tbuckley/cabot-search huggingface dataset:
Correlations Between Serum Bilirubin Levels and Diabetic Nephropathy Progression Among Japanese Type 2 Diabetic Patients: A Prospective Cohort Study (Diabetes Distress and Care Registry at Tenri [DDCRT 5])
Authors: Tsuyoshi Mashitani, Yasuaki Hayashino, Shintarou Okamura, Satoru Tsujii, Hitoshi Ishii
Journal: Diabetes Care (2013)

OBJECTIVE To assess the correlations between serum bilirubin levels and diabetic nephropathy development and progression in type 2 diabetic patients. RESEARCH DESIGN AND METHODS Longitudinal data were obtained from 2,511 type 2 diabetic patients registered in a Japanese diabetes registry. To assess the independent correlations between serum bilirubin levels and either the development or progression of diabetic nephropathy, we used logistic regression analysis adjusted for potential confounders. RESULTS The median follow-up period was 503.4 days (range 238-777). The mean patient age, BMI, and HbA1c level was 65.2 years, 24.7 kg/m(2), and 7.5% (58.5 mmol/mol), respectively. Baseline serum bilirubin levels were significantly associated with the urinary albumin-creatinine ratio at baseline (P < 0.001) and 1 year after registration (P < 0.001). Multivariable adjusted odds ratios for progression from microalbuminuria to macroalbuminuria for the second, third, and fourth quartile of serum bilirubin levels were 0.89 (95% CI 0.49-1.58), 0.93 (0.47-1.83), and 0.33 (0.13-0.84), respectively, showing a statistically significant linear trend across categories (P = 0.032). However, this trend disappeared after adjustment for hemoglobin levels. CONCLUSIONS Serum bilirubin levels were associated with diabetic nephropathy progression in type 2 diabetic patients independent of possible confounders. Serum bilirubin levels might be the link in the correlation between hemoglobin levels and nephropathy progression.
Conserved Features and Evolutionary Shifts of the EDA Signaling Pathway Involved in Vertebrate Skin Appendage Development
Authors: Sophie Pantalacci, Arnaud Chaumot, Gérard Benoît, Alexa Sadier, Frédéric Delsuc, Emmanuel J. P. Douzery, Vincent Laudet
Journal: Molecular Biology and Evolution (2008)

It is widely accepted that evolutionary changes in conserved developmental signaling pathways play an important role in morphological evolution. However, few in silico studies were interested in tracking such changes in a signaling pathway. The Ectodysplasin (EDA) pathway provides an opportunity to fill this gap because it is involved in vertebrate skin appendage development such as scales, teeth, hair, and feathers that take an obvious part in the adaptation of species to their environment. We benefited from the large amount of genomic data now available to explore the evolution of the upstream genes of the EDA pathway. In mammals, these genes are eda (encoding 2 ligands, EDA-A1 and EDA-A2), edar (EDA-A1 receptor), edaradd (EDA receptor [EDAR] adapter), xedar (EDA-A2 receptor), and troy (a XEDAR-related receptor). We show that the evolution of EDA pathway genes combines both strongly conserved features and evolutionary shifts. These shifts are found at different signaling levels (from the ligand to intracellular signaling) and at different taxonomic levels (class, suborder, and genera). Although conserved features likely participate to the similarities found in the early development of vertebrate skin appendages, these shifts might account for innovations and specializations. Moreover, our study demonstrates that we can now benefit from the large number of sequenced vertebrate genomes to explore the evolution of specific signaling pathways and thereby to open new perspectives for developmental biology and evolutionary developmental biology.
Fetal risk from ACE inhibitors in the first trimester
Authors: A. A. Mitchell
Journal: BMJ (2011)

Evidence is reassuring, but risks remain from the hypertension itself

As in the general population, management of hypertension in pregnant women is complicated by factors that may be difficult to control (such as diabetes, obesity, and smoking). However, the choice of antihypertensive drug is uniquely complicated in pregnancy, because the clinician not only has to consider the comparative safety and efficacy of various drugs from the mother’s perspective, but also consider the effects on the fetus. Rising rates of hypertension related to obesity and diabetes heighten this concern. Furthermore, therapeutic choices cannot wait until pregnancy is recognised—because about half of pregnancies (at least in the United States) are unplanned, fetal exposure early in the first trimester is a distinct possibility. Thus, fetal concerns should be taken into account when prescribing antihypertensives to all women of childbearing potential—a considerable clinical population. In the linked retrospective cohort study (doi: 10.1136/bmj.d5931), Li and colleagues assess the association between the use of angiotensin converting enzyme (ACE) inhibitors in mothers during the first trimester and the risk of malformations in their offspring.1 

Few studies have been large and …
High-intensity training following lung cancer surgery: a randomised controlled trial
Authors: E. Edvardsen, O. H. Skjonsberg, I. Holme, L. Nordsletten, F. Borchsenius, S. A. Anderssen
Journal: Thorax (2014)

<h3>Background</h3> Many patients with lung cancer are deconditioned with poor physical fitness. Lung resection reduces physical fitness further, impairing the patient9s ability to function in daily life. <h3>Methods</h3> We conducted a single-blind randomised controlled trial of high-intensity endurance and strength training (60 min, three times a week, 20 weeks), starting 5–7 weeks after surgery. The control group received standard postoperative care. The primary outcome was the change in peak oxygen uptake measured directly during walking until exhaustion. Other outcomes included changes in pulmonary function, muscular strength by one-repetition maximum (1RM), total muscle mass measured by dual energy X-ray absorptiometry, daily physical functioning and quality of life (QoL). <h3>Results</h3> The intention-to-treat analysis of the 61 randomised patients showed that the exercise group had a greater increase in peak oxygen uptake (3.4 mL/kg/min between-group difference, p=0.002), carbon monoxide transfer factor (Tlco) (5.2% predicted, p=0.007), 1RM leg press (29.5 kg, p&lt;0.001), chair stand (2.1 times p&lt;0.001), stair run (4.3 steps, p=0.002) and total muscle mass (1.36 kg, p=0.012) compared with the controls. The mean±SD QoL (SF-36) physical component summary score was 51.8±5.5 and 43.3±11.3 (p=0.006), and the mental component summary score was 55.5±5.3 and 46.6±14.0 (p=0.015) in the exercise and control groups, respectively. <h3>Conclusions</h3> In patients recently operated for lung cancer, high-intensity endurance and strength training was well tolerated and induced clinically significant improvements in peak oxygen uptake, Tlco, muscular strength, total muscle mass, functional fitness and QoL. This study may provide a basis for exercise therapy after lung cancer surgery. <h3>Trial registration number</h3> NCT01748981.
Correlation Between Natural and Antibody-Dependent Cell-Mediated Cytotoxicity Against Tumor Targets in the Mouse. I. Distribution of the Reactivity
Authors: Angela Santoni, Ronald B. Herberman, Howard T. Holden
Journal: JNCI Journal of the National Cancer Institute (1979)

Direct comparison of natural killer (NK) activity against mouse tumor cells and antibody-dependent cell-mediated cytotoxicity (ADCC) against mouse tumor target cells coated with alloantisera indicated that the effector cells shared similar distribution patterns and had similar characteristics. The same lymphoid cell populations were tested simultaneously for NK activity and for ADCC. For ADCC, an 18-hour 51Cr release cytotoxicity assay was used. All the characteristics of the NK activity were the same regardless of whether the 51Cr release assay was performed for the usual 4 hours or for 18 hours. The levels of NK and ADCC reactivities of individual mice fluctuated in parallel; i.e., animals with high or low NK activity had correspondingly high or low ADCC. Peak activity for both functions occurred in mice between 5 and 9 weeks of age. Both effector activities were high in CBA and C3Hf mice and in several strains of nude mice, intermediate in C57BL/6 and BALB/c mice, and low in SJL mice. Organ distribution for both activities also correlated well, with the highest activities in cells from the spleen and peritoneal cavity, intermediate activities in cells from the lymph nodes and bone marrow, and the lowest activities in the cells from the thymus. Agents such as lymphocytic choriomeningitis virus that are capable of augmenting NK activity had a similar effect on ADCC. Conversely, when NK activity was depressed by the presence of murine sarcoma virus-induced tumors, ADCC was also depressed. Although the two effector functions produced synergistic results against target cells sensitive to NK, susceptibility to NK activity was not a prerequisite for susceptibility to ADCC; target cells resistant to NK activity could be lysed when they were coated with alloantibody.
Effect of Misclassified Underlying Cause of Death on Survival Estimates of Colon and Rectal Cancer
Authors: D. Yin, C. R. Morris, J. H. Bates, R. R. German
Journal: JNCI Journal of the National Cancer Institute (2011)

Inaccurate coding of patients' Underlying Cause of Death (UCOD) has constrained cause-specific survival estimates for colon and rectal cancers. Using California data from the Accuracy of Cancer Mortality study, we compared the cancer site data from the California Cancer Registry (CCR) with UCODs reported on death certificates and reclassified the UCODs based on cancer registry data when they disagreed. We then calculated 1-, 3-, 5-, and 10-year cause-specific survival for colon and rectal cancers separately, before and after the reclassification. Records from 26 312 colon and 10 687 rectal cancer patients were examined. UCOD records disagreed with CCR records for 700 (6%) of 11 404 colon cancer deaths and with 1958 (39%) of 5011 rectal cancer deaths, and 82% of the misclassified rectal cancer deaths were coded as colon cancer deaths in the UCOD. Reclassification decreased cause-specific survival for both colon and rectal cancers, but the impact was more pronounced for rectal cancer (eg, 5-year cause-specific survival of colon cancer decreased by 2.8% and of rectal cancer decreased by 20.0% relative to previous estimates; absolute rates changed from 65.4% to 63.6%, and 81.2% to 64.9%, respectively, after reclassification). Interchangeable use of the terms colon cancer and colorectal cancer is likely to be one of the reasons for UCOD misclassification. Educational measures could improve the accuracy of UCOD for colon and rectal cancer deaths.
Effects of calcium channel blocker on responses of blood flow, function, arrhythmias, and extent of infarction following reperfusion in conscious baboons.
Authors: S F Vatner, T A Patrick, D R Knight, W T Manders, J T Fallon
Journal: Circulation Research (1988)

Two groups of chronically instrumented, conscious baboons were studied. The effects of coronary artery occlusion for 3 hours and reperfusion for 1 week were examined on measurements of left ventricular function, ischemic-zone wall thickness, regional myocardial blood flow, arrhythmias, and extent of necrosis. The experimental group of animals (n = 7) was treated with the calcium channel blocker nisoldipine (0.1 microgram/kg/min) from 1 hour after coronary occlusion to 3 hours after coronary reperfusion. The control group (n = 6) received the vehicle (n = 4) or saline (n = 2). The effects of coronary artery occlusion and reperfusion on arterial pressure, left ventricular systolic pressure, heart rate, and left ventricular dP/dt were similar in both groups. Systolic wall thickening was reversed to paradoxical wall thinning during occlusion in both groups, and there was no recovery to systolic wall thickening over the 1-week period in either group. There were differences in regional blood flow; during coronary artery occlusion, nisoldipine increased blood flow significantly in the endocardium and epicardium of nonischemic and ischemic zones. There was a major difference in the number of arrhythmic beats per minute on reperfusion; during reperfusion, the number of arrhythmias rose markedly in the vehicle-treated group but actually fell in the nisoldipine-treated group. The size of areas at risk, infarcts, infarcts related to the area at risk, and amount of total creatine kinase (CK) and MB-CK appearing in blood were not significantly different in the two groups. Thus, in the conscious baboon, nisoldipine administered 1 hour after coronary artery occlusion exerted a marked effect in diminishing reperfusion-induced arrhythmias and improved blood flow to the ischemic zone during occlusion but did not salvage ischemic tissue.
Olsalazine or sulphasalazine in first attacks of ulcerative colitis? A double blind study.
Authors: S S Rao, S A Dundas, C D Holdsworth, P A Cann, K R Palmer, C L Corbett
Journal: Gut (1989)

Olsalazine (2 g/day) and sulphasalazine (3 g/day) were compared in a double blind three centre trial in 37 patients presenting with first attack of distal colitis. Sigmoidoscopic appearances, rectal biopsies, and symptom and stool diary records were used to assess benefit and adverse effects. Both groups showed a similar decrease in stool frequency (p less than 0.001). The proportion of unformed stools was also decreased, but to a lesser extent (p less than 0.05) in those taking olsalazine (78% v 55%; p less than 0.001) compared with those taking sulphasalazine (72% v 28%; p less than 0.001). There was a diminution in the proportion of stools containing blood in both groups (olsalazine: 61% v 22%; p less than 0.001/sulphasalazine: 67% v 37%; p less than 0.001). Sigmoidoscopic and histological appearances and clinical activity improved significantly and to a similar extent in both groups. Intolerance was encountered in two patients on olsalazine and four on sulphasalazine; intolerance to sulphasalazine being even higher (five of seven patients) in a preliminary study using a dose of sulphasalazine releasing the same amount of 5-aminosalicylic acid as 2 g olsalazine. Olsalazine was at least as effective as sulphasalazine in the treatment of new patients with distal colitis, and in a dose releasing an equivalent amount of 5-aminosalicylic acid was better tolerated.
Ozone interaction with rodent lung. III. Oxidation of reduced glutathione and formation of mixed disulfides between protein and nonprotein sulfhydryls.
Authors: A J DeLucia, M G Mustafa, M Z Hussain, C E Cross
Journal: Journal of Clinical Investigation (1975)

Nonprotein sulfhydryls (NPSH), a major source of cellular reducing substances, were examined in lung tissue after short-term exposure of rats to O3. While the NPSH level was unaffected by low-level exposures (e.g., 0.8 ppm for up to 24 h or 1.5 ppm for up to 8 h), it was significantly lowered by higher exposure regimens (e.g., 25 per cent after 2 ppm for 8 h and 49 per cent after 4 ppm for 6 h). After exposure to 4 ppm O3 for 6 h the level of reduced glutathione (GSH), which accounted for approximately 90 per cent of NPSH in the lung, decreased 40 per cent but without a rise in the level of oxidized gluathione (GSSG). Treatment of lung homogenate with borohydride led to recovery of NPSH in exposed lungs to control values, suggesting that NPSH or GSH oxidation during in vivo O3 exposure resulted in formation of mixed disulfides with other sulfhydryl (SH) groups of lung tissue. Extracts of borohydride-treated particulate and supernatant fractions of lung homogenate were analyzed for NPSH by paper chromatography. From this analysis GSH appeared to be the only NPSH bound to lung tissue proteins via mixed disulfide linkage. The formation of mixed disulfides appeared to be a transient phenomenon. Immediately after a 4-h exposure to 3 ppm O3 the level of mixed disulfides was small (15 per cent of the total NPSH) but attained a peak (equivalent to 0.6 mumol NPSH/lung) after a recovery for 24 h. However, the level diminished considerably within 48 h of recovery.
Hemizygous Deficiency of Krüppel-Like Factor 2 Augments Experimental Atherosclerosis
Authors: G. Brandon Atkins, Yunmei Wang, Ganapati H. Mahabeleshwar, Hong Shi, Huiyun Gao, Daiji Kawanami, Viswanath Natesan, Zhiyong Lin, Daniel I. Simon, Mukesh K. Jain
Journal: Circulation Research (2008)

Krüppel-like factor (KLF)2 is a central regulator of endothelial and monocyte/macrophage gene expression and function in vitro. Although the composite effects of KLF2 in these 2 cell types predict that it likely inhibits vascular inflammation, the role of KLF2 in this process in vivo is uncharacterized. In this study, we provide evidence that hemizygous deficiency of KLF2 increased diet-induced atherosclerosis in apolipoprotein E-deficient mice. Our studies highlight an important role for KLF2 in primary macrophage foam cell formation via the potential regulation of the key lipid binding protein adipocyte protein 2/fatty acid-binding protein 4. These novel observations establish that KLF2 is an atheroprotective factor.
The Diagnosis and Therapy of Tuberculosis During the Past 100 Years
Authors: Denis A. Mitchison
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Methods for the radiographic diagnosis of tuberculosis have improved from simple fluoroscopy to computerized tomography. Although direct smear examination is still the most widely used bacteriological method of diagnosis, cultural methods with selective liquid media are sensitive and rapid. The use of antituberculosis drugs has changed tuberculosis from a disease with about a 50% mortality, treated by measures to collapse the affected lung lesions and by rest for the patient, to a condition successfully curable by chemotherapy. Key steps in the development of modern chemotherapy regimens were the demonstrations in clinical trials that (1) streptomycin was effective; (2) combination of drugs prevented the emergence of drug-resistant Mycobacterium tuberculosis; (3) chemotherapy under domiciliary conditions was effective and did not put family members at risk of infection; (4) patient compliance could be assisted by fully supervised intermittent regimens, or more effectively, by (5) shortening treatment by the introduction of rifampin and pyrazinamide, the two most potent sterilizing drugs, into the regimens. Regimens were divided into an initial intensive phase, while bacterial populations were high, and a longer continuation phase to complete sterilization. Pyrazinamide was shown to sterilize only in the intensive phase. The treatment of nonpulmonary tuberculosis followed the same plan, but when bacterial populations are low, fewer drugs are required in combination.
Neutrophil protein kinase Cδ as a mediator of stroke-reperfusion injury
Authors: Wen-Hai Chou, Doo-Sup Choi, Hong Zhang, Dezhi Mu, Tom McMahon, Viktor N. Kharazia, Clifford A. Lowell, Donna M. Ferriero, Robert O. Messing
Journal: Journal of Clinical Investigation (2004)

Thrombolysis is widely used to intervene in acute ischemic stroke, but reestablishment of circulation may paradoxically initiate a reperfusion injury. Here we describe studies with mice lacking protein kinase Cδ (PKCδ) showing that absence of this enzyme markedly reduces reperfusion injury following transient ischemia. This was associated with reduced infiltration of peripheral blood neutrophils into infarcted tissue and with impaired neutrophil adhesion, migration, respiratory burst, and degranulation in vitro. Total body irradiation followed by transplantation with bone marrow from PKCδ-null mice donors reduced infarct size and improved neurological outcome in WT mice, whereas marrow transplantation from WT donors increased infarction and worsened neurological scores in PKCδ-null mice. These results indicate an important role for neutrophil PKCδ in reperfusion injury and strongly suggest that PKCδ inhibitors could prove useful in the treatment of stroke.
The Role of the Thymus in Immune Reconstitution in Aging, Bone Marrow Transplantation, and HIV-1 Infection
Authors: Barton F. Haynes, M. Louise Markert, Gregory D. Sempowski, Dhavalkumar D. Patel, Laura P. Hale
Journal: Annual Review of Immunology (2000)

The human thymus is a complex chimeric organ comprised of central (thymic epithelial space) and peripheral (perivascular space) components that functions well into adult life to produce naive T lymphocytes. Recent advances in identifying thymic emigrants and development of safe methods to study thymic function in vivo in adults have provided new opportunities to understand the role that the human thymus plays in immune reconstitution in aging, in bone marrow transplantation, and in HIV-1 infection. The emerging concept is that there are age-dependent contributions of thymic emigrants and proliferation of postthymic T cells to maintain the peripheral T cell pool and to contribute to T cell regeneration, with the thymus contributing more at younger ages and peripheral T cell expansion contributing more in older subjects. New studies have revealed a dynamic interplay between postnatal thymus output and peripheral T cell pool proliferation, which play important roles in determining the nature of immune reconstitution in congenital immunodeficiency diseases, in bone marrow transplantation, and in HIV-1 infection. In this paper, we review recent data on human postnatal thymus function that, taken together, support the notion that the human thymus is functional well into the sixth decade and plays a role throughout life to optimize human immune system function.
Proposed Medical Benefit Society
Authors: J. W. H. D. Harris
Journal: BMJ (1883)

Inhibition of thiamine transporters has been proposed as a putative mechanism for the observation of Wernicke’s encephalopathy and subsequent termination of clinical development of fedratinib, a Janus kinase inhibitor (JAKi). This study aimed to determine the potential for other JAKi to inhibit thiamine transport using human epithelial colorectal adenocarcinoma (Caco-2) and thiamine transporter (THTR) overexpressing cells and to better elucidate the structural basis for interacting with THTR. Only JAKi containing a 2,4-diaminopyrimidine were observed to inhibit thiamine transporters. Fedratinib inhibited thiamine uptake into Caco-2 cells (IC<sub>50</sub> = 0.940 <i>µ</i>M) and THTR-2 (IC<sub>50</sub> = 1.36 <i>µ</i>M) and, to a lesser extent, THTR-1 (IC<sub>50</sub> = 7.10 <i>µ</i>M) overexpressing cells. Two other JAKi containing this moiety, AZD1480 and cerdulatinib, were weaker inhibitors of the thiamine transporters. Other JAKi—including monoaminopyrimidines, such as momelotinib, and nonaminopyrimidines, such as filgotinib—did not have any inhibitory effects on thiamine transport. A pharmacophore model derived from the minimized structure of thiamine suggests that 2,4-diaminopyrimidine–containing compounds can adopt a conformation matching several key features of thiamine. Further studies with drugs containing a 2,4-diaminopyrimidine resulted in the discovery that the antibiotic trimethoprim also potently inhibits thiamine uptake mediated by THTR-1 (IC<sub>50</sub> = 6.84 <i>µ</i>M) and THTR-2 (IC<sub>50</sub> = 5.56 <i>µ</i>M). Fedratinib and trimethoprim were also found to be substrates for THTR, a finding with important implications for their disposition in the body. In summary, our results show that not all JAKi have the potential to inhibit thiamine transport and further establish the interaction of these transporters with xenobiotics.