全文获取类型
收费全文 | 6857篇 |
免费 | 725篇 |
国内免费 | 11篇 |
专业分类
耳鼻咽喉 | 61篇 |
儿科学 | 242篇 |
妇产科学 | 120篇 |
基础医学 | 1091篇 |
口腔科学 | 158篇 |
临床医学 | 798篇 |
内科学 | 1133篇 |
皮肤病学 | 498篇 |
神经病学 | 533篇 |
特种医学 | 492篇 |
外科学 | 753篇 |
综合类 | 125篇 |
预防医学 | 613篇 |
眼科学 | 87篇 |
药学 | 554篇 |
中国医学 | 4篇 |
肿瘤学 | 331篇 |
出版年
2022年 | 56篇 |
2021年 | 97篇 |
2020年 | 86篇 |
2019年 | 113篇 |
2018年 | 130篇 |
2017年 | 109篇 |
2016年 | 104篇 |
2015年 | 119篇 |
2014年 | 151篇 |
2013年 | 198篇 |
2012年 | 264篇 |
2011年 | 291篇 |
2010年 | 182篇 |
2009年 | 192篇 |
2008年 | 273篇 |
2007年 | 293篇 |
2006年 | 299篇 |
2005年 | 314篇 |
2004年 | 262篇 |
2003年 | 260篇 |
2002年 | 232篇 |
2001年 | 227篇 |
2000年 | 235篇 |
1999年 | 205篇 |
1998年 | 146篇 |
1997年 | 140篇 |
1996年 | 124篇 |
1995年 | 122篇 |
1994年 | 75篇 |
1993年 | 78篇 |
1992年 | 160篇 |
1991年 | 157篇 |
1990年 | 144篇 |
1989年 | 154篇 |
1988年 | 148篇 |
1987年 | 146篇 |
1986年 | 123篇 |
1985年 | 117篇 |
1984年 | 92篇 |
1983年 | 73篇 |
1982年 | 63篇 |
1981年 | 62篇 |
1979年 | 73篇 |
1978年 | 56篇 |
1977年 | 61篇 |
1976年 | 52篇 |
1975年 | 60篇 |
1974年 | 64篇 |
1973年 | 59篇 |
1972年 | 49篇 |
排序方式: 共有7593条查询结果,搜索用时 46 毫秒
91.
92.
Evaluation of an animal model system for cryptosporidiosis: therapeutic efficacy of paromomycin and hyperimmune bovine colostrum-immunoglobulin. 总被引:8,自引:0,他引:8
下载免费PDF全文
![点击此处可从《Clinical and Vaccine Immunology : CVI》网站下载免费的PDF全文](/ch/ext_images/free.gif)
S Tzipori W Rand J Griffiths G Widmer J Crabb 《Clinical and Vaccine Immunology : CVI》1994,1(4):450-463
Several immunodeficient rodent models currently exist in which persistent, largely asymptomatic, Cryptosporidium parvum infections can be established. Piglets, in contrast, develop a self-limiting diarrheal illness. We have consequently developed an animal model system in which scid mice were used to screen drugs for inhibitory activity against C. parvum, after which the drugs' therapeutic potential was evaluated with piglets. Paromomycin and hyperimmune bovine colostrum-immunoglobulin were selected to evaluate this system. C. paravum infections in suckling scid mice tended to be associated with villus surfaces, while in weaned and in older scid mice infections were more commonly localized in abscessed crypts. Rates of oocyst shedding in suckling scid mice were 50 to 200 times higher than in weaned mice and therefore made suckling mice a considerably more sensitive model for drug testing. Paromomycin given in high doses over 9 to 10 days was not toxic to either scid mice (3,000 mg/kg of body weight per day) or piglets (500 mg/kg/day). Paromomycin treatment was very effective against villus surface infections in suckling mice and considerably less effective against infections in inaccessible sites such as abscessed crypts and stomach pits seen in weaned and adult scid mice. The therapeutic efficacy of paromomycin in piglets depended on the severity of the diarrheal illness. Mild to moderate diarrhea and infection were cleared after paromomycin treatment of piglets infected with one C. parvum isolate. However, paromomycin had no impact on severely affected piglets infected with a second isolate, presumably because of a rapid transit time through the gut. In contrast to paromomycin hyperimmune bovine colostrum-immunoglobulin treatment reduced the rate of C. parvum infection moderately in scid mice and only slightly in piglets, again probably because of a rapid transit time through the gut and inactivation in the stomach. It was also clear that the impact of effective drugs against C. parvum can be detected within 5 days after the onset of treatment in either model. 相似文献
93.
Functional consequences of ROMK mutants linked to antenatal Bartter's syndrome and implications for treatment 总被引:4,自引:0,他引:4
The antenatal variant of Bartter's syndrome is an autosomal recessive
kidney disease characterized by polyhydramnios, premature delivery,
hypokalemic alkalosis and hypercalciuria. It is genetically heterogeneous,
having been linked recently to mutations in an ATP- sensitive, renal outer
medullary K+channel, ROMK, and earlier to mutations in the Na-K-2Cl
co-transporter, NKCC2. We characterized four of the mutations reported in
three heterozygous ROMK variants of antenatal Bartter's and found that each
expressed a distinct phenotype in Sf9 cells. One mutation expressed normal
function and appears to be an allelic polymorphism. The other three
mutations produced channels with significantly reduced K+fluxes. However,
the mechanisms in each case were different and reflected abnormalities in
phosphorylation, proteolytic processing or protein trafficking. The
different mechanisms may be important in the design of appropriate therapy
for patients with this disease.
相似文献
94.
Detecting pre-ovulatory luteinizing hormone surges in urine 总被引:2,自引:1,他引:2
Kesner JS; Knecht EA; Krieg EF Jr; Wilcox AJ; O'Connor JF 《Human reproduction (Oxford, England)》1998,13(1):15-21
The study objectives were to determine (i) if pre-ovulatory luteinizing
hormone (LH) surges, undetected in urine by two immunoradiometric assays
(IRMA), were detectable by an ultrasensitive immunofluorometric assay
(IFMA) and (ii) the influence of creatinine adjustment on the detection and
timing of the urinary LH surges. Daily urine specimens were contributed by
healthy 25-36 year old volunteers during 14 ovulatory menstrual cycles for
an epidemiological study conducted in 1983-1985. Specimens were selected as
having been previously assayed by two IRMA without consistently detecting
LH surges. These urine specimens were remeasured using an IFMA and adjusted
for creatinine concentration. IFMA measurements revealed unambiguous LH
surges in all cycles. Adjusting IRMA urinary LH values for creatinine
concentrations revealed previously undetected LH surges in four of eight
cycles. Creatinine adjustment also altered the timing of IRMA and IFMA LH
surges by 1-5 days. These results demonstrate an IFMA that detects pre-
ovulatory LH surges in unpreserved, frozen urine from cycles where such
surges were previously undetectable. Further, creatinine adjustment can
markedly affect detection and timing of the onset and peak of the urinary
LH surge. While our analysis suggests that this adjustment improves the
validity of the LH measure, this requires further investigation.
相似文献
95.
An investigation into the noise levels in a clinical chemistry laboratory has been carried out. It was shown that although the levels were insufficient to cause damage to hearing, they exceeded the criteria of acceptability for offices and workshops. 相似文献
96.
97.
Pollard PJ Brière JJ Alam NA Barwell J Barclay E Wortham NC Hunt T Mitchell M Olpin S Moat SJ Hargreaves IP Heales SJ Chung YL Griffiths JR Dalgleish A McGrath JA Gleeson MJ Hodgson SV Poulsom R Rustin P Tomlinson IP 《Human molecular genetics》2005,14(15):2231-2239
The nuclear-encoded Krebs cycle enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDHB, -C and -D), act as tumour suppressors. Germline mutations in FH predispose individuals to leiomyomas and renal cell cancer (HLRCC), whereas mutations in SDH cause paragangliomas and phaeochromocytomas (HPGL). In this study, we have shown that FH-deficient cells and tumours accumulate fumarate and, to a lesser extent, succinate. SDH-deficient tumours principally accumulate succinate. In situ analyses showed that these tumours also have over-expression of hypoxia-inducible factor 1alpha (HIF1alpha), activation of HIF1alphatargets (such as vascular endothelial growth factor) and high microvessel density. We found no evidence of increased reactive oxygen species in our cells. Our data provide in vivo evidence to support the hypothesis that increased succinate and/or fumarate causes stabilization of HIF1alpha a plausible mechanism, inhibition of HIF prolyl hydroxylases, has previously been suggested by in vitro studies. The basic mechanism of tumorigenesis in HPGL and HLRCC is likely to be pseudo-hypoxic drive, just as it is in von Hippel-Lindau syndrome. 相似文献
98.
Cryptosporidium parvum Infection of Human Intestinal Xenografts in SCID Mice Induces Production of Human Tumor Necrosis Factor Alpha and Interleukin-8 总被引:2,自引:0,他引:2
下载免费PDF全文
![点击此处可从《Infection and immunity》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Karl B. Seydel Tonghai Zhang Gretchen A. Champion Carl Fichtenbaum Paul E. Swanson Saul Tzipori Jeffrey K. Griffiths Samuel L. Stanley Jr. 《Infection and immunity》1998,66(5):2379-2382
The protozoan parasite Cryptosporidium parvum invades intestinal epithelial cells and can cause life-threatening diarrhea in immunocompromised individuals. Despite the clinical importance of this organism, much remains to be learned about the pathogenesis of C. parvum-induced diarrhea. To explore the role of the intestinal inflammatory response in C. parvum disease, using C. parvum oocysts we infected human intestinal xenografts in severe combined immunodeficient (SCID) mice. Seven days after infection, we found levels of human tumor necrosis factor alpha and interleukin-8 in C. parvum-infected human intestinal xenografts that were significantly higher than those seen in uninfected control xenografts. These results demonstrate that human intestinal cells produce proinflammatory cytokines in response to C. parvum infection and establish SCID-HU-INT mice as a model system to study the interactions of C. parvum with the human intestine. 相似文献
99.
The antibody response to the synthetic polypeptide poly (L Tyr, L Glu)-poly (DL Ala)--poly (L Lys) designated (T,G)-A--L, was investigated in inbred, congenic, F1 and F2 hybrid strains of mice. The antibody response was analysed at both low (10 microgram) and high (50 microgram) immunizing doses of (T,G)-A--L. Antibodies were measured using both a modified Farr assay and a plate binding assay. At low immunizing doses it was found that all of the congenic and non-congenic (low responder x low responder) F1 hybrids were low responders. However, the quantitative antibody response of one non-congenic (low responder x low responder) F2 hybrid segregated in a 1:1 ratio of high responders to low responders, suggesting some form of complementation of (T,G)-A--L Ir genes. At high immunizing doses it was found that congenic and non-congenic (low responder x low responder) F1 hybrids were all high responders, indicating a complementation of Ir genes to (T,G)-A--L. This complementation was confirmed using two different routes of immunization, namely footpad and intraperitoneal. Furthermore the quantitative antibody responses of (low responder x low responder) F2 hybrids segregate in a 1:1 ratio of high responders to low responders. The class of antibodies produced to (T,G)-A--L in (low responder x low responder) F1 hybrids was determined by gel filtration on Sephadex G-200, and found to be predominantly IgG, with lesser amounts of IgM. 相似文献
100.
Transgenic and Natural Mouse Models of Proteolipid Protein (PLP)-Related Dysmyelination and Demyelination 总被引:2,自引:0,他引:2
I.R. Griffiths A. Schneider J. Anderson K-A. Nave 《Brain pathology (Zurich, Switzerland)》1995,5(3):275-281
The X chromosome-linked PLP/DM-20 gene is the CNS myelin gene most frequently associated with mutations, resulting in dysmyelination in several species including man (Pelizaeus-Merzbacher disease, X-linked Spastic Paraplegia). The pathology of most PLP gene mutations is characterized by hypomyelination, glial cell proliferation, increased numbers of microglia, and premature oligodendrocyte death. In most mutants, residual myelin structures have an abnormal ultrastructure and periodicity. Surprisingly, transgenic mice which carry extra copies of the wild type PLP gene show dysmyelination, demonstrating that the PLP gene is dosage sensitive. Pathological changes of transgenic mice vary from the phenotype of natural mutants. Specifically, many Golgi saccules of oligodendrocytes are vacuolated and the cytoplasm contains autophagic vacuoles hinting at a perturbation in protein trafficking. In fact, upon transgenic overexpression PLP becomes a prominent peripheral myelin protein, whereas in normal Schwann cells PLP is restricted from entering the myelin compartment. Surprisingly, transgenic animals which overexpress PLP/DM-20 at a low level appear normal during early development, but later spontaneously demyelinate. The mechanisms underlying this demyelination phenotype is unknown but an immune-mediated process has been suggested. All attempts to correct the phenotype of natural PLP mutants, such as jimpy mice, with a wild type transgene have had little effects, indicating a dominant-negative effect of the mutant gene product. On the other hand, mice with a targeted disruption of the PLP/DM-20 gene have suprisingly minor clinical signs. This suggests that the lethal phenotype associated with the majority of PLP gene mutations is a complex combination of loss and gain-of-function effects of a mutant myelin protein. 相似文献