全文获取类型
收费全文 | 422篇 |
免费 | 75篇 |
专业分类
耳鼻咽喉 | 2篇 |
儿科学 | 13篇 |
妇产科学 | 3篇 |
基础医学 | 80篇 |
口腔科学 | 26篇 |
临床医学 | 44篇 |
内科学 | 100篇 |
皮肤病学 | 10篇 |
神经病学 | 10篇 |
特种医学 | 17篇 |
外科学 | 59篇 |
综合类 | 7篇 |
预防医学 | 19篇 |
眼科学 | 13篇 |
药学 | 53篇 |
肿瘤学 | 41篇 |
出版年
2024年 | 1篇 |
2022年 | 3篇 |
2021年 | 5篇 |
2020年 | 3篇 |
2019年 | 7篇 |
2018年 | 6篇 |
2017年 | 6篇 |
2016年 | 9篇 |
2015年 | 3篇 |
2014年 | 8篇 |
2013年 | 13篇 |
2012年 | 16篇 |
2011年 | 17篇 |
2010年 | 13篇 |
2009年 | 12篇 |
2008年 | 18篇 |
2007年 | 15篇 |
2006年 | 23篇 |
2005年 | 24篇 |
2004年 | 25篇 |
2003年 | 25篇 |
2002年 | 22篇 |
2001年 | 18篇 |
2000年 | 18篇 |
1999年 | 18篇 |
1998年 | 13篇 |
1997年 | 16篇 |
1996年 | 15篇 |
1995年 | 6篇 |
1994年 | 6篇 |
1993年 | 21篇 |
1992年 | 23篇 |
1991年 | 6篇 |
1990年 | 2篇 |
1989年 | 5篇 |
1988年 | 3篇 |
1987年 | 4篇 |
1986年 | 7篇 |
1985年 | 4篇 |
1984年 | 5篇 |
1983年 | 7篇 |
1982年 | 4篇 |
1980年 | 2篇 |
1979年 | 7篇 |
1978年 | 7篇 |
1977年 | 1篇 |
1976年 | 2篇 |
1975年 | 2篇 |
1966年 | 1篇 |
排序方式: 共有497条查询结果,搜索用时 15 毫秒
101.
Renal stone disease (nephrolithiasis) affects 3–5% of the population and is often associated with hypercalciuria. Hypercalciuric
nephrolithiasis is a familial disorder in over 35% of patients and may occur as a monogenic disorder that is more likely to
manifest itself in childhood. Studies of these monogenic forms of hypercalciuric nephrolithiasis in humans, e.g. Bartter syndrome,
Dent’s disease, autosomal dominant hypocalcemic hypercalciuria (ADHH), hypercalciuric nephrolithiasis with hypophosphatemia,
and familial hypomagnesemia with hypercalciuria have helped to identify a number of transporters, channels and receptors that
are involved in regulating the renal tubular reabsorption of calcium. Thus, Bartter syndrome, an autosomal disease, is caused
by mutations of the bumetanide-sensitive Na–K–Cl (NKCC2) co-transporter, the renal outer-medullary potassium (ROMK) channel,
the voltage-gated chloride channel, CLC-Kb, the CLC-Kb beta subunit, barttin, or the calcium-sensing receptor (CaSR). Dent’s
disease, an X-linked disorder characterized by low molecular weight proteinuria, hypercalciuria and nephrolithiasis, is due
to mutations of the chloride/proton antiporter 5, CLC-5; ADHH is associated with activating mutations of the CaSR, which is
a G-protein-coupled receptor; hypophosphatemic hypercalciuric nephrolithiasis associated with rickets is due to mutations
in the type 2c sodium–phosphate co-transporter (NPT2c); and familial hypomagnesemia with hypercalciuria is due to mutations
of paracellin-1, which is a member of the claudin family of membrane proteins that form the intercellular tight junction barrier
in a variety of epithelia. These studies have provided valuable insights into the renal tubular pathways that regulate calcium
reabsorption and predispose to hypercalciuria and nephrolithiasis. 相似文献
102.
Parafibromin is a nuclear protein with a functional monopartite nuclear localization signal 总被引:1,自引:0,他引:1
Bradley KJ Bowl MR Williams SE Ahmad BN Partridge CJ Patmanidi AL Kennedy AM Loh NY Thakker RV 《Oncogene》2007,26(8):1213-1221
Parafibromin is a nuclear protein with a tumour suppressor role in the development of non-hereditary and hereditary parathyroid carcinomas, and the hyperparathyroidism-jaw tumour (HPT-JT) syndrome, which is associated with renal and uterine tumours. Nuclear localization signal(s), (NLS(s)), of the 61 kDa parafibromin remain to be defined. Utilization of computer-prediction programmes, identified five NLSs (three bipartite (BP) and two monopartite (MP)). To investigate their functionality, wild-type (WT) and mutant parafibromin constructs tagged with enhanced green fluorescent protein or cMyc were transiently expressed in COS-7 cells, or human embryonic kidney 293 (HEK293) cells, and their subcellular locations determined by confocal fluorescence microscopy. Western blot analyses of nuclear and cytoplasmic fractions from the transfected cells were also performed. WT parafibromin localized to the nucleus and deletions or mutations of the three predicted BP and one of the predicted MP NLSs did not affect this localization. In contrast, deletions or mutations of a MP NLS, at residues 136-139, resulted in loss of nuclear localization. Furthermore, the critical basic residues, KKXR, of this MP NLS were found to be evolutionarily conserved, and over 60% of all parafibromin mutations lead to a loss of this NLS. Thus, an important functional domain of parafibromin, consisting of an evolutionarily conserved MP NLS, has been identified. 相似文献
103.
Parafibromin mutations in hereditary hyperparathyroidism syndromes and parathyroid tumours 总被引:2,自引:0,他引:2
Bradley KJ Cavaco BM Bowl MR Harding B Cranston T Fratter C Besser GM Conceição Pereira M Davie MW Dudley N Leite V Sadler GP Seller A Thakker RV 《Clinical endocrinology》2006,64(3):299-306
Objective To investigate two patients with the hyperparathyroidism‐jaw tumour (HPT‐JT) syndrome and three patients with familial isolated hyperparathyroidism (FIHP), together with 31 parathyroid tumours (2 HPT‐JT, 2 FIHP and 27 sporadic) for HRPT2 mutations. The HPT‐JT syndrome and FIHP are autosomal dominant disorders that may be caused by abnormalities of the HRPT2 gene, located on chromosome 1q31.2. HRPT2 encodes a 531 amino acid protein, parafibromin, which interacts with human homologues of the yeast Paf1 complex. Design Leukocyte and tumor DNA was used with HRPT2‐specific primers for polymerase chain reaction amplification of the 17 exons and their splice junctions, and the DNA sequences of the polymerase chain reaction products determined. Results Three heterozygous germline HRPT2 mutations, two in HPT‐JT and one in FIHP patients, were identified. These consisted of one 1‐bp duplication (745dup1bp), 1 nonsense (Arg234Stop) and 1 missense (Asp379Asn) mutation. One parathyroid tumour from an FIHP patient was demonstrated to harbour a germline deletion of 1 bp together with a somatic missense (Leu95Pro) mutation, consistent with a ‘two‐hit’ model for hereditary cancer. The 27 sporadic benign parathyroid tumours did not harbour any HRPT2 somatic mutations. Six HRPT2 polymorphisms with allele frequencies ranging from 2% to 15% were detected. Conclusions Our results have identified three novel HRPT2 mutations (two germline and one somatic). The Asp379Asn mutation is likely to disrupt interaction with the human homologue of the yeast Paf1 complex, and the demonstration of combined germline and somatic HRPT2 mutations in a parathyroid tumour provide further evidence for the tumour suppressor role of the HRPT2 gene. 相似文献
104.
Sameer Thakker Jesse Persily Paxton Voigt Jennifer Blakemore Frederick Licciardi Bobby B. Najari 《Journal of assisted reproduction and genetics》2021,38(5):1071
PurposeTo characterize the demographic differences between infertile/sub-fertile women who utilized infertility services vs. those that do not.MethodsA retrospective analysis of cross-sectional data obtained during the 2011–2013, 2013–2015, and 2015–2017 cycles of National Survey for Family Growth from interviews administered in home for randomly selected participants by a National Center of Health Statistics (NCHS) surveyor was used to analyze married, divorced, or women with long-term partners who reported difficulty having biological children (sub-fertile/infertile women). Demographic differences such as formal marital status, education, race, and religion were compared between women who presented for infertility care vs. those that did not. The primary outcome measure was presenting for infertility evaluation and subsequently utilizing infertility services. Healthcare utilization trends such as having a usual place of care and insurance status were also included as exposures of interest in the analysis.ResultsOf the 12,456 women included in the analysis 1770 (15.3%) had used infertility services and 1011 (8.3%) said it would be difficult for them to have a child but had not accessed infertility services. On univariate analysis, compared to women who used infertility services, untreated women had lower average household incomes (295.3 vs. 229.8% of the federal poverty line respectively). Untreated women also had lower levels of education and were more likely to be divorced or never have married. In terms of health status, unevaluated women were less likely to have a usual place for healthcare (87.3%) as compared to women presenting for fertility care (91.9%) (p = 0.004). When examining insurance status, 23.3% of unevaluated women were uninsured as compared to 8.3% of evaluated women. On multivariate analysis, infertile women without insurance were at 0.37 odds of utilizing infertility care compared to women with insurance.ConclusionsDemographic factors are associated with the utilization of infertility care. Insurance status is a significant predictor of whether or not infertile women will access treatment. Data from the three most recent NSFG surveys along with prior analyses demonstrate the need for expanded insurance coverage in order to address the socioeconomic disparities between infertile women who are accessing services vs. those that are not.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10815-021-02149-6. 相似文献
105.
106.
Paediatric inpatient utilisation in a district general hospital was studied for 20 general practices covering a population of 26,433 children. The factors influencing the rate and route of admission (general practitioner (GP) or accident and emergency department) were analysed for 894 emergency non-traumatic admissions over a 12 month period. The overall rate of acute, nontraumatic admission was 33.8/1000; 35% of these admissions were via the accident and emergency department. Asthma was the most common reason for admission (16.1%); 56.9% of the admissions resulted from respiratory tract illness and 44% were for an infective illness. There was a significant variation in the route and rate of admission across practices. Admission rates ranged from 10 to 70/1000 children under 15 and the proportion via the accident and emergency department from 19% to 85%. The proportion of admissions via the accident and emergency department for each practice was highly negatively correlated with the number of GPs in the practice, the number of children under 15 registered, and positively correlated with the unemployment rate attributed to the list. Using multiple logistic regression analysis, the risk of being admitted via the accident and emergency department relative to GP admission was shown to be higher for older children (odds ratio for each year of age 1.05) and less for children registered with large practices with more GPs (odds ratio for each extra GP 0.36) or practices with more children under 15 (odds ratio per extra child 0.9991). Access to hospital as measured by isochrone bars and social characteristics of the ward of residence of each child admitted were not associated with the route of admission. The admission rate for each practice was positively, but not statistically significantly, associated with the unemployment rate attributed to the list, the unemployment rate of the ward where the practice was located, and the percentage of admissions via accident and emergency, and negatively associated with the percentage of the list under 15 years. 相似文献
107.
The H(2) antagonists, ranitidine and famotidine, exhibit saturable absorptive transport across Caco-2 cell monolayers and human intestine via a yet unidentified mechanism. A photoreactive derivative of famotidine has been synthesized and evaluated as a photoaffinity probe for the putative transporter protein(s). The probe irreversibly inhibited ranitidine transport across Caco-2 cell monolayers and irreversibly increased the transepithelial electrical resistance (TEER) after UV activation. Photoaffinity labeling was protected by a molar excess of famotidine. 相似文献
108.
High-throughput screening for stability and inhibitory activity of compounds toward cytochrome P450-mediated metabolism 总被引:3,自引:0,他引:3
With the advent of combinatorial chemistry and high-throughput screening technology, thousands of molecules can now be rapidly synthesized and screened for biological activity against large numbers of protein targets, greatly increasing the speed with which lead compounds are identified during the early stages of drug discovery. However, rapid optimization of parameters that determine whether a high-affinity ligand or a potent inhibitor will become a successful drug remains a challenge in improving the efficiency of the drug discovery process. Parameters that define absorption, distribution, metabolism, and excretion properties of drug candidates are important determinants of therapeutic efficacy, and thus should be optimized during early stages of drug discovery. Although the speed with which drugs are screened for properties such as absorption, cytochrome P450 (CYP) inhibition, and metabolic stability has increased over the past several years, the screening rate/capacity is still several orders of magnitude lower than those for high-throughput methods used in lead identification, resulting in a bottleneck in the drug discovery process. This review discusses current methods used in the in vitro screening of drugs for their stability toward CYP-mediated oxidative metabolism. This is a critical screen in the drug discovery process because metabolism by CYP represents an important clearance mechanism for the vast majority of compounds, thus affecting their oral bioavailability and/or duration of action. 相似文献
109.
110.
Lundberg I Damström Thakker K Hällström T Forsell Y 《Social psychiatry and psychiatric epidemiology》2005,40(6):475-483
OBJECTIVE: The study had two objectives: (i) to analyse determinants of non-participation in a general population study of mental disorder in Stockholm, and (ii) to determine whether associations between mental disorder and some potential determinants were different among participants and non-participants in the study. METHODS: The study was based on a questionnaire including potential risk factors for mental disorder and symptom scales. The study group was a random sample of the Stockholm County population aged 20-64 years (19,742 persons). Replies were obtained from 10,441 participants, i. e. the response rate was 53%. The symptom scales were used to identify a group with increased likelihood of mental disorder, screening-positive, and a group with low likelihood of mental disorder, screening-negative. Random samples of the screening-positive and screening-negative respondents were summoned for interview concerning psychiatric symptoms. The database of respondents and non-respondents was linked to several population registers. RESULTS: The participation was higher in females, among older persons, married persons, among persons with higher income and education and among those born in the Nordic countries. There seemed to be little further risk indicator based selection to interview participation. The associations between in-patient psychiatric care and register variables were strong and similar among participants and non-participants. CONCLUSIONS: The occurrence of mental disorders is likely to be underestimated in studies with this design and with substantial dropout rates. However, the study participants can most likely be a base for generalising risk indicators for, or social consequences of,mental disorder, to the general population. 相似文献