tbuckley/cabot-search huggingface dataset:
Evidence of Splanchnic-Brain Signaling in Inhibition of Ingestive Behavior by Middle Molecules
Authors: ABDEL-HAFIZ MAMOUN, PER SÖDERSTEN, BJÖRN ANDERSTAM, JONAS BERGSTRÖM
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Anorexia, nausea, and vomiting are common symptoms of uremic intoxication. Fractions in the middle molecule weight range, isolated from normal urine and uremic plasma ultrafiltrate, inhibit ingestive behavior in the rat. To investigate their site of action and specificity, male rats were injected intraperitoneally, intravenously, or intracerebroventricularly with concentrated fractions of uremic plasma ultrafiltrate or normal urine (molecular weight range: 1.0 to 5.0 kD) and tested for ingestive and sexual behavior. An intraperitoneal injection of 0.5 ml of urine fraction (10:1) or 2.0 ml of uremic plasma ultrafiltrate fraction (25:1) inhibited carbohydrate intake by 76.3 and 45.9%, respectively, but an intravenous injection had no effect. However, intravenous injection of higher doses inhibited carbohydrate ingestion. An intracerebroventricular injection of 5 or 10 μl of urine (20:1) middle molecule fraction inhibited carbohydrate intake by 13.4 and 41.6%, respectively. An injection of 5 or 10 μl of uremic plasma ultrafiltrate (125:1) middle molecule fraction inhibited carbohydrate intake by 22.6 and 49.5%, respectively. Injections of the corresponding fraction from normal plasma ultrafiltrate had no effect. Injection of urine or uremic plasma ultrafiltrate middle molecule fractions did not affect the display of sexual behavior. These results suggest that middle molecule fractions from uremic plasma ultrafiltrate or normal urine act in the splanchnic region and/or brain to inhibit food intake and that the effect is specific for ingestive behavior.
Development of a Standardized Screening Rule for Tuberculosis in People Living with HIV in Resource-Constrained Settings: Individual Participant Data Meta-analysis of Observational Studies
Authors: Haileyesus Getahun, Wanitchaya Kittikraisak, Charles M. Heilig, Elizabeth L. Corbett, Helen Ayles, Kevin P. Cain, Alison D. Grant, Gavin J. Churchyard, Michael Kimerling, Sarita Shah, Stephen D. Lawn, Robin Wood, Gary Maartens, Reuben Granich, Anand A. Date, Jay K. Varma
Journal: PLoS Medicine (2011)

Background The World Health Organization recommends the screening of all people living with HIV for tuberculosis (TB) disease, followed by TB treatment, or isoniazid preventive therapy (IPT) when TB is excluded. However, the difficulty of reliably excluding TB disease has severely limited TB screening and IPT uptake in resource-limited settings. We conducted an individual participant data meta-analysis of primary studies, aiming to identify a sensitive TB screening rule. Methods and Findings We identified 12 studies that had systematically collected sputum specimens regardless of signs or symptoms, at least one mycobacterial culture, clinical symptoms, and HIV and TB disease status. Bivariate random-effects meta-analysis and the hierarchical summary relative operating characteristic curves were used to evaluate the screening performance of all combinations of variables of interest. TB disease was diagnosed in 557 (5.8%) of 9,626 people living with HIV. The primary analysis included 8,148 people living with HIV who could be evaluated on five symptoms from nine of the 12 studies. The median age was 34 years. The best performing rule was the presence of any one of: current cough (any duration), fever, night sweats, or weight loss. The overall sensitivity of this rule was 78.9% (95% confidence interval [CI] 58.3%–90.9%) and specificity was 49.6% (95% CI 29.2%–70.1%). Its sensitivity increased to 90.1% (95% CI 76.3%–96.2%) among participants selected from clinical settings and to 88.0% (95% CI 76.1%–94.4%) among those who were not previously screened for TB. Negative predictive value was 97.7% (95% CI 97.4%–98.0%) and 90.0% (95% CI 88.6%–91.3%) at 5% and 20% prevalence of TB among people living with HIV, respectively. Abnormal chest radiographic findings increased the sensitivity of the rule by 11.7% (90.6% versus 78.9%) with a reduction of specificity by 10.7% (49.6% versus 38.9%). Conclusions Absence of all of current cough, fever, night sweats, and weight loss can identify a subset of people living with HIV who have a very low probability of having TB disease. A simplified screening rule using any one of these symptoms can be used in resource-constrained settings to identify people living with HIV in need of further diagnostic assessment for TB. Use of this algorithm should result in earlier TB diagnosis and treatment, and should allow for substantial scale-up of IPT. Please see later in the article for the Editors' Summary
DOT for all patients with smear-positive pulmonary TB in London?
Authors: R D Barker
Journal: Thorax (2003)

Supervised drug taking is frequently seen as the answer to rising levels of tuberculosis. Djuretic et al advocate directly observed therapy (DOT) for all patients with smear-positive pulmonary tuberculosis in London.1 At first sight the experience of instituting DOT in New York City appears especially impressive, with a 21% reduction in case rates and 39% decrease in drug resistant isolates. However, these reductions occurred at the same time as close attention was paid to drug regimens, the use of drug combinations, increased staffing levels, and the payment …
Observations on Personal Infestation by the Acarus scabiei
Authors: T. M. Clayton
Journal: BMJ (1944)

MEDICAL MEMORANDAMEIAJORAmade, and the loop proximal to the strangulation identified.This was brought outside the abdomen on the left side, at its nearest point to the strangulation but without any undue tension.No further manipulation was carried out, and the abdomen was closed.A Paul's tube was inserted into this loop, which was about the middle of the small intestine; it will be noted that the ileostomy was performed on the side opposite to the strangulation in order to leave room for a later operation near the site of obstruction.FuLrthermore, the loop of ileum was brought entirely outside the abdomen in order to ensure complete drainage: an ordinary ileostomy, with a catheter, would probably not have sufficed.Intravenous saline was continued, and five days after the ileostomy the patient was again brought to the theatre.Under spinal anaesthesia (light percaine) an oblique incision was made over the right iliac fossa.and the proximal and distal loops of the hernia were identified.These were clamped some three inches from tlle point of strangulation, divided, and an end-to-end anastomosis per- formed.The loops entering the hernial sac were closed off and oversewn.No great amount of manipulation was carried out, as the incision was immediately over the site of the anastomosis, and, further-more, it was unnecessary to divide the respective mesenteries; the ends of the gut were just apposed to each other and anastomosed.At the conclusion of the operation the wound was sealed off by
Identification of a Tumor Suppressor Relay between the FOXP3 and the Hippo Pathways in Breast and Prostate Cancers
Authors: Weiquan Li, Lizhong Wang, Hiroto Katoh, Runhua Liu, Pan Zheng, Yang Liu
Journal: Cancer Research (2011)

Abstract Defective expression of LATS2, a negative regulator of YAP oncoprotein, has been reported in cancer of prostate, breast, liver, brain, and blood origins. However, no transcriptional regulators for the LATS2 gene have been identified. Here we report that spontaneous mutation of the transcription factor FOXP3 reduces expression of the LATS2 gene in mammary epithelial cells. shRNA-mediated silencing of FOXP3 in normal or malignant mammary epithelial cells of mouse and human origin repressed LATS2 expression and increased YAP protein levels. LATS2 induction required binding of FOXP3 to a specific sequence in the LATS2 promoter, and this interaction contributed to FOXP3-mediated growth inhibition of tumor cells. In support of these results, reduced expression and somatic mutations of FOXP3 correlated strongly with defective LATS2 expression in microdissected prostate cancer tissues. Thus, defective expression of LATS2 is attributable to FOXP3 defects and may be a major independent determinant of YAP protein elevation in cancer. Our findings identify a novel mechanism of LATS2 downregulation in cancer and reveal an important tumor suppressor relay between the FOXP3 and HIPPO pathways which are widely implicated in human cancer. Cancer Res; 71(6); 2162–71. ©2011 AACR.
Prenatal diagnosis of fetal aneuploidies: post-genomic developments
Authors: Sinuhe Hahn, Laird G Jackson, Bernhard G Zimmermann
Journal: Genome Medicine (2010)

Prenatal diagnosis of fetal aneuploidies and chromosomal anomalies is likely to undergo a profound change in the near future. On the one hand this is mediated by new technical developments, such as chromosomal microarrays, which allow a much more precise delineation of minute sub-microscopic chromosomal aberrancies than the classical G-band karyotype. This will be of particular interest when investigating pregnancies at risk of unexplained development delay, intellectual disability or certain forms of autism. On the other hand, great strides have been made in the non-invasive determination of fetal genetic traits, largely through the analysis of cell-free fetal nucleic acids. It is hoped that, with the assistance of cutting-edge tools such as digital PCR or next generation sequencing, the long elusive goal of non-invasive prenatal diagnosis for fetal aneuploidies can finally be attained.
Bevacizumab-Induced Reversible Posterior Leukoencephalopathy Syndrome and Successful Retreatment in a Patient With Glioblastoma
Authors: Emil Lou, Scott Turner, Ashley Sumrall, David A. Reardon, Annick Desjardins, Katherine B. Peters, John H. Sampson, Henry S. Friedman, James J. Vredenburgh
Journal: Journal of Clinical Oncology (2011)
Importance of Minimal Residual Disease Testing During the Second Year of Therapy for Children With Acute Lymphoblastic Leukemia
Authors: Glenn M. Marshall, Michelle Haber, Edward Kwan, Ling Zhu, Daniella Ferrara, Chengyuan Xue, Michael J. Brisco, Pamela J. Sykes, Alexander Morley, Boyd Webster, Luciano Dalla Pozza, Keith Waters, Murray D. Norris
Journal: Journal of Clinical Oncology (2003)

Purpose: A high level of minimal residual disease (MRD) after induction chemotherapy in children with acute lymphoblastic leukemia (ALL) is an indicator of relative chemotherapy resistance and a risk factor for relapse. However, the significance of MRD in the second year of therapy is unclear. Moreover, it is unknown whether treatment intervention can alter outcome in patients with detectable MRD. Patients and Methods: We assessed the prognostic value of MRD testing in bone marrow samples from 85 children at 1, 12, and 24 months from diagnosis using clone-specific polymerase chain reaction primers designed to detect clonal antigen receptor gene rearrangements. These children were part of a multicenter, randomized clinical trial, which, in the second year of treatment, compared a 2-month reinduction-reintensification followed by maintenance chemotherapy with standard maintenance chemotherapy alone. Results: MRD was detected in 69% of patients at 1 month, 25% at 12 months, and 28% at 24 months from diagnosis. By univariate analysis, high levels of MRD at 1 month, or the presence of any detectable MRD at 12 or 24 months from diagnosis, were highly predictive of relapse. Multivariate analysis showed that MRD testing at 1 and 24 months each had independent prognostic significance. Intensified therapy at 12 months from diagnosis did not improve prognosis in those patients who were MRD positive at 12 months from diagnosis. Conclusion: Clinical outcome in childhood ALL can be predicted with high accuracy by combining the results of MRD testing at 1 and 24 months from diagnosis.
The PKC/NF-κB Signaling Pathway Induces APOBEC3B Expression in Multiple Human Cancers
Authors: Brandon Leonard, Jennifer L. McCann, Gabriel J. Starrett, Leah Kosyakovsky, Elizabeth M. Luengas, Amy M. Molan, Michael B. Burns, Rebecca M. McDougle, Peter J. Parker, William L. Brown, Reuben S. Harris
Journal: Cancer Research (2015)

Abstract Overexpression of the antiviral DNA cytosine deaminase APOBEC3B has been linked to somatic mutagenesis in many cancers. Human papillomavirus infection accounts for APOBEC3B upregulation in cervical and head/neck cancers, but the mechanisms underlying nonviral malignancies are unclear. In this study, we investigated the signal transduction pathways responsible for APOBEC3B upregulation. Activation of protein kinase C (PKC) by the diacylglycerol mimic phorbol-myristic acid resulted in specific and dose-responsive increases in APOBEC3B expression and activity, which could then be strongly suppressed by PKC or NF-κB inhibition. PKC activation caused the recruitment of RELB, but not RELA, to the APOBEC3B promoter, implicating noncanonical NF-κB signaling. Notably, PKC was required for APOBEC3B upregulation in cancer cell lines derived from multiple tumor types. By revealing how APOBEC3B is upregulated in many cancers, our findings suggest that PKC and NF-κB inhibitors may be repositioned to suppress cancer mutagenesis, dampen tumor evolution, and decrease the probability of adverse outcomes, such as drug resistance and metastasis. Cancer Res; 75(21); 4538–47. ©2015 AACR.
The Functional Basis for Hemophagocytic Lymphohistiocytosis in a Patient with Co-inherited Missense Mutations in the Perforin (<i>PFN1</i>) Gene
Authors: Ilia Voskoboinik, Marie-Claude Thia, Annette De Bono, Kylie Browne, Erika Cretney, Jacob T. Jackson, Phillip K. Darcy, Stephen M. Jane, Mark J. Smyth, Joseph A. Trapani
Journal: The Journal of Experimental Medicine (2004)

About 30% of cases of the autosomal recessive immunodeficiency disorder hemophagocytic lymphohistiocytosis are believed to be caused by inactivating mutations of the perforin gene. We expressed perforin in rat basophil leukemia cells to define the basis of perforin dysfunction associated with two mutations, R225W and G429E, inherited by a compound heterozygote patient. Whereas RBL cells expressing wild-type perforin (67 kD) efficiently killed Jurkat target cells to which they were conjugated, the substitution to tryptophan at position 225 resulted in expression of a truncated (∼45 kD) form of the protein, complete loss of cytotoxicity, and failure to traffic to rat basophil leukemia secretory granules. By contrast, G429E perforin was correctly processed, stored, and released, but the rat basophil leukemia cells possessed reduced cytotoxicity. The defective function of G429E perforin mapped downstream of exocytosis and was due to its reduced ability to bind lipid membranes in a calcium-dependent manner. This study elucidates the cellular basis for perforin dysfunctions in hemophagocytic lymphohistiocytosis and provides the means for studying structure–function relationships for lymphocyte perforin.
Comorbidity and Mortality Results From a Randomized Prostate Cancer Screening Trial
Authors: E. David Crawford, Robert Grubb, Amanda Black, Gerald L. Andriole, Ming-Hui Chen, Grant Izmirlian, Christine D. Berg, Anthony V. D'Amico
Journal: Journal of Clinical Oncology (2010)

Estimates of prostate cancer-specific mortality (PCSM) were similar for men randomly assigned to intervention compared with usual care on the Prostate, Lung, Colorectal and Ovarian PC screening study. However, results analyzed by comorbidity strata remain unknown.
Diabetes, Obesity, and Hypertension May Enhance Associations between AirPollution and Markers of Systemic Inflammation
Authors: Sara D. Dubowsky, Helen Suh, Joel Schwartz, Brent A. Coull, Diane R. Gold
Journal: Environmental Health Perspectives (2006)

Airborne particulate matter (PM) may lead to increased cardiac risk through an inflammatory pathway. Therefore, we investigated associations between ambient PM and markers of systemic inflammation among repeated measures from 44 senior citizens (≥ 60 years of age) and examined susceptibility by conditions linked to chronic inflammation. Mixed models were used to identify associations between concentrations of fine PM [aerodynamic diameter ≤ 2.5 μm (PM2.5)] averaged over 1–7 days and measures of C-reactive protein (CRP), interleukin-6 (IL-6), and white blood cells (WBCs). Effect modification was investigated for diabetes, obesity, hypertension, and elevated mean inflammatory markers. We found positive associations between longer moving averages of PM2.5 and WBCs across all participants, with a 5.5% [95% confidence interval (CI), 0.10 to 11%] increase per interquartile increase (5.4 μg/m3) of PM2.5 averaged over the previous week. PM2.5 and CRP also exhibited positive associations among all individuals for averages longer than 1 day, with the largest associations for persons with diabetes, obesity, and hypertension. For example, an interquartile increase in the 5-day mean PM2.5 (6.1 μg/m3) was associated with a 14% increase in CRP (95% CI, −5.4 to 37%) for all individuals and an 81% (95% CI, 21 to 172%) increase for persons with diabetes, obesity, and hypertension. Persons with diabetes, obesity, and hypertension also exhibited positive associations between PM2.5 and IL-6. Individuals with elevated mean inflammatory markers exhibited enhanced associations with CRP, IL-6, and WBCs. We found modest positive associations between PM2.5 and indicators of systemic inflammation, with larger associations suggested for individuals with diabetes, obesity, hypertension, and elevated mean inflammatory markers.
Intent-to-treat analysis of the placebo-controlled trial of letrozole for extended adjuvant therapy in early breast cancer: NCIC CTG MA.17
Authors: J.N. Ingle, D. Tu, J.L. Pater, H.B. Muss, S. Martino, N.J. Robert, M.J. Piccart, M. Castiglione, L.E. Shepherd, K.I. Pritchard, R.B. Livingston, N.E. Davidson, L. Norton, E.A. Perez, J.S. Abrams, D.A. Cameron, M.J. Palmer, P.E. Goss
Journal: Annals of Oncology (2008)
Efficient Moment-Based Inference of Admixture Parameters and Sources of Gene Flow
Authors: Mark Lipson, Po-Ru Loh, Alex Levin, David Reich, Nick Patterson, Bonnie Berger
Journal: Molecular Biology and Evolution (2013)

The recent explosion in available genetic data has led to significant advances in understanding the demographic histories of and relationships among human populations. It is still a challenge, however, to infer reliable parameter values for complicated models involving many populations. Here, we present MixMapper, an efficient, interactive method for constructing phylogenetic trees including admixture events using single nucleotide polymorphism (SNP) genotype data. MixMapper implements a novel two-phase approach to admixture inference using moment statistics, first building an unadmixed scaffold tree and then adding admixed populations by solving systems of equations that express allele frequency divergences in terms of mixture parameters. Importantly, all features of the model, including topology, sources of gene flow, branch lengths, and mixture proportions, are optimized automatically from the data and include estimates of statistical uncertainty. MixMapper also uses a new method to express branch lengths in easily interpretable drift units. We apply MixMapper to recently published data for Human Genome Diversity Cell Line Panel individuals genotyped on a SNP array designed especially for use in population genetics studies, obtaining confident results for 30 populations, 20 of them admixed. Notably, we confirm a signal of ancient admixture in European populations-including previously undetected admixture in Sardinians and Basques-involving a proportion of 20-40% ancient northern Eurasian ancestry.
Ionic Mechanism of Delayed Afterdepolarizations in Ventricular Cells Isolated From Human End-Stage Failing Hearts
Authors: Arie O. Verkerk, Marieke W. Veldkamp, Antonius Baartscheer, Cees A. Schumacher, Corinne Klöpping, Antoni C.G. van Ginneken, Jan H. Ravesloot
Journal: Circulation (2001)

Background Animal studies have shown that the Ca 2+ -activated Cl − current ( I Cl(Ca) ) and the Na + /Ca 2+ exchange current ( I Na/Ca ) contribute to the transient inward current ( I ti ). I ti is responsible for the proarrhythmic delayed afterdepolarizations (DADs). We investigated the ionic mechanism of I ti and DADs in human cardiac cells. Methods and Results Human ventricular cells were enzymatically isolated from explanted hearts of patients with end-stage heart failure and studied with patch-clamp methodology. I ti s were elicited in the presence of 1 μmol/L norepinephrine by trains of repetitive depolarizations from −80 to +50 mV. DADs were induced in the presence of 1 μmol/L norepinephrine at a stimulus frequency of 1 Hz. I ti currents were inwardly directed over the voltage range between −110 and + 50 mV. Neither the Cl − channel blocker 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid nor changes in [Cl − ] i affected I ti or DAD amplitude. This excludes an important role for I Cl(Ca) . Blockade of Na + /Ca 2+ exchange by substitution of all extracellular Na + by Li + , conversely, completely inhibited I ti . In rabbit, I Cl(Ca) density in ventricular cells isolated from control hearts did not differ significantly from that in ventricular cells isolated from failing hearts. Conclusions In contrast to many animal species, I ti and DADs in human ventricular cells from failing hearts consist only of I Na/Ca . In rabbits, heart failure per se does not alter I Cl(Ca) density, suggesting that I Cl(Ca) may also be absent during DADs in nonfailing human ventricular cells.
Stacking the Deck for Drug Discovery in Diabetic Nephropathy
Authors: Matthew D. Breyer
Journal: Journal of the American Society of Nephrology (2008)

In the years after the introduction of life-saving insulin therapy for the treatment of diabetes, diabetic nephropathy emerged as a complication of chronic diabetes.[1][1],[2][2] Diabetic nephropathy has since metamorphosed from a clinical rarity to the single major cause of kidney failure in the
Rapid and Sensitive p53 Alteration Analysis in Biopsies from Lung Cancer Patients Using a Functional Assay and A Universal Oligonucleotide Array
Authors: Coralie Fouquet, Martine Antoine, Pascaline Tisserand, Reyna Favis, Marie Wislez, Fréderic Commo, Nathalie Rabbe, Marie France Carette, Bernard Milleron, Francis Barany, Jacques Cadranel, Gérard Zalcman, Thierry Soussi
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Molecular profiling of alterations associated with lung cancer holds the promise to define clinical parameters such as response to treatment or survival. Because &amp;lt;5% of small cell lung cancers and &amp;lt;30% of non-small cell lung cancers are surgically resectable, molecular analysis will perforce rely on routinely available clinical samples such as biopsies. Identifying tumor mutations in such samples will require a sensitive and robust technology to overcome signal from excess amounts of normal DNA. Experimental Design: p53 mutation status was assessed from the DNA and RNA of biopsies collected prospectively from 83 patients with lung cancer. Biopsies were obtained either by conventional bronchoscopy or computed tomography-guided percutaneous biopsy. Matched surgical specimens were available for 22 patients. Three assays were used: direct sequencing; a functional assay in yeast; and a newly developed PCR/ligase detection reaction/Universal DNA array assay. Results: Using the functional assay, p53 mutation was found in 62% of biopsies and 64% of surgical specimens with a concordance of 80%. The sensitivity of the functional assay was determined to be 5%. Direct sequencing confirmed mutations in 92% of surgical specimens but in only 78% of biopsies. The DNA array confirmed 100% of mutations in both biopsies and surgical specimens. Using this newly developed DNA array, we demonstrate the feasibility of directly identifying p53 mutations in clinical samples containing &amp;lt;5% of tumor cells. Conclusions: The versatility and sensitivity of this new array assay should allow additional development of mutation profiling arrays that could be applied to biological samples with a low tumor cell content such as bronchial aspirates, bronchoalveolar lavage fluid, or serum.