crisis with subsequent resolution in 10 days after PLEX. Conclusion Takotsubo cardiomyopathy can be one of the manifestations of myasthenia crisis with or without coexisting Grave's disease. These patients might benefit from meticulous fluid status and cardiac monitoring while administering rescue treatments like IVIG and PLEX. PMID:29201468
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Chronic wasting disease in free-ranging Wisconsin white-tailed deer
Joly, D.O.; Ribic, C.A.; Langenberg, J.A.; Beheler, K.; Batha, C.A.; Dhuey, B.J.; Rolley, R.E.; Bartelt, G.; VanDeelen, T.R.; Samuel, M.D.
2003-01-01
Three White-tailed Deer shot within 5 km during the 2001 hunting season in Wisconsin tested positive for chronic wasting disease, a prion disease of cervids. Subsequent sampling within 18 km showed a 3% prevalence (n=476). This discovery represents an important range extension for chronic wasting disease into the eastern United States.
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Deeg, Cornelia A; Thurau, Stephan R; Gerhards, Hartmut; Ehrenhofer, Marion; Wildner, Gerhild; Kaspers, Bernd
2002-09-01
Equine recurrent uveitis (ERU) is an inflammatory eye disease with high similarity to uveitis in man. It is the only spontaneous animal model for uveitis and the most frequent eye disease in horses affecting up to 10% of the population. To further investigate the pathophysiology of ERU we now report the establishment of an inducible uveitis model in horses. An ERU-like disease was elicited in seven out of seven horses by injection of interphotoreceptor retinoid-binding protein (IRBP) in complete Freund's adjuvant. Control horses did not develop uveitis. The disease model is characterized by a highly reproducible disease course and recurrent episodes with an identical time course elicited in all horses by repeated IRBP injections. The histology revealed the formation of lymphoid follicle-like structures in the eyes and an intraocular infiltration dominated by CD3(+) lymphocytes, morphological patterns typical for the spontaneous disease. Antigen-specific T cell proliferation of PBL was monitored prior to clinical uveitis and during disease episodes. An initial T cell response to IRBP-derived peptides was followed by epitope spreading to S-antigen-derived peptides in response to subsequent immunizations. Thus, horse experimental uveitis represents a valuable disease model for comparative studies with the spontaneous disease and the investigation of immunomodulatory therapeutic approaches after onset of the disease.
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Computer-assisted initial diagnosis of rare diseases
Piñol, Marc; Vilaplana, Jordi; Teixidó, Ivan; Cruz, Joaquim; Comas, Jorge; Vilaprinyo, Ester; Sorribas, Albert
2016-01-01
Introduction. Most documented rare diseases have genetic origin. Because of their low individual frequency, an initial diagnosis based on phenotypic symptoms is not always easy, as practitioners might never have been exposed to patients suffering from the relevant disease. It is thus important to develop tools that facilitate symptom-based initial diagnosis of rare diseases by clinicians. In this work we aimed at developing a computational approach to aid in that initial diagnosis. We also aimed at implementing this approach in a user friendly web prototype. We call this tool Rare Disease Discovery. Finally, we also aimed at testing the performance of the prototype. Methods. Rare Disease Discovery uses the publicly available ORPHANET data set of association between rare diseases and their symptoms to automatically predict the most likely rare diseases based on a patient’s symptoms. We apply the method to retrospectively diagnose a cohort of 187 rare disease patients with confirmed diagnosis. Subsequently we test the precision, sensitivity, and global performance of the system under different scenarios by running large scale Monte Carlo simulations. All settings account for situations where absent and/or unrelated symptoms are considered in the diagnosis. Results. We find that this expert system has high diagnostic precision (≥80%) and sensitivity (≥99%), and is robust to both absent and unrelated symptoms. Discussion. The Rare Disease Discovery prediction engine appears to provide a fast and robust method for initial assisted differential diagnosis of rare diseases. We coupled this engine with a user-friendly web interface and it can be freely accessed at http://disease-discovery.udl.cat/. The code and most current database for the whole project can be downloaded from https://github.com/Wrrzag/DiseaseDiscovery/tree/no_classifiers. PMID:27547534
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Parker, Nicole S; Anderson, Nolan R; Richmond, Douglas S; Long, Elizabeth Y; Wise, Kiersten A; Krupke, Christian H
2017-03-01
A 2 year study was conducted to determine whether western bean cutworm (Striacosta albicosta Smith) (WBC) larval feeding damage increases severity of the fungal disease Gibberella ear rot [Fusarium graminearum (Schwein.) Petch] in field corn (Zea mays L.). The effect of a quinone-outside inhibiting fungicide, pyraclostrobin, on Gibberella ear rot severity and mycotoxin production, both with and without WBC pressure, was also evaluated. The impact of each variable was assessed individually and in combination to determine the effect of each upon ear disease severity. There was a positive correlation between the presence of WBC larvae in field corn and Gibberella ear rot severity under inoculated conditions in the 2 years of the experiment. An application of pyraclostrobin did not impact Gibberella ear rot development when applied at corn growth stage R1 (silks first emerging). Feeding damage from WBC larvae significantly increases the development of F. graminearum in field corn. We conclude that an effective integrated management strategy for Gibberella ear rot should target the insect pest first, in an effort to limit disease severity and subsequent mycotoxin production by F. graminearum in kernels. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.
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Excessive daytime sleepiness and subsequent development of Parkinson disease.
Abbott, R D; Ross, G W; White, L R; Tanner, C M; Masaki, K H; Nelson, J S; Curb, J D; Petrovitch, H
2005-11-08
To determine if excessive daytime sleepiness (EDS) can predate future Parkinson disease (PD). EDS was assessed in 3,078 men aged 71 to 93 years in the Honolulu-Asia Aging Study from 1991 to 1993. All were free of prevalent PD and dementia. Follow-up for incident PD was based on three repeat neurologic assessments from 1994 to 2001. During the course of follow-up, 43 men developed PD (19.9/10,000 person-years). After age adjustment, there was more than a threefold excess in the risk of PD in men with EDS vs men without EDS (55.3 vs 17.0/10,000 person-years; odds ratio [OR] = 3.3; 95% CI = 1.4 to 7.0; p = 0.004). Additional adjustment for insomnia, cognitive function, depressed mood, midlife cigarette smoking and coffee drinking, and other factors failed to alter the association between EDS and PD (OR = 2.8; 95% CI = 1.1 to 6.4; p = 0.014). Other sleep related features such as insomnia, daytime napping, early morning grogginess, and frequent nocturnal awakening showed little relation with the risk of PD. Excessive daytime sleepiness may be associated with an increased risk of developing Parkinson disease.
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Development of respiratory syncytial virus (RSV) vaccines for infants.
Gerretsen, Hannah E; Sande, Charles J
2017-06-01
2017 will mark the 60 th anniversary since the first isolation of RSV in children. In spite of concerted efforts over all these years, the goal of developing an effective vaccine against paediatric RSV disease has remained elusive. One of the main hurdles standing in the way of an effective vaccine is the fact that the age incidence of severe disease peaks within the first 3 months of life, providing limited opportunity for intervention. In addition to this complexity, the spectre of failed historical vaccines, which increased the risk of illness and death upon subsequent natural infection, has substantially increased the safety criteria against which modern vaccines will be assessed. This review traces the history of RSV vaccine development for young infants and analyses the potential reasons for the failure of historic vaccines. It also discusses recent breakthroughs in vaccine antigen design and the progressive evolution of platforms for the delivery of these antigens to seronegative infants. © 2017 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
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The clinical characteristics of retinal vasculitis in HLA-B27-positive patients.
Braakenburg, Arthur Menno; Rothova, Aniki
2014-06-01
To investigate the ocular and systemic manifestations of retinal vasculitis in HLA-B27-positive patients. Retrospective noncomparative case series of 9 HLA-B27-positive patients with uveitis and retinal vasculitis. Main outcome measures consisted of ocular and angiographic findings and assessment of any additional systemic disorders. Three male and 6 female HLA-B27-positive patients with a median age of 32 years were diagnosed with retinal vasculitis. Concurrent intraocular inflammation was noted in all patients. All patients suffered from extensive vasculitis of the large retinal veins. Five patients developed retinal vasculitis at the onset of uveitis and the remaining 4 exhibited retinal vasculitis 1-15 years after the onset of uveitis. Vascular occlusions occurred in 4 patients and subsequent neovascularizations developed in 3. Three patients were diagnosed with an HLA-B27-associated systemic disease. Retinal vasculitis may develop in the wake of HLA-B27-associated uveitis and might represent a rare manifestation of HLA-B27-associated disease.
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Crawford, Natalie D; Ford, Chandra; Galea, Sandro; Latkin, Carl; Jones, Kandice C; Fuller, Crystal M
2013-01-01
Discrimination can influence risk of disease by promoting unhealthy behaviors (e.g., smoking, alcohol use). Whether it influences the formation of high-risk social ties that facilitate HIV transmission is unclear. Using cross-sectional data from a cohort of illicit drug users, this study examined the association between discrimination based on race, drug use and prior incarceration and risky sex and drug ties. Negative binomial regression models were performed. Participants who reported discrimination based on race and drug use had significantly more sex and drug-using ties. But, after accounting for both racial and drug use discrimination, only racial discrimination was associated with increased sex, drug-using, and injecting ties. Drug users who experience discrimination and subsequently develop more sex and drug-using ties, increase their risk of contracting HIV. Future longitudinal studies illuminating the pathways linking discrimination and social network development may guide intervention development and identify drug-using subpopulations at high risk for disease transmission.
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Sessa, Rosa; Di Pietro, Marisa; Filardo, Simone; Bressan, Alessia; Mazzuti, Laura; Serafino, Sara; Fantauzzi, Alessandra; Turriziani, Ombretta
2017-01-01
Cardiovascular disease (CVD) is a major public health problem in developed countries with over 17 million deaths per year. In the last decade, several infectious agents rather than any single pathogen, including Chlamydia pneumoniae and human immunodeficiency virus (HIV), have been shown to contribute to the development of atherosclerosis and subsequent cardiovascular events by inducing systemic inflammation and/or acting directly on the vascular wall. For the first time, we evaluated C. pneumonia DNA in peripheral blood mononuclear cells from HIV patients by real-time polymerase chain reaction in order to shed light on C. pneumonia as a co-factor with HIV in the development of CVDs. C. pneumonia DNA was not detected in our virologically suppressed HIV patients (<37 copies/mL). This finding may be related to high CD4+T cell count (>500 cells/μl) found in HIV patients suggesting functional cell-mediated immunity as a fundamental mechanism for the clearance of chlamydial infection in this population. Larger studies are needed to confirm this hypothesis.
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Dodds, K N; Beckett, E A H; Evans, S F; Grace, P M; Watkins, L R; Hutchinson, M R
2016-01-01
In the central nervous system, bidirectional signaling between glial cells and neurons (‘neuroimmune communication') facilitates the development of persistent pain. Spinal glia can contribute to heightened pain states by a prolonged release of neurokine signals that sensitize adjacent centrally projecting neurons. Although many persistent pain conditions are disproportionately common in females, whether specific neuroimmune mechanisms lead to this increased susceptibility remains unclear. This review summarizes the major known contributions of glia and neuroimmune interactions in pain, which has been determined principally in male rodents and in the context of somatic pain conditions. It is then postulated that studying neuroimmune interactions involved in pain attributed to visceral diseases common to females may offer a more suitable avenue for investigating unique mechanisms involved in female pain. Further, we discuss the potential for primed spinal glia and subsequent neurogenic inflammation as a contributing factor in the development of peripheral inflammation, therefore, representing a predisposing factor for females in developing a high percentage of such persistent pain conditions. PMID:27622932
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[Syndrome of emotional burnout among women-physicians elderly].
Myakotnykh, V S; Borovkova, T A
2017-01-01
The article presents the results of a comparative study of clinical symptoms of syndrome of emotional burnout among 84 working in the specialty physician of older women and 48 officially ceasing operations in this specialty. The findings suggest that burnout can take place among representatives of older age and more it is continued, provided professional activities. The cessation of the work activities leads to stress, often with the subsequent development post-traumatic stress disorder and stress-induced diseases. However in this case the clinical symptoms of the syndrome of emotional burnout, does not disappear, but only happens their clinical transformation attach various psychosomatic disorders. Thus, the elderly, suffering the syndrome of emotional burnout, are at high risk group with regard to the formation and development of diseases, associated with stress and require close monitoring in the framework of the compulsory program of medical examination.
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Aghajan, Yasmin; Yoon, Janet M; Crawford, John Ross
2017-04-24
Severe neuropathy is a known adverse effect of vincristine in patients with Charcot-Marie-Tooth disease (CMT). We present the case of a 16-year-old girl with anaplastic medulloblastoma treated with gross total resection and high-dose craniospinal radiation with adjuvant vincristine chemotherapy who developed acute-onset severe quadriplegia and vocal cord paralysis. Vincristine and radiation therapy were discontinued. Although her neuropathy slowly improved over several weeks, she developed metastatic extraneural medulloblastoma and died 5 months after diagnosis. Subsequent genetic testing revealed previously asymptomatic and undiagnosed CMT1A. Our case highlights the importance of early recognition of acute vincristine neurotoxicity that should raise suspicion of an underlying hereditary neuropathy. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
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Partial hypopituitarism and Langerhans cell histiocytosis
Balaguruswamy, S; Chattington, P D
2011-01-01
A case of multisystem Langerhans cell histiocytosis with pituitary involvement nearly 20 years after initial presentation. A 48-year-old man had histiocytosis X 22 years ago initially involving the groin; subsequently his external auditory meatus, scalp, gum, mandibular bone, perineum and axilla were involved and treated. The pituitary gland was involved 4 years ago. A thyrotropin-releasing hormone test showed delayed response suggestive of hypothalamic disease. Prolactin levels were normal. A gonadotropin-releasing hormone test showed impaired testosterone and gonadotrophin response in keeping with pituitary disease. A glucagon stimulation test showed an impaired growth hormone response but a normal cortisol increase. MRI pituitary showed an empty sella. There was no evidence of diabetes insipidus. Bone mineral densitometry was normal. He has partial hypopituitarism needing thyroxine and testosterone replacement. He also developed type 2 diabetes mellitus 9 years ago. He is closely monitored for any development of diabetes insipidus and the need for growth hormone supplementation. PMID:22715201
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Psychosocial antecedents of hostility in persons with coronary heart disease.
Sofhauser, Cynthia D
2003-09-01
Although it is known that hostility precedes coronary heart disease (CHD), little is known about factors that influence the development and progression of hostile characteristics. The relations among hostility, self-esteem, self-concept, and psychosocial residual were conceptualized within the modeling and role-modeling theoretical framework and examined in a sample of 85 persons with CHD. There were significant associations between all variables. Regression analyses revealed that self-esteem, mistrust residual, isolation residual, and self-concept contributed significantly, accounting for 31% of the variation in hostility scores. These findings provide support for the belief that the development of hostility in persons with CHD is related to beliefs and attitudes about the self and others. Persons with self-esteem need deficits, and a subsequent build up of negative psychosocial residual, have poor self-concepts. This poor self-concept is hostile in nature and reflects a mistrust of others and a deep sense of isolation.
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B lymphocytes not required for progression from insulitis to diabetes in non-obese diabetic mice.
Charlton, B; Zhang, M D; Slattery, R M
2001-12-01
Previous studies have implicated B lymphocytes in the pathogenesis of diabetes in the non-obese diabetic (NOD) mouse. While it is clear that B lymphocytes are necessary, it has not been clear at which stage of disease they play a role; early, late or both. To clarify when B lymphocytes are needed, T lymphocytes were transferred from 5-week-old NOD female mice to age-matched NOD/severe combined immunodeficiency (SCID) recipient mice. NOD/SCID mice, which lack functionally mature T and B lymphocytes, do not normally develop insulitis or insulin-dependent diabetes melitus (IDDM). The NOD/SCID mice that received purified T lymphocytes from 5-week-old NOD mice subsequently developed insulitis and diabetes even though they did not have detectable B lymphocytes. This suggests that while B lymphocytes may be essential for an initial priming event they are not requisite for disease progression in the NOD mouse.
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Radford, Elizabeth J; Ito, Mitsuteru; Shi, Hui; Corish, Jennifer A; Yamazawa, Kazuki; Isganaitis, Elvira; Seisenberger, Stefanie; Hore, Timothy A; Reik, Wolf; Erkek, Serap; Peters, Antoine H F M; Patti, Mary-Elizabeth; Ferguson-Smith, Anne C
2014-08-15
Adverse prenatal environments can promote metabolic disease in offspring and subsequent generations. Animal models and epidemiological data implicate epigenetic inheritance, but the mechanisms remain unknown. In an intergenerational developmental programming model affecting F2 mouse metabolism, we demonstrate that the in utero nutritional environment of F1 embryos alters the germline DNA methylome of F1 adult males in a locus-specific manner. Differentially methylated regions are hypomethylated and enriched in nucleosome-retaining regions. A substantial fraction is resistant to early embryo methylation reprogramming, which may have an impact on F2 development. Differential methylation is not maintained in F2 tissues, yet locus-specific expression is perturbed. Thus, in utero nutritional exposures during critical windows of germ cell development can impact the male germline methylome, associated with metabolic disease in offspring. Copyright © 2014, American Association for the Advancement of Science.
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Farrell, Richard J; Alsahli, Mazen; Jeen, Yoon-Tae; Falchuk, Kenneth R; Peppercorn, Mark A; Michetti, Pierre
2003-04-01
We assessed the relationship between antibodies to infliximab (ATI) and the loss of response postinfliximab, infusion reactions and, in a randomized trial, investigated whether intravenous hydrocortisone premedication can reduce ATI. Initially, we prospectively evaluated clinical response, adverse events, and ATI levels in 53 consecutive patients with Crohn's disease who received 199 infliximab (5 mg/kg) infusions. Subsequently, 80 patients with Crohn's disease were randomized to intravenous hydrocortisone 200 mg or placebo immediately before their first and subsequent infliximab infusions. The primary endpoint was reduction in median ATI levels at week 16. Analysis was by intention to treat. Nineteen of our initial 53 patients (36%) developed ATI, including all 7 patients with serious infusion reactions (median ATI level, 19.6 microg/mL). Eleven of 15 patients (73%) who lost their initial response were ATI positive compared with none of 21 continuous responders, (8.9 vs. 0.7 microg/mL, P < 0.0001). Administering a second infusion within 8 weeks of the first (OR, 0.13; 95% CI, 0.03-0.5; P = 0.0007) or concurrent immunosuppressants (OR, 0.19; 95% CI, 0.04-1.03; P = 0.007) significantly reduced ATI formation. In the placebo-controlled trial, ATI levels were lower at week 16 among hydrocortisone-treated patients (1.6 vs. 3.4 microg/mL, P = 0.02), and 26% of hydrocortisone-treated patients developed ATI compared with 42% of placebo-treated patients, P = 0.06. Loss of initial response and infusion reactions post-infliximab is strongly related to ATI formation and level. Administering a second infusion within 8 weeks of the first and concurrent immunosuppressant therapy significantly reduce ATI formation. Intravenous hydrocortisone premedication significantly reduces ATI levels but does not eliminate ATI formation or infusion reactions.
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Transgenerational programming of nephron deficits and hypertension.
Briffa, Jessica F; Wlodek, Mary E; Moritz, Karen M
2018-06-07
Exposure to a sub-optimal environment in the womb can result in poor fetal growth and impair the normal development of organs. The kidney, specifically the process of nephrogenesis, has been shown to be impacted by many common pregnancy exposures including an inadequate diet, poor placental function, maternal stress as well as maternal smoking and alcohol consumption. This can result in offspring being born with a reduced nephron endowment, which places these individuals at increased risk of hypertension and chronic kidney disease (CKD). Of recent interest is whether this disease risk can be passed on to subsequent generations and, if so, what are the mechanisms and pathways involved. In this review, we highlight the growing body of evidence that a low birth weight and hypertension, which are both major risk factors for cardiovascular and CKD, can be transmitted across generations. However, as yet there is little data as to whether a low nephron endowment contributes to this disease transmission. The emerging data suggests transmission can occur both through both the maternal and paternal lines, which likely involves epigenetic mechanisms such chromatin remodelling (DNA methylation and histone modification) and non-coding RNA modifications. In addition, females who were born small and/or have a low nephron endowment are at an increased risk for pregnancy complications, which can influence the growth and development of the next generation. Future animal studies in this area should include examining nephron endowment across multiple generations and determining adult renal function. Clinically, long term follow-up studies of large birth cohorts need to be undertaken to more clearly determine the impact a sub-optimal environment in one generation has on the health outcomes in the second, and subsequent, generation. Copyright © 2018. Published by Elsevier Ltd.
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Hypertension, End-Stage Renal Disease and Rehabilitation: A Look at Black Americans.
ERIC Educational Resources Information Center
Livingston, Ivor Lensworth; Ackah, Samuel
1992-01-01
Reviews the important relationship between end-stage renal disease (ESRD) and hypertension for African Americans; and considers issues associated with ESRD and the subsequent need for kidney transplants, including organ availability. Individual and societal implications of these diseases are discussed. (SLD)
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Early Disseminated Lyme Disease Masquerading as Mononucleosis: A Case Report.
Tumminello, Richard; Glaspey, Lindsey; Bhamidipati, Anita; Sheehan, Patrick; Patel, Sundip
2017-12-01
Disseminated Lyme disease can be difficult to diagnose, as it begins with nonspecific signs and symptoms, which, if not treated correctly, can lead to atrioventricular conduction blocks and meningitis. In addition, the diagnosis can be further complicated by potentially false-positive test results. We report a case of early-disseminated Lyme disease presenting with Borrelia meningitis and concomitant Lyme carditis, which was misdiagnosed as mononucleosis. A young, previously healthy patient had been hiking in the woods of upstate New York and 4 weeks later developed fever, night sweats, and myalgias. He was diagnosed with mononucleosis via a positive rapid heterophile agglutination antibody test to the Epstein-Barr virus at a walk-in clinic and was started on medications, but then subsequently developed left hip pain, a facial droop, and a very long first-degree atrioventricular conduction block. He went to the Emergency Department, where he had testing that confirmed disseminated Lyme disease. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case highlights the difficulty in early diagnosis of disseminated Lyme disease and how a potentially false-positive laboratory test can lead to the complications of Borrelia meningitis and Lyme carditis in untreated young healthy patients. Emergency physicians need to consider Lyme disease in patients with nonspecific signs and symptoms, especially if they have been outdoors for prolonged periods of time in Lyme-endemic areas. Copyright © 2017 Elsevier Inc. All rights reserved.
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Does the vaginal microbiota play a role in the development of cervical cancer?
Kyrgiou, Maria; Mitra, Anita; Moscicki, Anna-Barbara
2017-01-01
Persistent infection with oncogenic human papillomavirus (HPV) is necessary but not sufficient for the development of cervical cancer. The factors promoting persistence as well those triggering carcinogenetic pathways are incompletely understood. Rapidly evolving evidence indicates that the vaginal microbiome (VM) may play a functional role (both protective and harmful) in the acquisition and persistence of HPV, and subsequent development of cervical cancer. The first studies examining the VM and the presence of an HPV infection using next-generation sequencing techniques identified higher microbial diversity in HPV-positive as opposed to HPV-negative women. Furthermore, there appears to be a temporal relationship between the VM and HPV infection in that specific community state types may be correlated with a higher chance of progression or regression of the infection. Studies describing the VM in women with preinvasive disease (squamous intraepithelial neoplasia [SIL]) consistently demonstrate a dysbiosis in women with the more severe disease. Although it is plausible that the composition of the VM may influence the host's innate immune response, susceptibility to infection, and the development of cervical disease, the studies to date do not prove causality. Future studies should explore the causal link between the VM and the clinical outcome in longitudinal samples from existing biobanks. Copyright © 2016 Elsevier Inc. All rights reserved.
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Planning and implementing a nationwide football-based health-education programme.
Dvorak, Jiri; Fuller, Colin W; Junge, Astrid
2012-01-01
Communicable and non-communicable diseases place enormous social and economic burdens on developed and developing countries. Health education leading to changes in people's attitudes and behaviours remains the best approach for reducing the problem of communicable diseases while there is evidence that programmes providing regular physical exercise and advocating a controlled diet can reduce the prevalence of many non-communicable diseases. Hence, the delivery of health education and physical activity within a single coherent programme offers great potential for simultaneously addressing both health issues. Since 2006, FIFA has developed and tested a novel football-based health-education programme for children entitled '11 for Health', which is aimed at increasing children's levels of physical activity while also delivering 11 simple health messages. When new interventions of this type are published in the scientific literature, it is often not possible to describe important background information about the project that could assist other researchers in developing and implementing similar programmes. This paper attempts to bridge this gap by describing the aims and objectives, organisation, planning, implementation and monitoring requirements needed to deliver FIFA's '11 for Health' programme, first as a pilot project and subsequently as a nationwide project, through a tripartite arrangement between FIFA, the national Football Association and the Government Ministries in Mauritius.
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Planning and implementing a nationwide football-based health-education programme
Dvorak, Jiri; Fuller, Colin W; Junge, Astrid
2012-01-01
Communicable and non-communicable diseases place enormous social and economic burdens on developed and developing countries. Health education leading to changes in people's attitudes and behaviours remains the best approach for reducing the problem of communicable diseases while there is evidence that programmes providing regular physical exercise and advocating a controlled diet can reduce the prevalence of many non-communicable diseases. Hence, the delivery of health education and physical activity within a single coherent programme offers great potential for simultaneously addressing both health issues. Since 2006, FIFA has developed and tested a novel football-based health-education programme for children entitled ‘11 for Health’, which is aimed at increasing children's levels of physical activity while also delivering 11 simple health messages. When new interventions of this type are published in the scientific literature, it is often not possible to describe important background information about the project that could assist other researchers in developing and implementing similar programmes. This paper attempts to bridge this gap by describing the aims and objectives, organisation, planning, implementation and monitoring requirements needed to deliver FIFA's ‘11 for Health’ programme, first as a pilot project and subsequently as a nationwide project, through a tripartite arrangement between FIFA, the national Football Association and the Government Ministries in Mauritius. PMID:22144002
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Does the vaginal microbiota play a role in the development of cervical cancer?
Kyrgiou, Maria; Mitra, Anita; Moscicki, Anna-Barbara
2016-01-01
Persistent infection with oncogenic Human Papillomavirus (HPV) is necessary but not sufficient for the development of cervical cancer. The factors promoting persistence as well those triggering carcinogenetic pathways are incompletely understood. Rapidly evolving evidence indicates that the vaginal microbiome (VM) may play a functional role (both protective and harmful) in the acquisition and persistence of HPV, and subsequent development of cervical cancer. The first studies examining the vaginal microbiome and the presence of an HPV infection using next generation sequencing techniques (NGS) identified higher microbial diversity in HPV-positive as opposed to HPV-negative women. Furthermore, there appears to be a temporal relationship between the VM and HPV infection in that specific community state types (CSTs) may be correlated with a higher chance of progression or regression of the infection. Studies describing the VM in women with pre-invasive disease (squamous intra-epithelial neoplasia – SIL) consistently demonstrate a dysbiosis in women with the more severe disease. Although it is plausible that the composition of the VM may influence the host innate immune response, susceptibility to infection and the development of cervical disease, the studies to date do not prove causality. Future studies should explore the causal link between the VM and the clinical outcome in longitudinal samples from existing biobanks. PMID:27477083
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Milgrom, Sarah A; Nieto, Yago; Pinnix, Chelsea C; Smith, Grace L; Wogan, Christine F; Rondon, Gabriela; Medeiros, L Jeffrey; Kebriaei, Partow; Dabaja, Bouthaina S
2016-07-28
Patients who undergo allogeneic stem cell transplantation and subsequent radiation therapy uncommonly develop graft-versus-host disease within the irradiated area. We quantified the incidence of this complication, which is a novel contribution to the field. From 2010 to 2014, 1849 patients underwent allogeneic stem cell transplantation, and 41 (2 %) received radiation therapy afterward. Of these, two patients (5 %) developed graft-versus-host disease within the irradiated tissues during or immediately after radiation therapy. The first patient is a 37-year-old white man who had Hodgkin lymphoma; he underwent allogeneic stem cell transplantation from a matched unrelated donor and received radiation therapy for an abdominal and pelvic nodal recurrence. After 28.8 Gy, he developed grade 4 gastrointestinal graft-versus-host disease, refractory to tacrolimus and steroids, but responsive to pentostatin and photopheresis. The other patient is a 24-year-old white man who had acute leukemia; he underwent allogeneic stem cell transplantation from a matched related donor and received craniospinal irradiation for a central nervous system relapse. After 24 cobalt Gy equivalent, he developed severe cutaneous graft-versus-host disease, sharply delineated within the radiation therapy field, which was responsive to tacrolimus and methylprednisolone. We conclude that graft-versus-host disease within irradiated tissues is an uncommon but potentially serious complication that may follow radiation therapy in patients who have undergone allogeneic stem cell transplantation. Clinicians must be aware of this complication and prepared with strategies to mitigate risk. Patients who have undergone allogeneic stem cell transplantation represent a unique population that may offer novel insight into the pathways involved in radiation-related inflammation.
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Prescott, Susan L; Tang, Mimi L K
2005-05-02
A family history of allergy and asthma identifies children at high risk of allergic disease. Dietary restrictions in pregnancy are not recommended. Avoiding inhalant allergens during pregnancy has not been shown to reduce allergic disease, and is not recommended. Breastfeeding should be recommended because of other beneficial effects, but if breast feeding is not possible, a hydrolysed formula is recommended (rather than conventional cow's milk formulas) in high-risk infants only. Maternal dietary restrictions during breastfeeding are not recommended. Soy formulas and other formulas (eg, goat's milk) are not recommended for reducing food allergy risk. Complementary foods (including normal cow's milk formulas) should be delayed until a child is aged at least 4-6 months, but a preventive effect from this measure has only been demonstrated in high-risk infants. There is no evidence that an elimination diet after age 4-6 months has a protective effect, although this needs additional investigation. Further research is needed to determine the relationship between house dust mite exposure at an early age and the development of sensitisation and disease; no recommendation can yet be made about avoidance measures for preventing allergic disease. No recommendations can be made about exposure to pets in early life and the development of allergic disease. If a family already has pets it is not necessary to remove them, unless the child develops evidence of pet allergy (as assessed by an allergy specialist). Women should be advised not to smoke while pregnant, and parents should be advised not to smoke. No recommendations can be made on the use of probiotic supplements (or other microbial agents) for preventing allergic disease at this time. Immunotherapy may be considered as a treatment option for children with allergic rhinitis, and may prevent the subsequent development of asthma.
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The next decade of vaccines: societal and scientific challenges.
Moxon, E Richard; Siegrist, Claire-Anne
2011-07-23
Vaccines against microbial diseases have improved the health of millions of people. In the next decade and beyond, many conceptual and technological scientific advances offer extraordinary opportunities to expand the portfolio of immunisations against viral and bacterial diseases and to pioneer the first vaccines against human parasitic and fungal diseases. Scientists in the public and private sectors are motivated as never before to bring about these innovations in immunisation. Many societal factors threaten to compromise realisation of the public health gains that immunisation can achieve in the next decade and beyond--understanding these factors is imperative. Vaccines are typically given to healthy individuals and safety issues loom high on the list of public concerns. The public needs to regain confidence in immunisation and trust the organisations responsible for the research, development, and implementation of vaccines. In the past, by use of a judicious amalgam of knowledge and empiricism, successful vaccines were largely developed by microbiologists who identified antigens that induced immune responses to conserved pathogen components. In the future, vaccines need to be developed against deadly diseases for which this strategy is often not feasible because of the extensive antigenic variability of relevant pathogens. High microbial diversity means that immunity after natural infection is often ineffective for prevention of disease on subsequent exposure, for example in HIV infection and malaria. Additionally, vaccines need to be generated to protect the people who are most vulnerable because of age or underlying diseases. Thus, in the future, a much deeper understanding of the immunological challenges--including the diversifying role of host genetics and environmental factors, leading perhaps to more personalised approaches-will be the touchstone for rational design and development of adjuvants that result in novel safe and effective vaccines. Copyright © 2011 Elsevier Ltd. All rights reserved.
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Previous Cancer/Lymphoma and Refractory Inflammatory Bowel Disease.
Bernheim, Oren; Axelrad, Jordan; Itzkowitz, Steven H; Colombel, Jean-Frederic
2015-09-14
Immunomodulators and biologic agents are effective in treating inflammatory bowel diseases (IBDs), and recent evidence supports their introduction earlier in the disease course. An important concern to both patients and physicians considering immunosuppression (IS) for the treatment of IBD is the potential associated cancer risk. Several important clinical questions deserve attention with respect to IBD therapy and cancer. First, does medical therapy for IBD predispose to developing cancer? Second, in an IBD patient with a history of cancer, does IBD therapy impact cancer recurrence? Third, once cancer develops in an IBD patient, is the cancer outcome different? Finally, in an IBD patient with current cancer, does the cancer therapy affect IBD outcomes? In a recent multicentric study, patients were identified based on a diagnosis of IBD and cancer with subsequent exposure to anti-tumor necrosis factor α (anti-TNFα arm), thiopurines or methotrexate (antimetabolite arm) or without subsequent IS exposure (control arm). Two hundred and fifty-five patients met the inclusion criteria. Prior cancers included 121 solid, 62 gastrointestinal, 55 dermatologic and 17 hematologic malignancies. During the follow-up period, 75 (29.4%) patients developed incident cancer: 36 (14.1%) a new cancer, 33 (12.9%) a recurrent cancer and 6 (2.4%) a new and recurrent cancer. Incident cancer rate per 100 person-years for patients exposed to anti-TNFα, anti-metabolites and controls was 2.6 with 795 person-years of follow-up, 14.8 with 122 person-years of follow-up and 8.52 with 422 person-years of follow-up, respectively. In this series of IBD patients with a history of cancer, exposure to IS following a cancer diagnosis was not associated with an increased risk of incident cancer compared to patients who did not receive these agents. Prospective data are needed to confirm these findings. © 2015 S. Karger AG, Basel.
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[Osmotic demyelination syndrome in Addison crisis and severe hyponatremia].
Andersen, Signe Elisabeth Bødker; Stausbøl-Grøn, Brian; Rasmussen, Torsten Bloch
2008-12-08
Acute adrenal insufficiency is a life threatening disease with dehydration, hypotension, cerebral dysfunction and gastrointestinal symptoms accompanied by low plasma sodium and high plasma potassium. Osmotic demyelination syndrome (ODS) can occur rarely following correction of plasma sodium. We describe a case with extremely low plasma sodium and subsequent development of ODS. Correction which is too slow may lead to cerebral oedema, brain stem herniation and low sodium encephalopathy. Correction which is too fast may cause ODS. The dilemma is accentuated by concomitant Addison crisis.
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Mechanism of selective lesion of the cardiovascular system in psycho-emotional stress
NASA Technical Reports Server (NTRS)
Repin, Y. M.; Startsev, V. G.
1979-01-01
A species predisposition to hypertensive and ischemic heart disease occurs in mammals only at the level of primates, and is associated with social regulation of biological reactions. The specific physiological mechanism giving rise to psychonerogenic pathology may be an inhibition of the motor component of the agressive-defensive response. Repeated combination of pursuit with subsequent immobilization resulted in four out of five experimental baboons developing serious arterial hypertension and ischemic lesion of the heart which lasted many years.
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Chin, Hui-Lin; Lee, Le Ye; Koh, Pei Lin
2018-04-17
We report a rare case of severe congenital dyserythropoietic anemia type 1 with fetal onset. Our patient presented with fetal hydrops from 19 weeks of gestation, requiring multiple intrauterine transfusions. At birth, she had severe hemolytic anemia with severe jaundice, and was subsequently transfusion dependent. She eventually developed severe iron overload and fulminant liver failure before her demise at 5 months of age. Genetic testing revealed a novel mutation in CDAN1.
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Bal, CS; Chawla, Madhavi
2010-01-01
Development of hyperbilirubinemia, concurrent or subsequent to hyperthyroidism, can be due to thyrotoxicosis per se, or due to drug treatment of hyperthyroidism. Other rare conditions: autoimmune thyroid disease, or causes unrelated to hyperthyroidism like viral hepatitis, alcohol abuse, sepsis, cholangitis, or as a side effect of certain medications. In this article, we review these causes of co-existent hyperthyroidism and jaundice. We also highlight the changes to be expected while interpreting thyroid function tests vis-a-vis liver function tests in this subgroup of patients. PMID:21713219
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Stetler, R. Anne; Leak, Rehana K.; Gan, Yu; Li, Peiying; Hu, Xiaoming; Jing, Zheng; Chen, Jun; Zigmond, Michael J.; Gao, Yanqin
2014-01-01
Preconditioning is a phenomenon in which brief episodes of a sublethal insult induce robust protection against subsequent lethal injuries. Preconditioning has been observed in multiple organisms and can occur in the brain as well as other tissues. Extensive animal studies suggest that the brain can be preconditioned to resist acute injuries, such as ischemic stroke, neonatal hypoxia/ischemia, trauma, and agents that are used in models of neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease. Effective preconditioning stimuli are numerous and diverse, ranging from transient ischemia, hypoxia, hyperbaric oxygen, hypothermia and hyperthermia, to exposure to neurotoxins and pharmacological agents. The phenomenon of “cross-tolerance,” in which a sublethal stress protects against a different type of injury, suggests that different preconditioning stimuli may confer protection against a wide range of injuries. Research conducted over the past few decades indicates that brain preconditioning is complex, involving multiple effectors such as metabolic inhibition, activation of extra- and intracellular defense mechanisms, a shift in the neuronal excitatory/inhibitory balance, and reduction in inflammatory sequelae. An improved understanding of brain preconditioning should help us identify innovative therapeutic strategies that prevent or at least reduce neuronal damage in susceptible patients. In this review, we focus on the experimental evidence of preconditioning in the brain and systematically survey the models used to develop paradigms for neuroprotection, and then discuss the clinical potential of brain preconditioning. In a subsequent components of this two-part series, we will discuss the cellular and molecular events that are likely to underlie these phenomena. PMID:24389580
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Calf health from birth to weaning. III. housing and management of calf pneumonia
2011-01-01
Calfhood diseases have a major impact on the economic viability of cattle operations. A three part review series has been developed focusing on calf health from birth to weaning. In this paper, the last of the three part series, we review disease prevention and management with particular reference to pneumonia, focusing primarily on the pre-weaned calf. Pneumonia in recently weaned suckler calves is also considered, where the key risk factors are related to the time of weaning. Weaning of the suckler calf is often combined with additional stressors including a change in nutrition, environmental change, transport and painful husbandry procedures (castration, dehorning). The reduction of the cumulative effects of these multiple stressors around the time of weaning together with vaccination programmes (preconditioning) can reduce subsequent morbidity and mortality in the feedlot. In most studies, calves housed individually and calves housed outdoors with shelter, are associated with decreased risk of disease. Even though it poses greater management challenges, successful group housing of calves is possible. Special emphasis should be given to equal age groups and to keeping groups stable once they are formed. The management of pneumonia in calves is reliant on a sound understanding of aetiology, relevant risk factors, and of effective approaches to diagnosis and treatment. Early signs of pneumonia include increased respiratory rate and fever, followed by depression. The single most important factor determining the success of therapy in calves with pneumonia is early onset of treatment, and subsequent adequate duration of treatment. The efficacy and economical viability of vaccination against respiratory disease in calves remains unclear. PMID:22018053
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Effect of enrofloxacin on Haemophilus parasuis infection, disease and immune response.
Macedo, Nubia; Cheeran, Maxim C J; Rovira, Albert; Holtcamp, Andrew; Torremorell, Montserrat
2017-02-01
Haemophilus parasuis, the causative agent of Glasser's disease, is a pathogen that colonizes the upper respiratory tract (URT) of pigs, invades the bloodstream and causes polyserositis. Because antimicrobials are highly effective against H. parasuis, we hypothesized that they could have a detrimental effect on the establishment of an immune response if given at the time of URT colonization. In this study, we characterized clinical outcomes and antibody and IFN-γ responses to H. parasuis in pigs treated with enrofloxacin before or after low dose inoculation with a pathogenic H. parasuis strain. Pigs that were only inoculated with the agent (EXP group) and pigs that were treated with enrofloxacin and then inoculated (ABT/EXP group) developed signs of disease starting at 4days post inoculation (DPI), presented a significant increase in serum IgG and were protected against a subsequent homologous challenge. In contrast, pigs treated with antibiotic after inoculation (EXP/ABT group) neither showed signs of disease nor seroconverted (IgG) after low dose inoculation. EXP/ABT pigs as well as naïve control pigs [enrofloxacin only (ABT) and challenge only (CHA)] were susceptible to challenge. Variable levels of antibodies in bronchioalveolar fluid and IFN-γ in peripheral blood mononuclear cells were observed after H. parasuis inoculation, but were not associated with protection. In summary, only pigs treated before low dose H. parasuis inoculation seroconverted and were protected against subsequent challenge. Results from this study can help determine timing of antimicrobial use and contribute to our current understanding of judicious antibiotic use. Copyright © 2016 Elsevier B.V. All rights reserved.
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Eckerström, Marie; Göthlin, Mattias; Rolstad, Sindre; Hessen, Erik; Eckerström, Carl; Nordlund, Arto; Johansson, Boo; Svensson, Johan; Jonsson, Michael; Sacuiu, Simona; Wallin, Anders
2017-01-01
Subjective cognitive decline (SCD) and biomarker-based "at-risk" concepts such as "preclinical" Alzheimer's disease (AD) have been developed to predict AD dementia before objective cognitive impairment is detectable. We longitudinally evaluated cognitive outcome when using these classifications. Memory clinic patients ( n = 235) were classified as SCD ( n = 122): subtle cognitive decline ( n = 36) and mild cognitive impairment ( n = 77) and subsequently subclassified into SCDplus and National Institute on Aging-Alzheimer's Association (NIA-AA) stages 0 to 3. Mean (standard deviation) follow-up time was 48 (35) months. Proportion declining cognitively and prognostic accuracy for cognitive decline was calculated for all classifications. Among SCDplus patients, 43% to 48% declined cognitively. Among NIA-AA stage 1 to 3 patients, 50% to 100% declined cognitively. The highest positive likelihood ratios (+LRs) for subsequent cognitive decline (+LR 6.3), dementia (+LR 3.4), and AD dementia (+LR 6.5) were found for NIA-AA stage 2. In a memory clinic setting, NIA-AA stage 2 seems to be the most successful classification in predicting objective cognitive decline, dementia, and AD dementia.
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Zheng, Zhipeng; Wang, Hanying; Jiang, Hanliang; Chen, Enguo; Zhang, Jun; Xie, Xinyou
2017-11-01
Pulmonary epithelioid hemangioendothelioma (P-EHE) is a rare tumor, with no established standard treatment. Overexpression of vascular endothelial growth factor receptor 2 (VEGFR-2) has been reported in some P-EHE patients. Apatinib, a new small molecule tyrosine kinase inhibitor that specifically targets VEGFR-2, has therapeutic benefits in some advanced tumors. However, its efficacy in P-EHE cases has not been reported. Herein, we presented a 44-year-old man with recurrent hemoptysis for approximately 9 years. After hospitalization, relevant examinations were conducted. The disease was subsequently diagnosed as P-EHE. The patient underwent pulmonary lobectomy, but subsequently developed multiple metastases. Within the tumor, CD31, CK, and Vimentin were found to be positive, while CD34 was negative. Apatinib was initially administered 250 mg daily doses and after 1 month was increased to 500 mg daily. He showed noticeable symptomatic improvements and positive imaging changes in the first month of treatment. However, the disease progressed in the following month, despite the increased apatinib dose. Apatinib is possibly a new treatment for P-EHE. However, further clinical trials are necessary to confirm an effective dose and the efficacy and safety of apatinib in P-EHE treatment.
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Heart-lung transplantation for cystic fibrosis and subsequent domino heart transplantation.
Yacoub, M H; Banner, N R; Khaghani, A; Fitzgerald, M; Madden, B; Tsang, V; Radley-Smith, R; Hodson, M
1990-01-01
Between September 1984 and October 1988, 27 patients underwent combined heart-lung transplantation for treatment of end-stage respiratory disease caused by cystic fibrosis. The actuarial patient survival was 78% at 1 year and 72% at 2 years. Bacterial respiratory infections were common in the early postoperative period and necessitated vigorous medical therapy. The dose of cyclosporine required in these patients was higher than in conventional transplant recipients, and this contributed to an increased cost of postoperative care. Lung function was greatly improved after transplantation, and long-term survivors achieved an excellent quality of life. Lymphoproliferative disorders developed in two patients; these disorders regressed after a reduction in immunosuppression. Two patients required retransplantation: one because of obliterative bronchiolitis and the other because of recurrent respiratory infections associated with a moderate tracheal stenosis and severe deterioration in lung function. A modification of the technique used for heart-lung transplantation allowed 20 hearts from cystic fibrosis patients to be used for subsequent heart transplantation. Immediate heart function was satisfactory in all cases. The actuarial survival of the recipients of these domino heart transplants was 75% at 1 year. No coronary artery disease was present in the 12 patients who have undergone coronary angiography at 1 year.
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Long, Jessica B.; Wang, Rong; Hu, Xin; Yu, James B.; Huntington, Scott F.; Abel, Gregory A.; Mougalian, Sarah S.; Podoltsev, Nikolai A.; Gore, Steven D.; Gross, Cary P.; Ma, Xiaomei; Davidoff, Amy J.
2017-01-01
Background There are inconsistent and limited data regarding the risk of myeloid neoplasms (MN) among breast cancer survivors who received radiotherapy (RT) in the absence of chemotherapy. Concern about subsequent MN might influence the decision to use adjuvant RT for women with localized disease. As patients with therapy-related MN have generally poor outcomes, the presumption of subsequent MN being therapy-related could affect treatment recommendations. Methods We used the Surveillance, Epidemiology, and End Results (SEER)–Medicare linked database to study older women with in-situ or stage 1–3 breast cancer diagnosed 2001–2009 who received surgery. Chemotherapy and RT were ascertained using Medicare claims, and new MN diagnoses were captured using both SEER registry and Medicare claims. We excluded women who received chemotherapy for initial treatment, and censored at receipt of subsequent chemotherapy. Competing-risk survival analysis was used to assess the association between RT and risk of subsequent MN adjusting for relevant characteristics. Results Median follow-up for 60,426 eligible patients was 68 months (interquartile range, 46 to 92 months), with 47.6% receiving RT. In total, 316 patients (0.52%) were diagnosed with MN; the cumulative incidence per 10,000 person-years was 10.6 vs 9.0 among RT-treated vs non-RT-treated women, respectively (p = .004); the increased risk of subsequent MN persisted in the adjusted analysis (hazard ratio = 1.36, 95% confidence interval: 1.03–1.80). The results were consistent in multiple sensitivity analyses. Conclusions Our data suggest that RT is associated with a significant risk of subsequent MN among older breast cancer survivors, though the absolute risk increase is very small. These findings suggest the benefits of RT outweigh the risks of development of subsequent MN. PMID:28902882
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Nagata, Naoki; Yamanaka, Shinya
2014-01-31
Induced pluripotent stem cell technology makes in vitro reprogramming of somatic cells from individuals with various genetic backgrounds possible. By applying this technology, it is possible to produce pluripotent stem cells from biopsy samples of arbitrarily selected individuals with various genetic backgrounds and to subsequently maintain, expand, and stock these cells. From these induced pluripotent stem cells, target cells and tissues can be generated after certain differentiation processes. These target cells/tissues are expected to be useful in regenerative medicine, disease modeling, drug screening, toxicology testing, and proof-of-concept studies in drug development. Therefore, the number of publications concerning induced pluripotent stem cells has recently been increasing rapidly, demonstrating that this technology has begun to infiltrate many aspects of stem cell biology and medical applications. In this review, we discuss the perspectives of induced pluripotent stem cell technology for modeling human diseases. In particular, we focus on the cloning event occurring through the reprogramming process and its ability to let us analyze the development of complex disease-harboring somatic mosaicism.
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Strategies in Ebola virus disease (EVD) diagnostics at the point of care.
Coarsey, Chad T; Esiobu, Nwadiuto; Narayanan, Ramswamy; Pavlovic, Mirjana; Shafiee, Hadi; Asghar, Waseem
2017-11-01
Ebola virus disease (EVD) is a devastating, highly infectious illness with a high mortality rate. The disease is endemic to regions of Central and West Africa, where there is limited laboratory infrastructure and trained staff. The recent 2014 West African EVD outbreak has been unprecedented in case numbers and fatalities, and has proven that such regional outbreaks can become a potential threat to global public health, as it became the source for the subsequent transmission events in Spain and the USA. The urgent need for rapid and affordable means of detecting Ebola is crucial to control the spread of EVD and prevent devastating fatalities. Current diagnostic techniques include molecular diagnostics and other serological and antigen detection assays; which can be time-consuming, laboratory-based, often require trained personnel and specialized equipment. In this review, we discuss the various Ebola detection techniques currently in use, and highlight the potential future directions pertinent to the development and adoption of novel point-of-care diagnostic tools. Finally, a case is made for the need to develop novel microfluidic technologies and versatile rapid detection platforms for early detection of EVD.
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Fiedorowicz, Jess G; Ellingrod, Vicki L; Kaplan, Mariana J; Sen, Srijan
2015-09-01
We sought to prospectively determine whether the onset of internship stress and any subsequent depression alters physiological markers of early vascular disease We explored potential mechanisms linking stress and depression to vascular disease in a prospective cohort of 37 participants exposed to medical internship stress, an established precipitant of depressive symptomatology. Change in depressive symptom score from baseline over one year of internship stress was inversely correlated with change in the reactive hyperemia index (RHI), a measure of peripheral endothelial function (r=0.41, p=0.01). The change in depressive symptoms in the first six months of internship was similarly related to change in RHI over one year (r=0.38, p=0.02). While the development of depressive symptoms did not significantly impact changes in endothelial progenitor cells (EPCs), EPCs did significantly decrease with the year of internship stress (11.9 to 3.4cells/ml blood; p=0.01). Endothelial function may be a critical link between stress, depression, and cardiovascular disease and a feasible surrogate outcome for prospective studies. Copyright © 2015 Elsevier Inc. All rights reserved.
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Fiedorowicz, Jess G.; Ellingrod, Vicki L.; Kaplan, Mariana J.; Sen, Srijan
2015-01-01
Objective We sought to prospectively determine whether the onset of internship stress and any subsequent depression alters physiological markers of early vascular disease Methods We explored potential mechanisms linking stress and depression to vascular disease in a prospective cohort of 37 participants exposed to medical internship stress, an established precipitant of depressive symptomatology. Results Change in depressive symptom score from baseline over one year of internship stress was inversely correlated with change in the reactive hyperemia index (RHI), a measure of peripheral endothelial function (r=0.41, p=0.01). The change in depressive symptoms in the first six months of internship was similarly related to change in RHI over one year (r=0.38, p=0.02). While the development of depressive symptoms did not significantly impact changes in endothelial progenitor cells (EPCs), EPCs did significantly decrease with the year of internship stress (11.9 to 3.4 cells/ml blood; p=0.01). Conclusion Endothelial function may be a critical link between stress, depression, and cardiovascular disease and a feasible surrogate outcome for prospective studies. PMID:26115588
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Resiliency or restoration: management of sudden oak death before and after outbreak
Richard Cobb; Peter Hartsough; Noam Ross; Janet Klein; David LaFever; Susan Frankel; David Rizzo
2017-01-01
Forests at risk to diseases caused by invasive Phytophthora pathogens can be grouped into two broad classes: those already invaded by the focal pathogen where disease has emerged or those at significant risk of invasion and subsequent emergence of disease. This dichotomy represents distinct management scenarios â treating after or before disease...
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Yang, Chunzhang; Wang, Herui; Zhu, Dongwang; Hong, Christopher S.; Dmitriev, Pauline; Zhang, Chao; Li, Yan; Ikejiri, Barbara; Brady, Roscoe O.; Zhuang, Zhengping
2015-01-01
Gaucher disease is caused by mutations of the GBA1 gene, which encodes the lysosomal anchored gluococerebrosidase (GCase). GBA1 mutations commonly result in protein misfolding, abnormal chaperone recognition, and premature degradation, but are less likely to affect catalytic activity. In the present study, we demonstrate that the Hsp90/HOP/Cdc37 complex recruits Hsp27 after recognition of GCase mutants with subsequent targeting of GCase mutant peptides to degradation mechanisms such as VCP and the 26S proteasome. Inhibition of Hsp27 not only increased the quantity of enzyme but also enhanced GCase activity in fibroblasts derived from patients with Gaucher disease. These findings provide insight into a possible therapeutic strategy for protein misfolding diseases by correcting chaperone binding and altering subsequent downstream patterns of protein degradation. PMID:25583479
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Yang, Chunzhang; Wang, Herui; Zhu, Dongwang; Hong, Christopher S; Dmitriev, Pauline; Zhang, Chao; Li, Yan; Ikejiri, Barbara; Brady, Roscoe O; Zhuang, Zhengping
2015-01-27
Gaucher disease is caused by mutations of the GBA1 gene, which encodes the lysosomal anchored gluococerebrosidase (GCase). GBA1 mutations commonly result in protein misfolding, abnormal chaperone recognition, and premature degradation, but are less likely to affect catalytic activity. In the present study, we demonstrate that the Hsp90/HOP/Cdc37 complex recruits Hsp27 after recognition of GCase mutants with subsequent targeting of GCase mutant peptides to degradation mechanisms such as VCP and the 26S proteasome. Inhibition of Hsp27 not only increased the quantity of enzyme but also enhanced GCase activity in fibroblasts derived from patients with Gaucher disease. These findings provide insight into a possible therapeutic strategy for protein misfolding diseases by correcting chaperone binding and altering subsequent downstream patterns of protein degradation.
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Equine monocytic ehrlichiosis (Potomac horse fever): a review.
Mulville, P
1991-11-01
In the late 1970s, a new infectious disease in horses, involving acute enteritis, was recognised in the Potomac River area of Maryland, U.S.A. The causative agent was identified subsequently as a new species of rickettsial organism, later named Ehrlichia risticii. Since then, the disease has been reported in many other states, and in enzootic areas vaccination is common. Signs associated with the clinical disease included depression, fever, anorexia, decreased or absent intestinal sounds, profuse watery diarrhoea and laminitis. However, considerable variation in clinical manifestations has been reported in both the natural and experimental disease. Accurate diagnosis depends on serological testing; currently, the immunofluorescent antibody test (IFA) is used widely, although an enzyme-linked immunosorbent assay (ELISA) has been developed recently. Mortality in untreated cases is 15 to 35 per cent. Antibiotics of the tetracycline series have shown activity against the organism in vitro, in an in vivo murine model and appear to be useful in clinical cases.
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Non-alcoholic fatty liver disease, diet and gut microbiota
Finelli, Carmine; Tarantino, Giovanni
2014-01-01
Non-alcoholic fatty liver disease (NAFLD) is a severe liver disease that is increasing in prevalence with the worldwide epidemic of obesity and its related insulin-resistance state. Evidence for the role of the gut microbiota in energy storage and the subsequent development of obesity and some of its related diseases is now well established. More recently, a new role of gut microbiota has emerged in NAFLD. The gut microbiota is involved in gut permeability, low-grade inflammation and immune balance, it modulates dietary choline metabolism, regulates bile acid metabolism and produces endogenous ethanol. All of these factors are molecular mechanisms by which the microbiota can induce NAFLD or its progression toward overt non-alcoholic steatohepatitis. Modification of the gut microbiota composition and/or its biochemical capacity by specific dietary or pharmacological interventions may advantageously affect host metabolism. Large-scale intervention trials, investigating the potential benefit of prebiotics and probiotics in improving cardiometabolic health in high-risk populations, are fervently awaited. PMID:26417275
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Nitric Oxide Homeostasis in Neurodegenerative Diseases.
Hannibal, Luciana
2016-01-01
The role of nitric oxide in the pathogenesis and progression of neurodegenerative illnesses such as Parkinson's and Alzheimer's diseases has become prominent over the years. Increased activity of the enzymes that produce reactive oxygen species, decreased activity of antioxidant enzymes and imbalances in glutathione pools mediate and mark the neurodegenerative process. Much of the oxidative damage of proteins is brought about by the overproduction of nitric oxide by nitric oxide synthases (NOS) and its subsequent reactivity with reactive oxygen species. Proteomic methods have advanced the field tremendously, by facilitating the quantitative assessment of differential expression patterns and oxidative modifications of proteins and alongside, mapping their non-canonical functions. As a signaling molecule involved in multiple biochemical pathways, the level of nitric oxide is subject to tight regulation. All three NOS isoforms display aberrant patterns of expression in Alzheimer's disease, altering intracellular signaling and routing oxidative stress in directions that are uncompounded. This review discusses the prime factors that control nitric oxide biosynthesis, reactivity footprints and ensuing effects in the development of neurodegenerative diseases.
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Tomasello, Giovanni; Mazzola, Margherita; Leone, Angelo; Sinagra, Emanuele; Zummo, Giovanni; Farina, Felicia; Damiani, Provvidenza; Cappello, Francesco; Gerges Geagea, Alice; Jurjus, Abdo; Bou Assi, Tarek; Messina, Massimiliano; Carini, Francesco
2016-12-01
Microbiota refers to the population of microorganisms (bacteria, viruses and fungi) that inhabit the entire gastrointestinal tract, more particularly the colon whose role is to maintain the integrity of the intestinal mucosa and control the proliferation of pathogenic bacteria. Alteration in the composition of the gut microbiota is called dysbiosis. Dysbiosis redisposes to inflammatory bowel diseases such as ulcerative colitis, Crohn disease and indeterminate colitis. The purpose of this literature review is to elucidate the influence of diet on the composition of the gastrointestinal microbiota in the healthy gut and the role of diet in the development of dysbiosis. The "Western diet", in particular a low - fiber high fat/high carbohydrate diet is one factor that can lead to severe dysbiosis. In contrast, "mediterranean" and vegetarian diets that includes abundant fruits, vegetables, olive oil and oily fish are known for their anti-inflammatory effects and could prevent dysbiosis and subsequent inflammatory bowel disease.
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China's Air Quality and Respiratory Disease Mortality Based on the Spatial Panel Model.
Cao, Qilong; Liang, Ying; Niu, Xueting
2017-09-18
Background : Air pollution has become an important factor restricting China's economic development and has subsequently brought a series of social problems, including the impact of air pollution on the health of residents, which is a topical issue in China. Methods : Taking into account this spatial imbalance, the paper is based on the spatial panel data model PM 2.5 . Respiratory disease mortality in 31 Chinese provinces from 2004 to 2008 is taken as the main variable to study the spatial effect and impact of air quality and respiratory disease mortality on a large scale. Results : It was found that there is a spatial correlation between the mortality of respiratory diseases in Chinese provinces. The spatial correlation can be explained by the spatial effect of PM 2.5 pollutions in the control of other variables. Conclusions : Compared with the traditional non-spatial model, the spatial model is better for describing the spatial relationship between variables, ensuring the conclusions are scientific and can measure the spatial effect between variables.
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Simone, Chiara; Ramirez, Agnese; Bucchia, Monica; Rinchetti, Paola; Rideout, Hardy; Papadimitriou, Dimitra; Re, Diane B.; Corti, Stefania
2016-01-01
Spinal Muscular Atrophy (SMA) is a genetic neurological disease that causes infant mortality; no effective therapies are currently available. SMA is due to homozygous mutations and/or deletions in the Survival Motor Neuron 1 (SMN1) gene and subsequent reduction of the SMN protein, leading to the death of motor neurons. However, there is increasing evidence that in addition to motor neurons, other cell types are contributing to SMA pathology. In this review, we will discuss the involvement of non-motor neuronal cells, located both inside and outside the central nervous system, in disease onset and progression. These contribution of non-motor neuronal cells to disease pathogenesis has important therapeutic implications: in fact, even if SMN restoration in motor neurons is needed, it has been shown that optimal phenotypic amelioration in animal models of SMA requires a more widespread SMN correction. It will be crucial to take this evidence into account before clinical translation of the novel therapeutic approaches that are currently under development. PMID:26681261
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Tarrade, Anne; Panchenko, Polina; Junien, Claudine; Gabory, Anne
2015-01-01
The recent and rapid worldwide increase in non-communicable diseases challenges the assumption that genetic factors are the primary contributors to such diseases. A new concept of the 'developmental origins of health and disease' (DOHaD) is at stake and therefore requires a paradigm shift. Maternal obesity and malnutrition predispose offspring to develop metabolic syndrome, a vicious cycle leading to transmission to subsequent generation(s), with differences in response and susceptibility according to the sex of the individual. The placenta is a programming agent of adult health and disease. Adaptations of placental phenotype in response to maternal diet and metabolic status alter fetal nutrient supply. This implies important epigenetic changes that are, however, still poorly documented in DOHaD studies, particularly concerning overnutrition. The aim of this review is to discuss the emerging knowledge on the relationships between the effect of maternal nutrition or metabolic status on placental function and the risk of diseases later in life, with a specific focus on epigenetic mechanisms and sexual dimorphism. Explaining the sex-specific causal variables and how males versus females respond and adapt to environmental perturbations should help physicians and patients to anticipate disease susceptibility. © 2015. Published by The Company of Biologists Ltd.
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Gottschalk, M G; Cooper, J D; Chan, M K; Bot, M; Penninx, B W J H; Bahn, S
2015-08-01
Although social anxiety disorder (SAD) is strongly associated with the subsequent development of a depressive disorder (major depressive disorder or dysthymia), no underlying biological risk factors are known. We aimed to identify biomarkers which predict depressive episodes in SAD patients over a 2-year follow-up period. One hundred sixty-five multiplexed immunoassay analytes were investigated in blood serum of 143 SAD patients without co-morbid depressive disorders, recruited within the Netherlands Study of Depression and Anxiety (NESDA). Predictive performance of identified biomarkers, clinical variables and self-report inventories was assessed using receiver operating characteristics curves (ROC) and represented by the area under the ROC curve (AUC). Stepwise logistic regression resulted in the selection of four serum analytes (AXL receptor tyrosine kinase, vascular cell adhesion molecule 1, vitronectin, collagen IV) and four additional variables (Inventory of Depressive Symptomatology, Beck Anxiety Inventory somatic subscale, depressive disorder lifetime diagnosis, BMI) as optimal set of patient parameters. When combined, an AUC of 0.86 was achieved for the identification of SAD individuals who later developed a depressive disorder. Throughout our analyses, biomarkers yielded superior discriminative performance compared to clinical variables and self-report inventories alone. We report the discovery of a serum marker panel with good predictive performance to identify SAD individuals prone to develop subsequent depressive episodes in a naturalistic cohort design. Furthermore, we emphasise the importance to combine biological markers, clinical variables and self-report inventories for disease course predictions in psychiatry. Following replication in independent cohorts, validated biomarkers could help to identify SAD patients at risk of developing a depressive disorder, thus facilitating early intervention. Copyright © 2015 Elsevier Inc. All rights reserved.
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Wang, Tsung-Yang; Wei, Han-Ting; Liou, Ying-Jay; Su, Tung-Ping; Bai, Ya-Mei; Tsai, Shih-Jen; Yang, Albert C; Chen, Tzeng-Ji; Tsai, Chia-Fen; Chen, Mu-Hong
2016-11-15
Previous studies suggested a relationship between posttraumatic stress disorder (PTSD) in the specific population (i.e., war survivors and veterans) and subsequent dementia risk. However, whether patients with PTSD in the general population were at an increased risk for developing dementia in later life remained unclear. The Cox regression analysis was performed using data from the Taiwan National Health Insurance Research Database. The study sample comprised 1750 patients diagnosed with PTSD between 2001 and 2009 and 7000 age-/sex-matched individuals without PTSD. Those who developed dementia during follow-up to the end of 2011 were identified. After adjusting for demographic data and medical and psychiatric comorbidities, PTSD was an independent risk factor for the risk for subsequent dementia (hazard ratio [HR]=4.37; 95% confidence interval [CI]: 2.53-7.55). There was a dose-dependent relationship between PTSD severity indicated by the frequency of psychiatric clinics visiting of PTSD (times per year) and the risk of subsequent dementia (<5: HR: 2.81, 95% CI: 1.50-5.29; 5-10: 6.90, 95% CI: 3.09-15.40;>10: HR: 18.13, 95% CI: 9.13-36.00). Furthermore, patients with depressive disorder and medical comorbidities, such as cerebrovascular diseases, diabetes mellitus, and head injuries, exhibited a higher risk for developing dementia. Our study suggested a significant dose-dependent association between PTSD and its severity and an increased risk of developing dementia later in life. The importance of mental care for trauma victims would increase in the coming century, and our findings broadened another era for the end result of a widely prevalent psychiatric disorder. Copyright © 2016 Elsevier B.V. All rights reserved.
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Whitehead, Stephen S
2016-01-01
Dengue is caused by four serotype-distinct dengue viruses (DENVs), and developing a multivalent vaccine against dengue has not been straightforward since partial immunity to DENV may predispose to more severe disease upon subsequent DENV infection. The vaccine that is furthest along in development is CYD™, a live attenuated tetravalent vaccine (LATV) produced by Sanofi Pasteur. Although the multi-dose vaccine demonstrated protection against severe dengue, its overall efficacy was limited by DENV serotype, serostatus at vaccination, region and age. The National Institute of Allergy and Infectious Diseases has developed the LATV dengue vaccines TV003/TV005. A single dose of either TV003 or TV005 induced seroconversion to four DENV serotypes in 74-92% (TV003) and 90% (TV005) of flavivirus seronegative adults and elicited near-sterilizing immunity to a second dose of vaccine administered 6-12 months later. The important differences in the structure, infectivity and immune responses to TV003/TV005 are compared with CYD™.
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Naqshbandi Hayward, Mariam; Paquette-Warren, Jann; Harris, Stewart B
2016-07-26
Given the dramatic rise and impact of chronic diseases and gaps in care in Indigenous peoples in Canada, a shift from the dominant episodic and responsive healthcare model most common in First Nations communities to one that places emphasis on proactive prevention and chronic disease management is urgently needed. The Transformation of Indigenous Primary Healthcare Delivery (FORGE AHEAD) Program partners with 11 First Nations communities across six provinces in Canada to develop and evaluate community-driven quality improvement (QI) initiatives to enhance chronic disease care. FORGE AHEAD is a 5-year research program (2013-2017) that utilizes a pre-post mixed-methods observational design rooted in participatory research principles to work with communities in developing culturally relevant innovations and improved access to available services. This intensive program incorporates a series of 10 inter-related and progressive program activities designed to foster community-driven initiatives with type 2 diabetes mellitus as the action disease. Preparatory activities include a national community profile survey, best practice and policy literature review, and readiness tool development. Community-level intervention activities include community and clinical readiness consultations, development of a diabetes registry and surveillance system, and QI activities. With a focus on capacity building, all community-level activities are driven by trained community members who champion QI initiatives in their community. Program wrap-up activities include readiness tool validation, cost-analysis and process evaluation. In collaboration with Health Canada and the Aboriginal Diabetes Initiative, scale-up toolkits will be developed in order to build on lessons-learned, tools and methods, and to fuel sustainability and spread of successful innovations. The outcomes of this research program, its related cost and the subsequent policy recommendations, will have the potential to significantly affect future policy decisions pertaining to chronic disease care in First Nations communities in Canada. Current ClinicalTrial.gov protocol ID NCT02234973 . Date of Registration: July 30, 2014.
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Aicardi-Goutières syndrome: a model disease for systemic autoimmunity.
Lee-Kirsch, M A; Wolf, C; Günther, C
2014-01-01
Systemic autoimmunity is a complex disease process that results from a loss of immunological tolerance characterized by the inability of the immune system to discriminate self from non-self. In patients with the prototypic autoimmune disease systemic lupus erythematosus (SLE), formation of autoantibodies targeting ubiquitous nuclear antigens and subsequent deposition of immune complexes in the vascular bed induces inflammatory tissue injury that can affect virtually any organ system. Given the extraordinary genetic and phenotypic heterogeneity of SLE, one approach to the genetic dissection of complex SLE is to study monogenic diseases, for which a single gene defect is responsible. Considerable success has been achieved from the analysis of the rare monogenic disorder Aicardi-Goutières syndrome (AGS), an inflammatory encephalopathy that clinically resembles in-utero-acquired viral infection and that also shares features with SLE. Progress in understanding the cellular and molecular functions of the AGS causing genes has revealed novel pathways of the metabolism of intracellular nucleic acids, the major targets of the autoimmune attack in patients with SLE. Induction of autoimmunity initiated by immune recognition of endogenous nucleic acids originating from processes such as DNA replication/repair or endogenous retro-elements represents novel paradigms of SLE pathogenesis. These findings illustrate how investigating rare monogenic diseases can also fuel discoveries that advance our understanding of complex disease. This will not only aid the development of improved tools for SLE diagnosis and disease classification, but also the development of novel targeted therapeutic approaches. © 2013 British Society for Immunology.
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Kawasaki disease with G6PD deficiency--report of one case and literature review.
Chen, Chia-Hao; Lin, Li-Yan; Yang, Kuender D; Hsieh, Kai-Sheng; Kuo, Ho-Chang
2014-06-01
Kawasaki disease (KD) is a systemic vasculitis primarily affecting children who are younger than 5 years. The most serious complications are coronary artery aneurysms and sequelae of vasculitis with the subsequent development of coronary artery aneurysm. According to the literature, intravenous immunoglobulin (IVIG) plus high-dose aspirin (acetylsalicylic acid) were standard treatment for KD, whereas low-dose aspirin (3-5 mg/kg/day) was used for thrombocytosis in KD via antiplatelet effect. However, aspirin has been reported to have hemolytic potential in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. We report a child with G6PD-deficiency who has KD, and review the literature. Copyright © 2012. Published by Elsevier B.V.
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Resolving TYK2 locus genotype-to-phenotype differences in autoimmunity
Dendrou, Calliope A.; Cortes, Adrian; Shipman, Lydia; Evans, Hayley G.; Attfield, Kathrine E.; Jostins, Luke; Barber, Thomas; Kaur, Gurman; Kuttikkatte, Subita Balaram; Leach, Oliver A.; Desel, Christiane; Faergeman, Soren L.; Cheeseman, Jane; Neville, Matt J.; Sawcer, Stephen; Compston, Alastair; Johnson, Adam R.; Everett, Christine; Bell, John I.; Karpe, Fredrik; Ultsch, Mark; Eigenbrot, Charles; McVean, Gil; Fugger, Lars
2017-01-01
Thousands of genetic variants have been identified that contribute to the development of complex diseases, but determining how to fully elucidate their biological consequences for translation into clinical benefit is challenging. Conflicting evidence regarding the functional impact of genetic variants in the tyrosine kinase 2 (TYK2) gene, which is differentially associated with common autoimmune diseases, currently obscures the potential of TYK2 as a therapeutic target. We aimed to resolve this conflict by performing genetic meta-analysis across disorders, subsequent molecular, cellular, in vivo and structural functional follow-up and epidemiological studies. Our data revealed a protective homozygous effect that defined a signaling optimum between autoimmunity and immunodeficiency and identified TYK2 as a potential drug target for multiple autoimmune disorders. PMID:27807284
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The retinal funduscope demonstration project
NASA Technical Reports Server (NTRS)
Wilhelm, Jim
1994-01-01
A lightweight, relatively inexpensive electronic and photographic instrument has been re-developed for the detection, monitoring, and objective quantification of ocular/ systemic disease or physiological alterations of the retina, blood vessels, or other structures in the anterior and posterior chambers of the eye. The instrument can be operated with little training. It can function with a human or animal subject seated, recumbent, inverted, or in almost any other orientation; and in a hospital, laboratory, field, or other environment. The instrument produces video images that can be viewed directly and/or digitized for simultaneous or subsequent analysis. It can also be equipped to produce photographs and/or fitted with adaptors to produce stereoscopic or magnified images ot the skin, nose, ear, throat, or mouth to detect lesions or diseases.
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A critical review of clinical trials in systemic lupus erythematosus
Mahieu, Mary A.; Strand, Vibeke; Simon, Lee S.; Lipsky, Peter E.; Ramsey-Goldman, Rosalind
2016-01-01
One challenge in caring for patients with systemic lupus erythematosus (SLE) is a paucity of approved therapeutics for treatment of the diverse disease manifestations. In the last 60 years, only one drug, belimumab, has been approved for SLE treatment. Critical evaluation of investigator initiated and pharma-sponsored randomized controlled trials (RCTs) highlights barriers to successful drug development in SLE, including disease heterogeneity, inadequate trial size or duration, insufficient dose finding before initiation of large trials, handling of background medications, and choice of primary endpoint. Herein we examine lessons learned from landmark SLE RCTs and subsequent advances in trial design, as well as discuss efforts to address limitations in current SLE outcome measures that will improve detection of true therapeutic responses in future RCTs. PMID:27497257
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Mohammed, Noor; Subramanian, Venkataraman
2016-01-01
Ulcerative colitis (UC) is a chronic inflammatory bowel condition characterised by a relapsing and remitting course. Symptom control has been the traditional mainstay of medical treatment. It is well known that histological inflammatory activity persists despite adequate symptom control and absence of endoscopic inflammation. Current evidence suggests that presence of histological inflammation poses a greater risk of disease relapse and subsequent colorectal cancer risk. New endoscopic technologies hold promise for developing endoscopic markers of mucosal inflammation. Achieving endoscopic and histological remission appears be the future aim of medical treatments for UC. This review article aims to evaluate the use of endoscopy as a tool in assessment of mucosal inflammation UC and its correlation with disease outcomes. PMID:27895420
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The rise of biosimilars: potential benefits and drawbacks in rheumatoid arthritis.
Yoo, Dae Hyun
2014-08-01
Although biologic agents are effective in the treatment of rheumatoid arthritis, the high price of drugs and restricted health care budgets have restricted easy access to biologics. Eventually, the use of biologic disease-modifying antirheumatic drugs might be inversely associated with disease activity in countries with low gross domestic product. The EMA approved an infliximab biosimilar for the first time in September 2013. The first approval of a biosimilar monoclonal antibody by a major regulatory authority provided a global standard for subsequent biosimilars and for biopharmaceutical companies developing biosimilars. Biosimilars with a highly similar quality and efficacy profile at an acceptable lower cost would significantly increase affordability of biologic disease-modifying antirheumatic drugs in the treatment of rheumatoid arthritis. Here, we will review the current status of first biosimilar antibody agent and the potential discussion points raised against biosimilars. In addition, the importance of awareness on biosimilars for stakeholders is discussed.
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The Role of Gluten in Celiac Disease and Type 1 Diabetes.
Serena, Gloria; Camhi, Stephanie; Sturgeon, Craig; Yan, Shu; Fasano, Alessio
2015-08-26
Celiac disease (CD) and type 1 diabetes (T1D) are autoimmune conditions in which dietary gluten has been proven or suggested to play a pathogenic role. In CD; gluten is established as the instigator of autoimmunity; the autoimmune process is halted by removing gluten from the diet; which allows for resolution of celiac autoimmune enteropathy and subsequent normalization of serological markers of the disease. However; an analogous causative agent has not yet been identified for T1D. Nevertheless; the role of dietary gluten in development of T1D and the potentially beneficial effect of removing gluten from the diet of patients with T1D are still debated. In this review; we discuss the comorbid occurrence of CD and T1D and explore current evidences for the specific role of gluten in both conditions; specifically focusing on current evidence on the effect of gluten on the immune system and the gut microbiota.
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A review of antiviral drugs and other compounds with activity against feline herpesvirus-1
Thomasy, S. M.; Maggs, D. J.
2016-01-01
Feline herpesvirus type 1 (FHV-1) is a common and important cause of ocular surface disease, dermatitis, respiratory disease, and potentially intraocular disease in cats. However, many antiviral drugs developed for the treatment of humans infected with herpesviruses have been used to treat cats infected with FHV-1. Translational use of drugs in this manner ideally requires methodical investigation of their in vitro efficacy against FHV-1 followed by pharmacokinetic and safety trials in normal cats. Subsequently, placebo-controlled efficacy studies in experimentally-inoculated animals should be performed followed, finally, by carefully designed and monitored clinical trials in client-owned animals. This review is intended to provide a concise review of the available literature regarding the efficacy of antiviral drugs and other compounds with proven or putative activity against FHV-1, as well as a discussion of their safety in cats. PMID:27091747
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Along a TNF-paved road from dead parasites in red cells to cerebral malaria, and beyond.
Clark, I A
2009-10-01
This is a personal account of how tumour necrosis factor (TNF) the prototype of a group of host-origin mediators, often known as pro-inflammatory cytokines, came into parasitology, and was subsequently realised to be central to the pathogenesis of most disease pathology. This contribution summarizes an example of how a curiosity-driven outsider, with initially no intention of heading this way, and no relevant experience, and with no more than the simplest of plans but an ambition to read as widely as it takes, and (most importantly) allowed to follow his head, can be what is required to give fresh insight into understanding a disease. It also gives the author's views on aspects of how the field of malaria disease pathogenesis seems to be developing. The hope is to inspire another generation to follow a similarly original course.
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Complications of cirrhosis. A 50 years flashback.
Møller, Søren; Bendtsen, Flemming
2015-06-01
In patients with cirrhosis and portal hypertension, it is largely the frequency and severity of complications relating to the diseased liver, degree of portal hypertension and hemodynamic derangement that determine the prognosis. It can be considered as a multiple organ failure that apart from the liver involves the heart, lungs, kidneys, the immune systems and other organ systems. Progressive fibrosis of the liver and subsequent metabolic impairment leads to a systemic and splanchnic arteriolar vasodilatation. With the progression of the disease development of portal hypertension leads to formation of esophageal varices and ascites. The circulation becomes hyperdynamic with cardiac, pulmonary as well as renal consequences for dysfunction and reduced survival. Infections and a changed cardiac function known as cirrhotic cardiomyopathy may be involved in further aggravation of other complications such as renal failure precipitating the hepatorenal syndrome. Patients with end-stage liver disease and related complications as for example the hepatopulmonary syndrome can only radically be treated by liver transplantation.
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Midkine and multiple sclerosis
Takeuchi, Hideyuki
2014-01-01
Multiple sclerosis (MS) is an autoimmune neurological disease characterized by inflammatory demyelination with subsequent neuronal damage in the CNS. MS and its animal model, experimental autoimmune encephalomyelitis (EAE), have been thought as autoreactive Th1 and Th17 cell-mediated diseases. CD4+CD25+FoxP3+ regulatory T-cell (Treg) plays a pivotal role in autoimmune tolerance, and tolerogenic dendritic cells (DCreg) drive the development of inducible Treg cells. Thus, a dysfunction in the development of Treg and DCreg leads to the development of autoimmune diseases. However, the factors that regulate Treg and DCreg are largely unknown. We recently showed that removal of midkine (MK) suppressed EAE due to an expansion of the Treg cell population as well as a decrease in the numbers of autoreactive Th1 and Th17 cells. MK decreased the Treg cell population by suppressing the phosphorylation of STAT5, which is essential for the expression of Foxp3, the master transcriptional factor of Treg cell differentiation. Furthermore, MK reduces the DCreg cell population by inhibiting the phosphorylation of STAT3, which is critical for DCreg development. Blockade of MK signalling by a specific RNA aptamer significantly elevated the population of DCreg and Treg cells and ameliorated EAE without detectable adverse effects. Therefore, the inhibition of MK may provide an effective therapeutic strategy against autoimmune diseases including MS. Linked Articles This article is part of a themed section on Midkine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-4 PMID:24460675
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Benefit of interpregnancy HIV viral load suppression on subsequent maternal and infant outcomes.
Stewart, Robert D; Wells, C Edward; Roberts, Scott W; Rogers, Vanessa L; McElwee, Barbara S; McIntire, Donald D; Sheffield, Jeanne S
2014-09-01
The objective of the study was to determine whether interpregnancy human immunodeficiency virus (HIV) viral load suppression affects outcomes in subsequent pregnancies. This is a retrospective review of all women who delivered 2 consecutive pregnancies while diagnosed with HIV from Jan. 1, 1984, until Jan. 1, 2012. Medical records were reviewed for maternal, infant, and delivery data. Pregnancies were divided into index and subsequent pregnancy and analyzed for outcomes. During the study period, 172 HIV-infected women who delivered 2 pregnancies at our institution were identified. There was no difference in median HIV viral load at presentation or delivery between the index and subsequent pregnancies. During the subsequent pregnancy, more women presented on antiretroviral therapy (ART) and more often remained compliant with ART; however, there was no difference in vertical transmission risk between the pregnancies. Of those with a viral load less than 1000 copies/mL at the end of their index pregnancy (n = 103), 57 (55%) presented for their subsequent pregnancy with a viral load still less than 1000 copies/mL. Those women who maintained the viral load suppression between pregnancies were more likely to present for their subsequent pregnancy on ART, maintained a greater viral load suppression and CD4 counts during the pregnancy, and had fewer vertical transmissions compared with those who presented with higher viral loads in their subsequent pregnancy (0% vs 9%, P = .02). Maintaining an HIV viral load suppression between pregnancies is associated with improved HIV disease status at delivery in subsequent pregnancies. Interpregnancy HIV viral load suppression is associated with less vertical transmission, emphasizing the importance of maintaining HIV disease control between pregnancies. Copyright © 2014 Mosby, Inc. All rights reserved.
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[Orphan drugs: some legal, ethical and economics aspects].
Pabst, J Y
2001-09-01
Besides well-known diseases, about 5,000 identified are classed as "orphan" because of the lack of any response in terms of diagnosis, prevention and treatment. The development of drugs for these diseases, intended for a limited number of patients, often requires considerable research, and subsequently, cost. The aim of the present article is to discuss the ethical, political and economic problems relevant to the development and disposal of drugs specifically designed for these diseases, now commonly called "orphan" drugs. These questions have been raised at discussions and dialogues at the European Parliament where European regulations on orphan drugs were adopted on December 15, 1999. These regulations (141/2000/EEC) came into effect in the European Union on January 22, 2000, and are widely inspired from the American model. The regulations stipulate that the criterion for designation of the drug is based on a disease prevalence of 5/10000). Advantages commonly recognized for the orphan drug status concern: community registration (centralized marketing approval), eligibility for grants and national or community fiscal support, lower or canceled registration fees, technical contribution via the European drug agency (EMEA), and exclusive rights for a 10-year period. On May 12, 2000, the European Commission completed the status by adopting rules establishing the criteria used for designating a drug as an orphan drug. This document implements the dispositions available to pharmaceutical firms inciting them to invest in the development of orphan drugs.
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Nutrigenetics and modulation of oxidative stress.
Da Costa, Laura A; Badawi, Alaa; El-Sohemy, Ahmed
2012-01-01
Oxidative stress develops as a result of an imbalance between the production and accumulation of reactive species and the body's ability to manage them using exogenous and endogenous antioxidants. Exogenous antioxidants obtained from the diet, including vitamin C, vitamin E, and carotenoids, have important roles in preventing and reducing oxidative stress. Individual genetic variation affecting proteins involved in the uptake, utilization and metabolism of these antioxidants may alter their serum levels, exposure to target cells and subsequent contribution to the extent of oxidative stress. Endogenous antioxidants include the antioxidant enzymes superoxide dismutase, catalase, glutathione peroxidase, paraoxanase, and glutathione S-transferase. These enzymes metabolize reactive species and their by-products, reducing oxidative stress. Variation in the genes coding these enzymes may impact their enzymatic antioxidant activity and, thus, the levels of reactive species, oxidative stress, and risk of disease development. Oxidative stress may contribute to the development of chronic disease, including osteoporosis, type 2 diabetes, neurodegenerative diseases, cardiovascular disease, and cancer. Indeed, polymorphisms in most of the genes that code for antioxidant enzymes have been associated with several types of cancer, although inconsistent findings between studies have been reported. These inconsistencies may, in part, be explained by interactions with the environment, such as modification by diet. In this review, we highlight some of the recent studies in the field of nutrigenetics, which have examined interactions between diet, genetic variation in antioxidant enzymes, and oxidative stress. Copyright © 2012 S. Karger AG, Basel.
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Guidelines for the treatment of childhood-onset Graves’ disease in Japan, 2016
Minamitani, Kanshi; Sato, Hirokazu; Ohye, Hidemi; Harada, Shohei; Arisaka, Osamu
2017-01-01
Abstract. Purpose behind developing these guidelines: Over one decade ago, the “Guidelines for the Treatment of Graves’ Disease with Antithyroid Drug, 2006” (Japan Thyroid Association (JTA)) were published as the standard drug therapy protocol for Graves’ disease. The “Guidelines for the Treatment of Childhood-Onset Graves’ Disease with Antithyroid Drug in Japan, 2008” were published to provide guidance on the treatment of pediatric patients. Based on new evidence, a revised version of the “Guidelines for the Treatment of Graves’ Disease with Antithyroid Drug, 2006” (JTA) was published in 2011, combined with the “Handbook of Radioiodine Therapy for Graves’ Disease 2007” (JTA). Subsequently, newer findings on pediatric Graves’ disease have been reported. Propylthiouracil (PTU)-induced serious hepatopathy is an important problem in pediatric patients. The American Thyroid Association’s guidelines suggest that, in principle, physicians must not administer PTU to children. On the other hand, the “Guidelines for the Treatment of Graves’ Disease with Antithyroid Drug, 2011” (JTA) state that radioiodine therapy is no longer considered a “fundamental contraindication” in children. Therefore, the “Guidelines for the Treatment of Childhood-Onset Graves’ Disease with Antithyroid Drug in Japan, 2008” required revision. PMID:28458457
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Buja, Alessandra; Sartor, Gino; Scioni, Manuela; Vecchiato, Antonella; Bolzan, Mario; Rebba, Vincenzo; Sileni, Vanna Chiarion; Palozzo, Angelo Claudio; Montesco, Maria; Del Fiore, Paolo; Baldo, Vincenzo; Rossi, Carlo Riccardo
2018-02-07
Cutaneous melanoma is a major concern in terms of healthcare systems and economics. The aim of this study was to estimate the direct costs of melanoma by disease stage, phase of diagnosis, and treatment according to the pre-set clinical guidelines drafted by the AIOM (Italian Medical Oncological Association). Based on the AIOM guidelines for malignant cutaneous melanoma, a highly detailed decision-making model was developed describing the patient's pathway from diagnosis through the subsequent phases of disease staging, surgical and medical treatment, and follow-up. The model associates each phase potentially involving medical procedures with a likelihood measure and a cost, thus enabling an estimation of the expected costs by disease stage and clinical phase of melanoma diagnosis and treatment according to the clinical guidelines. The mean per-patient cost of the whole melanoma pathway (including one year of follow-up) ranged from €149 for stage 0 disease to €66,950 for stage IV disease. The costs relating to each phase of the disease's diagnosis and treatment depended on disease stage. It is essential to calculate the direct costs of managing malignant cutaneous melanoma according to clinical guidelines in order to estimate the economic burden of this disease and to enable policy-makers to allocate appropriate resources.
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Enzyme-Responsive Nanomaterials for Controlled Drug Delivery
Hu, Quanyin; Katti, Prateek S.; Gu, Zhen
2015-01-01
Enzymes underpin physiological function and exhibit dysregulation in many disease-associated microenvironments and aberrant cell processes. Exploiting altered enzyme activity and expression for diagnostics, drug targeting, and drug release is tremendously promising. When combined with booming research in nanobiotechnology, enzyme-responsive nanomaterials for controlled drug release have achieved significant development and been studied as an important class of drug delivery devices in nanomedicine. In this review, we describe enzymes such as proteases, phospholipase and oxidoreductases that serve as delivery triggers. Subsequently, we explore recently developed enzyme-responsive nanomaterials with versatile applications for extracellular and intracellular drug delivery. We conclude by discussing future opportunities and challenges in this area. PMID:25251024
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[Advances of portable electrocardiogram monitor design].
Ding, Shenping; Wang, Yinghai; Wu, Weirong; Deng, Lingli; Lu, Jidong
2014-06-01
Portable electrocardiogram monitor is an important equipment in the clinical diagnosis of cardiovascular diseases due to its portable, real-time features. It has a broad application and development prospects in China. In the present review, previous researches on the portable electrocardiogram monitors have been arranged, analyzed and summarized. According to the characteristics of the electrocardiogram (ECG), this paper discusses the ergonomic design of the portable electrocardiogram monitor, including hardware and software. The circuit components and software modules were parsed from the ECG features and system functions. Finally, the development trend and reference are provided for the portable electrocardiogram monitors and for the subsequent research and product design.
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Enzyme-responsive nanomaterials for controlled drug delivery
NASA Astrophysics Data System (ADS)
Hu, Quanyin; Katti, Prateek S.; Gu, Zhen
2014-10-01
Enzymes underpin physiological function and exhibit dysregulation in many disease-associated microenvironments and aberrant cell processes. Exploiting altered enzyme activity and expression for diagnostics, drug targeting, and drug release is tremendously promising. When combined with booming research in nanobiotechnology, enzyme-responsive nanomaterials used for controlled drug release have achieved significant development and have been studied as an important class of drug delivery strategies in nanomedicine. In this review, we describe enzymes such as proteases, phospholipases and oxidoreductases that serve as delivery triggers. Subsequently, we explore recently developed enzyme-responsive nanomaterials with versatile applications for extracellular and intracellular drug delivery. We conclude by discussing future opportunities and challenges in this area.
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Virdis, Francesco; Tacci, Sara; Messina, Federico; Varcada, Massimo
2013-11-27
We present a case of a 19-year-old man with a 6-year history of Crohn's disease (CD), previously treated with 6-mercaptopurine, who was admitted to our department for Epstein-Barr virus (EBV) infection and subsequently developed a hemophagocytic lymphohistiocytosis (HLH). HLH is a rare disease which causes phagocytosis of all bone marrow derived cells. It can be a primary form as a autosomic recessive disease, or a secondary form associated with a variety of infections; EBV is the most common, the one with poorer prognosis. The incidence of lymphoproliferative disorders was increased in patients with inflammatory bowel disease (IBD) treated with thiopurines. Specific EBV-related clinical and virological management should be considered when treating a patient with IBD with immunosuppressive therapy. Moreover EBV infection in immunosuppressed patient can occur with more aggressive forms such as encephalitis and diffuse large B cell lymphoma. Our case confirms what is described in the literature; patients with IBD, particularly patients with CD receiving thiopurine therapy, who present 5 d of fever and cervical lymphadenopathy or previous evidence of lymphopenia should be screened for HLH.
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Alduraywish, Shatha A; Standl, Marie; Lodge, Caroline J; Abramson, Michael J; Allen, Katrina J; Erbas, Bircan; von Berg, Andrea; Heinrich, Joachim; Lowe, Adrian J; Dharmage, Shyamali C
2017-02-01
The march from early aeroallergen sensitization to subsequent respiratory allergy is well established, but it is unclear whether early life food sensitization precedes and further increases risk of allergic airway disease. To assess the association between food sensitization in the first 2 years of life and subsequent asthma and allergic rhinitis by age 10-12 years. We used data from two independent cohorts: the high-risk Melbourne Atopic Cohort Study (MACS) (n = 620) and the population-based LISAplus (n = 3094). Food sensitization was assessed at 6, 12, and 24 months in MACS and 24 months in LISAplus. Multiple logistic regressions were used to estimate associations between sensitization to food only, aeroallergen only, or both and allergic airway disease. When compared to non-sensitized children, sensitization to food only at 12 months in MACS and 24 months in LISAplus was associated with increased risk of current asthma (aOR = 2.2; 95% CI 1.1, 4.6 in MACS and aOR = 4.9; 2.4, 10.1 in LISAplus). Similar results were seen for allergic rhinitis. Additionally, cosensitization to food and aeroallergen in both cohorts at any tested point was a stronger predictor of asthma (at 24 months, aOR = 8.3; 3.7, 18.8 in MACS and aOR = 14.4; 5.0, 41.6 in LISAplus) and allergic rhinitis (at 24 months, aOR = 3.9; 1.9, 8.1 in MACS and aOR = 7.6; 3.0, 19.6 in LISAplus). In both cohorts, food sensitization (with or without aeroallergen sensitization) in the first two years of life increased the risk of subsequent asthma and allergic rhinitis. These findings support the role of early life food sensitization in the atopic march and suggest trials to prevent early onset have the potential to reduce the development of allergic airways disease. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Pre-symptomatic autoimmunity in rheumatoid arthritis: when does the disease start?
Tracy, Alexander; Buckley, Christopher D; Raza, Karim
2017-06-01
It is well recognised that a state of autoimmunity, in which immunological tolerance is broken, precedes the development of symptoms in the majority of patients with rheumatoid arthritis (RA). For individuals who will later develop seropositive disease, this manifests as autoantibodies directed against proteins that have undergone specific post-translational modifications. There is evidence that the induction of this autoantibody response occurs at peripheral extra-articular mucosal sites, such as the periodontium and lung. In addition to their utility as diagnostic markers, these autoantibodies may have a pathogenic role that helps localise disease to the synovium. Alongside the development of autoantibodies, other factors contributing to pre-symptomatic autoimmunity may include dysbiosis of the gastrointestinal tract, abnormal development of lymphoid tissue, and dysregulated autonomic and lipid-mediated anti-inflammatory signalling. These factors combine to skew the balance between pro-inflammatory and anti-inflammatory signalling in a manner that is permissive for the development of clinical arthritis. We present data to support the concept that the transitions from at-risk states to systemic autoimmunity and then to classifiable RA depend on multiple "switches". However, further prospective studies are necessary to define the molecular basis of these switches and the specific features of pre-symptomatic autoimmunity, so that preventative treatments can be targeted to individuals at high risk for RA. In this review, we analyse mechanisms that may contribute to the development of autoimmunity in at-risk individuals and discuss the relationship between this pre-symptomatic state and subsequent development of RA.
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Torres, Diogo; Myers, John A; Eshraghi, Leah W; Riley, Elizabeth C; Soliman, Pamela T; Milam, Michael R
2015-01-01
Our study compares breast cancer survivors without a secondary diagnosis of uterine cancer (BC) to breast cancer survivors with a diagnosis of uterine cancer (BUC) to determine clinical characteristics that increase the odds of developing uterine cancer. A total of 7,228 breast cancer survivors were surveyed. A case-control study was performed with 173 BUC patients matched by age and race in a 1:5 ratio to 865 BC patients. Multivariable logistic regression examined which factors influence the odds of developing uterine cancer. A total of 5,980 (82.3 %) women did not have a previous hysterectomy at the time of breast cancer diagnosis, of which 173 (2.9 %) subsequently developed uterine cancer. There was no significant difference in body mass index (BMI) (34.4 vs. 34.1, p = 0.388) or age (52.3 vs. 52.3 years, p = 0.999) between the two groups. Increased odds for developing uterine cancer were found in patients with a personal history of hypertension [odds ratio (OR) = 1.62, 95 % confidence interval (CI) 1.45-2.70, p < 0.001], gallbladder disease (OR = 1.30, 95 % CI 1.14-1.55, p = 0.005), and thyroid disease (OR = 1.55, 95 % CI 1.37-1.69, p < 0.001). More than 80 % of women in both groups expressed a desire for a blood test to estimate the risk of uterine cancer (80.4 % BUC vs. 91.2 % BC, p < 0.001). Hypertension, gallbladder disease, and thyroid disease in breast cancer survivors increase the odds of developing uterine cancer. Breast cancer survivors also express significant interest in potential serum tests to assess the risk of developing uterine cancer.
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The Honolulu Liver Disease Cluster at the Medical Center: Its Mysteries and Challenges
Teschke, Rolf; Eickhoff, Axel
2016-01-01
In 2013, physicians at the Honolulu Queen’s Medical Center (QMC) noticed that seven liver disease patients reported the use of OxyELITE Pro (OEP), a widely consumed dietary supplement (DS). Assuming a temporal association between OEP use and disease, they argued that OEP was the cause of this mysterious cluster. Subsequent reexamination, however, has revealed that this QMC cohort is heterogeneous and not a cluster with a single agent causing a single disease. It is heterogeneous because patients used multiple DS’s and drugs and because patients appeared to have suffered from multiple liver diseases: liver cirrhosis, liver failure by acetaminophen, hepatotoxicity by non-steroidal antiinflammatory drugs (NSAIDs), resolving acute viral hepatitis by hepatitis B virus (HBV), herpes simplex virus (HSV), and varicella zoster virus (VZV), and suspected hepatitis E virus (HEV). Failing to exclude these confounders and to consider more viable diagnoses, the QMC physicians may have missed specific treatment options in some of their patients. The QMC physicians unjustifiably upgraded their Roussel Uclaf Causality Assessment Method (RUCAM) causality scores so that all patients would appear to be “probable” for OEP. However, subsequent RUCAM reassessments by our group demonstrated a lack of causality for OEP in the evaluated QMC cases. The QMC’s questionable approaches explain the extraordinary accumulation of suspected OEP cases at the QMC in Hawaii as single place, whereas similar cohorts were not published by any larger US liver center, substantiating that the problem is with the QMC. In this review article, we present and discuss new case data and critically evaluate upcoming developments of problematic regulatory assessments by the US Centers for Disease Control and Prevention (CDC), the Hawaii Department of Health (HDOH), and the Food and Drug Administration (FDA), as based on invalid QMC conclusions, clarifying now also basic facts and facilitating constructive discussions. PMID:27043544
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GATA3 controls the specification of prosensory domain and neuronal survival in the mouse cochlea
Luo, Xiong-jian; Deng, Min; Xie, Xiaoling; Huang, Liang; Wang, Hui; Jiang, Lichun; Liang, Guoqing; Hu, Fang; Tieu, Roger; Chen, Rui; Gan, Lin
2013-01-01
HDR syndrome (also known as Barakat syndrome) is a developmental disorder characterized by hypoparathyroidism, sensorineural deafness and renal disease. Although genetic mapping and subsequent functional studies indicate that GATA3 haplo-insufficiency causes human HDR syndrome, the role of Gata3 in sensorineural deafness and auditory system development is largely unknown. In this study, we show that Gata3 is continuously expressed in the developing mouse inner ear. Conditional knockout of Gata3 in the developing inner ear disrupts the morphogenesis of mouse inner ear, resulting in a disorganized and shortened cochlear duct with significant fewer hair cells and supporting cells. Loss of Gata3 function leads to the failure in the specification of prosensory domain and subsequently, to increased cell death in the cochlear duct. Moreover, though the initial generation of cochleovestibular ganglion (CVG) cells is not affected in Gata3-null mice, spiral ganglion neurons (SGNs) are nearly depleted due to apoptosis. Our results demonstrate the essential role of Gata3 in specifying the prosensory domain in the cochlea and in regulating the survival of SGNs, thus identifying a molecular mechanism underlying human HDR syndrome. PMID:23666531
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Kumaran, Muthu S.; Narang, Tarun; Jitendriya, Madhukara; Tirumale, Rajalakshmi; Manjunath, Suraj; Savio, Jayanthi
2017-01-01
Tuberculosis (TB) is still a major public health problem in the world, with many factors contributing to this burden, including poor living conditions, overcrowding, poverty, malnutrition, illiteracy, and rapid spread of human immunodeficiency virus infection. Cutaneous tuberculosis is a less common form of extrapulmonary tuberculosis, and in this paucibacillary form the diagnosis depends on histopathology, tuberculin positivity, and response to treatment. The diagnosis is even more difficult in cases with drug resistant Mycobacterium tuberculosis due to lack of awareness and lack of facilities to diagnose drug resistant tuberculosis. In this article, we describe an unusual case of multidrug resistant lupus vulgaris (LV), in a 34-year-old male who responded to anti-tubercular treatment (ATT) initially, but developed recurrent disease which failed to respond to standard four-drug ATT; subsequently, tissue culture showed growth of multidrug resistant M. tuberculosis. Subsequently, he also developed cutaneous squamous cell carcinoma. This article aims to exemplify a grave complication that can occur in long-standing case of LV, the limitations faced by clinicians in developing countries where tuberculosis is endemic, and classical methods of proving drug resistance are generally unavailable or fail. PMID:28761842
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Yang, Hyo-Joon; Lim, Seon Hee; Lee, Changhyun; Choi, Ji Min; Yang, Jong In; Chung, Su Jin; Choi, Seung Ho; Im, Jong Pil; Kim, Sang Gyun; Kim, Joo Sung
2016-07-01
It is often difficult to differentiate gastric mucosa-associated lymphoid tissue (MALT) lymphoma from Helicobacter pylori-associated follicular gastritis, and thus, it becomes unclear how to manage these diseases. This study aimed to explore the management strategy for and the long-term outcomes of suspicious gastric MALT lymphoma detected by forceps biopsy during screening upper endoscopy. Between October 2003 and May 2013, consecutive subjects who were diagnosed with suspicious gastric MALT lymphomas by screening endoscopy in a health checkup program in Korea were retrospectively enrolled. Suspicious MALT lymphoma was defined as a Wotherspoon score of 3 or 4 upon pathological evaluation of the biopsy specimen. Of 105,164 subjects who underwent screening endoscopies, 49 patients with suspicious MALT lymphomas who underwent subsequent endoscopy were enrolled. Eight patients received a subsequent endoscopy without H. pylori eradication (subsequent endoscopy only group), and 41 patients received H. pylori eradication first followed by endoscopy (eradication first group). MALT lymphoma development was significantly lower in the eradication first group (2/41, 4.9%) than in the subsequent endoscopy only group (3/8, 37.5%, P = 0.026). Notably, among 35 patients with successful H. pylori eradication, there was only one MALT lymphoma patient (2.9%) in whom complete remission was achieved, and there was no recurrence during a median 45 months of endoscopic follow-up. H. pylori eradication with subsequent endoscopy would be a practical management option for suspicious MALT lymphoma detected in a forceps biopsy specimen obtained during screening upper endoscopy.
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Harnessing Functional Genomics to Reverse Chemoresistance in Breast Cancer
2008-10-01
lymphoproliferative syndrome This is a rare immunodeficiency disease characterized by fatal or near-fatal Epstein–Barr virus-induced infectious ... mononucleosis in childhood, subsequent hypogammaglob- ulinaemia and a markedly increased risk of lymphoma or other lymphoproliferative diseases
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Norrie disease: first mutation report and prenatal diagnosis in an Indian family.
Ghosh, Manju; Sharma, Shipra; Shastri, Shivaram; Arora, Sadhna; Shukla, Rashmi; Gupta, Neerja; Deka, Deepika; Kabra, Madhulika
2012-11-01
Norrie Disease (ND) is a rare X-linked recessive disorder characterised by congenital blindness due to severe retinal dysgenesis. Hearing loss and intellectual disability is present in 30-50 % cases. ND is caused by mutations in the NDP gene, located at Xp11.3. The authors describe mutation analysis of a proband with ND and subsequently prenatal diagnosis. Sequence analysis of the NDP gene revealed a hemizygous missense mutation arginine to serine in codon 41 (p.Arg41Ser) in the affected child. Mother was carrier for the mutation. In a subsequent di-chorionic di-amniotic pregnancy, the authors performed prenatal diagnosis by mutation analysis on chorionic villi sample at 11 wk of gestation. The fetuses were unaffected. This is a first mutation report and prenatal diagnosis of a familial case of Norrie disease from India. The importance of genetic testing of Norrie disease for confirmation, carrier testing, prenatal diagnosis and genetic counseling is emphasized.
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Zheng, Tingting; Ni, Yueqiong; Li, Jun; Chow, Billy K. C.; Panagiotou, Gianni
2017-01-01
Background: A range of computational methods that rely on the analysis of genome-wide expression datasets have been developed and successfully used for drug repositioning. The success of these methods is based on the hypothesis that introducing a factor (in this case, a drug molecule) that could reverse the disease gene expression signature will lead to a therapeutic effect. However, it has also been shown that globally reversing the disease expression signature is not a prerequisite for drug activity. On the other hand, the basic idea of significant anti-correlation in expression profiles could have great value for establishing diet-disease associations and could provide new insights into the role of dietary interventions in disease. Methods: We performed an integrated analysis of publicly available gene expression profiles for foods, diseases and drugs, by calculating pairwise similarity scores for diet and disease gene expression signatures and characterizing their topological features in protein-protein interaction networks. Results: We identified 485 diet-disease pairs where diet could positively influence disease development and 472 pairs where specific diets should be avoided in a disease state. Multiple evidence suggests that orange, whey and coconut fat could be beneficial for psoriasis, lung adenocarcinoma and macular degeneration, respectively. On the other hand, fructose-rich diet should be restricted in patients with chronic intermittent hypoxia and ovarian cancer. Since humans normally do not consume foods in isolation, we also applied different algorithms to predict synergism; as a result, 58 food pairs were predicted. Interestingly, the diets identified as anti-correlated with diseases showed a topological proximity to the disease proteins similar to that of the corresponding drugs. Conclusions: In conclusion, we provide a computational framework for establishing diet-disease associations and additional information on the role of diet in disease development. Due to the complexity of analyzing the food composition and eating patterns of individuals our in silico analysis, using large-scale gene expression datasets and network-based topological features, may serve as a proof-of-concept in nutritional systems biology for identifying diet-disease relationships and subsequently designing dietary recommendations. PMID:29033850
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Concise Review: Cardiac Disease Modeling Using Induced Pluripotent Stem Cells.
Yang, Chunbo; Al-Aama, Jumana; Stojkovic, Miodrag; Keavney, Bernard; Trafford, Andrew; Lako, Majlinda; Armstrong, Lyle
2015-09-01
Genetic cardiac diseases are major causes of morbidity and mortality. Although animal models have been created to provide some useful insights into the pathogenesis of genetic cardiac diseases, the significant species differences and the lack of genetic information for complex genetic diseases markedly attenuate the application values of such data. Generation of induced pluripotent stem cells (iPSCs) from patient-specific specimens and subsequent derivation of cardiomyocytes offer novel avenues to study the mechanisms underlying cardiac diseases, to identify new causative genes, and to provide insights into the disease aetiology. In recent years, the list of human iPSC-based models for genetic cardiac diseases has been expanding rapidly, although there are still remaining concerns on the level of functionality of iPSC-derived cardiomyocytes and their ability to be used for modeling complex cardiac diseases in adults. This review focuses on the development of cardiomyocyte induction from pluripotent stem cells, the recent progress in heart disease modeling using iPSC-derived cardiomyocytes, and the challenges associated with understanding complex genetic diseases. To address these issues, we examine the similarity between iPSC-derived cardiomyocytes and their ex vivo counterparts and how this relates to the method used to differentiate the pluripotent stem cells into a cardiomyocyte phenotype. We progress to examine categories of congenital cardiac abnormalities that are suitable for iPSC-based disease modeling. © AlphaMed Press.
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Piroth, Tobias; Pauly, Marie-Christin; Schneider, Christian; Wittmer, Annette; Möllers, Sven; Döbrössy, Máté; Winkler, Christian; Nikkhah, Guido
2014-01-01
Restorative cell therapy concepts in neurodegenerative diseases are aimed at replacing lost neurons. Despite advances in research on pluripotent stem cells, fetal tissue from routine elective abortions is still regarded as the only safe cell source. Progenitor cells isolated from distinct first-trimester fetal CNS regions have already been used in clinical trials and will be used again in a new multicenter trial funded by the European Union (TRANSEURO). Bacterial contamination of human fetal tissue poses a potential risk of causing infections in the brain of the recipient. Thus, effective methods of microbial decontamination and validation of these methods are required prior to approval of a neurorestorative cell therapy trial. We have developed a protocol consisting of subsequent washing steps at different stages of tissue processing. Efficacy of microbial decontamination was assessed on rat embryonic tissue incubated with high concentrations of defined microbe solutions including representative bacterial and fungal species. Experimental microbial contamination was reduced by several log ranks. Subsequently, we have analyzed the spectrum of microbial contamination and the effect of subsequent washing steps on aborted human fetal tissue; 47.7% of the samples taken during human fetal tissue processing were positive for a microbial contamination, but after washing, no sample exhibited bacterial growth. Our data suggest that human fetal tissue for neural repair can carry microbes of various species, highlighting the need for decontamination procedures. The decontamination protocol described in this report has been shown to be effective as no microbes could be detected at the end of the procedure.
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Dezsi, Gabi; Ozturk, Ezgi; Salzberg, Michael R; Morris, Margaret; O'Brien, Terence J; Jones, Nigel C
2016-09-01
The absence epilepsies are presumed to be caused by genetic factors, but the influence of environmental exposures on epilepsy development and severity, and whether this influence is transmitted to subsequent generations, is not well known. We assessed the effects of environmental enrichment on epilepsy and anxiety outcomes in multiple generations of GAERS - a genetic rat model of absence epilepsy that manifests comorbid elevated anxiety-like behaviour. GAERS were exposed to environmental enrichment or standard housing beginning either prior to, or after epilepsy onset, and underwent EEG recordings and anxiety testing. Then, we exposed male GAERS to early enrichment or standard housing and generated F1 progeny, which also underwent EEG recordings. Hippocampal CRH mRNA expression and DNA methylation were assessed using RT-PCR and pyrosequencing, respectively. Early environmental enrichment delayed the onset of epilepsy in GAERS, and resulted in fewer seizures in adulthood, compared with standard housed GAERS. Enrichment also reduced the frequency of seizures when initiated in adulthood. Anxiety levels were reduced by enrichment, and these anti-epileptogenic and anxiolytic effects were heritable into the next generation. We also found reduced expression of CRH mRNA in GAERS exposed to enrichment, but this was not due to changes in DNA methylation. Environmental enrichment produces disease-modifying effects on genetically determined absence epilepsy and anxiety, and these beneficial effects are transferable to the subsequent generation. Reduced CRH expression was associated with these phenotypic improvements. Environmental stimulation holds promise as a naturalistic therapy for genetically determined epilepsy which may benefit subsequent generations. Copyright © 2016 Elsevier Inc. All rights reserved.
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First report of mango malformation disease caused by Fusarium pseudocircinatum in Mexico
USDA-ARS?s Scientific Manuscript database
Mango (Mangifera indica L.) malformation disease (MMD) is one of the most important diseases affecting this crop worldwide, causing severe economic loss due to reduction of yield. Subsequent to the first report in India in 1891 (3), MMD has spread worldwide to most mango-growing regions. Several spe...
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Johnson, Laura A; Luke, Amy; Sauder, Kay; Moons, David S; Horowitz, Jeffrey C; Higgins, Peter D R
2012-03-01
The natural history of Crohn's disease follows a path of progression from an inflammatory to a fibrostenosing disease, with most patients requiring surgical resection of fibrotic strictures. Potent antiinflammatory therapies reduce inflammation but do not appear to alter the natural history of intestinal fibrosis. The aim of this study was to determine the relationship between intestinal inflammation and fibrogenesis and the impact of a very early "top-down" interventional approach on fibrosis in vivo. In this study we removed the inflammatory stimulus from the Salmonella typhimurium mouse model of intestinal fibrosis by eradicating the S. typhimurium infection with levofloxacin at sequential timepoints during the infection. We evaluated the effect of this elimination of the inflammatory stimulus on the natural history of inflammation and fibrosis as determined by gross pathology, histopathology, mRNA expression, and protein expression. Fibrogenesis is preceded by inflammation. Delayed eradication of the inflammatory stimulus by antibiotic treatment represses inflammation without preventing fibrosis. Early intervention significantly ameliorates but does not completely prevent subsequent fibrosis. This study demonstrates that intestinal fibrosis develops despite removal of an inflammatory stimulus and elimination of inflammation. Early intervention ameliorates but does not abolish subsequent fibrosis, suggesting that fibrosis, once initiated, is self-propagating, suggesting that a very early top-down interventional approach may have the most impact on fibrostenosing disease. Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.
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Tracey, Rebecca; Haque, Md. M.; Skinner, Michael K.
2012-01-01
Environmental factors during fetal development can induce a permanent epigenetic change in the germ line (sperm) that then transmits epigenetic transgenerational inheritance of adult-onset disease in the absence of any subsequent exposure. The epigenetic transgenerational actions of various environmental compounds and relevant mixtures were investigated with the use of a pesticide mixture (permethrin and insect repellant DEET), a plastic mixture (bisphenol A and phthalates), dioxin (TCDD) and a hydrocarbon mixture (jet fuel, JP8). After transient exposure of F0 gestating female rats during the period of embryonic gonadal sex determination, the subsequent F1–F3 generations were obtained in the absence of any environmental exposure. The effects on the F1, F2 and F3 generations pubertal onset and gonadal function were assessed. The plastics, dioxin and jet fuel were found to promote early-onset female puberty transgenerationally (F3 generation). Spermatogenic cell apoptosis was affected transgenerationally. Ovarian primordial follicle pool size was significantly decreased with all treatments transgenerationally. Differential DNA methylation of the F3 generation sperm promoter epigenome was examined. Differential DNA methylation regions (DMR) were identified in the sperm of all exposure lineage males and found to be consistent within a specific exposure lineage, but different between the exposures. Several genomic features of the DMR, such as low density CpG content, were identified. Exposure-specific epigenetic biomarkers were identified that may allow for the assessment of ancestral environmental exposures associated with adult onset disease. PMID:22389676
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Applying World Wide Web technology to the study of patients with rare diseases.
de Groen, P C; Barry, J A; Schaller, W J
1998-07-15
Randomized, controlled trials of sporadic diseases are rarely conducted. Recent developments in communication technology, particularly the World Wide Web, allow efficient dissemination and exchange of information. However, software for the identification of patients with a rare disease and subsequent data entry and analysis in a secure Web database are currently not available. To study cholangiocarcinoma, a rare cancer of the bile ducts, we developed a computerized disease tracing system coupled with a database accessible on the Web. The tracing system scans computerized information systems on a daily basis and forwards demographic information on patients with bile duct abnormalities to an electronic mailbox. If informed consent is given, the patient's demographic and preexisting medical information available in medical database servers are electronically forwarded to a UNIX research database. Information from further patient-physician interactions and procedures is also entered into this database. The database is equipped with a Web user interface that allows data entry from various platforms (PC-compatible, Macintosh, and UNIX workstations) anywhere inside or outside our institution. To ensure patient confidentiality and data security, the database includes all security measures required for electronic medical records. The combination of a Web-based disease tracing system and a database has broad applications, particularly for the integration of clinical research within clinical practice and for the coordination of multicenter trials.
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Regulation of defensive function on gingival epithelial cells can prevent periodontal disease.
Fujita, Tsuyoshi; Yoshimoto, Tetsuya; Kajiya, Mikihito; Ouhara, Kazuhisa; Matsuda, Shinji; Takemura, Tasuku; Akutagawa, Keiichi; Takeda, Katsuhiro; Mizuno, Noriyoshi; Kurihara, Hidemi
2018-05-01
Periodontal disease is a bacterial biofilm-associated inflammatory disease that has been implicated in many systemic diseases. A new preventive method for periodontal disease needs to be developed in order to promote the health of the elderly in a super-aged society. The gingival epithelium plays an important role as a mechanical barrier against bacterial invasion and a part of the innate immune response to infectious inflammation in periodontal tissue. The disorganization of cell-cell interactions and subsequent inflammation contribute to the initiation of periodontal disease. These make us consider that regulation of host defensive functions, epithelial barrier and neutrophil activity, may become novel preventive methods for periodontal inflammation. Based on this concept, we have found that several agents regulate the barrier function of gingival epithelial cells and suppress the accumulation of neutrophils in the gingival epithelium. We herein introduce the actions of irsogladine maleate, azithromycin, amphotericin B, and Houttuynia cordata (dokudami in Japanese), which is commonly used in traditional medicine, on the epithelial barrier and neutrophil migration in gingival epithelial cells in vivo and in vitro , in order to provide support for the clinical application of these agents to the prevention of periodontal inflammation.
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Crosstalk between Long Noncoding RNAs and MicroRNAs in Health and Disease.
Bayoumi, Ahmed S; Sayed, Amer; Broskova, Zuzana; Teoh, Jian-Peng; Wilson, James; Su, Huabo; Tang, Yao-Liang; Kim, Il-Man
2016-03-11
Protein-coding genes account for only a small part of the human genome; in fact, the vast majority of transcripts are comprised of non-coding RNAs (ncRNAs) including long ncRNAs (lncRNAs) and small ncRNAs, microRNAs (miRs). Accumulating evidence indicates that ncRNAs could play critical roles in regulating many cellular processes which are often implicated in health and disease. For example, ncRNAs are aberrantly expressed in cancers, heart diseases, and many other diseases. LncRNAs and miRs are therefore novel and promising targets to be developed into biomarkers for diagnosis and prognosis as well as treatment options. The interaction between lncRNAs and miRs as well as its pathophysiological significance have recently been reported. Mechanistically, it is believed that lncRNAs exert "sponge-like" effects on various miRs, which subsequently inhibits miR-mediated functions. This crosstalk between two types of ncRNAs frequently contributes to the pathogenesis of the disease. In this review, we provide a summary of the recent studies highlighting the interaction between these ncRNAs and the effects of this interaction on disease pathogenesis and regulation.
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Crosstalk between Long Noncoding RNAs and MicroRNAs in Health and Disease
Bayoumi, Ahmed S.; Sayed, Amer; Broskova, Zuzana; Teoh, Jian-Peng; Wilson, James; Su, Huabo; Tang, Yao-Liang; Kim, Il-man
2016-01-01
Protein-coding genes account for only a small part of the human genome; in fact, the vast majority of transcripts are comprised of non-coding RNAs (ncRNAs) including long ncRNAs (lncRNAs) and small ncRNAs, microRNAs (miRs). Accumulating evidence indicates that ncRNAs could play critical roles in regulating many cellular processes which are often implicated in health and disease. For example, ncRNAs are aberrantly expressed in cancers, heart diseases, and many other diseases. LncRNAs and miRs are therefore novel and promising targets to be developed into biomarkers for diagnosis and prognosis as well as treatment options. The interaction between lncRNAs and miRs as well as its pathophysiological significance have recently been reported. Mechanistically, it is believed that lncRNAs exert “sponge-like” effects on various miRs, which subsequently inhibits miR-mediated functions. This crosstalk between two types of ncRNAs frequently contributes to the pathogenesis of the disease. In this review, we provide a summary of the recent studies highlighting the interaction between these ncRNAs and the effects of this interaction on disease pathogenesis and regulation. PMID:26978351
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Barnes, D C; Demetriou, J L
2017-05-01
To report the outcomes and complications of a cohort of dogs with primary and recurrent anal sac adenocarcinoma managed with surgery as the first-line treatment. To report the use of lymph node cytology for identification of metastatic disease. Retrospective review of case records of a single referral centre population of dogs diagnosed with anal sac adenocarcinoma. Fifty-two clinical cases were identified. Altered ultrasonographic appearance of lymph nodes was highly consistent with metastatic disease as assessed by cytology and histopathology. Seven of 58 (12%) perineal surgeries had reported minor complications and seven (12%) others required further surgical intervention. Minor controllable intraoperative bleeding was the only complication noted associated with lymph node extirpation in two of 39 (5%) metastectomy procedures. Six dogs (12%) suffered local recurrence and 22 (42%) developed subsequent or recurrent nodal metastatic disease. From the time of detection of disease recurrence, median additional survival associated with a second surgical intervention was 283 days. Coeliotomy for lymph node metastatectomy in dogs with adenocarcinoma of the anal sac has low morbidity and should be considered in patients presenting with evidence of regional metastatic disease both at initial presentation and with recurrent disease. © 2017 British Small Animal Veterinary Association.
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Bhatia, Shipra; Gordon, Christopher T.; Foster, Robert G.; Melin, Lucie; Abadie, Véronique; Baujat, Geneviève; Vazquez, Marie-Paule; Amiel, Jeanne; Lyonnet, Stanislas; van Heyningen, Veronica; Kleinjan, Dirk A.
2015-01-01
Disruption of gene regulation by sequence variation in non-coding regions of the genome is now recognised as a significant cause of human disease and disease susceptibility. Sequence variants in cis-regulatory elements (CREs), the primary determinants of spatio-temporal gene regulation, can alter transcription factor binding sites. While technological advances have led to easy identification of disease-associated CRE variants, robust methods for discerning functional CRE variants from background variation are lacking. Here we describe an efficient dual-colour reporter transgenesis approach in zebrafish, simultaneously allowing detailed in vivo comparison of spatio-temporal differences in regulatory activity between putative CRE variants and assessment of altered transcription factor binding potential of the variant. We validate the method on known disease-associated elements regulating SHH, PAX6 and IRF6 and subsequently characterise novel, ultra-long-range SOX9 enhancers implicated in the craniofacial abnormality Pierre Robin Sequence. The method provides a highly cost-effective, fast and robust approach for simultaneously unravelling in a single assay whether, where and when in embryonic development a disease-associated CRE-variant is affecting its regulatory function. PMID:26030420
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Effect of household pet ownership on infant immune response and subsequent sensitization
Simpson, Angela
2010-01-01
Sensitization to pets is a major risk factor for asthma. There are many reports on the relationship between household pets, sensitization to the pet, and sensitization to other allergens, often with conflicting results. Pet ownership is not random, and household pets are associated with exposures other than pet allergens. We will review some of the evidence regarding the effects of household pets on infant immune responses, focusing on data from birth cohort studies. It remains unclear precisely why some children develop specific sensitizations to pets whilst others do not in the face of equivalent exposures, but it is likely to be due to gene-environment interactions. Further long-term follow-up of children in whom neonatal and infant immune responses have been measured is necessary to understand how these events occur and how they relate to subsequent disease. PMID:21437047
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Mechanisms of transgenerational inheritance of addictive-like behaviors.
Vassoler, F M; Sadri-Vakili, G
2014-04-04
Genetic factors are implicated in the heritability of drug abuse. However, even with advances in current technology no specific genes have been identified that are critical for the transmission of drug-induced phenotypes to subsequent generations. It is now evident that epigenetic factors contribute to disease heritability and represent a link between genes and the environment. Recently, epigenetic mechanisms have been shown to underlie drug-induced structural, synaptic, and behavioral plasticity by coordinating the expression of gene networks within the brain. Therefore, the epigenome provides a direct mechanism for drugs of abuse to influence the genetic events involved in the development of addiction as well as its heritability to subsequent generations. In this review we discuss the mechanisms underlying intergenerational epigenetic transmission, highlight studies that demonstrate this phenomenon with particular attention to the field of addiction, and identify gaps for future studies. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.
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Mistry, Hiten D; Gill, Carolyn A; Kurlak, Lesia O; Seed, Paul T; Hesketh, John E; Méplan, Catherine; Schomburg, Lutz; Chappell, Lucy C; Morgan, Linda; Poston, Lucilla
2015-01-01
Preeclampsia is a pregnancy-specific condition affecting 2-7% of women and a leading cause of perinatal and maternal morbidity and mortality. Deficiencies of specific micronutrient antioxidant activities associated with copper, selenium, zinc, and manganese have previously been linked to preeclampsia at the time of disease. Our aims were to investigate whether maternal plasma micronutrient concentrations and related antioxidant enzyme activities are altered before preeclampsia onset and to examine the dependence on genetic variations in these antioxidant enzymes. Predisease plasma samples (15±1 weeks׳ gestation) were obtained from women enrolled in the international Screening for Pregnancy Endpoints (SCOPE) study who subsequently developed preeclampsia (n=244) and from age- and BMI-matched normotensive controls (n=472). Micronutrient concentrations were measured by inductively coupled plasma mass spectrometry; associated antioxidant enzyme activities, selenoprotein-P, ceruloplasmin concentration and activity, antioxidant capacity, and markers of oxidative stress were measured by colorimetric assays. Sixty-four tag-single-nucleotide polymorphisms (SNPs) within genes encoding the antioxidant enzymes and selenoprotein-P were genotyped using allele-specific competitive PCR. Plasma copper and ceruloplasmin concentrations were modestly but significantly elevated in women who subsequently developed preeclampsia (both P<0.001) compared to controls (median (IQR), copper, 1957.4 (1787, 2177.5) vs 1850.0 (1663.5, 2051.5) µg/L; ceruloplasmin, 2.5 (1.4, 3.2) vs 2.2 (1.2, 3.0) µg/ml). There were no differences in other micronutrients or enzymes between groups. No relationship was observed between genotype for SNPs and antioxidant enzyme activity. This analysis of a prospective cohort study reports maternal micronutrient concentrations in combination with associated antioxidant enzymes and SNPs in their encoding genes in women at 15 weeks׳ gestation that subsequently developed preeclampsia. The modest elevation in copper may contribute to oxidative stress, later in pregnancy, in those women that go on to develop preeclampsia. The lack of evidence to support the hypothesis that functional SNPs influence antioxidant enzyme activity in pregnant women argues against a role for these genes in the etiology of preeclampsia. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
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Modeling of leishmaniasis infection dynamics: novel application to the design of effective therapies
2012-01-01
Background The WHO considers leishmaniasis as one of the six most important tropical diseases worldwide. It is caused by parasites of the genus Leishmania that are passed on to humans and animals by the phlebotomine sandfly. Despite all of the research, there is still a lack of understanding on the metabolism of the parasite and the progression of the disease. In this study, a mathematical model of disease progression was developed based on experimental data of clinical symptoms, immunological responses, and parasite load for Leishmania amazonensis in BALB/c mice. Results Four biologically significant variables were chosen to develop a differential equation model based on the GMA power-law formalism. Parameters were determined to minimize error in the model dynamics and time series experimental data. Subsequently, the model robustness was tested and the model predictions were verified by comparing them with experimental observations made in different experimental conditions. The model obtained helps to quantify relationships between the selected variables, leads to a better understanding of disease progression, and aids in the identification of crucial points for introducing therapeutic methods. Conclusions Our model can be used to identify the biological factors that must be changed to minimize parasite load in the host body, and contributes to the design of effective therapies. PMID:22222070
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Targeting Nonsense Mutations in Diseases with Translational Read-Through-Inducing Drugs (TRIDs).
Nagel-Wolfrum, Kerstin; Möller, Fabian; Penner, Inessa; Baasov, Timor; Wolfrum, Uwe
2016-04-01
In recent years, remarkable advances in the ability to diagnose genetic disorders have been made. The identification of disease-causing genes allows the development of gene-specific therapies with the ultimate goal to develop personalized medicines for each patient according to their own specific genetic defect. In-depth genotyping of many different genes has revealed that ~12% of inherited genetic disorders are caused by in-frame nonsense mutations. Nonsense (non-coding) mutations are caused by point mutations, which generate premature termination codons (PTCs) that cause premature translational termination of the mRNA, and subsequently inhibit normal full-length protein expression. Recently, a gene-based therapeutic approach for genetic diseases caused by nonsense mutations has emerged, namely the so-called translational read-through (TR) therapy. Read-through therapy is based on the discovery that small molecules, known as TR-inducing drugs (TRIDs), allow the translation machinery to suppress a nonsense codon, elongate the nascent peptide chain, and consequently result in the synthesis of full-length protein. Several TRIDs are currently under investigation and research has been performed on several genetic disorders caused by nonsense mutations over the years. These findings have raised hope for the usage of TR therapy as a gene-based pharmacogenetic therapy for nonsense mutations in various genes responsible for a variety of genetic diseases.
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Leishmania vaccines: progress and problems.
Kedzierski, L; Zhu, Y; Handman, E
2006-01-01
Leishmania are protozoan parasites spread by a sandfly insect vector and causing a spectrum of diseases collectively known as leishmaniasis. The disease is a significant health problem in many parts of the world resulting in an estimated 12 million new cases each year. Current treatment is based on chemotherapy, which is difficult to administer, expensive and becoming ineffective due to the emergence of drug resistance. Leishmaniasis is considered one of a few parasitic diseases likely to be controllable by vaccination. The relatively uncomplicated leishmanial life cycle and the fact that recovery from infection renders the host resistant to subsequent infection indicate that a successful vaccine is feasible. Extensive evidence from studies in animal models indicates that solid protection can be achieved by immunisation with protein or DNA vaccines. However, to date no such vaccine is available despite substantial efforts by many laboratories. Advances in our understanding of Leishmania pathogenesis and generation of host protective immunity, together with the completed Leishmania genome sequence open new avenues for vaccine research. The major remaining challenges are the translation of data from animal models to human disease and the transition from the laboratory to the field. This review focuses on advances in anti-leishmania vaccine development over the recent years and examines current problems hampering vaccine development and implementation.
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Menasherow, Sophia; Erster, Oran; Rubinstein-Giuni, Marisol; Kovtunenko, Anita; Eyngor, Evgeny; Gelman, Boris; Khinich, Evgeny; Stram, Yehuda
2016-06-01
Lumpy skin disease (LSD) is a constant threat to the Middle East including the State of Israel. During vaccination programs it is essential for veterinary services and farmers to be able to distinguish between animals affected by the cattle-borne virulent viruses and vaccinated animals, subsequently affected by the vaccine strain. This study describes an improved high resolution-melting (HRM) test that exploits a 27 base pair (bp) fragment of the LSDV126 extracellular enveloped virion (EEV) gene that is present in field viruses but is absent from the Neethling vaccine strain. This difference leads to ∼0.5 °C melting point change in the HRM assay, when testing the quantitative PCR (qPCR) products generated from the virulent field viruses compared to the attenuated vaccine. By exploiting this difference, it could be shown using the newly developed HRM assay that virus isolated from vaccinated cattle that developed disease symptoms behave similarly to vaccine virus control, indicating that the vaccine virus can induce disease symptoms. This assay is not only in full agreement with the previously published PCR gradient and restriction fragment length polymorphism (RFLP) tests but it is faster with, fewer steps, cheaper and dependable. Copyright © 2016 Elsevier B.V. All rights reserved.
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Chen, Huang-Chi; Chiu, Ying-Ming
2012-03-14
Behçet's disease is characterized by recurrent oral ulcers, genital ulcers, uveitis and skin lesions. Myelodysplastic syndrome (MDS) is characterized by problems due to ineffective hematopoiesis. Several studies have identified a relationship between MDS and Behçet's disease, especially intestinal Behçet's disease. Trisomy 8 seems to play an important role in these disorders as well. The present case was a 24-year-old woman who had a huge tonsil ulcer with initial symptoms of odynophagia and intermittent fever. We also noted folliculitis on her upper back. Five days later, she began to experience diarrhea and abdominal pain. Abdominal computed tomography and subsequent surgery revealed ileum perforation and enterocolitis with multiple ulcers. Later, she was admitted again for a vulvar suppurative ulcer and suspicious Bartholin's cyst infection. The patient's clinical presentations met the criteria for Behçet's disease. Six months after the bowel perforation event, we noted the development of pancytopenia in a routine laboratory examination. All the examinations led to the diagnosis of MDS with trisomy 8. The most unusual finding was that multiple large vessel thrombi developed during follow-up. Previous studies have suggested that trisomy 8 in MDS leads to concurrent intestinal Behçet's disease. Moreover, the inflammatory and immune genes related to thrombus formation are overexpressed in cases of MDS with trisomy 8. Trisomy 8 must play a role in thrombosis. Further studies are needed to help clarify the pathophysiology and pathogenesis of these disorders.
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Pecci, Alessandro; Klersy, Catherine; Gresele, Paolo; Lee, Kieran J D; De Rocco, Daniela; Bozzi, Valeria; Russo, Giovanna; Heller, Paula G; Loffredo, Giuseppe; Ballmaier, Matthias; Fabris, Fabrizio; Beggiato, Eloise; Kahr, Walter H A; Pujol-Moix, Nuria; Platokouki, Helen; Van Geet, Christel; Noris, Patrizia; Yerram, Preethi; Hermans, Cedric; Gerber, Bernhard; Economou, Marina; De Groot, Marco; Zieger, Barbara; De Candia, Erica; Fraticelli, Vincenzo; Kersseboom, Rogier; Piccoli, Giorgina B; Zimmermann, Stefanie; Fierro, Tiziana; Glembotsky, Ana C; Vianello, Fabrizio; Zaninetti, Carlo; Nicchia, Elena; Güthner, Christiane; Baronci, Carlo; Seri, Marco; Knight, Peter J; Balduini, Carlo L; Savoia, Anna
2014-02-01
MYH9-related disease (MYH9-RD) is a rare autosomal-dominant disorder caused by mutations in the gene for nonmuscle myosin heavy chain IIA (NMMHC-IIA). MYH9-RD is characterized by a considerable variability in clinical evolution: patients present at birth with only thrombocytopenia, but some of them subsequently develop sensorineural deafness, cataract, and/or nephropathy often leading to end-stage renal disease (ESRD). We searched for genotype-phenotype correlations in the largest series of consecutive MYH9-RD patients collected so far (255 cases from 121 families). Association of genotypes with noncongenital features was assessed by a generalized linear regression model. The analysis defined disease evolution associated to seven different MYH9 genotypes that are responsible for 85% of MYH9-RD cases. Mutations hitting residue R702 demonstrated a complete penetrance for early-onset ESRD and deafness. The p.D1424H substitution associated with high risk of developing all the noncongenital manifestations of disease. Mutations hitting a distinct hydrophobic seam in the NMMHC-IIA head domain or substitutions at R1165 associated with high risk of deafness but low risk of nephropathy or cataract. Patients with p.E1841K, p.D1424N, and C-terminal deletions had low risk of noncongenital defects. These findings are essential to patients' clinical management and genetic counseling and are discussed in view of molecular pathogenesis of MYH9-RD. © 2013 WILEY PERIODICALS, INC.
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Rheumatic heart disease screening: Current concepts and challenges.
Dougherty, Scott; Khorsandi, Maziar; Herbst, Philip
2017-01-01
Rheumatic heart disease (RHD) is a disease of poverty, is almost entirely preventable, and is the most common cardiovascular disease worldwide in those under 25 years. RHD is caused by acute rheumatic fever (ARF) which typically results in cumulative valvular lesions that may present clinically after a number of years of subclinical disease. Therapeutic interventions, therefore, typically focus on preventing subsequent ARF episodes (with penicillin prophylaxis). However, not all patients with ARF develop symptoms and not all symptomatic cases present to a physician or are correctly diagnosed. Therefore, if we hope to control ARF and RHD at the population level, we need a more reliable discriminator of subclinical disease. Recent studies have examined the utility of echocardiographic screening, which is far superior to auscultation at detecting RHD. However, there are many concerns surrounding this approach. Despite the introduction of the World Heart Federation diagnostic criteria in 2012, we still do not really know what constitutes the most subtle changes of RHD by echocardiography. This poses serious problems regarding whom to treat and what to do with the rest, both important decisions with widespread implications for already stretched health-care systems. In addition, issues ranging from improving the uptake of penicillin prophylaxis in ARF/RHD-positive patients, improving portable echocardiographic equipment, understanding the natural history of subclinical RHD and how it might respond to penicillin, and developing simplified diagnostic criteria that can be applied by nonexperts, all need to be effectively tackled before routine widespread screening for RHD can be endorsed.
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Nitrative and Oxidative Stress in Toxicology and Disease
Roberts, Ruth A.; Laskin, Debra L.; Smith, Charles V.; Robertson, Fredika M.; Allen, Erin M. G.; Doorn, Jonathan A.; Slikker, William
2009-01-01
Persistent inflammation and the generation of reactive oxygen and nitrogen species play pivotal roles in tissue injury during disease pathogenesis and as a reaction to toxicant exposures. The associated oxidative and nitrative stress promote diverse pathologic reactions including neurodegenerative disorders, atherosclerosis, chronic inflammation, cancer, and premature labor and stillbirth. These effects occur via sustained inflammation, cellular proliferation and cytotoxicity and via induction of a proangiogenic environment. For example, exposure to the ubiquitous air pollutant ozone leads to generation of reactive oxygen and nitrogen species in lung macrophages that play a key role in subsequent tissue damage. Similarly, studies indicate that genes involved in regulating oxidative stress are altered by anesthetic treatment resulting in brain injury, most notable during development. In addition to a role in tissue injury in the brain, inflammation, and oxidative stress are implicated in Parkinson's disease, a neurodegenerative disease characterized by the loss of dopamine neurons. Recent data suggest a mechanistic link between oxidative stress and elevated levels of 3,4-dihydroxyphenylacetaldehyde, a neurotoxin endogenous to dopamine neurons. These findings have significant implications for development of therapeutics and identification of novel biomarkers for Parkinson's disease pathogenesis. Oxidative and nitrative stress is also thought to play a role in creating the proinflammatory microenvironment associated with the aggressive phenotype of inflammatory breast cancer. An understanding of fundamental concepts of oxidative and nitrative stress can underpin a rational plan of treatment for diseases and toxicities associated with excessive production of reactive oxygen and nitrogen species. PMID:19656995
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Rheumatic heart disease screening: Current concepts and challenges
Dougherty, Scott; Khorsandi, Maziar; Herbst, Philip
2017-01-01
Rheumatic heart disease (RHD) is a disease of poverty, is almost entirely preventable, and is the most common cardiovascular disease worldwide in those under 25 years. RHD is caused by acute rheumatic fever (ARF) which typically results in cumulative valvular lesions that may present clinically after a number of years of subclinical disease. Therapeutic interventions, therefore, typically focus on preventing subsequent ARF episodes (with penicillin prophylaxis). However, not all patients with ARF develop symptoms and not all symptomatic cases present to a physician or are correctly diagnosed. Therefore, if we hope to control ARF and RHD at the population level, we need a more reliable discriminator of subclinical disease. Recent studies have examined the utility of echocardiographic screening, which is far superior to auscultation at detecting RHD. However, there are many concerns surrounding this approach. Despite the introduction of the World Heart Federation diagnostic criteria in 2012, we still do not really know what constitutes the most subtle changes of RHD by echocardiography. This poses serious problems regarding whom to treat and what to do with the rest, both important decisions with widespread implications for already stretched health-care systems. In addition, issues ranging from improving the uptake of penicillin prophylaxis in ARF/RHD-positive patients, improving portable echocardiographic equipment, understanding the natural history of subclinical RHD and how it might respond to penicillin, and developing simplified diagnostic criteria that can be applied by nonexperts, all need to be effectively tackled before routine widespread screening for RHD can be endorsed. PMID:28163427
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Dostálová, G; Bělohlávek, J; Vítek, L; Muchová, L; Skvařilová, M; Karetová, D; Jirátová, K; Kvasnička, J; Vondráková, D; Toman, O; Linhart, A
2012-10-01
The incidence of cardiovascular (CV) diseases and acute myocardial infarction (AMI) in Czech Republic is de-clining. In spite of this in a proportion of patients AMI occurs in young age. The aim of our project was to assess the character of risk factors, precipitating diseases and the quality of care in young AMI survivors. We included 132 patients (97 men and 35 women) in whom AIM with ST elevations occurred before age of 45 years in men and age of 50 years in women. Several results were compared to a control group composed of 84 healthy volunteers of comparable age. We assessed the course of the disease, extent of coronary involvement, subsequent therapy and control of risk factors after 3 years from the index event. Smoking represented the main risk factor - 85% patents were active smokers at the time of AMI and 9% were former smokers, 64% patients had a positive family history of CV disease. We found a higher prevalence of dyslipidemia history in men. In spite of high rate of statin use, laboratory examination during follow-up revealed higher triglyceride values and low levels of HDL-cholesterol in both genders. All together 23% of patients had a history of provoking underlying disease or precipitating factors (inflammatory diseases, malignancies, combined thrombophilias, drug abuse). In total 95% of patients underwent coronary angiography during the acute phase of AMI, the median time from pain onset to intervention was 9 hours. Most patients had single vessel disease, 14% had even coronary angiogram without clinically significant stenosis. The subsequent care was satisfactory concerning the rate of drug prescriptions. However, target lipid values were not reached in 78% patients and blood pressure targets in 37%. In patients who suffered AMI in young age, risk factors are dominated by smoking and positive family history of CV diseases. One fifth of patients suffer from other underlying disease (inflammatory disease, malignancies, combined thrombophilia) or have another precipitating factor (febrile disease, drug abuse). The acute care seems unsatisfactory due to late arrival of most patients to catheterization laboratories (underestimation of the disease, incorrect initial diagnosis). Subsequent therapy is well composed but lacks in intensity.
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Proposed clinical case definition for cytomegalovirus-immune recovery retinitis.
Ruiz-Cruz, Matilde; Alvarado-de la Barrera, Claudia; Ablanedo-Terrazas, Yuria; Reyes-Terán, Gustavo
2014-07-15
Cytomegalovirus (CMV) retinitis has been extensively described in patients with advanced or late human immunodeficiency virus (HIV) disease under ineffective treatment of opportunistic infection and antiretroviral therapy (ART) failure. However, there is limited information about patients who develop active cytomegalovirus retinitis as an immune reconstitution inflammatory syndrome (IRIS) after successful initiation of ART. Therefore, a case definition of cytomegalovirus-immune recovery retinitis (CMV-IRR) is proposed here. We reviewed medical records of 116 HIV-infected patients with CMV retinitis attending our institution during January 2003-June 2012. We retrospectively studied HIV-infected patients who had CMV retinitis on ART initiation or during the subsequent 6 months. Clinical and immunological characteristics of patients with active CMV retinitis were described. Of the 75 patients under successful ART included in the study, 20 had improvement of CMV retinitis. The remaining 55 patients experienced CMV-IRR; 35 of those developed CMV-IRR after ART initiation (unmasking CMV-IRR) and 20 experienced paradoxical clinical worsening of retinitis (paradoxical CMV-IRR). Nineteen patients with CMV-IRR had a CD4 count of ≥50 cells/µL. Six patients with CMV-IRR subsequently developed immune recovery uveitis. There is no case definition for CMV-IRR, although this condition is likely to occur after successful initiation of ART, even in patients with high CD4 T-cell counts. By consequence, we propose the case definitions for paradoxical and unmasking CMV-IRR. We recommend close follow-up of HIV-infected patients following ART initiation. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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Choi, Mun Hee; Yoon, Jung Han; Yong, Suk Woo
2017-10-15
Postganglionic cardiac sympathetic denervation is evident in patients with early-stage Parkinson's disease (PD). Cardiac iodine-123-meta-iodobenzylguanidine (MIBG) uptake is correlated with the non-motor symptoms of PD, suggesting that low cardiac MIBG uptake may reflect wider alpha-synuclein pathology. In addition, low cardiac MIBG could be related to orthostatic hypotension in PD, which may affect cognition. However, the prognostic validity of baseline MIBG scintigraphy in terms of the risk of subsequent dementia remains unclear. We investigated whether cardiac MIBG uptake was associated with a later risk of dementia. We retrospectively enrolled 93 drug-naive patients with de novo PD who underwent MIBG scanning on initial evaluation. The patients visited our outpatient clinic every 3-6months and were followed-up for a minimum of 4years from the time they were begun on dopaminergic medication. The predictive powers of baseline MIBG cardiac scintigraphic data in terms of dementia development were evaluated using Cox's proportional hazard models. During a mean follow-up period of 6.7years, 27 patients with PD (29.0%) developed dementia. These patients had less baseline MIBG uptake than did others (delayed H/M ratios: 1.19 vs. 1.31). Multivariate Cox's proportional hazard modeling revealed that both MIBG uptake (hazard ratio [HR] 3.40; p=0.004) and age (HR 1.08, p=0.01) significantly predicted dementia development. A reduction in cardiac MIBG uptake by PD patients may be associated with a subsequent risk of dementia; reduced uptake may reflect wider extension of alpha-synuclein pathology in PD. Copyright © 2017 Elsevier B.V. All rights reserved.
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Early Elevations of the Complement Activation Fragment C3a and Adverse Pregnancy Outcomes
Lynch, Anne M.; Gibbs, Ronald S.; Murphy, James R.; Giclas, Patricia C.; Salmon, Jane E.; Holers, V. Michael
2016-01-01
OBJECTIVE To estimate whether elevations of complement C3a early in pregnancy are predictive of the subsequent development of adverse pregnancy outcomes. METHODS A plasma sample was obtained from each enrolled pregnant woman before 20 weeks of gestation. The cohort (n=1,002) was evaluated for the development of adverse pregnancy outcomes defined as hypertensive diseases of pregnancy (gestational hypertension or preeclampsia), preterm birth (before 37 weeks of gestation), premature rupture of the membranes, pregnancy loss (during the embryonic and fetal period), intrauterine growth restriction, and the composite outcome of any adverse outcome. RESULTS One or more adverse pregnancy outcomes occurred in 211 (21%) of the cohort. The mean levels (ng/mL) of C3a in early pregnancy were significantly (P=<.001) higher among women with one or more adverse outcomes (858±435) compared with women with an uncomplicated pregnancy (741±407). Adjusted for parity and prepregnancy body mass index, women with levels of C3a in the upper quartile in early pregnancy were three times more likely to have an adverse outcome later in pregnancy compared with women in the lowest quartile (95% confidence interval, 1.8–4.8; P<.001). The link between early elevated C3a levels and adverse pregnancy outcomes was driven primarily by individual significant (P<.05) associations of C3a with hypertensive diseases of pregnancy, preterm birth, and premature rupture of the membranes. CONCLUSION Elevated C3a as early as the first trimester of pregnancy is an independent predictive factor for adverse pregnancy outcomes, suggesting that complement-related inflammatory events in pregnancy contribute to the subsequent development of poor outcomes at later stages of pregnancy. PMID:21173647
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Yen, Michael; Chen, Jenny; Ausayakhun, Somsanguan; Kunavisarut, Paradee; Vichitvejpaisal, Pornpattana; Ausayakhun, Sakarin; Jirawison, Choeng; Shantha, Jessica; Holland, Gary N; Heiden, David; Margolis, Todd P; Keenan, Jeremy D
2014-01-01
Purpose To determine risk factors predictive of retinal detachment in patients with cytomegalovirus (CMV) retinitis in a setting with limited access to ophthalmic care. Design Case-control study. Methods Sixty-four patients with CMV retinitis and retinal detachment were identified from the Ocular Infectious Diseases and Retina Clinics at Chiang Mai University. Three control patients with CMV retinitis but no retinal detachment were selected for each case, matched by calendar date. The medical records of each patient were reviewed, with patient-level and eye-level features recorded for the clinic visit used to match cases and controls, and also for the initial clinic visit at which CMV retinitis was diagnosed. Risk factors for retinal detachment were assessed separately for each of these time points using multivariate conditional logistic regression models that included 1 eye from each patient. Results Patients with a retinal detachment were more likely than controls to have low visual acuity (OR, 1.24 per line of worse vision on the logMAR scale; 95%CI, 1.16-1.33) and bilateral disease (OR, 2.12; 95%CI, 0.92-4.90). Features present at the time of the initial diagnosis of CMV retinitis that predicted subsequent retinal detachment included bilateral disease (OR, 2.68; 95%CI, 1.18-6.08) and lesion size (OR, 2.64 per 10% increase in lesion size; 95%CI, 1.41-4.94). Conclusion Bilateral CMV retinitis and larger lesion sizes, each of which is a marker of advanced disease, were associated with subsequent retinal detachment. Earlier detection and treatment may reduce the likelihood that patients with CMV retinitis develop a retinal detachment. PMID:25448999
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Early-life antibiotic use and subsequent diagnosis of food allergy and allergic diseases.
Hirsch, A G; Pollak, J; Glass, T A; Poulsen, M N; Bailey-Davis, L; Mowery, J; Schwartz, B S
2017-02-01
Antibiotic use in early life has been linked to disruptions in the microbiome. Such changes can disturb immune system development. Differences have been observed in the microbiota of children with and without allergies, but there have been few studies on antibiotic use and allergic disease. We evaluated associations of early-life antibiotic use with subsequent occurrence of food allergy and other allergies in childhood using electronic health record data. We used longitudinal data on 30 060 children up to age 7 years from Geisinger Clinic's electronic health record to conduct a sex- and age-matched case-control study to evaluate the association between antibiotic use and milk allergy, non-milk food allergies, and other allergies. For each outcome, we estimated conditional logistic regression models adjusting for race/ethnicity, history of Medical Assistance, and mode of birth delivery. Models were repeated separately for penicillins, cephalosporins and macrolides. There were 484 milk allergy cases, 598 non-milk food allergy cases and 3652 other allergy cases. Children with three or more antibiotic orders had a greater odds of milk allergy (Odds Ratio; 95% Confidence interval) (1.78; 1.28-2.48), non-milk food allergy (1.65; 1.27-2.14), and other allergies (3.07; 2.72-3.46) compared with children with no antibiotic orders. Associations were strongest at younger ages and differed by antibiotic class. We observed associations between antibiotic orders and allergic diseases, providing evidence of a potentially modifiable clinical practice associated with paediatric allergic disease. Differences by antibiotic class should be further explored, as this knowledge could inform paediatric treatment decisions. © 2016 John Wiley & Sons Ltd.
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Public health interventions for epidemics: implications for multiple infection waves.
Wessel, Lindsay; Hua, Yi; Wu, Jianhong; Moghadas, Seyed M
2011-02-25
Epidemics with multiple infection waves have been documented for some human diseases, most notably during past influenza pandemics. While pathogen evolution, co-infection, and behavioural changes have been proposed as possible mechanisms for the occurrence of subsequent outbreaks, the effect of public health interventions remains undetermined. We develop mean-field and stochastic epidemiological models for disease transmission, and perform simulations to show how control measures, such as drug treatment and isolation of ill individuals, can influence the epidemic profile and generate sequences of infection waves with different characteristics. We demonstrate the impact of parameters representing the effectiveness and adverse consequences of intervention measures, such as treatment and emergence of drug resistance, on the spread of a pathogen in the population. If pathogen resistant strains evolve under drug pressure, multiple outbreaks are possible with variability in their characteristics, magnitude, and timing. In this context, the level of drug use and isolation capacity play an important role in the occurrence of subsequent outbreaks. Our simulations for influenza infection as a case study indicate that the intensive use of these interventions during the early stages of the epidemic could delay the spread of disease, but it may also result in later infection waves with possibly larger magnitudes. The findings highlight the importance of intervention parameters in the process of public health decision-making, and in evaluating control measures when facing substantial uncertainty regarding the epidemiological characteristics of an emerging infectious pathogen. Critical factors that influence population health including evolutionary responses of the pathogen under the pressure of different intervention measures during an epidemic should be considered for the design of effective strategies that address short-term targets compatible with long-term disease outcomes.
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Early Life Antibiotic Use and Subsequent Diagnosis of Food Allergy and Allergic Diseases
Hirsch, Annemarie G.; Pollak, Jonathan; Glass, Thomas A.; Poulsen, Melissa N.; Bailey-Davis, Lisa; Mowery, Jacob; Schwartz, Brian S.
2016-01-01
Background Antibiotic use in early life has been linked to disruptions in the microbiome. Such changes can disturb immune system development. Differences have been observed in the microbiota of children with and without allergies, but there have been few studies on antibiotic use and allergic disease. Objective We evaluated associations of early-life antibiotic use with subsequent occurrence of food allergy and other allergies in childhood using electronic health record data. Methods We used longitudinal data on 30,060 children up to age 7 years from Geisinger Clinic’s electronic health record to conduct a sex and age matched case-control study to evaluate the association between antibiotic use and milk allergy, non-milk food allergies, and other allergies. For each outcome, we estimated conditional logistic regression models adjusting for race/ethnicity, history of Medical Assistance, and mode of birth delivery. Models were repeated separately for penicillins, cephalosporins, and macrolides. Results There were 484 milk allergy cases, 598 non-milk food allergy cases, and 3652 other allergy cases. Children with three or more antibiotic orders had a greater odds of milk allergy (odds ratio; 95% confidence interval) (1.78; 1.28–2.48), non-milk food allergy (1.65; 1.27–2.14), and other allergies (3.07; 2.72–3.46) compared to children with no antibiotic orders. Associations were strongest at younger ages and differed by antibiotic class. Conclusions and Clinical Relevance We observed associations between antibiotic orders and allergic diseases, providing evidence of a potentially modifiable clinical practice associated with pediatric allergic disease. Differences by antibiotic class should be further explored, as this knowledge could inform pediatric treatment decisions. PMID:27562571
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Yen, Michael; Chen, Jenny; Ausayakhun, Somsanguan; Kunavisarut, Paradee; Vichitvejpaisal, Pornpattana; Ausayakhun, Sakarin; Jirawison, Choeng; Shantha, Jessica; Holland, Gary N; Heiden, David; Margolis, Todd P; Keenan, Jeremy D
2015-01-01
To determine risk factors predictive of retinal detachment in patients with cytomegalovirus (CMV) retinitis in a setting with limited access to ophthalmic care. Case-control study. Sixty-four patients with CMV retinitis and retinal detachment were identified from the Ocular Infectious Diseases and Retina Clinics at Chiang Mai University. Three control patients with CMV retinitis but no retinal detachment were selected for each case, matched by calendar date. The medical records of each patient were reviewed, with patient-level and eye-level features recorded for the clinic visit used to match cases and controls, and also for the initial clinic visit at which CMV retinitis was diagnosed. Risk factors for retinal detachment were assessed separately for each of these time points using multivariate conditional logistic regression models that included 1 eye from each patient. Patients with a retinal detachment were more likely than controls to have low visual acuity (odds ratio [OR], 1.24 per line of worse vision on the logMAR scale; 95% confidence interval [CI], 1.16-1.33) and bilateral disease (OR, 2.12; 95% CI, 0.92-4.90). Features present at the time of the initial diagnosis of CMV retinitis that predicted subsequent retinal detachment included bilateral disease (OR, 2.68; 95% CI, 1.18-6.08) and lesion size (OR, 2.64 per 10% increase in lesion size; 95% CI, 1.41-4.94). Bilateral CMV retinitis and larger lesion sizes, each of which is a marker of advanced disease, were associated with subsequent retinal detachment. Earlier detection and treatment may reduce the likelihood that patients with CMV retinitis develop a retinal detachment. Copyright © 2015 Elsevier Inc. All rights reserved.
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Baumeister, Judith; Fischer, Ruediger; Eckenberg, Peter; Henninger, Kerstin; Ruebsamen-Waigmann, Helga; Kleymann, Gerald
2007-01-01
The efficacy of BAY 57-1293, a novel non-nucleosidic inhibitor of herpes simplex virus 1 and 2 (HSV-1 and HSV-2), bovine herpesvirus and pseudorabies virus, was studied in the guinea pig model of genital herpes in comparison with the licensed drug valaciclovir (Valtrex). Early therapy with BAY 57-1293 almost completely suppressed the symptoms of acute HSV-2 infection, and reduced virus shedding and viral load in the sacral dorsal root ganglia by up to three orders of magnitude, resulting in decreased latency and a greatly diminished frequency of subsequent recurrent episodes. In contrast, valaciclovir showed only moderate effects in this set of experiments. When treatment was initiated late during the course of disease after symptoms were apparent, that is, a setting closer to most clinical situations, the efficacy of therapy with BAY 57-1293 was even more pronounced. Compared with valaciclovir, BAY 57-1293 halved the time necessary for complete healing. Moreover, the onset of action was fast, so that only very few animals developed new lesions after treatment commenced. Finally, in a study addressing the treatment of recurrent disease in animals whose primary infection had remained untreated BAY 57-1293 was efficient in suppressing the episodes. In summary, superior potency and efficacy of BAY 57-1293 over standard treatment with valaciclovir was demonstrated in relevant animal models of human genital herpes disease in terms of abrogating an HSV infection, reducing latency and the frequency of subsequent recurrences. Furthermore, BAY 57-1293 shortens the time to healing even if initiation of therapy is delayed.
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Mota-Anaya, Evelin; Yumpo-Cárdenas, Daniel; Alva-Bravo, Edmundo; Wright-Nunes, Julie; Mayta-Tristán, Percy
2016-08-08
Chronic kidney disease (CKD) affects 50 million people globally. Several studies show the importance of implementing interventions that enhance patients knowledge about their disease. In 2011 the Kidney Disease Knowledge Survey (KiKS) was developed: a questionnaire that assesses the specific knowledge about chronic kidney disease in pre-dialysis patients. To translate to Spanish, culturally adapt and validate the Kidney Disease Knowledge Survey questionnaire in a population of patients with pre-dialysis chronic kidney disease. We carried out a Spanish translation and cross-cultural adaptation of the Kidney Disease Knowledge Survey questionnaire. Subsequently, we determined its validity and reliability. We determined the validity through construct validity; and reliability by evaluating its internal consistency and its intra-observer reliability (test-retest). We found a good internal consistency (Kuder-Richardson = 0.85). The intra-observer reliability was measured by the intra-class correlation coefficient that yielded a value of 0.78 (95% CI: 0.5-1.0). This value indicated a good reproducibility; also, the mean difference of -1.1 test-retest SD 6.0 (p = 0.369) confirms this finding. The translated Spanish version of the Kidney Disease Knowledge Survey is acceptable and equivalent to the original version; it also has a good reliability, validity and reproducibility. Therefore, it can be used in a population of patients with pre-dialysis chronic kidney disease.
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Kipandula, Wakisa; Young, Simon A; MacNeill, Stuart A; Smith, Terry K
2018-06-01
Diseases caused by the pathogenic kinetoplastids continue to incapacitate and kill hundreds of thousands of people annually throughout the tropics and sub-tropics. Unfortunately, in the countries where these neglected diseases occur, financial obstacles to drug discovery and technical limitations associated with biochemical studies impede the development of new, safe, easy to administer and effective drugs. Here we report the development and optimisation of a Crithidia fasciculata resazurin viability assay, which is subsequently used for screening and identification of anti-crithidial compounds in the MMV and GSK open access chemical boxes. The screening assay had an average Z' factor of 0.7 and tolerated a maximum dimethyl sulfoxide concentration of up to 0.5%. We identified from multiple chemical boxes two compound series exhibiting nanomolar potency against C. fasciculata, one centred around a 5-nitrofuran-2-yl scaffold, a well-known moiety in several existing anti-infectives, and another involving a 2-(pyridin-2-yl) pyrimidin-4-amine scaffold which seems to have pan-kinetoplastid activity. This work facilitates the future use of C. fasciculata as a non-pathogenic and inexpensive biological resource to identify mode of action/protein target(s) of potentially pan-trypanocidal potent compounds. This knowledge will aid in the development of new treatments for African sleeping sickness, Chagas disease and leishmaniasis. Copyright © 2018 Elsevier B.V. All rights reserved.
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Wainwright, CL; McGrath, JC
2009-01-01
A themed section in this issue of Br J Pharmacol, on ‘Advances in Nutritional Pharmacology’, provides a valuable and timely update on progress in this area. The value of dietary components to improvement in health and, particularly, to prevention of cardiovascular disease and cancer, is frequently reported in the media and therefore often captures the attention of the wider public. Understanding the pharmacological mechanisms by which nutritional elements confer their health benefits enables us to keep the public informed, but also aids in the identification of new targets for drug development. In recent years there has been significant progress in this field. Four rapidly developing areas are reviewed. Vosper (2009) covers the identification of a receptor for niacin and the subsequent development of selective agonists as lipid lowering agents. Wu-Wong (2009) describes the development of new Vitamin D analogues for the treatment of cardiovascular disease. de Roos et al. (2009) provide detailed insight into how omega-3 fatty acids, also known as longchain n-3 polyunsaturated fatty acids (PUFAs) protect against cardiovascular disease. Zhou et al. (2009) cover the mechanisms underlying the beneficial effects of resveretrol in protection against cancer. These reviews are complimented by three key original articles focusing on endogenous mechanisms of weight control involving endocannabinoids (Izzo et al., 2009), a circulating protein, the soluble leptin receptor (Zhang & Scarpace, 2009) and a treatment, zinc plus cyclo-(His-Pro) (CHP), known to increase insulin metabolism (Song et al., 2009). PMID:19732059
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History and Practice: Antibodies in Infectious Diseases.
Hey, Adam
2015-04-01
Antibodies and passive antibody therapy in the treatment of infectious diseases is the story of a treatment concept which dates back more than 120 years, to the 1890s, when the use of serum from immunized animals provided the first effective treatment options against infections with Clostridium tetani and Corynebacterium diphtheriae. However, after the discovery of penicillin by Fleming in 1928, and the subsequent introduction of the much cheaper and safer antibiotics in the 1930s, serum therapy was largely abandoned. However, the broad and general use of antibiotics in human and veterinary medicine has resulted in the development of multi-resistant strains of bacteria with limited to no response to existing treatments and the need for alternative treatment options. The combined specificity and flexibility of antibody-based treatments makes them very valuable tools for designing specific antibody treatments to infectious agents. These attributes have already caused a revolution in new antibody-based treatments in oncology and inflammatory diseases, with many approved products. However, only one monoclonal antibody, palivizumab, for the prevention and treatment of respiratory syncytial virus, is approved for infectious diseases. The high cost of monoclonal antibody therapies, the need for parallel development of diagnostics, and the relatively small markets are major barriers for their development in the presence of cheap antibiotics. It is time to take a new and revised look into the future to find appropriate niches in infectious diseases where new antibody-based treatments or combinations with existing antibiotics, could prove their value and serve as stepping stones for broader acceptance of the potential for and value of these treatments.
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Inhalation of diesel exhaust and allergen alters human bronchial epithelium DNA methylation.
Clifford, Rachel L; Jones, Meaghan J; MacIsaac, Julia L; McEwen, Lisa M; Goodman, Sarah J; Mostafavi, Sara; Kobor, Michael S; Carlsten, Chris
2017-01-01
Allergic disease affects 30% to 40% of the world's population, and its development is determined by the interplay between environmental and inherited factors. Air pollution, primarily consisting of diesel exhaust emissions, has increased at a similar rate to allergic disease. Exposure to diesel exhaust may play a role in the development and progression of allergic disease, in particular allergic respiratory disease. One potential mechanism underlying the connection between air pollution and increased allergic disease incidence is DNA methylation, an epigenetic process with the capacity to integrate gene-environment interactions. We sought to investigate the effect of allergen and diesel exhaust exposure on bronchial epithelial DNA methylation. We performed a randomized crossover-controlled exposure study to allergen and diesel exhaust in humans, and measured single-site (CpG) resolution global DNA methylation in bronchial epithelial cells. Exposure to allergen alone, diesel exhaust alone, or allergen and diesel exhaust together (coexposure) led to significant changes in 7 CpG sites at 48 hours. However, when the same lung was exposed to allergen and diesel exhaust but separated by approximately 4 weeks, significant changes in more than 500 sites were observed. Furthermore, sites of differential methylation differed depending on which exposure was experienced first. Functional analysis of differentially methylated CpG sites found genes involved in transcription factor activity, protein metabolism, cell adhesion, and vascular development, among others. These findings suggest that specific exposures can prime the lung for changes in DNA methylation induced by a subsequent insult. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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Drug-eluting coronary stents – focus on improved patient outcomes
Jaffery, Zehra; Prasad, Amit; Lee, John H; White, Christopher J
2011-01-01
The development of stent has been a major advance in the treatment of obstructive coronary artery disease since the introduction of balloon angioplasty. Subsequently, neointimal hyperplasia within the stent leading to in-stent restenosis emerged as a major obstacle in long-term success of percutaneous coronary intervention. Recent introduction of drug-eluting stents is a major breakthrough to tackle this problem. This review article summarizes stent technology, reviews progress of drug-eluting stents and discusses quality of life, patient satisfaction, and acceptability of percutaneous coronary intervention. PMID:22915977
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Intestinal nodular lymphoid hyperplasia and extraintestinal lymphoma--a rare association.
Monsanto, P; Lérias, C; Almeida, N; Lopes, S; Cabral, J E; Figueiredo, P; Silva, M; Julião, M; Gouveia, H; Sofia, C
2012-06-01
Nodular lymphoid hyperplasia of the gastrointestinal tract is characterized by the presence of innumerable small discrete nodules involving a variable segment of the gastrointestinal tract. The association between nodular lymphoid hyperplasia and other benign and malignant diseases has been clearly described, with an increased risk of gastrointestinal tumours, namely gastrointestinal lymphoma. However, the association with extraintestinal lymphoma seems extremely rare. The authors present a clinical case of a patient with nodular lymphoid hyperplasia of the small and large intestine that subsequently developed an extraintestinal lymphoma (diffuse large B-cell lymphoma).
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Reconsidering the history of type 2 diabetes in India: emerging or re-emerging disease?
Weaver, Lesley Jo; Narayan, K M Venkat
2008-01-01
The emergence of type 2 diabetes in India, coinciding with the country's rapid economic development in the past several decades, is often characterized as a modern epidemic resulting directly from westernization. We draw on India's agricultural, linguistic, medical, economic, religious and gastronomic history to examine the possibility that type 2 diabetes mellitus may have existed in ancient India, having subsequently declined in the two centuries leading up to the present. The implications of such a possibility vis-a-vis the role of westernization in the global diabetes aetiology are discussed. Additionally, an argument is made for careful application of the terms 'westernization' and 'globalization' in discussions of chronic disease aetiology, where their often totalizing discourses may obscure the sociocultural particularities of manifestations of these conditions in various global arenas.
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Cognitive performance on Piagetian tasks by Alzheimer's disease patients.
Thornbury, J M
1992-02-01
The purpose of this study was to examine cognitive abilities in Alzheimer's disease (AD) patients using Piaget's child developmental theory. Thirty elderly AD patients and 30 elderly control subjects were given two traditional Piagetian measures, the Infant Psychological Development Scale and the Concrete Operations Test. Half of the AD subjects (15) were in Piaget's sensorimotor or preoperational stages, while the remaining half of the AD subjects and all elderly control subjects were in Piaget's concrete operational stage, chi 2 [1, N = 60] = 17.42, p less than .001. If subsequent studies confirm that AD patients' cognitive characteristics are similar to Piaget's theoretical model, nursing care might be individualized based on mental competence, thus minimizing the commonly observed caregiver overestimation and underestimation of the AD patient's ability to understand and cooperate.
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The biomechanics of leg ulceration.
Chant, A.
1999-01-01
Research performed in the late 1960s, using 24Na, suggested that the perfusion of skin and subcutaneous tissues is critically dependent on the relationship between capillary (Pc) and tissue pressures (Pt). Perfusion changes differed significantly between controls and patients with venous disease and the differences could be interpreted as evidence that Pt remained high in venous diseased patients. From this starting point, a biomechanical theory for the aetiology of venous ulceration was developed and tested by measuring skin elasticity, limb cross-sectional area and laser Doppler flux. The results confirm that, modelled as a two-compartment system (vascular and interstitial fluid), forces can be demonstrated sufficient to cause intermittent capillary closure and subsequent reperfusion injury. These forces are maximal in the gaiter area, the site of most leg ulcers. Images Figure 2 Figure 4 PMID:10364960
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Resolving TYK2 locus genotype-to-phenotype differences in autoimmunity.
Dendrou, Calliope A; Cortes, Adrian; Shipman, Lydia; Evans, Hayley G; Attfield, Kathrine E; Jostins, Luke; Barber, Thomas; Kaur, Gurman; Kuttikkatte, Subita Balaram; Leach, Oliver A; Desel, Christiane; Faergeman, Soren L; Cheeseman, Jane; Neville, Matt J; Sawcer, Stephen; Compston, Alastair; Johnson, Adam R; Everett, Christine; Bell, John I; Karpe, Fredrik; Ultsch, Mark; Eigenbrot, Charles; McVean, Gil; Fugger, Lars
2016-11-02
Thousands of genetic variants have been identified, which contribute to the development of complex diseases, but determining how to elucidate their biological consequences for translation into clinical benefit is challenging. Conflicting evidence regarding the functional impact of genetic variants in the tyrosine kinase 2 (TYK2) gene, which is differentially associated with common autoimmune diseases, currently obscures the potential of TYK2 as a therapeutic target. We aimed to resolve this conflict by performing genetic meta-analysis across disorders; subsequent molecular, cellular, in vivo, and structural functional follow-up; and epidemiological studies. Our data revealed a protective homozygous effect that defined a signaling optimum between autoimmunity and immunodeficiency and identified TYK2 as a potential drug target for certain common autoimmune disorders. Copyright © 2016, American Association for the Advancement of Science.
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Identification and functional validation of novel autoantigens in equine uveitis.
Deeg, Cornelia A; Pompetzki, Dirk; Raith, Albert J; Hauck, Stefanie M; Amann, Barbara; Suppmann, Sabine; Goebel, Thomas W F; Olazabal, Ursula; Gerhards, Hartmut; Reese, Sven; Stangassinger, Manfred; Kaspers, Bernd; Ueffing, Marius
2006-08-01
The development, progression, and recurrence of autoimmune diseases are frequently driven by a group of participatory autoantigens. We identified and characterized novel autoantigens by analyzing the autoantibody binding pattern from horses affected by spontaneous equine recurrent uveitis to the retinal proteome. Cellular retinaldehyde-binding protein (cRALBP) had not been described previously as autoantigen, but subsequent characterization in equine recurrent uveitis horses revealed B and T cell autoreactivity to this protein and established a link to epitope spreading. We further immunized healthy rats and horses with cRALBP and observed uveitis in both species with typical tissue lesions at cRALBP expression sites. The autoantibody profiling outlined here could be used in various autoimmune diseases to detect autoantigens involved in the dynamic spreading cascade or serve as predictive markers.
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Delos Reyes, Arthur P; Partsch, Hugo; Mosti, Giovanni; Obi, Andrea; Lurie, Fedor
2014-10-01
The International Compression Club, a collaboration of medical experts and industry representatives, was founded in 2005 to develop consensus reports and recommendations regarding the use of compression therapy in the treatment of acute and chronic vascular disease. During the recent meeting of the International Compression Club, member presentations were focused on the clinical application of intermittent pneumatic compression in different disease scenarios as well as on the use of inelastic and short stretch compression therapy. In addition, several new compression devices and systems were introduced by industry representatives. This article summarizes the presentations and subsequent discussions and provides a description of the new compression therapies presented. Copyright © 2014 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.
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Mucosal-associated invariant T cells in autoimmunity, immune-mediated diseases and airways disease.
Hinks, Timothy S C
2016-05-01
Mucosal-associated invariant T (MAIT) cells are a novel class of innate-like T cells, expressing a semi-invariant T-cell receptor (TCR) and able to recognize small molecules presented on the non-polymorphic MHC-related protein 1. Their intrinsic effector-memory phenotype, enabling secretion of pro-inflammatory cytokines, and their relative abundance in humans imply a significant potential to contribute to autoimmune processes. However, as MAIT cells were unknown until recently and specific immunological tools were unavailable, little is known of their roles in disease. Here I review observations from clinical studies and animal models of autoimmune and immune-mediated diseases including the roles of MAIT cells in systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and airways diseases. MAIT cell deficiencies are frequently observed in peripheral blood, and at sites of disease such as the airways in asthma. However, MAIT cells have a specific sensitivity to suppression by therapeutic corticosteroids that may confound many of these observations, as may the tendency of the surface marker CD161 to activation-induced down-regulation. Nonetheless, the dependence on bacteria for the development of MAIT cells suggests a potentially important protective role linking the influences of early life microbial exposures and subsequent development of autoimmunity. Conversely, MAIT cells could contribute to chronic inflammation either through TCR-independent activation, or potentially by TCR recognition of as yet undiscovered ligands. Future research will be greatly facilitated by the immunological tools that are now available, including murine genetic models and human and murine specific tetramers. © 2016 The Authors. Immunology published by John Wiley & Sons Ltd.
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Lyseen, A K; Nøhr, C; Sørensen, E M; Gudes, O; Geraghty, E M; Shaw, N T; Bivona-Tellez, C
2014-08-15
The application of GIS in health science has increased over the last decade and new innovative application areas have emerged. This study reviews the literature and builds a framework to provide a conceptual overview of the domain, and to promote strategic planning for further research of GIS in health. The framework is based on literature from the library databases Scopus and Web of Science. The articles were identified based on keywords and initially selected for further study based on titles and abstracts. A grounded theory-inspired method was applied to categorize the selected articles in main focus areas. Subsequent frequency analysis was performed on the identified articles in areas of infectious and non-infectious diseases and continent of origin. A total of 865 articles were included. Four conceptual domains within GIS in health sciences comprise the framework: spatial analysis of disease, spatial analysis of health service planning, public health, health technologies and tools. Frequency analysis by disease status and location show that malaria and schistosomiasis are the most commonly analyzed infectious diseases where cancer and asthma are the most frequently analyzed non-infectious diseases. Across categories, articles from North America predominate, and in the category of spatial analysis of diseases an equal number of studies concern Asia. Spatial analysis of diseases and health service planning are well-established research areas. The development of future technologies and new application areas for GIS and data-gathering technologies such as GPS, smartphones, remote sensing etc. will be nudging the research in GIS and health.
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Nøhr, C.; Sørensen, E. M.; Gudes, O.; Geraghty, E. M.; Shaw, N. T.; Bivona-Tellez, C.
2014-01-01
Summary Objectives The application of GIS in health science has increased over the last decade and new innovative application areas have emerged. This study reviews the literature and builds a framework to provide a conceptual overview of the domain, and to promote strategic planning for further research of GIS in health. Method The framework is based on literature from the library databases Scopus and Web of Science. The articles were identified based on keywords and initially selected for further study based on titles and abstracts. A grounded theory-inspired method was applied to categorize the selected articles in main focus areas. Subsequent frequency analysis was performed on the identified articles in areas of infectious and non-infectious diseases and continent of origin. Results A total of 865 articles were included. Four conceptual domains within GIS in health sciences comprise the framework: spatial analysis of disease, spatial analysis of health service planning, public health, health technologies and tools. Frequency analysis by disease status and location show that malaria and schistosomiasis are the most commonly analyzed infectious diseases where cancer and asthma are the most frequently analyzed non-infectious diseases. Across categories, articles from North America predominate, and in the category of spatial analysis of diseases an equal number of studies concern Asia. Conclusion Spatial analysis of diseases and health service planning are well-established research areas. The development of future technologies and new application areas for GIS and data-gathering technologies such as GPS, smartphones, remote sensing etc. will be nudging the research in GIS and health. PMID:25123730
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Biomarkers for IgA nephropathy on the basis of multi-hit pathogenesis.
Suzuki, Hitoshi
2018-05-08
IgA nephropathy (IgAN) is the most prevalent glomerular disease worldwide and is associated with a poor prognosis. Development of curative treatment strategies and approaches for early diagnosis is necessary. Renal biopsy is the gold standard for the diagnosis and assessment of disease activity. However, reliable biomarkers are needed for the noninvasive diagnosis of this disease and to more fully delineate the risk of progression. With regard to the pathogenesis of IgAN, the multi-hit hypothesis, including production of galactose-deficient IgA1 (Gd-IgA1; Hit 1), IgG or IgA autoantibodies that recognize Gd-IgA1 (Hit 2), and their subsequent immune complexes formation (Hit 3) and glomerular deposition (Hit 4), has been widely supported by many studies. Although the prognostic values of several biomarkers have been discussed, we recently developed a highly sensitive and specific diagnostic method by measuring serum levels of Gd-IgA1 and Gd-IgA1-containing immune complexes. In addition, urinary Gd-IgA1 may represent a disease-specific biomarker for IgAN. We also confirmed that there is a significant correlation between serum levels of these effector molecules and disease activity, suggesting that each can be considered a practical surrogate marker of therapeutic response. Thus, these disease-oriented specific serum and urine biomarkers may be useful for screening of potential IgAN with isolated hematuria, earlier diagnosis, disease activity, and eventually, response to treatment. In this review, we discuss these concepts, with a focus on potential clinical applications of these biomarkers.
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Santhanam, Rakesh; Luu, Van Thi; Weinhold, Arne; Goldberg, Jay; Oh, Youngjoo; Baldwin, Ian T.
2015-01-01
Plants maintain microbial associations whose functions remain largely unknown. For the past 15 y, we have planted the annual postfire tobacco Nicotiana attenuata into an experimental field plot in the plant’s native habitat, and for the last 8 y the number of plants dying from a sudden wilt disease has increased, leading to crop failure. Inadvertently we had recapitulated the common agricultural dilemma of pathogen buildup associated with continuous cropping for this native plant. Plants suffered sudden tissue collapse and black roots, symptoms similar to a Fusarium–Alternaria disease complex, recently characterized in a nearby native population and developed into an in vitro pathosystem for N. attenuata. With this in vitro disease system, different protection strategies (fungicide and inoculations with native root-associated bacterial and fungal isolates), together with a biochar soil amendment, were tested further in the field. A field trial with more than 900 plants in two field plots revealed that inoculation with a mixture of native bacterial isolates significantly reduced disease incidence and mortality in the infected field plot without influencing growth, herbivore resistance, or 32 defense and signaling metabolites known to mediate resistance against native herbivores. Tests in a subsequent year revealed that a core consortium of five bacteria was essential for disease reduction. This consortium, but not individual members of the root-associated bacteria community which this plant normally recruits during germination from native seed banks, provides enduring resistance against fungal diseases, demonstrating that native plants develop opportunistic mutualisms with prokaryotes that solve context-dependent ecological problems. PMID:26305938
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NASA Astrophysics Data System (ADS)
ZM, Sara Zafaranchi; Khoshaman, Kazem; Masoudi, Raheleh; Hemmateenejad, Bahram; Yousefi, Reza
2017-01-01
The imbalance of the calcium homeostasis in the lenticular tissues of diabetic patients is an important risk factor for development of cataract diseases. In the current study, the impact of elevated levels of calcium ions were investigated on structure and aggregation propensity of glycated lens crystallins using gel electrophoresis and spectroscopic assessments. The glycated proteins indicated significant resistance against calcium-induced structural insults and aggregation. While, glycated crystallins revealed an increased conformational stability; a slight instability was observed for these proteins upon interaction with calcium ions. Also, in the presence of calcium, the proteolytic pattern of native crystallins was altered and that of glycated protein counterparts remained almost unchanged. According to results of this study it is suggested that the structural alteration of lens crystallins upon glycation may significantly reduce their calcium buffering capacity in eye lenses. Therefore, under chronic hyperglycemia accumulation of this cataractogenic metal ion in the lenticular tissues may subsequently culminate in activation of different pathogenic pathways, leading to development of lens opacity and cataract diseases.
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DASH (Dietary Approaches to Stop Hypertension) Diet and Risk of Subsequent Kidney Disease.
Rebholz, Casey M; Crews, Deidra C; Grams, Morgan E; Steffen, Lyn M; Levey, Andrew S; Miller, Edgar R; Appel, Lawrence J; Coresh, Josef
2016-12-01
There are established guidelines for recommended dietary intake for hypertension treatment and cardiovascular disease prevention. Evidence is lacking for effective dietary patterns for kidney disease prevention. Prospective cohort study. Atherosclerosis Risk in Communities (ARIC) Study participants with baseline estimated glomerular filtration rate (eGFR) ≥ 60mL/min/1.73m 2 (N=14,882). The Dietary Approaches to Stop Hypertension (DASH) diet score was calculated based on self-reported dietary intake of red and processed meat, sweetened beverages, sodium, fruits, vegetables, whole grains, nuts and legumes, and low-fat dairy products, averaged over 2 visits. Cases were ascertained based on the development of eGFRs<60mL/min/1.73m 2 accompanied by ≥25% eGFR decline from baseline, an International Classification of Diseases, Ninth/Tenth Revision code for a kidney disease-related hospitalization or death, or end-stage renal disease from baseline through 2012. 3,720 participants developed kidney disease during a median follow-up of 23 years. Participants with a DASH diet score in the lowest tertile were 16% more likely to develop kidney disease than those with the highest score tertile (HR, 1.16; 95% CI, 1.07-1.26; P for trend < 0.001), after adjusting for sociodemographics, smoking status, physical activity, total caloric intake, baseline eGFR, overweight/obese status, diabetes status, hypertension status, systolic blood pressure, and antihypertensive medication use. Of the individual components of the DASH diet score, high red and processed meat intake was adversely associated with kidney disease and high nuts, legumes, and low-fat dairy products intake was associated with reduced risk for kidney disease. Potential measurement error due to self-reported dietary intake and lack of data for albuminuria. Consuming a DASH-style diet was associated with lower risk for kidney disease independent of demographic characteristics, established kidney risk factors, and baseline kidney function. Healthful dietary patterns such as the DASH diet may be beneficial for kidney disease prevention. Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
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What is the probability of successive cases of Legionnaires' disease occurring in European hotels?
Ricketts, K D; Slaymaker, E; Verlander, N Q; Joseph, C A
2006-04-01
Public health officials will normally take action at accommodation sites following an association with a cluster of cases of Legionnaires' disease. This paper seeks to determine the likelihood of such a cluster occurring at a site once it has been associated with a single case of the disease, and therefore whether more should be done at sites following individual cases. Information for UK residents reported to the EWGLINET system between 1993 and 2000 was included in a dataset. The size and country of hotel visited by the cases were divided into six country groups (France, Italy, Spain, Turkey, other Europe and other World), and eight size groups (<20 rooms, 20-49, 50-99, 100-199, 200-299, 300-399, 400-499, 500+). The data were investigated using Cox proportional hazards regression to model the probability of at least one further case following the first. The dataset comprised 793 cases that had stayed at 605 sites in 51 countries between 1993 and the end of 2000. This included 605 cases that were the first case associated with a site, and 188 subsequent cases. Following the first case, 16.6% of sites were associated with at least one subsequent case during the period under study. The probability of a subsequent case occurring within 6 months of the first varied by country and size group, with some combinations returning a probability >30%; the probability of a subsequent case occurring within 2 years of the first reached over 50% in some instances. There may be support for early intervention at some accommodation sites following a first case of Legionnaires' disease, in specific country and size groups.
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Ismail, Intan H; Boyle, Robert J; Licciardi, Paul V; Oppedisano, Frances; Lahtinen, Sampo; Robins-Browne, Roy M; Tang, Mimi L K
2016-12-01
An altered compositional signature and reduced diversity of early gut microbiota are linked to development of allergic disease. We investigated the relationship between dominant Bifidobacterium species during the early post-natal period and subsequent development of allergic disease in the first year of life. Faecal samples were collected at age 1 week, 1 month and 3 months from 117 infants at high risk of allergic disease. Bifidobacterium species were analysed by quantitative PCR and terminal restriction fragment length polymorphism. Infants were examined at 3, 6 and 12 months, and skin prick test was performed at 12 months. Eczema was diagnosed according to the UK Working Party criteria. The presence of B. catenulatum at 3 months was associated with a higher risk of developing eczema (OR adj = 4.5; 95% CI: 1.56-13.05, p adj = 0.005). Infants colonized with B. breve at 1 week (OR adj = 0.29; 95% CI: 0.09-0.95, p adj = 0.04) and 3 months (OR adj = 0.15; 95% CI: 0.05-0.44, p adj = 0.00001) had a reduced risk of developing eczema. Furthermore, the presence of B. breve at 3 months was associated with a lower risk of atopic sensitization at 12 months (OR adj = 0.38; 95% CI: 0.15-0.98, p adj = 0.05). B. breve colonization patterns were influenced by maternal allergic status, household pets and number of siblings. Temporal variations in Bifidobacterium colonization patterns early in life are associated with later development of eczema and/or atopic sensitization in infants at high risk of allergic disease. Modulation of the early microbiota may provide a means to prevent eczema in high-risk infants. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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USDA-ARS?s Scientific Manuscript database
Foot-and-mouth disease (FMD) is a highly contagious and economically important, transboundary viral disease of cloven-hoofed animals. It is known that a chronic, asymptomatic FMD syndrome may occur subsequent to acute FMD in adult ruminants. However, neither asymptomatic nor persistent infection has...
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USDA-ARS?s Scientific Manuscript database
Wheat blast is a devastating disease that was first identified in Brazil and has subsequently spread to surrounding countries in South America. In May 2011, disease scouting in a University of Kentucky wheat trial plot in Princeton, Kentucky identified a single plant with disease symptoms that diffe...
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Randall S. Morin; Andrew M. Liebhold; Patrick C. Tobin; Kurt W. Gottschalk; Eugene Luzader
2007-01-01
Beech bark disease (BBD) is an insect-fungus complex involving the beech scale insect (Cryptococcus fagisuga Lind.) and one of two canker fungi. Beech scale was introduced to Halifax, Nova Scotia around 1890, presumably with the fungus Neonectria coccinea var. faginata Lohm. The disease has subsequently spread...
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The Association Between Urine Output, Creatinine Elevation, and Death.
Engoren, Milo; Maile, Michael D; Heung, Michael; Jewell, Elizabeth S; Vahabzadeh, Christie; Haft, Jonathan W; Kheterpal, Sachin
2017-04-01
Acute kidney injury can be defined by a fall in urine output, and urine output criteria may be more sensitive in identifying acute kidney injury than traditional serum creatinine criteria. However, as pointed out in the Kidney Disease Improving Global Outcome guidelines, the association of urine output with subsequent creatinine elevations and death is poorly characterized. The purpose of this study was to determine what degrees of reduced urine output are associated with subsequent creatinine elevation and death. This was a retrospective cohort study of adult patients (age ≥18 years) cared for in a cardiovascular intensive care unit after undergoing cardiac operations in a tertiary care university medical center. All adult patients who underwent cardiac operations and were not receiving dialysis preoperatively were studied. The development of acute kidney injury was defined as an increase in creatinine of more than 0.3 mg/dL or by more than 50% above baseline by postoperative day 3. Acute kidney injury developed in 1,061 of 4,195 patients (25%). Urine output had moderate discrimination in predicting subsequent acute kidney injury (C statistic = .637 ± .054). Lower urine output and longer duration of low urine output were associated with greater odds of developing acute kidney injury and death. We found that there is similar accuracy in using urine output corrected for actual, ideal, or adjusted weight to discriminate future acute kidney injury by creatinine elevation and recommend using actual weight for its simplicity. We also found that low urine output is associated with subsequent acute kidney injury and that the association is greater for lower urine output and for low urine output of longer durations. Low urine output (<0.2 mL · kg -1 · h -1 ), even in the absence of acute kidney injury by creatinine elevation, is independently associated with mortality. Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.
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In vivo T cell depletion regulates resistance and morbidity in murine schistosomiasis
DOE Office of Scientific and Technical Information (OSTI.GOV)
Phillips, S.M.; Linette, G.P.; Doughty, B.L.
1987-08-01
These studies assessed the roles of subpopulations of T lymphocytes in inducing and modulating resistance to schistosomiasis and thereby influencing subsequent morbidity. C57BL/6 mice were depleted in vivo of Lyt-1+, Lyt-2+, and L3T4+ cells by the daily administration of monoclonal antibodies. The development of protective immunity, induced by exposure to irradiated Schistosoma mansoni cercariae as expressed in depleted animals, was compared to that demonstrated in undepleted, normal, and congenitally athymic C57BL/6 mice. The development of morbidity was determined by spleen weight, portal pressure and reticuloendothelial system activity. The results indicated that depletion of specific subpopulations of T lymphocytes minimally affectedmore » the primary development of parasites; however, depletion strongly influenced the development of resistance to the parasite and subsequent morbidity due to infection. Depletion of T lymphocytes by anti-Lyt-1+ or anti-L3T4+ antibody decreased the development of resistance, antibody and delayed-type hypersensitivity directed against schistosome antigens. Morbidity due to disease was increased. Depletion of Lyt-2+ cells produced opposite changes with augmented resistance and reduced morbidity. Congenitally athymic mice developed minimal resistance and morbidity. Moreover, resistance was inversely related to the morbidity shown by a given animal. These studies indicate that the development of protective immunity to S. mansoni cercariae is regulated by discrete subpopulations of T lymphocytes. The feasibility of decreasing morbidity by increasing specific immunologically mediated resistance is suggested.« less
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Böni, Christian; Al-Sheikh, Mayss; Hasse, Barbara; Eberhard, Roman; Kohler, Philipp; Hasler, Pascal; Erb, Stefan; Hoffmann, Matthias; Barthelmes, Daniel; Zweifel, Sandrine A
2017-12-04
To explore morphologic characteristics of choroidal lesions in patients with disseminated Mycobacterium chimaera infection subsequent to open-heart surgery. Nine patients (18 eyes) with systemic M. chimaera infection were reviewed. Activity of choroidal lesions were evaluated using biomicroscopy, fundus autofluorescence, enhanced depth imaging optical coherence tomography, fluorescein angiography/indocyanine green angiography, and optical coherence tomography angiography. Relationships of choroidal findings to systemic disease activity were sought. All 9 male patients, aged between 49 and 66 years, were diagnosed with endocarditis and/or aortic graft infection. Mean follow-up was 17.6 months. Four patients had only inactive lesions (mild disease). In all five patients (10 eyes) with progressive ocular disease, indocyanine green angiography was superior to other tests for revealing new lesions and active lesions correlated with hyporeflective choroidal areas on enhanced depth imaging optical coherence tomography. One eye with a large choroidal granuloma developed choroidal neovascularization. Optical coherence tomography angiography showed areas with reduced perfusion at the inner choroid. All 5 patients with progressive ocular disease had evidence of systemic disease activity within ±6 weeks' duration. Choroidal manifestation of disseminated M. chimaera infection indicates systemic disease activity. Multimodal imaging is suitable to recognize progressive ocular disease. We propose ophthalmologic screening examinations for patients with M. chimaera infection.
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Why miltefosine-a life-saving drug for leishmaniasis-is unavailable to people who need it the most.
Sunyoto, Temmy; Potet, Julien; Boelaert, Marleen
2018-01-01
Miltefosine, the only oral drug approved for the treatment of leishmaniasis-a parasitic disease transmitted by sandflies-is considered as a success story of research and development (R&D) by a public-private partnership (PPP). It epitomises the multiple market failures faced by a neglected disease drug: patients with low ability to pay, neglect by authorities and uncertain market size. Originally developed as an anticancer agent in the 1990s, the drug was registered in India in 2002 to treat the fatal visceral leishmaniasis. At the time, miltefosine was considered a breakthrough in the treatment, making it feasible to eliminate a regional disease. Today, access to miltefosine remains far from secure. The initial PPP agreement which includes access to the public sector is not enforced. The reality on the ground has been challenging: shortages due to inefficient supply chains, and use of a substandard product which led to a high number of treatment failures and deaths. Miltefosine received orphan drug status in the USA; when it was registered there in 2014, a priority review voucher (PRV) was awarded. The PRV, meant to facilitate drug development for neglected disease, was subsequently sold to another company for US$125 million without, to date, any apparent impact on drug access. At the heart of these concerns are questions on how to protect societal benefit of a drug developed with public investment, while clinicians worldwide struggle with its lack of affordability, limited availability and sustainability of access. This article analyses the reasons behind the postregistration access failure of miltefosine and provides the lessons learnt.
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Midkine and multiple sclerosis.
Takeuchi, Hideyuki
2014-02-01
Multiple sclerosis (MS) is an autoimmune neurological disease characterized by inflammatory demyelination with subsequent neuronal damage in the CNS. MS and its animal model, experimental autoimmune encephalomyelitis (EAE), have been thought as autoreactive Th1 and Th17 cell-mediated diseases. CD4(+) CD25(+) FoxP3(+) regulatory T-cell (Treg) plays a pivotal role in autoimmune tolerance, and tolerogenic dendritic cells (DCreg) drive the development of inducible Treg cells. Thus, a dysfunction in the development of Treg and DCreg leads to the development of autoimmune diseases. However, the factors that regulate Treg and DCreg are largely unknown. We recently showed that removal of midkine (MK) suppressed EAE due to an expansion of the Treg cell population as well as a decrease in the numbers of autoreactive Th1 and Th17 cells. MK decreased the Treg cell population by suppressing the phosphorylation of STAT5, which is essential for the expression of Foxp3, the master transcriptional factor of Treg cell differentiation. Furthermore, MK reduces the DCreg cell population by inhibiting the phosphorylation of STAT3, which is critical for DCreg development. Blockade of MK signalling by a specific RNA aptamer significantly elevated the population of DCreg and Treg cells and ameliorated EAE without detectable adverse effects. Therefore, the inhibition of MK may provide an effective therapeutic strategy against autoimmune diseases including MS. This article is part of a themed section on Midkine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-4. © 2013 The British Pharmacological Society.
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Foster, C A; Dreyfuss, M; Mandak, B; Meingassner, J G; Naegeli, H U; Nussbaumer, A; Oberer, L; Scheel, G; Swoboda, E M
1994-11-01
Skin diseases with an inflammatory component, regardless of their etiology, are characterized at some point by the extravasation and subsequent infiltration of leukocytes into the dermal and/or epidermal compartments. This trafficking pattern is determined by a complex series of events whereby the leukocytes interact with cell adhesion molecules (CAM), particularly those induced on endothelial cells following activation with various inflammatory mediators. Vascular CAMs belonging to the selectin family (i.e., P-selectin and E-selectin) are thought to mediate early and reversible events involving leukocyte rolling and margination along the lumenal surface of microvascular cells (post-capillary venules). Certain members of the immunoglobulin supergene family (i.e., VCAM-1 and ICAM-1) regulate later and irreversible steps which lead to firm attachment and subsequent diapedesis of leukocytes. Accumulating evidence suggests that if one blocks the ligand-binding sites between leukocytes and endothelial cells, or inhibits vascular CAM expression, hematopoietic cell extravasation and progressive inflammatory events can be greatly diminished. To identify such inhibitors we developed a cell-based Elisa using the human microvascular cell line HMEC-1. As reported in the present paper, this approach yielded a naturally-occurring, low molecular weight compound which potently inhibits cytokine-induced adhesion molecule expression on cultured endothelial cells, without modulating "house-keeping" proteins.
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Apatinib for the treatment of pulmonary epithelioid hemangioendothelioma
Zheng, Zhipeng; Wang, Hanying; Jiang, Hanliang; Chen, Enguo; Zhang, Jun; Xie, Xinyou
2017-01-01
Abstract Rationale: Pulmonary epithelioid hemangioendothelioma (P-EHE) is a rare tumor, with no established standard treatment. Overexpression of vascular endothelial growth factor receptor 2 (VEGFR-2) has been reported in some P-EHE patients. Apatinib, a new small molecule tyrosine kinase inhibitor that specifically targets VEGFR-2, has therapeutic benefits in some advanced tumors. However, its efficacy in P-EHE cases has not been reported. Patient concerns: Herein, we presented a 44-year-old man with recurrent hemoptysis for approximately 9 years. Diagnoses: After hospitalization, relevant examinations were conducted. The disease was subsequently diagnosed as P-EHE. Interventions: The patient underwent pulmonary lobectomy, but subsequently developed multiple metastases. Within the tumor, CD31, CK, and Vimentin were found to be positive, while CD34 was negative. Apatinib was initially administered 250 mg daily doses and after 1 month was increased to 500 mg daily. Outcomes: He showed noticeable symptomatic improvements and positive imaging changes in the first month of treatment. However, the disease progressed in the following month, despite the increased apatinib dose. Lessons: Apatinib is possibly a new treatment for P-EHE. However, further clinical trials are necessary to confirm an effective dose and the efficacy and safety of apatinib in P-EHE treatment. PMID:29137048
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[Monkey-pox, a model of emergent then reemergent disease].
Georges, A J; Matton, T; Courbot-Georges, M C
2004-01-01
The recent emergence of monkey pox in the United States of America highlights the problem (known for other infectious agents) of dissemination of pathogens outside their endemic area, and of subsequent global threats of variable gravity according to agents. It is a real emergency since monkey pox had been confined to Africa for several decades, where small epidemics occurred from time to time, monkey pox is a "miniature smallpox" which, in Africa, evolves on an endemic (zoonotic) mode with, as reservoirs, several species of wild rodents (mainly squirrels) and some monkey species. It can be accidentally transmitted to man then develops as epidemics, sometimes leading to death. The virus was imported in 2003 in the United States of America, via Gambia rats and wild squirrels (all African species), and infected prairie dogs (which are now in fashion as pets), then crossed the species barrier to man. In the United States of America, screening campaigns, epidemiological investigations, and subsequent treatments led to a rapid control of the epidemic, which is a model of emergent disease for this country. Therapeutic and preventive measures directly applicable to monkey pox are discussed. They can also be applied against other pox virus infections (including smallpox). The risk of criminal introduction of pox viruses is discussed since it is, more than ever, a real worldwide threat.
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Shen, Cheng-Che; Yang, Albert C; Hung, Jeng-Hsiu; Hu, Li-Yu; Chiang, Yung-Yen; Tsai, Shih-Jen
2016-01-01
Pelvic inflammatory disease (PID) a common infection in women that is associated with significant morbidity and is a major cause of infertility. A clear temporal causal relationship between PID and psychiatric disorders has not been well established. We used a nationwide population-based retrospective cohort study to explore the relationship between PID and the subsequent development of psychiatric disorders. We identified subjects who were newly diagnosed with PID between 1 January 2000 and 31 December 2002 in the Taiwan National Health Insurance Research Database. A comparison cohort was constructed for patients without PID. A total of 21 930 PID and 21 930 matched control patients were observed until diagnosed with psychiatric disorders, or until death, withdrawal from the NHI system, or until 31 December 2009. Adjusted hazard ratio (HR) of bipolar disorder, depressive disorder, anxiety disorder and sleep disorder in subjects with PID were significantly higher (HR: 2.671, 2.173, 2.006 and 2.251, respectively) than that of the controls during the follow-up. PID may increase the risk of subsequent newly diagnosed bipolar disorder, depressive disorder, anxiety disorder and sleep disorder, which will impair life quality. Our findings highlight that clinicians should pay particular attention to psychiatric comorbidities in PID patients.
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Wegner, Rhiana; Gong, Jie; Fang, Xiaoyi; Kaljee, Linda
2014-01-01
Individuals with greater social capital have better health outcomes. Investment in social capital likely increases one’s own social capital, bearing great implications for disease prevention and health promotion. In this study, the authors developed and validated the Social Capital Investment Inventory (SCII). Direct effects of social capital investment on perceived stress, and indirect effects through social capital were examined. 397 Participants from Beijing and Wuhan, China completed surveys. Analyses demonstrated that the SCII has a single factor structure and strong internal consistency. Structural equation modeling showed that individuals who invested more in social capital had greater bonding social capital, and subsequently less perceived stress. Results suggest that disease prevention and health promotion programs should consider approaches to encourage social capital investment; individuals may be able to reduce stress by increasing their investment in social capital. Future research is needed to provide additional empirical support for the SCII and observed structural relationships. PMID:25648725
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Barron, Henry; Hafizi, Sina; Mizrahi, Romina
2017-01-01
Psychotic disorders are heterogeneous and complex, involving many putative causal factors interacting along the course of disease development. Many of the factors implicated in the pathogenesis of psychosis also appear to be involved in disease onset and subsequent neuroprogression. Herein, we highlight the pertinent literature implicating inflammation and oxidative stress in the pathogenesis of psychosis, and the potential contribution of N-methyl-D-aspartate receptors (NMDARs). We also emphasize the role of peripubertal social stress in psychosis, and the ways in which hippocampal dysfunction can mediate dysregulation of the hypothalamic-pituitary-adrenal axis and cortisol release. Finally, we propose a model wherein inflammation and oxidative stress act as a first hit, producing altered parvalbumin interneuron development, NMDAR hypofunction, microglial priming, and sensitivity to a second hit of peripubertal social stress. With a greater understanding of how these factors interact, it may be possible to detect, prevent, and treat psychosis more effectively. © 2017 S. Karger AG, Basel.
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Guidelines for Mass Screening of Congenital Hypothyroidism (2014 revision)
Nagasaki, Keisuke; Minamitani, Kanshi; Anzo, Makoto; Adachi, Masanori; Ishii, Tomohiro; Onigata, Kazumichi; Kusuda, Satoshi; Harada, Shohei; Horikawa, Reiko; Minagawa, Masanori; Mizuno, Haruo; Yamakami, Yuji; Fukushi, Masaru; Tajima, Toshihiro
2015-01-01
Purpose of developing the guidelines: Mass screening for congenital hypothyroidism started in 1979 in Japan, and the prognosis for intelligence has been improved by early diagnosis and treatment. The incidence was about 1/4000 of the birth population, but it has increased due to diagnosis of subclinical congenital hypothyroidism. The disease requires continuous treatment, and specialized medical facilities should make a differential diagnosis and treat subjects who are positive in mass screening to avoid unnecessary treatment. The Guidelines for Mass Screening of Congenital Hypothyroidism (1998 version) were developed by the Mass Screening Committee of the Japanese Society for Pediatric Endocrinology in 1998. Subsequently, new findings on prognosis and problems in the adult phase have emerged. Based on these new findings, the 1998 guidelines were revised in the current document (hereinafter referred to as the Guidelines). Target disease/conditions: Primary congenital hypothyroidism. Users of the Guidelines: Physician specialists in pediatric endocrinology, pediatric specialists, physicians referring patients to pediatric practitioners, general physicians, laboratory technicians in charge of mass screening, and patients. PMID:26594093
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Hellström, Ann; Smith, Lois E H; Dammann, Olaf
2015-01-01
The immature retinas of preterm neonates are susceptible to insults that disrupt neurovascular growth, leading to retinopathy of prematurity. Suppression of growth factors due to hyperoxia and loss of the maternal–fetal interaction result in an arrest of retinal vascularisation (phase 1). Subsequently, the increasingly metabolically active, yet poorly vascularised, retina becomes hypoxic, stimulating growth factor-induced vasoproliferation (phase 2), which can cause retinal detachment. In very premature infants, controlled oxygen administration reduces but does not eliminate retinopathy of prematurity. Identification and control of factors that contribute to development of retinopathy of prematurity is essential to prevent progression to severe sight-threatening disease and to limit comorbidities with which the disease shares modifiable risk factors. Strategies to prevent retinopathy of prematurity will depend on optimisation of oxygen saturation, nutrition, and normalisation of concentrations of essential factors such as insulin-like growth factor 1 and ω-3 polyunsaturated fatty acids, as well as curbing of the effects of infection and inflammation to promote normal growth and limit suppression of neurovascular development. PMID:23782686
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Hajishengallis, George; Hajishengallis, Evlambia; Kajikawa, Tetsuhiro; Wang, Baomei; Yancopoulou, Despina; Ricklin, Daniel; Lambris, John D
2016-06-01
Periodontitis is a dysbiotic inflammatory disease leading to the destruction of the tooth-supporting tissues. Current therapies are not always effective and this prevalent oral disease continues to be a significant health and economic burden. Early clinical studies have associated periodontitis with elevated complement activity. Consistently, subsequent genetic and pharmacological studies in rodents have implicated the central complement component C3 and downstream signaling pathways in periodontal host-microbe interactions that promote dysbiosis and inflammatory bone loss. This review discusses these mechanistic advances and moreover focuses on the compstatin family of C3 inhibitors as a novel approach to treat periodontitis. In this regard, local application of the current lead analog Cp40 was recently shown to block both inducible and naturally occurring periodontitis in non-human primates. These promising results from non-human primate studies and the parallel development of Cp40 for clinical use highlight the feasibility for developing an adjunctive, C3-targeted therapy for human periodontitis. Copyright © 2016 Elsevier Ltd. All rights reserved.
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Rao, Krishna; Higgins, Peter D. R.
2016-01-01
Clostridium difficile infection (CDI) is a major source of morbidity and mortality for the US healthcare system, and frequently complicates the course of inflammatory bowel disease (IBD). Patients with IBD are more likely to be colonized with C. difficile and develop active infection than the general population. They are also more likely to have severe CDI and develop subsequent complications such as IBD flare, colectomy, or death. Even after successful initial treatment and recovery, recurrent CDI is common. Management of CDI in IBD is fraught with diagnostic and therapeutic challenges, since the clinical presentations of CDI and IBD flare have considerable overlap. Fecal microbiota transplantation can be successful in curing recurrent CDI when other treatments have failed, but may also trigger IBD flare and this warrants caution. New, experimental treatments including vaccines, monoclonal antibodies, and non-toxigenic strains of C. difficile offer promise but are not yet available for clinicians. A better understanding of the complex relationship between the gut microbiota, CDI, and IBD is needed. PMID:27120571
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One-Year Duration of Immunity Induced by Vaccination with a Canine Lyme Disease Bacterin▿
LaFleur, Rhonda L.; Callister, Steven M.; Dant, Jennifer C.; Jobe, Dean A.; Lovrich, Steven D.; Warner, Thomas F.; Wasmoen, Terri L.; Schell, Ronald F.
2010-01-01
Laboratory-reared beagles were vaccinated with a placebo or a bacterin comprised of Borrelia burgdorferi S-1-10 and ospA-negative/ospB-negative B. burgdorferi 50772 and challenged after 1 year with B. burgdorferi-infected Ixodes scapularis ticks. For the placebo recipients, spirochetes were recovered from 9 (60%) skin biopsy specimens collected after 1 month, and the organisms persisted in the skin thereafter. Ten (67%) dogs also developed joint infection (3 dogs), lameness or synovitis (7 dogs), or B. burgdorferi-specific antibodies (8 dogs). For the vaccine recipients, spirochetes were recovered from 6 (40%) skin biopsy specimens collected after 1 month. However, subsequent biopsy specimens were negative, and the dogs failed to develop joint infection (P = 0.224), lameness/synovitis (P = 0.006), or Lyme disease-specific antibody responses (P = 0.002). The bacterin provided a high level of protection for 1 year after immunization, and the addition of the OspC-producing B. burgdorferi 50772 provided enhanced protection. PMID:20237200
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2010-01-01
Background Idiopathic portal hypertension (IPH) is a disorder of unknown etiology and is characterized clinically by portal hypertension, splenomegaly, and hypersplenism accompanied by pancytopenia. This study evaluates the pathogenic concept of the disease by a systematic review of the literature and illustrates novel pathologic and laboratory findings. Case Presentation We report the first case of uncontrolled splenic hyperperfusion and enlargement with subsequent hypersplenism leading to life-threatening complications of IPH in infancy and emergent splenectomy. Conclusions Our results suggest that splenic NO and VCAM-1, rather than ET-1, have a significant impact on the development of IPH, even at a very early stage of disease. The success of surgical interventions targeting the splenic hyperperfusion suggests that the primary defect in the regulation of splenic blood flow seems to be crucial for the development of IPH. Thus, beside other treatment options splenectomy needs to be considered as a prime therapeutic option for IPH. PMID:20961440
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Genital warts in children: what do they mean?
Jayasinghe, Y; Garland, S M
2006-01-01
Human papillomaviruses (HPVs) are a diverse family of viruses, of which 30–40 genotypes specifically infect the genital tract. Genital HPVs are largely transmitted sexually, with most infections being asymptomatic and transient. In contrast, persistent infection with oncogenic genotypes in a minority is a strong risk factor, for subsequent development of high grade dysplasia, the precursor lesion to cervical neoplasia, which generally occurs after a long latency period. It is unknown whether there is a disease correlate in children chronically infected with oncogenic HPVs. Low risk HPV genotypes 6 and 11 are the primary cause of condylomata acuminata, although in children non‐genital genotypes are also found in a proportion, with the mode of transmission being either perinatal, horizontal, or sexual. The finding of asymptomatic HPV DNA in children, and correlation with live virus, infectivity, or disease is unclear. Long term follow up for children with anogenital warts is recommended, although there are no longitudinal studies available to clarify whether they are at risk of developing carcinoma in young adulthood. PMID:16670117
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[The pathogenetic substantiation of the periods of traumatic brain disease].
Romodanov, A P; Kop'ev, O V; Pedachenko, E G; Parkhomets, V P; Vasil'eva, I G
1990-01-01
Advances in the study of the molecular mechanisms of the pathogenesis of closed craniocerebral trauma (CCCT) which was conducted on an experimental model, a clinical equivalent of CCCT, allow one to form a new view of the course of traumatic disease and its division into periods. The data obtained provide evidence that increase of the pathological process in the posttraumatic period is of a skipping and cascade character. The existence of such breaks makes it possible to distinguish periods with consideration for the pathogenetic essence of the pathological changes. 1. The period of intensified metabolic processes, "conflagration of metabolism". 2. The period of development of energy deficit in the nerve tissue. 3. The period of development of cell intoxication processes and secondary structural changes. 4. The period of formation of posttraumatic homeostasis (a) in the regimen of stable homeostasis, (b) in the regimen of stress and subsequent exhaustion of the activity of adaptation systems with the formation of late-term progressive sequelae.
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Vickers, M. H.; Sloboda, D. M.
2012-01-01
Obesity and the metabolic syndrome have reached epidemic proportions worldwide with far-reaching health care and economic implications. The rapid increase in the prevalence of these disorders suggests that environmental and behavioral influences, rather than genetic causes, are fueling the epidemic. The developmental origins of health and disease hypothesis has highlighted the link between the periconceptual, fetal, and early infant phases of life and the subsequent development of metabolic disorders in later life. In particular, the impact of poor maternal nutrition on susceptibility to later life metabolic disease in offspring is now well documented. Several studies have now shown, at least in experimental animal models, that some components of the metabolic syndrome, induced as a consequence of developmental programming, are potentially reversible by nutritional or targeted therapeutic interventions during windows of developmental plasticity. This review will focus on critical windows of development and possible therapeutic avenues that may reduce metabolic and obesogenic risk following an adverse early life environment. PMID:22783205
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Fruitful research: drug target discovery for neurodegenerative diseases in Drosophila.
Konsolaki, Mary
2013-12-01
Although vertebrate model systems have obvious advantages in the study of human disease, invertebrate organisms have contributed enormously to this field as well. The conservation of genome structure and physiology among organisms poses unexpected peculiarities, and the redundancy in certain gene families or the presence of polymorphisms that can slightly alter gene expression can, in certain instances, bring invertebrate systems, such as Drosophila, closer to humans than mice and vice versa. This necessitates the analysis of disease pathways in multiple model organisms. The author highlights findings from Drosophila models of neurodegenerative diseases that have occurred in the past few years. She also highlights and discusses various molecular, genetic and genomic tools used in flies, as well as methods for generating disease models. Finally, the author describes Drosophila models of Alzheimer's, Parkinson's tri-nucleotide repeat diseases, and Fragile X syndrome and summarizes insights in disease mechanisms that have been discovered directly in fly models. Full genome genetic screens in Drosophila can lead to the rapid identification of drug target candidates that can be subsequently validated in a vertebrate system. In addition, the Drosophila models of neurodegeneration may often show disease phenotypes that are absent in equivalent mouse models. The author believes that the extensive contribution of Drosophila to both new disease drug target discovery, in addition to target validation, makes them indispensible to drug discovery and development.
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Bernstein, David I; Bravo, Fernando J; Pullum, Derek A; Shen, Hui; Wang, Mei; Rahman, Aquilur; Glazer, Robert I; Cardin, Rhonda D
2015-02-01
Current approved nucleoside therapies for genital herpes simplex virus (HSV) infections are effective but improved therapies are needed for treatment of both acute and recurrent diseases. The effects of N-methanocarbathymidine were evaluated and compared to acyclovir using guinea pig models of acute and recurrent infection. For acute disease following intravaginal inoculation of 10(6 )pfu HSV-2 (MS strain), animals were treated intraperitoneally beginning 24 h post-infection, and the effects on disease severity, vaginal virus replication, subsequent recurrences, and latent virus loads were evaluated. For evaluation of recurrent infection, animals were treated for 21 days beginning 14 days after infection and disease recurrence and recurrent shedding were evaluated. Treatment of the acute disease with N-methanocarbathymidine significantly reduced the severity of acute disease and decreased acute vaginal virus shedding more effectively than acyclovir. Significantly, none of the animals developed visible disease in the high-dose N-methanocarbathymidine group and this was the only group in which the number of days with recurrent virus shedding was reduced. Treatment of recurrent disease was equivalent to acyclovir when acyclovir was continuously supplied in the drinking water. N-methanocarbathymidine was effective as therapy for acute and recurrent genital HSV-2 disease in the guinea pig models. © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.
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Addison's Disease: A Diagnostic Dilemma.
Afroz, S; Bain, S
2017-07-01
Adrenal insufficiency is a rare disease, but is life threatening when overlooked. Addison's disease may be an acquired form of adrenal insufficiency due to the destruction or dysfunction of the adrenal cortex. It affects both glucocorticoid and mineralocorticoid function. Main presenting symptoms of Addison's disease such as fatigue, anorexia, vomiting and convulsion often mimics central nervous system (CNS) infections. We describe a case of Addison's disease who was initially misdiagnosed as a case of meningo-encephalitis subsequently renal tubular acidosis and finally Addison's disease. Addison's disease can remain unrecognized until acute crisis and sometimes it may be misdiagnosed.
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Green, Melissa J; Kariuki, Maina; Dean, Kimberlie; Laurens, Kristin R; Tzoumakis, Stacy; Harris, Felicity; Carr, Vaughan J
2017-12-26
Fetal exposure to infectious and noninfectious diseases may influence early childhood developmental functioning, on the path to later mental illness. Here, we investigated the effects of in utero exposure to maternal infection and noninfectious diseases during pregnancy on offspring developmental vulnerabilities at age 5 years, in the context of estimated effects for early childhood exposures to infectious and noninfectious diseases and maternal mental illness. We used population data for 66,045 children from an intergenerational record linkage study (the New South Wales Child Development Study), for whom a cross-sectional assessment of five developmental competencies (physical, social, emotional, cognitive, and communication) was obtained at school entry, using the Australian Early Development Census (AEDC). Child and maternal exposures to infectious or noninfectious diseases were determined from the NSW Ministry of Health Admitted Patients Data Collection (APDC) and maternal mental illness exposure was derived from both APDC and Mental Health Ambulatory Data collections. Multinomial logistic regression analyses were used to examine unadjusted and adjusted associations between these physical and mental health exposures and child developmental vulnerabilities at age 5 years. Among the physical disease exposures, maternal infectious diseases during pregnancy and early childhood infection conferred the largest associations with developmental vulnerabilities at age 5 years; maternal noninfectious illness during pregnancy also retained small but significant associations with developmental vulnerabilities even when adjusted for other physical and mental illness exposures and covariates known to be associated with early childhood development (e.g., child's sex, socioeconomic disadvantage, young maternal age, prenatal smoking). Among all exposures examined, maternal mental illness first diagnosed prior to childbirth conferred the greatest odds of developmental vulnerability at age 5 years. Prenatal exposure to infectious or noninfectious diseases appear to influence early childhood physical, social, emotional and cognitive developmental vulnerabilities that may represent intermediate phenotypes for subsequent mental disorders. © 2017 Association for Child and Adolescent Mental Health.
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Lambertus, Stanley; Bax, Nathalie M; Fakin, Ana; Groenewoud, Joannes M M; Klevering, B Jeroen; Moore, Anthony T; Michaelides, Michel; Webster, Andrew R; van der Wilt, Gert Jan; Hoyng, Carel B
2017-01-01
Each inherited retinal disorder is rare, but together, they affect millions of people worldwide. No treatment is currently available for these blinding diseases, but promising new options-including gene therapy-are emerging. Arguably, the most prevalent retinal dystrophy is Stargardt disease. In each case, the specific combination of ABCA4 variants (> 900 identified to date) and modifying factors is virtually unique. It accounts for the vast phenotypic heterogeneity including variable rates of functional and structural progression, thereby potentially limiting the ability of phase I/II clinical trials to assess efficacy of novel therapies with few patients. To accommodate this problem, we developed and validated a sensitive and reliable composite clinical trial endpoint for disease progression based on structural measurements of retinal degeneration. We used longitudinal data from early-onset Stargardt patients from the Netherlands (development cohort, n = 14) and the United Kingdom (external validation cohort, n = 18). The composite endpoint was derived from best-corrected visual acuity, fundus autofluorescence, and spectral-domain optical coherence tomography. Weighting optimization techniques excluded visual acuity from the composite endpoint. After optimization, the endpoint outperformed each univariable outcome, and showed an average progression of 0.41° retinal eccentricity per year (95% confidence interval, 0.30-0.52). Comparing with actual longitudinal values, the model accurately predicted progression (R2, 0.904). These properties were largely preserved in the validation cohort (0.43°/year [0.33-0.53]; prediction: R2, 0.872). We subsequently ran a two-year trial simulation with the composite endpoint, which detected a 25% decrease in disease progression with 80% statistical power using only 14 patients. These results suggest that a multimodal endpoint, reflecting structural macular changes, provides a sensitive measurement of disease progression in Stargardt disease. It can be very useful in the evaluation of novel therapeutic modalities in rare disorders.
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Bax, Nathalie M.; Fakin, Ana; Groenewoud, Joannes M. M.; Klevering, B. Jeroen; Moore, Anthony T.; Michaelides, Michel; Webster, Andrew R.; van der Wilt, Gert Jan; Hoyng, Carel B.
2017-01-01
Background Each inherited retinal disorder is rare, but together, they affect millions of people worldwide. No treatment is currently available for these blinding diseases, but promising new options—including gene therapy—are emerging. Arguably, the most prevalent retinal dystrophy is Stargardt disease. In each case, the specific combination of ABCA4 variants (> 900 identified to date) and modifying factors is virtually unique. It accounts for the vast phenotypic heterogeneity including variable rates of functional and structural progression, thereby potentially limiting the ability of phase I/II clinical trials to assess efficacy of novel therapies with few patients. To accommodate this problem, we developed and validated a sensitive and reliable composite clinical trial endpoint for disease progression based on structural measurements of retinal degeneration. Methods and findings We used longitudinal data from early-onset Stargardt patients from the Netherlands (development cohort, n = 14) and the United Kingdom (external validation cohort, n = 18). The composite endpoint was derived from best-corrected visual acuity, fundus autofluorescence, and spectral-domain optical coherence tomography. Weighting optimization techniques excluded visual acuity from the composite endpoint. After optimization, the endpoint outperformed each univariable outcome, and showed an average progression of 0.41° retinal eccentricity per year (95% confidence interval, 0.30–0.52). Comparing with actual longitudinal values, the model accurately predicted progression (R2, 0.904). These properties were largely preserved in the validation cohort (0.43°/year [0.33–0.53]; prediction: R2, 0.872). We subsequently ran a two-year trial simulation with the composite endpoint, which detected a 25% decrease in disease progression with 80% statistical power using only 14 patients. Conclusions These results suggest that a multimodal endpoint, reflecting structural macular changes, provides a sensitive measurement of disease progression in Stargardt disease. It can be very useful in the evaluation of novel therapeutic modalities in rare disorders. PMID:28355279
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Direskeneli, Haner; Aydin, Sibel Z; Kermani, Tanaz A; Matteson, Eric L; Boers, Maarten; Herlyn, Karen; Luqmani, Raashid A; Neogi, Tuhina; Seo, Philip; Suppiah, Ravi; Tomasson, Gunnar; Merkel, Peter A
2011-07-01
Giant cell (GCA) and Takayasu's arteritis (TAK) are 2 forms of large-vessel vasculitis (LVV) that involve the aorta and its major branches. GCA has a predilection for the cranial branches, while TAK tends to affect the extracranial branches. Both disorders may also cause nonspecific constitutional symptoms. Although some clinical features are more common in one or the other disorder and the ages of initial presentation differ substantially, there is enough clinical and histopathologic overlap between these disorders that some investigators suggest GCA and TAK may be 2 processes within the spectrum of a single disease. There have been few randomized therapeutic trials completed in GCA, and none in TAK. The lack of therapeutic trials in LVV is only partially explained by the rarity of these diseases. It is likely that the lack of well validated outcome measures for LVV and uncertainties regarding trial design contribute to the paucity of trials for these diseases. An initiative to develop a core set of outcome measures for use in clinical trials of LVV was launched by the international OMERACT Vasculitis Working Group in 2009 and subsequently endorsed by the OMERACT community at the OMERACT 10 meeting. Aims of this initiative include: (1) to review the literature and existing data related to outcome assessments in LVV; (2) to obtain the opinion of experts and patients on disease content; and (3) to formulate a research agenda to facilitate a more data-based approach to outcomes development.
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DIRESKENELI, HANER; AYDIN, SIBEL Z.; KERMANI, TANAZ A.; MATTESON, ERIC L.; BOERS, MAARTEN; HERLYN, KAREN; LUQMANI, RAASHID A.; NEOGI, TUHINA; SEO, PHILIP; SUPPIAH, RAVI; TOMASSON, GUNNAR; MERKEL, PETER A.
2013-01-01
Giant cell (GCA) and Takayasu’s arteritis (TAK) are 2 forms of large-vessel vasculitis (LVV) that involve the aorta and its major branches. GCA has a predilection for the cranial branches, while TAK tends to affect the extracranial branches. Both disorders may also cause nonspecific constitutional symptoms. Although some clinical features are more common in one or the other disorder and the ages of initial presentation differ substantially, there is enough clinical and histopathologic overlap between these disorders that some investigators suggest GCA and TAK may be 2 processes within the spectrum of a single disease. There have been few randomized therapeutic trials completed in GCA, and none in TAK. The lack of therapeutic trials in LVV is only partially explained by the rarity of these diseases. It is likely that the lack of well validated outcome measures for LVV and uncertainties regarding trial design contribute to the paucity of trials for these diseases. An initiative to develop a core set of outcome measures for use in clinical trials of LVV was launched by the international OMERACT Vasculitis Working Group in 2009 and subsequently endorsed by the OMERACT community at the OMERACT 10 meeting. Aims of this initiative include: (1) to review the literature and existing data related to outcome assessments in LVV; (2) to obtain the opinion of experts and patients on disease content; and (3) to formulate a research agenda to facilitate a more data-based approach to outcomes development. PMID:21724719
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Strategies in Ebola virus disease (EVD) diagnostics at the point of care
Coarsey, Chad T.; Esiobu, Nwadiuto; Narayanan, Ramswamy; Pavlovic, Mirjana; Shafiee, Hadi; Asghar, Waseem
2017-01-01
Ebola virus disease (EVD) is a devastating, highly infectious illness with a high mortality rate. The disease is endemic to regions of Central and West Africa, where there is limited laboratory infrastructure and trained staff. The recent 2014 West African EVD outbreak has been unprecedented in case numbers and fatalities, and has proven that such regional outbreaks can become a potential threat to global public health, as it became the source for the subsequent transmission events in Spain and the USA. The urgent need for rapid and affordable means of detecting Ebola is crucial to control the spread of EVD and prevent devastating fatalities. Current diagnostic techniques include molecular diagnostics and other serological and antigen detection assays; which can be time-consuming, laboratory-based, often require trained personnel and specialized equipment. In this review, we discuss the various Ebola detection techniques currently in use, and highlight the potential future directions pertinent to the development and adoption of novel point-of-care diagnostic tools. Finally, a case is made for the need to develop novel microfluidic technologies and versatile rapid detection platforms for early detection of EVD. PMID:28440096
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Sleep and metabolic control: waking to a problem?
Trenell, Michael I; Marshall, Nathaniel S; Rogers, Naomi L
2007-01-01
1. The aim of the present review is to outline: (i) the association between sleep and metabolism; (ii) how sleep duration influences the development of disease; and (iii) how sex differences, ageing and obesity may potentially influence the relationship between sleep, metabolic control and subsequent disease. 2. Sleep is associated with a number of endocrine changes, including a change in insulin action in healthy young individuals. Sleep duration shows a prospective U-shaped relationship with all-cause mortality, cardiovascular disease and Type 2 diabetes. 3. Chronic sleep restriction is becoming more common. Experimental sleep restriction impedes daytime glucose control and increases appetite. 4. The sex hormones oestrogen and testosterone influence sleep duration and quality and may account for sex differences in the prevalence of sleep-related disorders. 5. Ageing is associated with a decreased sleep duration, decreased muscle mass and impaired insulin action. 6. Obesity impairs insulin action and is associated with the incidence and severity of obstructive sleep apnoea. 7. Sleep plays an integral role in metabolic control. Consequently, insufficient sleep may represent a modifiable risk factor for the development of Type 2 diabetes. The challenge ahead is to identify how sex differences, ageing and obesity could potentially influence the relationship between sleep and metabolism.
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Mueller, Anne; O'Rourke, Jani; Grimm, Jan; Guillemin, Karen; Dixon, Michael F.; Lee, Adrian; Falkow, Stanley
2003-01-01
Long-term colonization of humans with Helicobacter pylori can cause the development of gastric B cell mucosa-associated lymphoid tissue lymphoma, yet little is known about the sequence of molecular steps that accompany disease progression. We used microarray analysis and laser microdissection to identify gene expression profiles characteristic and predictive of the various histopathological stages in a mouse model of the disease. The initial step in lymphoma development is marked by infiltration of reactive lymphocytes into the stomach and the launching of a mucosal immune response. Our analysis uncovered molecular markers of both of these processes, including genes coding for the immunoglobulins and the small proline-rich protein Sprr 2A. The subsequent step is characterized histologically by the antigen-driven proliferation and aggregation of B cells and the gradual appearance of lymphoepithelial lesions. In tissues of this stage, we observed increased expression of genes previously associated with malignancy, including the laminin receptor-1 and the multidrug-resistance channel MDR-1. Finally, we found that the transition to destructive lymphoepithelial lesions and malignant lymphoma is marked by an increase in transcription of a single gene encoding calgranulin A/Mrp-8. PMID:12552104
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Fetterman, Jessica L; Pompilius, Melissa; Westbrook, David G; Uyeminami, Dale; Brown, Jamelle; Pinkerton, Kent E; Ballinger, Scott W
2013-01-01
Cardiovascular disease is a major cause of morbidity and mortality in the United States. While many studies have focused upon the effects of adult second-hand smoke exposure on cardiovascular disease development, disease development occurs over decades and is likely influenced by childhood exposure. The impacts of in utero versus neonatal second-hand smoke exposure on adult atherosclerotic disease development are not known. The objective of the current study was to determine the effects of in utero versus neonatal exposure to a low dose (1 mg/m(3) total suspended particulate) of second-hand smoke on adult atherosclerotic lesion development using the apolipoprotein E null mouse model. Consequently, apolipoprotein E null mice were exposed to either filtered air or second-hand smoke: (i) in utero from gestation days 1-19, or (ii) from birth until 3 weeks of age (neonatal). Subsequently, all animals were exposed to filtered air and sacrificed at 12-14 weeks of age. Oil red-O staining of whole aortas, measures of mitochondrial damage, and oxidative stress were performed. Results show that both in utero and neonatal second-hand smoke exposure significantly increased adult atherogenesis in mice compared to filtered air controls. These changes were associated with changes in aconitase and mitochondrial superoxide dismutase activities consistent with increased oxidative stress in the aorta, changes in mitochondrial DNA copy number and deletion levels. These studies show that in utero or neonatal exposure to second-hand smoke significantly influences adult atherosclerotic lesion development and results in significant alterations to the mitochondrion and its genome that may contribute to atherogenesis.
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Fetterman, Jessica L.; Pompilius, Melissa; Westbrook, David G.; Uyeminami, Dale; Brown, Jamelle; Pinkerton, Kent E.; Ballinger, Scott W.
2013-01-01
Cardiovascular disease is a major cause of morbidity and mortality in the United States. While many studies have focused upon the effects of adult second-hand smoke exposure on cardiovascular disease development, disease development occurs over decades and is likely influenced by childhood exposure. The impacts of in utero versus neonatal second-hand smoke exposure on adult atherosclerotic disease development are not known. The objective of the current study was to determine the effects of in utero versus neonatal exposure to a low dose (1 mg/m3 total suspended particulate) of second-hand smoke on adult atherosclerotic lesion development using the apolipoprotein E null mouse model. Consequently, apolipoprotein E null mice were exposed to either filtered air or second-hand smoke: (i) in utero from gestation days 1–19, or (ii) from birth until 3 weeks of age (neonatal). Subsequently, all animals were exposed to filtered air and sacrificed at 12–14 weeks of age. Oil red-O staining of whole aortas, measures of mitochondrial damage, and oxidative stress were performed. Results show that both in utero and neonatal second-hand smoke exposure significantly increased adult atherogenesis in mice compared to filtered air controls. These changes were associated with changes in aconitase and mitochondrial superoxide dismutase activities consistent with increased oxidative stress in the aorta, changes in mitochondrial DNA copy number and deletion levels. These studies show that in utero or neonatal exposure to second-hand smoke significantly influences adult atherosclerotic lesion development and results in significant alterations to the mitochondrion and its genome that may contribute to atherogenesis. PMID:23825571
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Asher, Marc A; Lai, Sue-Min; Burton, Douglas C
2012-01-01
Retrospective study of a prospectively assembled cohort. To characterize the survival from subsequent spine surgery and the life survival of patients treated surgically for severe spinal deformity due to neuropathic diseases. Survivorship analysis is widely used to study the natural history of disease processes and of treatments provided, but has very seldom been used to study patients' course after surgery for spinal deformity associated with neuropathic diseases. Patients with neuropathic spinal deformity treated with primary posterior instrumentation and arthrodesis from 1989 through 2002 were identified and studied by review of charts and radiographs, and by mail survey. Subsequent spine surgery and death events, and the time interval from surgery were identified. Fifteen variables possibly influencing survivorship were studied. There were no perioperative deaths, spinal cord injuries, or acute wound infections in the 117 eligible patients. Reoperation and life survival statuses were available for 110 patients (94%) at an average follow-up of 11.89 years (±5.3; range: 2-20.9 yr). Twelve patients (11%) had subsequent spine surgery. Survival from subsequent spine surgery was 91% at 5 years, 90% at 10 and 15 years, and 72% at 20 years. Proximal fixation problems occurred in 4 patients. Twenty-two patients (20%) had died from 4 to 20 years postoperative. Life survival was 98% at 5 years, 89% at 10 years, 81% at 15 years, and 56% at 20 years. The only variable associated with life survival was the occurrence of one or more perioperative complications, P = 0.0032. The younger half of the series at operation (<13.75 yr) was significantly more likely to have one or more perioperative complications, P = 0.0068. Spinal deformity type and magnitude were similar for the younger and older halves of the patients. Life survival of the patients with cerebral-palsy and not-cerebral-palsy upper motor neuron disease was not different. One-hundred-two of 105 were at least satisfied or would have the surgery again for the same condition. Survival from subsequent spine operation was similar to adolescent idiopathic scoliosis series studied in the same manner. Life survival decline began at 4 years postoperative and was significantly associated with the occurrence of one or more perioperative complications. Even after successful spine deformity surgery, this population's health status is often precarious.
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Skin Lesions Associated with Nutritional Management of Maple Syrup Urine Disease
Uaariyapanichkul, Jaraspong; Saengpanit, Puthita; Damrongphol, Ponghatai; Suphapeetiporn, Kanya
2017-01-01
Introduction Maple syrup urine disease (MSUD) is an inborn error of branched chain amino acids (BCAAs) metabolism. We report an infant with MSUD who developed 2 episodes of cutaneous lesions as a result of isoleucine deficiency and zinc deficiency, respectively. Case Presentation A 12-day-old male infant was presented with poor milk intake and lethargy. The diagnosis of MSUD was made based on clinical and biochemical data. Management and Outcome Specific dietary restriction of BCAAs was given. Subsequently, natural protein was stopped as the patient developed hospital-acquired infections which resulted in an elevation of BCAAs. Acrodermatitis dysmetabolica developed and was confirmed to be from isoleucine deficiency. At the age of 6 months, the patient developed severe lethargy and was on natural protein exclusion for an extended period. Despite enteral supplementation of zinc sulfate, cutaneous manifestations due to zinc deficiency occurred. Discussion Skin lesions in MSUD patients could arise from multiple causes. Nutritional deficiency including isoleucine and zinc deficiencies can occur and could complicate the treatment course as a result of malabsorption, even while on enteral supplementation. Parenteral nutrition should be considered and initiated accordingly. Clinical status, as well as BCAA levels, should be closely monitored in MSUD patients. PMID:29209542
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Air pollution in early life and adult mortality from chronic rheumatic heart disease.
Phillips, David I W; Osmond, Clive; Williams, Martin L; Jones, Alexander
2017-08-01
Chronic rheumatic heart disease (RHD) remains a globally important cause of heart disease. The reasons for the continuing high prevalence of this disease are obscure, but it may have its origins in the poor social and economic conditions with which the disease has been consistently and strongly linked. Mortality studies from the UK have suggested the importance of adverse environmental factors in early life; these studies demonstrated specific geographical associations between high rates of chest infection during infancy and subsequent RHD. They raised the possibility that early air pollution, which is known to be strongly linked with chest infection during infancy, may predispose to RHD. We related estimates of air pollution and social conditions developed by Daly in 1951-52 for 78 urban areas in England and Wales to their subsequent RHD mortality rates at ages 35-74 in men and women during 1993-2012. There were strong relationships between domestic air pollution and RHD [relative risk per standard deviation (SD) increase in pollution 1.168, 95% confidence interval (CI): 1.128 to 1.210, P < 0.001). Inclusion of published data on social class, education, crowding and population density in multiple regression analyses showed that the air pollution association was independent of these; only overcrowding was separately linked with RHD. We present the first evidence of an association between air pollution in early life and RHD. Although there are several limitations to this study, the strength and consistency of the results, together with their biological plausibility, suggest a causal link. This deserves attention because it may have important consequences for the control of RHD in resource-poor countries where widespread use of biomass fuels and domestic pollution remain a problem. © The Author 2016; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association
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Gaucher disease: clinical profile and therapeutic developments.
Cox, Timothy M
2010-12-06
Gaucher disease is a rare inborn error of glycosphingolipid metabolism due to deficiency of lysosomal acid β-glucocerebrosidase; the condition has totemic significance for the development of orphan drugs. A designer therapy, which harnesses the mannose receptor to complement the functional defect in macrophages, ameliorates the principal clinical manifestations in hematopoietic bone marrow and viscera. While several aspects of Gaucher disease (particularly those affecting the skeleton and brain) are refractory to treatment, enzyme (replacement) therapy has become a pharmaceutical blockbuster. Human β-glucocerebrosidase was originally obtained from placenta and the Genzyme Corporation (Allston, MA) subsequently developed a recombinant product. After purification, the enzyme is modified to reveal terminal mannose residues which facilitate selective uptake of the protein, imiglucerase (Cerezyme(®)), in macrophage-rich tissues. The unprecedented success of Cerezyme has attracted fierce competition: two biosimilar agents, velaglucerase-alfa, VPRIV(®) (Shire Human Genetic Therapies, Dublin, Ireland) and taliglucerase-alfa (Protalix, Carmiel, Israel), are now approved or in late-phase clinical development as potential 'niche busters'. Oral treatments have advantages over biological agents for disorders requiring lifelong therapy and additional stratagems which utilize small, orally active molecules have been introduced; these include two chemically distinct compounds which inhibit uridine diphosphate glucose: N-acylsphingosine glucosyltransferase, the first step in the biosynthesis of glucosylceramide - a key molecular target in Gaucher disease and other glycosphingolipidoses. Academic and commercial enterprises in biotechnology have combined strategically to expand the therapeutic repertoire in Gaucher disease. The innovative potential of orphan drug legislation has been realized - with prodigious rewards for companies embracing its humanitarian precepts. In the era before enzyme therapy, bone marrow transplantation was shown to correct systemic disease in Gaucher patients by supplying a source of competent donor macrophages. As a radical advance on cell- or protein-replacement techniques, contemporary methods for transferring genes to autologous hematopoietic stem cells, and to the brain, merit further exploration. At present, the inflated pharmaceutical niche of Gaucher disease appears to be resilient, but if the remaining unmet needs of patients are to be convincingly addressed and commercial development sustained, courageous scientific investment and clinical experimentation will be needed.
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Gaucher disease: clinical profile and therapeutic developments
Cox, Timothy M
2010-01-01
Gaucher disease is a rare inborn error of glycosphingolipid metabolism due to deficiency of lysosomal acid β-glucocerebrosidase; the condition has totemic significance for the development of orphan drugs. A designer therapy, which harnesses the mannose receptor to complement the functional defect in macrophages, ameliorates the principal clinical manifestations in hematopoietic bone marrow and viscera. While several aspects of Gaucher disease (particularly those affecting the skeleton and brain) are refractory to treatment, enzyme (replacement) therapy has become a pharmaceutical blockbuster. Human β-glucocerebrosidase was originally obtained from placenta and the Genzyme Corporation (Allston, MA) subsequently developed a recombinant product. After purification, the enzyme is modified to reveal terminal mannose residues which facilitate selective uptake of the protein, imiglucerase (Cerezyme®), in macrophage-rich tissues. The unprecedented success of Cerezyme has attracted fierce competition: two biosimilar agents, velaglucerase-alfa, VPRIV® (Shire Human Genetic Therapies, Dublin, Ireland) and taliglucerase-alfa (Protalix, Carmiel, Israel), are now approved or in late-phase clinical development as potential ‘niche busters’. Oral treatments have advantages over biological agents for disorders requiring lifelong therapy and additional stratagems which utilize small, orally active molecules have been introduced; these include two chemically distinct compounds which inhibit uridine diphosphate glucose: N-acylsphingosine glucosyltransferase, the first step in the biosynthesis of glucosylceramide – a key molecular target in Gaucher disease and other glycosphingolipidoses. Academic and commercial enterprises in biotechnology have combined strategically to expand the therapeutic repertoire in Gaucher disease. The innovative potential of orphan drug legislation has been realized – with prodigious rewards for companies embracing its humanitarian precepts. In the era before enzyme therapy, bone marrow transplantation was shown to correct systemic disease in Gaucher patients by supplying a source of competent donor macrophages. As a radical advance on cell- or protein-replacement techniques, contemporary methods for transferring genes to autologous hematopoietic stem cells, and to the brain, merit further exploration. At present, the inflated pharmaceutical niche of Gaucher disease appears to be resilient, but if the remaining unmet needs of patients are to be convincingly addressed and commercial development sustained, courageous scientific investment and clinical experimentation will be needed. PMID:21209725