Retrospective analysis of antiretroviral HIV treatment success based on medical history or guided by the reverse hybridisation LiPA HIV genotyping system

The changes in viral load and CD4(+) count at 3 and 6 months in a group of 166 HIV-infected patients was evaluated. The new therapy was chosen based on the medical history procedures for 70 patients, and in 96 patients it was guided by the partial or complete result of the line probe assay (LiPA) HIV RT and Protease resistance tests. The absolute difference from the baseline of the log viral load at 3 and 6 months was significantly different between the two groups when adjusted for baseline viral load (P < 0.0001) and stayed significant when intention-to-treat analysis was carried out (P < 0.001). The absolute difference of the CD4(+) count was not significantly different when adjusted for baseline CD4(+) (P = 0.854, 3 months; P = 0.06, 6 months). The proportion of patients with a viral load 相似文献   

Clinical,immunological, and molecular analysis in a large cohort of patients with X-linked agammaglobulinemia: an Italian multicenter study

A questionnaire-based retrospective clinical and immunological survey was conducted in 73 males with a definite diagnosis of X-linked agammaglobulinemia based on BTK sequence analysis. Forty-four were sporadic and 29 familial cases. At December 2000, the patients' ages ranged from 2 to 33 years; mean age at diagnosis and mean duration of follow-up were 3.5 and 10 years respectively. After the mid-1980s all but 2 were on intravenous immunoglobulin (IVIG) substitution therapy, with residual IgG >500 mg/dl in 94% of the patients at the time of enrollment. Respiratory infections were the most frequent manifestation both prior to diagnosis and over follow-up. Chronic lung disease (CLD) was present in 24 patients, in 15 already at diagnosis and in 9 more by 2000. The cumulative risk to present at diagnosis with CLD increased from 0.17 to 0.40 and 0.78 when the diagnosis was made at the ages of 5, 10, and 15 years respectively. For the 9 patients who developed CLD during follow-up, the duration of follow-up, rather than age at diagnosis; previous administration of intramuscular immunoglobulin; and residual IgG levels had a significant effect on the development of CLD. Chronic sinusitis was present in 35 patients (48%), in 15 already at diagnosis and in 20 by 2000. Sistemic infections such as sepsis and meningitis/meningoencephalitis decreased over follow-up, probably due to optimal protection provided by high circulating IgG levels reached with IVIG.     

Cystic fibrosis mutations and immotile cilia syndrome

The immotile cilia syndrome (ICS) presents with autosomal recessive inheritance and is a chronic respiratory disease supposed to be caused by different genetic determinants. The hypothesis that cystic fibrosis (CF) heterozygotes may have a predisposition to develop bronchial or respiratory diseases other than CF prompted us to look for CF mutations in patients with ICS. Five patients, as well as the parents and two healthy brothers of one patient were tested for 12 CF mutations, for the polymorphic GATT repeat in intron 6a and for the CF gene flanking markers XV-2c, KM19, MP6d-9, J3.11. None of the 12 mutations at the CF locus have been detected in the ICS patients and no linkage was found between ICS and the polymorphic markers. Thus, based on our data, ICS and CF seem to be two different clinical entities.     

Using linked markers to infer the age of a mutation

Advances in sequencing and genotyping technologies over the last decade have enabled geneticists to easily characterize genetic variation at the nucleotide level. Hundreds of genes harboring mutations associated with genetic disease have now been identified by positional cloning. Using variation at closely linked genetic markers, it is possible to predict the times in the past at which particular mutations arose. Such studies suggest that many of the rare mutations underlying human genetic disorders are relatively young. Studies of variation at genetic markers linked to particular mutations can provide insights into human geographic history, and historical patterns of natural selection and disease, that are not available from other sources. We review two approaches for estimating allele age using variation at linked genetic markers. A phylogenetic approach aims to reconstruct the gene tree underlying a sample of chromosomes carrying a particular mutation, obtaining a “direct” estimate of allele age from the age of the root of this tree. A population genetic approach relies on models of demography, mutation, and/or recombination to estimate allele age without explicitly reconstructing the gene tree. Phylogenetic methods are best suited for studies of ancient mutations, while population genetic methods are better suited for studies of recent mutations. Methods that rely on recombination to infer the ages of alleles can be fine‐tuned by choosing linked markers at optimal map distances to maximize the information available about allele age. A limitation of methods that rely on recombination is the frequent lack of a fine‐scale linkage map. Maximum likelihood and Bayesian methods for estimating allele age that rely on intensive numerical computation are described, as well as “composite” likelihood and moment‐based methods that lead to simple estimators. The former provide more accurate estimates (particularly for large samples of chromosomes) and should be employed if computationally practical. Hum Mutat 18:87–100, 2001. © 2001 Wiley‐Liss, Inc.     

Mutation detection in the alpha-1 antitrypsin gene (PI) using denaturing gradient gel electrophoresis

A method for mutation detection in the alpha-1 antitrypsin gene (protease inhibitor 1; PI) has been developed using denaturing gradient gel electrophoresis of PCR amplified gene fragments. Using this experimental approach, all common phenotypes and mutations could be detected. Denaturing gradient gel electrophoresis (DGGE) was compared with standard isoelectric focusing (IEF) in 20 potential alpha1-antitrypsin deficient patients and their relatives. The genotype determined by DGGE was found to be more reliable in some cases than IEF, which is essential for a proper diagnosis of alpha-1 antitrypsin malfunctioning.     

Sequence analysis of hepatitis B virus genomes from an infant with acute severe hepatitis and a hepatitis B e antigen-positive carrier mother

It is well known that fulminant hepatitis B can occur in infants born to hepatitis B e antigen (HBeAg)-negative hepatitis B virus (HBV) carrier mothers, whereas fulminant hepatitis and severe hepatitis are uncommon in infants born to HBeAg-positive mothers. We have encountered an infant with severe acute hepatitis B born to a HBeAg-positive mother. The aim of this study was to determine whether HBV variants contribute to the pathogenesis of fulminant hepatitis and severe hepatitis in an infant born to an HBeAg-positive mother. The nucleotide sequence of HBV genomes from the infant and his HBeAg-positive carrier mother was analyzed. All HBV isolated from the infant and his mother were subtype adr. The sequences of the cloned HBV genomes, each including a part of the X and precore/core regions, isolated from the infant were almost identical (homology of 99.1-99.9%) to those from his mother. There was no mutation in any of the 17 clones examined at nucleotides 1762 and 1764 in the core promoter, which is reported to be associated with fulminant hepatitis. A point mutation at nucleotide 1758 in the second AT-rich region of the basic core promoter was present in all clones. None of the clones had a point mutation at nucleotide 1896 of the precore region. In this study, no specific HBV variants contributing to the development of neonatal severe hepatitis were found. There is a possibility that host factors rather than viral factors play an important role in some cases of severe neonatal hepatitis B.     

Heritability and molecular genetic studies of endometriosis

Endometriosis is a common disease defined as the growth of endometrial tissue outside the uterine cavity that often results in a vast array of gynaecological problems including dyspareunia, dysmenorrhoea, pelvic pain and infertility. Despite the increasing evidence that supports a genetic component to this common gynaecological condition, the basic aetiology and pathogenesis of endometriosis remain unknown. It is likely that endometriosis is a common polygenic/multifactorial disease caused by an interaction between multiple genes as well as the environment. Such conditions do not have a clear Mendelian pattern of inheritance. Recent molecular cytogenetic studies on endometriotic tissue and an established endometriosis-derived cell line provide novel evidence that acquired chromosome-specific alterations may be involved in endometriosis, possibly reflecting clonal expansion of chromosomally abnormal cells. Molecular DNA studies examining the role of loss of heterozygosity in endometriotic lesions has identified candidate tumour suppressor gene loci, including 5q, 6q, 9p, 11q and 22q, that may play a role in the malignant transformation of endometriotic implants to endometrioid ovarian cancers. Evidence of mutations in the tumour suppressor PTEN gene in the endometrioid subtype of epithelial ovarian cancer further suggests that somatic genetic alterations represent early events in the transformation of benign endometriotic cells. Genetic factors are also likely to influence individual susceptibility to endometriosis. There is now evidence that heritable allelic differences in drug-metabolizing enzymes play an important role in the development of endometriosis. Further studies are warranted to identify major susceptibility gene(s) and the mechanism involved in endometriosis to assist in the development of better methods for early detection, diagnosis and prevention.