tbuckley/cabot-search huggingface dataset:
Antioxidant enzyme polymorphisms and neuropsychological outcomes in medulloblastoma survivors: a report from the Childhood Cancer Survivor Study
Authors: J. Brackett, K. R. Krull, M. E. Scheurer, W. Liu, D. K. Srivastava, M. Stovall, T. E. Merchant, R. J. Packer, L. L. Robison, M. F. Okcu
Journal: Neuro-Oncology (2012)

Psychological or neurocognitive impairment is often seen in medulloblastoma survivors after craniospinal radiation; however, significant variability in outcomes exists. This study investigated the role of antioxidant enzyme polymorphisms in moderating this outcome and hypothesized that patients who had polymorphisms associated with lower antioxidant enzyme function would have a higher occurrence of impairment. From the Childhood Cancer Survivor Study (CCSS) cohort, 109 medulloblastoma survivors and 143 siblings were identified who completed the CCSS Neurocognitive Questionnaire (NCQ) and the Brief Symptom Inventory-18 (BSI-18) and who provided buccal DNA samples. Real-time polymerase chain reaction (PCR) allelic discrimination was used for SOD2 (rs4880), GPX1 (rs1050450), and GSTP1 (rs1695 and rs1138272) genotyping and PCR for GSTM1 and GSTT1 gene deletions. Outcomes on NCQ and BSI-18 subscale scores were examined in association with genotypes and clinical factors, including age at diagnosis, sex, and radiation dose, using univariate and multivariate analysis of variance. Patients <7 years of age at diagnosis displayed more problems with task efficiency (P < .001) and fewer problems with somatic complaints (P = .004) than did patients ≥7 years of age. Female patients reported more organization problems than did male patients (P = .02). Patients with homozygous GSTM1 gene deletion reported higher anxiety (mean null genotype = 47.3 ± 9.2, non-null = 43.9 ± 7.8; P = .04), more depression (null = 51.0 ± 9.8, non-null = 47.0 ± 9.4; P = .03), and more global distress (null = 50.2 ± 9.7, non-null = 45.2 ± 9.9; P = .01). All associations for the GSTM1 polymorphism remained statistically significant in a multivariate model controlling for age, sex, and radiation dose. Homozygous GSTM1 gene deletion was consistently associated with greater psychological distress in medulloblastoma survivors across multiple domains, suggesting that this genotype may predispose patients for increased emotional late effects.
The Dystrophin Glycoprotein Complex
Authors: Karen A. Lapidos, Rahul Kakkar, Elizabeth M. McNally
Journal: Circulation Research (2004)

The dystrophin glycoprotein complex (DGC) is a specialization of cardiac and skeletal muscle membrane. This large multicomponent complex has both mechanical stabilizing and signaling roles in mediating interactions between the cytoskeleton, membrane, and extracellular matrix. Dystrophin, the protein product of the Duchenne and X-linked dilated cardiomyopathy locus, links cytoskeletal and membrane elements. Mutations in additional DGC genes, the sarcoglycans, also lead to cardiomyopathy and muscular dystrophy. Animal models of DGC mutants have shown that destabilization of the DGC leads to membrane fragility and loss of membrane integrity, resulting in degeneration of skeletal muscle and cardiomyocytes. Vascular reactivity is altered in response to primary degeneration in striated myocytes and arises from a vascular smooth muscle cell–extrinsic mechanism.
Increased interleukin 4 and immunoglobulin E production in transgenic mice overexpressing NK1 T cells.
Authors: A Bendelac, R D Hunziker, O Lantz
Journal: The Journal of Experimental Medicine (1996)

Natural Killer (NK)1.1+ (NK1) T cells are a specialized subset of alpha/beta T cells that coexpress surface receptors that are normally associated with the NK cell lineage of the innate immune system. On recognition of the conserved, major histocompatibility complex class I-like CD1 molecule, these cells are able to release explosive bursts of interleukin 4 (IL-4), a cytokine that promotes the T helper type 2 (Th2) effector class of an immune response. A unique feature of their T cell receptor (TCR) repertoire is the expression of an invariant TCR alpha chain, V alpha 14-J alpha 281, and of a restricted but polyclonal set of V beta gene families, V beta 8, V beta 7, and V beta 2. Here, we show that transgenic expression of this TCR alpha chain during thymic development is sufficient information to bias the differentiation of mainstream thymocytes towards the NK1 developmental pathway. It markedly increases the frequency of cells with the NK1 pattern of T cell differentiation and also has drastic consequences for the selection of the V beta repertoire. Transgenic CD4 cells exhibited a 10-100-fold increase in IL-4 production on mitogen stimulation in vitro and in vivo, and baseline levels of the Th2-controlled serum immunoglobulin isotypes, IgE and IgG1, were also selectively elevated in vivo.
Effects of chronic ethanol intake on mobilization and excretion of cholesterol in baboons.
Authors: C Karsenty, E Baraona, M J Savolainen, C S Lieber
Journal: Journal of Clinical Investigation (1985)

To investigate the effects of chronic ethanol administration on the mobilization and excretion of cholesterol, turnover and balance studies were carried out in baboons pair-fed cholesterol-free diets containing 50% of energy either as ethanol or as additional carbohydrate for several years. Ethanol feeding increased free cholesterol in all plasma lipoprotein fractions, and esterified cholesterol in very low density lipoprotein, intermediate density lipoprotein, and high density lipoprotein (HDL). The major increase occurred in HDL, mainly as esterified cholesterol. The latter was associated with decreased transfer of esterified cholesterol from HDL to low density lipoprotein. By contrast, the smaller increase in HDL-free cholesterol was associated with increased turnover in the plasma, increased splanchnic uptake, and increased fecal excretion of plasma cholesterol, mainly as neutral steroids. Cholesterol extraction predominated over release in the splanchnic vascular bed, suggesting that the excess of cholesterol excreted in the feces originated in extrasplanchnic tissues. Thus, these findings indicate that alcohol consumption favors mobilization of tissue free cholesterol for hepatic removal and excretion. By contrast the increase in HDL-cholesterol (mainly esterified) appears to be a poor indicator of cholesterol mobilization.
Oxidized LDL Induces Proliferation and Hypertrophy in Human Umbilical Vein Endothelial Cells via Regulation of p27Kip1 Expression
Authors: Stefan Seibold, Dorothea Schürle, Alexandra Heinloth, Gunter Wolf, Martin Wagner, Jan Galle
Journal: Journal of the American Society of Nephrology (2004)

Oxidized LDL (OxLDL) induces proliferation in human umbilical vein endothelial cells (HUVEC). The influence of OxLDL on the cyclin-dependent kinase inhibitor p27(Kip1), on the activity of the small GTPase RhoA as a known regulator of p27(Kip1), and on resulting cell proliferation and hypertrophy was studied. HUVEC were stimulated with OxLDL (1 to 50 mug/ml). Proliferation was quantified by (3)H-thymidine incorporation, colorimetric 3-(4,5-dimethyl-2-thiazyl)-2,5-diphenyl-2h-tetrazolium bromide assay, and cell count and was compared with proliferation of HUVEC that were transfected with dominant negative RhoA or treated with the Rho-kinase inhibitor Y27632. Hypertrophy was quantified by (3)H-leucine incorporation and by planimetry. p27(Kip1) expression was determined by Western blot analysis. p27(Kip1) was downregulated by transient transfection with antisense oligonucleotides. Low concentrations of OxLDL induced proliferation of HUVEC, paralleled by a persistent decrease of p27(Kip1) expression. With the use of antisense oligonucleotides, further downregulation of p27(Kip1) expression enhanced the OxLDL-induced proliferative response. High concentrations of OxLDL resulted in cellular hypertrophy and caused a delayed increase in p27(Kip1) expression after initial downregulation. Concomitant, OxLDL caused a significant activation of the small GTPase RhoA. In cells that were transfected with dominant negative RhoA, the effect of OxLDL on p27(Kip1) expression and on cellular proliferation was abolished. HUVEC that were preincubated with the Rho-kinase inhibitor Y27632 also showed a significantly decreased proliferative response to OxLDL stimulation. In summary, OxLDL has a dual effect on cell-cycle progression via regulation of p27(Kip1) expression, resulting in cellular proliferation and hypertrophy, involving activation of RhoA. OxLDL may importantly contribute to vascular hyperplasia in atherosclerosis and other diseases associated with increased levels of OxLDL.
Frequent multiple hepatitis C virus infections among injection drug users in a prison setting
Authors: Son T. Pham, Rowena A. Bull, James M. Bennett, William D. Rawlinson, Gregory J. Dore, Andrew R. Lloyd, Peter A. White
Journal: Hepatology (2010)

Recent data indicate that multiple hepatitis C virus (HCV) infections (mixed infection, superinfection, and reinfection) are common among injection drug users (IDUs). In this study, we identified and characterized multiple HCV infection episodes among HCV-seronegative IDU prison inmates (n = 488) enrolled in the Hepatitis C Incidence and Transmission Study cohort. Incident HCV infection with detectable HCV RNA was identified in 87 subjects, 48 of whom completed additional follow-up to screen for reinfection or superinfection. All HCV RNA–detectable samples were tested for multiple infection through a series of specifically designed nested reverse-transcription polymerase chain reaction (nRT-PCR) with sequencing and HCV RNA level measurement. Sequencing revealed that 22 of 87 (25.3%) subjects were infected by two or more viruses. Nine (10.3%) subjects were designated as prevalent cases of incident mixed infection, because two distinct HCV strains were detected at the first viremic time point. Fifteen further cases of multiple HCV infection (superinfection or reinfection) were identified, two of which also showed baseline incident mixed infections. The incidence of new HCV infection (superinfection and reinfection) during follow-up was 40/100 person-years (95% confidence interval, 33-44/100 person-years). Spontaneous clearance of viruses from one subtype and persistence of the other subtype after mixed infection was observed in eight subjects. In these subjects, the virus with higher HCV RNA levels superseded the other. Conclusion: This study comprehensively analyzed frequent multiple HCV infections in a high-risk cohort and provides further insight into infection dynamics and immunity after exposure to variant viral strains. The data presented suggest that HCV RNA levels play an important role in viral competition. (Hepatology 2010;52:1564-1572)
Human gene for torsion dystonia located on chromosome 9q32-q34
Authors: Laurie Ozelius, Patricia L. Kramer, Carol B. Moskowitz, David J. Kwiatkowski, Mitchell F. Brin, Susan B. Bressman, Deborah E. Schuback, Catherine T. Falk, Neil Risch, Deborah de Leon, Robert E. Burke, Jonathan Haines, James F. Gusella, Stanley Fahn, Xandra O. Breakefield
Journal: Neuron (1989)
Effect of monocrotaline ingestion on the distribution of protein and angiotensin converting enzyme activity in the rat lung.
Authors: D J Shale, M S Wiseman, W O Cookson
Journal: Thorax (1986)

The alveolar accumulation of protein and angiotensin converting enzyme activity was compared with the development of right ventricular hypertrophy in male rats after different periods of monocrotaline exposure. Total doses of monocrotaline were varied by dividing the animals into three groups in which ingestion was limited to three, seven, and 15 days. These groups were studied 21 days after the start of monocrotaline exposure and compared with a group treated continuously for 28 days. The total lung weight increased after three or more days of treatment, while after seven days there was significant alveolar accumulation of protein, which was paralleled by an increase in angiotensin converting enzyme activity in alveolar lavage fluid. Identical changes also occurred after 15 and 28 days of exposure to monocrotaline. Lung angiotensin converting enzyme activity was decreased after three days9 ingestion of monocrotaline and did not alter further with longer periods of exposure. None of these effects of monocrotaline in the three and seven day treatment groups was associated with right ventricular hypertrophy, which occurred only in animals treated for 15 or more days. The effects of monocrotaline ingestion on the lung were dose related and had no causal relationship to the development of right ventricular hypertrophy.
Analysis of hepatocellular proliferation: Study of archival liver tissue is facilitated by an endogenous marker of DNA replication
Authors: Ravikumar P. Vemuru, Emma Aragona, Sanjeev Gupta
Journal: Hepatology (1992)

ABSTRACT Assessment of liver regeneration with endogenous genes that are expressed during DNA replication is physiological, specific and direct. To determine whether H3 histone messenger RNA expression (which is tightly coupled with DNA synthesis) could be used for this purpose, we initially examined liver regeneration in a mouse model. After partial hepatectomy, RNA transblot studies showed induction of H3 histone messenger RNA expression in regenerating mouse livers. In situ molecular hybridization demonstrated that the overall pattern of H3 histone messenger RNA expression correlated with [ 3 H]thymidine labeling of hepatocytes. After partial hepatectomy, H3 histone messenger RNA expression in hepatocytes peaked at 48 hr (&gt;60 times greater than at 24 hr; p &lt; 0.001) and then rapidly declined. Although hepatocyte labeling with [ 3 H]thymidine showed similar kinetics of liver regeneration, use of this parameter resulted in overestimation of the proliferative compartment when it was compared with H3 histone messenger RNA expression. Next we determined whether H3 histone messenger RNA expression could be used to study hepatocellular proliferation in archival human material. H3 histone messenger RNA—expressing hepatocytes were identified on in situ hybridization in patients with acute or chronic active hepatitis and active cirrhosis, but not inactive cirrhosis. These studies demonstrate that H3 histone messenger RNA is expressed in a phasic manner during liver regeneration. Use of H3 histone messenger RNA expression to evaluate hepatocellular proliferation should facilitate clinical studies and greatly advance our understanding of the pathophysiology of liver regeneration. (HEPATOLOGY 1992;16:968-973.)
Magnesium Intake, C-Reactive Protein, and the Prevalence of Metabolic Syndrome in Middle-Aged and Older U.S. Women
Authors: Yiqing Song, Paul M. Ridker, JoAnn E. Manson, Nancy R. Cook, Julie E. Buring, Simin Liu
Journal: Diabetes Care (2005)

OBJECTIVE—The aim of this study was to examine whether and to what extent magnesium intake is related to systemic inflammation and the metabolic syndrome. RESEARCH DESIGN AND METHODS—We performed a cross-sectional analysis on data from 11,686 women ≥45 years of age participating in the Women’s Health Study who were initially free of cardiovascular disease and cancer and had no use of postmenopausal hormones. RESULTS—In age- and BMI-adjusted analyses, magnesium intake was inversely associated with plasma C-reactive protein (CRP) concentrations; CRP concentrations were 12% lower in the highest intake quintile than in the lowest (P for trend &amp;lt;0.0001). This association was not appreciably altered by further adjustment for other potential confounding variables including dietary factors; the mean CRP concentrations for ascending quintiles of magnesium intake were 1.50, 1.39, 1.35, 1.34, and 1.31 mg/l (P for trend = 0.0003). This inverse association was stronger for women with a BMI ≥25 kg/m2 (P &amp;lt; 0.0001 for interaction) and those who were current or past smokers (P = 0.0009 for interaction). After adjustment for confounding lifestyle and dietary factors, women in the highest quintile of magnesium intake had 27% lower risk of the metabolic syndrome (defined according to the National Cholesterol Education Program criteria) compared with those in the lowest quintile of intake (odds ratio 0.73 [95% CI 0.60–0.88], P for trend = 0.0008). CONCLUSIONS—Our results suggest that magnesium intake is inversely associated with systemic inflammation and the prevalence of the metabolic syndrome in middle-aged and older women.
II. Meta-Analysis of Alendronate for the Treatment of Postmenopausal Women
Authors: Ann Cranney, George Wells, Andrew Willan, Lauren Griffith, Nicole Zytaruk, Vivian Robinson, Dennis Black, Jonathan Adachi, Beverley Shea, Peter Tugwell, Gordon Guyatt
Journal: Endocrine Reviews (2002)

To review the effect of alendronate on bone density and fractures in postmenopausal women.We searched MEDLINE, EMBASE, Current Contents, and the Cochrane Controlled trials registry from 1980 to 1999, and we examined citations of relevant articles and proceedings of international meetings.We included 11 trials that randomized women to alendronate or placebo and measured bone density for at least 1 yr.For each trial, three independent reviewers assessed the methodological quality and abstracted data.The pooled relative risk (RR) for vertebral fractures in patients given 5 mg or more of alendronate was 0.52 [95% confidence interval (CI), 0.43-0.65]. The RR of nonvertebral fractures in patients given 10 mg or more of alendronate was 0.51 (95% CI 0.38-0.69), an appreciably greater effect than for the 5 mg dose. We found a similar reduction in RR across nonvertebral fracture types; in particular, RR reductions for fractures traditionally thought to be "osteoporotic," such as hip and forearm, were very similar to RR reductions for "nonosteoporotic" fractures. Individual studies showed similar results, reflected in the P values of the test of heterogeneity (P = 0.99 for vertebral and 0.88 for nonvertebral fractures). Alendronate produced positive effects on the percentage change in bone density, which increased with both dose and time. After 3 yr of treatment with 10 mg of alendronate or more, the pooled estimate of the difference in percentage change between alendronate and placebo was 7.48% (95% CI 6.12-8.85) for the lumbar spine (2-3 yr), 5.60% (95% CI 4.80-6.39) for the hip (3-4 yr), 2.08% (95% CI 1.53-2.63) for the forearm (2-4 yr), and 2.73% (95% CI 2.27-3.20) for the total body (3 yr). Heterogeneity of the treatment effect of alendronate was not consistently explained by any of our a priori hypotheses; in particular, the effect was very similar in prevention and treatment studies. The pooled RR for discontinuing medication due to adverse effects for 5 mg or greater of alendronate was 1.15 (95% CI 0.93-1.42). The pooled RR for discontinuing medication due to gastro-intestinal (GI) side effects for 5 mg or greater was 1.03 (0.81-1.30, P = 0.83), and the pooled RR for GI adverse effects with continuation of medication was 1.03 (0.98 to 1.07) P = 0.23.Alendronate increases bone density in both early postmenopausal women and those with established osteoporosis while reducing the rate of vertebral fracture over 2-3 yr of treatment. Reductions in nonvertebral fractures are evident among postmenopausal women without prevalent fractures and have bone mineral density (BMD) levels below the World Health Organization threshold for osteoporosis. The impact on fractures appears consistent across all fracture types, casting doubt on traditional distinctions between osteoporotic and nonosteoporotic fractures.
British Thoracic Society adult community acquired pneumonia audit 2009/10
Authors: W. S. Lim, M. Woodhead
Journal: Thorax (2011)

<h3>Abstract</h3> The first COVID-19 case in Mexico was confirmed on 26 February 2020 and by May 3 the number of registered cases had risen to 30,927. However the rate of transmission varied greatly from city to city. We used data on temperature, humidity and ultraviolet radiation (UV) from 45 cities all over the country to explore whether there was an association between these variables and rates of transmission and rates of accumulation of COVID-19 ascribed deaths. The advantage of an in-country study of this kind is that many of the variables that can confound international studies are held constant (e.g. public health policies, methods of reporting, cultural, behavioural and genetic factors). Although the official statistics undoubtedly greatly underestimate the situation in Mexico due to lack of testing, they are underestimated in all cities so this should not introduce bias across the sample. We found that temperature and humidity had no discernible association with transmission rates but that UV during the transmission period was negatively correlated with rates of transmission, suggesting a sterilizing effect. UV in the January preceding the epidemic had a slightly higher association with transmission rates than UV during the transmission period itself. We also found negative associations of UV in the transmission period and in January with rate of cumulative deaths, but at lower levels of statistical significance. We conclude that in addition to a sterilizing effect during the transmission period, UV may have a physiological effect in reducing transmission and deaths due to COVID-19, most likely through the medium of vitamin D production in the body. This follows the growing body of medical evidence that vitamin D deficiency is associated with severity of COVID-19. However, we also found a negative correlation between altitude and rates of COVID-19 transmission, distinct and independent of the UV effect, which may indicate that other physiological processes are also present. In a multiple regression, altitude and UV together accounted for 18% of the variation in transmission rates between cities.
Phagocytosis without inflammation
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

The rare brain disorder Nasu-Hakola disease is a fatal neurodegenerative syndrome that has been linked to mutations in immune signaling proteins, but the mechanism had not been explored. In a study on page 647, Takahashi et al. connect this disease to defects in phagocytic cells that are required for removal of apoptotic cells and suppression of inflammation in the brain.






Figure 

Phagocytosis of apoptotic neurons (red) by microglial cells (green) requires TREM2.




The link to disease involves the TREM2 (triggering receptor expressed on myeloid cells-2) receptor and its associated adaptor protein DAP12, both known to be mutated in patients with Nasu-Hakola disease. TREMs are orphan receptors that associate with DAP12 to transmit signals in a variety of myeloid cells. The signals are primarily stimulatory: TREM1 signaling activates macrophages and neutrophils and can amplify Toll-like receptor signals, and TREM2 activates immature dendritic cells. TREM2 is also expressed on microglial cells (phagocytic cells in the brain that remove apoptotic cells and debris from the brain), but its function on these cells had not been examined until now.

Intrigued by the connection between TREM2 and Nasu-Hakola disease, Takahashi and colleagues examined the function of this molecule on primary murine microglial cells. They found that TREM2 ligation triggered phagocytosis of beads and apoptotic neurons in a process that required actin reorganization and the activation of the signaling molecule Erk. TREM2-stimulated phagocytosis did not coincide with activation of the cell or secretion of proinflammatory cytokines.

Impaired phagocytosis in the absence of TREM2 or functional DAP12 confirmed their role in phagocytosis. This experiment, however, also revealed a more striking finding. The loss of TREM2 provoked the microglial cells into producing inflammatory cytokines such as TNF and IL-1β, suggesting that TREM2 signals actively interfere with these pathways under normal circumstances. When TREM2 is missing, the lack of interference may explain the defective phagocytosis and aberrant activation of microglial cells that accompanies the buildup of cellular debris in the brain.