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1.
Mutation analysis of the spastin gene (SPG4) in patients with hereditary spastic paraparesis 总被引:8,自引:2,他引:8 下载免费PDF全文
Lindsey JC Lusher ME McDermott CJ White KD Reid E Rubinsztein DC Bashir R Hazan J Shaw PJ Bushby KM 《Journal of medical genetics》2000,37(10):759-765
BACKGROUND—Hereditary spastic paraparesis is a genetically heterogeneous condition. Recently, mutations in the spastin gene were reported in families linked to the common SPG4 locus on chromosome 2p21-22.
OBJECTIVES—To study a population of patients with hereditary spastic paraparesis for mutations in the spastin gene (SPG4) on chromosome 2p21-22.
METHODS—DNA from 32 patients (12 from families known to be linked to SPG4) was analysed for mutations in the spastin gene by single strand conformational polymorphism analysis and sequencing. All patients were also examined clinically.
RESULTS—Thirteen SPG4 mutations were identified, 11 of which are novel. These mutations include missense, nonsense, frameshift, and splice site mutations, the majority of which affect the AAA cassette. We also describe a nucleotide substitution outside this conserved region which appears to behave as a recessive mutation.
CONCLUSIONS—Recurrent mutations in the spastin gene are uncommon. This reduces the ease of mutation detection as a part of the diagnostic work up of patients with hereditary spastic paraparesis. Our findings have important implications for the presumed function of spastin and schemes for mutation detection in HSP patients.
Keywords: spastin; hereditary spastic paraparesis; mutation; recessive 相似文献
OBJECTIVES—To study a population of patients with hereditary spastic paraparesis for mutations in the spastin gene (SPG4) on chromosome 2p21-22.
METHODS—DNA from 32 patients (12 from families known to be linked to SPG4) was analysed for mutations in the spastin gene by single strand conformational polymorphism analysis and sequencing. All patients were also examined clinically.
RESULTS—Thirteen SPG4 mutations were identified, 11 of which are novel. These mutations include missense, nonsense, frameshift, and splice site mutations, the majority of which affect the AAA cassette. We also describe a nucleotide substitution outside this conserved region which appears to behave as a recessive mutation.
CONCLUSIONS—Recurrent mutations in the spastin gene are uncommon. This reduces the ease of mutation detection as a part of the diagnostic work up of patients with hereditary spastic paraparesis. Our findings have important implications for the presumed function of spastin and schemes for mutation detection in HSP patients.
Keywords: spastin; hereditary spastic paraparesis; mutation; recessive 相似文献
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Folayan Morenike Oluwatoyin Ibigbami Olanrewaju Brown Brandon El Tantawi Maha Uzochukwu Benjamin Ezechi Oliver C. Aly Nourhan M. Abeldaño Giuliana Florencia Ara Eshrat Ayanore Martin Amogre Ayoola Oluwagbemiga O. Osamika Bamidele Emmanuel Ellakany Passent Gaffar Balgis Idigbe Ifeoma Ishabiyi Anthonia Omotola Jafer Mohammed Khan Abeedha Tu-Allah Khalid Zumama Lawal Folake Barakat Lusher Joanne Nzimande Ntombifuthi P. Popoola Bamidele Olubukola Quadri Mir Faeq Ali Rashwan Maher Roque Mark Shamala Anas Al-Tammemi Ala’a B. Yousaf Muhammad Abrar Abeldaño Zuñiga Roberto Ariel Okeibunor Joseph Chukwudi Nguyen Annie Lu 《AIDS and behavior》2022,26(3):739-751
AIDS and Behavior - The aim of the study was to assess if there were significant differences in the adoption of COVID-19 risk preventive behaviors and experience of food insecurity by people living... 相似文献
4.
The overall effectiveness of prophylaxis in severe haemophilia 总被引:1,自引:1,他引:1
The aim of this retrospective review was to assess the overall effectiveness of prophylaxis when compared with on-demand treatment of haemophilic patients. Twenty-five children (22 with severe haemophilia A and three with severe haemophilia B) were evaluated. Five haemophilia A patients received primary prophylaxis (instituted before the onset of any joint bleed) while the other 17 haemophilia A and all three haemophilia B patients were on secondary prophylaxis. We compared factor usage, number of bleeding episodes, emergency room (ER) visits and hospitalizations while on prophylaxis to those while on demand therapy. All subjects were male, the median age at time of review was 11.4 years and at start of prophylaxis was 4.5 years. Thirteen of the 25 patients (52%) required indwelling venous catheters for access, seven of these had one or more (one-six) episodes of line sepsis. Haemophilia A patients received an average of 23.8 U kg(-1) (20-30 U kg(-1)) of recombinant factor VIII three times a week while haemophilia B patients received 50 U kg(-1) recombinant FIX twice weekly. There was a significant reduction in the mean number of major bleeds on prophylaxis from 15.5 to 1.9 per year and a significant decrease in target joints, ER visits and hospitalizations. Although factor usage per year was higher on prophylaxis, there was an overall reduction in number of bleeds and resultant decrease in hospitalizations and ER visits. By preventing new target joints, prophylaxis can lead to reduction in long-term morbidity and a better quality of life despite increased central lines and higher factor usage. 相似文献
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The fact that patients with hemophilia treated with clotting factor and HIV 1-seronegative subjects with congenital anemias given repeated blood transfusions both have decreased ratios of T4/T8 lymphocytes and diminished NK cell activity indicates that these immunological abnormalities can be due to repeated exposure to blood and blood products, and are not necessarily indicative of HIV 1 infection. To search for an immunological change specific for HIV 1 infection we tested 36 hemophiliacs (22 HIV 1-seropositive, 14 HIV 1-seronegative), and 27 normal subjects for peripheral blood lymphocytes which coexpress Leu 2, a marker associated with suppressor/cytotoxic cells, and Leu 7, an NK cell marker. Compared to normal subjects, seropositive hemophiliacs showed a 2.5-fold increase in Leu 2+ Leu 7+ cells. No increase in this population was seen in the seronegative hemophiliacs. An increase in the percentage of Leu 2+ Leu 7+ cells is therefore an immunological alteration associated with HIV 1 infection but not blood product exposure per se. 相似文献
6.
Lusher JM 《Seminars in thrombosis and hemostasis》2002,28(3):273-276
The first of the prospective multicenter studies in previously untreated patients (PUPs) with a recombinant factor VIII (FVIII) concentrate began in January 1989. Over the past 11 years, PUP studies have amassed a great deal of information concerning safety, efficacy, and inhibitor development of the two "first-generation" recombinant (r) FVIII concentrates (Kogenate and Recombinate) and of two "second-generation" products (ReFacto and Kogenate FS, which is formulated with sucrose rather than with albumin). Each of these products has proved to be safe, effective, and well-tolerated. Side effects have been rare and mild in nature. There have been no clinical reactions to hamster or murine proteins. During the course of the multinational PUP trials with Kogenate, Recombinate, and ReFacto, inhibitors developed in 29.7, 31, and 33%, respectively, of severely affected PUPs. Half of these were high titer and half were low titer. In each of these trials, several inhibitors were transient. PUPs and minimally treated patients (MTPs) in the Kogenate SF trial have not been followed long enough to determine the incidence of inhibitor development; however, the product appears to be safe and effective. Following demonstration of safety and efficacy with each rFVIII concentrate in previously treated patients with hemophilia A, studies in PUPs began. In general, the prospective trials in PUPs with each recombinant product were conducted similarly, allowing comparison of data. This article is intended to provide a review of the experience with both first- and second-generation rFVIII products in the prospective clinical trials in PUPs. 相似文献
7.
Clinical and pathologic findings in hereditary spastic paraparesis with spastin mutation 总被引:3,自引:0,他引:3
White KD Ince PG Lusher M Lindsey J Cookson M Bashir R Shaw PJ Bushby KM 《Neurology》2000,55(1):89-94
OBJECTIVE: To describe a family with chromosome 2p-linked hereditary spastic paraparesis (HSP) associated with dementia and illustrate the cerebral pathology associated with this disorder. BACKGROUND: HSP comprises a heterogeneous group of inherited disorders in which the main clinical feature is severe, progressive lower limb spasticity. Nongenetic classification relies on characteristics such as mode of inheritance, age at onset, and the presence or absence of additional neurologic features. Several loci have been identified for autosomal dominant pure HSP. The most common form, which links to chromosome 2p (SPG4), has recently been shown to be due to mutations in spastin, the gene encoding a novel AAA-containing protein. RESULTS: The authors report four generations of a British family with autosomal dominant HSP in whom haplotype analysis indicates linkage to chromosome 2p. In addition, a missense mutation has been identified in exon 10 of the spastin gene (A1395G). Dementia was documented clinically in one member of the family, two other affected family members were reported to have had late onset memory loss, and a younger affected individual showed evidence of memory disturbance and learning difficulties. Autopsy of the demented patient confirmed changes in the spinal cord typical of HSP and also demonstrated specific cortical pathology. There was neuronal depletion and tau-immunoreactive neurofibrillary tangles in the hippocampus and tau-immunoreactive balloon cells were seen in the limbic and neocortex. The substantia nigra showed Lewy body formation. The pathologic findings are not typical of known tauopathies. CONCLUSIONS: The authors confirm that chromosome 2p-linked HSP can be associated with dementia and that this phenotype may be associated with a specific and unusual cortical pathology. 相似文献
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AIMS: Firstly to test alcohol abusers attentional bias towards alcohol-related stimuli. Secondly, to shed light onto other factors that may influence the alcohol Stroop effect by considering variables including mood status in the analyses. Finally, to examine severity of dependence on Stroop performance. DESIGN: Repeated measures with alcohol versus control group as the between participant factors and within participant factors were the reaction times to different types of stimuli. Standard multiple regression was used to determine predictors of Stroop performance. A repeated measures design was used with severity of dependence as the between participant factors and Stroop reaction times as the within participant factors. SETTING: South and East London, UK. PARTICIPANTS: Sixty-four alcoholics in treatment and 64 community controls from general practice participated in the study. MEASUREMENTS: Alcohol dependence severity was measured using the SADQ, mood was measured with the POMS-SF and a computerised emotional Stroop task was employed to measure attentional bias. FINDINGS: Regardless of demographic factors and mood status, alcoholics responded significantly slower to alcohol-related than neutral words when compared to controls. When severity of alcohol dependence was used as between participant factors, no significant differences were found with Stroop performance between high and low alcohol severity groups. CONCLUSIONS: Alcohol-related stimuli are distracting to heavy users of alcohol, independent of demographic, mood and dependence status. Findings offer insight into the development of alcohol dependence and the issues that surround the alcohol Stroop paradigm. 相似文献
10.
Lusher JM 《BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy》2000,13(4):289-298
In the short time span since the cloning of the human genes for factors VIII, IX and VII, recombinant factor (rF)VIII, rFIX and rFVIIa concentrates have been produced and standardised, have entered clinical trials, and have been licensed for clinical use in the US, Europe and elsewhere. Even more recently, a new generation of recombinant clotting factor concentrates has emerged, including rFVIII concentrates formulated with sucrose rather than human serum albumin and a B-domain-deleted rFVIII preparation. Additionally, rFVIII concentrates which contain no human or animal proteins in their manufacture are in development, as is a combination rFVIII plus recombinant von Willebrand factor concentrate. The clinical experience in previously treated patients with each of the existing recombinant products has documented that inhibitor development is not increased with any of them. As expected, there has been no reported instance of disease transmission with any of the recombinant clotting factor concentrates. Since their introduction, usage of each of the recombinant clotting factor concentrates has dramatically increased in countries where these products are licensed, available and affordable. 相似文献