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31.
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
32.
Berry V; Ionides AC; Moore AT; Plant C; Bhattacharya SS; Shiels A 《Human molecular genetics》1996,5(3):415-419
Inherited cataract is a clinically and genetically heterogeneous disease.
Here we report the identification of a new locus for an autosomal dominant
anterior polar cataract on the short arm of chromosome 17. To map this new
locus we performed genetic linkage analysis with microsatellite markers in
a four-generation pedigree. After exclusion of seven candidate loci for
cataract, we obtained significant positive LOD scores for markers D17S849
(Z = 4.01 / theta = 0.05) and D17S796 (Z = 4.17 / theta = 0.05). Multipoint
analysis gave a maximum LOD score of 5.2 (theta max = 0.06) between these
two markers. From haplotype analysis, the cataract locus lies in the 13 cM
interval between markers D17S849 and D17S796. This study provides the first
genetic mapping of an autosomal dominant anterior polar cataract.
相似文献
33.
Background
Genetic polymorphisms of the TCF7L2 gene are strongly associated with large increments in type 2 diabetes risk in different populations worldwide. In this study, we aimed to confirm the effect of the TCF7L2 polymorphism rs7903146 on diabetes risk in a Brazilian population and to assess the use of this genetic marker in improving diabetes risk prediction in the general population. 相似文献34.
Marjolijn Bornebroek Joost Haan Marion LC Maat-Schieman Sjoerd G Van Duinen Raymund AC Roos 《Brain pathology (Zurich, Switzerland)》1996,6(2):111-114
Hereditary cerebral hemorrhage with amyloidosis - Dutch type (HCHWA-D) is an autosomal dominant disease caused by deposition of β-amyloid in the leptomeningeal arteries and cortical arterioles, in addition to preamyloid deposits and amyloid plaques in the brain parenchyma.
The disease is due to a point mutation at codon 693 of the amyloid precursor protein (βPP) gene at chromosome 21. Since this point mutation is diagnostic for HCHWA-D, presymptomatic testing is feasible and offered, together with genetic counselling and psychological support, to subjects at risk. HCHWA-D is clinically characterized by recurrent strokes, in addition to dementia, which can occur after the first stroke but also preceding it. Radiological studies revealed focal lesions (hemorrhages, hemorrhagic and non-hemorrhagic infarctions) and diffuse white matter damage. Diffuse white matter hyperintensities on MRI are an early symptom of HCHWA-D since they have been found on MRI scans of subjects who had not suffered a stroke.
The presence of the diagnostic point mutation makes HCHWA-D a useful model to study the effects of cerebral amyloid angiopathy in vivo. The characteristic pathological abnormalities and its implications for Alzheimer's disease will be discussed in Part II of this article 相似文献
The disease is due to a point mutation at codon 693 of the amyloid precursor protein (βPP) gene at chromosome 21. Since this point mutation is diagnostic for HCHWA-D, presymptomatic testing is feasible and offered, together with genetic counselling and psychological support, to subjects at risk. HCHWA-D is clinically characterized by recurrent strokes, in addition to dementia, which can occur after the first stroke but also preceding it. Radiological studies revealed focal lesions (hemorrhages, hemorrhagic and non-hemorrhagic infarctions) and diffuse white matter damage. Diffuse white matter hyperintensities on MRI are an early symptom of HCHWA-D since they have been found on MRI scans of subjects who had not suffered a stroke.
The presence of the diagnostic point mutation makes HCHWA-D a useful model to study the effects of cerebral amyloid angiopathy in vivo. The characteristic pathological abnormalities and its implications for Alzheimer's disease will be discussed in Part II of this article 相似文献
35.
Variations of the origin of the artery of the sinoatrial node in normal human hearts 总被引:8,自引:0,他引:8
Summary The artery of the sino-atrial node was studied in 100 normal human hearts after injection of each coronary artery with coloured gelatine containing a radiopaque substance. The hearts belonged to 69 males and 31 females, being 64 Caucasians and 36 non-Caucasians (Negroes and Mulattoes) whose age ranged from 7 to 80 years. Since the individuals had committed suicide or were victims of accidents, their hearts, after pathologists' evaluation, were considered normal. The sinoatrial node of the normal human heart is supplied by the right coronary artery more frequently (58%±4.9% of the cases) than by the left (42%±4.9). The right anterior medial atrial artery, originating from the right coronary at the level of the medial third of the right anterior quadrant of the atrial dome, is most frequently (50%±5) responsible for the blood supply of the sinoatrial node. Among the branches of the left coronary artery, the left anterior medial atrial artery, originating at the level of the medial third of the left. anterior quadrant of the atrial cupola, was the most frequent blood supplier (25%±4.3) of the sinoatrial node. The origin of the artery of the sinoatrial node from the proximal portion or trunk of the left coronary artery was less frequent (12%±3.2) than the origin from the circumflex artery (30%±4.5). Neither sex nor race influenced the variations of the origin of the sino-atrial node.
Variations d'origine de l'artère du noeud sinu-atrial du coeur humain normal
Résumé L'a. du noeud sinu-atrial a été étudiée sur 100 coeurs humains normaux après injection de chaque a. coronaire à la gélatine colorée additionnée d'une substance radio-opaque. Les coeurs provenaient de 69 hommes et 31 femmes, 64 caucasiens et 36 non caucasiens (nègres et mulâtres) âgés de 7 à 80 ans. Ces sujets étant décédés par suicide ou des suites d'accidents, leurs coeurs ont été considérés comme normaux après examen anatomo-pathologique. Le noeud sinu-atrial du coeur humain est vascularisé par l'a. coronaire droite plus fréquemment (58 %±4,9) que par l'a. coronaire gauche (42 %±4). L'a. atriale antéro-médiale droite, issue de l'a. coronaire droite au niveau du tiers médial du quadrant antérieur droit du dôme atrial est l'artère la plus fréquemment en cause (50 %±5) dans la vascularisation du noeud sinuatrial. Parmi les branches de l'a. coronaire gauche, l'a. atriale antéro-médiale gauche, née au niveau du tiers médial du quadrant antérieur gauche du dôme atrial, était la branche la plus fréquemment en cause (25 %±4,3) dans la vascularisation du noeud sinu-atrial. La naissance de l'a. du noeud sinu-atrial à partir de la partie proximale ou du tronc de l'a. coronaire gauche était moins fréquente (12 %±3,2) que son origine à partir du rameau circonflexe (30 %±4,5). Les variations d'origine de l'a. du noeud sinu-atrial n'apparaissaient pas influencées par le sexe ou la race.相似文献
36.
Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial 总被引:36,自引:0,他引:36
J W Eschbach J C Egrie M R Downing J K Browne J W Adamson 《The New England journal of medicine》1987,316(2):73-78
We administered recombinant human erythropoietin to 25 anemic patients with end-stage renal disease who were undergoing hemodialysis. The recombinant human erythropoietin was given intravenously three times weekly after dialysis, and transfusion requirements, hematocrit, ferrokinetics, and reticulocyte responses were monitored. Over a range of doses between 15 and 500 units per kilogram of body weight, dose-dependent increases in effective erythropoiesis were noted. At 500 units per kilogram, changes in the hematocrit of as much as 10 percentage points were seen within three weeks, and increases in ferrokinetics of three to four times basal values, as measured by erythron transferrin uptake, were observed. Of 18 patients receiving effective doses of recombinant human erythropoietin, 12 who had required transfusions no longer needed them, and in 11 the hematocrit increased to 35 percent or more. Along with the rise in hematocrit, four patients had an increase in blood pressure, and a majority had increases in serum creatinine and potassium levels. No organ dysfunction or other toxic effects were observed, and no antibodies to the recombinant hormone were formed. These results demonstrate that recombinant human erythropoietin is effective, can eliminate the need for transfusions with their risks of immunologic sensitization, infection, and iron overload, and can restore the hematocrit to normal in many patients with the anemia of end-stage renal disease. 相似文献
37.
Viability of partially damaged human embryos after cryopreservation 总被引:10,自引:13,他引:10
Van den Abbeel E; Camus M; Van Waesberghe L; Devroey P; Van Steirteghem AC 《Human reproduction (Oxford, England)》1997,12(9):2006-2010
In our centre, embryos are judged to have survived cryopreservation if at
least half of the initial number of blastomeres remain intact. Therefore
both fully intact and partially damaged embryos are transferred. The aim of
this study was to investigate the viability of partially damaged human
embryos after cryopreservation. We retrospectively analysed the
implantation and in-vivo development of embryos which were either fully
intact or had lost some blastomeres after cryopreservation. Oocytes were
collected following stimulation with the gonadotrophin-releasing hormone
(GnRH)-agonist Buserelin and human menopausal gonadotrophin. Supernumerary
multicellular embryos with not more than 20% of their volume filled with
anucleate fragments were frozen on day 2 or day 3 of the cycle using a slow
cooling procedure with dimethylsulphoxide as the cryoprotectant. Following
slow thawing, 431 fully intact embryos were transferred in 314 embryo
transfer procedures and 488 partially damaged embryos were transferred in
327 such procedures. The percentage of gestational sacs with fetal
heartbeat obtained after transfer of fully intact embryos was almost three
times higher than that after transfer of partially damaged embryos (11.4
versus 3.5%). Forty-five children (birth rate 10% per embryo transfer) were
born after transfer of fully intact embryos and 14 after transfer of
embryos from which some blastomeres had been lost following
cryopreservation. In conclusion, although children have been delivered
after transfer of partially damaged embryos, the aim of a cryopreservation
programme must be to obtain fully intact embryos after thawing.
相似文献
38.
39.
Esaki Muthu Shankar Ramachandran Vignesh Kailapuri G Murugavel Pachamuthu Balakrishnan Ramalingam Sekar Charmaine AC Lloyd Suniti Solomon Nagalingeswaran Kumarasamy 《AIDS research and therapy》2007,4(1):1-7
Background
CD4+ T lymphocyte (CD4) cell count testing is the standard method for determining eligibility for antiretroviral therapy (ART), but is not widely available in sub-Saharan Africa. Total lymphocyte counts (TLCs) have not proven sufficiently accurate in identifying subjects with low CD4 counts. We developed clinical algorithms using TLCs, hemoglobin (Hb), and body mass index (BMI) to identify patients who require ART. 相似文献40.
Genetic requirements for salmonella-induced cytopathology in human monocyte-derived macrophages
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Infection of human macrophages with Salmonella enterica serovar Typhimurium or Salmonella enterica serovar Dublin produces delayed cytotoxicity characterized by cell detachment and associated apoptosis. Using a site-specific mutant in the SpvB active site, we verify that the ADP-ribosylation activity of SpvB is required for delayed cytotoxicity in human macrophages infected with Salmonella: SipB and the type III protein secretion system (TTSS) encoded by Salmonella pathogenicity island 1 (SPI1) are not involved, whereas the SPI2 TTSS is absolutely required for SpvB-dependent cytotoxicity. Furthermore, we show that infection of macrophage cultures with wild-type or sipB mutant bacteria led to a complete loss of polymerized actin in over half of the cells after 24 h. In contrast, macrophages infected with the spvB or SPI2 (ssaV or ssaJ) mutant strain retained normal F-actin filaments, despite similar numbers of intracellular bacteria. We conclude that SpvB and a functional SPI2 TTSS are essential for Salmonella-induced delayed cytotoxicity of human macrophages. 相似文献