tbuckley/cabot-search huggingface dataset:
Association of the Multidrug Resistance-1 Gene Single-Nucleotide Polymorphisms with the Tacrolimus Dose Requirements in Renal Transplant Recipients
Authors: Dany Anglicheau, Céline Verstuyft, Pierre Laurent-Puig, Laurent Becquemont, Marie-Hélène Schlageter, Bruno Cassinat, Philippe Beaune, Christophe Legendre, Eric Thervet
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. The immunosuppressive drug tacrolimus, whose pharmacokinetic characteristics display large interindividual variations, is a substrate for P-glycoprotein (P-gp), the product of the multidrug resistance-1 (<i>MDR1</i>) gene. Some of the single nucleotide polymorphisms (SNP) of <i>MDR1</i> reported correlated with the <i>in vivo</i> activity of P-gp. Because P-gp is known to control tacrolimus intestinal absorption, it was postulated that these polymorphisms are associated with tacrolimus pharmacokinetic variations in renal transplant recipients. The objective of this study was to evaluate in a retrospective study of 81 renal transplant recipients the effect on tacrolimus dosages and concentration/dose ratio of four frequent <i>MDR1</i> SNP possibly associated with P-gp function (T-129C in exon 1b, 1236C&gt;T in exon 12, 2677G&gt;T,A in exon 21, and 3435C&gt;T in exon 26). As in the general population, the SNP in exons 12, 21, and 26 were frequent (16, 17.3, and 22.2% for the variant homozygous genotype, respectively) and exhibited incomplete linkage disequilibrium. One month after tacrolimus introduction, exon 21 SNP correlated significantly with the daily tacrolimus dose (<i>P</i> ≤ 0.05) and the concentration/dose ratio (<i>P</i> ≤ 0.02). Tacrolimus dose requirements were 40% higher in homozygous than wild-type patients for this SNP. The concentration/dose ratio was 36% lower in the wild-type patients, suggesting that, for a given dose, their tacrolimus blood concentration is lower. Haplotype analysis substantiated these results and suggested that exons 26 and 21 SNP may be associated with tacrolimus dose requirements. Genotype monitoring of the <i>MDR1</i> gene reliably predicts the optimal dose of tacrolimus in renal transplant recipients and may predict the initial daily dose needed by individual patients to obtain adequate immunosuppression. E-mail: Dany.Anglicheau@biomedicale. univ-paris5.fr
Carbon Monoxide Poisoning Deaths Associated With Camping—Georgia, March 1999
Authors: R Wheeler, MA Koponen, AB John, PJ Meehan, Newton County, KE Powell
Journal: JAMA (1999)

Carbon monoxide (CO) is an odorless, colorless, nonirritating gas produced by the incomplete combustion of carbon-based fuels. CO exposure is responsible for more fatal unintentional poisonings in the United States than any other agent, with the highest incidence occurring during the cold-weather months (1 ). Although most of these deaths occur in residences or motor vehicles (2 ), two incidents among campers in Georgia illustrate the danger of CO in outdoor settings. This report describes the two incidents, which resulted in six deaths, and provides recommendations for avoiding CO poisoning in outdoor settings. Cases 1‐4. On the afternoon of March 14, 1999, a 51-year-old man, his 10-year-old son, a 9-year-old boy, and a 7-year-old girl were found dead inside a zipped-up, 10-foot by 14-foot, two-room tent at their campsite in southeast Georgia (a pet dog also died). A propane gas stove, still burning, was found inside the tent; the stove apparently had been brought inside to provide warmth. The occupants had died during the night. Postmortem carboxyhemoglobin (COHb) levels measured 50%, 63%, 69%, and 63%, respectively, in the four decedents (in the general U.S. population, COHb concentrations average 1% in nonsmokers and 4% in smokers [3 ]).
Trusting in a better future: the global environment facility.
Authors: W C Holton
Journal: Environmental Health Perspectives (2000)

Individual countries acting alone cannot solve environmental problems that span national borders. The Global Environment Facility (GEF) was created in 1991 to serve as a mechanism for international cooperation in the funding of grants to address concerns in four areas of the global environment: biological diversity, climate change, international waters, and ozone layer depletion. To date, more than 500 projects have been funded with over $2 billion of GEF funds and another $5 billion leveraged from public and private sources, including $2 billion in matching funds from developing countries.
The forgotten role of lymphangitis in Crohn's disease
Authors: H J Van Kruiningen, J.-F. Colombel
Journal: Gut (2007)

<h3></h3> Research into Crohn’s disease has recently been focused on the genetics of the patient, the gastrointestinal flora, the gut epithelium and mucosal immune responses. For over 60 years pathologists have reported that the fundamental alteration in Crohn’s disease occurs in regional lymphatics of the intestine—the disease is a lymphocytic and granulomatous lymphangitis. At an earlier time, experimental sclerosis of regional intestinal lymphatics of the pig produced a chronic segmental enteritis with many features of Crohn’s disease, including lymphocytic and granulomatous lymphangitis of the bowel wall and enteroenteric and enterocutaneous fistulas. In Crohn’s disease, differences in the anatomic distribution of vasa recta appear to explain long-segment disease of the ileum and short-segment disease of the more proximal intestine. A variety of bacteria and viruses cause lymphangitis, suggesting that microorganisms may be at the centre of the basic changes in Crohn’s disease. Dietary antigens and lipids are worthy of consideration as well. Now that antibodies to label lymphatics are available, attention should be directed at defining the initial damage to lymphatic endothelium and agents that might be responsible.
Reduced cholesterol metastability of hepatic bile and its further decline in gall bladder bile in patients with cholesterol gall stones.
Authors: K Nakano, K Chijiiwa
Journal: Gut (1993)

The reduced metastability of biliary cholesterol in the gall bladder bile of patients with cholesterol gall stones has been well shown. The purpose of this study was to examine the hypothesis that such a difference in metastability already exists in hepatic bile. Paired hepatic and gall bladder bile samples were collected from 10 patients with cholesterol gall stones and six patients without gall stones. Cholesterol nucleation time, biliary lipid concentration, vesicular cholesterol distribution, and biliary protein concentration were measured and compared. The nucleation time in the hepatic bile of patients with cholesterol gall stones was significantly shorter than the gall stone free patients (8.2 (7.2) v 15.7 (5.8) days, p < 0.05), and was associated with a greater concentration of biliary lipid despite the lack of a difference in the cholesterol saturation index (CSI) and total protein concentration. During the storage of bile in the gall bladder, the nucleation time became quicker in the patients with cholesterol gall stone (2.9 (1.7) days) while it was similar in the gall stone free patients (17.3 (5.7) days) compared with that of the corresponding hepatic bile. These differences were associated with a higher CSI (1.44 (0.33) v 1.13 (0.14), p < 0.05) and a greater vesicular cholesterol distribution (19.7 (11.9) v 4.4 (1.4)%, p < 0.01) in the patients with cholesterol gall stones than the gall stone free patients. The concentrations of total lipid and protein in gall bladder bile were not significantly different between the two groups. In conclusion, patients with cholesterol gall stones produce less metastable hepatic bile by the evidence of shorter nucleation time. During the storage of the bile in the gall bladder, the metastability is reduced further only in the cholesterol gall stone patients but not in the gall stone free patients.
Impact of Latent Epstein-Barr Virus Infection on Outcome in Children and Adolescents With Hodgkin's Lymphoma
Authors: Alexander Claviez, Markus Tiemann, Heike Lüders, Matthias Krams, Reza Parwaresch, Günther Schellong, Wolfgang Dörffel
Journal: Journal of Clinical Oncology (2005)

Purpose The prognostic significance of latent Epstein-Barr virus (EBV) infection in Hodgkin's lymphoma (HL) is debated controversially. Especially in the pediatric age group, no conclusive data are available. Patients and Methods Eight hundred forty-two children and adolescents (median age, 13.7 years) from pediatric multicenter treatment studies HD-90 and HD-95 were studied for latent EBV infection in Hodgkin's and Reed-Sternberg cells by immunostaining against latent membrane protein 1 (LMP-1). Results were compared with established risk factors. Results Two hundred sixty-three patients (31%) were LMP positive. EBV infection correlated with sex (39% male v 23% female; P &lt; .001), histologic subtype (69% mixed cellularity v 22% nodular sclerosis v 6% lymphocyte predominance; P &lt; .001) and young age. With a median follow-up of 4.9 years, 820 patients (97%) are alive. Probability of overall survival at 10 years (± standard deviation) for EBV-negative and -positive patients was 98.1% ± 0.6% and 95.1% ± 1.4%, respectively (P = .017 by log-rank test). A negative effect of EBV infection became evident for patients with nodular sclerosis subtype Bennett II (P = .02), and those treated for advanced stages (P = .003). In multivariate analysis, LMP positivity was an independent factor for adverse outcome (RR = 3.08). Probability of failure-free survival (FFS) in LMP positive and negative patients was 89.1% ± 2.3% and 84.1% ± 3.9%, respectively (P = .86). Conclusion With effective combined treatment modalities in pediatric HL, latent EBV infection has no influence on FFS but is associated with an inferior overall survival in crucial subgroups.
Sex Steroid Treatment of Constitutionally Tall Stature*
Authors: Stenvert L. S. Drop, Wouter J. de Waal, Sabine M. P. F. de Muinck Keizer-Schrama
Journal: Endocrine Reviews (1998)

I. Introduction II. Normal vs. Extremes of Growth A. Defining CTS B. Endocrinology of CTS III. Endocrinology of Bone Growth and Maturation IV. Sex Steroid Action on Bone Growth and Maturation V. Height Prediction A. Skeletal maturity or BA B. Computed assisted skeletal age-scoring systems C. Accuracy of height prediction D. New prediction equations in constitutionally tall children VI. Treatment of CTS: General Concepts VII. Treatment of Constitutionally Tall Boys A. T treatment modalities B. Height reduction C. Effects on gonadal function D. Other clinical effects VIII. Estrogen Treatment in Tall Girls A. Estrogen treatment modalities B. Height reduction C. Effects on gonadal function D. Other adverse effects IX. Alternative Treatment Modalities and Future Research X. Conclusions and Recommendations
Overt nephrogenic diabetes insipidus in mice lacking the CLC-K1 chloride channel
Authors: Yoshihiro Matsumura, Shinichi Uchida, Yoshiaki Kondo, Hiroaki Miyazaki, Shigeru B.H. Ko, Atsushi Hayama, Tetuji Morimoto, Wen Liu, Mikio Arisawa, Sei Sasaki, Fumiaki Marumo
Journal: Nature Genetics (1999)
Extracolonic polyposis in familial adenomatous polyposis: so near and yet so far
Authors: A D Spigelman
Journal: Gut (2004)

There is a need to develop effective preventative and/or curative strategies for duodenal polyposis in patients with familial adenomatous polyposis

Extracolonic polyps in familial adenomatous polyposis (FAP) were described in the stomach by Hauser in 1895 and in the duodenum by Funkenstein in 1904.1 These findings postdate the first description of colonic lesions consistent with polyposis, described by Menzel in 1721, although this case is probably a description of inflammatory polyps.1 The first case of adenomatous polyposis may have been recorded by Corvisart in 1847.1 However, the first definite accounts of the disease were given by Chargelaigue in 1859 in a 16 year old girl and a 21 year old man.1 While polyposis has thus been reasonably well described for hundreds of years and the coexistence of extracolonic polyps in this syndrome has been known for over 100 years, it was not until …
Dietary Fat, Fat Subtypes, and Breast Cancer in Postmenopausal Women: a Prospective Cohort Study
Authors: E. Velie, M. Kulldorff, C. Schairer, G. Block, D. Albanes, A. Schatzkin
Journal: JNCI Journal of the National Cancer Institute (2000)

Background: The intake of total dietary fat and of certain fat subtypes has been shown to be strongly associated with breast cancer in international comparisons and in animal experiments. However, observational epidemiologic studies have generally reported either weak positive or no associations. To extend the prospective epidemiologic evidence on this question, we examined the association between adult dietary intake of fat, fat subtypes, and breast cancer in a large, prospective cohort of postmenopausal women. Methods: Participants were selected from a national breast cancer mammography screening program conducted from 1973 through 1981 at 29 centers throughout the United States. From 1987 through 1989, 40022 postmenopausal women satisfactorily completed a mailed, self-administered questionnaire that included a 60-item National Cancer Institute/Block food-frequency questionnaire. Women were then followed for an average of 5.3 years; 996 women developed breast cancer. Risk was assessed by use of Cox proportional hazard regression, with age as the underlying time metric. All statistical tests were two-sided. Results: Compared with women in the lowest quintile (Q1) of percentage of energy from total fat, the adjusted risk ratio (RR) and 95% confidence interval (CI) for women in the highest quintile (Q5) was 1.07 (95% CI = 0.86–1.32). In analyses stratified by history of benign breast disease (BBD), a positive association was observed among only women with no history of BBD (RR Q5 versus Q1 = 2.20; 95% CI = 1.41–3.42; test for trend, P = .0003). The increased risk in these women appeared to be attributable to unsaturated fat intake and oleic acid in particular. Conclusions: In this study, there was no overall association between fat intake during adulthood and breast cancer risk; however, among women with no history of BBD, there appeared to be a positive association between total and unsaturated fat intake and breast cancer risk.
Spermatozoa capture HIV-1 through heparan sulfate and efficiently transmit the virus to dendritic cells
Authors: Ana Ceballos, Federico Remes Lenicov, Juan Sabatté, Christian Rodríguez Rodrígues, Mercedes Cabrini, Carolina Jancic, Silvina Raiden, Mónica Donaldson, Rodolfo Agustín Pasqualini, Clara Marin-Briggiler, Mónica Vazquez-Levin, Francisco Capani, Sebastián Amigorena, Jorge Geffner
Journal: The Journal of Experimental Medicine (2009)

Semen is the main vector for HIV-1 dissemination worldwide. It contains three major sources of infectious virus: free virions, infected leukocytes, and spermatozoa-associated virions. We focused on the interaction of HIV-1 with human spermatozoa and dendritic cells (DCs). We report that heparan sulfate is expressed in spermatozoa and plays an important role in the capture of HIV-1. Spermatozoa-attached virus is efficiently transmitted to DCs, macrophages, and T cells. Interaction of spermatozoa with DCs not only leads to the transmission of HIV-1 and the internalization of the spermatozoa but also results in the phenotypic maturation of DCs and the production of IL-10 but not IL-12p70. At low values of extracellular pH (∼6.5 pH units), similar to those found in the vaginal mucosa after sexual intercourse, the binding of HIV-1 to the spermatozoa and the consequent transmission of HIV-1 to DCs were strongly enhanced. Our observations support the notion that far from being a passive carrier, spermatozoa acting in concert with DCs might affect the early course of sexual transmission of HIV-1 infection.
Initiating and maintaining resistance training in older adults: a social cognitive theory-based approach
Authors: R A Winett, D M Williams, B M Davy
Journal: British Journal of Sports Medicine (2008)

Numerous research studies performed in “lab-gyms” with supervised training have demonstrated that simple, brief (20–30 min) resistance training protocols performed 2–3/week following the American College of Sports Medicine’s guidelines positively affect risk factors associated with heart disease, cancers, diabetes, sarcopenia and other disabilities. For more than a decade, resistance training has been recommended for adults, particularly older adults, as a prime preventive intervention, and increasing the prevalence of resistance training is an objective of Healthy People 2010 . However, the prevalence rate for resistance training is only estimated at 10–15% for older adults, despite the leisure time of older adults and access to facilities in developed countries. The reasons that the prevalence rate remains low include public health policy not emphasising resistance training, misinformation, and the lack of theoretically driven approaches demonstrating effective transfer and maintenance of training to minimally supervised settings once initial, generally successful, supervised training is completed. Social cognitive theory (SCT) has been applied to physical activity and aerobic training with some success, but there are aspects of resistance training that are unique including its intensity, progression, precision, and time and place specificity. Social cognitive theory, particularly with a focus on self-regulation and response expectancy and affect within an ecological context, can be directly applied to these unique aspects of resistance training for long-term maintenance.
Regional, Geographic, and Racial/Ethnic Variation in Glycemic Control in a National Sample of Veterans With Diabetes
Authors: Leonard E. Egede, Mulugeta Gebregziabher, Kelly J. Hunt, Robert N. Axon, Carrae Echols, Gregory E. Gilbert, Patrick D. Mauldin
Journal: Diabetes Care (2011)

We performed a retrospective analysis of a national cohort of veterans with diabetes to better understand regional, geographic, and racial/ethnic variation in diabetes control as measured by HbA(1c).A retrospective cohort study was conducted in a national cohort of 690,968 veterans with diabetes receiving prescriptions for insulin or oral hypoglycemic agents in 2002 that were followed over a 5-year period. The main outcome measures were HbA(1c) levels (as continuous and dichotomized at ≥8.0%).Relative to non-Hispanic whites (NHWs), HbA(1c) levels remained 0.25% higher in non-Hispanic blacks (NHBs), 0.31% higher in Hispanics, and 0.14% higher in individuals with other/unknown/missing racial/ethnic group after controlling for demographics, type of medication used, medication adherence, and comorbidities. Small but statistically significant geographic differences were also noted with HbA(1c) being lowest in the South and highest in the Mid-Atlantic. Rural/urban location of residence was not associated with HbA(1c) levels. For the dichotomous outcome poor control, results were similar with race/ethnic group being strongly associated with poor control (i.e., odds ratios of 1.33 [95% CI 1.31-1.35] and 1.57 [1.54-1.61] for NHBs and Hispanics vs. NHWs, respectively), geographic region being weakly associated with poor control, and rural/urban residence being negligibly associated with poor control.In a national longitudinal cohort of veterans with diabetes, we found racial/ethnic disparities in HbA(1c) levels and HbA(1c) control; however, these disparities were largely, but not completely, explained by adjustment for demographic characteristics, medication adherence, type of medication used to treat diabetes, and comorbidities.
Keratinocyte Growth Factor Expression and Activity in Cancer: Implications for Use in Patients With Solid Tumors
Authors: Paul W. Finch, Jeffrey S. Rubin
Journal: JNCI Journal of the National Cancer Institute (2006)

Keratinocyte growth factor (KGF) is a locally acting epithelial mitogen that is produced by cells of mesenchymal origin and has an important role in protecting and repairing epithelial tissues. Use of recombinant human KGF (palifermin) in patients with hematologic malignancies reduces the incidence and duration of severe oral mucositis experienced after intensive chemoradiotherapy. These results suggest that KGF may be useful in the treatment of patients with other kinds of tumors, including those of epithelial origin. However, its application in this context raises issues that were not pertinent to its use in hematologic cancer because epithelial tumor cells, unlike blood cells, often express the KGF receptor (FGFR2b). Thus, it is important to examine whether KGF could promote the growth of epithelial tumors or protect such tumor cells from the effects of chemotherapy agents. Analyses of KGF and FGFR2b expression in tumor specimens and of KGF activity on transformed cells in vitro and in vivo do not indicate a definitive role for KGF in tumorigenesis. On the contrary, restoring FGFR2b expression to certain malignant cells can induce cell differentiation or apoptosis. However, other observations suggest that, in specific situations, KGF may contribute to epithelial tumorigenesis. Thus, further studies are warranted to examine the nature and extent of KGF involvement in these settings. In addition, clinical trials in patients with solid tumors are underway to assess the potential benefits of using KGF to protect normal tissue from the adverse effects of chemoradiotherapy and its possible impact on clinical outcome.
Antitumor Activity of PR-171, a Novel Irreversible Inhibitor of the Proteasome
Authors: Susan D. Demo, Christopher J. Kirk, Monette A. Aujay, Tonia J. Buchholz, Maya Dajee, Mark N. Ho, Jing Jiang, Guy J. Laidig, Evan R. Lewis, Francesco Parlati, Kevin D. Shenk, Mark S. Smyth, Congcong M. Sun, Marcy K. Vallone, Tina M. Woo, Christopher J. Molineaux, Mark K. Bennett
Journal: Cancer Research (2007)

Abstract Clinical studies with bortezomib have validated the proteasome as a therapeutic target for the treatment of multiple myeloma and non-Hodgkin's lymphoma. However, significant toxicities have restricted the intensity of bortezomib dosing. Here we describe the antitumor activity of PR-171, a novel epoxyketone-based irreversible proteasome inhibitor that is currently in clinical development. In comparison to bortezomib, PR-171 exhibits equal potency but greater selectivity for the chymotrypsin-like activity of the proteasome. In cell culture, PR-171 is more cytotoxic than bortezomib following brief treatments that mimic the in vivo pharmacokinetics of both molecules. Hematologic tumor cells exhibit the greatest sensitivity to brief exposure, whereas solid tumor cells and nontransformed cell types are less sensitive to such treatments. Cellular consequences of PR-171 treatment include the accumulation of proteasome substrates and induction of cell cycle arrest and/or apoptosis. Administration of PR-171 to animals results in the dose-dependent inhibition of the chymotrypsin-like proteasome activity in all tissues examined with the exception of the brain. PR-171 is well tolerated when administered for either 2 or 5 consecutive days at doses resulting in &amp;gt;80% proteasome inhibition in blood and most tissues. In human tumor xenograft models, PR-171 mediates an antitumor response that is both dose and schedule dependent. The antitumor efficacy of PR-171 delivered on 2 consecutive days is stronger than that of bortezomib administered on its clinical dosing schedule. These studies show the tolerability, efficacy, and dosing flexibility of PR-171 and provide validation for the clinical testing of PR-171 in the treatment of hematologic malignancies using dose-intensive schedules. [Cancer Res 2007;67(13):6383–91]