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31.
Molecular basis of the functional podocin-nephrin complex: mutations in the NPHS2 gene disrupt nephrin targeting to lipid raft microdomains 总被引:10,自引:0,他引:10
Huber TB Simons M Hartleben B Sernetz L Schmidts M Gundlach E Saleem MA Walz G Benzing T 《Human molecular genetics》2003,12(24):3397-3405
Hereditary nephrotic syndrome is a heterogeneous disease, characterizedby heavy proteinuria and renal failure. Mutations of NPHS1 orNPHS2, the genes encoding for nephrin and podocin, lead to earlyonset of heavy proteinuria, and rapid progression to end-stagerenal disease, suggesting that both proteins are essential forthe integrity of the glomerular filter. Podocin is a stomatinprotein family member with a predicted hairpin-like structurelocalizing to the insertion site of the slit diaphragm of podocytes,the visceral glomerular epithelial cells of the kidney. Herewe investigate the pathomechanisms of different disease-causingpodocin mutations. We show that wild-type podocin is targetedto the plasma membrane, and forms homo-oligomers involving thecarboxy and amino terminal cytoplasmic domains. The associationof podocin with specialized lipid raft microdomains of the plasmamembrane was a prerequisite for recruitment of nephrin intorafts. In contrast, disease-causing mutations of podocin (R138Qand R138X) failed to recruit nephrin into rafts either becausethese mutants were retained in the endoplasmic reticulum (R138Q),or because they failed to associate with rafts (R138X) despitetheir presence in the plasma membrane. None of the mutants didaugment nephrin signaling, suggesting that lipid raft targetingfacilitates nephrin signaling. Our findings demonstrate thatthe failure of mutant podocin to recruit nephrin into lipidrafts may be essential for the pathogenesis of NPHS2.
* To whom correspondence should be addressed. Tel: +49 7612703559;Fax: +49 7612706362; Email: benzing{at}med1.ukl.uni-freiburg.de
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Circuit dynamics and coding strategies in rodent somatosensory cortex 总被引:14,自引:0,他引:14
Previous experimental studies of both cortical barrel and thalamic barreloid neuron responses in rodent somatosensory cortex have indicated an active role for barrel circuitry in processing thalamic signals. Previous modeling studies of the same system have suggested that a major function of the barrel circuit is to render the response magnitude of barrel neurons particularly sensitive to the temporal distribution of thalamic input. Specifically, thalamic inputs that are initially synchronous strongly engage recurrent excitatory connections in the barrel and generate a response that briefly withstands the strong damping effects of inhibitory circuitry. To test this experimentally, we recorded responses from 40 cortical barrel neurons and 63 thalamic barreloid neurons evoked by whisker deflections varying in velocity and amplitude. This stimulus evoked thalamic response profiles that varied in terms of both their magnitude and timing. The magnitude of the thalamic population response, measured as the average number of evoked spikes per stimulus, increased with both deflection velocity and amplitude. On the other hand, the degree of initial synchrony, measured from population peristimulus time histograms, was highly correlated with the velocity of whisker deflection, deflection amplitude having little or no effect on thalamic synchrony. Consistent with the predictions of the model, the cortical population response was determined largely by whisker velocity and was highly correlated with the degree of initial synchrony among thalamic neurons (R(2) = 0.91), as compared with the average number of evoked thalamic spikes (R(2) = 0.38). Individually, the response of nearly all cortical cells displayed a positive correlation with deflection velocity; this homogeneity is consistent with the dependence of the cortical response on local circuit interactions as proposed by the model. By contrast, the response of individual thalamic neurons varied widely. These findings validate the predictions of the modeling studies and, more importantly, demonstrate that the mechanism by which the cortex processes an afferent signal is inextricably linked with, and in fact determines, the saliency of neural codes embedded in the thalamic response. 相似文献
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35.
Human neutrophil-mediated nonoxidative antifungal activity against Cryptococcus neoformans 下载免费PDF全文
It has long been appreciated that polymorphonuclear leukocytes (PMN) kill Cryptococcus neoformans, at least in part via generation of fungicidal oxidants. The aim of this study was to examine the contribution of nonoxidative mechanisms to the inhibition and killing of C. neoformans. Treatment of human PMN with inhibitors and scavengers of respiratory burst oxidants only partially reversed anticryptococcal activity, suggesting that both oxidative and nonoxidative mechanisms were operative. To define the mediators of nonoxidative anticryptococcal activity, PMN were fractionated into cytoplasmic, primary (azurophil) granule, and secondary (specific) granule fractions. Incubation of C. neoformans with these fractions for 18 h resulted in percent inhibition of growth of 67.4 +/- 3.4, 84.6 +/- 4.4, and 29.2 +/- 10.5 (mean +/- standard error, n = 3), respectively. Anticryptococcal activity of the cytoplasmic fraction was abrogated by zinc and depletion of calprotectin. Antifungal activity of the primary granules was significantly reduced by pronase treatment, boiling, high ionic strength, and magnesium but not calcium. Fractionation of the primary granules by reverse phase high-pressure liquid chromatography on a C(4) column over an acetonitrile gradient revealed multiple peaks with anticryptococcal activity. Of these, peaks 1 and 6 had substantial fungistatic and fungicidal activity. Peak 1 was identified by acid-urea polyacrylamide gel electrophoresis (PAGE) and mass spectroscopy as human neutrophil proteins (defensins) 1 to 3. Analysis of peak 6 by sodium dodecyl sulfate-PAGE revealed multiple bands. Thus, human PMN have nonoxidative anticryptococcal activity residing principally in their cytoplasmic and primary granule fractions. Calprotectin mediates the cytoplasmic activity, whereas multiple proteins, including defensins, are responsible for activity of the primary granules. 相似文献
36.
Neuronal origins, peptide phenotypes and target distributions were determined for sensory and autonomic nerves projecting to the eyelid. The retrograde tracer, Fluoro-Ruby, was injected into the superior tarsal muscle and meibomian gland of Sprague-Dawley rats. Labelled neurons were observed within the pterygopalatine (31 ± 6 of a total of 8238 ± 1610 ganglion neurons), trigeminal (173 ± 43 of 62 082 ± 5869) and superior cervical ganglia (184 ± 35 of 21 900 ± 1741). Immunostaining revealed vasoactive intestinal polypeptide immunoreactivity (VIP-ir) in nearly all Fluoro-Ruby-labelled pterygopalatine ganglion neurons (86 ± 5%) but only rarely in trigeminal (0.3 ± 0.3%) or superior cervical (1.4 ± 1.4%) ganglion neurons. Calcitonin gene-related peptide (CGRP)-ir was not observed in pterygopalatine or superior cervical ganglion somata, but was present in 24 ± 4% of trigeminal neurons. Bright dopamine β-hydroxylase (DBH) immunofluorescence was observed in the majority of eyelid-projecting neurons within the superior cervical ganglia (65 ± 5%) and lighter staining was detected in pterygopalatine neurons (63 ± 3%), but no DBH-ir was observed in trigeminal neurons. Examination of eyelid sections revealed dense VIP-ir innervation of meibomian gland acini and vasculature and modest distribution within tarsal muscle. CGRP-ir fibers surrounded ductal and vascular elements of the meibomian gland and the perimeter of tarsal muscle. DBH-ir fibers were associated with meibomian gland blood vessels and acini, and were more densely distributed within tarsal muscle. This study provides evidence for prominent meibomian gland innervation by parasympathetic pterygopalatine ganglion VIP-ir neurons, with more restricted innervation by sensory trigeminal CGRP-ir and sympathetic neurons. Tarsal muscle receives abundant sympathetic innervation, as well as moderate parasympathetic and sensory CGRP-ir projections. The eyelid contains substantial non-CGRP-ir sensory innervation, the targets of which remain undetermined. The distribution of identified autonomic and sensory fibers is consistent with the idea that meibomian gland function, as well as that of the tarsal muscle, is regulated by peripheral innervation. 相似文献
37.
Simons FE Silas P Portnoy JM Catuogno J Chapman D Olufade AO Pharmd 《The Journal of allergy and clinical immunology》2003,111(6):1244-1248
BACKGROUND: H(1)-antihistamines are widely used for symptom relief in allergic disorders in infants and children; however, there are few prospective, randomized, double-blind, controlled studies of these medications in young children, and to date, no such studies have been conducted in infants. OBJECTIVE: This prospective, randomized, parallel-group, double-blind, placebo-controlled study was designed to evaluate the safety of the H(1)-antihistamine cetirizine, particularly with regard to central nervous system and cardiac effects, in infants age 6 to 11 months, inclusive. METHODS: Infants who met the entry criteria for age and had a history of treatment with an H(1)-antihistamine for an allergic or other disorder were randomized to receive 0.25 mg/kg cetirizine orally or matching placebo twice daily orally for 1 week. RESULTS: The mean daily dose in cetirizine-treated infants was 4.5 +/- 0.7 mg (SD). No differences in all-cause or treatment-related adverse events were observed between the cetirizine- and placebo-treated groups. A trend was observed toward fewer adverse events and sleep-related disturbances in the cetirizine group compared with the placebo group. No prolongation in the linear corrected QT interval was observed in cetirizine-treated infants compared with either baseline values or with values in placebo-treated infants. CONCLUSIONS: We have documented the safety of cetirizine in this short-term investigation, the first randomized, double-blind, placebo-controlled study of any H(1)-antihistamine in infants. Additional prospective, randomized, double-blind, placebo-controlled, long-term studies of cetirizine and other H(1)-antihistamines are needed in this population. 相似文献
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39.
This paper describes the tragic case of a young woman who died of cancer of
the colon after successfully donating eggs to her younger sister. Although
there is no direct link between her operation and the subsequent
development of bowel carcinoma, this case imparts a feeling of unease when
seen in conjunction with other cases reported during the last few years. It
is a reminder that little is known of the long-term consequences of some
aspects of assisted conception. Women undergoing ovarian stimulation for
themselves or a matched recipient have the right to be advised, in an
agreed format, that there is some concern about unproven potential risks
from the stimulatory drugs. The safety of egg donors must assume priority
over all other considerations, including lack of donors or any moral
position. The recent decision by the Human Fertilisation and Embryology
Authority (HFEA) to withdraw any form of payment or recompense to egg
donors does not seem to us to be based on a balance of scientific advances,
patient needs and the ethics of gamete supply. They state that the
intention to withdraw payments was implicit in the 1990 Human Fertilisation
and Embryology (HFE) Act. However the Act was based on the Warnock report
made 6 years earlier. Even in 1990 ovum donation was uncommon and fertility
drugs had not yet caused any unease. The Act provided the HFEA with
discretionary powers to issue directions so that the future policies would
be consistent with any emerging new medical evidence. It is imperative that
the HFEA provide convincing evidence on how the current policy of payment
to donors harms society, donors or recipients, and how in the UK the new
policy will improve medical practice in assisted conception. Successful
pilot studies must precede the implementation of any new policy. Failure to
do this could cause irreversible harm to the practice of assisted
conception using donor gametes, which will ultimately be against the basic
aims of the 1990 HFE Act.
相似文献
40.
Synergy between the genes for butyrylcholinesterase K variant and apolipoprotein E4 in late-onset confirmed Alzheimer's disease 总被引:5,自引:2,他引:5
The allelic frequency of the gene for the K variant of
butyrylcholinesterase (BCHE-K) was 0.17 in 74 subjects with late-onset (age
> 65 years) histopathologically diagnosed Alzheimer's disease (AD),
which was higher than the frequencies in 104 elderly control subjects
(0.09), in 14 early-onset cases of confirmed AD (0.07) and in 29 confirmed
cases of other dementia (0.10). The association of BCHE-K with late-onset
AD was limited to carriers of the epsilon 4 allele of the apolipoprotein E
gene (APOE), among whom the presence of BCHE-K gave an odds ratio of
confirmed late-onset AD of 6.9 (95% C.I. 1.65-29) in subjects > 65 years
and of 12.8 (1.9-86) in subjects > 75 years. In APOE epsilon 4 carriers
over 75 years, only 1/22 controls, compared with 10/24 confirmed late-onset
AD cases, had BCHE-K. We suggest that BCHE-K, or a nearby gene on
chromosome 3, acts in synergy with APOE epsilon 4 as a susceptibility gene
for late-onset AD.
相似文献