tbuckley/cabot-search huggingface dataset:
Live-attenuated virus vaccines for respiratory syncytial and parainfluenza viruses: applications of reverse genetics
Authors: Brian R. Murphy, Peter L. Collins
Journal: Journal of Clinical Investigation (2002)

The future of vaccine designRespiratory syncytial virus (RSV) and the human parainfluenza viruses (PIVs) are enveloped nonsegmented negative-strand RNA viruses of the paramyxovirus family.RSV is the leading cause of severe viral respiratory disease in infants and children, and in the United States RSV is responsible for 73,000 to 126,000 annual hospitalizations of infants younger than 1 year of age (1).Two antigenic subgroups of RSV, designated A and B, have been distinguished on the basis of antigenic and sequence dimorphism that is most pronounced for the ectodomain of the G protein, one of the two major protective antigens.Although there is substantial cross-reactivity between the two subgroups, they are sufficiently distinct that an effective RSV vaccine likely will need to represent both.The human PIV serotypes 1, 2, and 3 also cause severe respiratory tract disease that leads to hospitalization of infants and young children (2).PIV1, PIV2, and PIV3 are distinct serotypes that do not induce significant cross-neutralization or cross-protection.In a long term study of infants and children over a 20-year period, PIV1, PIV2, and PIV3 were identified as etiologic agents responsible for 6.0%, 3.2%, and 11.5%, respectively, of hospitalizations for pediatric respiratory tract disease (1).In total, the three PIVs accounted for only slightly less than the 23% of hospitalizations for pediatric respiratory tract disease caused by RSV.Therefore, there is a need for a vaccine to protect against these three serotypes of PIV and the two antigenic subgroups of RSV.An additional pediatric vaccine will likely be needed for the newly described but related human respiratory tract pathogen human metapneumovirus (3).
Adenosine deaminase (ADA) isoenzyme analysis in pleural effusions: diagnostic role, and relevance to the origin of increased ADA in tuberculous pleurisy
Authors: L Valdes, E San Jose, D Alvarez, JM Valle
Journal: European Respiratory Journal (1996)

The rise in adenosine deaminase (ADA) activity in the pleural fluid of tuberculous pleurisy patients, though used for diagnosis, is of unknown origin. In this work, we determined ADA activity and the activities of 2'-deoxyadenosine deaminase and ADA-2 in 350 patients. We also considered whether the results throw light on the origin of high pleural fluid ADA in tuberculous pleurisy and estimated the diagnostic efficiency of 2'-deoxyadenosine deaminase, ADA-2 and total ADA activities with and without the inclusion of the 2'-deoxyadenosine deaminase/ADA activity ratio in a combined criterion. The 350 pleural effusions were classified by previously established criteria as transudates (60 males/18 females) or as tuberculous (49 males/27 females), neoplastic (50 males/39 females), parapneumonic (36 males/19 females), empyematous (11 males/3 females), or miscellaneous (25 males/13 females) exudates. Total ADA, ADA-2 and 2'-deoxyadenosine deaminase activities were, respectively, 127.5 +/- 2.9, 103 +/- 29.5 and 42.8 +/- 14 U.L-1 in tuberculous exudates. With diagnostic thresholds of 47, 40 and 22 U.L-1 respectively, the sensitivities of ADA, ADA-2 and 2'-deoxyadenosine deaminase for tuberculosis were 100, 100 and 95%; their specificities 91, 96 and 92%; and their efficiencies 93, 97 and 93%, respectively. One hundred and one effusions (all 76 tuberculous, 12 neoplastic, 4 parapneumonic and 9 empyematous exudates) had total ADA levels > 47 U.L-1; of these, 8 neoplastic, 1 parapneumonic and all the tuberculous exudates had a 2'-deoxyadenosine deaminase/ADA activity ratio < 0.49. The criterion of simultaneously having ADA > 47 U.L-1, ADA-2 > 40 U.L-1 and a 2'-deoxyadenosine deaminase/ADA activity ratio < 0.49 was satisfied by all the tuberculous effusions but only eight others (all neoplastic) (sensitivity 100%, specificity 97%, efficiency 98%). We conclude that: 1) high total ADA activity in tuberculous pleural effusions is due mainly to an increase in ADA-2, and, therefore, originated from the only known source monocytes and macrophages; 2) ADA-2 was a more efficient diagnostic marker of tuberculous pleurisy than total ADA activity, although the difference was not statistically significant; and 3) among effusions with high total ADA the 2'-deoxyadenosine deaminase/ADA activity ratio differentiates tuberculous effusions from empyemas and parapneumonic effusions, but fails to discriminate well between tuberculous and neoplastic effusions.
Mechanism of Inhibitory Effect of Warfarin on Mesangial Cell Proliferation
Authors: MOTOKO YANAGITA, KENJI ISHII, HARUNOBU OZAKI, HIDENORI ARAI, TORU NAKANO, KAZUMASA OHASHI, KENSAKU MIZUNO, TORU KITA, TOSHIO DOI
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Because proliferation of mesangial cells is a hallmark of glomerular diseases, understanding the regulatory mechanism of mesangial proliferation is important for the treatment. Warfarin has long been used to treat glomerular diseases, although its mechanism of effect on mesangial proliferation has remained unknown. Therefore, this study was conducted to examine whether warfarin can inhibit mouse mesangial cell proliferation by focusing on Gas6, which has been shown to be activated by vitamin K-dependent γ-carboxylation. In mesangial cells, Gas6 and its receptor Axl were expressed. In addition, exogenous Gas6 phosphorylated Axl, activated extracellular signal-regulated kinase, and stimulated [ 3 H]-thymidine incorporation in mouse mesangial cells. This study also examined whether endogenous Gas6 stimulates mesangial proliferation. Conditioned medium (CM) from serum-starved mesangial cells could stimulate [ 3 H]-thymidine incorporation and phosphorylate extracellular signal-regulated kinase, whereas CM in the presence of warfarin could not. Simultaneous administration of vitamin K could cancel the inhibitory effect of warfarin. These results suggest that vitamin K-dependent growth factors in the CM are critical for mesangial proliferation. Addition of the extracellular domain of Axl to the CM inhibited its mitogenic effect on mesangial cells, suggesting that this vitamin K-dependent growth factor is Gas6. It is concluded that Gas6 is an endogenous mitogen in mesangial cells, and warfarin inhibits mesangial proliferation possibly by inhibiting γ-carboxylation of Gas6. This study sheds light on the regulation of mesangial proliferation and may lead to a new therapeutic strategy for glomerular diseases.
Effects of anti-M1 prime monoclonal antibody, MEMP1972A following allergen challenge in patients with mild asthma
Authors: Gail Gauvreau, Louis-Philippe Boulet, Donald Cockcroft, Beth Davis, Mark Fitzgerald, Richard Leigh, Barbro Dahlen, Irvin Mayers, Heleen Scheerens, Romeo Maciuca, John Matthews, Jeffrey Harris, Paul O'Byrne
Journal: European Respiratory Journal (2012)

Background : Elevated serum IgE is associated with allergic asthma. Membrane IgE includes the M1 prime epitope, present in human IgE-switched memory B cells and plasmablasts. MEMP1972A, a therapeutic antibody specific for M1-prime that depletes M1-prime-expressing cells.

Aim: To test proof-of-activity of MEMP1972A.

Methods : This randomized, double-blind, controlled study ([NCT01196039][1]) assessed the activity and safety of MEMP1972A in adults with mild asthma after allergen inhalation challenge (AIC). Subjects (n=29) were randomized (1:1) to intravenous MEMP1972A (5 mg/kg) or placebo every 4 weeks for 12 weeks. The primary outcome was the area under the curve (AUC) of the late asthmatic response (LAR) at Wk 12. Secondary outcomes included early asthmatic response (EAR). Serum total IgE and allergen-specific IgE were measured to confirm mechanistic activity of MEMP1972A. Other exploratory biomarkers were measured eg sputum and blood eosinophils.

Results: MEMP1972A treatment was well tolerated. At Wk 12, MEMP1972A reduced the LAR AUC by 36% (90% CI: -14, 69, p=0.21) and the EAR AUC by 26% (6, 43, p=0.046) vs placebo. AIC at screening and Wk 12 induced a ∼2-fold increase in allergen-specific IgE which was abrogated by MEMP1972A and more than ∼10-fold increase in sputum eosinophils, which was reduced by MEMP1972A at Wk 12. MEMP1972A reduced total IgE by ∼20% at Wk 8, and blood eosinophils by ∼45% at Wk 28 vs baseline.

Conclusions: Attenuation of EAR, LAR, serum IgE, sputum and blood eosinophils following AIC is consistent with the mechanism of action of MEMP1972A. Depletion of the M1 prime-expressing B-cell lineage may be effective for the treatment of allergic asthma.

 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01196039&atom=%2Ferj%2F40%2FSuppl_56%2F3087.atom
Pyrimidine salvage in Giardia lamblia.
Authors: S M Aldritt, P Tien, C C Wang
Journal: The Journal of Experimental Medicine (1985)

We have found that the anaerobic protozoan parasite Giardia lamblia is incapable of de novo pyrimidine metabolism, as shown by its inability to incorporate orotate, bicarbonate, and aspartate into the pyrimidine nucleotide pool. Results from high performance liquid chromatography of pyrimidine and pyrimidine nucleoside pulse-labeled nucleotide pools and enzyme assays suggest that the parasite satisfies its pyrimidine nucleotide needs predominantly through salvage of uracil by a cytoplasmic uracil phosphoribosyltransferase. Exogenous uridine and cytidine are primarily converted to uracil by the action of uridine hydrolase and cytidine deaminase before incorporation into nucleotide pools. Direct salvage of cytosine occurs to a relatively limited extent via cytosine phosphoribosyltransferase. G. lamblia relies on salvage of exogenous thymidine for ribosylthymine monophosphate (TMP) synthesis, accomplished primarily through the action of a 100,000 g-pelletable thymidine phosphotransferase.
Urocortin II mediates pro-inflammatory effects in human colonocytes via corticotropin-releasing hormone receptor 2 
Authors: A. C Moss, P. Anton, T. Savidge, P. Newman, A. S Cheifetz, J. Gay, S. Paraschos, M. W. Winter, M. P Moyer, K. Karalis, E. Kokkotou, C. Pothoulakis
Journal: Gut (2007)

<b>Background/Aims:</b> Urocortin II (UcnII) is a neuropeptide that binds with high affinity to the corticotropin-releasing hormone receptor 2 (CRHR2) in peripheral tissues. UcnII is synthesised in the intestine, but its role in human intestinal inflammation is largely unknown. <b>Methods:</b> Responses of human colonic epithelial cells expressing CRHR2 to stimulation by UcnII were measured using ELISA, western blot analysis, real-time reverse transcription-PCR (RT-PCR) and interleukin (IL)8 promoter activity. Expression levels of CRHR2 and UcnII in human colitis were determined by immunofluorescence and real-time RT-PCR in mucosal biopsies from patients with Crohn's and ulcerative colitis, and in human intestinal xenografts after exposure to <i>Clostridium difficile</i> toxin A. <b>Results:</b> It is reported here that expression of CRHR2 mRNA and protein in human colonic epithelial cells (HT-29) are increased by exposure to <i>C difficile</i> toxin A or tumour necrosis factor (TNF)α. Stimulation of non-transformed NCM460 colonocytes overexpressing CRHR2α receptor with UcnII resulted in a time- and concentration-dependent increase in IL8 production. UcnII stimulation also led to activation of nuclear factor-κB (NF-κB) and mitogen-acivated protein (MAP) kinase in these cells, as evidenced by degradation of IκBα and phosphorylation of the p65 subunit of NF-κB and extracellularly regulated kinase (ERK) 1/2. Furthermore, expression of UcnII and CRHR2 mRNA was increased in mucosal samples of patients with inflammatory bowel disease, and after exposure of human intestinal xenografts to <i>C difficile</i> toxin A. <b>Conclusions:</b> These results suggest that UcnII has pro-inflammatory effects in human intestinal cells via the CRHR2α receptor and may play an important role in the pathophysiology of colitis in humans.
Can Indirect Tests Detect a Known Recombination Event in Human mtDNA?
Authors: D. J. White, N. J. Gemmell
Journal: Molecular Biology and Evolution (2009)

Whether human mitochondrial DNA (mtDNA) recombines sufficiently to influence its evolution, evolutionary analysis, and disease etiology, remains equivocal. Overall, evidence from indirect studies of population genetic data suggests that recombination is not occurring at detectable levels. This may be explained by no, or low, recombination or, alternatively, current indirect tests may be incapable of detecting recombination in human mtDNA. To investigate the latter, we have tested whether six well-established indirect tests of recombination could detect recombination in a human mtDNA data set, in which its occurrence had been empirically confirmed. Three showed statistical evidence for recombination (r2 vs. distance, the Homoplasy test, Neighborhood Similarity Score), and three did not (D′ vs. distance, Max Chi Squared, Pairwise Homoplasy Index). Possible reasons for detection failure are discussed. Further, evidence from earlier studies suggesting a lack of recombination in mtDNA in humans is reconsidered, taking into account the appropriateness of the tests used, based on our new findings.
Diabetes Patients Requiring Glucose-Lowering Therapy and Nondiabetics With a Prior Myocardial Infarction Carry the Same Cardiovascular Risk
Authors: Tina Ken Schramm, Gunnar H. Gislason, Lars Køber, Søren Rasmussen, Jeppe N. Rasmussen, Steen Z. Abildstrøm, Morten Lock Hansen, Fredrik Folke, Pernille Buch, Mette Madsen, Allan Vaag, Christian Torp-Pedersen
Journal: Circulation (2008)

Previous studies reveal major differences in the estimated cardiovascular risk in diabetes mellitus, including uncertainty about the risk in young patients. Therefore, large studies of well-defined populations are needed.All residents in Denmark > or = 30 years of age were followed up for 5 years (1997 to 2002) by individual-level linkage of nationwide registers. Diabetes patients receiving glucose-lowering medications and nondiabetics with and without a prior myocardial infarction were compared. At baseline, 71 801 (2.2%) had diabetes mellitus and 79 575 (2.4%) had a prior myocardial infarction. Regardless of age, age-adjusted Cox proportional-hazard ratios for cardiovascular death were 2.42 (95% confidence interval [CI], 2.35 to 2.49) in men with diabetes mellitus without a prior myocardial infarction and 2.44 (95% CI, 2.39 to 2.49) in nondiabetic men with a prior myocardial infarction (P=0.60), with nondiabetics without a prior myocardial infarction as the reference. Results for women were 2.45 (95% CI, 2.38 to 2.51) and 2.62 (95% CI, 2.55 to 2.69) (P=0.001), respectively. For the composite of myocardial infarction, stroke, and cardiovascular death, the hazard ratios in men with diabetes only were 2.32 (95% CI, 2.27 to 2.38) and 2.48 (95% CI, 2.43 to 2.54) in those with a prior myocardial infarction only (P=0.001). Results for women were 2.48 (95% CI, 2.43 to 2.54) and 2.71 (95% CI, 2.65 to 2.78) (P=0.001), respectively. Risks were similar for both diabetes types. Analyses with adjustments for comorbidity, socioeconomic status, and prophylactic medical treatment showed similar results, and propensity score-based matched-pair analyses supported these findings.Patients requiring glucose-lowering therapy who were > or = 30 years of age exhibited a cardiovascular risk comparable to nondiabetics with a prior myocardial infarction, regardless of sex and diabetes type. Therefore, requirement for glucose-lowering therapy should prompt intensive prophylactic treatment for cardiovascular diseases.
Hyperglycemia and Acute Coronary Syndrome
Authors: Prakash Deedwania, Mikhail Kosiborod, Eugene Barrett, Antonio Ceriello, William Isley, Theodore Mazzone, Philip Raskin
Journal: Circulation (2008)

Hyperglycemia is common and associated with markedly increased mortality rates in patients hospitalized with acute coronary syndromes (ACS). Despite the fact that several studies have documented this association, hyperglycemia remains underappreciated as a risk factor, and it is frequently untreated in ACS patients. This is in large part due to limitations of prior studies, and the remaining critical gaps in our understanding of the relationship between hyperglycemia and poor outcomes. The main objective of the present statement is to summarize the current state of knowledge regarding the association between elevated glucose and patient outcomes in ACS and to outline the most important knowledge gaps in this field. These gaps include the need to specifically define hyperglycemia, develop optimal ways of measuring and tracking glucose values during ACS hospitalization, and better understand the physiological mechanisms responsible for poor outcomes associated with hyperglycemia. The most important issue, however, is whether elevated glucose is a direct mediator of adverse outcomes in ACS patients or just a marker of greater disease severity. Given the marked increase in short- and long-term mortality associated with hyperglycemia, there is an urgent need for definitive large randomized trials to determine whether treatment strategies aimed at glucose control will improve patient outcomes and to define specific glucose treatment targets. Although firm guidelines will need to await completion of these clinical trials, the present statement also provides consensus recommendations for hyperglycemia management in patients with ACS on the basis of the available data.
Cystamine Suppresses Polyalanine Toxicity in a Mouse Model of Oculopharyngeal Muscular Dystrophy
Authors: Janet E. Davies, Claudia Rose, Sovan Sarkar, David C. Rubinsztein
Journal: Science Translational Medicine (2010)

Oculopharyngeal muscular dystrophy (OPMD) is caused by a trinucleotide repeat expansion mutation in the coding region of the gene encoding PABPN1 (polyadenylate-binding protein nuclear 1). Mutant PABPN1 with a polyalanine tract expansion forms aggregates within the nuclei of skeletal muscle fibers. There is currently no effective treatment. We have developed cell and mouse models of OPMD and have identified the aggregation of mutant PABPN1 and apoptosis as therapeutic targets. Here, we show that transglutaminase activity is increased in muscle from OPMD model mice. Elevated transglutaminase 2 expression enhances, whereas TG2 knockdown suppresses, the toxicity and aggregation of mutant PABPN1 in cells. Cystamine protects against the toxicity of mutant PABPN1 and exerts its effect via the inhibition of transglutaminase 2, as cystamine treatment is unable to further reduce the protective effect of transglutaminase 2 knockdown on mutant PABPN1 toxicity in cells. Cystamine also reduces the aggregation and toxicity of mutant PABPN1 in human cells. In a mouse model of OPMD, cystamine treatment reduced the elevated transglutaminase activity, attenuated muscle weakness, reduced aggregate load, and decreased apoptotic markers in muscle. Therefore, inhibitors of transglutaminase 2 should be considered as possible therapeutics for OPMD.
Preload maintenance protects against a depression in left ventricular systolic, but not diastolic, function immediately after ultraendurance exercise * Commentary
Authors: M Y Hassan, T D Noakes, P Berlyn, R Shave, K George
Journal: British Journal of Sports Medicine (2006)

Objective: To investigate indices of left ventricular (LV) function before and after a 224 km Ironman triathlon, specifically in the presence of unaltered haemodynamic loading. Method: LV loading and function were assessed before and after the race using M mode and Doppler echocardiography in 39 (mean (SD) age 33 (8) years, body mass 77.6 (8.6) kg; 36 male) triathletes in the Trendelenburg position. Specifically left ventricular end diastolic volume (LVEDV) was assessed to estimate preload, and systolic blood pressure to estimate afterload as well as heart rate (HR). Systolic functional indices included ejection fraction (EF) and the end systolic pressure/volume ratio (ESPV), and diastolic functional indices included peak mitral flow velocity in early (E) and atrial (A) filling as well as the ratio E/A. Data obtained before and after the race were compared by t tests, and delta LV functional indices were correlated with delta heart rate. Results: Preload (LVEDV: 143 (34) ml before v 147 (34) ml after) and afterload (systolic blood pressure 121 (13) v 115 (20) mm Hg) were not significantly altered after the race (p&gt;0.05), nor were EF (61 (8)% v 58 (10)%) and ESPV (2.4 (0.9) v 2.1 (0.8) mm Hg/cm 3 ). The diastolic filling ratio E/A was significantly reduced after the race (1.73 (0.25) v 1.54 (0.23); p&lt;0.05) due primarily to a reduction in E. HR was significantly higher after the race (57 (9) v 75 (8) beats/min; p&lt;0.05), but delta HR was not related to delta E/A (p&gt;0.05). Conclusion: When preload and afterload are unaltered after the race, because of the adoption of a unique assessment posture, LV systolic function is not depressed. A depression in LV diastolic function persists which is not explained by an increase in heart rate after the race.
Additional 7000 UK women may have faulty PIP implants
Authors: A. O'Dowd
Journal: BMJ (2012)

The scale of the scandal over breast implants made by the discredited French manufacturer Poly Implant Prosthese (PIP) is larger than was first thought.

The government has confirmed that an additional 7000 women in the United Kingdom could be affected by the scandal, which emerged last year when it became known that the now bankrupt French company had used non-medical grade silicone.

The NHS in England has advised women with the implants not to have them removed automatically but to seek clinical advice and, when advised to do so, have them removed. In cases where the devices were originally implanted by the NHS (often after mastectomy for cancer) women are also entitled to have them replaced by the NHS.

The …
Influence of exercise on oxidant stress products in elite Indian cyclists
Authors: Chhavi Lekhi, Pradeep H Gupta, Balwant Singh
Journal: British Journal of Sports Medicine (2007)

The influence of exercise on free-radical chemistry is not well understood. It is yet to be confirmed whether an adequate biochemical defence system exists in the human body to provide protection from oxy-centred radicals generated by exercise. Fifty trained elite cyclists undertaking exhaustive endurance training were compared with a control group of 50 sedentary workers. Serum malondialdehyde (MDA), uric acid, superoxide dismutase (SOD), catalase, vitamin E, vitamin C and susceptibility to oxidative stress were assessed. Exhaustive exercise resulted in significantly (p&lt;0.05) higher concentrations of serum MDA, vitamin E and vitamin C, significantly (p&lt;0.001) higher SOD activity, but less significantly (p&lt;0.01) higher concentrations of uric acid and significantly (p&lt;0.05) lower catalase activity in elite cyclists than in the controls. Alterations in the activities of erythrocyte scavenger enzymes (SOD) and higher level of non-enzymatic defences in trained subjects may not be sufficient to counteract the increase in reactive oxygen species produced by endurance training.