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11.
12.
Distribution of mutations in the PEX gene in families with X-linked hypophosphataemic rickets (HYP) 总被引:8,自引:0,他引:8
Rowe PS; Oudet CL; Francis F; Sinding C; Pannetier S; Econs MJ; Strom TM; Meitinger T; Garabedian M; David A; Macher MA; Questiaux E; Popowska E; Pronicka E; Read AP; Mokrzycki A; Glorieux FH; Drezner MK; Hanauer A; Lehrach H; Goulding JN; O'Riordan JL 《Human molecular genetics》1997,6(4):539-549
Mutations in the PEX gene at Xp22.1 (phosphate-regulating gene with
homologies to endopeptidases, on the X-chromosome), are responsible for
X-linked hypophosphataemic rickets (HYP). Homology of PEX to the M13 family
of Zn2+ metallopeptidases which include neprilysin (NEP) as prototype, has
raised important questions regarding PEX function at the molecular level.
The aim of this study was to analyse 99 HYP families for PEX gene
mutations, and to correlate predicted changes in the protein structure with
Zn2+ metallopeptidase gene function. Primers flanking 22 characterised
exons were used to amplify DNA by PCR, and SSCP was then used to screen for
mutations. Deletions, insertions, nonsense mutations, stop codons and
splice mutations occurred in 83% of families screened for in all 22 exons,
and 51% of a separate set of families screened in 17 PEX gene exons.
Missense mutations in four regions of the gene were informative regarding
function, with one mutation in the Zn2+-binding site predicted to alter
substrate enzyme interaction and catalysis. Computer analysis of the
remaining mutations predicted changes in secondary structure,
N-glycosylation, protein phosphorylation and catalytic site molecular
structure. The wide range of mutations that align with regions required for
protease activity in NEP suggests that PEX also functions as a protease,
and may act by processing factor(s) involved in bone mineral metabolism.
相似文献
13.
Rigor and resistance to stretch in vertebrate smooth muscle 总被引:2,自引:0,他引:2
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OBJECTIVE: Because the survival rate has increased for extremely low birth weight neonates, many have raised the concern that the rate of developmental disability among survivors will also increase. To address this concern, we analyzed changes over time in survival and major neurosensory impairment in a sample of extremely low birth weight infants born between July 1, 1979, and June 30, 1994. METHODS: The study sample included 513 infants with birth weights of 501 to 800 g who were cared for in either of the two neonatal intensive care units that serve a 17-county region in northwest North Carolina and who were born to mothers residing in that region. At 1 year of age (corrected for gestation), survivors were examined by a pediatrician and were tested using the Bayley Scales of Infant Development. Major neurosensory impairment was defined as cerebral palsy, a Bayley Mental Developmental Index <68, or blindness. A total of 209/216 (97%) of survivors were examined at 1 year of age. Epoch of birth was defined as follows: epoch 1, July 1, 1979 to June 30, 1984; epoch 2, July 1, 1984 to June 30, 1989; and epoch 3, July 1, 1989 to June 30, 1994. RESULTS: Survival rates for epochs 1, 2, and 3 were, respectively, 24/120 (20%), 63/175 (36%), and 129/218 (59%). In contrast, the proportions with a major neurosensory impairment did not increase over time; rates for successive epochs were 6/24 (25%), 17/61 (28%), and 26/124 (21%). Rates of cerebral palsy were 3/24 (13%), 12/61 (20%), and 9/124 (7%); rates of delayed mental development were 4/24 (17%), 12/61 (20%), and 17/124 (14%); and rates of blindness were 2/24 (8%), 0/62, and 5/124 (4%), respectively. CONCLUSIONS: This analysis suggests that the increasing survival of extremely low birth weight neonates since the late 1970s has not resulted in an increased rate of major developmental problems identifiable at 1 year of age. 相似文献
17.
Oberyszyn TM; Conti CJ; Ross MS; Oberyszyn AS; Tober KL; Rackoff AI; Robertson FM 《Carcinogenesis》1998,19(3):445-455
The beta2 integrin (CD 18/CD 11 a, b, c) family of proteins mediate
adherence of leukocytes to vascular endothelium and the associated ligand,
intercellular adhesion molecule-1 (ICAM-1; CD 54), interacts with beta2
integrin proteins to allow transendothelial migration of leukocytes into
sites of inflammation. The present study examines the function of these
proteins in a murine model of acute cutaneous inflammation induced
following topical application of 12-O- tetradecanoylphorbol-13-acetate
(TPA) to the dorsal epidermis of SENCAR mice and in a model of skin
multistage carcinogenesis. At 24 h following topical application of TPA to
the dorsal epidermis of mice, dermal leukocytes expressed higher levels of
beta2 integrin protein compared with the lower levels of beta2 integrin
protein expression by peripheral blood leukocytes. ICAM-1 protein was
localized to epidermal keratinocytes and vascular endothelium in
TPA-treated skin and to proliferating papilloma cells. Intravenous (i.v.)
injection of either 50 microg anti-beta2 integrin antibody alone or in
combination with anti-ICAM-1 antibody significantly inhibited both
TPA-stimulated neutrophil infiltration into the dermis (P < 0.001) and
myeloperoxidase (MPO) activity (P < 0.03 anti-beta2 integrin antibody; P
< 0.01 anti- beta2 integrin + ICAM-1 adhesion molecule antibodies), but
had no effect on TPA-induced epidermal hyperplasia. In addition, injection
of either anti-ICAM-1 adhesion molecule antibody alone (P < 0.004) or in
combination with anti-beta2 integrin antibody (P < 0.001) significantly
inhibited TPA-induced production of 7,8-dihydroxy-2'-deoxyguanosine (8-
OHdG) immunoreactive proteins by epidermal keratinocytes. Beta2
integrin/ICAM-1 adhesion molecules work in concert to regulate migration,
retention and functional activation of leukocytes within the dermis during
TPA-induced skin inflammation and within stromal tissue of papillomas that
form during multi-stage carcinogenesis. Agents that inhibit these
receptor/ligand interactions may be useful in defining the roles of
specific cell populations in cutaneous inflammation and multistage
carcinogenesis and may also have potential as anti-promoting and
anti-progression agents.
相似文献
18.
Aberrant crypt focus promotion and glucose intolerance: correlation in the rat across diets differing in fat, n-3 fatty acids and energy 总被引:1,自引:0,他引:1
Koohestani N; Chia MC; Pham NA; Tran TT; Minkin S; Wolever TM; Bruce WR 《Carcinogenesis》1998,19(9):1679-1684
McKeown-Eyssen (Cancer Epidemiol. Biomarkers Prevent., 3, 687-695, 1994)
and Giovannucci (Cancer Causes Control, 6, 164-179, 1995), noting the
striking similarity in lifestyle risk factors for colorectal cancer and
insulin resistance, proposed that the hyperinsulinemia, glycemia and
hypertriglyceridemia associated with insulin resistance promotes colon
cancer. To compare the effect of diet on colon cancer promotion and insulin
resistance in the F344 rat, we assessed the effect of fat, n-3 fatty acids
and energy in pairwise comparisons on average size of aberrant crypt foci
(ACF) and on glucose intolerance in the same animals in a single
experiment. Diets high in fat and energy increased and diets with increased
n-3 fatty acids and calorie restriction decreased both ACF growth and
glucose intolerance compared with control diets. The measures of promotion
of colon cancer and insulin resistance were strongly correlated (n = 98, r
= 0.67, P < 0.001). In addition, both were highly correlated with daily
energy intake (r = 0.62 and 0.66) and were also correlated with basal
(post-prandial) insulin, glucose and triglycerides (r = 0.31-0.53, P <
0.01). We concluded that ACF growth and glucose intolerance are correlated
for a wide range of diets and that increased circulating energy (glucose
and triglycerides) may lead to both colon cancer promotion and insulin
resistance.
相似文献
19.
20.
The role of defective fibrinolysis caused by elevated activity of plasminogen activator inhibitor-1 (PAI-1) in promoting fibrin deposition in vivo has not been well established. The present study compared the efficacy of thrombin or ancrod, a venom-derived enzyme that clots fibrinogen, to induce fibrin formation in rabbits with elevated PAI-1 levels. One set of male New Zealand rabbits received intravenous endotoxin to increase endogenous PAI-1 activity followed by a 1-hour infusion of ancrod or thrombin; another set of normal rabbits received intravenous human recombinant PAI-1 (rPAI-1) during an infusion of ancrod or thrombin. Thirty minutes after the end of the infusion, renal fibrin deposition was assessed by histopathology. Animals receiving endotoxin, rPAI-1, ancrod, or thrombin alone did not develop renal thrombi. All endotoxin-treated rabbits developed fibrin deposition when infused with ancrod (n = 4) or thrombin (n = 6). Fibrin deposition occurred in 7 of 7 rabbits receiving both rPAI-1 and ancrod and in only 1 of 6 receiving rPAI-1 and thrombin (P < .01). In vitro, thrombin but not ancrod was inactivated by normal rabbit plasma and by purified antithrombin III or thrombomodulin. The data indicate that elevated levels of PAI-1 promote fibrin deposition in rabbits infused with ancrod but not with thrombin. In endotoxin-treated rabbits, fibrin deposition that occurs with thrombin infusion may be caused by decreased inhibition of procoagulant activity and not increased PAI-1 activity. 相似文献