tbuckley/cabot-search huggingface dataset:
Organotins Disrupt the 11β-Hydroxysteroid Dehydrogenase Type 2–Dependent Local Inactivation of Glucocorticoids
Authors: Atanas G. Atanasov, Lyubomir G. Nashev, Steven Tam, Michael E. Baker, Alex Odermatt
Journal: Environmental Health Perspectives (2005)

Organotins, important environmental pollutants widely used in agricultural and industrial applications, accumulate in the food chain and induce imposex in several marine species as well as neurotoxic and immunotoxic effects in higher animals. Reduced birth weight and thymus involution, observed upon exposure to organotins, can also be caused by excessive glucocorticoid levels. We now demonstrate that organotins efficiently inhibit 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), converting active 11β-hydroxyglucocorticoids into inactive 11-ketoglucocorticoids, but not 11β-HSD1, which catalyzes the reverse reaction. Di- and tributyltin as well as di- and triphenyltin inhibited recombinant and endogenous 11β-HSD2 in lysates and intact cells with IC50 values between 500 nM and 3 μM. Dithiothreitol protected 11β-HSD2 from organotin-dependent inhibition, indicating that organotins act by binding to one or more cysteines. Mutational analysis and 3-D structural modeling revealed several important interactions of cysteines in 11β-HSD2. Cys90, Cys228, and Cys264 were essential for enzymatic stability and catalytic activity, suggesting that disruption of such interactions by organotins leads to inhibition of 11β-HSD2. Enhanced glucocorticoid concentrations due to disruption of 11β-HSD2 function may contribute to the observed organotin-dependent toxicity in some glucocorticoid-sensitive tissues such as thymus and placenta.
Human rhinoviruses in Chinese adults with acute respiratory tract infection
Authors: Zichun Xiang, Richard Gonzalez, Zhong Wang, Yan Xiao, Lan Chen, Taisheng Li, Guy Vernet, Gláucia Paranhos-Baccalà, Qi Jin, Jianwei Wang
Journal: Journal of Infection (2010)

ObjectiveTo evaluate the roles of human rhinoviruses (HRVs) in acute respiratory tract infections (ARTIs) in Chinese adults and determine the association between species of HRV and clinical presentations.MethodsRT-PCR methods were used to detect HRVs in throat and nasal swabs collected from 6104 adult patients with ARTIs from December 2005 to April 2008 in Beijing, China.ResultsHRV strains were detected in 271 ARTIs cases, 65% of which tested positive for HRV-A, 25% for HRV-B, and 10% for HRV-C. Aside from fever, pharyngeal congestion and headache were the most common clinical symptoms observed in the HRVs infected patients. HRV-A infected patients had a higher percentage of upper respiratory symptoms than patients infected by the two other HRV species. Systemic symptoms such as chilliness and myalgia were more frequent in people infected by HRV-B. The three HRV species exhibited unique infection timing when analyzed monthly.ConclusionHRV-C can be detected in adult patients with acute upper respiratory tract infections, but is not the predominant species in this population.
Factors affecting successful endoscopic sclerotherapy for oesophageal varices.
Authors: J D Rose, M D Crane, P M Smith
Journal: Gut (1983)

Forty patients with bleeding oesophageal varices were studied during treatment by endoscopic sclerotherapy to discover what factors determine successful outcome. Large varices required more injections than small varices for obliteration, and rebleeding during treatment occurred only in patients with large varices. Radiological studies with sclerosant contrast mixture showed that in two groups of varices of comparable size, intravenous sclerosant was significantly more effective, leading to thrombosis in 8/10 as opposed to only 3/10 after paravasal injection (p less than 0.05). Intravenous contrast was rapidly cleared upwards, whereas paravasal contrast formed a rounded opacity alongside the vein that persisted for approximately 90 minutes, responsible for the complications of oesophageal ulceration and stenosis.
Harvard Dropouts: Some Psychiatric Findings
Authors: ARMAND M. NICHOLI
Journal: American Journal of Psychiatry (1967)

Harvard undergraduates who had consulted a psychiatrist before dropping out of college and had been diagnosed as having a specific psychiatric disorder were defined as "psychiatric dropouts." in comparing these students with all other dropouts, the author found that they are equally as likely to return, attain honors, and graduate as are "nonpsychiatric dropouts." Psychiatric consultation was, however, four times as frequent among dropouts as among the student population at large. Depression plays a significant role in the student's decision to leave college, and the author offers his formulation of the dynamics of the dropout phenomenon.
Effect of Type 2 Diabetes Mellitus on Left Ventricular Geometry and Systolic Function in Hypertensive Subjects
Authors: Vittorio Palmieri, Jonathan N. Bella, Donna K. Arnett, Jennifer E. Liu, Albert Oberman, Min-Yan Schuck, Dalane W. Kitzman, Paul N. Hopkins, Derek Morgan, D. C. Rao, Richard B. Devereux
Journal: Circulation (2001)

Background —Type 2 diabetes is a cardiovascular risk factor. It remains to be elucidated in a large, population-based sample whether diabetes is associated with changes in left ventricular (LV) structure and systolic function independent of obesity and systolic blood pressure (BP). Methods and Results —Among 1950 hypertensive participants in the HyperGEN Study without overt coronary heart disease or significant valve disease, 20% (n=386) had diabetes. Diabetics were more likely to be women, black, older, and have higher BMI and waist/hip ratio than were nondiabetics. After adjustment for age and sex, diabetics had higher systolic BP, pulse pressure, and heart rate; lower diastolic BP; and longer duration of hypertension than nondiabetics. LV mass and relative wall thickness were higher in diabetic than nondiabetic subjects independent of covariates. Compared with nondiabetic hypertensives, diabetics had lower stress-corrected midwall shortening, independent of covariates, without difference in LV EF. Insulin levels and insulin resistance were higher in non–insulin-treated diabetics (n=195) than nondiabetic (n=1439) subjects (both P &lt;0.01). Insulin resistance positively but weakly related to LV mass and relative wall thickness. Conclusions —In a relatively healthy, population-based sample of hypertensive adults, type 2 diabetes was associated with higher LV mass, more concentric LV geometry, and lower myocardial function, independent of age, sex, body size, and arterial BP. structural and functional abnormalities in addition to, and independent of, atherosclerosis. 13 14 In the Framingham cohort, diabetes was associated with higher LV mass in women but not men. 15 High blood pressure (BP), obesity, and abnormal lipid profile, which often coexist with diabetes, tend to be associated with preclinical cardiovascular abnormalities 16 and may contribute to the association of diabetes with cardiovascular events. Cardiac features of diabetic and nondiabetic hypertensive subjects remain incompletely described in population-based samples. Therefore, we compared clinical and metabolic characteristics, LV geometry, and systolic function between diabetic and nondiabetic hypertensive participants in the Hypertension Genetic Epidemiology Network (HyperGEN) Study.
Small Apolipoprotein(a) Size Predicts Mortality in End-Stage Renal Disease
Authors: J. Craig Longenecker, Michael J. Klag, Santica M. Marcovina, Neil R. Powe, Nancy E. Fink, Federico Giaculli, Josef Coresh
Journal: Circulation (2002)

The high mortality rate in end-stage renal disease has engendered interest in nontraditional atherosclerotic cardiovascular disease (ASCVD) risk factors that are more prevalent in end-stage renal disease, such as elevated lipoprotein(a) [Lp(a)] levels. Previous studies suggest that high Lp(a) levels and small apolipoprotein(a) [apo(a)] isoform size are associated with ASCVD, but none have investigated the relationship between Lp(a) level, apo(a) size, and mortality.
Soluble endostatin is a novel inhibitor of epithelial repair in idiopathic pulmonary fibrosis
Authors: A G Richter, S McKeown, S Rathinam, L Harper, P Rajesh, D F McAuley, R Heljasvaara, D R Thickett
Journal: Thorax (2008)

Background and aim: Aberrant angiogenesis and defective epithelial repair are key features of idiopathic pulmonary fibrosis (IPF). Endostatin is an antiangiogenic peptide with known effects on endothelial cells. This study aimed to establish the levels of endostatin in the bronchoalveolar lavage fluid (BALF) in IPF and to investigate its actions on distal lung epithelial cells (DLEC) and primary type II cells. Methods: 20 patients with IPF and 10 controls underwent BAL. Endostatin was measured by ELISA. BALF cytokines and matrix metalloproteinase (MMP)-3 were measured by Luminex array. Primary DLEC monolayers were wounded and treated with endostatin. Apoptosis and cell viability were assessed. Results: Endostatin was elevated in the BALF and plasma of patients with IPF compared with normal controls. There was a negative correlation between endostatin, forced vital capacity and gas transfer. Endostatin correlated with a number of proinflammatory cytokines and MMP3. Physiological endostatin doses inhibited DLEC wound repair by 44% in an effect that was partially FasL and caspase dependent. Endostatin increased apoptosis rates by 8% and reduced their viability by 34%. Similar effects of endostatin were seen in primary type II cells in terms of inhibition of wound repair and proliferation. Conclusions: Elevated BALF endostatin levels correlated with a number of elevated cytokines, MMP3 and lung function in IPF. Endostatin is a novel inhibitor of DLEC wound repair, inducing apoptosis and reducing cell viability in a FasL and caspase dependent manner. Endostatin may play a role in aberrant epithelial repair in IPF.
Receptor interacting protein kinase 3 is a critical early mediator of acetaminophen-induced hepatocyte necrosis in mice
Authors: Anup Ramachandran, Mitchell R. McGill, Yuchao Xie, Hong-Min Ni, Wen-Xing Ding, Hartmut Jaeschke
Journal: Hepatology (2013)

Acetaminophen (APAP) overdose is a major cause of hepatotoxicity and acute liver failure in the U.S., but the pathophysiology is incompletely understood. Despite evidence for apoptotic signaling, hepatic cell death after APAP is generally considered necrotic in mice and in humans. Recent findings suggest that the receptor interacting protein kinase 3 (RIP3) acts as a switch from apoptosis to necrosis (programmed necrosis). Thus, the aim of the current investigation was to determine if RIP3 is involved in APAP-induced liver cell death. APAP (200-300 mg/kg) caused glutathione depletion and protein adduct formation, oxidant stress, mitochondrial release of apoptosis inducing factor, and nuclear DNA fragmentation resulting in centrilobular necrosis in C57Bl/6J mice. Inhibiting RIP3 protein induction with antisense morpholinos in wild-type animals or using RIP3-deficient mice had no effect on protein adduct formation but attenuated all other parameters, including necrotic cell death, at 6 hours after APAP. In addition, cultured hepatocytes from RIP3-deficient mice showed reduced injury compared to wild-type cells after 24 hours. Interestingly, APAP-induced mitochondrial translocation of dynamin-related protein 1 (Drp1), the initiator of mitochondrial fission, was inhibited by reduced RIP3 protein expression and the Drp1 inhibitor MDIVI reduced APAP-induced cell death at 24 hours. All of these protective effects were lost after 24 hours in vivo or 48 hours in vitro. Conclusion: RIP3 is an early mediator of APAP hepatotoxicity, involving modulation of mitochondrial dysfunction and oxidant stress. Controlling RIP3 expression could be a promising new approach to reduce APAP-induced liver injury, but requires complementary strategies to control mitochondrial dysfunction for long-term protection. (Hepatology 2013; 58:2099–2108)
Resource implications of patients with multidrug resistant tuberculosis
Authors: V L C White
Journal: Thorax (2000)

<h3>BACKGROUND</h3> Multidrug resistant tuberculosis (MDR TB) requires a complex drug regimen and lengthy multidisciplinary care. The financial cost of successful management of each case is potentially large. <h3>METHODS</h3> The costs of managing nine HIV negative patients with pulmonary MDR TB were compared with 18 age group and ethnicity matched controls with fully sensitive disease. Calculations included: cost of outpatient visits and inpatient stays including negative pressure isolation; costs of drug provision and toxicity monitoring; costs of additional procedures and multidisciplinary referrals. <h3>RESULTS</h3> The mean cost of managing a case of pulmonary MDR TB was in excess of £60 000 and for sensitive disease it was £6040. <h3>CONCLUSIONS</h3> Clinicians and healthcare commissioning authorities may both be underestimating the costs of managing MDR TB, and accordingly the consequences for units dealing with such cases may be serious. Funding of care for MDR TB in the UK requires strategic decisions at regional or governmental level.
Hypermethylation and Silencing of the Putative Tumor Suppressor<b><i>Tazarotene-Induced Gene 1</i></b>in Human Cancers
Authors: Emile M. Youssef, Xu-qi Chen, Eisaku Higuchi, Yutaka Kondo, Guillermo Garcia-Manero, Reuben Lotan, Jean-Pierre J. Issa
Journal: Cancer Research (2004)

Abstract A variety of tumor suppressor genes are down-regulated by hypermethylation during carcinogenesis. Using methylated CpG amplification-representation difference analysis, we identified a DNA fragment corresponding to the Tazarotene-induced gene 1 (TIG1) promoter-associated CpG island as one of the genes hypermethylated in the leukemia cell line K562. Because TIG1 has been proposed to act as a tumor suppressor, we tested the hypothesis that cytosine methylation of the TIG1 promoter suppresses its expression and causes a loss of responsiveness to retinoic acid in some neoplastic cells. We examined TIG1 methylation and expression status in 53 human cancer cell lines and 74 primary tumors, including leukemia and head and neck, breast, colon, skin, brain, lung, and prostate cancer. Loss of TIG1 expression was strongly associated with TIG1 promoter hypermethylation (P &amp;lt; 0.001). There was no correlation between TIG1 promoter methylation and that of retinoid acid receptor β2 (RARβ2), another retinoic-induced putative tumor suppressor gene (P = 0.78). Treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine for 5 days restored TIG1 expression in all eight silenced cell lines tested. TIG1 expression was also inducible by treatment with 1 μm all-trans-retinoic acid for 3 days except in densely methylated cell lines. Treatment of the K562 leukemia cells with demethylating agent combined with all-trans-retinoic acid induced apoptosis. These findings indicate that silencing of TIG1 promoter by hypermethylation is common in human cancers and may contribute to the loss of retinoic acid responsiveness in some neoplastic cells.
β-Catenin/Wnt Signaling Regulates Expression of the Membrane Type 3 Matrix Metalloproteinase in Gastric Cancer
Authors: Andrew M. Lowy, Wilson M. Clements, John Bishop, Ling Kong, Tera Bonney, Karena Sisco, Bruce Aronow, Cecilia Fenoglio-Preiser, Joanna Groden
Journal: Cancer Research (2006)

Abstract Activation of Wnt signaling through β-catenin dysregulation occurs in numerous human tumors, including gastric cancer. The specific consequences of Wnt signaling in gastric cancer, however, are not well characterized. This study shows that the introduction of mutant β-catenin into gastric cancer cell lines by adenoviral infection enhances invasiveness and proliferation and up-regulates the expression of the gene encoding the matrix metalloproteinase (MMP) family member membrane type 3 MMP (MT3-MMP). Up-regulation of MT3-MMP is critical to the invasive phenotype as shown by small interfering RNA (siRNA) studies. Immunohistochemical staining also showed that MT3-MMP was highly expressed in gastric cancers with activating β-catenin mutations. These observations suggest that Wnt activation may contribute to gastric cancer progression by increasing the invasiveness of neoplastic cells in the stomach via up-regulation of MT3-MMP expression. (Cancer Res 2006; 66(9): 4734-41)
Normal levels of anticoagulant heparan sulfate are not essential for normal hemostasis
Authors: Sassan HajMohammadi, Keiichi Enjyoji, Marc Princivalle, Patricia Christi, Miroslav Lech, David Beeler, Helen Rayburn, John J. Schwartz, Samad Barzegar, Ariane I. de Agostini, Mark J. Post, Robert D. Rosenberg, Nicholas W. Shworak
Journal: Journal of Clinical Investigation (2003)

Endothelial cell production of anticoagulant heparan sulfate (HSact) is controlled by the Hs3st1 gene, which encodes the rate-limiting enzyme heparan sulfate 3-O-sulfotransferase-1 (3-OST-1). In vitro, HSact dramatically enhances the neutralization of coagulation proteases by antithrombin. The in vivo role of HSact was evaluated by generating Hs3st1–/– knockout mice. Hs3st1–/– animals were devoid of 3-OST-1 enzyme activity in plasma and tissue extracts. Nulls showed dramatic reductions in tissue levels of HSact but maintained wild-type levels of tissue fibrin accumulation under both normoxic and hypoxic conditions. Given that vascular HSact predominantly occurs in the subendothelial matrix, mice were subjected to a carotid artery injury assay in which ferric chloride administration induces de-endothelialization and occlusive thrombosis. Hs3st1–/– and Hs3st1+/+ mice yielded indistinguishable occlusion times and comparable levels of thrombin•antithrombin complexes. Thus, Hs3st1–/– mice did not show an obvious procoagulant phenotype. Instead, Hs3st1–/– mice exhibited genetic background–specific lethality and intrauterine growth retardation, without evidence of a gross coagulopathy. Our results demonstrate that the 3-OST-1 enzyme produces the majority of tissue HSact. Surprisingly, this bulk of HSact is not essential for normal hemostasis in mice. Instead, 3-OST-1–deficient mice exhibited unanticipated phenotypes suggesting that HSact or additional 3-OST-1–derived structures may serve alternate biologic roles.
THERAPEUTIC DEVELOPMENT AND MANAGEMENT OF AN ADOLESCENT RESIDENTIAL TREATMENT SERVICE IN A STATE HOSPITAL
Authors: JAMES F. SUESS, ARTHUR Y. HOSHINO
Journal: American Journal of Psychiatry (1961)

A total of 47 adolescent patients (26 males and 21 females) were treated in our units in 2⅓ years of operation. This total includes those patients previously mentioned who were subsequently found to be untreatable. There were 39 schizophrenics, 4 neurotics and 4 character disorders. Disposition of the patients did not significantly differ according to the sexes: 24 left the hospital as improved. These patients spent an average of 8 months (range 3 to 22 months) in the units. Sixteen adolescents are now in the units in active treatment and have spent an average of 11 months there (range 1 to 27 months). Seven patients were transferred unimproved to other parts of the hospital after spending an average of 12 months (range 1 to 23 months) before transfer. The 7 treatment failures were characterized as follows: Two patients were completely uncommunicative, one on the basis of organic damage, the other being severely autistic from early childhood. Two patients were in fact too old for the unit, being 20 years or over. One patient was a homosexual sociopath. One patient regressed to the point of being a completely infantile nursing problem who could not be adequately cared for in these active units. Finally, 1 of the older adolescents, having shown some definite improvement after 1 year, reached a plateau with little further change and was transferred to the insulin unit for further treatment. It is our opinion that an adolescent unit is a necessary part of any adult state hospital which admits these emotionally disturbed patients. We feel that a unit such as ours can be established wherever there is interest in the care and treatment of the adolescent, by making full use of available hospital milieu and community facilities. This presentation was not intended to contain the dynamic transactions and interpersonal operations of the patients and personnel in the units or of the parents and the hospital staff. This will be the subject of a latter report.
Genome-Wide Associations Between Hybrid Sterility QTL and Marker Transmission Ratio Distortion
Authors: L. C. Moyle
Journal: Molecular Biology and Evolution (2006)

Marker transmission ratio distortion (TRD) in genetic mapping populations is frequently ascribed to selection against allelic combinations that cause hybrid incompatibility. Accordingly, genomic regions of TRD should be nonrandomly associated (colocated) with loci that underlie hybrid incompatibility. To directly test this hypothesis, we evaluated the genome-wide qualitative and quantitative agreement between chromosomal regions exhibiting marker TRD and those known to contain hybrid incompatibility quantitative trait locus (QTL). Incompatibility data came from a near-isogenic line (NIL) analysis of pollen and seed sterility in a cross between two Solanum (formerly Lycopersicon) species. We assessed (1) whether these incompatibility loci are colocated with markers that show significant TRD in two earlier generations preceding these introgression lines and (2) whether the magnitude of marker distortion quantitatively matches the estimated strength of selection against each incompatibility locus. We found evidence that TRD regions are chromosomally colocated with hybrid incompatibility loci more frequently than is expected by chance: pollen sterility QTLs were most closely associated with distorted heterozygote frequencies in later-generation backcrosses. Nonetheless, there was no evidence for an association between TRD and seed sterility and little evidence of a quantitative association between the magnitude of marker TRD and the fitness effects of heterospecific alleles at each chromosomal location. We propose and test a model (the "dance partner" model) to explain several cases where regions of TRD are not associated with hybrid incompatibility loci. Under this model, some NILs containing greater than one heterospecific introgression may not express hybrid incompatibility phenotypes because they carry both appropriate genetic dance partners required for a fully functional interaction. Accordingly, negative interactions expressed in earlier backcross generations are masked in these double-introgression NILs. Based on this model, we identify the location of several new putative pairwise interactors underlying hybrid incompatibility in this species cross.