tbuckley/cabot-search huggingface dataset:
WNK kinases regulate thiazide-sensitive Na-Cl cotransport
Authors: Chao-Ling Yang, Jordan Angell, Rose Mitchell, David H. Ellison
Journal: Journal of Clinical Investigation (2003)

Pseudohypoaldosteronism type II (PHAII) is an autosomal dominant disorder of hyperkalemia and hypertension. Mutations in two members of the WNK kinase family, WNK1 and WNK4, cause the disease. WNK1 mutations are believed to increase WNK1 expression; the effect of WNK4 mutations remains unknown. The clinical phenotype of PHAII is opposite to Gitelman syndrome, a disease caused by dysfunction of the thiazide-sensitive Na-Cl cotransporter. We tested the hypothesis that WNK kinases regulate the mammalian thiazide-sensitive Na-Cl cotransporter (NCC). Mouse WNK4 was cloned and expressed in Xenopus oocytes with or without NCC. Coexpression with WNK4 suppressed NCC activity by more than 85%. This effect did not result from defects in NCC synthesis or processing, but was associated with an 85% reduction in NCC abundance at the plasma membrane. Unlike WNK4, WNK1 did not affect NCC activity directly. WNK1, however, completely prevented WNK4 inhibition of NCC. Some WNK4 mutations that cause PHAII retained NCC-inhibiting activity, but the Q562E WNK4 demonstrated diminished activity, suggesting that some PHAII mutations lead to loss of NCC inhibition. Gain-of-function WNK1 mutations would be expected to inhibit WNK4 activity, thereby activating NCC, contributing to the PHAII phenotype. Together, these results identify WNK kinases as a previously unrecognized sodium regulatory pathway of the distal nephron. This pathway likely contributes to normal and pathological blood pressure homeostasis.
HIV infection and stroke: current perspectives and future directions
Authors: Laura A Benjamin, Alan Bryer, Hedley CA Emsley, Saye Khoo, Tom Solomon, Myles D Connor
Journal: The Lancet Neurology (2012)

HIV infection can result in stroke via several mechanisms, including opportunistic infection, vasculopathy, cardioembolism, and coagulopathy. However, the occurrence of stroke and HIV infection might often be coincidental. HIV-associated vasculopathy describes various cerebrovascular changes, including stenosis and aneurysm formation, vasculitis, and accelerated atherosclerosis, and might be caused directly or indirectly by HIV infection, although the mechanisms are controversial. HIV and associated infections contribute to chronic inflammation. Combination antiretroviral therapies (cART) are clearly beneficial, but can be atherogenic and could increase stroke risk. cART can prolong life, increasing the size of the ageing population at risk of stroke. Stroke management and prevention should include identification and treatment of the specific cause of stroke and stroke risk factors, and judicious adjustment of the cART regimen. Epidemiological, clinical, biological, and autopsy studies of risk, the pathogenesis of HIV-associated vasculopathy (particularly of arterial endothelial damage), the long-term effects of cART, and ideal stroke treatment in patients with HIV are needed, as are antiretrovirals that are without vascular risk.
Human Connective Tissue Growth Factor Is Expressed in Advanced Atherosclerotic Lesions
Authors: Barry S. Oemar, Annick Werner, Jean-Marie Garnier, Dai-Do Do, Nelson Godoy, Markus Nauck, Winfried Ma¨rz, Joachim Rupp, Michael Pech, Thomas F. Lu¨scher
Journal: Circulation (1997)

Background Atherosclerosis affects certain but not all vascular beds of the human circulation. Its molecular mechanisms are only partially understood. Human connective tissue growth factor (hCTGF) is a novel cysteine-rich, secreted polypeptide. hCTGF is implicated in connective tissue formation, which may play an important role in atherosclerosis. Methods and Results By using a differential cloning technique, we isolated a cDNA clone from a human aorta cDNA library, which is identical to hCTGF. Northern analysis shows that hCTGF mRNA was expressed at 50- to 100-fold higher levels in atherosclerotic blood vessels compared with normal arteries. In vascular smooth muscle cells, high-level expression of hCTGF mRNA was induced by transforming growth factor-β1. Using in situ hybridization and immunohistochemistry, we found that all advanced atherosclerotic lesions of human carotid arteries (eight patients; mean age, 69; age range, 57 to 85 years) and femoral arteries (two patients; mean age, 71.5 years) that we tested expressed high levels of both hCTGF mRNA and protein. hCTGF expression was localized mainly to smooth muscle cells in the plaque lesions that are negative for proliferating cell nuclear antigen staining. In addition, some CD-31–positive endothelial cells of plaque vessels expressed high levels of hCTGF mRNA and protein. hCTGF-positive cells were found predominantly in areas with extracellular matrix accumulation and fibrosis. In contrast, in normal arteries, we were unable to detect either hCTGF mRNA or immunoreactive hCTGF protein. Conclusions In the present study, we have shown for the first time that both hCTGF mRNA and protein are expressed in human arteries in vivo and that hCTGF may represent a novel factor expressed at high levels specifically in advanced lesions and may play a role in the development and progression of atherosclerosis.
Mortality in Relation to Smoking: Ten Years' Observations of British Doctors
Authors: R. Doll, A. B. Hill
Journal: BMJ (1964)

The mortality of nearly 41000 medically qualified men and women in the United Kingdom has been observed for twelve years.  During the first 10 years 4597 of the men and 366 of the women died.  These deaths have been analyzed in relation to the smoking habits reported by doctors in reply to a questionnaire dispatched to them in 1951 (both sexes) and again in 1957 and 1960.  An association with smoking is found in differing degrees in men for seven causes of death and no association was found with the remaining 61% of the death rate and this includes such major causes as other forms of cancer cerebrovascular accidents hypertension myocardial degeneration suicide and accident.  A linear rise of death rate was observed from nonsmoker to light medium and heavy smokers which indicates that there is no smoking threshold which must be reached before the death rate from cancer of the lung shows a response.  The death rate continues to fall step by step the longer smoking has been given up.  Whether smoking acts synergistically with air pollution upon the respiratory tract is not known.  Some suggest a reasonable conclusion that cigarette smoking is one of the more important etiological factors in chronic bronchitis in Great Britain and relying on clinical evidence it could be said that possibly chronic bronchitis itself plays a part in producing cancer of the lung.  Tobacco and alcohol play some part in the production of cancers of the upper respiratory and digestive tracts.  Excess mortality due to coronary disease without hypertension is limited to cigarette smokers which is marked at under age 55 but disappears at over age 75.  Evidence supports the claim that cigarette smoking is one of the causes of coronary thrombosis under age 75.  Continued smoking may prevent or delay the healing of a chronic gastric ulcer and thereby it may increase the mortality rate.  Mortality from alcoholism and cirrhosis of the liver is specially high in heavy smokers.  There appears to be no cause of mortality which is lessened by smoking.
Excision of Expanded GAA Repeats Alleviates the Molecular Phenotype of Friedreich's Ataxia
Authors: Yanjie Li, Urszula Polak, Angela D Bhalla, Natalia Rozwadowska, Jill Sergesketter Butler, David R Lynch, Sharon Y R Dent, Marek Napierala
Journal: Molecular Therapy (2015)

Friedreich's ataxia (FRDA) is an autosomal recessive neurological disease caused by expansions of guanine-adenine-adenine (GAA) repeats in intron 1 of the frataxin (FXN) gene. The expansion results in significantly decreased frataxin expression. We report that human FRDA cells can be corrected by zinc finger nuclease-mediated excision of the expanded GAA repeats. Editing of a single expanded GAA allele created heterozygous, FRDA carrier-like cells and significantly increased frataxin expression. This correction persisted during reprogramming of zinc finger nuclease-edited fibroblasts to induced pluripotent stem cells and subsequent differentiation into neurons. The expression of FRDA biomarkers was normalized in corrected patient cells and disease-associated phenotypes, such as decreases in aconitase activity and intracellular ATP levels, were reversed in zinc finger nuclease corrected neuronal cells. Genetically and phenotypically corrected patient cells represent not only a preferred disease-relevant model system to study pathogenic mechanisms, but also a critical step towards development of cell replacement therapy.
Does Sampson see any alternative?
Authors: Larry Katzenstein
Journal: Nature Medicine (1997)

US embraces alternative medicinePopular as it is-Americans spend an estimated $14 billion a year on alternative medicines and treatments-alternalive medicine has surely never attracted more scientific attention than in recent months.Despite director of the National Institute of Health (NIH) Harold Varmus' plea to reduce funding for the Office of Alternative Medicine (OAM), successful government lobbying looks to have achieved a two-thirds increase in the OAM budget to $20 million for FY98.The NIH itself spends around $40 million on alternative medicine research, such as the recently approved marijuana and St. John's Wort trials.However, last month, at the same time that an NIH consensus meeting was giving acupuncture the thumbs up, the NIH came under fire from John Porter (Rep.-lllinois), who chairs the House of Representatives spending committee that funds it.Porter criticized the organization for not paying enough attention to the practice of "mindbody" medicine-the power of the mind to heal-in which he has become a firm believer since rest and relaxation during the summer months, intead of surgery, "cured" him of a back problem.But alternative medicine is not getting all its own way.Within recent weeks the US Food and Drug Administration has issued warnings about the content of herbal Fen-Phen, and other alternative treatments will soon come under close scientific scrutiny in a new peer-reviewed journal.
Sources of proteins in human bile.
Authors: B M Mullock, L J Shaw, B Fitzharris, J Peppard, M J Hamilton, M T Simpson, T M Hunt, R H Hinton
Journal: Gut (1985)

The proteins of 46 human bile specimens, collected by several different routes have been studied by crossed immunoelectrophoresis, by rocket immunoelectrophoresis and by radioimmunoassay. The results were analysed by plotting the variation in the bile: plasma ratio of particular proteins against molecular weight and by examination of the correlation between the concentrations of different proteins in the biles of different patients. Our results show that the majority of human bile proteins derive from plasma although bile specific proteins are always present. The majority of plasma proteins appear to enter bile by a 9sieving9 mechanism which results in an inverse relationship between the bile: plasma ratio and the molecular weight. In addition there was a very high degree of correlation between the biliary concentrations of alpha 2-macroglobulin, IgG, haptoglobin, haemopexin, albumin, prealbumin, and orosomucoid. A number of other proteins namely thyroxine binding globulin, GC globulin and alpha 2HS-glycoprotein appeared in bile at concentrations greater than those expected if entry is by the sieving mechanism. These three proteins, however, are of rather low molecular weight and the reason for the lack of correlation appears to be individual variation in the 9pore size9, presumably reflecting variation in the porosity of tight junction between hepatocytes. Although the majority of human bile proteins would appear to enter bile by a molecular weight-dependent pathway, four proteins, namely secretory IgA, IgM, haemoglobin and caeruloplasmin, showed significant deviation from the predicted relationship and probably enter bile at least partly by transport across cells. The concentration of beta 2-glycoprotein I was also much greater than expected from its molecular weight. The reason for this is not yet clear but may well reflect a very efficient and specific transport mechanism.
746 NARLAPREVIR AND PEGINTERFERON ALFA-2B FOR 2 WEEKS IN CHRONIC HEPATITIS C GENOTYPE 1 PATIENTS, FOLLOWED BY PEGINTERFERON ALFA-2B AND RIBAVIRIN FOR 24/48 WEEKS: FINAL RESULTS
Authors: J. de Bruijne, J.F. Bergmann, C.J. Weegink, R. Molenkamp, J. Schinkel, M.A. Treitel, E.A. Hughes, A. van Vliet, R.J. de Knegt, H.W. Reesink, H.L.A. Janssen
Journal: Journal of Hepatology (2010)
Effects of human interleukin 1 and human tumor necrosis factor on human T lymphocyte colony formation.
Authors: J R Zucali, G J Elfenbein, K C Barth, C A Dinarello
Journal: Journal of Clinical Investigation (1987)

The growth of T lymphocyte colonies in agar is dependent on the cooperation of a number of different cell types and their products. Among these interacting cells are monocytes and/or macrophages. Monocytes are capable of producing both interleukin 1 (IL-1) and tumor necrosis factor (TNF). These two factors display a positive influence on T cell colony formation. Recombinant IL-1 and recombinant TNF were both shown to stimulate T cell colony growth in a dose-dependent manner, and this stimulation could be blocked by prior incubation with anti-IL-1 or anti-TNF, respectively. In addition, conditioned medium obtained from monocytes cultured in the presence of endotoxin also stimulated T cell colony formation. This stimulation by monocyte-conditioned medium was partially suppressed by incubation with anti-TNF or anti-IL-1, while incubation with both antibodies together displayed greater suppression. In conclusion, monocytes produce at least two factors, IL-1 and TNF, which can stimulate T cell colony formation by peripheral blood lymphocytes.
Surgery for Obesity
Authors: Ronald A. Malt, Frederick G. Guggenheim
Journal: New England Journal of Medicine (1976)

Seeking surgical relief for her morbid obesity, a patient epitomized her resolution in this way: "I always thought I had a 'condition.' Now I know I have a disease. A disease can be treated." Evidence like the article in this issue of the Journal (p. 6) shows that adverse genetic and neonatal influences can become diseases in adolescent and adult life that foster obesity as inexorably as certain neurologic or endocrine abnormalities.Surgical management is an appropriate consideration for patients with morbid obesity who have failed to lose weight under strict medical supervision. The most direct operations are those that . . .
Diet and New Lesions of the Coronary Arteries
Authors: Mark R. Goldstein
Journal: JAMA (1990)

To the Editor.—  Dr Blankenhorn and colleagues 1 presented angiogram data from analysis of the placebo cohort of the Cholesterol Lowering Atherosclerosis Study indicating that the increasing consumption of total fat; polyunsaturated fat; and lauric, oleic, and linoleic acids was associated with a subsequent increase in the risk of developing new coronary artery lesions. The association of new lesions with increasing consumption of total fat and lauric acid is not surprising. On the contrary, the association of new lesions with increasing consumption of polyunsaturated fat and oleic and linoleic acid is perplexing.  A recent large-population, cross-sectional study suggested that the consumption of polyunsaturated and monounsaturated fat was associated with a lower coronary risk profile. 2 The Seven Countries Study demonstrated a significant association with entry dietary oleic acid intake and decreased all-cause and coronary heart disease mortality at 15 years. 3 Other studies have suggested beneficial effects on lipoprotein metabolism
Pregnancy and the Nephrotic Syndrome
Authors: J. W. W. Studd, J. D. Blainey
Journal: BMJ (1969)

Nineteen patients with nephrotic syndrome, 13 with histological diagnosis, were studied throughout 31 pregnancies. Eight were diagnosed for the first time during pregnancy.Antenatal problems due to severe oedema, urinary tract infection, and refractory orthochromic anaemia were encountered. Eight patients were hypertensive at booking, and in two of these pregnancy was terminated; three others had a significant increase in blood pressure. In 12 of the remaining pregnancies a rise in blood pressure of 20 mm. Hg or more occurred towards term.There were 29 live births (including one set of twins), one stillbirth due to a cord accident, and one neonatal death. The infant birth weight, apart from being affected by hypertension, was related to the maternal serum albumin level.The patients have been under observation for up to 20 years. Fifteen have not shown any deterioration of renal function during the prolonged period of observation. One developed oliguric renal failure immediately post partum and three others died, two, four, and 12 years after their pregnancies.
PLGA nanoparticles loaded with host defense peptide LL37 promote wound healing
Authors: Kiran Kumar Chereddy, Charles-Henry Her, Michela Comune, Claudia Moia, Alessandra Lopes, Paolo E. Porporato, Julie Vanacker, Martin C. Lam, Lars Steinstraesser, Pierre Sonveaux, Huijun Zhu, Lino S. Ferreira, Gaëlle Vandermeulen, Véronique Préat
Journal: Journal of Controlled Release (2014)
Bassoon Speeds Vesicle Reloading at a Central Excitatory Synapse
Authors: Stefan Hallermann, Anna Fejtova, Hartmut Schmidt, Annika Weyhersmüller, R. Angus Silver, Eckart D. Gundelfinger, Jens Eilers
Journal: Neuron (2010)

Sustained rate-coded signals encode many types of sensory modalities. Some sensory synapses possess specialized ribbon structures, which tether vesicles, to enable high-frequency signaling. However, central synapses lack these structures, yet some can maintain signaling over a wide bandwidth. To analyze the underlying molecular mechanisms, we investigated the function of the active zone core component Bassoon in cerebellar mossy fiber to granule cell synapses. We show that short-term synaptic depression is enhanced in Bassoon knockout mice during sustained high-frequency trains but basal synaptic transmission is unaffected. Fluctuation and quantal analysis as well as quantification with constrained short-term plasticity models revealed that the vesicle reloading rate was halved in the absence of Bassoon. Thus, our data show that the cytomatrix protein Bassoon speeds the reloading of vesicles to release sites at a central excitatory synapse.
Carbon cost of pragmatic randomised controlled trials: retrospective analysis of sample of trials
Authors: K. Lyle, L. Dent, S. Bailey, L. Kerridge, I. Roberts, R. Milne
Journal: BMJ (2009)

To calculate the global warming potential, in carbon dioxide (CO(2)) equivalent emissions, from a sample of pragmatic randomised controlled trials.Retrospective analysis. Data source Internal data held by NIHR Evaluation, Trials and Studies Coordinating Centre. Studies included All eligible pragmatic randomised controlled trials funded by the NIHR Health Technology Assessment programme during 2002 and 2003.CO(2) equivalents for trial activities calculated with standard conversion factors.12 pragmatic randomised controlled trials involving more than 4800 participants and a wide range of technologies were included. The average CO(2) emission generated by the trials was 78.4 (range 42.1-112.7) tonnes. This is equivalent to that produced in one year by approximately nine people in the United Kingdom. Commuting to work by the trial team generated the most emissions (average 21 (11.5-35.0) tonnes per trial), followed by study centres' fuel use (18 (9.3-32.2) tonnes per trial), trial team related travel (15 (2.0-29.0) tonnes per trial), and participant related travel (13 (0-46.7) tonnes per trial).CO(2) emissions from pragmatic randomised controlled trials are generated in areas where steps could be taken to reduce them. A large proportion of the CO(2) emissions come from travel related to various aspects of a trial. The results of this research are likely to underestimate the total CO(2) emissions associated with the trials studied, because of the sources of information available. Further research is needed to explore the additional CO(2) emissions generated by clinical trials, over and above those generated by routine care. The results from this project will feed into NIHR guidelines that will advise researchers on how to reduce CO(2) emissions.
Cigarette Smoking
Authors: C. DAVID JENKINS, RAY H. ROSENMAN, STEPHEN J. ZYZANSKI
Journal: Circulation (1968)

The association of the incidence of coronary heart disease (CHD) with smoking habits was studied for 4½ years in over 3,000 healthy, employed men, aged 39 to 59 years, at intake into a prospective, epidemiological investigation. The risk of CHD was significantly associated both with current and former cigarette usage. More specifically, this association was found to prevail in men suffering symptomatic and fatal myocardial infarction but not in men sustaining silent myocardial infarction or angina pectoris only and was much stronger in younger than in older age groups. Altered risk of CHD was not found in pipe or cigar smokers. Cigarette habits at intake were associated with differences in serum lipids and other risk variables, but when the latter were controlled statistically, the smoking-CHD associations remained. The cigarette-CHD relationship was studied further in men with and without the coronary-prone behavior pattern (type A). In the younger age decade the increased risk of CHD associated with moderate and heavy cigarette smoking occurred primarily in men with the type A behavior pattern.
GOLPH3 Links the Golgi, DNA Damage, and Cancer
Authors: Matthew D. Buschman, Juliati Rahajeng, Seth J. Field
Journal: Cancer Research (2015)

Abstract GOLPH3 is the first example of an oncogene that functions in secretory trafficking at the Golgi. The discovery of GOLPH3′s roles in both cancer and Golgi trafficking raises questions about how GOLPH3 and the Golgi contribute to cancer. Our recent investigation of the regulation of GOLPH3 revealed a surprising response by the Golgi upon DNA damage that is mediated by DNA-PK and GOLPH3. These results provide new insight into the DNA damage response with important implications for understanding the cellular response to standard cancer therapeutic agents. Cancer Res; 75(4); 624–7. ©2015 AACR.