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91.
ENU mutagenesis identifies mice with mitochondrial branched-chain aminotransferase deficiency resembling human maple syrup urine disease 下载免费PDF全文
Wu JY Kao HJ Li SC Stevens R Hillman S Millington D Chen YT 《The Journal of clinical investigation》2004,113(3):434-440
Tandem mass spectrometry was applied to detect derangements in the pathways of amino acid and fatty acid metabolism in N-ethyl-N-nitrosourea-treated (ENU-treated) mice. We identified mice with marked elevation of blood branched-chain amino acids (BCAAs), ketoaciduria, and clinical features resembling human maple syrup urine disease (MSUD), a severe genetic metabolic disorder caused by the deficiency of branched-chain alpha-keto acid dehydrogenase (BCKD) complex. However, the BCKD genes and enzyme activity were normal. Sequencing of branched-chain aminotransferase genes (Bcat) showed no mutation in the cytoplasmic isoform (Bcat-1) but revealed a homozygous splice site mutation in the mitochondrial isoform (Bcat-2). The mutation caused a deletion of exon 2, a marked decrease in Bcat-2 mRNA, and a deficiency in both BCAT-2 protein and its enzyme activity. Affected mice responded to a BCAA-restricted diet with amelioration of the clinical symptoms and normalization of the amino acid pattern. We conclude that BCAT-2 deficiency in the mouse can cause a disease that mimics human MSUD. These mice provide an important animal model for study of BCAA metabolism and its toxicity. Metabolomics-guided screening, coupled with ENU mutagenesis, is a powerful approach in uncovering novel enzyme deficiencies and recognizing important pathways of genetic metabolic disorders. 相似文献
92.
Corbett M Chambers SL Shadbolt B Hillman LC Taupin D 《The Medical journal of Australia》2004,181(8):423-427
OBJECTIVES: To determine the response to colorectal cancer (CRC) screening by colonoscopy, through direct invitation or through invitation by general practitioners. DESIGN AND SETTING: Two-way comparison of randomised population sampling versus cluster sampling of a representative general practice population in the Australian Capital Territory, May 2002 to January 2004. INTERVENTION: Invitation to screen, assessment for eligibility, interview, and colonoscopy. SUBJECTS: 881 subjects aged 55-74 years were invited to screen: 520 from the electoral roll (ER) sample and 361 from the general practice (GP) cluster sample. MAIN OUTCOME MEASURES: Response rate, participation rate, and rate of adenomatous polyps in the screened group. RESULTS: Participation was similar in the ER arm (35.1%; 95% CI, 30.2%-40.3%) and the GP arm (40.1%; 95% CI, 29.2%-51.0%) after correcting for ineligibility, which was higher in the ER arm. Superior eligibility in the GP arm was offset by the labour of manual record review. Response rates after two invitations were similar for the two groups (ER arm: 78.8%; 95% CI, 75.1%-82.1%; GP arm: 81.7%; 95% CI, 73.8%-89.6%). Overall, 53.4% ineligibility arose from having a colonoscopy in the past 10 years (ER arm, 98/178; GP arm, 42/84). Of 231 colonoscopies performed, 229 were complete, with 32% of subjects screened having adenomatous polyps. CONCLUSIONS: Colonoscopy-based CRC screening yields similar response and participation rates with either random population sampling or general practice cluster sampling, with population sampling through the electoral roll providing greater ease of recruitment. 相似文献
93.
3-Aminopropanal (3-AP), a degradation product of polyamines such as spermine, spermidine and putrescine, is a lysosomotropic small aldehyde that causes apoptosis or necrosis of most cells in culture, apparently by inducing moderate or extensive lysosomal rupture, respectively, and secondary mitochondrial changes. Here, using the human neuroblastoma SH-SY5Y cell line, we found simultaneous occurrence of apoptotic and necrotic cell death when cultures were exposed to 3-AP in concentrations that usually are either nontoxic, or only cause apoptosis. At 30 mM, but not at 10 mM, the lysosomotropic base and proton acceptor NH3 completely blocked the toxic effect of 3-AP, proving that 3-AP is lysosomotropic and suggesting that the lysosomal membrane proton pump of neuroblastoma cells is highly effective, creating a lower than normal lysosomal pH and, thus, extensive intralysosomal accumulation of lysosomotropic drugs. A wave of internal oxidative stress, secondary to changes in mitochondrial membrane potential, followed and gave rise to further lysosomal rupture. The preincubation of cells for 24 h with a chain-breaking free radical-scavenger, alpha-tocopherol, before exposure to 3-AP, significantly delayed both the wave of oxidative stress and the secondary lysosomal rupture, while it did not interfere with the early 3-AP-mediated phase of lysosomal break. Obviously, the reported oxidative stress and apoptosis/necrosis are consequences of lysosomal rupture with ensuing release of lysosomal enzymes resulting in direct/indirect effects on mitochondrial permeability, membrane potential, and electron transport. The induced oxidative stress seems to act as an amplifying loop causing further lysosomal break that can be partially prevented by alpha-tocopherol. Perhaps secondary brain damage during a critical post injury period can be prevented by the use of drugs that temporarily raise lysosomal pH, inactivate intralysosomal 3-AP, or stabilize lysosomal membranes against oxidative stress. 相似文献
94.
Hillman H 《Medical hypotheses》2003,61(2):190-193
Forty-two proper questions about the research methods, the structure, physiology, biochemistry, pathology and theory of cell biology and 27 more about neurobiology are listed. These have not hitherto been addressed in the literature, other than in my previous publications. The answers to some of them show anomalies in current views, or draw attention to control experiments, which have never been done. Progress will be limited until these important questions are addressed. 相似文献
95.
Dowdy SC Constantinou CL Hartmann LC Keeney GL Suman VJ Hillman DW Podratz KC 《Gynecologic oncology》2003,91(3):563-568
OBJECTIVE: Previous reports indicate that cytoreduction and salvage therapy with P32 or whole abdominal radiation may improve survival in patients with positive findings at second-look laparotomy (SLL). The aim of this investigation was to determine whether these findings held true with extended follow-up and a larger patient cohort. METHODS: From 1977 (the year platinum-based chemotherapy was introduced to our institution) to 1989, 150 patients had persistent disease at SLL. Relevant clinical information was extracted through retrospective chart review. RESULTS: One hundred forty-five patients were followed until death, with a median follow-up of 15.4 years for the 5 living patients. Median actuarial survival from the time of SLL was 18 months. Tumor grade (P = 0.003) and pre- and post-SLL tumor size (P < 0.0001) were significant determinants of survival by univariate analysis. Patients with microscopic disease or those with < or =1 cm disease rendered microscopic at SLL had improved survival relative to those with < or =1 cm and macroscopic disease following SLL (P = 0.03) (median survivals of 3.3, 2.5, and 1.4 years, respectively). In contrast, median survival of those with >1 cm disease cytoreduced to microscopic disease was no different than those with macroscopic residual, even if < or =1 cm (1.3 and 1.0 years, respectively). After adjusting for tumor size, salvage treatment was not a significant predictor of survival. CONCLUSION: With long-term follow-up there was no suggestion that the type of salvage therapy (e.g., P32 or WART) influenced survival. Rather, low-grade disease and low tumor burdens following cytoreduction were associated with improved survival on multivariate analysis. 相似文献
96.
INTRODUCTION: Quantitative measurement of vocal fold movements can be done either with high-speed imaging or with short interval, color-filtered double strobe flash-stroboscopy. The physical and technical elements of this new technique are described. METHODS: Two special strobe units (KAY Elemetrics RLS 9100) are used in a master-slave configuration. In this way an adjustable interval of 0.1-2.0 ms between flashes is introduced. The strobe flashes are color filtered and are separated by a brief interval. By this means a double exposure is created in each video frame.Real-time visualization of opening and closing velocities over the entire length of the vocal fold from anterior to posterior is possible.Quantification is possible off-line after image calibration. CONCLUSION: Short-interval, color-filtered double-strobe flash stroboscopy allows quantitative measurement of the velocity of vocal fold movements during vibration at different pitches and sound pressure levels (SPL). Images gained with this new technique provide information about a dynamic property (velocity) of the vocal fold within a single image.Therefore, its use could be helpful from the aspect of clinical documentation. 相似文献
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100.
Gait analysis alters decision-making in cerebral palsy 总被引:3,自引:0,他引:3
Cook RE Schneider I Hazlewood ME Hillman SJ Robb JE 《Journal of pediatric orthopedics》2003,23(3):292-295
This study was designed to assess the impact of gait analysis on the treatment of patients with cerebral palsy. One hundred two ambulant patients with cerebral palsy were assessed clinically and with gait analysis. Separate treatment proposals for each patient were recorded after clinical examination and after gait analysis. The results of the two methods of assessment were compared. After clinical assessment, 71 of the 102 patients evaluated were recommended for a surgical procedure and 31 for nonoperative treatment. After gait analysis, the indications for treatment were confirmed in 91 cases (89%). Clinical assessment by the same orthopedic surgeon was in close agreement with gait analysis in identifying an indication for surgery. There was less agreement in the type or level of operation recommended. Gait analysis altered the decision in 106 of 267 operations (40%). There was good agreement for bone surgery, suggesting that clinical evaluation of torsional problems was fairly reliable. The poorer agreement seen for soft tissue operations probably reflects the difficulties in assessing tone-related problems in these patients clinically. This study confirms the value of gait analysis for decision-making in cerebral palsy. 相似文献