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Glucagon‐like peptide‐1 receptor (GLP‐1R) agonists such as exendin‐4 (Ex‐4) affect eating and metabolism and are potential candidates for treating obesity and type II diabetes. In the present study, we tested whether vagal afferents mediate the eating‐inhibitory and avoidance‐inducing effects of Ex‐4. Subdiaphragmatic vagal deafferentation (SDA) blunted the short‐term (< 1 h) but not long‐term eating‐inhibitory effect of i.p.‐infused Ex‐4 (0.1 μg/kg) in rats. A dose of 1 μg/kg Ex‐4 reduced 0.5, 1, 2 and 4 h cumulative food intake in SDA and sham‐operated rats to a similar extent. Paradoxically, SDA but not sham rats developed a conditioned flavour avoidance (CFA) after i.p. Ex‐4 (0.1 μg/kg). SDA completely blunted the induction of c‐Fos expression by Ex‐4 in the hypothalamic paraventricular nucleus. Ex‐4, however, increased the number of c‐Fos expressing cells, independent of intact vagal afferents, in the nucleus accumbens and in the central nucleus of the amygdala, the lateral external parabrachial nucleus, the caudal ventrolateral medulla and the dorsal vagal complex. These data suggest that intact vagal afferents are only necessary for the full expression of the early satiating effect of Ex‐4 but not for later eating‐inhibitory actions, when circulating Ex‐4 might reach the brain via the circulation. Our data also dissociate the satiating and avoidance‐inducing effects of the low Ex‐4 dose tested under our conditions and suggest that vagal afferent signalling may protect against the development of CFA. Taken together, these findings reveal a complex role of vagal afferents in mediating the effects of GLP‐1R activation on ingestive behaviour.  相似文献   
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Background Primary cutaneous B‐cell lymphomas (PCBCL) are subdivided into the aggressive form, primary cutaneous diffuse large B‐cell lymphoma, leg type (PCLBCL, LT) and two subtypes of indolent behaviour (primary cutaneous follicle centre lymphoma and primary cutaneous marginal zone B‐cell lymphoma). The difference in clinical behaviour can be explained by the tumour cell itself, or the lymphoma microenvironment including the antitumour immune response. Objectives To investigate the presence of regulatory T cells (Treg), CD4+CD25+FOXP3+, in the microenvironment of PCBCL in correlation with clinical outcome. Methods Tumour specimens of 55 consecutive cases of PCBCL were blinded and analysed for FOXP3, CD4 and CD25 expression by immunohistochemistry. Confocal images were taken with a Leica SP5. Statistical analyses were performed to determine significance. The test was considered significant when P < 0·05. Results The CD4 and FOXP3 expression as well as the CD4/FOXP3 ratio were significantly increased in PCBCL of indolent behaviour in contrast to PCLBCL, LT (P = 0·0002 for CD4, P < 0·0001 for FOXP3 and P = 0·0345 for FOXP3/CD4 ratio). CD25 expression did not differ in the three groups (P = 0·9414). Within the group of patients with PCLBCL, LT we identified a subgroup with FOXP3+ tumour cells as demonstrated by CD20/FOXP3 double stainings. Patients with FOXP3+ PCLBCL, LT tumour cells showed a better prognosis on Kaplan–Meier analysis. Conclusion High numbers of Treg in the lymphoma microenvironment correlate with a better prognosis in PCBCL. In PCLBCL, LT the presence of FOXP3+ tumour cells is beneficial for prognosis suggesting that FOXP3 expression of PCLBCL, LT tumour cells might serve as a tumour suppressor.  相似文献   
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Peripheral GLP-1 is produced by post-translational processing of pro-glucagon in enteroendocrine L-cells and is released in response to luminal nutrient (primarily carbohydrate and fat) stimulation. GLP-1 is well known for its potent insulinotropic and gluco-regulatory effects. GLP-1 receptors (GLP-1R) are expressed in the periphery and in several brain areas that are implicated in the control of eating. Both central and peripheral administration of GLP-1 have been shown to reduce food intake. Unresolved, however, is whether these effects reflect functions of endogenous GLP-1. Data collected in our laboratory indicate that in chow-fed rats: 1) Remotely controlled, intra-meal intravenous (IV) or intraperitoneal (IP) GLP-1 infusions selectively reduce meal size; 2) hindbrain GLP-1R activation is involved in the eating-inhibitory effect of IV infused GLP-1, whereas intact abdominal vagal afferents are necessary for the eating-inhibitory effect of IP, but not IV, infused GLP-1; 3) GLP-1 degradation in the liver prevents a systemic increase in endogenous GLP-1 during normal chow meals in rats; and 4) peripheral or hindbrain GLP-1R antagonism by exendin-9 does not affect spontaneous eating. Also, although our data indicate that peripheral GLP-1 can act in two different sites to inhibit eating, they argue against a role of systemic increases in endogenous GLP-1 in satiation in chow-fed rats. Therefore, further studies should examine whether a local paracrine action of GLP-1 in the intestine or and endocrine action in the hepatic-portal area is physiologically relevant for satiation.  相似文献   
86.
Few standardised data are available on mortality rates in patients with Clostridium difficile infection (CDI). The literature often reports 'attributable' mortality or cannot be universally applied. We aimed to investigate the pattern and trends in all-cause mortality in a large unselected cohort of patients affected by CDI. This was done by means of a retrospective cohort study between 2002 and 2008 of all patients with positive stool toxin tests indicating CDI in one National Health Service (NHS) Trust, comprising three general hospitals and seven community hospitals. Vital status of the patients was determined from two sources. In total, 2571 patients with a first episode of CDI were identified (1638 females; median age 82.1 years). Cumulative mortality at 7 days, 14 days, 30 days and 1 year was 13.4%, 20.8%, 32.5% and 58.7%, respectively. There was no significant difference in mortality between sex, year of diagnosis or hospital site. Mortality at 30 days increased incrementally from 3.4% in those aged <40 years to 41% in those >90 years. Mortality rates were significantly higher than reported by previous studies but were remarkably consistent over the time period and between different hospitals within the Trust. Prognosis falls with increasing age, and the age of this cohort may explain the high 30-day absolute mortality. CDI infection is associated with high early mortality. To reduce mortality, new interventions need to be introduced soon after diagnosis. There is a need for standardised outcome data for CDI.  相似文献   
87.
We report a 62-year-old Chinese woman with a 2-year history of lichen planus presenting with extensive violaceous maculopapules and plaques 1 week after taking an oral preparation of Chinese herbs. The patient developed vesiculobullous skin lesions 7 weeks later. Histopathological examination showed subepidermal blisters and adjacent bandlike lymphocytic infiltration. Direct immunofluorescence revealed linear deposits of IgG and C3 along the basement membrane zone. Indirect immunofluorescence showed IgG antibody deposition along the epidermal side of salt-split human skin. Circulating anti-bullous pemphigoid 180 antibodies were detected by ELISA. Lichen planus pemphigoides (LPP) was diagnosed. To our knowledge, this is the first report of LPP associated with oral Chinese herbs.  相似文献   
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Schizophrenia is associated with increased risk for multiple metabolic abnormalities, including altered glucose homeostasis, type-2 diabetes, obesity, and cardiovascular disease. Some of the metabolic alterations can already exist in psychosis-prone subjects prior to the onset of chronic schizophrenic disease and pharmacotherapy, indicating that they may have a developmental origin. In the present study, we tested the hypothesis that metabolic alterations pertinent to schizophrenic disease can be primed by an environmental risk factor associated with the disorder, namely prenatal exposure to immune challenge. We used a well-established mouse model of prenatal immune challenge induced by maternal gestational treatment with poly(I:C) (=“polyriboinosinic-polyribocytidilic acid”), an analog of double-stranded RNA that stimulates a cytokine-associated viral-like acute phase response. Metabolic effects were studied using high-resolution computed tomography and fully automated indirect calorimetry system, along with an oral glucose tolerance test and plasma cytokine and corticosterone measurements. We found that prenatal immune activation caused altered glycemic regulation and abnormal ingestive behavior in periadolescence and led to an adult onset of excess visceral and subcutaneous fat deposition. These effects were accompanied by age-dependent changes in peripheral secretion of proinflammatory (interleukin [IL]-6 and tumor necrosis factor [TNF]-α) and T cell–related (IL-2 and interferon [IFN]-γ) cytokines and by increased release of the stress hormone corticosterone in periadolescence. Our findings show that schizophrenia-relevant metabolic and physiological abnormalities can be primed by prenatal viral-like immune activation, but at the same time, our study emphasizes that this environmental insult is unlikely to precipitate the full spectrum of metabolic and immunological changes pertinent to chronic schizophrenic disease.  相似文献   
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