tbuckley/cabot-search huggingface dataset:
Acid-Base Status Determines the Renal Expression of Ca2+ and Mg2+ Transport Proteins
Authors: Tom Nijenhuis, Kirsten Y. Renkema, Joost G.J. Hoenderop, Rene[Combining Acute Accent] J.M. Bindels
Journal: Journal of the American Society of Nephrology (2006)

Chronic metabolic acidosis results in renal Ca2+ and Mg2+ wasting, whereas chronic metabolic alkalosis is known to exert the reverse effects. It was hypothesized that these adaptations are mediated at least in part by the renal Ca2+ and Mg2+ transport proteins. The aim of this study, therefore, was to determine the effect of systemic acid-base status on renal expression of the epithelial Ca2+ channel TRPV5, the Ca2+-binding protein calbindin-D28K, and the epithelial Mg2+ channel TRPM6 in relation to Ca2+ and Mg2+ excretion. Chronic metabolic acidosis that was induced by NH4Cl loading or administration of the carbonic anhydrase inhibitor acetazolamide for 6 d enhanced calciuresis accompanied by decreased renal TRPV5 and calbindin-D28K mRNA and protein abundance in wild-type mice. In contrast, metabolic acidosis did not affect Ca2+ excretion in TRPV5 knockout (TRPV5−/−) mice, in which active Ca2+ reabsorption is effectively abolished. This demonstrates that downregulation of renal Ca2+ transport proteins is responsible for the hypercalciuria. Conversely, chronic metabolic alkalosis that was induced by NaHCO3 administration for 6 d increased the expression of Ca2+ transport proteins accompanied by diminished urine Ca2+ excretion in wild-type mice. However, this Ca2+-sparing action persisted in TRPV5−/− mice, suggesting that additional mechanisms apart from upregulation of active Ca2+ transport contribute to the hypocalciuria. Furthermore, chronic metabolic acidosis decreased renal TRPM6 expression, increased Mg2+ excretion, and decreased serum Mg2+ concentration, whereas chronic metabolic alkalosis resulted in the exact opposite effects. In conclusion, these data suggest that regulation of Ca2+ and Mg2+ transport proteins contributes importantly to the effects of acid-base status on renal divalent handling.
Rabbit model of Lyme borreliosis: erythema migrans, infection-derived immunity, and identification of Borrelia burgdorferi proteins associated with virulence and protective immunity.
Authors: D M Foley, R J Gayek, J T Skare, E A Wagar, C I Champion, D R Blanco, M A Lovett, J N Miller
Journal: Journal of Clinical Investigation (1995)

Erythema migrans (EM), persistent skin infection, and visceral dissemination can be induced reproducibly in the adult male New Zealand White rabbit by intradermal injection of as few as 10(3) Borrelia burgdorferi. EM was found to persist for 7 +/- 3 d. Skin culture positivity (infection) cleared within a mean of 6.7 +/- 1.4 wk after infection and similarly visceral infection was not demonstrated after 8 wk; infection-derived immunity to intradermal challenge was evident 5 mo after initial infection. The extent of the protection against EM and dermal infection induced by untreated infection was directly related to the extent of prior in vitro passage of the B31 strain. Initial infection with as few as 4 x 10(3) B31 passage 4 induced complete protection against EM and skin infection upon subsequent challenge with 4 x 10(7) B31, passage 4. Initial infection with B31 passage 27 led to partial protection against EM along with complete protection against skin infection. Initial infection with passage 47 led to partial protection against EM, but conferred no protection against skin infection. Using serum from rabbits fully immune to reinfection, we defined a set of B. burgdorferi proteins present in virulent B31, but absent in the avirulent American Type Culture Collection B31 strain, termed "va" for virulent strain associated. The va proteins of B31 passages 1, 27, and 47 differed strikingly, thus raising the possibility that these changes may relate in a causal way to the differences in induction of protective immunity observed.
The Na+-dependent chloride-bicarbonate exchanger SLC4A8 mediates an electroneutral Na+ reabsorption process in the renal cortical collecting ducts of mice
Authors: Françoise Leviel, Christian A. Hübner, Pascal Houillier, Luciana Morla, Soumaya El Moghrabi, Gaëlle Brideau, Hassan Hatim, Mark D. Parker, Ingo Kurth, Alexandra Kougioumtzes, Anne Sinning, Vladimir Pech, Kent A. Riemondy, R. Lance Miller, Edith Hummler, Gary E. Shull, Peter S. Aronson, Alain Doucet, Susan M. Wall, Régine Chambrey, Dominique Eladari
Journal: Journal of Clinical Investigation (2010)

Regulation of sodium balance is a critical factor in the maintenance of euvolemia, and dysregulation of renal sodium excretion results in disorders of altered intravascular volume, such as hypertension. The amiloride-sensitive epithelial sodium channel (ENaC) is thought to be the only mechanism for sodium transport in the cortical collecting duct (CCD) of the kidney. However, it has been found that much of the sodium absorption in the CCD is actually amiloride insensitive and sensitive to thiazide diuretics, which also block the Na-Cl cotransporter (NCC) located in the distal convoluted tubule. In this study, we have demonstrated the presence of electroneutral, amiloride-resistant, thiazide-sensitive, transepithelial NaCl absorption in mouse CCDs, which persists even with genetic disruption of ENaC. Furthermore, hydrochlorothiazide (HCTZ) increased excretion of Na+ and Cl- in mice devoid of the thiazide target NCC, suggesting that an additional mechanism might account for this effect. Studies on isolated CCDs suggested that the parallel action of the Na+-driven Cl-/HCO3- exchanger (NDCBE/SLC4A8) and the Na+-independent Cl-/HCO3- exchanger (pendrin/SLC26A4) accounted for the electroneutral thiazide-sensitive sodium transport. Furthermore, genetic ablation of SLC4A8 abolished thiazide-sensitive NaCl transport in the CCD. These studies establish what we believe to be a novel role for NDCBE in mediating substantial Na+ reabsorption in the CCD and suggest a role for this transporter in the regulation of fluid homeostasis in mice.
Trends in Hospitalizations for Diabetes Among Children and Young Adults
Authors: Joyce M. Lee, Megumi J. Okumura, Gary L. Freed, Ram K. Menon, Matthew M. Davis
Journal: Diabetes Care (2007)

The purpose of this study was to examine national trends in hospitalizations associated with diabetes for U.S. children and young adults.The study included hospital discharges for individuals aged 0-29 years with a diagnosis of diabetes (250.xx) in the Nationwide Inpatient Sample (1993-2004). Outcomes were weighted, nationally representative estimates of the frequency of population-adjusted hospital discharges and hospital charges (2004 $U.S.).Among individuals aged 0-29 years, population-adjusted rates of hospitalizations associated with diabetes over the 12-year period increased by 38% (99.1 of 100,000 in 1993 and 136.4 of 100,000 in 2004; P < 0.001 for curvilinear trend). Age-specific increases in annual hospitalizations for diabetes occurred primarily among individuals aged 20-24 years (152.6 of 100,000 in 1993 and 222.2 of 100,000 in 2004) and 25-29 years (224.9 of 100,000 in 1993 and 331.2 of 100,000 in 2004). Trends in hospitalizations among younger individuals showed no significant patterns. Hospitalization rates were consistently higher for females than for males, with a greater rate of increase for females (42%) than for males (29%) (P < 0.001). Inflation-adjusted total charges for diabetes hospitalizations increased 130%, from $1.05 billion in 1993 to $2.42 billion in 2004.The number of young adults hospitalized with diabetes in the U.S. has increased significantly over the last decade. Sex-specific differences in hospitalization rates and trends in obesity among U.S. children may amplify future trends in diabetes hospitalizations and corresponding rapid growth in associated health care expenditures.
Mean platelet volume improves upon the megathrombocyte index but cannot replace the blood film examination in the evaluation of thrombocytopenia
Authors: Svetislava J. Vukelja, Jayashree Krishnan, Louis F. Diehl
Journal: American Journal of Hematology (1993)

The measurement of the number of platelets larger than 3 microns (megathrombocyte index) is the first element in the evaluation of thrombocytopenia. This is currently performed by counting the number of large platelets on the peripheral blood film. The MPV (mean platelet volume) is an automated measurement of the platelet volume. This study examines the mean values, correlations, sensitivity, specificity and the receiver operating characteristic curve (comparison of two tests) to determine which of these tests better separates the production state. For increased vs. decreased production, the MPV was 10.0 + 1.9 fL and 8.0 + 1.5 fL (P < .0001) respectively and the megathrombocyte index (MEGA) was 19.0 + 17.6% and 11.5 + 14.9% (P < .007) respectively. The correlation with the state of production was better for MPV (R = .47) than for MEGA (R = .20). For the MPV a sensitivity of 80% occurred with the MPV > or = 8.4 fL with a specificity of 71%. For a MEGA > or = 6%, the sensitivity was 80% but the specificity was 43%. For any MPV the sensitivity and specificity were better than for any MEGA. The Receiver Operating Characteristic Curve demonstrated that the MPV is a better test than the MEGA for separating the production into increased and decreased states. The MPV is a better test than the MEGA and will add to, but not replace, examination of the peripheral blood film in the diagnosis of thrombocytopenia.
Biomarker Discovery, Development, and Implementation in France: A Report from the French National Cancer Institute and Cooperative Groups
Authors: Fabrice Andre, Frederique Nowak, Monica Arnedos, Ludovic Lacroix, Patrice Viens, Fabien Calvo
Journal: Clinical Cancer Research (2012)

Abstract Biomarkers are increasingly changing the medical practice in oncology. One of the major challenges in the field of personalized medicine or biologically adapted therapies is to ensure a rapid and extensive implementation of emerging biomarkers as soon as proof of their medical usefulness is obtained. A special program has been developed in France to facilitate the assessment and use of biomarkers. The French National Cancer Institute has set up a total of 28 laboratories in public hospitals to perform biomarker testing for clinical use. This program is enabling all patients who present with cancer to receive free testing for biomarkers, such as K-Ras, epidermal growth factor receptor, c-Kit, and Braf mutations. Funding for these laboratories comes from the French Ministry of Health. The future of these laboratories includes the development of DNA arrays and multiplex technologies for clinical use. Toward that end, the French National Cancer Institute is financing several large clinical trials that several large clinical trials are currently evaluating the feasibility and medical utility of DNA arrays and next-generation sequencing in the context of academic centers. The programs are being run by cooperative groups. Clin Cancer Res; 18(6); 1555–60. ©2012 AACR.
Death and other time-related events after valve replacement.
Authors: E H Blackstone, J W Kirklin
Journal: Circulation (1985)

A total of 1533 patients received primary aortic and/or mitral valve replacement, with or without tricuspid valve surgery or other associated cardiac procedures, from January 1, 1975, to July 1, 1979. Actuarial survival at 5 years was 74%. The hazard function (instantaneous risk) of death was highest immediately after operation. Among the incremental risk factors for premature death from any cause were preoperative NYHA class, any valve lesion other than aortic stenosis, aortic cross-clamp time, and combined aortic and mitral valve replacement. Ten modes of death were identified, each with its unique hazard function and risk factors. The commonest mode was cardiac failure. Sudden death was the next commonest, and the early phase of its hazard function peaked about 3 weeks after operation. Seventy-five patients (6.7% of the 1533) had 103 valve reoperations in the follow-up period. Actuarial survival after reoperation was less than that after the primary operation; whether the reoperation was the first, second, or third was a risk factor. Actuarial freedom from prosthetic valve endocarditis (PVE) was 97% at 1 year, and that of periprosthetic leakage without evident infection was 98.8%; the hazard function for the event PVE had an early phase peaking at about 6 weeks and a constant low phase throughout, whereas that of periprosthetic leakage had a single early peaking phase. After reoperations, the actuarial freedom from PVE and periprosthetic leakage was less than that after the original operation. The risk factors for the development of periprosthetic leakage without evident infection were similar but not identical to those for PVE. Among patients receiving a bioprosthesis, 91% were free of bioprosthetic degeneration 5 years after operation. The hazard function was single and continuously rising, and young age and female gender were risk factors. Actuarial freedom from acute prosthetic thrombosis was 97.9% at 5 years. The single hazard function for this event peaked at 10 months. The risk of thrombosis was higher in female patients. The uses of this integrated study, and the inferences from it, are described.
Reliability and validity of 4-metre gait speed in COPD
Authors: Samantha S.C. Kon, Mehul S. Patel, Jane L. Canavan, Amy L. Clark, Sarah E. Jones, Claire M. Nolan, Paul Cullinan, Michael I. Polkey, William D-C. Man
Journal: European Respiratory Journal (2012)

In community-dwelling older adults, usual gait speed over 4 m (4MGS) consistently predicts greater risk of adverse health outcomes. The aims of the present study were to assess the reliability of the 4MGS and the relationship with established health outcome measures in chronic obstructive pulmonary disease (COPD). Test-retest and interobserver reliability of the 4MGS were measured in 80 and 58 COPD patients, respectively. In 586 COPD patients, the 4MGS, as well as forced expiratory volume in 1 s (FEV1), the incremental shuttle walk (ISW), Medical Research Council (MRC) dyspnoea scale and St George's Respiratory Questionnaire (SGRQ) were measured. Participants were stratified according to "slow" (<0.8 m·s(-1)) or "normal" 4MGS (≥0.8 m·s(-1)). Intra-class correlation coefficients for test-retest and interobserver reliability were 0.97 and 0.99, respectively. There was a significant positive correlation between 4MGS with ISW (ρ = 0.78; p<0.001) and a negative correlation with MRC dyspnoea scale and SGRQ (ρ = -0.55 and -0.44; p<0.001 for both). COPD patients with slow 4MGS had significantly reduced ISW and higher MRC dyspnoea scale and SGRQ than those with preserved walking speed, despite similar FEV1 % predicted. The 4MGS is reliable in COPD, correlates with exercise capacity, dyspnoea and health-related quality of life, and has potential as a simple assessment tool in COPD.
Improved Glucose Control With Weight Loss, Lower Insulin Doses, and No Increased Hypoglycemia With Empagliflozin Added to Titrated Multiple Daily Injections of Insulin in Obese Inadequately Controlled Type 2 Diabetes
Authors: Julio Rosenstock, Ante Jelaska, Guillaume Frappin, Afshin Salsali, Gabriel Kim, Hans J. Woerle, Uli C. Broedl
Journal: Diabetes Care (2014)

OBJECTIVE We investigated the efficacy and safety of the sodium glucose cotransporter 2 inhibitor, empagliflozin, added to multiple daily injections of insulin (MDI insulin) in obese patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS Patients inadequately controlled on MDI insulin ± metformin (mean HbA1c 8.3% [67 mmol/mol]; BMI 34.8 kg/m2; insulin dose 92 international units/day) were randomized and treated with once-daily empagliflozin 10 mg (n = 186), empagliflozin 25 mg (n = 189), or placebo (n = 188) for 52 weeks. Insulin dose was to remain stable in weeks 1–18, adjusted to meet glucose targets in weeks 19–40, then stable in weeks 41–52. The primary end point was change from baseline in HbA1c at week 18. Secondary end points were changes from baseline in insulin dose, weight, and HbA1c at week 52. RESULTS Adjusted mean ± SE changes from baseline in HbA1c were −0.50 ± 0.05% (−5.5 ± 0.5 mmol/mol) for placebo versus −0.94 ± 0.05% (−10.3 ± 0.5 mmol/mol) and −1.02 ± 0.05% (−11.1 ± 0.5 mmol/mol) for empagliflozin 10 mg and empagliflozin 25 mg, respectively, at week 18 (both P &amp;lt; 0.001). At week 52, further reductions with insulin titration resulted in changes from baseline in HbA1c of −0.81 ± 0.08% (−8.9 ± 0.9 mmol/mol), −1.18 ± 0.08% (−12.9 ± 0.9 mmol/mol), and −1.27 ± 0.08% (−13.9 ± 0.9 mmol/mol) with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively, and final HbA1c of 7.5% (58 mmol/mol), 7.2% (55 mmol/mol), and 7.1% (54 mmol/mol), respectively. More patients attained HbA1c &amp;lt;7% (&amp;lt;53 mmol/mol) with empagliflozin (31–42%) versus placebo (21%; both P &amp;lt; 0.01). Empagliflozin 10 mg and empagliflozin 25 mg reduced insulin doses (−9 to −11 international units/day) and weight (−2.4 to −2.5 kg) versus placebo (all P &amp;lt; 0.01) at week 52. CONCLUSIONS In obese, difficult-to-treat patients with T2DM inadequately controlled on high MDI insulin doses, empagliflozin improved glycemic control and reduced weight without increasing the risk of hypoglycemia and with lower insulin requirements.
NIMA-Related Kinases Defective in Murine Models of Polycystic Kidney Diseases Localize to Primary Cilia and Centrosomes
Authors: Moe R. Mahjoub, Melissa L. Trapp, Lynne M. Quarmby
Journal: Journal of the American Society of Nephrology (2005)

A key feature of the polycystic kidney diseases is aberrant cell proliferation, a consequence of dysfunctional ciliary signaling. The NIMA-related kinases (Nek) Nek1 and Nek8 carry the causal mutations of two of the eight established mouse models of polycystic kidneys. Nek proteins have roles in cell cycle and may contribute to coordinate regulation of cilia and cell-cycle progression. Herein is reported that in a mouse kidney epithelial cell line, mNek1 localizes to centrosomes in interphase and remains associated with the mitotic spindle pole during mitosis. In contrast, mNek8 localizes to the proximal region of the primary cilium and is not observed in dividing cells. Knockdown of mNek8 by siRNA does not affect ciliary assembly. Taken together with the phenotypes of the mutant mice, these data suggest that mNek1 and mNek8 provide links between cilia, centrosomes, and cell-cycle regulation.
Plasma Isoflavone Level and Subsequent Risk of Breast Cancer Among Japanese Women: A Nested Case-Control Study From the Japan Public Health Center-Based Prospective Study Group
Authors: Motoki Iwasaki, Manami Inoue, Tetsuya Otani, Shizuka Sasazuki, Norie Kurahashi, Tsutomu Miura, Seiichiro Yamamoto, Shoichiro Tsugane
Journal: Journal of Clinical Oncology (2008)

Because they have large variations in consumption, Asian countries are suitable settings for studies of the effect of relatively high-dose isoflavone intake on breast cancer risk. Nevertheless, no prospective study from Asia has assessed blood or urine levels as biomarkers of isoflavone intake.A total of 24,226 women ages 40 to 69 years in the Japan Public Health Center-based prospective study who responded to the baseline questionnaire and provided blood in 1990 to 1995 were observed to December 2002. During a mean 10.6 years of follow-up, 144 patients newly diagnosed with breast cancer were identified. Two matched controls for each patient were selected from the cohort. Isoflavone levels were assessed by plasma level and food frequency questionnaire, and the odds ratio of breast cancer according to isoflavone level was estimated using a conditional logistic regression model.We found a statistically significant inverse association between plasma genistein and risk of breast cancer, but no association for plasma daidzein. Adjusted odds ratios for the highest versus lowest quartile of plasma level were 0.34 for genistein (95% CI, 0.16 to 0.74; P for trend, .02) and 0.71 for daidzein (95% CI, 0.35 to 1.44; P for trend, .54). Median plasma genistein values in the control group were 31.9 ng/mL for the lowest and 353.9 ng/mL for the highest quartile groups. Regarding dietary intake of isoflavones, nonsignificant inverse associations were observed for both genistein and daidzein.This nested case-control study found an inverse association between plasma genistein and the risk of breast cancer in Japan.
Angiotensin II Type 2 Receptor Is Upregulated in Human Heart With Interstitial Fibrosis, and Cardiac Fibroblasts Are the Major Cell Type for Its Expression
Authors: Yoshiaki Tsutsumi, Hiroaki Matsubara, Naohiko Ohkubo, Yasukiyo Mori, Yoshihisa Nozawa, Satoshi Murasawa, Kazuhisa Kijima, Katsuya Maruyama, Hiroya Masaki, Yasutaka Moriguchi, Yasunobu Shibasaki, Hiroshi Kamihata, Mitsuo Inada, Toshiji Iwasaka
Journal: Circulation Research (1998)

Abstract —The expression pattern of angiotensin (Ang) II type 2 receptor (AT 2 -R) in the remodeling process of human left ventricles (LVs) remains poorly defined. We analyzed its expression at protein, mRNA, and cellular levels using autopsy, biopsy, or operation LV samples from patients with failing hearts caused by acute (AMI) or old (OMI) myocardial infarction and idiopathic dilated cardiomyopathy (DCM) and also examined functional biochemical responses of failing hearts to Ang II. In autopsy samples from the nonfailing heart group, the ratio of AT 1 -R and AT 2 -R was 59% and 41%, respectively. The expression of AT 2 -R was markedly increased in DCM hearts at protein (3.5-fold) and mRNA (3.1-fold) levels compared with AMI or OMI. AT 1 -R protein and mRNA levels in AMI hearts showed 1.5- and 2.1-fold increases, respectively, whereas in OMI and DCM hearts, AT 1 -R expression was significantly downregulated. AT 1 -R–mediated response in inositol phosphate production was significantly attenuated in LV homogenate from failing hearts compared with nonfailing hearts. AT 2 -R sites were highly localized in the interstitial region in either nonfailing or failing heart, whereas AT 1 -R was evenly distributed over myocardium at lower densities. Mitogen-activated protein kinase (MAPK) activation by Ang II was significantly decreased in fibroblast compartment from the failing hearts, and pretreatment with AT 2 -R antagonist caused an additional significant increase in Ang II–induced MAPK activity (36%). Cardiac hypertrophy suggested by atrial and brain natriuretic peptide levels was comparably increased in OMI and DCM, whereas accumulation of matrix proteins such as collagen type 1 and fibronectin was much more prominent in DCM than in OMI. These findings demonstrate that (1) AT 2 -R expression is upregulated in failing hearts, and fibroblasts present in the interstitial regions are the major cell type responsible for its expression, (2) AT 2 -R present in the fibroblasts exerts an inhibitory effect on Ang II–induced mitogen signals, and (3) AT 1 -R in atrial and LV tissues was downregulated during chronic heart failure, and AT 1 -R–mediated functional biochemical responsiveness was decreased in the failing hearts. Thus, the expression level of AT 2 -R is likely determined by the extent of interstitial fibrosis associated with heart failure, and the expression and function of AT 1 -R and AT 2 -R are differentially regulated in failing human hearts.