Helicobacter Hypothesis for Idiopathic Parkinsonism: Before and Beyond

We challenge the concept of idiopathic parkinsonism (IP) as inevitably progressive neurodegeneration, proposing a natural history of sequential microbial insults with predisposing host response. Proof-of-principle that infection can contribute to IP was provided by case studies and a placebo-controlled efficacy study of Helicobacter eradication. "Malignant" IP appears converted to "benign", but marked deterioration accompanies failure. Similar benefit on brady/hypokinesia from eradicating "low-density" infection favors autoimmunity. Although a minority of UK probands are urea breath test positive for Helicobacter , the predicted probability of having the parkinsonian label depends on the serum H. pylori antibody profile, with clinically relevant gradients between this "discriminant index" and disease burden and progression. In IP, H. pylori antibodies discriminate for persistently abnormal bowel function, and specific abnormal duodenal enterocyte mitochondrial morphology is described in relation to H. pylori infection. Slow intestinal transit manifests as constipation from the prodrome. Diarrhea may flag secondary small-intestinal bacterial overgrowth. This, coupled with genetically determined intense inflammatory response, might explain evolution from brady/hypokinetic to rigidity-predominant parkinsonism.     

Regulation of glutathione S-transferases of Zea mays in plants and cell cultures

An antiserum to glutathione S-transferase (EC 2.5.1.18) from maize (Zea mays L.) responsible for herbicide detoxification has been raised in rabbit. The antiserum was specific to the M_r 26000 subunit of the enzyme from maize seedlings and suspension-cultured cells, and recognized the isoenzymes active toward both atrazine and metolachlor. When plants were treated for 24 h with the herbicide antidote N,N-diallyl-2-2-dich-loroacetamide (DDCA), enzyme activities toward metolachlor were doubled in the roots and this was associated with a 70% increase in immunodetectable protein. Translation of polysomal RNA in vitro showed that the increase in the transferase in root tissue was brought about by a ninefold increase in mRNA activity encoding the enzyme. Treatment of suspension-cultured cells with cinnamic acid, metolachlor and DDCA raised enzyme activities but did not increase synthesis of glutathione S-transferase. In cultured maize cells, enzyme synthesis was maximal in mid-logarithmic phase, coinciding with the highest levels of enzyme activity. When callus cultures were established from the shoots of a maize line known to conjugate chloro-s-triazines, enzyme activity towards atrazine was lost during primary dedifferentiation. However, levels of total immunodetectable enzyme and activity toward metolachlor were increased in cultured cells compared with the parent shoot tissue.     

Histopathological studies ofSporothrix schenckii-inoculated mice

Defense mechanisms againstSporothrix schenckii were studied using mouse models. After an intracutaneous injection of the yeast form ofS. schenckii to the dorsal skin of the congenitally athymic nude and normal heterozygote littermate mice, nodules were formed. They regressed and disappeared in 10 weeks in the case of normal mice. On the other hand, nodules and then ulceration developed progressively in nude mice until all animals expired by dissemination of microorganisms at the 11th week of inoculation. Histopathologically the migrated cells were similar in both the normal and the nude mice, particularly during the early phase (within 24 h), with infiltration by PMNs being predominant. Fragmentation ofS. schenckii commenced early during the 12–24 h stage of inoculation in the normal mice, while such fragmentation was scarce in nude mice even though numerous PMNs accumulated. Microscopic observations in the early stages (within 24 h of inoculation) suggested that the lack of killing activity by PMNs in nude mice contributes more to the impaired defense than the lack of macrophage activation by T-cells.     

Les génotypes responsables de mucoviscidose ou d’absence bilatérale des canaux déférents ABCD

Over the last decade, the genetic basis for CBAVD has been identified by its association with CFTR gene mutations, and CBAVD is now generally considered to be a mild or incomplete form of CF. In this review, the author summarizes the main results of compilation of CFTR gene analysis conducted in French laboratories for 3,923 patients with CF and 800 males with CABVD. The degree of clinical expression can be affected by several variables, including the molecular mechanisms by which the various CFTR mutations impair or disrupt the function of the CFTR chloride channel. Phenotypic expression of CFTR mutational genotypes varies from severe, progressive pulmonary disease with pancreatic insufficiency (CF-PI), to mild pulmonary disease with pancreatic sufficiency (PS) or singleorgan forms of “CFTR-opathies”. In CF, a total of 310 different CFTR mutations accounting for 94% of 7,846 CF alleles have generated almost 500 different genotypes, comprising 2 severe mutations in 88% of cases (CF-PI), one severe mutation in trans to a mild mutation in 11% (CF-PS), and 2 mild mutations in 1% of identified genotypes. In CBAVD, 137 mutations scattered over the whole gene were identified in 60% of 1,600 CBAVD alleles during the study. Among the 150 characterized mutational CFTR genotypes, compound heterozygosity was the rule, and the most frequent CBAVD combinations were ΔF508/5T (35%), ΔF508/other mutation (30%, including ΔF508/R117H-7T: 5,6%), and 5T/other mutation (17%). No combination of two severe mutations was found in CBAVD (0%); by contrast with the CF population, 88% of genotypes identified in CBAVD comprised a severe mutation in trans to a mild mutation, and 12% consisted of 2 mild mutations. A total of 22 genotypes were shared by both CF and CBAVD. The role of the 5T allele as a splicing variant with variable, incomplete disease penetrance in CBAVD is reviewed. Other haplotype backgrounds, such as the TG12 sequence and the M470V polymorphism, may influence CFTR splicing and/or function. This study confirms the high molecular heterogeneity of CFTR mutations in CBAVD and emphasizes the importance of extensive CFTR analysis in these patients. Longterm follow-up studies of CBAVD patients are necessary in order to predict the phenotypic consequences of numerous CFTR mutational genotypes.     

Species richness, environmental fluctuations, and temporal change in total community biomass

Theory and empirical results suggest that high biodiversity should often cause lower temporal variability in aggregate community properties such as total community biomass. We assembled microbial communities containing 2 to 8 species of competitors in aquatic microcosms and found that the temporal change in total community biomass was positively but insignificantly associated with diversity in a constant temperature environment. There was no evidence of any trend in variable temperature environments. Three non-exclusive mechanisms might explain the lack of a net stabilising effect of species richness on temporal change. (1) A direct destabilising effect of diversity on population level variances caused some populations to vary more when embedded in more diverse communities. (2) Similar responses of the different species to environmental variability might have limited any insurance effect of increased species richness. (3) Large differences in the population level variability of different species (i.e., unevenness) could weaken the relation between species richness and community level stability. These three mechanisms may outweigh the stabilising effects of increases in total community biomass with diversity, statistical averaging, and slightly more negative covariance in more diverse communities. Our experiment and analyses advocate for further experimental investigations of diversity-variability relations.