tbuckley/cabot-search huggingface dataset:
Neutralization of the IL-17 axis diminishes neutrophil invasion and protects from ischemic stroke
Authors: Mathias Gelderblom, Anna Weymar, Christian Bernreuther, Joachim Velden, Priyadharshini Arunachalam, Karin Steinbach, Ellen Orthey, Thiruma V. Arumugam, Frank Leypoldt, Olga Simova, Vivien Thom, Manuel A. Friese, Immo Prinz, Christoph Hölscher, Markus Glatzel, Thomas Korn, Christian Gerloff, Eva Tolosa, Tim Magnus
Journal: Blood (2012)
Russia's ban on methadone for drug users in Crimea will worsen the HIV/AIDS epidemic and risk public health
Authors: M. Kazatchkine
Journal: BMJ (2014)

Injecting drug use drives the huge HIV/AIDS epidemic in the region, but Russian law does not permit the substitution treatment that is shown to help. The end of its provision on 1 May will have huge repercussions, says <b>Michel Kazatchkine</b>
An Outbreak of Exposure to a Novel Synthetic Cannabinoid
Authors: Andrew A Monte, Alvin C Bronstein, Dazhe J Cao, Kennon J Heard, Jason A Hoppe, Christopher O Hoyte, Janetta L Iwanicki, Eric J Lavonas
Journal: New England Journal of Medicine (2014)

Young men in Colorado presented with altered mental status and seizures after ingestion of a synthetic cannabinoid known as “black mamba.” Medical toxicologists and public health and law enforcement officials identified 263 cases of exposure to this novel substance.
Assessment of stability, toxicity and immunogenicity of new polymeric nanoreactors for use in enzyme replacement therapy of MNGIE
Authors: Caroline De Vocht, An Ranquin, Ronnie Willaert, Jo A. Van Ginderachter, Tamara Vanhaecke, Vera Rogiers, Wim Versées, Patrick Van Gelder, Jan Steyaert
Journal: Journal of Controlled Release (2009)
Targeted eicosanoid lipidomics of exhaled breath condensate provide a distinct pattern in the aspirin-intolerant asthma phenotype
Authors: Marek Sanak, Anna Gielicz, Grażyna Bochenek, Marek Kaszuba, Ewa Niżankowska-Mogilnicka, Andrew Szczeklik
Journal: Journal of Allergy and Clinical Immunology (2011)
Outcome and profile of ventricular septal rupture with cardiogenic shock after myocardial infarction: a report from the SHOCK Trial Registry
Authors: Venu Menon, John G Webb, L.David Hillis, Lynn A Sleeper, Rasha Abboud, Vladimir Dzavik, James N Slater, Robert Forman, E.Scott Monrad, J.David Talley, Judith S Hochman
Journal: Journal of the American College of Cardiology (2000)

OBJECTIVES We wished to assess the profile and outcomes of patients with ventricular septal rupture (VSR) in the setting of cardiogenic shock (CS) complicating acute myocardial infarction (MI). BACKGROUND Cardiogenic shock is often seen with VSR complicating acute MI. Despite surgical therapy, mortality in such patients is high. METHODS We analyzed 939 patients enrolled in the SHOCK Trial Registry of CS in acute infarction, comparing 55 patients whose shock was associated with VSR with 884 patients who had predominant left ventricular failure. RESULTS Rupture occurred a median 16 h after infarction. Patients with VSR tended to be older (p = 0.053), were more often female (p = 0.002) and less often had previous infarction (p < 0.001), diabetes mellitus (p = 0.015) or smoking history (p = 0.033). They also underwent right-heart catheterization, intra-aortic balloon pumping and bypass surgery significantly more often. Although patients with rupture had less severe coronary disease, their in-hospital mortality was higher (87% vs. 61%, p < 0.001). Surgical repair was performed in 31 patients with rupture (21 had concomitant bypass surgery); 6 (19%) survived. Of the 24 patients managed medically, only 1 survived. CONCLUSIONS There is a high in-hospital mortality rate when CS develops as a result of VSR. Ventricular septal rupture may occur early after infarction, and women and the elderly may be more susceptible. Although the prognosis is poor, surgery remains the best therapeutic option in this setting.
Abstract 4980: Inhibiting carbonic anhydrase IX targets hypoxic small cell lung cancer cells
Authors: Jennifer L. Bryant, Suzanne L. Meredith, Roben G. Gieling, Brian A. Telfer, Muhammad Babur, Claudiu T. Supuran, Kaye J. Williams, Anne White
Journal: Cancer Research (2014)

Abstract Small-cell lung cancer (SCLC) is an extremely aggressive disease, exhibiting acquired resistance to therapy and poor patient prognosis. Therapy resistance can in part be attributed to tumor hypoxia. Hypoxic SCLC cells up-regulate carbonic anhydrase IX (CA IX) in order to survive. CA IX is involved in pH maintenance of cells and presents a novel therapeutic target for SCLC. This study aimed to investigate the potential of inhibiting CA IX in SCLC as a novel therapeutic target. Hypoxic conditions (0.1% O2) increased CA IX expression over 24 hours in both COR-L24 and DMS 79 SCLC cells in culture. S4 belongs to a sulfamate class of carbonic anhydrase inhibitors and has shown anti-metastatic properties in breast cancer xenografts. Treatment with 30μM and 100μM S4 significantly decreased CA IX protein levels in hypoxic COR-L24 and DMS 79 SCLC cells, respectively (p&amp;lt;0.05 for both treatments). Exposure to S4 for 24 hours resulted in predominantly hypoxic cell death in both cell lines (p&amp;lt;0.05). Combining S4 with etoposide (0.3µM) and cisplatin (0.5µM) chemotherapeutic agents resulted in additional cell death, which was also seen under normoxic conditions (20% O2). Sub-cutaneous xenograft tumors were grown in nude mice using either COR-L24 or DMS 79 SCLC cells. Resultant tumors (1000mm3) expressed CA IX largely adjacent to regions of necrosis. Treating mice with 50mg/kg S4 on two consecutive days each week resulted in greater necrosis than saline controls, coupled with up-regulation of CA IX. Analyzing tumors for characteristic neuroendocrine (pro-opiomelanocortin) and epithelial (cytokeratin) markers revealed heterogeneous expression; however, this did not correlate with CA IX expression and is not altered in response to treatment. In summary, CA IX is upregulated in hypoxic SCLC cells and tumors. Inhibition of CA IX resulted in hypoxic cell death and had an additive effect to the response observed with chemotherapy treatment alone. This suggests that directly targeting hypoxic SCLC cells via CA IX inhibition holds promise in improving treatment outcome for this aggressive disease. Citation Format: Jennifer L. Bryant, Suzanne L. Meredith, Roben G. Gieling, Brian A. Telfer, Muhammad Babur, Claudiu T. Supuran, Kaye J. Williams, Anne White. Inhibiting carbonic anhydrase IX targets hypoxic small cell lung cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4980. doi:10.1158/1538-7445.AM2014-4980
HIV-1 Protease Catalytic Efficiency Effects Caused by Random Single Amino Acid Substitutions
Authors: M. Parera, G. Fernandez, B. Clotet, M. A. Martinez
Journal: Molecular Biology and Evolution (2006)

Protein evolution has occurred by successive fixation of individual mutations. The probability of fixation depends on the fitness of the mutation, and the arising variant can be deleterious, neutral, or beneficial. Despite its relevance, only few studies have estimated the distribution of fitness effects caused by random single mutations on protein function. The human immunodeficiency virus type 1 (HIV-1) protease was chosen as a model protein to quantify protein's tolerability to random single mutations. After determining the enzymatic activity of 107 single random mutants, we found that 86% of single mutations were deleterious for the enzyme catalytic efficiency and 54% lethal. Only 2% of the mutations significantly increased the catalytic efficiency of the enzyme. These data demonstrate the vulnerability of HIV-1 protease to single random mutations. When a second random mutagenesis library was constructed from an HIV-1 protease carrying a highly deleterious single mutation (D30N), a higher proportion of mutations with neutral or beneficial effect were found, 26% and 9%, respectively. Importantly, antagonist epistasis was observed between deleterious mutations. In particular, the mutation N88D, lethal for the wild-type protease, restored the wild-type catalytic efficiency when combined with the highly deleterious mutation D30N. The low tolerability to single random substitutions shown here for the wild-type HIV-1 protease contrasts with its in vivo ability to generate an adaptive variation. Thus, the antagonist epistasis between deleterious or lethal mutations may be responsible for increasing the protein mutational robustness and evolvability.
WHO-defined ‘myelodysplastic syndrome with isolated del(5q)’ in 88 consecutive patients: survival data, leukemic transformation rates and prevalence of JAK2, MPL and IDH mutations
Authors: M M Patnaik, T L Lasho, C M Finke, N Gangat, D Caramazza, S G Holtan, A Pardanani, R A Knudson, R P Ketterling, D Chen, J D Hoyer, C A Hanson, A Tefferi
Journal: Leukemia (2010)

The 2008 World Health Organization (WHO) criteria were used to identify 88 consecutive Mayo Clinic patients with 'myelodysplastic syndrome with isolated del(5q)' (median age 74 years; 60 females). In all, 60 (68%) patients were followed up to the time of their death. Overall median survival was 66 months; leukemic transformation was documented in five (5.7%) cases. Multivariable analysis identified age >or=70 years (P=0.01), transfusion need at diagnosis (P=0.04) and dysgranulopoiesis (P=0.02) as independent predictors of shortened survival; the presence of zero (low risk), one (intermediate risk) or >or=2 (high risk) risk factors corresponded to median survivals of 102, 52 and 27 months, respectively. Janus kinase 2 (JAK2), thrombopoietin receptor (MPL), isocitrate dehydrogenase 1 (IDH1) and IDH2 mutational analysis was performed on archived bone marrows in 78 patients; JAK2V617F and MPLW515L mutations were shown in five (6.4%) and three (3.8%) patients, respectively, and did not seem to affect phenotype or prognosis. IDH mutations were not detected. Survival was not affected by serum ferritin and there were no instances of death directly related to iron overload. The current study is unique in its strict adherence to WHO criteria for selecting study patients and providing information on long-term survival, practical prognostic factors, baseline risk of leukemic transformation and the prevalence of JAK2, MPL and IDH mutations.
Coronary Arteriolar Dilation to Acidosis
Authors: Hiroshi Ishizaka, Siva R. Gudi, John A. Frangos, Lih Kuo
Journal: Circulation (1999)

Background —We previously demonstrated that coronary arteriolar dilation in response to acidosis is mediated by the opening of ATP-sensitive potassium (K ATP ) channels. However, the signal transduction involved in the K ATP -channel activation during acidosis has not been elucidated. A recent study in cardiac myocytes implied that pertussis toxin (PTX)–sensitive G proteins may be involved in the signal transduction for K ATP -channel activation. However, it remains unclear whether this transduction process also occurs in the vascular tissue and, in particular, whether it exerts functional dilation in response to acidosis. Methods and Results —To examine the signaling pathway for acidosis-induced dilation, porcine coronary arterioles were isolated, cannulated, and pressurized for in vitro study. The GTPase activity in reconstituted G proteins was examined at different levels of pH. Extravascular acidosis (pH 7.3 to 7.0) produced a graded dilation of coronary arterioles. This dilation was not affected by removal of endothelium but was significantly attenuated after inhibition of K ATP channels and G proteins by glibenclamide and PTX, respectively. Glibenclamide and PTX attenuated the acidosis-induced arteriolar dilation to the same extent, and combined administration of both inhibitors did not further inhibit the vasodilation. These results indicated that both inhibitors act on the same vasodilatory pathway. Furthermore, vasodilation of coronary arterioles to the K ATP -channel opener pinacidil and to the endothelium-independent vasodilator sodium nitroprusside was not affected by PTX. Because PTX inhibited acidosis-induced vasodilation without inhibiting K ATP -channel function, it is suggested that PTX inhibits the vasodilatory pathway upstream from K ATP channels. GTPase activity in reconstituted G proteins was significantly enhanced by a reduction in pH, indicating that G proteins were directly activated by acidosis. Conclusions —On the basis of these findings, we conclude that acidosis-induced coronary arteriolar dilation is mediated by the opening of smooth muscle K ATP channels through the activation of PTX-sensitive G proteins.
Intermediate-density lipoprotein and cholesterol-rich very low density lipoprotein in angiographically determined coronary artery disease.
Authors: R Tatami, H Mabuchi, K Ueda, R Ueda, T Haba, T Kametani, S Ito, J Koizumi, M Ohta, S Miyamoto, A Nakayama, H Kanaya, H Oiwake, A Genda, R Takeda
Journal: Circulation (1981)

The relationship between the concentrations of intermediate-density lipoprotein (IDL) and other lipoproteins and the extent of coronary artery disease (CAD) was studied in 182 consecutive patients evaluated by selective coronary cineangiography. On univariate analysis, the extent of CAD correlated significantly and positively with very low density lipoprotein (VLDL) cholesterol, IDL cholesterol and low-density lipoprotein (LDL) cholesterol, and negatively with high-density lipoprotein (HDL) cholesterol. Analysis of four subgroups divided by IDL cholesterol and LDL cholesterol levels indicated that moderately increased levels of IDL cholesterol were closely associated with a high frequency of CAD. Moreover, multi-variate regression analysis demonstrated that IDL cholesterol for men, LDL cholesterol for men and women and HDL cholesterol for men were significant variables of use in the final weighting procedure. IDL cholesterol was closely associated with cholesterol-rich VLDL. This study shows that IDL and cholesterol-rich VLDL combine to contribute to the development of CAD.
Resveratrol Improves Myocardial Perfusion in a Swine Model of Hypercholesterolemia and Chronic Myocardial Ischemia
Authors: Michael P. Robich, Robert M. Osipov, Reza Nezafat, Jun Feng, Richard T. Clements, Cesario Bianchi, Munir Boodhwani, Michael A. Coady, Roger J. Laham, Frank W. Sellke
Journal: Circulation (2010)

Background— Resveratrol may provide protection against coronary artery disease. We hypothesized that supplemental resveratrol will improve cardiac perfusion in the ischemic territory of swine with hypercholesterolemia and chronic myocardial ischemia. Methods and Results— Yorkshire swine were fed either a normal diet (control, n=7), a hypercholesterolemic diet (HCC, n=7), or a hypercholesterolemic diet with supplemental resveratrol (100 mg/kg/d orally, HCRV, n=7). Four weeks later, an ameroid constrictor was placed on the left circumflex artery. Animals underwent cardiac MRI and coronary angiography 7 weeks later before euthanasia and tissue harvest. Total cholesterol was lowered about 30% in HCRV animals ( P &lt;0.001). Regional wall motion analysis demonstrated a significant decrease in inferolateral function from baseline to 7 weeks in HCC swine ( P =0.04). There was no significant change in regional function in HCRV swine from baseline to 7 weeks ( P =0.32). Tissue blood flow during stress was 2.8-fold greater in HCRV swine when compared with HCC swine ( P =0.04). Endothelium-dependent microvascular relaxation response to Substance P was diminished in HCC swine, which was rescued by resveratrol treatment ( P =0.004). Capillary density (PECAM-1 staining) demonstrated fewer capillaries in both HCC and HCRV swine versus control swine ( P =0.02). Immunoblot analysis demonstrated significantly greater expression in HCRV versus HCC swine of the following markers of angiogenesis: VEGF ( P =0.002), peNOS (ser1177) ( P =0.04), NFkB ( P =0.004), and pAkt (thr308) ( P =0.001). Conclusions— Supplemental resveratrol attenuates regional wall motion abnormalities, improves myocardial perfusion in the collateral dependent region, preserves endothelium-dependent coronary vessel function, and upregulates markers of angiogenesis associated with the VEGF signaling pathway.
Cleaning and Disinfection Practices in Digestive Endoscopy in Spain: Results of a National Survey
Authors: E. Brullet, J. Ramirez-Armengol, R. Campo
Journal: Endoscopy (2001)

Disinfection and surveil- lance of it are important for ensuring safety in gastrointestinal endoscopy. The aim of this survey was to assess the current status of disinfection in gastrointestinal endoscopy units in Spain. An anonymous questionnaire on cleaning and disinfection methods was sent to gastrointestinal endoscopy units at 244 public hospitals in Spain. A minimum standard of disinfection (MSD) was defined to evaluate the appropriateness of disinfection practices. A total of 144 centers responded (58 %). All units perform manual washing of endoscopes before disinfection. Automatic washers are available in only 23 % of the centers. Selective cleaning of internal channels is systematically performed in 85 % of the centers. Glutar aldehyde-based disinfectants are the most commonly employed (84 % of units). The time of exposure to the disinfectant is at least 10 min in 97 % of units, but 20 min or more in only 36 % of them. Endoscopic accessories are sterilized in 57 % of centers. The MSD was complied with by 79 % of the units evaluated. Compliance with the MSD was significantly lower in small units (P = 0.0005) performing small numbers of examinations per month. Quality control tests on the efficacy of disinfection methods are conducted at 66 % of the centers. Specialized personnel record disinfection procedures in 85 % of the centers and supervise them in 55 % of the centers. Half of the units have inadequate equipment and facilities. This survey suggests that cleaning and disinfection practices in gastrointestinal endoscopy units in Spain have improved in recent years, and that there is a good compliance with standard guidelines. Most units should improve their equipment and facilities in order to provide better comfort and safety for patients and staff.
S102 KGF enhances pulmonary production of pro-epithelial repair factors in a human in vivo model of acute lung injury
Authors: M. Shyamsundar, C. M. O'Kane, C. Calfee, S. T. McKeown, C. Taggart, M. A. Matthay, D. F. McAuley
Journal: Thorax (2010)

<h3>Introduction</h3> Keratinocyte Growth Factor (KGF) has been suggested as a possible intervention for acute lung injury. In vitro it enhances epithelial repair. In the human ex vivo perfused lung model KGF supplementation after LPS-induced injury was associated with improved alveolar fluid clearance indicating improved epithelial function. We hypothesised that KGF pre-treatment in the in vivo human LPS model of lung injury would reduce epithelial injury and increase production of mediators that induce epithelial repair. <h3>Methods</h3> 36 subjects were randomised to either placebo or recombinant human KGF (Palifermin) 60 μg/kg/day for 3 days prior to inhalation of 50 μg <i>E Coli</i> LPS. 6 h after LPS inhalation subjects underwent bronchoalveolar lavage (BAL). BAL concentrations of SP-D, RAGE, MMP-9 and CRP were measured by ELISA. Total protein was measured by Bradford assay. Markers of LPS-induced pulmonary inflammation were measured using multiplex bead array (CXCL8, TNFα, MCP-1, IL-6, MMP-7/-8) or ELISA (HMGB1 and Calgranulin C). Permeability was assessed by BAL IgG:total protein ratio. <h3>Results</h3> KGF increased BAL SP-D (Abstract S102 Figure 1A) but not RAGE. KGF increased BAL MMP-9 by 77% (p=0.04). KGF increased BAL IL-6 by 84% (p=0.03) and CRP (Abstract S102 Figure 1B). KGF did not alter BAL total white cell count or neutrophilia, TNFα, CXCL8, MCP-1, HMGB1 or Calgranulin C. KGF did not alter BAL total protein or permeability index. Increased frequency of altered taste or tongue sensation (p=0.01) and of facial erythema (p=0.005) were observed in the KGF-treated group. There were no serious adverse events. <h3>Conclusion</h3> KGF specifically increased the production of several factors that are key for epithelial migration and wound healing including MMP-9 and IL-6, and increased the production of SP-D, a marker of type II alveolar epithelial cell proliferation. Furthermore it increases the production of BAL CRP which in the pulmonary compartment acts as an opsonin, aiding the clearance of apoptotic cells (or bacteria). However, KGF pre-treatment did not alter the inflammatory infiltrate or permeability change in response to inhaled LPS. Data suggest that KGF may promote a healing environment within the damaged alveoli and support further investigation of KGF as a treatment for lung injury.
Effect of Acute Mitral Insufficiency of Various Degrees on Mean Arterial Blood Pressure, Coronary Blood Flow Cardiac Output and Oxygen Consumption
Authors: RENÉ WÉGRIA, GERHARD MUELHEIMS, ROBERT JREISSATY, JIRO NAKANO
Journal: Circulation Research (1958)

In anesthetized dog, acute mitral insufficiency of variable severity results in an increase in coronary blood flow and myocardial oxygen consumption. The increase in oxygen consumption is interpreted as meaning either that the left ventricle expends a significant amount of energy in regurgitating blood into the left atrium during mitral insufficiency, or that mitral insufficiency induces a decrease of the efficiency of the left ventricle or both.
Single lung transplantation for end stage emphysema.
Authors: N P Briffa, C Dennis, T Higenbottam, S A Nashef, S R Large, J Wallwork, F C Wells
Journal: Thorax (1995)

BACKGROUND-- The first successful single lung transplantation was carried out in 1983 for pulmonary fibrosis. Because of the inherent advantages of single lung transplantation, a transplantation programme has been started for patients with end stage lung disease due to emphysema. METHODS-- Between October 1990 and August 1993 25 patients with severe emphysema (15 men, mean age 51 years) received a single lung transplant at our institution. All patients were severely disabled with a mean (SD) 12 minute walking distance of 281 (165) metres. There were five deaths in the series, four in the first 20 days and one on day 503. Two patients suffered graft compression by air trapping in the native lung. Bronchial narrowing requiring insertion of endobronchial stenting occurred in four patients. RESULTS-- Mean (SD) FEV1 improved from a preoperative value of 17.8(13%) predicted to a six month value of 53.6(13)%, and FEV1/FVC from 23.8(12)% to 68.6(15)%. After the transplant 12 patients are in New York Heart Association (NYHA) class I and the rest of the survivors are in NYHA II. Actuarial survival was 82% at one year and 74% at three years. CONCLUSIONS-- Single lung transplantation is an effective treatment for end stage lung disease due to emphysema and carries an acceptable mortality and morbidity.
How to Analyze Clinical Research Reports
Authors: Cyril Abrahams
Journal: JAMA (1987)

The authors of this useful book comment in the preface that pathologists (and this could apply to all physicians), after completing formal education, face a lifetime of continuing education if they want to avoid obsolescence. This continued learning is mainly derived from reading scientific studies. However, the authors maintain that most studies published in journals are flawed. Hence, the book sets out to teach the pathologist how to read a study critically to benefit from the information and not be misled.