tbuckley/cabot-search huggingface dataset:
Functional genetic polymorphisms and female reproductive disorders: Part II--endometriosis
Authors: C.B. Tempfer, M. Simoni, B. Destenaves, B.C.J.M. Fauser
Journal: Human Reproduction Update (2008)

Endometriosis has a strong genetic component, and numerous genetic studies have been reported.We have systematically reviewed these studies and included 114 in our final selection.We found no consistent evidence linking endometriosis with specific polymorphisms in genes encoding inflammatory mediators, proteins involved in sex steroid metabolism, vascular function and tissue remodelling. Although a number of polymorphisms have been associated with endometriosis in selected populations, the associations have not been independently confirmed, either because only single studies were carried out on these markers/genes or because other studies reported no association. The most solid evidence linking specific polymorphisms to endometriosis came from studies investigating glutathione-S-transferase, a phase II detoxification enzyme. Carriage of the GSTT1 null deletion variant showed consistent association with endometriosis with a 29% increased risk; however, it cannot be excluded that this result was due to publication bias, and this association should be independently confirmed in large-scale, well-designed case-control studies.The evidence of an association between genetic polymorphisms and endometriosis is weak. Carriage of the GSTT1 null deletion may moderately increase the risk of this disease. We suggest that the methodology of association studies should be improved in order to identify and validate associations in endometriosis.
Predictive factors for development of the no-reflow phenomenon in patients with reperfused anterior wall acute myocardial infarction
Authors: Katsuomi Iwakura, Hiroshi Ito, Shigeo Kawano, Yasunori Shintani, Koichi Yamamoto, Akinobu Kato, Masashi Ikushima, Koji Tanaka, Masashi Kitakaze, Masatsugu Hori, Yorihiko Higashino, Kenshi Fujii
Journal: Journal of the American College of Cardiology (2001)
Chemotactic activity of elastin-derived peptides.
Authors: R M Senior, G L Griffin, R P Mecham
Journal: Journal of Clinical Investigation (1980)

Elastin-derived peptides, produced by digesting human aortic elastin and bovine ligament elastin with human neutrophil elastase, were tested for chemotactic activity. At 100 micrograms protein/ml, elastin digests were nearly as active for monocytes as saturating amounts of complement-derived chemotactic activity. Neutrophils and alveolar macrophages showed less response to elastin peptidces than did monocytes. Fractionation of the digests by gel filtration chromatography disclosed that maximal chemotactic activity eluted in fractions corresponding to 14,000-20,000 mol wt containing most of the desmosine cross-links in the digests. Whole human serum and rabbit anti-elastin immunoglobulin inhibited the chemotactic activity. Purified desmosine also showed chemotactic activity for monocytes, maximal at 10 nM. These findings suggest that elastin-degradation products enriched in cross-linking regions recruit inflammatory cells in vivo and that elastin proteolysis, characteristic of emphysema, may be a signal for recruitment of mononuclear phagocytes into the lungs.
The non-canonical NOTCH ligand DLK1 exhibits a novel vascular role as a strong inhibitor of angiogenesis
Authors: Patricia Rodríguez, María Angeles Higueras, Alvaro González-Rajal, Arántzazu Alfranca, Marta Fierro-Fernández, Rosa Ana García-Fernández, Maria José Ruiz-Hidalgo, María Monsalve, Fernando Rodríguez-Pascual, Juan Miguel Redondo, Jose Luis de la Pompa, Jorge Laborda, Santiago Lamas
Journal: Cardiovascular Research (2011)

The epidermal growth factor-like protein Delta-like 1 (DLK1) regulates multiple differentiation processes. It resembles NOTCH ligands structurally and is considered a non-canonical ligand. Given the crucial role of the NOTCH pathway in angiogenesis, we hypothesized that DLK1 could regulate angiogenesis by interfering with NOTCH. We therefore investigated the expression and function of DLK1 in the vascular endothelium and its role in the regulation of angiogenesis. We report DLK1 expression in the endothelium of different species, including human, cow, pig, and mouse. Angiogenesis was studied by using in vitro and in vivo models of angiotube formation in endothelial cells, retinal phenotypes in Dlk1-null mice, and vessel development in zebrafish. DLK1 overexpression strongly inhibited angiotube formation, whereas lung endothelial cells from Dlk1-null mice were highly angiogenic. In vivo studies demonstrated DLK1-mediated inhibition of neovessel formation and revealed an altered pattern of angiogenesis in the retinas of Dlk1-null mice. The expression of human DLK1 in zebrafish embryos severely altered the formation of intersegmental vessels, while knockdown of the orthologous gene was associated with ectopic and increased tumour-induced angiogenesis. NOTCH-dependent signalling as determined by gene expression reporters was inhibited by the presence of DLK1 in vascular endothelial cells. In contrast, Dlk1-null mice showed increased levels of NOTCH downstream targets, such as Snail and Slug. Our results unveil a novel inhibitory role for DLK1 in the regulation of angiogenesis, mediated by antagonism of the NOTCH pathway, and establish the basis for investigating its action in pathological settings.
A Phase I Study of 7-<i>t</i>-Butyldimethylsilyl-10-Hydroxycamptothecin in Adult Patients with Refractory or Metastatic Solid Malignancies
Authors: Susanne M. Arnold, John J. Rinehart, Eleftheria Tsakalozou, John R. Eckardt, Scott Z. Fields, Brent J. Shelton, Philip A. DeSimone, Bryan K. Kee, Jeffrey A. Moscow, Markos Leggas
Journal: Clinical Cancer Research (2010)

Abstract Purpose: 7-t-Butyldimethylsilyl-10-hydroxycamptothecin (AR-67) is a novel third generation camptothecin selected for development based on the blood stability of its pharmacologically active lactone form and its high potency in preclinical models. Here, we report the initial phase I experience with i.v. AR-67 in adults with refractory solid tumors. Experimental Design and Methods: AR-67 was infused over 1 hour daily five times, every 21 days, using an accelerated titration trial design. Plasma was collected on the 1st and 4th day of cycle 1 to determine pharmacokinetic parameters. Results: Twenty-six patients were treated at nine dosage levels (1.2-12.4 mg/m2/d). Dose-limiting toxicities were observed in five patients and consisted of grade 4 febrile neutropenia, grade 3 fatigue, and grade 4 thrombocytopenia. Common toxicities included leukopenia (23%), thrombocytopenia (15.4%), fatigue (15.4%), neutropenia (11.5%), and anemia (11.5%). No diarrhea was observed. The maximum tolerated dosage was 7.5 mg/m2/d. The lactone form was the predominant species in plasma (&amp;gt;87% of area under the plasma concentration-time curve) at all dosages. No drug accumulation was observed on day 4. Clearance was constant with increasing dosage and hematologic toxicities correlated with exposure (P &amp;lt; 0.001). A prolonged partial response was observed in one subject with non–small cell lung cancer. Stable disease was noted in patients with small cell lung cancer, non–small cell lung cancer, and duodenal cancer. Conclusions: AR-67 is a novel, blood-stable camptothecin with a predictable toxicity profile and linear pharmacokinetics. The recommended phase II dosage is 7.5 mg/m2/d five times every 21 days. Clin Cancer Res; 16(2); 673–80
HIV Seroprevalence Among Suicide Victims in New York City, 1991–1993
Authors: Peter M. Marzuk, Kenneth Tardiff, Andrew C. Leon, Charles S. Hirsch, Nancy Hartwell, Laura Portera, M. Irfan Iqbal
Journal: American Journal of Psychiatry (1997)

OBJECTIVE: The authors sought to determine the HIV seroprevalence among suicide victims in New York City. METHOD: All suicides of city residents from 1991 through 1993 were studied. The crude proportion of all suicide victims who were HIV positive and the proportion adjusted to the age, gender, and racial/ethnic characteristics of the New York City population were determined. The demographically adjusted proportion was then contrasted with HIV seroprevalence estimates for the New York City general population. HIV-seropositive suicide victims were assessed for pathological findings suggestive of HIV-related illnesses. RESULTS: The crude proportion of all suicide victims who were HIV seropositive was 0.088, and the demographically adjusted proportion was 0.049. Over 90% of all HIV-positive suicide victims were aged 25 to 54 years, and almost 90% were men. Among black and Hispanic men aged 35 to 54 years who committed suicide, the proportion who were HIV seropositive was 0.252—the highest seropositive rate of any demographic group. More than two-thirds of HIV-seropositive suicide victims had no HIV-related pathology or AIDS-indicator conditions at autopsy. CONCLUSIONS: The demographically adjusted proportion of suicide victims who were HIV positive (approximately 0.038 to 0.059), contrasted with the HIV seroprevalence estimates for the New York City general population (approximately 0.014 to 0.032), the absence of HIV-related pathology among suicide victims, and the likelihood that many HIV-positive individuals had other risk factors for suicide, such as substance abuse, suggests that a positive HIV serostatus is associated, at most, with a modest elevation in suicide risk. (Am J Psychiatry 1997; 154:1720–1725)
The antitumor effects of IFN-α are abrogated in a STAT1-deficient mouse
Authors: Gregory B. Lesinski, Mirela Anghelina, Jason Zimmerer, Timothy Bakalakos, Brian Badgwell, Robin Parihar, Yan Hu, Brian Becknell, Gerard Abood, Abhik Ray Chaudhury, Cynthia Magro, Joan Durbin, William E. Carson
Journal: Journal of Clinical Investigation (2003)

IFN-α activates the signal transducer and activator of transcription (STAT) family of proteins; however, it is unknown whether IFN-α exerts its antitumor actions primarily through a direct effect on malignant cells or by stimulating the immune system. To investigate the contribution of STAT1 signaling within the tumor, we generated a STAT1-deficient melanoma cell line, AGS-1. We reconstituted STAT1 into AGS-1 cells by retroviral gene transfer. The resulting cell line (AGS-1STAT1) showed normal regulation of IFN-α–stimulated genes (e.g., H2k, ISG-54) as compared with AGS-1 cells infected with the empty vector (AGS-1MSCV). However, mice challenged with the AGS-1, AGS-1STAT1, and AGS-1MSCV cell lines exhibited nearly identical survival in response to IFN-α treatment, indicating that restored STAT1 signaling within the tumor did not augment the antitumor activity of IFN-α. In contrast, STAT1–/– mice could not utilize exogenous IFN-α to inhibit the growth of STAT1+/+ melanoma cells in either an intraperitoneal tumor model or in the adjuvant setting. The survival of tumor-bearing STAT1–/– mice was identical regardless of treatment (IFN-α or PBS). Additional cell depletion studies demonstrated that NK cells mediated the antitumor effects of IFN-α. Thus, STAT1-mediated gene regulation within immune effectors was necessary for mediating the antitumor effects of IFN-α in this experimental system.
Gastric Lymphoma and Helicobacter pylori
Authors: Peter G. Isaacson
Journal: New England Journal of Medicine (1994)

In 1983, Warren and Marshall discovered a spiral urease-producing organism in the human stomach, later classified as Helicobacter pylori1. H. pylori has been shown to be strongly associated with peptic ulcer disease, and antibiotic therapy to eradicate this organism is an important treatment for duodenal and gastric ulcers2. In many countries, the prevalence of H. pylori infection in adults is 35 percent or more, although most infected people have no symptoms.H. pylori has also been associated with gastric carcinoma. Correa described four steps already taken to establish the association3. The first was to observe that H. . . .
Benefits of Liraglutide Treatment in Overweight and Obese Older Individuals With Prediabetes
Authors: Sun H. Kim, Fahim Abbasi, Cindy Lamendola, Alice Liu, Danit Ariel, Patricia Schaaf, Kaylene Grove, Vanessa Tomasso, Hector Ochoa, Yeheng V. Liu, Yii-Der Ida Chen, Gerald Reaven
Journal: Diabetes Care (2013)

The aim was to evaluate the ability of liraglutide to augment weight loss and improve insulin resistance, cardiovascular disease (CVD) risk factors, and inflammation in a high-risk population for type 2 diabetes (T2DM) and CVD.We randomized 68 older individuals (mean age, 58±8 years) with overweight/obesity and prediabetes to this double-blind study of liraglutide 1.8 mg versus placebo for 14 weeks. All subjects were advised to decrease calorie intake by 500 kcal/day. Peripheral insulin resistance was quantified by measuring the steady-state plasma glucose (SSPG) concentration during the insulin suppression test. Traditional CVD risk factors and inflammatory markers also were assessed.Eleven out of 35 individuals (31%) assigned to liraglutide discontinued the study compared with 6 out of 33 (18%) assigned to placebo (P=0.26). Subjects who continued to use liraglutide (n=24) lost twice as much weight as those using placebo (n=27; 6.8 vs. 3.3 kg; P<0.001). Liraglutide-treated subjects also had a significant improvement in SSPG concentration (-3.2 vs. 0.2 mmol/L; P<0.001) and significantly (P≤0.04) greater lowering of systolic blood pressure (-8.1 vs. -2.6 mmHg), fasting glucose (-0.5 vs. 0 mmol/L), and triglyceride (-0.4 vs. -0.1 mmol/L) concentration. Inflammatory markers did not differ between the two groups, but pulse increased after liraglutide treatment (6.4 vs. -0.9 bpm; P=0.001).The addition of liraglutide to calorie restriction significantly augmented weight loss and improved insulin resistance, systolic blood pressure, glucose, and triglyceride concentration in this population at high risk for development of T2DM and CVD.
Role of glucocorticoids on inflammatory response in nonimmunosuppressed patients with pneumonia: a pilot study
Authors: C. Montón, S. Ewig, A. Torres, M. El-Ebiary, X Filella, A. Rañó, A. Xaubet
Journal: European Respiratory Journal (1999)

Five cases of presumed nicotine withdrawal delirium among brain-injured patients treated in a neurologic intensive care unit are presented. Each patient had a history of heavy tobacco use and experienced dramatic and sustained clinical improvement within hours of transdermal nicotine replacement. These preliminary observations suggest that nicotine withdrawal may be an under-recognized cause of delirium in patients with acute brain injury.
Targeting Carcinoma-Associated Fibroblasts Within the Tumor Stroma With a Fibroblast Activation Protein-Activated Prodrug
Authors: W. N. Brennen, D. M. Rosen, H. Wang, J. T. Isaacs, S. R. Denmeade
Journal: JNCI Journal of the National Cancer Institute (2012)

Fibroblasts undergo a morphological transformation to a reactive phenotype in the tumor microenvironment characterized by the expression of proteins such as fibroblast activation protein (FAP), a post-prolyl endopeptidase with expression largely restricted to carcinoma-associated fibroblasts. Thapsigargin (TG) is a highly toxic natural plant product that triggers a rise in intracellular calcium levels and apoptosis. FAP is therefore a provocative target for the activation of prodrugs consisting of a FAP-specific peptide coupled to a potent cytotoxic analog of TG. The efficacy of FAP-activated peptidyl-TG prodrugs was tested in vitro in cell proliferation assays and effects on intracellular calcium in human cancer cell lines. The effects of FAP-activated prodrugs on tumor growth and host toxicity were tested in Balb-C nude MCF-7 and LNCaP xenograft mice (n = 9–11 per group). P values were calculated using permutation tests based on 50 000 permutations. Mixed effects models were used to account for correlations among replicate measures. All statistical tests were two-sided. FAP-activated prodrugs killed human cancer cells at low nanomolar concentrations (MCF-7 cells: IC 50 = 3.5nM). Amino acid-12ADT analogs from FAP-cleaved prodrugs, but not uncleaved prodrugs, produced a rapid rise in intracellular calcium within minutes of exposure. Immunohistochemical analysis of xenografts exposed to FAP-prodrugs documented stromal-selective cell death of fibroblasts, pericytes, and endothelial cells of sufficient magnitude to inhibit growth of MCF-7 and LNCaP xenografts with minimal systemic toxicity, whereas non-FAP cleavable prodrugs were inactive. MCF-7 and LNCaP xenografts treated with a FAP-activated prodrug had maximal treated-to-control tumor volume ratios of 0.36 (treated: mean = 0.206mm 3 , 95% CI = 0.068 to 0.344mm 3 ; control: mean = 0.580mm 3 , 95% CI = 0.267 to 0.893mm 3 ) and 0.24 (treated: mean = 0.131mm 3 , 95% CI = 0.09 to 0.180mm 3 ; control: mean = 0.543mm 3 , 95% CI = 0.173 to 0.913mm 3 ), respectively, on day 21 after therapy. This study validates the proteolytic activity of FAP as a target for the activation of a systemically delivered cytotoxic prodrug and demonstrates that targeted killing of cells within the stromal compartment of the tumor microenvironment can produce a therapeutic response.
Methods of appointment and qualifications of club doctors and physiotherapists in English professional football: some problems and issues
Authors: I Waddington, M Roderick, R Naik
Journal: British Journal of Sports Medicine (2001)

Objective —To examine the methods of appointment, experience, and qualifications of club doctors and physiotherapists in professional football. Methods —Semistructured tape recorded interviews with 12 club doctors, 10 club physiotherapists, and 27 current and former players. A questionnaire was also sent to 90 club doctors; 58 were returned. Results —In almost all clubs, methods of appointment of doctors are informal and reflect poor employment practice: posts are rarely advertised and many doctors are appointed on the basis of personal contacts and without interview. Few club doctors had prior experience or qualifications in sports medicine and very few have a written job description. The club doctor is often not consulted about the appointment of the physiotherapist; physiotherapists are usually appointed informally, often without interview, and often by the manager without involving anyone who is qualified in medicine or physiotherapy. Half of all clubs do not have a qualified (chartered) physiotherapist; such unqualified physiotherapists are in a weak position to resist threats to their clinical autonomy, particularly those arising from managers' attempts to influence clinical decisions. Conclusions —Almost all aspects of the appointment of club doctors and physiotherapists need careful re-examination.
Diagnosing Severe Falciparum Malaria in Parasitaemic African Children: A Prospective Evaluation of Plasma PfHRP2 Measurement
Authors: Ilse C. E. Hendriksen, Juliet Mwanga-Amumpaire, Lorenz von Seidlein, George Mtove, Lisa J. White, Rasaq Olaosebikan, Sue J. Lee, Antoinette K. Tshefu, Charles Woodrow, Ben Amos, Corine Karema, Somporn Saiwaew, Kathryn Maitland, Ermelinda Gomes, Wirichada Pan-Ngum, Samwel Gesase, Kamolrat Silamut, Hugh Reyburn, Sarah Joseph, Kesinee Chotivanich, Caterina I. Fanello, Nicholas P. J. Day, Nicholas J. White, Arjen M. Dondorp
Journal: PLoS Medicine (2012)

In African children, distinguishing severe falciparum malaria from other severe febrile illnesses with coincidental Plasmodium falciparum parasitaemia is a major challenge. P. falciparum histidine-rich protein 2 (PfHRP2) is released by mature sequestered parasites and can be used to estimate the total parasite burden. We investigated the prognostic significance of plasma PfHRP2 and used it to estimate the malaria-attributable fraction in African children diagnosed with severe malaria.Admission plasma PfHRP2 was measured prospectively in African children (from Mozambique, The Gambia, Kenya, Tanzania, Uganda, Rwanda, and the Democratic Republic of the Congo) aged 1 month to 15 years with severe febrile illness and a positive P. falciparum lactate dehydrogenase (pLDH)-based rapid test in a clinical trial comparing parenteral artesunate versus quinine (the AQUAMAT trial, ISRCTN 50258054). In 3,826 severely ill children, Plasmadium falciparum PfHRP2 was higher in patients with coma (p = 0.0209), acidosis (p<0.0001), and severe anaemia (p<0.0001). Admission geometric mean (95%CI) plasma PfHRP2 was 1,611 (1,350-1,922) ng/mL in fatal cases (n = 381) versus 1,046 (991-1,104) ng/mL in survivors (n = 3,445, p<0.0001), without differences in parasitaemia as assessed by microscopy. There was a U-shaped association between log(10) plasma PfHRP2 and risk of death. Mortality increased 20% per log(10) increase in PfHRP2 above 174 ng/mL (adjusted odds ratio [AOR] 1.21, 95%CI 1.05-1.39, p = 0.009). A mechanistic model assuming a PfHRP2-independent risk of death in non-malaria illness closely fitted the observed data and showed malaria-attributable mortality less than 50% with plasma PfHRP2≤174 ng/mL. The odds ratio (OR) for death in artesunate versus quinine-treated patients was 0.61 (95%CI 0.44-0.83, p = 0.0018) in the highest PfHRP2 tertile, whereas there was no difference in the lowest tertile (OR 1.05; 95%CI 0.69-1.61; p = 0.82). A limitation of the study is that some conclusions are drawn from a mechanistic model, which is inherently dependent on certain assumptions. However, a sensitivity analysis of the model indicated that the results were robust to a plausible range of parameter estimates. Further studies are needed to validate our findings.Plasma PfHRP2 has prognostic significance in African children with severe falciparum malaria and provides a tool to stratify the risk of "true" severe malaria-attributable disease as opposed to other severe illnesses in parasitaemic African children.
Larval Papule as a Sign of Scabies
Authors: Walter B. Shelley
Journal: JAMA (1976)

NO CLINICAL sign in the skin is better known than the thread-like burrow hollowed out by the female itch mite. Truly a tunnel of love, it is in this burrow that copulation, ovulation, and birth of the larvae occur.<sup>1</sup>Pathognomonic as it is for scabies, the burrow has somewhat blunted our appreciation of the lesion produced by the developmental or junior forms of<i>Sarcoptes scabiei</i>, viz, the papule. It is exquisitely pruritic and arises quickly in response to a larval or nymphal mite boring into the outermost epidermis. Thus, the papule is surmounted by a virtually invisible chamber for the critical moulting phase. In the absence of burrows, it is these papules that must receive our closest attention in the search for the agent causing scabies. This communication outlines the prolonged complex diagnostic struggle that was eventually won only by finding the larval itch mite within its moulting chamber
How Metformin Acts in PCOS Pregnant Women
Authors: Daniela Romualdi, Simona De Cicco, Donatella Gagliano, Matteo Busacca, Giuseppe Campagna, Antonio Lanzone, Maurizio Guido
Journal: Diabetes Care (2013)

Metformin has been reported to reduce the risk of gestational diabetes (GD) in women with polycystic ovarian syndrome (PCOS). However, little is known about the mechanisms of action of this drug during pregnancy. In the attempt to fill this gap, we performed a prospective longitudinal study providing a detailed examination of glucose and insulin metabolism in pregnant women with PCOS undergoing metformin therapy.