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1.
Considerations in using linkage analysis as a presymptomatic test for Huntington''s disease. 总被引:2,自引:0,他引:2
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The polymorphic locus D4S10 that is genetically linked to the locus for Huntington's disease (HD) has made possible a presymptomatic test for those at risk. Because the symptoms of this progressively debilitating and fatal illness are not usually manifest until adulthood, the outcome of the test will influence major decisions about career, marriage, and procreation. Several differential diagnoses must be considered before using the test if HD is not confirmed in at least one family member. Review of a large number of pedigrees has shown that 40% of persons at risk do not have appropriate family structure for a linkage test. Furthermore, uncooperative or inaccessible relatives may make this test infeasible for many others who wish to be tested. Linkage phase, which must be known in the affected parent for an informative test, can be determined using one or more of 12 probe-enzyme combinations for D4S10. Although the polymorphism information content (PIC) value for any one RFLP is less than 40%, the PIC value for the haplotype of the two G8 HindIII, pK083 EcoRI, and R7 BglII RFLPs is greater than 88%. We have developed a scheme to incorporate linkage data and age at onset information adjusted for censored observations, sex of affected parent, and familial correlation for age at onset, using the computer program MLINK for calculation of risk of having HD. Simulated experiments showed that proper age at onset adjustment is crucial to the calculation of the probability of risk. A formal presymptomatic testing protocol, including pre- and post-test counselling, psychological testing, and paternity testing is recommended. Many of these considerations are illustrated in several actual test cases. 相似文献
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3.
Anticipation in Huntington''s disease is inherited through the male line but may originate in the female. 总被引:19,自引:7,他引:19
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Data from the US National Huntington's Disease Roster have been analysed in terms of the difference in age of onset (AO) between affected parents and affected offspring, that is, in terms of 'anticipation'. While mean AO in offspring of affected mothers did not differ greatly from AO in their mothers, the distribution of AO in the offspring of affected fathers falls into two groups, the larger group showing an AO only slightly younger than their affected fathers and a small group whose AO was, on average, 24 years younger than their affected fathers. Analysis of the grandparental origin of the Huntington allele suggests that while propensity to anticipation is heritable for a number of generations through the male line, it originates at the time of differentiation of the germ line of a male who acquires the Huntington allele from his mother. It is suggested that major anticipation indicates an epigenetic change in methylation of the nucleic acid of the genome, which is imposed in the course of the 'genomic imprinting', that is, in the mechanism by which the parental origin of alleles is indicated. 相似文献
4.
J. M. Vance M. A. Pericak-Vance R. C. Elston P. M. Conneally K. K. Namboodiri R. S. Wappner P. L. Yu John M. Optiz 《American journal of medical genetics. Part A》1980,7(2):131-140
Serum and/or plasma samples from 360 Whites and 126 Blacks were assayed for activity of the lysosomal hydrolase α-N-acetyl-D-glucosaminidase (NAG). The samples from the Blacks had an increased mean (0.50 nm/ml/min) and standard deviation (0.30 nm/ml/min) compared to those from the Whites (0.29 nm/ml/min and 0.10 nm/ml/min, respectively). After loge transformation and admixture analysis, it was possible to demonstrate the presence of 3 distributions of NAG activity in Blacks and at least 2 in Whites. Segregation analysis of the NAG activity of 29 White half-sib twin families indicated that a genetic model for the inheritance of NAG activity provided a better fit (P < 0.01) with the data than the “environmental” model. Thus, the study suggests the presence of a genetic polymorphism for NAG activity in Black and White populations. The presence of alleles for high and low NAG activity in the normal population could lead to incorrect interpretation of serum carrier tests for Sanfilippo syndrome, type B. 相似文献
5.
Alcoholism susceptibility loci: confirmation studies in a replicate sample and further mapping 总被引:15,自引:0,他引:15
Foroud T Edenberg HJ Goate A Rice J Flury L Koller DL Bierut LJ Conneally PM Nurnberger JI Bucholz KK Li TK Hesselbrock V Crowe R Schuckit M Porjesz B Begleiter H Reich T 《Alcoholism, clinical and experimental research》2000,24(7):933-945
BACKGROUND: There is substantial evidence for a significant genetic component to the risk for alcoholism. A previous study reported linkage to chromosomes 1, 2, and 7 in a large data set that consisted of 105 families, each with at least three alcoholic members. METHODS: Additional genotyping in the 105 families has been completed in the chromosomal regions identified in the initial analyses, and a replication sample of 157 alcoholic families ascertained under identical criteria has been genotyped. Two hierarchical definitions of alcoholism were employed in the linkage analyses: (1) Individuals who met both Feighner and DSM-III-R criteria for alcohol dependence represented a broad definition of disease; and (2) individuals who met ICD-10 criteria for alcoholism were considered affected under a more severe definition of disease. RESULTS: Genetic analyses of affected sibling pairs supported linkage to chromosome 1 (LOD = 1.6) in the replication data set as well as in a combined analysis of the two samples (LOD = 2.6). Evidence of linkage to chromosome 7 increased in the combined data (LOD = 2.9). The LOD score on chromosome 2 in the initial data set increased after genotyping of additional markers; however, combined analyses of the two data sets resulted in overall lower LOD scores (LOD = 1.8) on chromosome 2. A new finding of linkage to chromosome 3 was identified in the replication data set (LOD = 3.4). CONCLUSIONS: Analyses of a second large sample of alcoholic families provided further evidence of genetic susceptibility loci on chromosomes 1 and 7. Genetic analyses also have identified susceptibility loci on chromosomes 2 and 3 that may act only in one of the two data sets. 相似文献
6.
7.
Pelizaeus-Merzbacher disease: tight linkage to proteolipid protein gene exon variant. 总被引:8,自引:0,他引:8
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J A Trofatter S R Dlouhy W DeMyer P M Conneally M E Hodes 《Proceedings of the National Academy of Sciences of the United States of America》1989,86(23):9427-9430
Pelizaeus-Merzbacher disease (PMD) is a human X chromosome-linked dysmyelination disorder of the central nervous system for which the genetic defect has not yet been established. The jimpy mutation jp of the mouse is an X chromosome-linked disorder of myelin formation. The mutation is at an intron/exon splice site in the mouse gene for proteolipid protein (PLP). With the jimpy mouse mutation as a precedent, we focused our attention on the human PLP gene, which is found at Xq22. The polymerase chain reaction was used to amplify the exons of the PLP gene of an affected male from a large Indiana PMD kindred. DNA sequencing showed a C----T transition at nucleotide 40 of the second exon. An affected third cousin also showed this sequence variation, while two unaffected male relatives (sons of an obligate carrier female) had the normal cytidine nucleotide. Allele-specific oligonucleotides were used to generate data for linkage studies on the above mentioned PMD kindred. Our results show tight linkage (theta = 0) of PMD to PLP with a lod (logarithm of odds) score of 4.62. In six other unrelated PMD kindreds, only the normal-sequence oligonucleotide hybridized, which indicates genetic heterogeneity. The radical nature of the predicted amino acid change (proline to leucine), suggests that the PMD-causing defect may have been delineated in one kindred. 相似文献
8.
J M Grubber A M Saunders A R Crane-Gatherum W K Scott E R Martin C S Haynes P M Conneally G W Small A D Roses J L Haines M A Pericak-Vance 《Neuroscience letters》1999,269(2):115-119
Butyrylcholinesterase (BCHE) is an enzyme expressed in most human tissues. Recently, an increased odds of carrying the K variant of BCHE (BCHE-K) was reported among Alzheimer disease (AD) cases as compared with controls. We tested our data set of 245 sporadic AD cases and 241 controls for an association between BCHE-K, APOE4, and AD using logistic regression and chi-square analyses. The sib transmission disequilibrium test (S-TDT) was also used to test for differences in BCHE-K allele frequencies between 163 discordant sib-pairs selected from multiplex AD families. No statistically significant differences were noted between BCHE-K case and control allele frequencies even after stratifying by APOE4 status. S-TDT analysis between the BCHE-K variant and AD was also not significant (P = 0.52). We conclude that BCHE-K is not a major genetic risk factor for AD in our study population. 相似文献
9.
10.
T O'Riordan P Kavanagh G Mellotte E Conneally E Mulvihill J A Keogh C O Moráin 《Irish medical journal》1990,83(2):72-73
A 49-year-old male developed bloody diarrhoea whilst on a visit to India. Sigmoidoscopy and rectal biopsy showed acute colitis. Shigella dysentery type I was isolated from stool culture. Cytotoxin production by the organism was demonstrated. The patient developed acute renal failure, thrombocytopaenia and microangiopathic haemolytic anaemia. He required mechanical ventilation, haemodialysis, blood transfusion and antibiotic therapy and achieved a complete recovery. This is an unusual case of haemolytic uraemic syndrome complicating shigellosis in an adult. 相似文献