tbuckley/cabot-search huggingface dataset:
Luxury Primary Care — Market Innovation or Threat to Access?
Authors: Troyen A. Brennan
Journal: New England Journal of Medicine (2002)

Primary care practitioners in several states have recently decided to restructure their practices in a way that enables them to see a much smaller number of patients and to spend more time with the ones they do see. Patients enrolled in these practices, referred to as "luxury primary care," pay an annual fee to the practice. In return for this annual fee, they can expect certain amenities that are not currently part of primary care, such as access to their physicians 24 hours a day, 7 days a week, using cell phones or prompt paging devices.1 When they see their . . .
Resistin reduces mitochondria and induces hepatic steatosis in mice by the protein kinase C/protein kinase G/p65/PPAR gamma coactivator 1 alpha pathway
Authors: Lei Zhou, Xiaolan Yu, Qingjie Meng, Hongqiang Li, Congcong Niu, Yun Jiang, Yuxi Cai, Minghui Li, Qiang Li, Chaoqiang An, Le Shu, Ao Chen, Handong Su, Yin Tang, Shen Yin, Silja Raschke, Kristin Eckardt, Jürgen Eckel, Zaiqing Yang
Journal: Hepatology (2012)

Obesity is associated with many severe chronic diseases and deciphering its development and molecular mechanisms is necessary for promoting treatment. Previous studies have revealed that mitochondrial content is down-regulated in obesity, diabetes, and nonalcoholic fatty liver disease (NAFLD) and proposed that NAFLD and diabetes are mitochondrial diseases. However, the exact mechanisms underlying these processes remain unclear. In this study, we discovered that resistin down-regulated the content and activities of mitochondria, enhanced hepatic steatosis, and induced insulin resistance (IR) in mice. The time course indicated that the change in mitochondrial content was before the change in fat accumulation and development of insulin resistance. When the mitochondrial content was maintained, resistin did not stimulate hepatic fat accumulation. The present mutation study found that the residue Thr464 of the p65 subunit of nuclear factor kappa B was essential for regulating mitochondria. A proximity ligation assay revealed that resistin inactivated peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC-1α) and diminished the mitochondrial content by promoting the interaction of p65 and PGC-1α. Signaling-transduction analysis demonstrated that resistin down-regulated mitochondria by a novel protein kinase C/protein kinase G/p65/PGC-1α-signaling pathway.Resistin induces hepatic steatosis through diminishing mitochondrial content. This reveals a novel pathway for mitochondrial regulation, and suggests that the maintenance of normal mitochondrial content could be a new strategy for treatment of obesity-associated diseases.
Long-term Engraftment of Single Genetically Modified Human Epidermal Holoclones Enables Safety Pre-assessment of Cutaneous Gene Therapy
Authors: Fernando Larcher, Elena Dellambra, Laura Rico, Sergio Bondanza, Rodolfo Murillas, Claudia Cattoglio, Fulvio Mavilio, José L Jorcano, Giovanna Zambruno, Marcela Del Rio
Journal: Molecular Therapy (2007)

Predicting the risks of permanent gene therapy approaches involving the use of integrative gene-targeting vectors has become a critical issue after the unfortunate episode of a clinical trial in children with X-linked severe combined immunodeficiency (X-SCID). Safety pre-assessment of single isolated gene-targeted stem cells or their derivative clones able to regenerate their tissue of origin would be a major asset in addressing untoward gene therapy effects in advance. Human epidermal stem cells, which have extensive proliferative potential in vitro, theoretically offer such a possibility as a method of assessment. By means of optimized organotypic culture and grafting methods, we demonstrate the long-term in vivo regenerative capacity of single gene-targeted human epidermal stem cell clones (holoclones). Both histopathological analysis of holoclone-derived grafts in immunodeficient mice and retroviral insertion site mapping performed in the holoclone in vitro and after grafting provide proof of the feasibility of pre-assessing genotoxicity risks in isolated stem cells before transplantation into patients. Our results provide an experimental basis for previously untested assumptions about the in vivo behavior of epidermal stem cells prospectively isolated in vitro and pave the way for a safer approach to cutaneous gene therapy. Predicting the risks of permanent gene therapy approaches involving the use of integrative gene-targeting vectors has become a critical issue after the unfortunate episode of a clinical trial in children with X-linked severe combined immunodeficiency (X-SCID). Safety pre-assessment of single isolated gene-targeted stem cells or their derivative clones able to regenerate their tissue of origin would be a major asset in addressing untoward gene therapy effects in advance. Human epidermal stem cells, which have extensive proliferative potential in vitro, theoretically offer such a possibility as a method of assessment. By means of optimized organotypic culture and grafting methods, we demonstrate the long-term in vivo regenerative capacity of single gene-targeted human epidermal stem cell clones (holoclones). Both histopathological analysis of holoclone-derived grafts in immunodeficient mice and retroviral insertion site mapping performed in the holoclone in vitro and after grafting provide proof of the feasibility of pre-assessing genotoxicity risks in isolated stem cells before transplantation into patients. Our results provide an experimental basis for previously untested assumptions about the in vivo behavior of epidermal stem cells prospectively isolated in vitro and pave the way for a safer approach to cutaneous gene therapy.
Enzymology of Cancer Cells
Authors: George Weber
Journal: New England Journal of Medicine (1977)

This paper attempts to integrate the relevant quantitative and qualitative differences in the enzymology of the cancer cell discriminating it from that of the normal cell. In cancer cells an ordered pattern of enzymatic imbalance is linked with the malignant transformation and the gradations in the expression of the neoplastic properties (progression). The metabolic imbalance confers biologic advantages on the cancer cells. This insight into the molecular biology of neoplasia singles out key enzymes as sensitive targets of anti-cancer drugs.Clinical Strategy of Treatment of Neoplastic DiseasesThe success in the treatment of infectious diseases is in contrast to the . . .
Abstract 14907: 123I-MIBG Myocardial Scintigraphy Predicts The Impairment In Myocardial Functional Reserve During Dobutamine Stress Test In Patients With Idiopathic Dilated Cardiomyopathy
Authors: Satoru Ohshima, Satoshi Isobe, Daisuke Hayashi, Toyoaki Murohara
Journal: Circulation (2011)

Background: Little is known about the relationship between myocardial denervation and myocardial functional reserve by beta-adrenergic stimulation in failing heart. Objective: We investigated wheth...
Chronic ethanol administration to rats decreases receptor-operated mobilization of intracellular ionic calcium in cultured hepatocytes and inhibits 1,4,5-inositol trisphosphate production: relevance to impaired liver regeneration.
Authors: B H Zhang, B P Hornsfield, G C Farrell
Journal: Journal of Clinical Investigation (1996)

We tested the hypothesis that ethanol impairs liver regeneration by abrogating receptor-mediated elevation of cytosolic free calcium ([Ca2+]i). In rats fed for 16 weeks with ethanol, hepatocellular proliferation induced by partial hepatectomy was greatly impaired. Similarly, EGF-induced DNA synthesis was reduced in cultured hepatocytes from ethanol-fed rats. There was no change in the number or affinity of EGF receptors on hepatocytes from ethanol-fed rats. Despite this, EGF-mediated production of inositol 1,4,5-trisphosphate (Ins[1,4,5]P3) was lower in hepatocytes from ethanol-fed rats, and the EGF-induced [Ca2+]i transient appeared to be abrogated. When vasopressin or phenylephrine were used as cell surface receptor ligands, hepatocytes cultured from ethanol-fed rats exhibited major reductions in Ins(1,4,5)P3 synthesis. This was associated with greatly truncated [Ca2+]i transients. These changes were not due to an effect on the Ins(1,4,5)P3 receptor on the endoplasmic reticulum or to a decrease in the size of the Ins(1,4,5)P3-mobilizable intracellular Ca+2 store. Further, mobilization of the same Ca2+ store by 2,5-di-tert-butylhydroquinone or thapsigargin restored the ability of hepatocytes from ethanol-fed rats to proliferate when exposed to EGF. It is concluded that chronic ethanol consumption inhibits liver regeneration by a mechanism that is, at least partly, the result of impaired receptor-operated [Ca2+]i signaling due to reduced generation of Ins(1,4,5)P3.
Trimodality of isoniazid elimination: phenotype and genotype in patients with tuberculosis.
Authors: D P Parkin, S Vandenplas, F J Botha, M L Vandenplas, H I Seifart, P D van Helden, B J van der Walt, P R Donald, P P van Jaarsveld
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

The study was undertaken to show that polymorphic isoniazid elimination in humans is trimodal; that the acetylator genotype and eliminator phenotype of the individual patient are concordant; and that the differences in the pharmacokinetic parameters of fast, intermediate, and slow eliminator subgroups are statistically significant. Sixty adult patients of both sexes and of mixed race with tuberculosis participated in the trial. The apparent elimination rate constant (k, h(-1)) and the area under the isoniazid concentration-time curve (AUC, mg/L/h), over the interval 2 to 6 h after oral isoniazid were determined in all patients; NAT2 allele composition was determined in 47 patients. Serum INH concentrations were determined by HPLC and genotypes by PCR/restriction enzyme analysis. Three eliminator phenotypes could be distinguished, and concordance between the phenotype and the genotype of the individual could be demonstrated. The isoniazid concentration-time profiles of the three eliminator subgroups were significantly different (p < 0.05). The NAT2*12A allele, which codes for fast acetylation, has a high frequency in the population studied, the intermediate acetylator genotype is constituted of codominant fast and slow alleles, and the distribution of phenotypes/genotypes in the population is consistent with Hardy-Weinberg predictions. The therapeutic implications of polymorphic isoniazid metabolism are discussed.
Teaching Nursing Homes Revisited
Authors: Edward L. Schneider
Journal: JAMA (1987)

A survey of American medical schools was conducted to examine the growth of teaching nursing home programs. Ninety percent (109/121) of schools surveyed reported affiliations with a nursing home(s) for teaching, research, and/or clinical care. Most affiliations occurred in the last six years and were typically with two or more nursing homes. They were usually 120 beds or more in size, and the majority were nonprofit or Veterans Administration units. Eighty-three percent (101/121) of medical schools had teaching programs involving nursing homes. Medical school courses that utilized nursing homes as teaching sites were largely selective or elective and were offered primarily in the senior year. Training programs involving residents were usually mandatory and mainly involved the departments of internal medicine and family practice. Fifty-five percent (66/121) of the schools had research programs involving nursing homes. (<i>JAMA</i>1987;257:2771-2775)
Prognosis of untreated hepatocellular carcinoma
Authors: Edoardo G. Giannini, Fabio Farinati, Francesca Ciccarese, Anna Pecorelli, Gian Lodovico Rapaccini, Mariella Di Marco, Luisa Benvegnù, Eugenio Caturelli, Marco Zoli, Franco Borzio, Maria Chiaramonte, Franco Trevisani
Journal: Hepatology (2014)

The prognosis of untreated patients with hepatocellular carcinoma (HCC) is heterogeneous, and survival data were mainly obtained from control arms of randomized studies. Clinical practice data on this topic are urgently needed, so as to help plan studies and counsel patients. We assessed the prognosis of 600 untreated patients with HCC managed by the Italian Liver Cancer Group. Prognosis was evaluated by subdividing patients according to the Barcelona Clinic Liver Cancer (BCLC) classification. We also assessed the main demographic, clinical, and oncological determinants of survival in the subgroup of patients with advanced HCC (BCLC C). Advanced (BCLC C: n = 138; 23.0%) and end-stage HCC (BCLC D; n = 210; 35.0%) represented the majority of patients. Overall median survival was 9 months, and the principal cause of death was tumor progression (n = 279; 46.5%). Patients' median survival progressively and significantly decreased as BCLC stage worsened (BCLC 0: 38 months; BCLC A: 25 months; BCLC B: 10 months; BCLC C: 7 months; BCLC D: 6 months; P < 0.0001). Female gender (hazard ratio [HR] = 0.55; 95% confidence interval [CI] = 0.33-0.90; P = 0.018), ascites (HR = 1.81; 95% CI = 1.21-2.71; P = 0.004), and multinodular (>3) HCC (HR = 1.79; 95% CI = 1.21-2.63; P = 0.003) were independent predictors of survival in patients with advanced HCC (BCLC C).BCLC adequately predicts the prognosis of untreated HCC patients. In untreated patients with advanced HCC, female gender, clinical decompensation of cirrhosis, and multinodular tumor are independent prognostic predictors and should be taken into account for patient stratification in future therapeutic studies.
gp91phox-Containing NADPH Oxidase Mediates Endothelial Dysfunction in Renovascular Hypertension
Authors: O. Jung, J.G. Schreiber, H. Geiger, T. Pedrazzini, R. Busse, R.P. Brandes
Journal: Circulation (2004)

Isoforms of the NADPH oxidase contribute to vascular superoxide anion (*O2-) formation and limit NO bioavailability. We hypothesized that the endothelial gp91phox-containing NADPH oxidase is predominant in generating the O2- to scavenge endothelial NO and thus is responsible for the development of endothelial dysfunction.Endothelial dysfunction was studied in aortic rings from wild-type (WT) and gp91phox-knockout (gp91phox-/-) mice with and without renovascular hypertension induced by renal artery clipping (2K1C). Hypertension induced by 2K1C was more severe in WT than in gp91phox-/- mice (158+/-2 versus 149+/-2 mm Hg; P<0.05). Endothelium-dependent relaxation to acetylcholine (ACh) was attenuated in rings from clipped WT but not from clipped gp91phox-/- mice. The reactive oxygen species (ROS) scavenger Tiron, PEG-superoxide dismutase, and the NADPH oxidase inhibitory peptide gp91ds-tat enhanced ACh-induced relaxation in aortae of clipped WT mice. Inhibition of protein kinase C, Rac, and the epidermal growth factor receptor kinase, elements involved in the activation of the NADPH oxidase, restored normal endothelium-dependent relaxation in vessels from clipped WT mice but had no effect on relaxations in those from gp91phox-/- mice. Relaxations to exogenous NO were attenuated in vessels from clipped WT but not clipped gp91phox-/- mice. After removal of the endothelium or treatment with PEG-superoxide dismutase, NO-induced relaxations were identical in vessels from clipped and sham-operated WT and gp91phox mice.These data indicate that the formation of O2- by the endothelial gp91phox-containing NADPH oxidase accounts for the reduced NO bioavailability in the 2K1C model and contributes to the development of renovascular hypertension and endothelial dysfunction.
Recurrent Myocardial Infarction with Normal Coronary Arteriography
Authors: Stephen P. Michaelson, Dennis L. Karsh, Steven Wolfson, Robert E. Lebson, Lawrence S. Cohen
Journal: New England Journal of Medicine (1977)

The syndrome of acute myocardial infarction with angiographically normal coronary arteries has been more frequently recognized since the availability of coronary angiography. Most of the patients described are young, and the syndrome is said to have a benign course and favorable prognosis.1 The subject of this case study, which was first reported in this Journal as a case of myocardial infarction with normal coronary arteries in 1970,2 has recently experienced a recurrent infarction, and has undergone restudy.Case ReportA 29-year-old man had been seen at the Newton-Wellesley Hospital in August, 1967, at the age of 19 years because of . . .
Conjoint high triglycerides and low HDL cholesterol across generations. Analysis of proband hypertriglyceridemia and lipid/lipoprotein disorders in first-degree family members.
Authors: D L Sprecher, M J Hein, P M Laskarzewski
Journal: Circulation (1994)

BACKGROUND To discern whether hypertriglyceridemia (hyper-TG, TG &gt; 95th percentile) and hypoalphalipoporteinemia (hypoalpha, high-density lipoprotein [HDL-C] &lt; or = 10th percentile) are jointly transmitted in families, we studied 385 probands with marked elevations in TG or cholesterol levels (TG or cholesterol &gt; 99th percentile in a previous visit) and their 2072-first-degree relatives in the Lipid Research Clinics' Family Study. Repeat TG measurement, with exclusion criterion of TG &lt; or = 95th percentile, resulted in 162 probands with hyper-TG. METHODS AND RESULTS When the proband demonstrated the conjoint trait (CT; ie, TG &gt; 95th percentile, HDL-C &lt; or = 10th percentile, n = 82), an average of 10.6% of first-degree relatives conjointly expressed hyper-TG and hypoalpha in contrast to only 4.1% of first-degree relatives of a proband who expressed high TG levels with normal HDL-C levels (TG &gt; 95th percentile, HDL-C &gt; 10th percentile, n = 80). Hyper-TG was expressed in 24.2% of first-degree relatives of probands with CT. However, hyper-TG was expressed in only 14.4% of first-degree degree relatives of probands with hyper-TG alone. CT probands and their family members tended to have more reported cardiac events and symptoms (P = .02 and .09, respectively) than those subjects associated with hyper-TG alone. CONCLUSIONS The differences in HDL-C-TG abnormalities between families related to hyper-TG probands with or without hypoalpha indicate that bottom decile HDL-C is not simply secondary to hyper-TG. A familial interaction is suggested between HDL-C and TG levels consistent with the transmission of hyper-TG and hypoalpha among first-degree relatives. Among subjects and their families with hyper-TG, those who in addition have low HDL-C demonstrate a tendency for more coronary artery disease than do those with normal HDL-C levels.
Mechanism of preconditioning. Ionic alterations.
Authors: C Steenbergen, M E Perlman, R E London, E Murphy
Journal: Circulation Research (1993)

The mechanism by which preconditioning (brief intermittent periods of ischemia and reflow) improves recovery of function and reduces enzyme release after a subsequent 30-minute period of ischemia was investigated in perfused rat hearts. Specifically, it was hypothesized that ischemia after preconditioning would result in a decreased production of H+ and therefore a smaller rise in [Na+]i and [Ca2+]i via Na(+)-H+ and Na(+)-Ca2+ exchange. To test this hypothesis we measured pHi, [Na+]i, [Ca2+]i, and cell high-energy phosphates during ischemia and reflow, and we correlated this with recovery of contractile function and release of creatine kinase during reflow. 31P nuclear magnetic resonance (NMR) was used to measure pHi and cell phosphates. [Na+]i was measured by 23Na NMR using the shift reagent thulium 1,4,7,10-tetraazacyclododecane-N,N,'N",N"'-tetramethylenephosph onate to distinguish intracellular from extracellular sodium. [Ca2+]i was measured by 19F NMR using hearts loaded with 1,2-bis(2-amino-5-fluorophenoxy)ethane-N,N,N',N'-tetraacetic acid, termed 5F-BAPTA. Basal time-averaged levels of pHi, [Na+]i, and [Ca2+]i were 7.07 +/- 0.08, 9.4 +/- 0.8 mM, and 715 +/- 31 nM, respectively. After 30 minutes of ischemia, in preconditioned hearts, pHi was 6.5 +/- 0.06, [Na+]i was 2.09 +/- 4.4 mM, [Ca2+]i was 2.1 +/- 0.4 microM, and ATP was negligible. In untreated hearts, after 30 minutes of ischemia, pHi was 6.3 +/- 0.08, [Na+]i was 26.7 +/- 3.8 mM, [Ca2+]i was 3.2 +/- 0.6 microM, and ATP was undetectable. During reperfusion after 30 minutes of ischemia, preconditioned hearts had significantly better recovery of contractile function than untreated hearts (71 +/- 9% versus 36 +/- 8% initial left ventricular developed pressure), and after 60 minutes of ischemia, preconditioned hearts had significantly less release of the intracellular enzyme creatine kinase (102 +/- 12 versus 164 +/- 17 IU/g dry wt). We also found that unpreconditioned hearts arrested with 16 mM MgCl2 (to inhibit calcium entry via calcium channels and Na(+)-Ca2+ exchange) before 30 minutes of ischemia recover function on reflow to the same extent as preconditioned hearts with or without magnesium arrest. Thus, preconditioning has no additional benefit in addition to magnesium arrest. In addition, in hearts that received 16 mM MgCl2 just before the 30-minute period of ischemia, preconditioning had no effect on the rise in [Ca2+]i during the 30-minute period of ischemia. These data support the hypothesis that preconditioning attenuates the increase in [Ca2+]i, [Na+]i, and [H+]i during ischemia, most likely because of reduced stimulation of Na(+)-H+ and Na(+)-Ca2+ exchange.(ABSTRACT TRUNCATED AT 400 WORDS)
Abbott pays $1.6bn for promoting off label use of valproic acid
Authors: B. Roehr
Journal: BMJ (2012)

The drug company Abbott Laboratories has agreed to pay $1.6bn (£0.9bn; €1.2bn) in penalties for improper promotion of the drug Depakote (valproic acid) in the US. The settlement is the second largest by a drug manufacturer and ends a four year investigation by federal and state officials.

The company acknowledged training a workforce to promote off label use of the drug to nursing homes to control agitation and aggression in older schizophrenia patients and in patients with dementia. The judgment says that Abbott also made illegal payments to doctors and pharmacists to encourage them to promote or prescribe valproic acid outside its …
Race, Poverty, and Potential Exposure of Middle-School Students to Air Emissions from Confined Swine Feeding Operations
Authors: Maria C. Mirabelli, Steve Wing, Stephen W. Marshall, Timothy C. Wilcosky
Journal: Environmental Health Perspectives (2005)

Previous studies suggest that airborne effluent from swine confined animal feeding operations (CAFOs) may affect the health and quality of life of adults and the prevalence of asthma symptoms among children. To investigate the extent to which public school students may be exposed to airborne effluent from swine CAFOs and to evaluate the association between schools’ demographic characteristics and swine CAFO exposures, we assessed the proximity of 226 schools to the nearest swine CAFO and conducted a survey of school employees to identify schools with noticeable livestock odor. We used publicly available information describing the enrollment of each school to assess the association between race and socioeconomic status (SES) and swine CAFO exposure. Odor from livestock was noticeable outside (n = 47, 21%) and inside (n = 19, 8%) school buildings. Schools with &lt; 63% enrollment of white students and ≥47% of students receiving subsidized lunches at school were located closer to swine CAFOs (mean = 4.9 miles) than were the remaining schools (mean = 10.8 miles) and were more likely to be located within 3 miles of an operation than were schools with high-white/high-SES enrollment (prevalence ratio = 2.63; 95% confidence interval, 1.59–4.33). The prevalence of reported livestock odor varied with SES (low SES, 25%; high SES, 17%). These analyses indicate that the potential for in-school exposure to pollution arising from swine CAFOs in North Carolina and the environmental health risks associated with such exposures vary according to the racial and economic characteristics of enrolled students.