Alzheimer's disease associated with mutations in presenilin 2 is rare and variably penetrant

Missense mutations in the presenilin 2 (PS-2) gene on chromosome 1 were sought by direct nucleotide sequence analysis of the open reading frame of 60 pedigrees with familial Alzheimer's disease (FAD). In the majority of these pedigrees, PS-1 and beta-amyloid precursor protein (beta APP) gene mutations had been excluded. While no additional PS-2 pathogenic mutations were detected, four silent nucleotide substitutions and alternative splicing of nucleotides 1338-1340 (Glu325) were observed. Analysis of additional members of a pedigree known to segregate a Met239Val mutation in PS-2 revealed that the age of onset of symptoms is highly variable (range 45-88 years). This variability is not attributable to differences in ApoE genotypes. These results suggest (i) that, in contrast to mutations in PS-1, mutations in PS-2 are a relatively rare cause of FAD; (ii) that other genetic or environmental factor modify the AD phenotype associated with PS-2 mutations; and (iii) that still other FAD susceptibility genes remain to be identified.      

Microglia activation in sepsis: a case-control study

Background  

infection induces an acute phase response that is accompanied by non-specific symptoms collectively named sickness behavior. Recent observations suggest that microglial cells play a role in mediating behavioral changes in systemic infections. In animal models for sepsis it has been shown that after inducing lipopolysaccharide, LPS, microglia in the brain were activated. The aim of this study was to investigate whether activation of microglia can be detected in patients who died of sepsis.     

First trimester maternal serum concentrations of fetal antigen 2 in normal pregnancies and those affected by trisomy 21

Serum concentrations of fetal antigen 2 (FA-2), the amino-propeptide of the alpha1 chain of collagen type I, were measured in peripheral blood from women with normal (n = 234) and trisomy 21 affected (n = 14) pregnancies between 9 and 11 weeks gestation. Serum FA-2 concentrations were seen to be stable throughout this period, and though raised FA-2 concentrations were seen at the 10th week of gestation, a statistically significant difference between normal and trisomy 21 affected pregnancies was not found overall. Therefore it seems unlikely that FA- 2 has a role in first trimester screening for trisomy 21, despite the fact that significantly higher FA-2 concentrations in trisomy 21 and significantly lower concentrations in trisomy 18 had been previously demonstrated in amniotic fluid in the second trimester.      

Immunology of gene therapy with adenoviral vectors in mouse skeletal muscle

Skeletal muscle is an attractive target for somatic gene transfer of both acquired and inherited disorders. Direct injection of adenoviral vectors in the skeletal muscle leads to recombinant gene expression in a large number of muscle fibers. Transgene expression has been transient in most organs and associated with substantial inflammation when experiments are performed in adult immune competent mice. In this report, we utilize a variety of in vivo and in vitro models of T and B cell function to characterize the nature of the immune response to adenoviral vectors injected into murine skeletal muscle. Cellular immunity dependent on CD4+ and CD8+ T cells contributes to the loss of recombinant gene expression and the development of localized inflammation. Antigen specific activation of T cells occurs to both viral proteins and the reporter gene beta-galactosidase. Systemic levels of neutralizing antibody to the capsid proteins of the vector are also generated. Destructive immune responses responsible for loss of transgene expression are largely directed against beta-galactosidase in that transgene expression was stable when beta-galactosidase was eliminated as a neoantigen in mice transgenic for lacZ. A strategy to prevent the cellular and humoral immunity to this therapy was developed based on transiently ablating CD4+ T cell activation at the time of vector delivery. Encouraging results were obtained when vector was administered with one of several immune modulating agents including cyclophosphamide, mAb to CD4+ cells, and mAb to CD40 ligand. These studies indicate that cellular and humoral immune responses are elicited in the context of gene therapy directed to skeletal muscle with adenoviral vectors. Transient ablation of CD4+ T cell activation prevents the effects responses of the CD8+ T and B cells.      

Non-disjunction of chromosome 18

A sample of 100 trisomy 18 conceptuses analysed separately and together with a published sample of 61 conceptuses confirms that an error in maternal meiosis II (MII) is the most frequent cause of non-disjunction for chromosome 18. This is unlike all other human trisomies that have been studied, which show a higher frequency in maternal meiosis I (MI). Maternal MI trisomy 18 shows a low frequency of recombination in proximal p and medial q, but not the reduction in proximal q observed in chromosome 21 MI non-disjunction. Maternal MII non-disjunction does not fit the entanglement model that predicts increased recombination, especially near the centromere. Whereas recent data on MII trisomy 21 show the predicted increase in recombination proximally, maternal MII trisomy 18 has non-significantly reduced recombination. Therefore, chromosome-specific factors must complicate the simple model of susceptible chiasma distributions interacting with age-dependent deterioration of the meiotic mechanism. For chromosome 18, 30% of tetrads are nullichiasmate in maternal MI non-disjunction, but nullichiasmates are not observed in maternal MII non-disjunction. Chiasma distributions from normal chromosome 18 meioses provide no evidence for normal disjunction from nullichiasmate tetrads. We extend this study to examine the remaining autosomes and find no evidence for normal disjunction from nullichiasmate tetrads generally.      

The molecular basis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in compound heterozygous patients: is there correlation between genotype and phenotype?

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most commonly recognized defect of mitochondrial beta-oxidation. It is potentially fatal, but shows a wide clinical spectrum. The aim of the present study was to investigate whether any correlation exists between MCAD genotype and disease phenotype. We determined the prevalence of the 14 known and seven previously unknown non-G985 mutations in 52 families with MCAD deficiency not caused by homozygosity for the prevalent G985 mutation. This showed that none of the non-G985 mutations are prevalent, and led to the identification of both disease- causing mutations in 14 families in whom both mutations had not previously been reported. We then evaluated the severity of the mutations identified in these 14 families. Using expression of mutant MCAD in Escherichia coli with or without co-overexpression of the molecular chaperonins GroESL we showed that five of the missense mutations affect the folding and/or stability of the protein, and that the residual enzyme activity of some of them could be modulated to a different extent depending on the amounts of available chaperonins. Thus, some of the missense mutations may result in relatively high levels of residual enzyme activity, whereas the mutations leading to premature stop codons will result in no residual enzyme activity. By correlating the observed types of mutations identified to the clinical/biochemical data in the 14 patients in whom we identified both disease-causing mutations, we show that a genotype/phenotype correlation in MCAD deficiency is not straightforward. Different mutations may contribute with different susceptibilities for disease precipitation, when the patient is subjected to metabolic stress, but other genetic and environmental factors may play an equally important role.      

Sonohysterographic evaluation of uterine abnormalities noted on hysterosalpingography

Transvaginal sonohysterography was performed on 40 consecutive patients with infertility or recurrent pregnancy loss and uterine abnormalities on hysterosalpingography. The findings were correlated with the hysterosalpingogram and subsequent diagnostic and/or operative hysteroscopy. Hysterosalpingography was incorrect in nine cases. Sonohysterography was more accurate than hysterosalpingography and provided more information about uterine abnormalities. Sonohysterography was in complete agreement with hysteroscopy. Diagnostic hysteroscopy can therefore be avoided if the sonohysterogram is normal. Sonohysterography also provides additional information on the relative proportion of the intracavitary and intramyometrial components of submucus myomas, as well as extracavitary myomas and the adnexae. This may help in planning the surgical procedure.      

Illness behaviour and antibiotic prescription in patients with respiratory tract symptoms.

BACKGROUND: Although the vast majority of respiratory tract symptoms are self-limiting, many patients visit their GP for these symptoms and antibiotics are over-prescribed. AIM: To explore determinants of patients visiting GPs for recent cough, sore throat, or earache; for being prescribed antibiotics; and for patients' satisfaction with visiting the GP. Design of the study: Second Dutch National Survey of General Practice (DNSGP-2) with a health interview and an additional questionnaire. SETTING: A total of 7057 adult patients of 163 GPs in the Netherlands. METHOD: Characteristics of patients and GPs as well as morbidity data were derived from the DNSGP-2 and a health interview. Characteristics of the symptoms, GPs' management and patients' satisfaction were measured by an additional written questionnaire. Data were analysed by means of multivariate logistic regression. RESULTS: About 40% of the responders (n = 1083) reported cough, sore throat, or earache in the 2 weeks preceding the interview and, of them, 250 visited their GP. Of this latter group, 97 patients were prescribed antibiotics. Apart from non-medical reasons, relevant medical factors played an important role in deciding to visit the GP. Smokers and patients with cardiac disease or diabetes mellitus were not especially inclined to see their GP. Smoking behaviour, fever, and views on respiratory tract symptoms and antibiotics of patients and GPs were associated with being prescribed antibiotics. Patients' perception of having been carefully examined was associated with their satisfaction, while receiving antibiotics was not. CONCLUSION: GPs should inform patients with clear elevated risk when to visit their GP in cases of cough, sore throat, or earache. There is still a need for GPs and patients to be better informed about the limited significance of single inflammation signs (for example, fever and green phlegm) as an indication for antibiotics. Careful examination of the patient contributes to patient satisfaction.