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101.
Anne Frühmesser Jonathon Blake Edda Haberlandt Bianka Baying Benjamin Raeder Heiko Runz Ana Spreiz Christine Fauth Vladimir Benes Gerd Utermann Johannes Zschocke Dieter Kotzot 《European journal of human genetics : EJHG》2013,21(10):1177-1180
Most balanced chromosomal aberrations are not associated with a clinical phenotype, however, in some patients they may disrupt gene structure. With the development of various next-generation sequencing techniques, fast and specific analyses of the breakpoint regions of chromosomal rearrangements are possible. Here, we report on a 19-year-old woman with a de novo balanced translocation t(2;8)(p13.2;q22.1) and a severe clinical phenotype including intellectual disability, epilepsy, behavioral features resembling autism, and minor dysmorphic features. By next-generation sequencing, we defined the breakpoints and found disruption of the exocyst complex component 6B (EXOC6B) gene in intron 1 on chromosome 2p13.2 involving two Alu elements with a homology of 81%. No gene was found at the respective breakpoint on chromosome 8. Expression analysis of the EXOC6B in blood lymphocytes and buccal smear revealed reduced expression in the patient in comparison with the control. Our findings in combination with one recently published case and one other patient listed in DECIPHER v5.1 indicate EXOC6B as a gene relevant for intellectual development and electrophysiological stability. 相似文献
102.
Simona Eva Zitnik Franz Rüschendorf Sebastian Müller Claudia Sengler Young‐Ae Lee Rupino W. Griffioen Paolo Meglio Ulrich Wahn Heiko Witt Renate Nickel 《Pediatric allergy and immunology》2009,20(6):551-555
Increased total and specific serum immunoglobulin E (IgE) levels are common characteristics of atopic diseases and their basal production is proposed to be under strong genetic control. Interleukin 13 (IL13) variants have been consistently associated with total serum IgE levels in white populations with a strongest association in non‐atopics. The aim of this study was to test the IL13 p.R130Q and c.1‐1111C>T variants in children with atopic dermatitis (AD) for associations with total serum IgE and early sensitization to common food and inhalant allergens and with asthma. We included 453 children with AD [participants of the Early Treatment of the Atopic Child (ETAC) study] that were followed from the age of 12–24 months for 3 yr. Total and specific IgE were determined at four time points. We genotyped the IL13 p.R130Q and c.1‐1111C>T variants by melting curve analysis. In children up to 4 yr of age, the 130Q allele was related to slightly higher total IgE levels compared to heterozygotes and 130R homozygotes. More importantly, both IL13 variants were significantly associated with sensitization to food allergens, with most significant results for sensitization to egg (p = 0.0001). Although early sensitization to hen’s egg represents a strong risk factor for subsequent sensitization to inhalant allergens and asthma, the investigated IL13 variants were not associated with these phenotypes at the age of 48–60 months. In summary IL13 variants contribute to elevated levels of total serum IgE in young atopic children and are strongly associated with sensitization to food allergens, particularly to hen’s egg. These findings suggest that IL13 variants play a major role not only in non‐cognate but also in allergen specific IgE synthesis. 相似文献
103.
Stefanie Birnbaum Kerstin U. Ludwig Heiko Reutter Stefan Herms Nilma A. De Assis Amalia Diaz‐Lacava Sandra Barth Carola Lauster Gül Schmidt Martin Scheer Mitra Saffar Markus Martini Rudolf H. Reich Franziska Schiefke Alexander Hemprich Simone Pötzsch Bernd Pötzsch Thomas F. Wienker Per Hoffmann Michael Knapp Franz‐Josef Kramer Markus M. Nöthen Elisabeth Mangold 《European journal of oral sciences》2009,117(6):766-769
Variants in the interferon regulatory factor 6 (IRF6) gene have repeatedly been associated with non‐syndromic cleft lip with or without cleft palate (NSCL/P). A recent study has suggested that the functionally relevant variant rs642961 is the underlying cause of the observed associations. We genotyped rs642961 in our Central European case–control sample of 460 NSCL/P patients and 952 controls. In order to investigate whether other IRF6 variants contribute independently to the etiology of NSCL/P, we also genotyped the non‐synonymous coding variant V274I (rs2235371) and five IRF6‐haplotype tagging single nucleotide polymorphisms (SNPs). A highly significant result was observed for rs642961 (P = 1.44 × 10?6) in our sample. The odds ratio was 1.75 [95% confidence interval (CI): 1.38–2.22] for the heterozygous genotype and 1.94 (95% CI: 1.21–3.10) for the homozygous genotype, values that are similar to those reported in a previously published family‐based study. Our results thus confirm the involvement of the IRF6 variant, rs642961, in the etiology of NSCL/P in the Central European population. We also found evidence suggestive of an independent protective effect of the coding variant V274I. In order to understand fully the genetic architecture of the IRF6 locus, it will be necessary to conduct additional SNP‐based and resequencing studies using large samples of patients. 相似文献
104.
Li F. Chan Louise A. Metherell Heiko Krude† Colin Ball‡ Stephen M. P. O'Riordan§¶ Colm Costigan¶ Sally A. Lynch¶ Martin O. Savage Paolo Cavarzere Adrian J. L. Clark 《Clinical endocrinology》2009,71(2):171-175
Objective Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease characterized by isolated glucocorticoid deficiency with preserved mineralocorticoid secretion. Mutations in the ACTH receptor (MC2R) account for approximately 25% of all FGD cases, but since these are usually missense mutations, a degree of receptor function is frequently retained. A recent report, however, suggested that disturbances in the renin–aldosterone axis were seen in some patients with potentially more severe MC2R mutations. Furthermore, MC2R knock out mice have overt aldosterone deficiency and hyperkalaemia despite preservation of a normal zona glomerulosa. We wished to determine whether a group of patients with severe nonsense mutations of the MC2R exhibited evidence of mineralocorticoid deficiency, thereby challenging the conventional diagnostic feature of FGD which might result in diagnostic misclassification.
Design Clinical review of patients with nonsense MC2R mutations.
Patients Between 1993 and 2008, 164 patients with FGD were screened for mutations in the MC2R. Totally 42 patients (34 families) were found to have mutations in the MC2R. Of these, 6 patients (4 families) were found to have homozygous nonsense or frameshift mutations.
Results Mild disturbances in the renin–angiotensin–aldosterone axis were noted in four out of six patients, ranging from slightly elevated plasma renin levels to low aldosterone levels, although frank mineralocorticoid deficiency or electrolyte disturbance were not found. No patient required fludrocortisone replacement.
Conclusion Severe nonsense and frameshift MC2R mutations are not associated with clinically significant mineralocorticoid deficiency and are thus unlikely to require long-term mineralocorticoid replacement. 相似文献
Design Clinical review of patients with nonsense MC2R mutations.
Patients Between 1993 and 2008, 164 patients with FGD were screened for mutations in the MC2R. Totally 42 patients (34 families) were found to have mutations in the MC2R. Of these, 6 patients (4 families) were found to have homozygous nonsense or frameshift mutations.
Results Mild disturbances in the renin–angiotensin–aldosterone axis were noted in four out of six patients, ranging from slightly elevated plasma renin levels to low aldosterone levels, although frank mineralocorticoid deficiency or electrolyte disturbance were not found. No patient required fludrocortisone replacement.
Conclusion Severe nonsense and frameshift MC2R mutations are not associated with clinically significant mineralocorticoid deficiency and are thus unlikely to require long-term mineralocorticoid replacement. 相似文献
105.
Müller O Traoré C Becher H Kouyaté B 《Tropical medicine & international health : TM & IH》2003,8(4):290-296
OBJECTIVE: To describe the pattern of fever-associated morbidity, treatment-seeking behaviour for fever episodes, and cause-specific mortality in young children of a malaria-holoendemic area in rural Burkina Faso. METHODS: In a longitudinal community-based intervention study, 709 representative children aged 6-31 months were followed daily over 6 months (including the main malaria transmission period) through village-based field staff. RESULTS: Of 1848 disease episodes, 1640 (89%) were fever episodes, and of those, 894 (55%) were attributed to malaria (fever + > or =5000 parasites/microl). Eighty-five percent of fever episodes were treated, mainly with chloroquine and paracetamol, 69% of treatments took place in households, 16% in local health centres, 13% in villages, and 1% in hospitals. Treatment-seeking in a health centre or hospital was associated with accessibility and disease severity. Cerebral malaria and malnutrition-associated diarrhoea were the most frequently diagnosed causes of death. While most children with a post-mortem diagnosis of diarrhoea had not received any treatment, children who died of malaria had often received insufficient treatment. In particular, there was a lack of an appropriate second-line treatment at formal health services after chloroquine treatment had failed to resolve symptoms. CONCLUSIONS: These findings call for more effective prevention and treatment of malaria, malnutrition and diarrhoea in rural African communities, as well as for better supervision of existing malaria treatment guidelines in formal health services. 相似文献
106.
RATIONALE AND OBJECTIVES: To evaluate prospectively diagnostic accuracy of 1 mol/L gadobutrol as a contrast agent for intraarterial x-ray digital subtraction angiography (DSA) in comparison to iodinated, nonionic contrast media and 0.5 mol/L gadolinium-DTPA. METHODS: Flush arteriograms (ascending, descending, abdominal aorta, iliac, and femoral arteries) and selective angiograms (carotid, renal, and visceral arteries) were obtained from bilateral femoral arterial access (5 F sheaths) in 10 domestic pigs (70 kg body weight). Digital subtracted angiograms were obtained during injection of undiluted 1 mol/L gadobutrol, 300 mg I/mL iopromide, or 0.5 mol/L gadopentetate. Injection parameters (volume and velocity) were similar for all three contrast agents. In paired arteries, two different contrast media were used during the same angiographic run. Diagnostic quality and accuracy of the angiograms were evaluated on a three-step scale by three independent blinded investigators. RESULTS: Sufficient nonselective angiographic images were obtained in 90% of cases using iodinated contrast material. Gadobutrol achieved sufficient nonselective angiograms in 64%. Selective angiograms were sufficient in 98% using iodinated contrast material, 90% using 1 mol/L Gadobutrol and 48% using 0.5 mol/L Gd-DTPA. Adverse reactions to any of the used contrast agents were not noted. CONCLUSION: One mol/L Gadobutrol solution allows x-ray digital subtraction angiography with a diagnostic accuracy equivalent to 300 mg/mL iodinated contrast media, if selective injections are performed. Flush aortograms are of inferior image quality to iodinated contrast material. 相似文献
107.
Phases of A beta-deposition in the human brain and its relevance for the development of AD 总被引:22,自引:0,他引:22
BACKGROUND: The deposition of the amyloid beta protein (Abeta) is a histopathologic hallmark of AD. The regions of the medial temporal lobe (MTL) are hierarchically involved in Abeta-deposition. OBJECTIVE: To clarify whether there is a hierarchical involvement of the regions of the entire brain as well and whether there are differences in the expansion of Abeta-pathology between clinically proven AD cases and nondemented cases with AD-related pathology, the authors investigated 47 brains from demented and nondemented patients with AD-related pathology covering all phases of beta-amyloidosis in the MTL (AbetaMTL phases) and four control brains without any AD-related pathology. METHODS: Abeta deposits were detected by the use of the Campbell-Switzer silver technique and by immunohistochemistry in sections covering all brain regions and brainstem nuclei. It was analyzed how often distinct regions exhibited Abeta deposits. RESULTS: In the first of five phases in the evolution of beta-amyloidosis Abeta deposits are found exclusively in the neocortex. The second phase is characterized by the additional involvement of allocortical brain regions. In phase 3, diencephalic nuclei, the striatum, and the cholinergic nuclei of the basal forebrain exhibit Abeta deposits as well. Several brainstem nuclei become additionally involved in phase 4. Phase 5, finally, is characterized by cerebellar Abeta-deposition. The 17 clinically proven AD cases exhibit Abeta-phases 3, 4, or 5. The nine nondemented cases with AD-related Abeta pathology show Abeta-phases 1, 2, or 3. CONCLUSIONS: Abeta-deposition in the entire brain follows a distinct sequence in which the regions are hierarchically involved. Abeta-deposition, thereby, expands anterogradely into regions that receive neuronal projections from regions already exhibiting Abeta. There are also indications that clinically proven AD cases with full-blown beta-amyloidosis may be preceded in early stages by nondemented cases exhibiting AD-related Abeta pathology. 相似文献
108.
Pei JJ Braak H Gong CX Grundke-Iqbal I Iqbal K Winblad B Cowburn RF 《Acta neuropathologica》2002,104(4):369-376
The major component of Alzheimer's disease (AD) neurofibrillary tangles (NFTs) is abnormally hyperphosphorylated tau aggregated as paired helical filaments (PHFs). Cell division cycle (cdc) 2 kinase is one of the main candidate kinases that phosphorylates normal tau in vitro at several sites seen in PHF-tau. Using brains staged according to Braak and Braak criteria, we investigated the role of cdc2 in neurofibrillary changes in the hippocampal formation, and the entorhinal and temporal cortices. Neurons with tangle-like inclusions positive for active cdc2 were found to appear first in the Pre-alpha layer of the entorhinal cortex, and then extend to other brain regions co-incident with the progressive sequence of neurofibrillary changes. This predictable progressive pattern is not associated with amyloid. The intraneuronal accumulation of active cdc2 appeared to precede the deposition of PHF-tau phosphorylated at Ser 202/Thr 205 sites. These data are consistent with the notion that cdc2 might be involved in the abnormal hyperphosphorylation of tau and consequently aggregation of tau into PHF at an early stage and that increased cdc2 activity is not consequent to the deposition of beta-amyloid in AD brain. 相似文献
109.
Ratzka A Vogel H Kliebenstein DJ Mitchell-Olds T Kroymann J 《Proceedings of the National Academy of Sciences of the United States of America》2002,99(17):11223-11228
Plants are attacked by a broad array of herbivores and pathogens. In response, plants deploy an arsenal of defensive traits. In Brassicaceae, the glucosinolate-myrosinase complex is a sophisticated two-component system to ward off opponents. However, this so-called "mustard oil bomb" is disarmed by a glucosinolate sulfatase of a crucifer specialist insect, diamondback moth, Plutella xylostella (Lepidoptera: Plutellidae). Sulfatase activity of this enzyme largely prevents the formation of toxic hydrolysis products arising from this plant defense system. Importantly, the enzyme acts on all major classes of glucosinolates, thus enabling diamondback moths to use a broad range of cruciferous host plants. 相似文献
110.
Dose reduction in CT examination of children by an attenuation-based on-line modulation of tube current (CARE Dose) 总被引:3,自引:0,他引:3
Greess H Nömayr A Wolf H Baum U Lell M Böwing B Kalender W Bautz WA 《European radiology》2002,12(6):1571-1576
In a controlled patient study we investigated the potential of attenuation-based on-line modulation of the tube current to reduce milliampere values (mAs) in CT examinations of children without loss of image quality. mAs can be reduced for non-circular patient cross sections without an increase in noise if tube current is reduced at those angular positions where the patient diameter and, consequently, attenuation are small. We investigated a technical approach with an attenuation-based on-line control for the tube current realised as a work-in-progress implementation. The CT projection data are analysed in real time to determine optimal mAs values for each projection angle. We evaluated mAs reduction for 100 spiral CT examinations with attenuation-based on-line modulation of the tube current in a group of children. Two radiologists evaluated image quality by visual interpretation in consensus. We compared the mAs values read from the CT scanner with preset mAs of a standard protocol. Four different scan regions were examined in spiral technique (neck, thorax, abdomen, thorax and abdomen). We found the mAs product to be reduced typically by 10-60% depending on patient geometry and anatomical regions. The mean reduction was 22.3% (neck 20%, thorax 23%, abdomen 23%, thorax and abdomen 22%). In general, no deterioration of image quality was observed. There was no correlation between the age and the mean mAs reduction in the different anatomical regions. By classifying the children respectively to their weight, there is a positive trend between increasing weight and mAs reduction. We conclude that mAs in spiral CT examinations of children can be reduced substantially by attenuation-based on-line modulation of the tube current without deterioration of image quality. Attenuation-based on-line modulation of tube current is efficient and practical for reducing dose exposure to children. 相似文献