全文获取类型
收费全文 | 590篇 |
免费 | 34篇 |
国内免费 | 9篇 |
专业分类
耳鼻咽喉 | 14篇 |
儿科学 | 56篇 |
妇产科学 | 7篇 |
基础医学 | 61篇 |
口腔科学 | 15篇 |
临床医学 | 40篇 |
内科学 | 129篇 |
皮肤病学 | 15篇 |
神经病学 | 29篇 |
特种医学 | 44篇 |
外科学 | 104篇 |
综合类 | 11篇 |
预防医学 | 21篇 |
眼科学 | 14篇 |
药学 | 39篇 |
肿瘤学 | 34篇 |
出版年
2023年 | 4篇 |
2021年 | 7篇 |
2019年 | 2篇 |
2018年 | 8篇 |
2017年 | 8篇 |
2016年 | 11篇 |
2015年 | 5篇 |
2014年 | 18篇 |
2013年 | 26篇 |
2012年 | 25篇 |
2011年 | 16篇 |
2010年 | 24篇 |
2009年 | 33篇 |
2008年 | 23篇 |
2007年 | 26篇 |
2006年 | 25篇 |
2005年 | 29篇 |
2004年 | 22篇 |
2003年 | 17篇 |
2002年 | 34篇 |
2001年 | 27篇 |
2000年 | 26篇 |
1999年 | 23篇 |
1998年 | 16篇 |
1997年 | 14篇 |
1996年 | 15篇 |
1995年 | 12篇 |
1994年 | 7篇 |
1993年 | 9篇 |
1992年 | 10篇 |
1991年 | 5篇 |
1990年 | 12篇 |
1989年 | 14篇 |
1988年 | 10篇 |
1987年 | 13篇 |
1986年 | 14篇 |
1985年 | 9篇 |
1984年 | 7篇 |
1983年 | 2篇 |
1982年 | 2篇 |
1981年 | 2篇 |
1980年 | 4篇 |
1979年 | 4篇 |
1978年 | 3篇 |
1976年 | 2篇 |
1973年 | 2篇 |
1970年 | 1篇 |
1969年 | 1篇 |
1967年 | 1篇 |
1931年 | 1篇 |
排序方式: 共有633条查询结果,搜索用时 0 毫秒
61.
Rives S Pahl HL Florensa L Bellosillo B Neusuess A Estella J Debatin KM Kohne E Schwarz K Cario H 《Haematologica》2007,92(5):674-677
Dominant mutations in the erythropoietin receptor (EPOR) gene account for only about 15% of cases of primary congenital erythrocytosis. To search for molecular alterations in patients with this disorder. Sixteen patients with Epo <10 mU/mL were studied, 3 were related. Analyses included EPOR and JAK2 gene sequencing, quantitative PRV-1 RT-PCR, and erythroid colony assays. A novel sporadic EPOR 1453G->A (Trp439Stop) mutation was detected. All familial cases, varied in phenotype, presented the EPOR 1414C->G (Tyr426Stop) mutation. JAK2 mutations are not involved in the pathogenesis of primary congenital erythrocytosis. 相似文献
62.
Iyengar SK Abboud HE Goddard KA Saad MF Adler SG Arar NH Bowden DW Duggirala R Elston RC Hanson RL Ipp E Kao WH Kimmel PL Klag MJ Knowler WC Meoni LA Nelson RG Nicholas SB Pahl MV Parekh RS Quade SR Rich SS Rotter JI Scavini M Schelling JR Sedor JR Sehgal AR Shah VO Smith MW Taylor KD Winkler CA Zager PG Freedman BI;Family Investigation of Nephropathy Diabetes Research Group 《Diabetes》2007,56(6):1577-1585
The Family Investigation of Nephropathy and Diabetes (FIND) was initiated to map genes underlying susceptibility to diabetic nephropathy. A total of 11 centers participated under a single collection protocol to recruit large numbers of diabetic sibling pairs concordant and discordant for diabetic nephropathy. We report the findings from the first-phase genetic analyses in 1,227 participants from 378 pedigrees of European-American, African-American, Mexican-American, and American Indian descent recruited from eight centers. Model-free linkage analyses, using a dichotomous definition for diabetic nephropathy in 397 sibling pairs, as well as the quantitative trait urinary albumin-to-creatinine ratio (ACR), were performed using the Haseman-Elston linkage test on 404 microsatellite markers. The strongest evidence of linkage to the diabetic nephropathy trait was on chromosomes 7q21.3, 10p15.3, 14q23.1, and 18q22.3. In ACR (883 diabetic sibling pairs), the strongest linkage signals were on chromosomes 2q14.1, 7q21.1, and 15q26.3. These results confirm regions of linkage to diabetic nephropathy on chromosomes 7q, 10p, and 18q from prior reports, making it important that genes underlying these peaks be evaluated for their contribution to nephropathy susceptibility. Large family collections consisting of multiple members with diabetes and advanced nephropathy are likely to accelerate the identification of genes causing diabetic nephropathy, a life-threatening complication of diabetes. 相似文献
63.
Schelling JR Abboud HE Nicholas SB Pahl MV Sedor JR Adler SG Arar NH Bowden DW Elston RC Freedman BI Goddard KA Guo X Hanson RL Ipp E Iyengar SK Jun G Kao WH Kasinath BS Kimmel PL Klag MJ Knowler WC Nelson RG Parekh RS Quade SR Rich SS Saad MF Scavini M Smith MW Taylor K Winkler CA Zager PG Shah VO;Family Investigation of Nephropathy Diabetes Research Group 《Diabetes》2008,57(1):235-243
64.
65.
Matthew C. Pahl Struan F. A. Grant Rudolph L. Leibel George Stratigopoulos 《Obesity reviews》2023,24(5):e13558
Genome-wide association studies have revealed a plethora of genetic variants that correlate with polygenic conditions. However, causal molecular mechanisms have proven challenging to fully define. Without such information, the associations are not physiologically useful or clinically actionable. By reviewing studies of the FTO locus in the genetic etiology of obesity, we wish to highlight advances in the field fueled by the evolution of technical and analytic strategies in assessing the molecular bases for genetic associations. Particular attention is drawn to extrapolating experimental findings from animal models and cell types to humans, as well as technical aspects used to identify long-range DNA interactions and their biological relevance with regard to the associated trait. A unifying model is proposed by which independent obesogenic pathways regulated by multiple FTO variants and genes are integrated at the primary cilium, a cellular antenna where signaling molecules that control energy balance convene. 相似文献
66.
Protein kinetics: structures of intermediates and reaction mechanism from time-resolved x-ray data 下载免费PDF全文
Schmidt M Pahl R Srajer V Anderson S Ren Z Ihee H Rajagopal S Moffat K 《Proceedings of the National Academy of Sciences of the United States of America》2004,101(14):4799-4804
We determine the number of authentic reaction intermediates in the later stages of the photocycle of photoactive yellow protein at room temperature, their atomic structures, and a consistent set of chemical kinetic mechanisms, by analysis of a set of time-dependent difference electron density maps spanning the time range from 5 micros to 100 ms. The successful fit of exponentials to right singular vectors derived from a singular value decomposition of the difference maps demonstrates that a chemical kinetic mechanism holds and that structurally distinct intermediates exist. We identify two time-independent difference maps, from which we refine the structures of the corresponding intermediates. We thus demonstrate how structures associated with intermediate states can be extracted from the experimental, time-dependent crystallographic data. Stoichiometric and structural constraints allow the exclusion of one kinetic mechanism proposed for the photocycle but retain other plausible candidate kinetic mechanisms. 相似文献
67.
LINKED ARTICLES
This is a rebuttal by the authors (Green et al., pp. 1523–1536 of this issue) to a commentary by Parrott, pp. 1518–1520 of this issue. To view the article by Green et al. visit http://dx.doi.org/10.1111/j.1476-5381.2011.01819.x. To view the commentary by Parrott visit http://dx.doi.org/10.1111/j.1476-5381.2012.01941.xWe thank Prof Parrott (Parrott 2012) for his interest in our review (Green et al., 2012). Our main aim was to discuss the problems that arise in interpreting data obtained when administering 3,4-methylenedioxymethamphetamine (MDMA) to experimental animals in terms of possible clinical consequences and vice versa, not to disparage the evidence that Ecstasy is neurotoxic in humans. We presented evidence that the pharmacokinetics of MDMA in rats and primates are fundamentally different from the pharmacokinetics of the drug in humans. Because the plasma half-life of the drug in rats is 10 times shorter than in humans, the acute adverse events in rats may be minimal compared with those in humans, and this includes body temperature and endocrine changes. Conversely, the rapid metabolism of the drug in rats to form neurotoxic metabolites may result in more severe long-term effects in that species than those that may occur in humans.We had no intention of suggesting that there was no evidence for some recreational Ecstasy users presenting with evidence of 5-HT neurotoxicity, albeit it is clear from the literature that some of this evidence remains open to several interpretations. What we did claim was that pure 3,4-methylenedioxymethamphetamine (MDMA) taken alone was unlikely to cause 5-HT neurotoxicity in man. Here we must emphasize the term MDMA, as it is crucial to our discussion. Parrott, in contrast, uses the term ‘Ecstasy/MDMA’ several times when discussing neurotoxicity (Parrott, 2012). This association of Ecstasy with MDMA is one of the major problems of translation that we addressed. The Ecstasy tablet that most recreational users buy and ingest is not necessarily MDMA. Indeed, in many cases, it clearly is not. The tablet is often adulterated with other compounds, and one investigation identified no less than 14 substances other than MDMA in Ecstasy tablets, which users nevertheless presumably believed contained only MDMA (Vogels et al., 2009). Many of the adulterants identified were also psychoactive and included compounds structurally related to MDMA such as 3,4-methylenedioxyethylamphetamine and 2-methylamino-1-(3,4-methylenedioxyphenyl)butane, which have poorly researched pharmacology and toxicology. In addition, most recreational users of Ecstasy also knowingly ingest other psychoactive compounds such as alcohol and cannabis. Alcohol, for example, alters the pharmacokinetics of MDMA (Hamida et al., 2009). While, as Parrott states, clinical studies have attempted to allow for these confounding factors in any examination of the physical and psychological effects of MDMA in humans, such analysis is always limited not only by the other compounds the evaluators are unaware of, but also drugs perhaps not even considered to be relevant by the user and therefore not disclosed. It is unlikely that coffee and ‘energy drinks’ such as Red Bull are always disclosed, but there is now good preclinical evidence that caffeine, which incidentally has also been found as an adulterant in Ecstasy tablets, enhances both the hyperthermia and neurotoxicity induced in rats by MDMA (Camarasa et al., 2006; Vanattou-Saïfoudine et al., 2010). And this brings us to the crux of the problem and weakness of all the clinical data cited by Parrott (2012). A basic tenet of all good clinical pharmacology is accurate knowledge of the doses administered, frequency of administration and any confounding factors such as other drugs being consumed. None of these data are available with any precision in the clinical studies quoted. Of course one has some indication as to dose (although as Vogels et al., (2009) reported, the dose contained in illicitly obtained tablets is highly variable) and frequency of drug ingestion, but this information is generally obtained from the user whose recall is likely to be limited or who decides to obfuscate. Crucially, the information can never take into account the problem of drug tablet adulteration. The fact that hair or urine samples detect MDMA merely shows the user has consumed the drug, not how much or when or what other drugs were taken concurrently.We never suggested that MDMA exposure was not going to be associated with physical or psychological change. However such changes are not necessarily associated with long-term neurotoxic damage. We have shown that long-term behavioural effects can occur in rats both with and without 5-HT neurotoxicity (Fone et al., 2002; Bull et al., 2003; Rodsiri et al., 2011). It is interesting that Parrott approvingly quotes the Verheyden et al. (2003) study in support of his contention that neurotoxic damage has occurred. Because this study noted that the majority of persons reporting chronic psychiatric problems reported ‘improved mental health’ after quitting the drug, this surely allows us to conclude that the drug had produced subacute changes rather than any that could be associated with long-term neurotoxic damage.A further limitation to any clinical study is that one cannot perform prospective studies with the aim of investigating whether long-term neurotoxic events occur, so weaknesses arise with regard to any psychological abnormalities observed. Are persons with high risk of psychiatric problems more likely to misuse the drug, or does the drug induce changes in high-risk individuals? If high risk also happened to be associated with 5-HT abnormalities in the brains, then any conclusion that MDMA has induced neurotoxicity is spurious.We most certainly did not suggest that MDMA acted as a neurotoxin only under conditions of severe hyperthermia as is stated by Parrot in his sixth paragraph (Parrott, 2012). We have been involved in many studies on the effects of MDMA on body temperature in rats (see Docherty and Green, 2010) including one that demonstrated that neurotoxicity can occur in the absence of hyperthermia (O''Shea et al., 1998) and another that showed that hyperthermia worsens neurotoxic damage (Green et al., 2004). In our review, what we did propose was that because of the very different pharmacokinetics of MDMA in rats and humans, it is probable that humans would suffer serious or fatal adverse events at plasma levels below those likely to be required to induce 5-HT neurotoxicity.We emphasize again that we are not denying the clinical observations reviewed by Parrott, but conclude that the effects seen cannot be ascribed solely to the effects of MDMA, as he seems to be proposing. We also repeat our contention that MDMA in combination with other drugs may induce neurotoxicity and this could be said to be supported by the clinical studies quoted by Parrott.Finally, we can but assume that Parrott concurs with our principal conclusion that ‘the doses currently being used to investigate the possible therapeutic benefits of MDMA are unlikely to produce any severe acute or importantly any long-term neurotoxic damage in the human brain’ as he used such a dose (100 mg or approximately 1.4 mg·kg −1) in one of his recent studies in human volunteers (Parrott et al., 2011). 相似文献68.
William E. Gillies FRACS FRACO FRCS Anne MV Brooks MD PhD FRACS FRACO FRACP 《Clinical & experimental ophthalmology》1996,24(3):169-187
Background: We have investigated the vascular perfusion of a wide variety of conditions of the anterior segment using fluorescein angiography.
Methods: The conditions were classified and findings reported according to the system set out below. Patients underwent full ocular examination. Fluorescein angiography of the anterior segment was carried out when indicated to investigate iris atrophy and neovascularisation. Specular microscopy of the corneal endothelium was used to detect changes in this tissue.
Results: The hypoperfusion was variable in degree and accompanied by varying degrees of iris hypoplasia and atrophy with neovascularisation. The degree of neovascularisation depended upon its rapidity of development, the pre-existing state of vascular perfusion and the underlying pathological condition.
Conclusions: Hypoperfusion with resultant ischaemia and neovascularisation is common in conditions of the anterior segment. An understanding of the changes is valuable in treating many conditions affecting the anterior segment. The changes observed may also occur elsewhere in the physical system and may be a significant part of the ageing process, either as scattered, disparate processes or as part of a general disease process. 相似文献
Methods: The conditions were classified and findings reported according to the system set out below. Patients underwent full ocular examination. Fluorescein angiography of the anterior segment was carried out when indicated to investigate iris atrophy and neovascularisation. Specular microscopy of the corneal endothelium was used to detect changes in this tissue.
Results: The hypoperfusion was variable in degree and accompanied by varying degrees of iris hypoplasia and atrophy with neovascularisation. The degree of neovascularisation depended upon its rapidity of development, the pre-existing state of vascular perfusion and the underlying pathological condition.
Conclusions: Hypoperfusion with resultant ischaemia and neovascularisation is common in conditions of the anterior segment. An understanding of the changes is valuable in treating many conditions affecting the anterior segment. The changes observed may also occur elsewhere in the physical system and may be a significant part of the ageing process, either as scattered, disparate processes or as part of a general disease process. 相似文献
69.
Intestinal absorption and biliary secretion of cholesterol in rats with nephrotic syndrome 总被引:3,自引:0,他引:3
Background: Nephrotic syndrome (NS) results in
hypercholesterolemia which is attributed to increased production and
decreased removal of cholesterol-rich lipoproteins. Adjustments in
intestinal absorption are reportedly involved in cholesterol homeostatis.
We therefore, studied the intestinal absorption and biliary excretion of
cholesterol in NS. Methods: We studied intestinal
absorption (by in vivo perfusion and in
vitro everted sac incubation techniques) and biliary secretion
(by common bile duct cannulation) of cholesterol in rats with
puromycin-induced NS. The results were compared with those obtained from
pair-fed control (PF) animals, those given free access to food (NL) or
those fed a hypercholerolemic diet (H-chol group). Micellar solutions of
Krebs' phosphate buffer containing trace amounts of
[14C]inulin and
[3H]cholesterol, as well as different concentrations
of unlabeled cholesterol, were used for absorption studies.
Results: The NS and H-chol groups showed severe and
comparable hypercholesterolemia. No significant difference was found in the
rate of biliary cholesterol secretion among the study groups. Likewise, the
rates of in vivo and in vitro
cholesterol absorptions in the NS and H-chol groups were comparable with
one another and similar to those found in the NL and PF groups. The rate of
in vitro cholesterol absorption was directly
proportional to its concentration in the incubation media at low
concentrations. However, the absorption rate showed a pattern consistent
with saturable transport at high cholesterol concentrations in all groups.
Conclusions: We conclude that intestinal absorption
and biliary secretion of cholesterol are not appreciably influenced by
either nephrotic or diet-induced hypercholesterolemia in rats. The data
further suggest that cholesterol absorption may be a saturable process. 相似文献