tbuckley/cabot-search huggingface dataset:
Novel PRKAG2 Mutation Responsible for the Genetic Syndrome of Ventricular Preexcitation and Conduction System Disease With Childhood Onset and Absence of Cardiac Hypertrophy
Authors: Michael H. Gollob, John J. Seger, Tanya N. Gollob, Terry Tapscott, Oscar Gonzales, Linda Bachinski, Robert Roberts
Journal: Circulation (2001)

We recently reported a mutation in the PRKAG2 gene to be responsible for a familial syndrome of ventricular preexcitation, atrial fibrillation, conduction defects, and cardiac hypertrophy. We now report a novel mutation in PRKAG2 causing Wolff-Parkinson-White syndrome and conduction system disease with onset in childhood and the absence of cardiac hypertrophy.DNA was extracted from white blood cells obtained from family members. PRKAG2 exons were amplified by polymerase chain reaction and were screened for mutations by direct sequencing. The genomic organization of the PRKAG2 gene was determined using inter-exon long-range polymerase chain reaction for cDNA sequence not available in the genome database. A missense mutation, Arg531Gly, was identified in all affected individuals but was absent in 150 unrelated individuals. The PRKAG2 gene was determined to consist of 16 exons and is at least 280 kb in size.We identified a novel mutation (Arg531Gly) in the gamma-2 regulatory subunit (PRKAG2) of AMP-activated protein kinase (AMPK) to be responsible for a syndrome associated with ventricular preexcitation and early onset of atrial fibrillation and conduction disease. These observations confirm an important functional role of AMPK in the regulation of ion channels specific to cardiac tissue. The identification of the cardiac ion channel(s) serving as substrate for AMPK not only would provide insight into the molecular basis of atrial fibrillation and heart block but also may suggest targets for the development of more specific therapy for these common rhythm disturbances.
Modafinil in sports: ethical considerations
Authors: K R Kaufman
Journal: British Journal of Sports Medicine (2005)

Performance enhancing agents are prohibited in athletic competition so that only athletic skills can determine outcomes. Modafinil is a novel non-addicting psychostimulant approved for treatment of narcolepsy. Does its use, especially for medical indications, violate the Olympic Movement Anti-Doping Code? This is discussed with reference to a current high profile case.
Open-Label Phase II Study Evaluating the Efficacy and Safety of Two Doses of Pertuzumab in Castrate Chemotherapy-Naive Patients With Hormone-Refractory Prostate Cancer
Authors: Johann Sebastian de Bono, Joaquim Bellmunt, Gerhardt Attard, Jean Pierre Droz, Kurt Miller, Aude Flechon, Cora Sternberg, Chris Parker, Gerhard Zugmaier, Veronica Hersberger-Gimenez, Louise Cockey, Malcolm Mason, John Graham
Journal: Journal of Clinical Oncology (2007)

Purpose To determine the prostate-specific antigen (PSA) 50% decline rate within 24 weeks of starting treatment with single-agent pertuzumab in castrate patients with hormone-refractory prostate cancer (HRPC). Patients and Methods Two independent Simon's two-stage designs were used to evaluate two doses of pertuzumab administered intravenously once every 3 weeks. An interim analysis of the first 23 assessable patients in the first cohort treated at 420 mg (loading dose of 840 mg) allowed termination of additional enrollment if ≤ three patients had a ≥ 50% decline in PSA after all patients had completed at least three cycles of therapy or withdrew due to insufficient therapeutic response, death, or study-related toxicity before completing three cycles. A second cohort of patients treated at 1,050 mg could be enrolled with the same design, and if more than three patients had a ≥ 50% decline in PSA, 27 more patients would be treated at 1,050 mg. Results Sixty-eight castrate, chemotherapy-naive men with HRPC were enrolled. A total of 35 patients were treated at 420 mg; no PSA declines ≥ 50% were observed at the interim analysis and recruitment was stopped. A total of 33 patients were then treated at 1,050 mg, and no PSA declines ≥ 50% were observed at the interim analysis. Pertuzumab was well tolerated. Conclusion Pertuzumab has no clinically significant single-agent activity in castrate patients with HRPC at either of the tested dose levels. This may reflect the continued presence of significant levels of intraprostatic androgen driving androgen receptor signaling.
Eltrombopag and Improved Hematopoiesis in Refractory Aplastic Anemia
Authors: Matthew J. Olnes, Phillip Scheinberg, Katherine R. Calvo, Ronan Desmond, Yong Tang, Bogdan Dumitriu, Ankur R. Parikh, Susan Soto, Angelique Biancotto, Xingmin Feng, Jay Lozier, Colin O. Wu, Neal S. Young, Cynthia E. Dunbar
Journal: New England Journal of Medicine (2012)

Severe aplastic anemia, which is characterized by immune-mediated bone marrow hypoplasia and pancytopenia, can be treated effectively with immunosuppressive therapy or allogeneic transplantation. One third of patients have disease that is refractory to immunosuppression, with persistent, severe cytopenia and a profound deficit in hematopoietic stem cells and progenitor cells. Thrombopoietin may increase the number of hematopoietic stem cells and progenitor cells.
Atorvastatin and Micronized Fenofibrate Alone and in Combination in Type 2 Diabetes With Combined Hyperlipidemia
Authors: Vasilios G. Athyros, Athanasios A. Papageorgiou, Valasia V. Athyrou, Dimokritos S. Demitriadis, Athanasios G. Kontopoulos
Journal: Diabetes Care (2002)

OBJECTIVE—This study evaluated the effect of a atorvastatin-fenofibrate combination on lipid profile, in comparison to each drug alone, in patients with type 2 diabetes and combined hyperlipidemia (CHL). RESEARCH DESIGN AND METHODS—A total of 120 consecutive patients, who were free of coronary artery disease (CAD) at entry, were studied for a period of 24 weeks. These patients were randomly assigned to atorvastatin (20 mg/day, n = 40), micronized fenofibrate (200 mg/day, n = 40), or a combination of both (atorvastatin 20 mg/day plus fenofibrate 200 mg/day, n = 40). The effect of treatment on LDL cholesterol, triglycerides (TGs), HDL cholesterol, apolipoprotein A-I and B, lipoprotein(a), and plasma fibrinogen (PF) was recorded. Moreover, the percentage of patients that reached the American Diabetes Association treatment goals and the estimated CAD risk status were calculated. RESULTS—No patient was withdrawn from the study because of side effects. The atorvastatin-fenofibrate combination reduced total cholesterol by 37%, LDL cholesterol by 46%, TGs by 50%, and PF by 20%, whereas it increased HDL cholesterol by 22% (P &amp;lt; 0.0001 for all). These changes were significantly better than those of both monotherapies. Of the patients on drug combination, 97.5% reached the LDL cholesterol treatment goal of &amp;lt;100 mg/dl, 100% reached the desirable TG levels of &amp;lt;200 mg/dl, and 60% reached the optimal HDL cholesterol levels of &amp;gt;45 mg/dl. These rates were significantly higher than those of both monotherapies. Combined treatment reduced the 10-year probability for myocardial infarction from 21.6 to 4.2%. CONCLUSIONS—The atorvastatin-fenofibrate combination has a highly beneficial effect on all lipid parameters and PF in patients with type 2 diabetes and CHL. It improved patients’ CAD risk status significantly more than each drug alone.
PKCλ regulates glucose-induced insulin secretion through modulation of gene expression in pancreatic β cells
Authors: Naoko Hashimoto, Yoshiaki Kido, Tohru Uchida, Tomokazu Matsuda, Kazuhisa Suzuki, Hiroshi Inoue, Michihiro Matsumoto, Wataru Ogawa, Sakan Maeda, Hiroaki Fujihara, Yoichi Ueta, Yasuo Uchiyama, Kazunori Akimoto, Shigeo Ohno, Tetsuo Noda, Masato Kasuga
Journal: Journal of Clinical Investigation (2005)

Altered regulation of insulin secretion by glucose is characteristic of individuals with type 2 diabetes mellitus, although the mechanisms that underlie this change remain unclear. We have now generated mice that lack the λ isoform of PKC in pancreatic β cells (βPKCλ–/– mice) and show that these animals manifest impaired glucose tolerance and hypoinsulinemia. Furthermore, insulin secretion in response to high concentrations of glucose was impaired, whereas the basal rate of insulin release was increased, in islets isolated from βPKCλ–/– mice. Neither the β cell mass nor the islet insulin content of βPKCλ–/– mice differed from that of control mice, however. The abundance of mRNAs for Glut2 and HNF3β was reduced in islets of βPKCλ–/– mice, and the expression of genes regulated by HNF3β was also affected (that of Sur1 and Kir6.2 genes was reduced, whereas that of hexokinase 1 and hexokinase 2 genes was increased). Normalization of HNF3β expression by infection of islets from βPKCλ–/– mice with an adenoviral vector significantly reversed the defect in glucose-stimulated insulin secretion. These results indicate that PKCλ plays a prominent role in regulation of glucose-induced insulin secretion by modulating the expression of genes important for β cell function.
Slit2 Prevents Neutrophil Recruitment and Renal Ischemia-Reperfusion Injury
Authors: Swasti Chaturvedi, Darren A. Yuen, Amandeep Bajwa, Yi-Wei Huang, Christiane Sokollik, Liping Huang, Grace Y. Lam, Soumitra Tole, Guang-Ying Liu, Jerry Pan, Lauren Chan, Yaro Sokolskyy, Manoj Puthia, Gabriela Godaly, Rohan John, Changsen Wang, Warren L. Lee, John H. Brumell, Mark D. Okusa, Lisa A. Robinson
Journal: Journal of the American Society of Nephrology (2013)

Neutrophils recruited to the postischemic kidney contribute to the pathogenesis of ischemia-reperfusion injury (IRI), which is the most common cause of renal failure among hospitalized patients. The Slit family of secreted proteins inhibits chemotaxis of leukocytes by preventing activation of Rho-family GTPases, suggesting that members of this family might modulate the recruitment of neutrophils and the resulting IRI. Here, in static and microfluidic shear assays, Slit2 inhibited multiple steps required for the infiltration of neutrophils into tissue. Specifically, Slit2 blocked the capture and firm adhesion of human neutrophils to inflamed vascular endothelial barriers as well as their subsequent transmigration. To examine whether these observations were relevant to renal IRI, we administered Slit2 to mice before bilateral clamping of the renal pedicles. Assessed at 18 hours after reperfusion, Slit2 significantly inhibited renal tubular necrosis, neutrophil and macrophage infiltration, and rise in plasma creatinine. In vitro, Slit2 did not impair the protective functions of neutrophils, including phagocytosis and superoxide production, and did not inhibit neutrophils from killing the extracellular pathogen Staphylococcus aureus. In vivo, administration of Slit2 did not attenuate neutrophil recruitment or bacterial clearance in mice with ascending Escherichia coli urinary tract infections and did not increase the bacterial load in the livers of mice infected with the intracellular pathogen Listeria monocytogenes. Collectively, these results suggest that Slit2 may hold promise as a strategy to combat renal IRI without compromising the protective innate immune response.
Mesenchymal Stem/Stromal Cells Protect the Ocular Surface by Suppressing Inflammation in an Experimental Dry Eye
Authors: Min Joung Lee, Ah Young Ko, Jung Hwa Ko, Hyun Ju Lee, Mee Kum Kim, Won Ryang Wee, Sang In Khwarg, Joo Youn Oh
Journal: Molecular Therapy (2014)

Dry eye syndrome (DES) is one of the most common ocular diseases affecting nearly 10% of the US population. Most of the currently available treatments are palliative, and few therapeutic agents target biological pathway of DES. Although DES is a multifactorial disease, it is well-known that inflammation in the ocular surface plays an important role in the pathogenesis of DES. Mesenchymal stem/stromal cells (MSCs) have been shown to repair tissues by modulating excessive immune responses in various diseases. Therefore, we here investigated the therapeutic potential of MSCs in a murine model of an inflammation-mediated dry eye that was induced by an intraorbital injection of concanavalin A. We found that a periorbital administration of MSCs reduced the infiltration of CD4+ T cells and the levels of inflammatory cytokines in the intraorbital gland and ocular surface. Also, MSCs significantly increased aqueous tear production and the number of conjunctival goblet cells. Subsequently, corneal epithelial integrity was well-preserved by MSCs. Together, the results demonstrate that MSCs protect the ocular surface by suppressing inflammation in DES, and suggest that MSCs may offer a therapy for a number of ocular surface diseases where inflammation plays a key role. Dry eye syndrome (DES) is one of the most common ocular diseases affecting nearly 10% of the US population. Most of the currently available treatments are palliative, and few therapeutic agents target biological pathway of DES. Although DES is a multifactorial disease, it is well-known that inflammation in the ocular surface plays an important role in the pathogenesis of DES. Mesenchymal stem/stromal cells (MSCs) have been shown to repair tissues by modulating excessive immune responses in various diseases. Therefore, we here investigated the therapeutic potential of MSCs in a murine model of an inflammation-mediated dry eye that was induced by an intraorbital injection of concanavalin A. We found that a periorbital administration of MSCs reduced the infiltration of CD4+ T cells and the levels of inflammatory cytokines in the intraorbital gland and ocular surface. Also, MSCs significantly increased aqueous tear production and the number of conjunctival goblet cells. Subsequently, corneal epithelial integrity was well-preserved by MSCs. Together, the results demonstrate that MSCs protect the ocular surface by suppressing inflammation in DES, and suggest that MSCs may offer a therapy for a number of ocular surface diseases where inflammation plays a key role.
Effects of high glucose concentrations on human mesangial cell proliferation.
Authors: F G Cosio
Journal: Journal of the American Society of Nephrology (1995)

High concentrations of glucose in vitro inhibit cell proliferation and stimulate matrix protein synthesis. These studies sought to characterize the relationship between the effects of glucose on cell proliferation and matrix synthesis and to assess the mechanism(s) responsible for these cellular effects of glucose. The initial experiments showed that high glucose levels stimulate fibronectin (FN) synthesis by human mesangial cells (HMC) but only in those cultures in which cell proliferation was inhibited by glucose. To assess whether this relationship was due to an effect of glucose on the capacity of HMC to respond to cytokines, the responses of HMC to serum or cytokines were measured in the presence of different glucose concentrations. High concentrations of glucose inhibited (3H)thymidine incorporation in response to serum and platelet-derived growth factor. Under the conditions of these experiments, transforming growth factor-beta (TGF-beta) also stimulated thymidine incorporation by HMC, and high glucose concentrations inhibited thymidine incorporation in response to TGF-beta. In contrast, high concentrations of glucose did not inhibit the stimulation of FN synthesis caused by platelet-derived growth factor, serum, or TGF-beta. The antiproliferative effects of high glucose levels were first observed after 48 h of incubation and were reversible after the withdrawal of high glucose from the media. The following evidence suggest that the effects of glucose may be mediated via protein kinase C (PKC): (1) incubation with high glucose concentrations caused an increase in HMC PKC levels; (2) PKC activation with phorbol esters inhibited HMC proliferation; and (3) depletion or inhibition of PKC stimulated HMC proliferation and prevented the antiproliferative effects of glucose. In contrast to these findings, inhibitors of protein glycosylation and myo-inositol supplementation of culture media did not prevent the antiproliferative effects of glucose. In conclusion, high glucose concentrations acutely and reversibly inhibit HMC proliferation, perhaps by a PKC-dependent mechanism. Because PKC can also stimulate FN synthesis, glucose-induced changes in PKC may explain the relationship between the effects of high glucose concentrations on cell proliferation and FN synthesis.
CpG Island Methylation of DNA Damage Response Genes in Advanced Ovarian Cancer
Authors: Jens M. Teodoridis, Jacqueline Hall, Sharon Marsh, Hilary D. Kannall, Catriona Smyth, Jorge Curto, Nadeem Siddiqui, Hani Gabra, Howard L. McLeod, Gordon Strathdee, Robert Brown
Journal: Cancer Research (2005)

Abstract We have determined the methylation frequencies of 24 CpG islands of genes associated with DNA damage responses or with ovarian cancer in 106 stage III/IV epithelial ovarian tumors. We have analyzed this data for whether there is evidence of a CpG island methylator phenotype or associations of CpG island methylation with response to chemotherapy in advanced ovarian cancer. Frequent methylation was observed for OPCML, DCR1, RASSF1A, HIC1, BRCA1, and MINT25 (33.3%, 30.7%, 26.4%, 17.3%, 12.3%, and 12.0%, respectively), whereas no methylation was observed for APAF-1, DAPK, FANCF, FAS, P14, P21, P73, SOCS-3, and SURVIVIN. The remaining genes showed only a low frequency of methylation, &amp;lt;10%. Unsupervised gene shaving identified a nonrandom pattern of methylation for OPCML, DCR1, RASSF1A, MINT25, HIC1, and SFRP1, supporting the concept of concordant methylation of these genes in ovarian cancer. Methylation of at least one of the group of genes involved in DNA repair/drug detoxification (BRCA1, GSTP1, and MGMT) was associated with improved response to chemotherapy (P = 0.013). We have examined the frequency of a polymorphism in the DNA methyltransferase gene DNMT3b6, which has been previously reported to affect gene transcription and cancer risk. The genetic polymorphism in the DNMT3b6 gene promoter (at position −149) is not significantly associated with the concordant methylation observed, but is weakly associated with the overall frequency of methylation at the genes examined (P = 0.04, n = 56). This supports the hypothesis that genetic factors affecting function of DNMT genes may underlie the propensity of tumors to acquire aberrant CpG island methylation.
Coronary risk in a cohort of Paralympic athletes
Authors: J A O Filho, X M Salvetti, M T de Mello, A C da Silva, B L Filho
Journal: British Journal of Sports Medicine (2006)

Objective: To determine the prevalence of coronary risk factors in Paralympic athletes and evaluate their risk of coronary events. Method: An observational prospective cross sectional study of 79 consecutive Brazilian Paralympic athletes (mean (SD) age 27.8 (6.7) years (median 26 years)). There were 56 men and 23 women, 67 with physical and 12 with visual disabilities. The occurrence of systemic hypertension, hypercholesterolaemia, diabetes mellitus, smoking, familial antecedents, obesity, and hypertriglyceridaemia was investigated. The risk of coronary events was calculated using the American Heart Association Coronary risk handbook , and also the 10 year probability of a coronary event using the Framingham risk score. Results: The prevalence of risk factors was: systemic hypertension, 11%; familial antecedents, 10%; smoking, 9%; hypertriglyceridaemia, 6%; hypercholesterolaemia, 1.3%; obesity, 4%; diabetes, 0%. They occurred in 51% of the Paralympic athletes: one factor (41%), two factors (4%), and three factors (6%). The risk of coronary events was absent in 80%, slight in 17%, and moderate in 3%. This could only be evaluated in 81% of the athletes, as 8% had amputations, 9% were young, and 2% had unknown familial antecedents. The Framingham risk score ranged from −14 to +6, predicting a 10 year probability of a coronary event of 3.3 (3.8)%. Conclusion: This study shows a reasonably high prevalence of coronary risk factors (51%), despite a low probability of coronary events in Paralympic athletes. The lipid and blood pressure profiles were similar in ambulatory and wheelchair athletes.
Diagnosis, treatment and prevention of ankle sprains: an evidence-based clinical guideline
Authors: Gino M Kerkhoffs, Michel van den Bekerom, Leon A M Elders, Peter A van Beek, Wim A M Hullegie, Guus M F M Bloemers, Elly M de Heus, Masja C M Loogman, Kitty C J G M Rosenbrand, Ton Kuipers, J W A P Hoogstraten, Rienk Dekker, Henk-Jan ten Duis, C Niek van Dijk, Maurits W van Tulder, Philip J van der Wees, Rob A de Bie
Journal: British Journal of Sports Medicine (2012)

Ankle injuries are a huge medical and socioeconomic problem. Many people have a traumatic injury of the ankle, most of which are a result of sports. Total costs of treatment and work absenteeism due to ankle injuries are high. The prevention of recurrences can result in large savings on medical costs. A multidisciplinary clinical practice guideline was developed with the aim to prevent further health impairment of patients with acute lateral ankle ligament injuries by giving recommendations with respect to improved diagnostic and therapeutic opportunities. The recommendations are based on evidence from published scientific research, which was extensively discussed by the guideline committee. This clinical guideline is helpful for healthcare providers who are involved in the management of patients with ankle injuries.
Doppler assessment of hypoxic pulmonary vasoconstriction and susceptibility to high altitude pulmonary oedema.
Authors: J L Vachiery, T McDonagh, J J Moraine, J Berre, R Naeije, H Dargie, A J Peacock
Journal: Thorax (1995)

BACKGROUND--Subjects with previous high altitude pulmonary oedema may have stronger than normal hypoxic pulmonary vasoconstriction. Susceptibility to high altitude pulmonary oedema may be detectable by echo Doppler assessment of the pulmonary vascular reactivity to breathing a hypoxic gas mixture at sea level. METHODS--The study included 20 healthy controls, seven subjects with a previous episode of high altitude pulmonary oedema, and nine who had successfully climbed to altitudes of 6000-8842 m during the 40th anniversary British expedition to Mount Everest. Echo Doppler measurements of pulmonary blood flow acceleration time (AT) and ejection time (ET), and of the peak velocity of the tricuspid regurgitation jet (TR), were obtained under normobaric conditions of normoxia (fraction of inspired oxygen, FIO2, 0.21), of hyperoxia (FIO2 1.0), and of hypoxia (FIO2 0.125). RESULTS--Hypoxia decreased AT/ET by mean (SE) 0.06 (0.01) in the control subjects, by 0.11 (0.01) in those susceptible to high altitude pulmonary oedema, and by 0.02 (0.02) in the successful high altitude climbers. Hypoxia increased TR in the three groups by 0.22 (0.06) (n = 14), 0.56 (0.13) (n = 5), and 0.18 (0.1) (n = 7) m/s, respectively. However, AT/ET and/or TR measurements outside the normal range, defined as mean +/- 2 SD of measurements obtained in the controls under hypoxia, were observed in only two of the subjects susceptible to high altitude pulmonary oedema and in five of the successful high altitude climbers. CONCLUSIONS--Pulmonary vascular reactivity to hypoxia is enhanced in subjects with previous high altitude pulmonary oedema and decreased in successful high altitude climbers. However, echo Doppler estimates of hypoxic pulmonary vaso-constriction at sea level cannot reliably identify subjects susceptible to high altitude pulmonary oedema or successful high altitude climbers from a normal control population.
Efficacy of short-term psychodynamic psychotherapy (STPP) with depressed breast cancer patients: results of a randomized controlled multicenter trial
Authors: M.E. Beutel, G. Weißflog, K. Leuteritz, J. Wiltink, A. Haselbacher, C. Ruckes, S. Kuhnt, Y. Barthel, B.H. Imruck, R. Zwerenz, E. Brähler
Journal: Annals of Oncology (2013)