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Eva Rother Bengt F. Belgardt Eva Tsaousidou Brigitte Hampel Ari Waisman Martin G. Myers Jr. Jens C. Brüning 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(44):18132-18137
Rat insulin promoter (RIP)-expressing neurons in the hypothalamus control body weight and energy homeostasis. However, genetic approaches to study the role of these neurons have been limited by the fact that RIP expression is predominantly found in pancreatic β-cells, which impedes selective targeting of neurons. To define the function of hypothalamic RIP-expressing neurons, we set out to acutely and selectively eliminate them via diphtheria toxin-mediated ablation. Therefore, the diphtheria toxin receptor transgene was specifically expressed upon RIP-specific Cre recombination using a RIP-Cre line first described by Herrera (RIPHER-Cre) [Herrera PL (2000) Development 127:2317–2322]. Using proopiomelanocortin–expressing cells located in the arcuate nucleus of the hypothalamus and in the pituitary gland as a model, we established a unique protocol of intracerebroventricular application of diphtheria toxin to efficiently ablate hypothalamic cells with no concomitant effect on pituitary proopiomelanocortin–expressing corticotrophs in the mouse. Using this approach to ablate RIPHER neurons in the brain, but not in the pancreas, resulted in decreased food intake and loss of body weight and fat mass. In addition, ablation of RIPHER neurons caused increased c-Fos immunoreactivity of neurons in the paraventricular nucleus (PVN) of the hypothalamus. Moreover, transsynaptic tracing of RIPHER neurons revealed labeling of neurons located in the PVN and dorsomedial hypothalamic nucleus. Thus, our experiments indicate that RIPHER neurons inhibit anorexigenic neurons in the PVN, revealing a basic orexigenic nature of these cells. 相似文献
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Cervical and ovarian cancers are the most common gynaecological cancers diagnosed during pregnancy. In early-stage cervical cancer during the first and at the beginning of the second trimester, the two main considerations for management of the patient are the tumour size (and stage) and nodal staging. MRI and laparoscopic lymphadenectomy are useful for clinicians planning a potentially conservative approach. The management of patients with locally advanced cervical disease is controversial and should be discussed on a case-by-case basis according to the tumour size, radiological findings, the term of pregnancy, and the patient's wishes. Different histological types of malignant ovarian diseases arise during pregnancy and their management depends on the diagnosis (histological subtypes, tumour differentiation, and nodal status), the tumour stage, and the trimester of the pregnancy. In patients with peritoneal spread or high-risk early-stage disease, neoadjuvant chemotherapy with pregnancy preservation could be appropriate. 相似文献
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Gruol DL Nelson TE Hao C Michael S Vukojevic V Ming Y Terenius L 《Alcoholism, clinical and experimental research》2012,36(3):443-456
Background: Studies at the behavioral and synaptic level show that effects of ethanol on the central nervous system can involve the opioid signaling system. These interactions may alter the function of a common downstream target. In this study, we examined Ca2+ channel function as a potential downstream target of interactions between ethanol and μ or κ opioid receptor signaling. Methods: The studies were carried out in a model system, undifferentiated PC12 cells transfected with μ or κ opioid receptors. The PC12 cells express L‐type Ca2+ channels, which were activated by K+ depolarization. Ca2+ imaging was used to measure relative Ca2+ flux during K+ depolarization and the modulation of Ca2+ flux by opioids and ethanol. Results: Ethanol, μ receptor activation, and κ receptor activation all reduced the amplitude of the Ca2+ signal produced by K+ depolarization. Pretreatment with ethanol or combined treatment with ethanol and μ or κ receptor agonists caused a reduction in the amplitude of the Ca2+ signal that was comparable to or smaller than that observed for the individual drugs alone, indicating an interaction by the drugs at a downstream target (or targets) that limited the modulation of Ca2+ flux through L‐type Ca2+ channels. Conclusions: These studies provide evidence for a cellular mechanism that could play an important role in ethanol regulation of synaptic transmission and behavior through interactions with the opioid signaling. 相似文献
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Lown MT Munyombwe T Harrison W West RM Hall CA Morrell C Jackson BM Sapsford RJ Kilcullen N Pepper CB Batin PD Hall AS Gale CP;Evaluation of Methods Management of Acute Coronary Events 《The American journal of cardiology》2012,109(3):307-313
Risk assessment is central to the management of acute coronary syndromes. Often, however, assessment is not complete until the troponin concentration is available. Using 2 multicenter prospective observational studies (Evaluation of Methods and Management of Acute Coronary Events [EMMACE] 2, test cohort, 1,843 patients; and EMMACE-1, validation cohort, 550 patients) of unselected patients with acute coronary syndromes, a point-of-admission risk stratification tool using frontal QRS-T angle derived from automated measurements and age for the prediction of 30-day and 2-year mortality was evaluated. Two-year mortality was lowest in patients with frontal QRS-T angles <38° and highest in patients with frontal QRS-T angles >104° (44.7% vs 14.8%, p <0.001). Increasing frontal QRS-T angle-age risk (FAAR) scores were associated with increasing 30-day and 2-year mortality (for 2-year mortality, score 0 = 3.7%, score 4 = 57%; p <0.001). The FAAR score was a good discriminator of mortality (C statistics 0.74 [95% confidence interval 0.71 to 0.78] at 30 days and 0.77 [95% confidence interval 0.75 to 0.79] at 2 years), maintained its performance in the EMMACE-1 cohort at 30 days (C statistics 0.76 (95% confidence interval 0.71 to 0.8] at 30 days and 0.79 (95% confidence interval 0.75 to 0.83] at 2 years), in men and women, in ST-segment elevation myocardial infarction and non-ST-segment elevation myocardial infarction, and compared favorably with the Global Registry of Acute Coronary Events (GRACE) score. The integrated discrimination improvement (age to FAAR score at 30 days and at 2 years in EMMACE-1 and EMMACE-2) was p <0.001. In conclusion, the FAAR score is a point-of-admission risk tool that predicts 30-day and 2-year mortality from 2 variables across a spectrum of patients with acute coronary syndromes. It does not require the results of biomarker assays or rely on the subjective interpretation of electrocardiograms. 相似文献