tbuckley/cabot-search huggingface dataset:
Identification and characterization of a pore-forming protein of human peripheral blood natural killer cells.
Authors: C C Liu, B Perussia, Z A Cohn, J D Young
Journal: The Journal of Experimental Medicine (1986)

We show here that human peripheral blood NK cells contain a pore-forming protein (PFP) with an Mr of 70,000-72,000 that assembles structural lesions (with an average internal diameter of 150-170 A) and forms functional channels. The PFP was isolated by affinity chromatography from human NK cells, using a specific anti-C9 antiserum as the immunoadsorbent. The NK cells were isolated from PBL by positive or negative selection by indirect rosetting using a panel of monoclonal antibodies directed against different NK and T cell surface antigens. PFP was identified in NK cells freshly isolated and isolated from cultured PBL, both stimulated with interleukin 2, but not in NK cell-depleted lymphocytes. In planar bilayers, the channels formed by the NK cell-derived PFP are highly voltage resistant, with most channels persisting in the open state once they have inserted into the bilayer. The unit conductances of these channels range 0.3-1 nS in 0.1 M NaCl. The channels show poor selectivity for monovalent and divalent ions. The PFP is also released from human NK cells stimulated with the calcium ionophore A23187, suggesting that this protein, like the one produced by murine CTL lines, may be similarly secreted during cell-mediated killing. Its identification in primary human NK cell cultures indicates that this protein may play an active role in NK cell-mediated killing.
Loss of Fibroblast HIF-1α Accelerates Tumorigenesis
Authors: Jung-whan Kim, Colin Evans, Alexander Weidemann, Norihiko Takeda, Yun Sok Lee, Christian Stockmann, Cristina Branco-Price, Filip Brandberg, Gustavo Leone, Michael C. Ostrowski, Randall S. Johnson
Journal: Cancer Research (2012)

Solid tumors consist of malignant cells and associated stromal components, including fibroblastic cells that contribute to tumor growth and progression. Although tumor fibrosis and aberrant vascularization contribute to the hypoxia often found in advanced tumors, the contribution of hypoxic signaling within tumor-associated fibroblasts to tumorigenesis remains unknown. In this study, we used a fibroblast-specific promoter to create mice in which key hypoxia regulatory genes, including VHL, HIF-1α, HIF-2α, and VEGF-A, were knocked out specifically in tumor stromal fibroblasts. We found that loss of HIF-1α and its target gene VEGF-A accelerated tumor growth in murine model of mammary cancer. HIF-1α and VEGF-A loss also led to a reduction in vascular density and myeloid cell infiltration, which correlated with improved tumor perfusion. Together, our findings indicate that the fibroblast HIF-1α response is a critical component of tumor vascularization.
Divided we fall (yet again)
Authors: T Grabham
Journal: BMJ (1994)

“Hang together or, most assuredly, we shall all hang separately,” “Unity is strength”, “United we stand - divided we fall,” - all time worn cliches but relevant to doctors today, facing an intransigent government that has little regard for the views of our - or any other - profession. Doctors have wide and varied responsibilities, and inevitably many separate representative bodies and a somewhat diffuse leadership have developed.

The “premier division” contains three or possibly four players: the General Medical Council, the royal colleges (and their conference), and the BMA. To these well defined groups may be added academic medicine and research together with many other smaller but important groupings, such as the Overseas Doctors Association and the Medical Women's Federation. The effectiveness of these bodies varies with the issues under consideration and the abilities of their current leadership. By and large, most seem to perform well when operating within their own specialist fields. But most have less authority and influence when dealing with the more general issues that face the whole profession such as broad medicopolitical matters, the great ethical problems, manpower, and training.

Lately the profession's ability to influence the government seems to have declined (if not disappeared), and …
Exosome-enclosed microRNAs in exhaled breath hold potential for biomarker discovery in patients with pulmonary diseases
Authors: Anirban Sinha, Amit Kumar Yadav, Samarpana Chakraborty, S.K. Kabra, R. Lodha, Manish Kumar, Ankur Kulshreshtha, Tavpritesh Sethi, Rajesh Pandey, Gaurav Malik, Saurabh Laddha, Arijit Mukhopadhyay, Debasis Dash, Balaram Ghosh, Anurag Agrawal
Journal: Journal of Allergy and Clinical Immunology (2013)
Deletions of the Derivative Chromosome 9 Do Not Influence the Response and the Outcome of Chronic Myeloid Leukemia in Early Chronic Phase Treated With Imatinib Mesylate: GIMEMA CML Working Party Analysis
Authors: Fausto Castagnetti, Nicoletta Testoni, Simona Luatti, Giulia Marzocchi, Marco Mancini, Simonetta Kerim, Emilia Giugliano, Francesco Albano, Antonio Cuneo, Elisabetta Abruzzese, Bruno Martino, Francesca Palandri, Marilina Amabile, Ilaria Iacobucci, Giuliana Alimena, Fabrizio Pane, Giovanni Martinelli, Giuseppe Saglio, Michele Baccarani, Gianantonio Rosti
Journal: Journal of Clinical Oncology (2010)

Deletions of the derivative chromosome 9 [der(9)] have been associated with a poor prognosis in chronic myeloid leukemia (CML) across different treatment modalities. In the imatinib era, the prognostic impact of der(9) deletions has been evaluated mainly in patients with late chronic-phase (CP) CML, giving partially conflicting results. Few data are available in the early CP setting. For this reason, in 2006, the European LeukemiaNet recommendations still considered der(9) deletions as a candidate adverse prognostic factor and required a careful monitoring of the patient.To investigate the prognostic value of der(9) deletions in early CP CML, we performed an analysis of three prospective imatinib trials of the Italian Group for Hematological Malignancies of the Adult (GIMEMA) CML Working Party.A fluorescent in situ hybridization (FISH) analysis of bone marrow cells was performed at diagnosis; der(9) deletions were detected in 60 (12%) of 521 evaluable patients. At 60 months, the cumulative incidence of complete cytogenetic response and major molecular response-and the probability of event-free survival, failure-free survival, progression-free survival, and overall survival-in patients with and without deletions were not statistically different.Our data strongly support the notion that, when investigated by FISH, der(9) deletions are not a poor prognostic factor in patients with early CP CML treated with imatinib.
Regulation of <i>RUNX3</i> Tumor Suppressor Gene Expression in Cutaneous Melanoma
Authors: Minoru Kitago, Steve R. Martinez, Takeshi Nakamura, Myung-Shin Sim, Dave S.B. Hoon
Journal: Clinical Cancer Research (2009)

RUNX3 is a known tumor suppressor gene in several carcinomas. Aberration in RUNX3 expression has not been described for cutaneous melanoma. Therefore, we assessed the expression of RUNX3 in cutaneous melanoma and its regulatory mechanisms relative to tumor progression.The expression of RUNX3 mRNA and miR-532-5p (microRNA) was assessed in melanoma lines and in primary and metastatic melanoma tumors.RUNX3 mRNA expression was down-regulated in 11 of 11 (100%) metastatic melanoma lines relative to normal melanocytes (P < 0.001). Among 123 primary and metastatic melanoma tumors and 12 normal skin samples, RUNX3 expression was significantly down-regulated in primary melanomas (n = 82; P = 0.02) and in melanoma metastasis (n = 41; P < 0.0001) versus normal skin (n = 12). This suggested that RUNX3 down-regulation may play a role in the development and progression of melanoma. RUNX3 promoter region hypermethylation was assessed as a possible regulator of RUNX3 expression using methylation-specific PCR. Assessment of RUNX3 promoter region methylation showed that only 5 of 17 (29%) melanoma lines, 2 of 52 (4%) primary melanomas, and 5 of 30 (17%) metastatic melanomas had hypermethylation of the promoter region. A microRNA (miR-532-5p) was identified as a target of RUNX3 mRNA sequences. miR-532-5p expression was shown to be significantly up-regulated in melanoma lines and metastatic melanoma tumors relative to normal melanocytes and primary melanomas, respectively. To investigate the relation between RUNX3 and miR-532-5p, anti-miR-532-5p was transfected into melanoma lines. Inhibition of miR-532-5p up-regulated both RUNX3 mRNA and protein expression.RUNX3 is down-regulated during melanoma progression and miR-532-5p is a regulatory factor of RUNX3 expression.
Presence of hypertension (HT), ischemic heart diseases (IHD) and a family history of hypertension are independently associated with reduced peak expiratory flow (PEF) values
Authors: Komalkirti Apte, Monica Barne, Bill Brashier, Sapna Madas, Jaideep Gogtay, Sushmeeta Chhowala, Basant Pachisia, Sundeep Salvi
Journal: European Respiratory Journal (2012)

Background: Reduced lung function has been shown to be an independent predictor of cardiovascular mortality in patients of hypertension and IHD in earlier studies.

We aimed to study the association between HT, IHD and PEF values amongst road transport workers from Andhra Pradesh State in India.

Methods: 7,154 bus drivers, conductors, garage workers and office-based workers of the Andhra Pradesh State Road Transport Corporation (APSRTC) were randomly selected from 24 bus depots and administered a health questionnaire, underwent blood pressure monitoring and performed peak flow metry using the EU scale peak flow meter (Breathometer®, Cipla Ltd., India). Current, past and family histories of cardiovascular and respiratory ailments were captured. Associations between PEF values and HT and IHD were studied using the chi square test and the values expressed as odds ratios.

Results: Presence of HT, IHD and a family history of HT were independently associated with low PEF values, defined as less than 80% predicted PEFR value [OR 1.3, 95% CI 1.1 – 1.5, p=0.008; OR 1.9, 95% CI 1.2 – 3.0, p=0.004; OR 1.2, 95% CI 1.0 – 1.4, p=0.039 respectively]. No difference in odds ratios were observed between different occupations.

Conclusion: PEF values less than 80% predicted are strongly associated with presence of HT, family history of HT and presence of IHD. Reduced peak flow values should stimulate the need for performing a cardiovascular assessment.
Effect of epidermal growth factor in the rat 5/6 renal ablation model.
Authors: D W Moskowitz, A N Schneider, P H Lane, P G Schmitz, K N Gillespie
Journal: Journal of the American Society of Nephrology (1992)

Acute administration of epidermal growth factor (EGF) has been shown to promote recovery from ischemic and nephrotoxic acute renal failure in vivo. The question of whether chronic subcutaneous administration of EGF (19.1 micrograms/day for 3 or 6 wk) could alter the course of chronic renal failure in rats subjected to 5/6 nephrectomy was studied. By week 6, there was no difference in renal function, as assessed by animal survival, BUN, urea and inulin clearances, proteinuria, renal morphometry, or renal size, between EGF- and vehicle-treated rats. This suggests that chronic renal insufficiency differs from acute tubular injury in its sensitivity to exogenous EGF. Unexpectedly, EGF significantly attenuated the rise in systolic blood pressure that occurred by the fourth week after 5/6 nephrectomy. The antihypertensive effect of EGF was still evident at week 5. Urinary flow rate, free water clearance, and excretion of total solutes, Na+, and K+, however, were not significantly altered by EGF at weeks 2, 4, 5, or 6, suggesting a mechanism other than increased natriuresis or diuresis for this antihypertensive effect.
Necrosis and apoptosis in the gastrointestinal tract.
Authors: A J Watson
Journal: Gut (1995)

Leading articleNecrosis and apoptosis in the gastrointestinal tract Cell death, once dismissed as a chaotic phenomenon unworthy of serious study, now finds itself the subject of some of the most exciting biomedical research today.This transformation was brought about by the realisation that cell death is the result of distinct cellular events rather than random disintegration.Although various modes of cell death exist, only the processes of necrosis and apoptosis have been described in detail.Necrosis is a passive process resulting from the destruction of critical cellular structures, whereas apoptosis requires the active participation of the cell in its own death and can be prevented by inhibitors of RNA and protein synthesis.'Recently, it has been dis-
Bronchiolitis obliterans organizing pneumonia secondary to amiodarone: a rare aetiology
Authors: JM Valle, D Alvarez, J Antunez, L Valdes
Journal: European Respiratory Journal (1995)

Bronchiolitis obliterans organizing pneumonia (BOOP) is a clinicopathological entity with well-defined diagnostic criteria, the aetiology of which is generally unknown. Among the adverse pulmonary effects of the drug amiodarone, BOOP is the least commonly reported in the literature. In this article we describe a case of amiodarone-induced BOOP.
Obesity, Adipokines, and Abdominal Aortic Aneurysm
Authors: Jonathan Golledge, Paula Clancy, Konrad Jamrozik, Paul E. Norman
Journal: Circulation (2007)

Background— Obesity is associated with occlusive artery disease but is not considered a risk factor for abdominal aortic aneurysm (AAA). We investigated the association between anthropometric measures of obesity, serum adipokines, and AAA. Methods and Results— As part of a population study, we screened 12 203 men 65 to 83 years of age for AAA using ultrasound; 875 had an AAA (≥30 mm). Cardiovascular risk factors and waist and hip circumference were recorded. Serum adipokines were measured in 952 men, 318 of whom had an AAA. Waist circumference (odds ratio [OR], 1.14; 95% confidence interval [CI], 1.06 to 1.22) and waist-to-hip ratio (OR, 1.22; 95% CI, 1.09 to 1.37) were independently associated with AAA after adjustment for other known risk factors. The association was stronger for AAA ≥40 mm (waist-to-hip ratio: OR, 1.53; 95% CI, 1.26 to 1.85). Serum resistin concentration was strongly independently associated with AAA (OR, 1.53; 95% CI, 1.32 to 1.76) and aortic diameter (β=0.19, P &lt;0.0001). Serum adiponectin was associated with AAA ≥30 mm (OR, 1.26; 95% CI, 1.07 to 1.50) but not AAA ≥40 mm (OR, 1.03; 95% CI, 0.77 to 1.39). Serum leptin was not associated with AAA. Conclusions— Measures of obesity are independently associated with AAA. Serum resistin concentrations were more strongly associated with aortic diameter than adipokines that are more intimately associated with adiposity. Further studies are required to investigate the mechanisms linking resistin and AAA.
CKD Increases the Risk of Age-Related Macular Degeneration
Authors: Gerald Liew, Paul Mitchell, Tien Yin Wong, Sudha K. Iyengar, Jie Jin Wang
Journal: Journal of the American Society of Nephrology (2008)

Age-related macular degeneration is the leading cause of irreversible blindness in the United States and often coexists with chronic kidney disease. Both conditions share common genetic and environmental risk factors. A total of 1183 participants aged 54+ were examined in the population-based, prospective cohort Blue Mountains Eye Study (Australia) to determine if chronic kidney disease increases the risk of age-related macular degeneration. Moderate chronic kidney disease (estimated glomerular filtration rate < 60 ml/min per 1.73 m2 based on the Cockcroft-Gault equation) was present in 24% of the population (286 of 1183). The 5-yr incidence of early age-related macular degeneration was 3.9% in participants with no/mild chronic kidney disease (35 of 897) and 17.5% in those with moderate chronic kidney disease (50 of 286). After adjusting for age, sex, cigarette smoking, hypertension, complement factor H polymorphism, and other risk factors, persons with moderate chronic kidney disease were 3 times more likely to develop early age-related macular degeneration than persons with no/mild chronic kidney disease (odds ratio = 3.2; 95% confidence interval, 1.8 to 5.7, P < 0.0001). Each SD (14.8 ml/min per 1.73 m2) decrease in Cockcroft-Gault estimated glomerular filtration rate was associated with a doubling of the adjusted risk for early age-related macular degeneration (odds ratio = 2.0; 95% confidence interval, 1.5 to 2.8, P < 0.0001). In conclusion, persons with chronic kidney disease have a higher risk of early age-related macular degeneration, suggesting the possibility of shared pathophysiologic mechanisms between the two conditions.
Relationship of Glucose Metabolism to Adrenergic Transmission in Rat Mesenteric Arteries
Authors: KAFAIT U. MALIK, JOHN C. McGIFF
Journal: Circulation Research (1974)

The vasoconstrictor response of perfused rat mesenteric arteries to stimulation of sympathetic nerve fibers is markedly potentiated by glucose deprivation; this potentiation is abolished or reduced when glucose or other sugars are added. The augmentation of the vasoconstrictor response to nerve stimulation produced by glucose deprivation presumably results from an increased release of the adrenergic transmitter, since (1) the response to injected norepinephrine is much less affected by glucose deprivation and (2) the increase in the vasoconstrictor response to either adrenergic stimulus produced by inhibition of neuronal reuptake by cocaine is unaltered by glucose deprivation. The inhibitory effect of glucose may involve its metabolite(s). Pyruvic and lactic acids inhibit the vasoconstrictor response to nerve stimulation previously augmented by glucose deprivation but do not affect adrenergic transmission in the presence of glucose. Also, the inhibitory effect of glucose on the potentiated response is abolished by the simultaneous infusion of 2-deoxy- D -glucose or iodoacetic acid, inhibitors of glucose metabolism. The inhibitory effect of glucose and its metabolite(s) on adrenergic transmission may also involve changes in the ionic permeability of the nerve terminal. In the absence of glucose, raising the Na + and K + concentrations affects the vasoconstrictor response differently, namely, Na + potentiates and K + attenuates the response. These effects are abolished by addition of glucose. In contrast, the effects of increased concentrations of either Ca 2+ (facilitation) or Mg 2+ (inhibition) on neurotransmission are unaffected by removal or restoration of glucose. We conclude that glucose deprivation does not affect adrenergic transmission by acting directly through Ca 2+ . Rather, glucose deprivation decreases pyruvate and possibly other products of glucose metabolism, and these decreases, in turn, alter the concentrations of Na + and K + within the neuron. These latter changes then enhance the availability of Ca 2+ and, thereby, increase the release of the adrenergic transmitter.
Leisure Time Physical Activity and Mortality
Authors: Hannah Arem, Steven C. Moore, Alpa Patel, Patricia Hartge, Amy Berrington de Gonzalez, Kala Visvanathan, Peter T. Campbell, Michal Freedman, Elisabete Weiderpass, Hans Olov Adami, Martha S. Linet, I.-Min Lee, Charles E. Matthews
Journal: JAMA Internal Medicine (2015)

The 2008 Physical Activity Guidelines for Americans recommended a minimum of 75 vigorous-intensity or 150 moderate-intensity minutes per week (7.5 metabolic-equivalent hours per week) of aerobic activity for substantial health benefit and suggested additional benefits by doing more than double this amount. However, the upper limit of longevity benefit or possible harm with more physical activity is unclear.
Ciprofloxacin decreases the rate of ethanol elimination in humans
Authors: J Tillonen, N Homann, M Rautio, H Jousimies-Somer, M Salaspuro
Journal: Gut (1999)

BACKGROUND Extrahepatic ethanol metabolism is postulated to take place via microbial oxidation in the colon, mediated by aerobic and facultative anaerobic bacteria. AIMS To evaluate the role of microbial ethanol oxidation in the total elimination rate of ethanol in humans by reducing gut flora with ciprofloxacin. METHODS Ethanol was administered intravenously at the beginning and end of a one week period to eight male volunteers. Between ethanol doses volunteers received 750 mg ciprofloxacin twice daily. RESULTS A highly significant (p=0.001) reduction in the ethanol elimination rate (EER) was detected after ciprofloxacin medication. Mean (SEM) EER was 107.0 (5.3) and 96.9 (4.8) mg/kg/h before and after ciprofloxacin, respectively. Faecal Enterobacteriaceae and Enterococcus sp. were totally absent after medication, and faecal acetaldehyde production capacity was significantly (p&lt;0.05) decreased from 0.91 (0.15) to 0.39 (0.08) nmol/min/mg protein. Mean faecal alcohol dehydrogenase (ADH) activity was significantly (p&lt;0.05) decreased after medication, but ciprofloxacin did not inhibit human hepatic ADH activity in vitro. CONCLUSIONS Ciprofloxacin treatment decreased the ethanol elimination rate by 9.4%, with a concomitant decrease in intestinal aerobic and facultative anaerobic bacteria, faecal ADH activity, and acetaldehyde production. As ciprofloxacin has no effect on liver blood flow, hepatic ADH activity, or cytochrome CYP2E1 activity, these effects are probably caused by the reduction in intestinal flora.
From comic relief to real understanding; how intestinal gas causes symptoms
Authors: E M M Quigley
Journal: Gut (2003)

Gas content and transit appear to conspire with the motor and sensory responses of the gut to produce gas related symptoms, both in normal individuals and especially in patients with irritable bowel syndrome (IBS). In relation to gas in IBS, two questions need to be addressed: do IBS patients produce more gas and what are the relationships between intestinal gas and symptoms? The balance of evidence seems to indicate that distension is a real phenomenon in IBS and that such distension accurately reflects gas content. More problematic is extrapolation of the observations relating symptoms to gas transit and retention.