No excess of DR*3/4 in Ashkenazi Jewish or Hispanic IDDM patients

The gene frequencies, haplotype relative risks, and zygotic assortments of HLA-DR in three ethnically defined samples of insulin-dependent diabetes mellitus (IDDM) patients were determined in a prospective family study. Although DR3 and DR4 were positively associated with IDDM in the probands of 123 northern European, 94 Ashkenazi Jewish, and 49 New York Hispanic families, significant excess of DR*3/4 heterozygotes was observed only among the probands from families of northern European ancestry. There was also a significant decrease in the frequency of Bw62,DR4 haplotypes derived by northern European patients from their mothers compared with their fathers. This difference, together with data reported in the literature, suggests that the expressivity of the susceptible genotype(s) in IDDM patients may be modified by protective maternal effects associated with Bw62,DR4 and probably other DR4 haplotypes. Samples of IDDM patients from populations with high frequencies of these modifiers should have different DR-gene frequencies contributed by fathers and mothers, capable of accounting for the observed Hardy-Weinberg disequilibrium. We postulate that, because the mechanism of action of these modifiers is distinct from that of the susceptibility gene, the difference must be considered in devising strategies for elucidation of the mode of inheritance of the disease and for understanding the molecular nature of the susceptibility.     

Chronic chorioamnionitis: a clinicopathologic study of 17 cases

The clinicopathologic features of 17 cases of an unusual variant of chorioamnionitis distinguished by a pure or predominantly chronic inflammatory infiltrate in the fetal membranes rather than the usual acute inflammatory reaction are reported. In six cases, there was an equal (one case) or minor (five cases) component of acute inflammation in the fetal membranes as well. Concomitant villitis, found in 11 cases, was almost uniformly lymphohistiocytic and destructive, but it varied greatly in severity. Immunoperoxidase stains for cytomegalovirus, herpes simplex I and II, and Toxoplasma gondii; Warthin-Starry, Gomori methenamine silver, Dieterle, Gram and acid fast stains; placental or amniotic fluid culture; and limited maternal serologic studies failed to identify a specific infectious etiology in any case. Seven women had experienced at least one previous spontaneous abortion, fetal death in utero, or preterm birth. No patient reported a history of fever, rash, or flu-like syndrome during pregnancy. Serious antenatal complications were numerous. Preterm birth occurred in 13 cases. Gestational age ranged from 25 to 42 weeks (mean 32 weeks) and birth weight ranged from 740 to 3,230 g (mean 2,100 g). When expressed as a percentile for gestational age, 47% of infants had a birth weight at or below the 25th percentile, and 76% were at or below the 50th percentile. Two infants were born with gross anomalies, and one infant died in the neonatal period.     

Single-copy IMH3 allele is sufficient to confer resistance to mycophenolic acid in Candida albicans and to mediate transformation of clinical Candida species

Parasexual genetic analysis of Candida albicans utilized the dominant selectable marker that conferred resistance to mycophenolic acid. We cloned and sequenced the IMH3(r) gene from C. albicans strain 1006, which was previously identified as resistant to mycophenolic acid (MPA) (A. K. Goshorn and S. Scherer, Genetics 123:213-218, 1989). MPA is an inhibitor of IMP dehydrogenase, an enzyme necessary for the de novo biosynthesis of GMP. G. A. Kohler et al. (J. Bacteriol. 179:2331-2338, 1997) have shown that the wild-type IMH3 gene, when expressed in high copy number, will confer resistance to this antibiotic. We demonstrate that the IMH3(r) gene from strain 1006 has three amino acid changes, two of which are nonconservative, and demonstrate that at least two of the three mutations are required to confer resistance to MPA. We used this gene as a dominant selectable marker in clinical isolates of C. albicans and Candida tropicalis. We also identified the presence of autonomously replicating sequence elements that permit autonomous replication in the promoter region of this gene. Finally, we found the excision of a phi-type long terminal repeat element outside the IMH3 open reading frame of the gene in some strains. We used the IMH3(r) allele to disrupt one allele of ARG4 in two clinical isolates, WO-1 and FC18, thus demonstrating that a single ectopic integration of this dominant selectable marker is sufficient to confer resistance to MPA.     

Efficacy of physiotherapy for musculoskeletal disorders: what can we learn from research?

In order to summarize the available clinical evidence for the efficacy of physiotherapy, 400 randomized clinical trials were identified from the literature. Studies were found by using bibliographic databases, citation tracking, and correspondence with researchers in the field. Focusing on disorders of the musculoskeletal system, a number of criterion based meta-analyses were performed on 180 trials in order to summarize the available evidence. For each randomized clinical trial in each meta-analysis a methodological score was calculated using a set of explicit criteria and weighting factors applied by two or three independent reviewers who were blinded as to the outcomes, the journal and the authors of the publication. In each meta-analysis the randomized clinical trials were ordered hierarchically depending on their score for methodological quality. Meta-analyses were performed for spinal manipulation, exercise therapy, traction, ultrasound, and laser therapy, and for disorders of the back, neck, shoulder and knee. In general, the methodological quality of the studies appeared to be low, and the efficacy of physiotherapy was shown to be convincing for only a few indications and treatments. On the other hand, because of the prevalence of serious methodological flaws, it cannot be concluded that physiotherapy has no effect.     

T cell subset alterations in idiopathic glomerulonephritis

Peripheral blood lymphocytes from 15 healthy controls and 59 patients with idiopathic glomerulonephritis were studied to determine whether an imbalance exists among human T cell subsets in these diseases. Twenty of the patients studied had a minimal change nephropathy (10 with nephrotic syndrome and 10 in sustained remission); 27 had a membranous glomerulonephritis (12 with nephrotic syndrome, six with isolated proteinuria and nine in complete remission); 12 patients had an IgA glomerulonephritis with heamaturia and mild proteinuria. Monoclonal antibodies directed at human T lymphocyte subsets termed OKT3, OKT4 and OKT8 were used in an indirect immunofluorescence assay in all cases. Patients with minimal change nephropathy, with or without nephrotic syndrome and patients with IgA glomerulonephritis showed mean values of OKT3⁺ cells (total peripheral T cells), helper OKT4⁺ cells, suppressor OKT8⁺ cells and OKT4⁺/OKT8⁺ cell ratio, in the normal range. Only the group of patients with membranous glomerulonephritis and nephrotic syndrome presented a mean OKT4⁺/OKT8⁺ ratio greater than the normal group (percentages: 2·43±0·3 vs 1·6±0·1 s.e.m.; P<0·02). This increased ratio was due to a reduction in the OKT8⁺ cell subset compared to the healthy subjects (percentages: 27·6±2·9 vs 36·8±1·4 s.e.m.; P<0·01). Our data shows that the functional lymphocyte disorders previously described in minimal change nephropathy and IgA glomerulonephritis are not due to a numerical imbalance of lymphocyte subsets. Such an imbalance of lymphocyte subsets was specifically observed in membranous glomerulonephritis with nephrotic syndrome. The true significance of this finding has to be clarified by longitudinal studies and functional tests.     

Microbiome as Mediator of Diet on Colorectal Cancer Risk: The Role of Vitamin D,Markers of Inflammation and Adipokines

Obesity and diet are associated with colorectal cancer (CRC) risk, and microbiome could mediate this risk factor. To investigate this interaction, we performed a case–control study (34 CRC cases and 32 controls) and analyzed fecal microbiota composition using 16S rRNA metabarcoding and sub-sequential shotgun analyses of genomic bacterial DNA to evaluate the role of microbiome and diet in CRC etiology, taking into account vitamin D and other risk biomarkers. Dietary habits were evaluated using a short questionnaire. Multivariate methods for data integration and mediation analysis models were used to investigate causal relationships. CRC cases were significantly more often deficient in vitamin D than controls (p = 0.04); FokI and CYP24A1 polymorphism frequency were different between cases and controls (p = 0.03 and p = 0.02, respectively). A diet poor in fatty fish and rich in carbohydrates was found to be significantly associated with CRC risk (p = 0.011). The mediation analysis confirmed the significant role of the microbiome in mediating CRC risk—increasing levels of Bifidobacteria/Escherichia genera ratio, an indicator of “healthy” intestinal microbiome, can overcome the effect of diet on CRC risk (p = 0.03). This study suggests that microbiome mediates the diet effect on CRC risk, and that vitamin D, markers of inflammation, and adipokines are other factors to consider in order to achieve a better knowledge of the whole carcinogenic process.     

Suicide in relation to AIDS

One of the array of clinical and ethical challenges faced by the practitioner who works with people with AIDS is dealing with clients who feel they prefer the option of suicide to living with the disease. The many dimensions of suicide among the terminally ill, including preemptive, surcease, and rational suicide, are explored. The critical issues addressed are the incidence of suicide in HIV-positive individuals, contributing factors associated with the risk of suicide among people with HIV /AIDS, and the clinical and ethical implication of this issue for the practitioner.