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121.
Phosphoinositide 3-kinase(p110alpha) plays a critical role for the induction of physiological, but not pathological, cardiac hypertrophy 总被引:1,自引:0,他引:1
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McMullen JR Shioi T Zhang L Tarnavski O Sherwood MC Kang PM Izumo S 《Proceedings of the National Academy of Sciences of the United States of America》2003,100(21):12355-12360
An unresolved question in cardiac biology is whether distinct signaling pathways are responsible for the development of pathological and physiological cardiac hypertrophy in the adult. Physiological hypertrophy is characterized by a normal organization of cardiac structure and normal or enhanced cardiac function, whereas pathological hypertrophy is associated with an altered pattern of cardiac gene expression, fibrosis, cardiac dysfunction, and increased morbidity and mortality. The elucidation of signaling cascades that play distinct roles in these two forms of hypertrophy will be critical for the development of more effective strategies to treat heart failure. We examined the role of the p110alpha isoform of phosphoinositide 3-kinase (PI3K) for the induction of pathological hypertrophy (pressure overload-induced) and physiological hypertrophy (exercise-induced) by using transgenic mice expressing a dominant negative (dn) PI3K(p110alpha) mutant specifically in the heart. dnPI3K transgenic mice displayed significant hypertrophy in response to pressure overload but not exercise training. dnPI3K transgenic mice also showed significant dilation and cardiac dysfunction in response to pressure overload. Thus, PI3K(p110alpha) appears to play a critical role for the induction of physiological cardiac growth but not pathological growth. PI3K(p110alpha) also appears essential for maintaining contractile function in response to pathological stimuli. 相似文献
122.
Julian GE Fewell JH Gadau J Johnson RA Larrabee D 《Proceedings of the National Academy of Sciences of the United States of America》2002,99(12):8157-8160
The question of how reproductives and sterile workers differentiate within eusocial groups has long been a core issue in sociobiology because it requires the loss of individual direct fitness in favor of indirect or group-level fitness gains. The evolution of social behavior requires that differentiation between workers and female reproductives be environmentally determined, because genetically determined sterility would be quickly eliminated. Nevertheless, we report clear evidence of genetic caste determination in populations of two seed harvester ant species common to the southwestern USA, Pogonomyrmex rugosus and Pogonomyrmex barbatus. The genetic differentiation between workers and queens is found only in areas of sympatry of the two species, and thus appears to arisen from hybridization. Our data suggest that this hybridization has had a profound historical effect on the caste determination systems and mating patterns of each of these species. 相似文献
123.
Savio D. Rodrigues Mansour Karimi Lennert Impens Els Van Lerberge Griet Coussens Stijn Aesaert Debbie Rombaut Dominique Holtappels Heba M. M. Ibrahim Marc Van Montagu Jeroen Wagemans Thomas B. Jacobs Barbara De Coninck Laurens Pauwels 《Proceedings of the National Academy of Sciences of the United States of America》2021,118(2)
124.
Drummond MF Becker DL Hux M Chancellor JV Duprat-Lomon I Kubin R Sagnier PP 《Chest》2003,124(2):526-535
STUDY OBJECTIVE: To evaluate costs, clinical consequences, and cost-effectiveness from a German and French health-care system perspective of sequential i.v./po moxifloxacin monotherapy compared to co-amoxiclav with or without clarithromycin (AMC +/- CLA) in patients with community-acquired pneumonia (CAP) who required parenteral treatment. METHODS: Costs and consequences over 21 days were evaluated based on clinical cure rates 5 to 7 days after treatment and health resource use reported for the TARGET multinational, prospective, randomized, open-label trial. This trial compared sequential i.v./po monotherapy with moxifloxacin (400 mg qd) to i.v./po co-amoxiclav (1.2 g i.v./625 mg po tid) with or without clarithromycin (500 mg bid) for 7 to 14 days in hospitalized patients with CAP. Since no country-by-treatment interaction was found in spite of some country differences for length of hospital stays, resource data (antimicrobial treatment, hospitalization, and out-of-hospital care) from all centers were pooled and valued using German and French unit prices to estimate CAP-related cost to the German Sickness Funds and French public health-care sector, respectively. RESULTS: Compared to AMC +/- CLA, treatment with moxifloxacin resulted in 5.3% more patients achieving clinical cure 5 to 7 days after therapy (95% confidence interval [CI], 1.2 to 11.8%), increased speed of response (1 day sooner for median time to first return to apyrexia, p = 0.008), and a reduction in hospital stay by 0.81 days (95% CI, - 0.01 to 1.63) within the 21-day time frame. Treatment with moxifloxacin resulted in savings of 266 euro and 381 euro for Germany and France respectively, primarily due to the shorter length of hospital stay. Cost-effectiveness acceptability curves show moxifloxacin has a > or = 95% chance of being cost saving from French and German health-care perspectives, and higher probability of being cost-effective at acceptability thresholds up to 2,000 euro per additional patient cured. CONCLUSION: i.v./po monotherapy with moxifloxacin shows clinical benefits including increased speed of response and is cost-effective compared to i.v./po AMC +/- CLA in the treatment of CAP. 相似文献
125.
Loss of EBNA1-specific memory CD4+ and CD8+ T cells in HIV-infected patients progressing to AIDS-related non-Hodgkin lymphoma
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We previously observed a loss of Epstein-Barr virus (EBV)-specific CD8+ T cells in subjects progressing to EBV-related non-Hodgkin lymphoma (NHL), correlating with loss of CD4+ T cells. The aim of the present study was to determine the role of EBV-specific CD4+ T cells in the development of NHL during chronic HIV infection. To this end, CD4+ and CD8+ memory T cells, capable of both proliferation and subsequent interferon gamma (IFNgamma) production, directed against a latent (Epstein-Barr virus nuclear antigen 1 [EBNA1]) and a lytic (BamH fragment Z left frame 1 [BZLF1]) EBV antigen were studied longitudinally in 9 progressors to NHL, 4 progressors to non-EBV-related AIDS, and 4 slow progressors to AIDS. In all 3 groups we observed a decline of EBV-specific memory CD4+ and CD8+ T-cell responses during HIV infection. However, whereas latent antigen EBNA1-specific CD4+ T cells were lost well before diagnosis in all subjects who developed an AIDS-related NHL (and EBNA1-specific CD8+ T cells were significantly lower compared with the other groups), these cells were better preserved in progressors to non-EBV-related disease and slow progressors. Loss of EBNA1-specific T-cell immunity thus might be important for progression to NHL. Interestingly, BZLF1-specific T cells were not lost in all progressors to NHL, suggesting a different function of these cells in the surveillance of EBV-infected B cells. 相似文献
126.
South Africa Every Death Counts Writing Group Bradshaw D Chopra M Kerber K Lawn JE Bamford L Moodley J Pattinson R Patrick M Stephen C Velaphi S 《Lancet》2008,371(9620):1294-1304
South Africa is one of the few developing countries with a national confidential inquiry into maternal deaths. 164 health facilities obtain audit data for stillbirths and neonatal deaths, and a new audit network does so for child deaths. Three separate reports have been published, providing valuable information about avoidable causes of death for mothers, babies, and children. These reports make health-system recommendations, many of which overlap and are intertwined with the scarcity of progress in addressing HIV/AIDS. The leaders of these three reports have united to prioritise actions to save the lives of South Africa's mothers, babies, and children. The country is off-track for the health-related Millennium Development Goals. Mortality in children younger than 5 years has increased, whereas maternal and neonatal mortality remain constant. This situation indicates the challenge of strengthening the health system because of high inequity and HIV/AIDS. Coverage of services is fairly high, but addressing the gaps in quality and equity is essential to increasing the number of lives saved. Consistent leadership and accountability to address crosscutting health system and equity issues, and to prevent mother-to-child transmission of HIV, would save tens of thousands of lives every year. Audit is powerful, but only if the data lead to action. 相似文献
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129.
Charlotte Bradbury Kate Fletcher Yongzhong Sun Carl Heneghan Chris Gardiner Andrea Roalfe Pollyanna Hardy Debbie McCahon Gail Heritage Helen Shackleford FD Richard Hobbs David Fitzmaurice 《British journal of haematology》2020,188(6):962-975
Venous thromboembolism (VTE) is prevalent and impactful, with a risk of death, morbidity and recurrence. Post-thrombotic syndrome (PTS) is a common consequence and associated with impaired quality of life (QoL). The ExACT study was a non-blinded, prospective, multicentred randomised controlled trial comparing extended versus limited duration anticoagulation following a first unprovoked VTE (proximal deep vein thrombosis or pulmonary embolism). Adults were eligible if they had completed ≥3 months anticoagulation (remaining anticoagulated). The primary outcome was time to first recurrent VTE from randomisation. The secondary outcomes included PTS severity, bleeding, QoL and D-dimers. Two-hundred and eighty-one patients were recruited, randomised and followed up for 24 months (mean age 63, male:female 2:1). There was a significant reduction in recurrent VTE for patients receiving extended anticoagulation [2·75 vs. 13·54 events/100 patient years, adjusted hazard ratio (aHR) 0·20 (95% confidence interval (CI): 0·09 to 0·46, P < 0·001)] with a non-significant increase in major bleeding [3·54 vs. 1·18 events/100 patient years, aHR 2·99 (95% CI: 0·81–11·05, P = 0·10)]. Outcomes of PTS and QoL were no different between groups. D-dimer results (on anticoagulation) did not predict VTE recurrence. In conclusion, extended anticoagulation reduced VTE recurrence but did not reduce PTS or improve QoL and was associated with a non-significant increase in bleeding. Results also suggest very limited clinical utility of D-dimer testing on anticoagulated patients. 相似文献
130.