tbuckley/cabot-search huggingface dataset:
Examining the Comorbidity Between Attention Deficit Hyperactivity Disorder and Bipolar I Disorder: A Meta-Analysis of Family Genetic Studies
Authors: Stephen V Faraone, Joseph Biederman, Janet Wozniak
Journal: American Journal of Psychiatry (2012)

Objective The existence of comorbidity between attention deficit hyperactivity disorder (ADHD) and bipolar I disorder has been documented in clinical and epidemiological studies, in studies of children and adults, and in diagnosed ADHD and bipolar I patient samples. Yet questions remain about the validity of diagnosing bipolar I disorder in ADHD youth. The authors aim to clarify these issues by reviewing family genetic studies of ADHD and bipolar I disorder. Method The authors applied random-effects meta-analysis to family genetic studies of ADHD and bipolar I disorder. Twenty bipolar proband studies provided 37 estimates of the prevalence of ADHD in 4,301 relatives of bipolar probands and 1,937 relatives of comparison probands. Seven ADHD proband studies provided 12 estimates of the prevalence of bipolar I disorder in 1,877 relatives of ADHD probands and 1,601 relatives of comparison probands. Results These studies found a significantly higher prevalence of ADHD among relatives of bipolar probands and a significantly higher prevalence of bipolar I disorder among relatives of ADHD probands. These results could not be accounted for by publication biases, unusual results from any one observation, sample characteristics, or study design features. The authors found no evidence of heterogeneity in the ADHD or bipolar family studies. Conclusions The results suggest that ADHD plus bipolar comorbidity cannot be accounted for by misdiagnoses, but additional research is needed to rule out artifactual sources of comorbidity. More research is also needed to determine whether comorbidity of ADHD and bipolar I disorder constitutes a familial subtype distinct from its constituent disorders, which if confirmed would have implications for diagnostic nosology and genetic studies.
Comment on Venskutonyte et al. Longitudinal Development of Left Ventricular Diastolic Dysfunction in Patients With Type 2 Diabetes. Diabetes Care 2014;37:3092–3097
Authors: Louise M. Burrell, Bryan Wai, Piyush M. Srivastava, Sheila K. Patel
Journal: Diabetes Care (2015)

We read with interest the results of the Diabetes Mellitus and Diastolic Dysfunction (DADD) Follow-Up (DADD-FU) study by Venskutonyte et al. (1), which concluded that the prevalence of left ventricular diastolic dysfunction (LVDD) was low and that LVDD improved or remained stable over a 6-year period. We suggest these results may not be generalizable to all patients with diabetes, particularly as those studied were free of clinically detectable cardiovascular disease and 52% were on diet or no treatment for diabetes; among the exclusions were insulin use, blood pressure >160/95 mmHg, and renal impairment. The DADD-FU study comprised two separate groups—those with LVDD enrolled in the original DADD trial ( n = 41) and …
Glutathione reductase activity, riboflavin status, and disease activity in rheumatoid arthritis.
Authors: D M Mulherin, D I Thurnham, R D Situnayake
Journal: Annals of the Rheumatic Diseases (1996)

To measure erythrocyte glutathione reductase (EGR) activity and riboflavin status, and their relations to disease activity, in rheumatoid arthritis patients compared to healthy controls.Patients with rheumatoid arthritis were classified as active if there were features of articular inflammation which required initiation or change of disease modifying therapy, and as inactive if they had little evidence of articular inflammation. EGR was measured in patients and healthy controls by a functional assay with or without the addition of flavin adenine dinucleotide (FAD). The ratio of stimulated EGR (with FAD added) to basal EGR (no added FAD), which measures riboflavin status, is known as the EGR activation coefficient (EGRAC). An EGRAC > or = 1.3 represents biochemical riboflavin deficiency.91 patients with rheumatoid arthritis, including 57 with active disease, and 220 healthy controls were studied. Both basal and stimulated EGR were significantly higher in patients with rheumatoid arthritis (P = 0.0001) than in controls. Biochemical riboflavin deficiency was identified in 41% controls and 33% patients with active rheumatoid arthritis but was significantly less frequent (9%) in patients with inactive compared to active disease (P = 0.02) or healthy controls (P = 0.0006). Pain score, articular index, C reactive protein, and erythrocyte sedimentation rate were increased in patients with riboflavin deficiency (all P < 0.02).Higher basal and stimulated EGR might be expected in patients with rheumatoid arthritis in response to chronic oxidative stress due to synovial inflammation. The association of riboflavin deficiency with increased disease activity suggests that impaired EGR activity could facilitate continuing inflammation in these patients.
An intracellular role for ABCG1-mediated cholesterol transport in the regulated secretory pathway of mouse pancreatic β cells
Authors: Jeffrey M. Sturek, J. David Castle, Anthony P. Trace, Laura C. Page, Anna M. Castle, Carmella Evans-Molina, John S. Parks, Raghavendra G. Mirmira, Catherine C. Hedrick
Journal: Journal of Clinical Investigation (2010)

Cholesterol is a critical component of cell membranes, and cellular cholesterol levels and distribution are tightly regulated in mammals. Recent evidence has revealed a critical role for pancreatic beta cell-specific cholesterol homeostasis in insulin secretion as well as in beta cell dysfunction in diabetes and the metabolic response to thiazolidinediones (TZDs), which are antidiabetic drugs. The ATP-binding cassette transporter G1 (ABCG1) has been shown to play a role in cholesterol efflux, but its role in beta cells is currently unknown. In other cell types, ABCG1 expression is downregulated in diabetes and upregulated by TZDs. Here we have demonstrated an intracellular role for ABCG1 in beta cells. Loss of ABCG1 expression impaired insulin secretion both in vivo and in vitro, but it had no effect on cellular cholesterol content or efflux. Subcellular localization studies showed the bulk of ABCG1 protein to be present in insulin granules. Loss of ABCG1 led to altered granule morphology and reduced granule cholesterol levels. Administration of exogenous cholesterol restored granule morphology and cholesterol content and rescued insulin secretion in ABCG1-deficient islets. These findings suggest that ABCG1 acts primarily to regulate subcellular cholesterol distribution in mouse beta cells. Furthermore, islet ABCG1 expression was reduced in diabetic mice and restored by TZDs, implicating a role for regulation of islet ABCG1 expression in diabetes pathogenesis and treatment.
The Impact of Severe Hypoglycemia and Impaired Awareness of Hypoglycemia on Relatives of Patients With Type 1 Diabetes
Authors: Hanne V. Jørgensen, Ulrik Pedersen-Bjergaard, Åse K. Rasmussen, Knut Borch-Johnsen
Journal: Diabetes Care (2003)

OBJECTIVE—Severe hypoglycemia is a major problem for patients with type 1 diabetes and their relatives. The aim of this study was to compare patients’ and relatives’ assessments of rates of severe hypoglycemia and state of awareness and to explore the influence on involvement and concern of relatives. RESEARCH DESIGN AND METHODS—A cross-sectional paired questionnaire survey on hypoglycemia and the state of awareness was used in our study comprising 284 unselected adult patients with type 1 diabetes and their closest cohabitant. The cohabitant questionnaires also addressed involvement and concern. RESULTS—The agreement between assessments of rates of severe hypoglycemia and state of awareness made by patients and cohabitants was weak (κ 0.404 and 0.442, respectively; P &amp;lt; 0.001). Cohabitants recalled more episodes of severe hypoglycemia than patients (2.7 vs. 1.6 episodes/patient-year; P &amp;lt; 0.001). Degree of involvement was positively related to the rate of severe hypoglycemia (P = 0.002) and negatively related to the state of awareness (P = 0.007) but not to level of HbA1c, duration of diabetes, or presence of late complications, except for peripheral neuropathy (P = 0.01). CONCLUSIONS—Cohabitants of patients with type 1 diabetes recall significantly more episodes of severe hypoglycemia than the patients. The rate of severe hypoglycemia and state of hypoglycemic awareness are the principal determinants of degree of cohabitants’ involvement in their partners’ disease.
Single-cell analysis: a novel approach to tumour necrosis factor- synthesis and secretion in sarcoidosis
Authors: P. Pantelidis, D.S. McGrath, A.M. Southcott, R.M. du Bois
Journal: European Respiratory Journal (2002)

Tumour necrosis factor (TNF)-α is thought to be a key early cytokine in the pathogenesis of sarcoidosis, despite conflicting data. Largely the product of mononuclear phagocyte activation, it is unclear whether TNF-α production at disease sites is a feature of all mononuclear phagocytes that accumulate there or whether it is secreted by a subset of these cells. Using the reverse haemolytic plaque assay, the aims of this study were to determine if the upregulation of TNF-α could be confirmed and to investigate whether this was monocyte or macrophage specific. The reverse haemolytic plaque assay allows the measurement of cytokine production at a single cell level. A greater number of alveolar macrophages produced TNF-α compared to autologous monocytes in sarcoidosis but not in controls and, based on cell size, it was confirmed that this was the product of more mature macrophages and that the secretion of TNF-α by monocytes and macrophages was heterogeneous: not all monocytes and macrophages secrete TNF-α. No differences in the average levels of TNF-α secretion by peripheral blood monocytes or alveolar macrophages were observed. This study has demonstrated that a subset of mononuclear phagocytes, mature macrophages, are responsible for tumour necrosis factor secretion and this could have implications for targeted management in sarcoidosis in the future.
Getting Around PLX4032: Studies Turn Up Unusual Mechanisms of Resistance to Melanoma Drug
Authors: R. S. Tuma
Journal: JNCI Journal of the National Cancer Institute (2011)

About half of all melanomas are driven by a mutation in the B-RAF gene, called V600 → E. So in 2009, when early small trials showed many patients with the mutation responding to a drug called PLX4032, researchers were jubilant. The drug is now in a pivotal phase III trial for metastatic melanoma; there is talk about accelerated approval; and its developers, Plexxikon and Roche, have already opened an expanded access program. The only bad news about PLX4032 so far is the duration of response: Patients are developing resistance to the small-molecule inhibitor in 2 – 18 months. Phase II trial results, announced in November, showed that 52% of patients with the mutation responded to PLX4032, but the median duration of response was 6.2 months.
Metacortandracin and 9-Alpha-Fluoro Hydrocortisone Acetate in Rheumatic Diseases
Authors: L. Villa, C. B. Ballabio, G. Sala
Journal: Annals of the Rheumatic Diseases (1955)

<h3>Abstract</h3> Gap junctions have well-established roles in cell-cell communication by way of forming permeable intercellular channels. Less is understood about their internalization, which forms double membrane vesicles containing cytosol and membranes from another cell, called connexosomes or annular gap junctions. Here, we systematically studied the fate of connexosomes in intact ovarian follicles. High pressure frozen, serial sectioned tissue was immunogold labeled for Connexin 43. Within a volume of electron micrographs, every labeled structure was categorized and counted. Surface area measurements indicate that large connexosomes undergo fission. Subsequent modifications are separation of inner and outer membranes, loss of Cx43 from the outer membrane, and outward budding of the modified membranes. We also documented several clear examples of organelle transfer from one cell to another by gap junction internalization. We discuss how connexosome formation and processing may be a novel means for gap junctions to mediate cell-cell communication.
Spotlight on sudden cardiac death
Authors: P Spooner
Journal: Cardiovascular Research (2001)

Sudden cardiac death (SCD) is a very common mechanism for cardiac mortality in all developed nations, yet means to identify individuals at increased risk for this condition and effective strategies for its prevention remain elusive. For many years the focus of SCD research has concentrated on averting those conditions that are its primary antecedents, such as athero-thrombotic coronary artery disease, hypertension and heart failure. Recently however, major advances have occurred in understanding those more immediate cellular and molecular influences that contribute to the overall prevalence of SCD and the mechanisms responsible for its initiation in both apparently healthy individuals and those with established cardiac diseases. This “Spotlight” issue of the Journal has been designed to highlight many of these new discoveries and the remarkable progress and challenges that characterize this field today.

A number of factors have contributed to the difficulties that characterize the historically slow pace of progress in SCD research. Rather than being associated with specific, identifiable symptoms, the pathophysiology of SCD, in most cases, is diffuse in presentation, unpredictable in time, and its major cause, initiation of lethal ventricular arrhythmias, appears highly varied in different individuals. As suggested by the most commonly used definition of SCD, “…any near instantaneous, electrically-based, cessation of cardiac output in individuals with otherwise uncompromised circulatory function,” the forms of cardiac disease from which it arises are broad, and include a full spectrum of conditions from structural malformations, to progressive acquired pathologies, as well as terminal manifestations of otherwise silent genetic susceptibilities that may express at any life stage. Recent discoveries concerning several of these latter conditions (e.g. the Long QT Syndromes) have, however, over the past five years, catapulted SCD research to the forefront of investigations on the molecular causes of cardiovascular disease; and continuing population and laboratory discoveries on the heritable … 

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Tracking a Hospital Outbreak of Carbapenem-Resistant <i>Klebsiella pneumoniae</i> with Whole-Genome Sequencing
Authors: Evan S. Snitkin, Adrian M. Zelazny, Pamela J. Thomas, Frida Stock, David K. Henderson, Tara N. Palmore, Julia A. Segre
Journal: Science Translational Medicine (2012)

Tracking a hospital outbreak of carbapenem-resistant Klebsiella pneumoniae with whole-genome sequencing revealed its origin and probable modes of transmission.
Chromothripsis and Focal Copy Number Alterations Determine Poor Outcome in Malignant Melanoma
Authors: Daniela Hirsch, Ralf Kemmerling, Sean Davis, Jordi Camps, Paul S. Meltzer, Thomas Ried, Timo Gaiser
Journal: Cancer Research (2012)

Abstract Genetic changes during tumorigenesis are usually acquired sequentially. However, a recent study showed that in 2% to 3% of all cancers a single catastrophic event, termed chromothripsis, can lead to massive genomic rearrangements confined to one or a few chromosomes. To explore whether the degree of genomic instability and chromothripsis influences prognosis in cancer, we retrospectively applied array-comparative genomic hybridization (aCGH) to 20 malignant melanomas that showed, despite comparable conventional clinical and pathologic parameters, a profoundly different clinical course. We compared 10 patients who died of malignant melanoma 3.7 years (median, range 0.9–7.6 years) after diagnosis with 10 patients who survived malignant melanoma and had a median disease-free survival of 14.8 years (range 12.5–16.7 years; P = 0.00001). We observed a striking association between the degree of chromosomal instability, both numerical and structural, and outcome. Malignant melanomas associated with good prognosis showed only few chromosomal imbalances (mean 1.6 alterations per case), predominantly whole chromosome or chromosome arm gains and losses, whereas malignant melanomas with poor prognosis harbored significantly more chromosomal aberrations (13.9 per case; P = 0.008). Array-based CGH showed that these aberrations were mostly focal events, culminating in two cases in a pattern consistent with the phenomenon of chromothripsis, which was confirmed by paired-end sequencing. This is the first description of chromothripsis in primary malignant melanomas. Our study therefore links focal copy number alterations and chromothripsis with poor outcome in patients with malignant melanomas (P = 0.0002) and provides a genetic approach to predict outcome in malignant melanomas. Cancer Res; 73(5); 1454–60. ©2012 AACR.
Pathological and radiological changes in resected lung specimens in Mycobacterium avium intracellulare complex disease
Authors: J Fujita, Y Ohtsuki, I Suemitsu, E Shigeto, I Yamadori, Y Obayashi, H Miyawaki, N Dobashi, T Matsushima, J Takahara
Journal: European Respiratory Journal (1999)

The present study was designed to evaluate the pathological and immunohistochemical findings of Mycobacterium avium intracellulare complex (MAC) lung infection. A retrospective study was performed in five cases with positive cultures for MAC in whom lung resections were performed between January 1989 and December 1996. A determination of whether or not MAC caused pulmonary disease was made using the 1997 criteria defined by the American Thoracic Society. In addition, MAC was cultured from all of the five lung specimens. Pathological and immunohistochemical findings as well as chest computed tomography (CT) findings were evaluated in these five patients. Pathological findings of bronchiectasis, bronchiolitis, centrilobular lesion, consolidation, cavity wall and nodules were demonstrated, respectively, in relation to chest CT findings. Extensive granuloma formation throughout the airways was clearly demonstrated. Immunohistochemical staining demonstrated: 1) epithelioid cells and giant cells; 2) myofibroblasts extensively infiltrating the cavity wall; and 3) B-cells detected in aggregates in the vicinity of the epithelioid granulomas. This study identified pathological and immunohistochemical characteristics of Mycobacterium avium complex infection relative to chest computed tomography findings and allowed the conclusion that bronchiectasis and bronchiolitis were definitely caused by Mycobacterium avium complex infection.
Gender differences in rising trends in cutaneous malignant melanoma in Spain, 1975-98
Authors: A. Nieto, M. Ruiz-Ramos, L. Abdel-Kader, M. Conde, F. Camacho
Journal: British Journal of Dermatology (2003)

Cutaneous malignant melanoma (CMM) morbidity and mortality rates have increased over the past several decades all around the world, but some developed countries have experienced recent declines in mortality from CMM among the young and middle-aged and even a reversal in the long-term increase in deaths attributable to CMM.To describe CMM mortality trends, by age and gender, in Spain between 1975 and 1998.Crude, age-adjusted, truncated, cumulative, age-specific and potential years of life lost rates of CMM mortality were calculated by gender. Age and period Poisson regression models were fitted to gender- and age-specific CMM mortality rates.In males there were marked increases in all CMM mortality rates between 1975 and 1994, followed by their decrease during 1995-98. In contrast, rates rose in females between 1975 and 1998. There were annual increases of 13% in the risk of dying among males and 33% among females. Relative risks of CMM mortality increased with age in both genders: (i) 21.75 (95% confidence interval, CI 17.32-27.30) in males, and (ii) 28.27 (95% CI 24.99-31.97) in females in the > or = 70-year-old group, when compared with those < 35 years.CMM mortality rates continue to rise in females while males have experienced a recent reversal of this trend in Spain. Emphasizing the danger of overexposure to ultraviolet radiation may be especially important in females.
Glutamine,<i>myo</i>-inositol, and organic brain osmolytes after portocaval anastomosis in the rat: Implications for ammonia-induced brain edema
Authors: J Córdoba, J Gottstein, A T Blei
Journal: Hepatology (1996)

Brain myo –inositol, an organic osmolyte, is decreased in cirrhotic patients with hepatic encephalopathy but appears unchanged in fulminant hepatic failure. An osmoregulatory response to the increase in brain glutamine may explain the decrease in brain myo –inositol; if this is the case, organic osmolytes may account for differences in the development of brain edema seen in acute or chronic liver failure. The response of myo –inositol and nine other organic osmolytes to the increase in brain glutamine at different time intervals after portacaval anastomosis (PCA) in the rat was studied. Organic osmolytes were measured in brain tissue and cerebrospinal fluid. Water in cerebral cortex was measured after ammonia infusion with the gravimetric method. Six weeks after PCA, despite an increase in brain glutamine (PCA, 16.4 ± 2 mmol.kg wt–1.kg wt–1; sham, 5 ± 1 mmol.L–1.kg wt–1), the content of total organic osmolytes did not increase (PCA, 44.1 ± 3; sham, 43 ± 4) because of a decrease of other osmolytes ( myo –inositol, 54%; urea, 39%; taurine, 33%; and glutamate, 8%). Brain myo –inositol was lower at 3 weeks (3.4 ± 0.5 kg wt–1) than at 1 day after PCA (4.7 ± 0.5 kg wt–1). An ammonia infusion resulted in brain edema at both time points. In conclusion, the reduction in brain myo –inositol in PCA rats is accompanied by the decrease of other organic osmolytes, supporting the view that changes in myo –inositol reflect an osmoregulatory response. The decrease in brain myo –inositol is more marked as time elapses after PCA. In a model in which short–term and large doses of ammonia were infused, the decrease in brain myo –inositol did not prevent the development of brain swelling. Understanding brain osmoregulatory mechanisms may provide new insights into hepatic encephalopathy and brain edema in fulminant hepatic failure.