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61.
The GAP-related domain of tuberin, the product of the TSC2 gene, is a target for missense mutations in tuberous sclerosis 总被引:5,自引:0,他引:5
Maheshwar MM; Cheadle JP; Jones AC; Myring J; Fryer AE; Harris PC; Sampson JR 《Human molecular genetics》1997,6(11):1991-1996
Tuberous sclerosis is an autosomal dominant trait in which the
dysregulation of cellular proliferation and differentiation results in the
development of hamartomatous growths in many organs. The TSC2 gene is one
of two genes determining tuberous sclerosis. Inactivating germline
mutations of TSC2 in patients with tuberous sclerosis and somatic loss of
heterozygosity at the TSC2 locus in the associated hamartomas indicate that
TSC2 functions as a tumour suppressor gene and that loss of function is
critical to expression of the tuberous sclerosis phenotype. The TSC2
product, tuberin, has a region of homology with the GTPase activating
protein rap1GAP and stimulates the GTPase activity of rap1a and rab5a in
vitro. Here we show that the region of homology between tuberin and human
rap1GAP and the murine GAP mSpa1 is more extensive than previously reported
and spans approximately 160 amino acid residues encoded within exons 34-38
of the TSC2 gene. Single strand conformation polymorphism analysis of these
exons in 173 unrelated patients with tuberous sclerosis and direct
sequencing of variant conformers together with study of additional family
members enabled characterisation of disease associated mutations in 14
cases. Missense mutations, which occurred in exons 36, 37 and 38 were
identified in eight cases, four of whom shared the same recurrent change
P1675L. Each of the five different missense mutations identified was shown
to occur de novo in at least one sporadic case of tuberous sclerosis. The
high proportion of missense mutations detected in the region of the TSC2
gene encoding the GAP-related domain supports its key role in the
regulation of cellular growth.
相似文献
62.
Assisted reproductive technology and complex chromosomal rearrangements: the limits of ICSI 总被引:4,自引:0,他引:4
Siffroi JP; Benzacken B; Straub B; Le Bourhis C; North MO; Curotti G; Bellec V; Alvarez S; Dadoune JP 《Molecular human reproduction》1997,3(10):847-851
Complex chromosomal rearrangements are very rare events in the human
population. According to our knowledge on the consequences of simple
reciprocal translocations for male fertility, translocations involving
three or more chromosomes are thought to lead to severe reproductive
impairments in terms of meiotic disturbance or chromosomal imbalance of
gametes. We report the case of a 48 year old man whose sperm count revealed
either oligozoospermia (<10(3) spermatozoa/ml) or azoospermia. He was
referred to the laboratory for in-vitro fertilization after
intracytoplasmic sperm injection. Cytogenetic investigations showed a
complex chromosomal rearrangement involving firstly a translocation between
the short arm of chromosome 7 and the long arm of chromosome 13 and
secondly a translocation between the short arm of the same chromosome 13
and the short arm of chromosome 9. Diagnosis was ascertained by
fluorescence in-situ hybridization and staining of the nucleolar organizer
regions. Theoretical study of the translocated chromosomes predicted a
'chain' configuration of the hexavalent at the pachytene stage of meiosis.
In all, 32 modes of segregation were considered and only one resulted
either in a normal or a balanced gamete karyotype. Genetic counselling and
choice of appropriate artificial reproduction technique are discussed.
相似文献
63.
64.
Alcohol use disorders in persons with co-occurring psychiatric disorders are associated with high rates of psy-chosocial instability and poorer treatment outcomes. Thus, assessment of alcohol use and abuse should become an integral part of psychiatric care. Because setf-report-based measures are frequently used, issues of reliability and validity in this population should be critically examined. The purpose of this article is to review and critique the existing empirical literature that has evaluated the psychometric integrity of self- report-based measures in psychiatric settings, and to outline a research agenda that promises to enhance the accuracy of alcohol assessment by persons receiving psychiatric treatment. 相似文献
65.
Conclusion The opening of the anal canal appears to be the factor which initiated the differentiation of the sphincter apparatus.The internal sphincter m. of the anus is entirely composed of smooth muscle as distinct from the striated fibers of the m. puborectalis, and the external sphincter which is a mixture of smooth and striated fibers (of skeletal type). It develops in the terminal part of the internal circular layer of the rectal m., outside which are longitudinal fibers which descend early to form the external sphincter (beginning around the third month).This study shows that the internal sphincter is scarcely evident before 12 SA. Thus continence between 10 and 12 SA (after the closure of the anal membrane) is closely related to the other components of the sphincter apparatus. On the other hand, the internal sphincter has become well formed after 28 to 30 SA and then plays a direct role in maintaining continence. 相似文献
66.
T cell epitope spreading to myelin oligodendrocyte glycoprotein in HLA-DR4 transgenic mice during experimental autoimmune encephalomyelitis 总被引:2,自引:0,他引:2
Klehmet J Shive C Guardia-Wolff R Petersen I Spack EG Boehm BO Weissert R Forsthuber TG 《Clinical immunology (Orlando, Fla.)》2004,111(1):53-60
Epitope spreading has been implicated in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and human multiple sclerosis (MS). T cell epitope spreading has been demonstrated in rodents for myelin basic protein (MBP) and proteolipid protein (PLP) determinants, but not for myelin oligodendrocyte glycoprotein (MOG), another important myelin antigen. Moreover, the role of human autoimmunity-associated MHC molecules in epitope spreading, including HLA-DR2 and DR4, has not been formally examined. To address these questions, we investigated epitope spreading to MOG determinants in HLA-DR4 (DRB1*0401) transgenic mice during EAE. The data show that upon induction of EAE in HLA-DR4 transgenic mice with the immunodominant HLA-DR4-restricted MOG peptide 97-108 (MOG(97-108); TCFFRDHSYQEE), the T cell response diversifies over time to MOG(181-200) (core: MOG(183-191); FVIVPVLGP) and MBP. The spreading epitope MOG(181-200) binds with high affinity to HLA-DRB1*0401 and is presented by human HLA-DRB1*0401+antigen presenting cells. Moreover, this epitope is encephalitogenic in HLA-DRB1*0401 transgenic mice. This study demonstrates intra- and intermolecular epitope spreading to MOG and MBP in "humanized" HLA-DR4 transgenic mice. 相似文献
67.
Shannon G. Farmakis Ann M. Barnes John C. Carey Stephen R. Braddock 《American journal of medical genetics. Part A》2019,179(3):455-466
The purpose of this study was to determine whether trisomy 18 patients are at an increased risk of tumor development and require formal tumor screening recommendations. A literature search of trisomy 18 patients with reports of tumors or malignancies, and compilation of all previously reported as well as new unreported cases was performed. 67 patients with trisomy 18 were found to have documented malignancies. 44 patients had hepatoblastomas, 21 patients had Wilms tumors, one patient had a functional neurogenic neoplasia, and one patient had Hodgkins lymphoma. The increasing numbers of reported malignancies in patients with trisomy 18 supports the indication for an early screening process. Specific screening recommendations are outlined consisting of imaging exams and laboratory values performed at specific intervals. 相似文献
68.
The University of Virginia School of Medicine has developed a student-initiated, faculty-assisted system to evaluate the faculty who teach the third-year clinical clerkships. All students complete an evaluation at the end of each clerkship, and the fourth-year class and student government compile the results and publish a detailed annual report of the data, offering constructive criticism and recommendations for change. Teaching faculty then review the report and respond to the student government, the faculty clerkship committee, and the student curriculum committee, addressing the contents of the report and initiating proposals to correct deficiencies and improve teaching. The experience of the first two administrations of this system (1988-1990) has been encouraging, and the authors suggest that the system will be applicable to the evaluation of clinical teaching on a universal basis. 相似文献
69.
Gonadotrophin-releasing hormone agonist dose-dependency of pituitary desensitization during controlled ovarian hyperstimulation in IVF 总被引:2,自引:2,他引:2
Janssens RM; Vermeiden JP; Lambalk CB; Schats R; Schoemaker J 《Human reproduction (Oxford, England)》1998,13(9):2386-2391
The aim of this study was to find the minimal effective daily s.c. dose of
the gonadotrophin-releasing hormone (GnRH) agonist, triptorelin acetate,
that suppresses the GnRH-induced release of luteinizing hormone (LH) at
time of human chorionic gonadotrophin (HCG) injection and thereby prevents
spontaneous LH surges during in-vitro fertilization (IVF) stimulation
cycles. Therefore, a double-blind, prospective and randomized titration
study was performed. A total of 48 IVF patients were divided into four
groups of 12 patients. Each group received a different dose of triptorelin
acetate, namely 5, 15, 50 or 100 microg s.c. daily. Standard ovarian
stimulation was carried out using urinary follicle stimulating hormone
(FSH) preparations. A 500 microg GnRH test was performed 90 min before the
HCG injection in order to measure the degree of pituitary desensitization.
Spontaneous LH surges were not detected in any of the groups, although
three patients in the 5 microg group had ovulated at the time of ovum
retrieval. The pituitary LH response to the GnRH test at time of HCG,
expressed as area under the curve (AUC), appeared to be dose-dependent.
Thus, a daily s.c. dose of 100 microg triptorelin acetate appears to be too
high, since adequate desensitization of the pituitary (i.e. no spontaneous
LH surge) can be achieved with doses as low as 15 and 50 microg.
相似文献
70.
Bals-Pratsch M; De Geyter C; Muller T; Frieling U; Lerchl A; Pirke KM; Hanker JP; Becker-Carus C; Nieschlag E 《Human reproduction (Oxford, England)》1997,12(5):896-904
Preliminary data have suggested that female infertility due to corpus
luteum insufficiency may be caused by subclinical hypothyroidism
[exaggerated thyroid-stimulating hormone (TSH) response to thyrotrophin-
releasing hormone (TRH) stimulation]. L-Thyroxine supplementation has been
recommended to achieve pregnancies in subclinical hypothyroid women. This
controlled study was carried out in order to investigate the biochemical
diagnosis of subclinical hypothyroidism as a possible infertility factor.
Five infertile patients (aged 25-36 years) with subclinical hypothyroidism
(n = 4, stimulated TSH >20 microU/ml) or primary hypothyroidism (n = 1)
and five healthy controls (aged 22-39 years) with normal thyroid function
(stimulated TSH <15 microU/ml), regular cycles and no history of
infertility were studied in the early follicular phase. In the pre-study
evaluation, eight of 23 volunteers (34.8%) had to be excluded because of
subclinical hypothyroidism with stimulated TSH values (TSHs) >15
microU/ml. Cycle function of patients and controls was compared by the
method of LH pulse pattern analysis. Therefore blood samples were drawn
every 10 min during a 24 h period. Sleep was recorded from midnight to 7
a.m. Repetition of the TRH tests at the end of the 24 h blood sampling
period confirmed the difference in stimulated TSH values of the two study
groups. Pulse analysis for luteinizing hormone (LH), TSH and prolactin
showed no differences between patients and controls for pulse frequency,
amplitude, height, length, area under curve (AUC) and the 24 h mean. Even
the hypothyroid patient had a normal LH pulse pattern. Additional
measurement of melatonin in pooled sera every 30 min gave the
well-documented diurnal profiles during day and night for both groups.
Patients had significantly higher melatonin values at seven time points
during the night. Peaks for LH, TSH, prolactin and cortisol were correlated
with the sleep stages wake, rapid eye movement, 1 + 2 and 3 + 4. We
concluded that corpus luteum insufficiency in female infertility cannot be
explained by subclinical hypothyroidism and thus should not be treated with
L-thyroxine for fertility reasons.
相似文献