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51.
Induction of hepatobiliary efflux transporters in acetaminophen-induced acute liver failure cases. 总被引:1,自引:0,他引:1
Sarah N Barnes Lauren M Aleksunes Lisa Augustine George L Scheffer Michael J Goedken Amy B Jakowski Ingrid M Pruimboom-Brees Nathan J Cherrington José E Manautou 《Drug metabolism and disposition》2007,35(10):1963-1969
Alterations in transporter expression may represent a compensatory mechanism of damaged hepatocytes to reduce accumulation of potentially toxic compounds. The present study was conducted to investigate the expression of hepatobiliary efflux transporters in livers from patients after toxic acetaminophen (APAP) ingestion, with livers from patients with primary biliary cirrhosis (PBC) serving as positive controls. mRNA and protein expression of multidrug resistance-associated protein (MRP) 1-6, multidrug resistance protein (MDR) 1-3/P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) in normal (n = 6), APAP overdose (n = 5), and PBC (n = 6) human liver samples were determined by branched DNA and Western blot analysis, respectively. Double immunohistochemical staining of P-gp and proliferating cell nuclear antigen (PCNA), a marker of proliferation, was performed on paraffin-embedded tissue sections. Compared with normal liver specimens, MRP1 and MRP4 mRNA levels were elevated after APAP overdose and in PBC. Up-regulation of MRP5, MDR1, and BCRP mRNA occurred in PBC livers. Protein levels of MRP4, MRP5, BCRP, and P-gp were increased in both disease states, with MRP1 and MRP3 protein also being induced in PBC. Increased P-gp protein was confirmed immunohistochemically and was found to localize to areas of PCNA-positive hepatocytes, which were detected in APAP overdose and PBC livers. The findings from this study demonstrate that hepatic efflux transporter expression is up-regulated in cases of APAP-induced liver failure and PBC. This adaptation may aid in reducing retention of byproducts of cellular injury and bile constituents within hepatocytes. The close proximity of P-gp and PCNA-positive hepatocytes during liver injury suggests that along with cell regeneration, increased efflux transporter expression is a critical response to hepatic damage to protect the liver from additional insult. 相似文献
52.
GL Marseglia S Savasta A Ravelli TM Gaino GR Burgio 《Acta paediatrica (Oslo, Norway : 1992)》1995,84(9):1086-1088
We report the case of a 9-year-old boy with a spinal cord meningioma whose only manifestations were recurrent episodes of chest pain lasting for 2 years. This case shows that spinal cord meningioma should be considered among the possible causative factors of chronic chest pain in childhood. Chest pain, meningioma, spinal tumors 相似文献
53.
54.
Ingrid E. Scheffer John M. Hutson Garry L. Warne Gordon Ennis 《Pediatric surgery international》1988,3(2-3):165-168
The commonly held hypothesis that androgens cause testicular descent in the male [9] predicts that excess endogeous androgens in the female fetus might cause descent of the ovary. To re-evaluate this prediction from a clinical perspective, a retrospective review was made of genotypic females with congenital adrenal hyperplasia and severe virilization. Patients with maximal virilization were included, since this is the group with the earlies and highest production of adrenal androgens during fetal development. Records were reviewed of five children in whom the external genitalia were completely or almost completely masculinized, who had been regarded as males with undescended testes at birth. The position of the ovaries was determined where possible from operative or pathological reports. In four patients the ovaries had been identified at operation, and were found to be in their normal position. In none were the ovaries in or adjacent to the inguinal canal. In the most recent patient, who presented in 1979, laparotomy was not performed because of the belief that the female internal genitalia were normal. In addition, review of the literature revealed two other similar female children with maximal virilization but documented normal ovarian position. The significance of these well-known findings has been ignored in recent studies of testicular descent. Failure of endogenous androgens to affect ovarian position supports the view that initiation of gonadal descent is independent of androgens. Since Müllerian inhibiting substance is the other recognizable hormone in the fetal testis apart from testosterone, it is suggested that it may be responsible for initiating gonadal descent. 相似文献
55.
Meller D Tseng SC 《Der Ophthalmologe : Zeitschrift der Deutschen Ophthalmologischen Gesellschaft》2000,97(2):100-107
Zusammenfassung
Fragestellung: Stellenwert der Transplantation von Amnionmembran (AMT) zur Rekonstruktion des perilimbalen Stromas bei Patienten mit Limbusinsuffizienz
(LI). Desweiteren wurde die Erfolgsrate der AMT mit oder ohne allogener Limbustransplantation (aLT) bei LI analysiert.
Patienten und Methode: 47 Augen von 42 Patienten mit einer zytologisch nachgewiesenen, ?tiologisch unterschiedlichen LI wurden prospektiv untersucht.
Die Patienten wurden in Abh?ngigkeit des Auspr?gungsgrades der LI in drei Gruppen eingeteilt. In Gruppe A (fokale/partielle
LI, 18 Augen) wurde nur eine AMT, in Gruppe B (moderate LI, 13 Augen) eine AMT und aLT und in Gruppe C (ausgepr?gte, komplette
LI, 16 Augen) eine AMT, aLT und perforierende Keratoplastik (pKP) durchgeführt. Mit Ausnahme der Gruppe A erfolgte bei allen
Patienten eine systemische Behandlung mit Cyclosporin A.
Ergebnisse: Alle bis auf 2 Augen, die als Grunderkrankung eine atopische Keratitis hatten, zeigten eine rasche Epithelialisierung (2–4
Wochen), eine reduzierte Entzündung, Vaskularisation und Narbenbildung im Bereich der von Amnionmembran gedeckten Oberfl?che,
die sich glatt und benetzt darstellte. In einem durchschnittlichen Nachbeobachtungszeitraum von 23 Monaten erzielten 38 Augen
(82.6%) eine verbesserte Sehsch?rfe. In 15 Augen wurde eine Zunahme um 6 oder mehr Sehsch?rfenstufen (SS), in 10 Augen um
4–5 SS und in 13 Augen um 1–3 SS beobachtet. In Gruppe A zeigten 16 von 18 Augen (88.9%), in Gruppe B 10 von 13 (77%) und
in Gruppe C 12 von 16 Augen (75%) eine Visuszunahme. Eine Absto?ung des Hornhauttransplantates trat in 12 von 16 Augen (75%)
in Gruppe C auf. Eine frühe, reversible Absto?ung des Limbustransplantates wurde in 3 von 29 (10.3%) Augen und eine rezidivierende
Limbusinsuffizienz in 8 von 29 (27.6%) Augen der Gruppen B und C beobachtet.
Schlu?folgerung: Bei einer fokalen LI mit oberfl?chlicher Hornhautbeteiligung ist die AMT ausreichend und somit der aLT überlegen, da hier
die systemische Applikation von Cyclosporin A entf?llt. Bei einer ausgepr?gten, kompletten LI ist eine zus?tzliche aLT erforderlich
und in diesen F?llen begünstigt die AMT durch Reduktion der Entzündung und Vaskularisation im perilimbalen Stroma die Prognose
der LT.
相似文献
56.
The role of NGF signaling in human limbal epithelium expanded by amniotic membrane culture 总被引:17,自引:0,他引:17
PURPOSE: Amniotic membrane (AM) transplantation facilitates rapid epithelialization in severe neurotrophic corneal ulcers. To elucidate its action mechanism, we investigated the expression of ligands and receptors of the neurotrophin family by human limbal epithelial (HLE) cells expanded on AM cultures. METHODS: Expression of nerve growth factor (NGF); neurotrophins (NT)3 and NT4; brain-derived neurotrophic factor (BDNF); tyrosine kinase-transducing receptors TrkA, TrkB, and TrkC; and a pan-NT low-affinity receptor (p75(NTR)) was examined by immunostaining in the normal human corneolimbus, HLE grown on intact epithelially denuded AM, and stratified HLE, after subcutaneous implantation in NIH-bg-nu-xid BR mice. NGF protein level was assayed by an ELISA in extracts of intact and epithelially denuded AM. K252a, a specific inhibitor of TrkA autophosphorylation, was added to test whether it would inhibit HLE expansion on AM culture. RESULTS: Strong positive TrkA staining was confined to the basal epithelial cell layer of normal corneal and limbal epithelia, with the highest intensity noted in the limbus. TrkA staining was also strongly positive in the basal layer of HLE cells cultured on intact and epithelially denuded AM and in basal and some suprabasal layers of stratified HLE transplanted in nude mice. Positive staining of p75(NTR) was noted in the full-thickness of the corneal epithelium but was limited to the superficial layers of the limbus and in HLE cells cultured on intact and epithelially denuded AM, but was weak in HLE transplanted to nude mice. Weak staining of NT3 and TrkC was noted in the suprabasal layers of corneal and limbal epithelia but was negative in the stratified HLE in nude mice. Negative staining of NGF, NT4, BDNF, and TrkB was noted in all specimens tested. The NGF protein level was readily measured as 35.6 +/- 9.1 and 41 +/- 12.5 pg/mg protein in the homogenate of the intact and epithelially denuded AM, respectively (P = 0.0256). K252a significantly inhibited the HLE outgrowth on intact AM culture (P = 0.024). CONCLUSIONS: The strong expression of TrkA but not p75(NTR) in the limbal basal epithelial cells in vivo suggests that NGF signaling favors limbal epithelial stem cell survival. Such a phenotype is preserved in HLE cells on AM. Blocking NGF signaling significantly retarded HLE expansion on AM, supporting the notion that NGF is important in expansion of limbal epithelial progenitor cells. Furthermore, a high and therapeutic level of NGF was present in AM. Collectively, these findings indicate that denervated neurotrophic ulcers are associated with poor epithelial stem cell function at the limbus. Future studies are needed to determine whether AM transplantation to heal such ulcers may include the promotion of nerve regeneration and survival of epithelial progenitor cells. 相似文献
57.
Amniotic membrane (AM) reconstructed human conjunctival surfaces recover a goblet cell density higher than normal. Cultured rabbit conjunctival epithelial cells (RCE) on AM preferentially exhibit non-goblet epithelial differentiation. It was thus wondered if conjunctival progenitor cells that might have been preserved during ex vivo expansion on AM can still differentiate into conjunctival non-goblet epithelial and goblet cells under the influence of mesenchymal cells. Fourteen day old AM cultures of RCE were subcutaneously implanted in Balb/c athymic mice for 11 days and processed for PAS staining and immunostaining with monoclonal antibodies to conjunctival goblet cell mucin (MUC5AC, AM3), glycocalyx (AMEM2), cornea specific cytokeratins K3 (AE5) and K12 (AK2) and basal cell specific cytokeratin K14. Cell cycle kinetics were measured by BrdU labelling for 1 or 7 days. The 7 day labelled RCE were chased for 14 days in the same primary culture. After subcutaneous implantation, conjunctival non-goblet epithelial cells increased stratification and formed occasional cysts. The resultant epithelial phenotype was conjunctival with many PAS-positive, MUC5AC-positive, and AM3-positive goblet cells, AMEM2-positive suprabasal and superficial cells, and K14-positive basal cells, but was not corneal (negative to AE5 and AK2 staining). Twenty four hr BrdU labelling showed a labelling index of 42.5%. A higher labelling index or 69% was noted after continuous BrdU labelling for 7 days. A large number of label retaining basal cells with a labelling index of 84% were noted following 14 days of chase. Conjunctival epithelial progenitor cells for goblet and non-goblet cell differentiation are preserved by AM in vitro as evidenced by being able to differentiate into goblet cells in a permissive stromal environment, and being slow-cycling, and label retaining. This information is useful for future ex vivo expansion of conjunctival epithelial stem cells for conjunctival surface reconstruction. 相似文献
58.
Phenotypic comparison of two Scottish families with mutations in different genes causing autosomal dominant nocturnal frontal lobe epilepsy 总被引:3,自引:0,他引:3
McLellan A Phillips HA Rittey C Kirkpatrick M Mulley JC Goudie D Stephenson JB Tolmie J Scheffer IE Berkovic SF Zuberi SM 《Epilepsia》2003,44(4):613-617
PURPOSE: Mutations in genes coding for the alpha 4 and beta 2 subunits of the neuronal nicotinic acetylcholine receptor receptor (CHRN) are known to cause autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Here we examined the phenotypes in two families, from the same ethnic and geographic backgrounds, with ADNFLE as a result of mutations in these two different subunits of CHRN. METHODS: All affected family members underwent a detailed clinical evaluation and review of available EEG, neuroimaging, and videotapes of seizures. The molecular study of family D is reported here; family S has a previously reported mutation in the beta 2 subunit of CHRN. RESULTS: A total of 16 individuals with ADNFLE were identified in the two families. In both families, seizure semiology, age at seizure onset, and the natural history of the seizure disorder was similar. Intrafamilial variation in terms of severity of epilepsy syndrome was present in both families. A significant number of individuals from each family had a history of psychological problems. The molecular study of family D revealed a Ser248Phe mutation in the alpha 4 subunit of CHRN. CONCLUSIONS: The epilepsy phenotype is not distinguishable in the two families who have ADNFLE as a result of mutations in genes coding for different CHRN subunits. This is likely to be due to the similar functional consequences of each mutation on the CHRN receptor. 相似文献
59.
Major vault protein, a marker of drug resistance, is upregulated in refractory epilepsy 总被引:16,自引:4,他引:12
Sisodiya SM Martinian L Scheffer GL van der Valk P Cross JH Scheper RJ Harding BN Thom M 《Epilepsia》2003,44(11):1388-1396
PURPOSE: The molecular basis of drug resistance in epilepsy is being explored. Two proteins associated with drug resistance in cancer, P-glycoprotein and multidrug resistance-associated protein 1, are upregulated in human epileptogenic pathologies. Other proteins associated with resistance in cancer include major vault protein (MVP) and breast cancer resistance protein (BCRP). We hypothesized that these proteins would also be upregulated in human epileptogenic pathologies. METHODS: Hippocampal sclerosis (HS), focal cortical dysplasia (FCD), and dysembryoplastic neuroepithelial tumor (DNT) were studied by using immunohistochemistry for MVP and BCRP. Nonepileptogenic control and histologically normal brain adjacent to epileptogenic tissue were used for comparison. RESULTS: MVP and BCRP were expressed ubiquitously in brain capillary endothelium. Ectopic upregulation of MVP was seen in hilar neurons in HS, dysplastic neurons in FCD, and lesional neurons in DNT. Only in HS cases were rare extralesional neurons immunoreactive. Glial upregulation was not seen. There was no qualitative upregulation of BCRP. CONCLUSIONS: These results show that more than one resistance protein may be upregulated in a given epileptogenic pathology and may contribute to drug resistance. Determination of the types, amounts, and distribution of such proteins will be necessary for rational treatment for drug resistance in epilepsy. 相似文献
60.
Sodium channel alpha1-subunit mutations in severe myoclonic epilepsy of infancy and infantile spasms