tbuckley/cabot-search huggingface dataset:
Phase II/III Study of Doxorubicin With Fluorouracil Compared With Streptozocin With Fluorouracil or Dacarbazine in the Treatment of Advanced Carcinoid Tumors: Eastern Cooperative Oncology Group Study E1281
Authors: Weijing Sun, Stuart Lipsitz, Paul Catalano, James A. Mailliard, Daniel G. Haller
Journal: Journal of Clinical Oncology (2005)

Purpose Optimal treatments for metastatic carcinoid tumor remain undefined, and the role of chemotherapy for symptomatic patients with progressive disease is uncertain. Patients and Methods Two hundred forty-nine patients with advanced carcinoid tumors were randomized to either doxorubicin with fluorouracil (FU/DOX) or streptozocin with fluorouracil (FU/STZ). Patients crossed over to the dacarbazine (DTIC) treatment after disease progression following first-line treatment (either FU/DOX or FU/STZ), and 73 patients were assigned to one of these three treatments based on their previous treatment or on abnormal baseline cardiac or renal function. Results In the randomized group, there was no difference between FU/DOX and FU/STZ in response rates (15.9% v 16%) and progression-free survival (4.5 v 5.3 months). FU/STZ (24.3 months) was superior to FU/DOX (15.7 months; P = .0267) in median survival. The response rate of crossover DTIC treatment was 8.2%, with a median survival of 11.9 months. Hematologic toxicities were the major treatment-related toxicities for both FU/DOX and FU/STZ, and mild to moderate renal toxicity was reported in 40 (34.8%) of 115 patients in the FU/STZ arm. Conclusion Response to all three treatment regimens were modest. FU/STZ improved survival compared with the doxorubicin-based regimen, suggesting that the combination should be considered to be an active regimen of therapy when chemotherapy is judged to be an option for selected patients with carcinoid tumors.
Genetic determinants of metabolism in health and disease: from biochemical genetics to genome-wide associations
Authors: Steven L Robinette, Elaine Holmes, Jeremy K Nicholson, Marc E Dumas
Journal: Genome Medicine (2012)

Increasingly sophisticated measurement technologies have allowed the fields of metabolomics and genomics to identify, in parallel, risk factors of disease; predict drug metabolism; and study metabolic and genetic diversity in large human populations. Yet the complementarity of these fields and the utility of studying genes and metabolites together is belied by the frequent separate, parallel applications of genomic and metabolomic analysis. Early attempts at identifying co-variation and interaction between genetic variants and downstream metabolic changes, including metabolic profiling of human Mendelian diseases and quantitative trait locus mapping of individual metabolite concentrations, have recently been extended by new experimental designs that search for a large number of gene-metabolite associations. These approaches, including metabolomic quantitiative trait locus mapping and metabolomic genome-wide association studies, involve the concurrent collection of both genomic and metabolomic data and a subsequent search for statistical associations between genetic polymorphisms and metabolite concentrations across a broad range of genes and metabolites. These new data-fusion techniques will have important consequences in functional genomics, microbial metagenomics and disease modeling, the early results and implications of which are reviewed.
Pediatric liver transplantation for langerhans' cell histiocytosis
Authors: Parissa Zandi, Yves Panis, Dominique Debray, Olivier Bernard, Didier Houssin
Journal: Hepatology (1995)

Langerhans' cell histiocytosis (LCH) represents 15% to 20% of sclerosing cholangitis (SC) in children. In LCH-associated SC, a very poor response to chemotherapy has been reported, and spontaneous prognosis is very bad. Few cases of orthotopic liver transplantation (OLT) for LCH have been reported and little is known about the risk of recurrence and the effect of immunosuppression after OLT. Since 1986, five children (mean age +/- SD, 12.6 +/- 3.6 years) underwent OLT for SC complicating LCH. All patients presented with growth retardation, and severe liver disease including repeated episodes of variceal bleeding (n = 5), liver insufficiency (n = 4), jaundice (n = 5), and ascitis (n = 4). Four patients presented with previous abdominal surgery (mesocaval shunt in two and explorative laparotomy in two). OLT was performed using a whole (n = 2) or a reduced liver graft (n = 3). Pathological examination of the recipient liver showed biliary cirrhosis in all cases. Three patients are alive and well 9 to 88 months after OLT. None presented with recurrence of LCH or SC within the liver graft or in other organs. General condition (including growth and puberty) improved dramatically in the three surviving patients. Absence of recurrence after up to 7 years of follow-up after liver transplantation in our patients, as well as in all other reported cases, is encouraging and shows that OLT may be indicated in end-stage liver disease complicating LCH. Furthermore, cyclosporine may be beneficial for preventing recurrence of LCH, in which autoimmunologic mechanisms have been advocated.
The Use of "Salufer" (Silico-Fluoride of Soda) as an Antiseptic
Authors: A. W. M. Robson
Journal: BMJ (1888)

y 19, 18. in a case of hay fever in which cocaine and the bromides had been given without result.He gave it in 30-grain doses at the; hours when the attacks usually came on, and found that the drug aborted the attacks.After taking antipyrin for some weeks the disease disappeared in this case.Sonnenberger, from an experience of 70 cases in which he used the drug in whooping-cough, concludes that it is a very useful remedy in such cases.He gave it to infants in doses of t to 1 § grain three times a day in syrup of tolu or raspberry, increasing the se to 10 or 15 grains for older children.The remedy must be used systematically to produce a good result in whooping-cough.Ia nervous vomiting, especially in the vomiting of pregnancy, antipyrin is useful.If the vomiting be periodic, the drug should be given a few hours before the usual appearance of the attack.hi sea-sickness the drug has been lauded as a specific, perhaps only to have its day as most other specifics for this disorder have had, Mlore than one medical man has, however, recorded the debt of gratitude he owes to this remedy in crossing the Atlantic, so that it kuay be tried in the hope that it may be of use.
Overexpression of the Na/Ca exchanger and reduced SERCa function
Authors: C Terracciano
Journal: Cardiovascular Research (2001)

sing Na / Ca exchanger function during the cardiac cycle Dear Sir, are intriguing but depend greatly on the assumption that We have read with great interest Dr Isenberg's editorial cytoplasmic [Na] is 9.6 mM.We will comment on this [1] published with our article [2] in Cardiovascular later.There are two further points to make regarding the Research.Dr Isenberg's analysis highlights the numerous calculations that may not be immediately apparent to the problems in studying Na / Ca exchanger function and CaReader.Firstly, it is important to note that the model cell is regulation and stresses once again that these areas of not in a steady-state.The size and time-course of the Ca physiology are far from being completely understood.We transient are fixed and, as Dr Isenberg mentions in the feel, however, that some clarification is required on the legend, the model does not incorporate effects of I on following points that arise from his assessment of our x
The long-term effects of non-invasive ventilation on airway remodeling are predicted by a short-term treatment period
Authors: Cedric Van Holsbeke, Wim Vos, Samir Vinchurkar, Jan De Backer, Denise Daems, Rodrigo Salgado, Wilfried De Backer
Journal: European Respiratory Journal (2013)

Introduction   Non invasive ventilation (NIV) can benefit hyperpcapnic COPD patients by airway remodeling and redistribution of flow towards better preserved lung zones [Int J COPD 2011;6:615-624]. This study aims to investigate whether the NIV treatment response already after 1 month can be related to the chronic response after 6 months of treatment.   Methods   Persistent hypercapnic COPD GOLD III patients after exacerbation, eligible for NIV treatment, were studied. Patients were treated with NIV on top of their normal pharmaceutical treatment plan. Lung function was assessed at baseline (during the hypercapnic period), after 1 month, and after 6 months. Lung function was evaluated by pulmonary function tests (PFT), blood gasses and functional respiratory imaging (FRI) [ERJ 2012;40:298-305].   Results   9 patients (5M, 65[57-75]years) were studied. Preliminary results show that FEV1 is not significantly changed by the treatment. Blood gasses (base excess, BE) and FRI based measured airway volumes (iVaw) do improve after treatment (Fig1). The treatment effect is larger after 6 months than after 1 month. The observed effect in iVaw after 1 month is a good predictor of the outcome after 6 months (Fig2).   Conclusion   FRI has the possibility to predict the long term outcome of NIV, based on short-term data.  Study supported by Air Liquide.
An intronic PICALM polymorphism, rs588076, is associated with allelic expression of a PICALMisoform
Authors: Ishita Parikh, Christopher Medway, Steven Younkin, David W Fardo, Steven Estus
Journal: Molecular Neurodegeneration (2014)

Although genome wide studies have associated single nucleotide polymorphisms (SNP)s near PICALM with Alzheimer's disease (AD), the mechanism underlying this association is unclear. PICALM is involved in clathrin-mediated endocytosis and modulates Aß clearance in vitro. Comparing allelic expression provides the means to detect cis-acting regulatory polymorphisms. Thus, we evaluated whether PICALM showed allele expression imbalance (AEI) and whether this imbalance was associated with the AD-associated polymorphism, rs3851179.We measured PICALM allelic expression in 42 human brain samples by using next-generation sequencing. Overall, PICALM demonstrated equal allelic expression with no detectable influence by rs3851179. A single sample demonstrated robust global PICALM allelic expression imbalance (AEI), i.e., each of the measured isoforms showed AEI. Moreover, the PICALM isoform lacking exons 18 and 19 (D18-19 PICALM) showed significant AEI in a subset of individuals. Sequencing these individuals and subsequent genotyping revealed that rs588076, located in PICALM intron 17, was robustly associated with this imbalance in D18-19 PICALM allelic expression (p = 9.54 x 10-5). This polymorphism has been associated previously with systolic blood pressure response to calcium channel blocking agents. To evaluate whether this polymorphism was associated with AD, we genotyped 3269 individuals and found that rs588076 was modestly associated with AD. However, when both the primary AD SNP rs3851179 was added to the logistic regression model, only rs3851179 was significantly associated with AD.PICALM expression shows no evidence of AEI associated with rs3851179. Robust global AEI was detected in one sample, suggesting the existence of a rare SNP that strongly modulates PICALM expression. AEI was detected for the D18-19 PICALM isoform, and rs588076 was associated with this AEI pattern. Conditional on rs3851179, rs588076 was not associated with AD risk, suggesting that D18-19 PICALM is not critical in AD. In summary, this analysis of PICALM allelic expression provides novel insights into the genetics of PICALM expression and AD risk.
Advances in inflammatory bowel disease pathogenesis: linking host genetics and the microbiome
Authors: Dan Knights, Kara G Lassen, Ramnik J Xavier
Journal: Gut (2013)

Studies of the genetics underlying inflammatory bowel diseases have increased our understanding of the pathways involved in both ulcerative colitis and Crohn's disease and focused attention on the role of the microbiome in these diseases. Full understanding of pathogenesis will require a comprehensive grasp of the delicate homeostasis between gut bacteria and the human host. In this review, we present current evidence of microbiome-gene interactions in the context of other known risk factors and mechanisms, and describe the next steps necessary to pair genetic variant and microbiome sequencing data from patient cohorts. We discuss the concept of dysbiosis, proposing that the functional composition of the gut microbiome may provide a more consistent definition of dysbiosis and may more readily provide evidence of genome-microbiome interactions in future exploratory studies.
Metabolic Syndrome and the Risk for Chronic Kidney Disease among Nondiabetic Adults
Authors: Manjula Kurella, Joan C. Lo, Glenn M. Chertow
Journal: Journal of the American Society of Nephrology (2005)

The metabolic syndrome is a risk factor for the development of diabetes and cardiovascular disease; however, no prospective studies have examined the metabolic syndrome as a risk factor for chronic kidney disease (CKD). A total of 10,096 nondiabetic participants who were in the Atherosclerosis Risk in Communities study and had normal baseline kidney function composed the study cohort. The metabolic syndrome was defined according to recent guidelines from the National Cholesterol Education Program. Incident CKD was defined as an estimated GFR (eGFR) <60 ml/min per 1.73 m2 at study year 9 among those with an eGFR > or =60 ml/min per 1.73 m2 at baseline. After 9 yr of follow-up, 691 (7%) participants developed CKD. The multivariable adjusted odds ratio (OR) of developing CKD in participants with the metabolic syndrome was 1.43 (95% confidence interval [CI], 1.18 to 1.73). Compared with participants with no traits of the metabolic syndrome, those with one, two, three, four, or five traits of the metabolic syndrome had OR of CKD of 1.13 (95% CI, 0.89 to 1.45), 1.53 (95% CI, 1.18 to 1.98), 1.75 (95% CI, 1.32 to 2.33), 1.84 (95% CI, 1.27 to 2.67), and 2.45 (95% CI, 1.32 to 4.54), respectively. After adjusting for the subsequent development of diabetes and hypertension during the 9 yr of follow-up, the OR of incident CKD among participants with the metabolic syndrome was 1.24 (95% CI, 1.01 to 1.51). The metabolic syndrome is independently associated with an increased risk for incident CKD in nondiabetic adults.
Identification and distribution of rare and new mutations of Alpha-1-antitrypsin in Germany
Authors: Christian Herr, Timm Greulich, Rembert Koczulla, Viktor Kotke, Claus Vogelmeier, Robert Bals
Journal: European Respiratory Journal (2014)

Rational:  Mutations in the SERPINA-1 gene encoding the alpha-1-antitrypsin (AAT) antiprotease are a risk factor for the development of a chronic obstructive pulmonary disease (COPD). The Z- and the S-Allele are the most frequent mutations that lead to AAT-deficiency. Besides these mutations, numerous alleles have been identified, that lead to AAT-deficiency. The aim of this study was the identification of patients with rare or unknown mutations from a AAT-screening program.   Methods:  Individuals with a suspected AAT-deficiency were genotyped by PCR-analysis and isoelectric focusing (IEF) of serum. In individuals with low serum levels and the absence of the S or the Z allele, we performed exon sequencing of the 3 non-coding (Exon Ia-c) and 4 coding exons. To identify rare and unknown mutations, we compared the patients sequence with a reference sequence and all published rare mutations.   Results:  Out of 16180 analyzed individuals 98,6 % could be identified by PCR-analysis and IEF. We analyzed 1,4 % by exon sequencing and found 25 new mutations. Out of the 237 sequenced people 34% were heterozygous for PiZ plus a rare at risk mutation and 5% had a combination of PiZ and Q0. 13,5 % carried a rare base allele and neither Z or Q0 and 5,3% had a combination of PiZ and a rare base allele. Among the new mutations we found 5 potential stop mutations. The most common rare at risk mutations we found were M-Heerlen (18%) followed by M-Procida (9,5%).   Conclusion:  Allel-specific PCR and isoelectric focusing are proven and reliable methods to diagnose AAT-deficient patients. Genomic sequencing and subsequent genetic analysis are the most powerful additions to identifiy rare and unknown mutations.
Leading the charge: Médecins Sans Frontières receives the 2015 Lasker~Bloomberg Public Service Award
Authors: Corinne L. Williams
Journal: Journal of Clinical Investigation (2015)

The 2014 Ebola outbreak in West Africa has been unprecedented in many respects, including its geographical spread, the number of individuals infected, and duration. Medecins Sans Frontieres (MSF, also known as Doctors Without Borders) was among the first organizations to respond to early reports of a hemorrhagic fever of unknown origin in Guinea. MSF called upon the international community to act early during the outbreak, but these early warnings were largely dismissed or thought to be overstated. MSF responders have worked tirelessly and continue to do so to provide care to those infected with Ebola, to educate affected communities, and to support local healthcare providers. For their bold leadership and unwavering support during the current Ebola outbreak in West Africa and their continued efforts to provide health care to people in crisis throughout the world, MSF is being recognized with the 2015 Lasker~Bloomberg Public Service Award (Figure 1).
Comparison of four prognostic scores in peripheral T-cell lymphoma
Authors: G. Gutiérrez-García, A. García-Herrera, T. Cardesa, A. Martínez, N. Villamor, G. Ghita, A. Martínez-Trillos, L. Colomo, X. Setoain, S. Rodríguez, E. Giné, E. Campo, A. López-Guillermo
Journal: Annals of Oncology (2010)
Inducible nitric oxide synthase in tangle-bearing neurons of patients with Alzheimer's disease.
Authors: Y Vodovotz, M S Lucia, K C Flanders, L Chesler, Q W Xie, T W Smith, J Weidner, R Mumford, R Webber, C Nathan, A B Roberts, C F Lippa, M B Sporn
Journal: The Journal of Experimental Medicine (1996)

In Alzheimer's disease (AD), affected neurons accumulate beta amyloid protein, components of which can induce mouse microglia to express the high-output isoform of nitric oxide synthase (NOS2) in vitro. Products of NOS2 can be neurotoxic. In mice, NOS2 is normally suppressed by transforming growth factor beta 1 (TGF-beta 1). Expression of TGF-beta 1 is decreased in brains from AD patients, a situation that might be permissive for accumulation of NOS2. Accordingly, we investigated the expression of NOS2 in patients with AD, using three monospecific antibodies: a previously described polyclonal and two new monoclonal antibodies. Neurofibrillary tangle-bearing neurons and neuropil threads contained NOS2 in brains from each of 11 AD patients ranging in age from 47 to 81 years. NOS2 was undetectable in brains from 6 control subjects aged 23-72 years, but was expressed in small amounts in 3 control subjects aged 77-87 years. Thus, human neurons can express NOS2 in vivo. The high-output pathway of NO production may contribute to pathogenesis in AD.
Leukaemia update. Part 1: diagnosis and management
Authors: N. F. Grigoropoulos, R. Petter, M. B. Van 't Veer, M. A. Scott, G. A. Follows
Journal: BMJ (2013)

#### Summary points

About 8000 people in the United Kingdom are diagnosed with leukaemia each year, and in 2010, 4504 people died in the UK from this disease.1 Leukaemia encompasses a clinically and pathologically diverse set of conditions whose incidence and prevalence are rising. In the past, leukaemia was classified on the basis of the morphological characteristics of abnormally proliferating leucocytes in the blood and bone marrow. Emerging genetic data, however, have shown genomic heterogeneity in what were thought to be homogeneous disorders, prompting the World Health Organization to revise the classification.2 Despite these advances, the profound immunological and haematological disturbances inherent in most leukaemias and the systemic side effects of chemotherapy remain complex challenges. This is a two part review with the first part focusing on the current diagnosis and management of leukaemia. The second part will consider the types of support patients need in the community.

#### Sources and selection criteria

We searched PubMed for clinical trials and the Cochrane Library for meta-analyses. We also sought expert opinion from experienced consultant haematologists. Keywords used were leuk(a)emia, chemotherapy, supportive care, and community care. We also reviewed guidelines from the British Committee for Standards in Haematology and the National Institute for Health and Clinical Excellence.

Leukaemia is a cancer of circulating white blood cells. Leukaemias are divided into acute and chronic types. When immature white blood cells or …
Effect of adenosine 3′,5′-monophosphate on production of glucose and ammonia by renal cortex
Authors: Anthony S. Pagliara, A. David Goodman
Journal: Journal of Clinical Investigation (1969)

In studies employing rat renal cortical slices, the addition of adenosine 3',5'-monophosphate (cyclic AMP) to the incubation medium caused an increase in production of glucose from glutamine, glutamate, alpha-ketoglutarate, fumarate, malate, and oxalacetate, but not from glycerol and fructose. These observations suggest that cyclic AMP accelerates a rate-limiting gluconeogenic reaction between oxalacetate and the triose phosphates. The addition to the medium of parathyroid hormone, which is known to increase renal cortical cyclic AMP, also stimulated glucose production from glutamine. When renal cortical slices were incubated in the presence of glutamine, the addition of cyclic AMP caused a fall in tissue glutamate concentration and a rise in ammonia production, as well as an increase in gluconeogenesis. These changes are similar to those observed in renal cortex of rats with induced metabolic acidosis. The present observations are consistent with a previously advanced hypothesis that cortical gluconeogenesis, ammonia production, and glutamate concentration may be interdependent.
Observations on the Control of Cerebral Blood Flow in the Sheep Fetus and Newborn Lamb
Authors: M. J. Purves, I. M. James
Journal: Circulation Research (1969)

Cerebral blood flow was measured with xenon 133 in 21 fetal sheep and 14 newborn lambs under 48 hours old. When the ewe breathed air, the average gray matter blood flow in the fetuses was 70.6 ml/100 g/min, the average white matter blood flow 15.4 ml/100 g/min and average gray matter oxygen consumption 2.06 ml/100 g/min. The corresponding values in the newborn lambs were 87.2, 17.8, and 2.98 ml/100 g/min. A reduction of fetal Pao 2 by 7 to 11 mm Hg at a constant Paco 2 or an increase of Paco 2 at constant Pao 2 caused a rise in blood flow and arterial pressure and a fall in vascular resistance. Intravenous catecholamines caused variable changes in blood flow but no significant change in gray matter oxygen consumption. Occlusion of the umbilical cord caused an average increase in gray matter blood flow of 50% of control, in white matter blood flow of 30%, and in gray matter oxygen consumption of 90%. By the end of the first hour, these values had fallen and were then similar to those seen in the newborn lamb. These changes were not seen in fetuses in which both vagi had been cut nor in two fetuses with a failing circulation.