Diminished Reovirus Capsid Stability Alters Disease Pathogenesis and Littermate Transmission

Reovirus is a nonenveloped mammalian virus that provides a useful model system for studies of viral infections in the young. Following internalization into host cells, the outermost capsid of reovirus virions is removed by endosomal cathepsin proteases. Determinants of capsid disassembly kinetics reside in the viral σ3 protein. However, the contribution of capsid stability to reovirus-induced disease is unknown. In this study, we found that mice inoculated intramuscularly with a serotype 3 reovirus containing σ3-Y354H, a mutation that reduces viral capsid stability, succumbed at a higher rate than those infected with wild-type virus. At early times after inoculation, σ3-Y354H virus reached higher titers than wild-type virus at several sites within the host. Animals inoculated perorally with a serotype 1 reassortant reovirus containing σ3-Y354H developed exaggerated myocarditis accompanied by elaboration of pro-inflammatory cytokines. Surprisingly, unchallenged littermates of mice infected with σ3-Y354H virus displayed higher titers in the intestine, heart, and brain than littermates of mice inoculated with wild-type virus. Together, these findings suggest that diminished capsid stability enhances reovirus replication, dissemination, lethality, and host-to-host spread, establishing a new virulence determinant for nonenveloped viruses.     

Microbial populations and activity in two soils of Tanzania as influenced by mercury

Summary The influence of mercury on microbial populations and activity of two soils from Tanzania was studied. Aretan (2-methoxyethylmercury chloride) slightly affected the microbial population of the Morogoro (Oxisol) soil, which was 10⁷ c.f.u./g in control soil and 10⁶ c.f.u./g in the presence of 2000 mg Hg/kg soil. Mercuric chloride at >8 mg Hg/kg soil increased the population slightly, with a sharp decrease at >100 mg Hg/kg soil, dropping ultimately to 10³ c.f.u./g at 2000 mg Hg/kg soil. In the Arusha (Andept) soil, the microbial response to the two mercury compounds was the opposite of that for the Morogoro soil. Aretan sharply reduced the nitrogenase activity of aerobically incubated Morogoro soils at Hg levels >24 mg/kg, resulting in very low activity at >50 mg Hg/kg soil. Mercuric chloride increased the activity, which showed a peak at 24 mg Hg/kg soils, followed by a sharp drop at 30 mg Hg/kg and remained low thereafter. In the Arusha soil, the activity was reduced gradually by both Aretan and HgCl₂. The response of the activity under anaerobic incubation in the Morogoro soil was the opposite of that under aerobic incubation, in that it was Aretan which at first increased the activity. In the Arusha soil the activity under anaerobic incubation decreased gradually over the entire range of added Hg. Nitrification was decreased by HgCl₂ atlevels of <2 and <10 mg Hg/kg soil in the Arusha and Morogoro soils, respectively. The tolerance to Hg by microorganisms in this study was in the order: total population > nitrogen fixers > nitrifiers. This may be explained in terms of species diversity of the microorganisms, which may be expected to follow the same sequence.

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Population et activités microbiennes dans deux sols de Tanzanie sous l'influence du mercure

Résumé On étudie l'influence du mercure sur les populations et les activités microbiennes de deux sols en provenance de Tanzanie. L'Aretan (chlorure de 2-méthoxyéthylmercure) n'affecte que faiblement la population microbienne du sol de Morogoro (oxisol), qui compte 10⁷ individus par g dans le sol témoin et 10⁶ individus en présence de 2000 mg de mercure par kg de sol. Le chlorure mercurique, à une dose supérieure à 8 mg de mercure par kg de sol, augmente quelque peu la population. Celle-ci décroît brutalement au delà de 100 mg de mercure par kg de sol, pour tomber finalement à 10³ individus par g à 2000 mg de mercure par kg de sol. Dans le sol d'Arusha (Andept), la réponse microbienne aux deux composés mercuriels est l'inverse de celle obtenue avec le sol de Morogoro. L'Aretan réduit fortement l'activité de la nitrogénase de sols de Morogoro incubés en aérobiose à des teneurs en mercure au delà de 24 mg par kg. L'activité devient très faible au delà de 50 mg de mercure par kg de sol. Le chlorure mercurique augmente cette activité, avec un pic de 24 mg de mercure par kg de sol, suivi d'une chute sévère à 30 mg de mercure par kg. L'activité demeure faible aux doses plus fortes. Dans le sol d'Arusha, l'activité est réduite progressivement tant par l'Aretan que par HgCl₂. La réponse de l'activité en incubation anaérobie dans le sol de Morogoro est l'inverse de celle en incubation aérobie en ceci que c'est l'Aretan, cette fois-ci, qui augmente d'abord l'activité. Dans le sol d'Arusha, l'activité en incubation anaérobie décroît progressivement sur l'échelle entière des concentrations d'ajout de mercure. La nitrification est réduite par HgCl₂ à des seuils au dessous de 2 et 10 mg de mercure par kg de sol, respectivement pour les sols d'Arusha et de Morogoro. La tolérance des microorganismes au mercure dans cette étude est dans l'ordre: population totale > fixateurs d'azote > nitrificateurs. Ceci peut être expliqué en termes de diversité des espèces de microorganismes qui suit vraisemblablement la même séquence.

     

Evaluation of eight and a half years of neonatal screening for haemoglobinopathies in Birmingham

A pilot neonatal screening programme for haemoglobinopathies linked with screening for phenylketonuria and congenital hypothyroidism was reviewed. During 1978 to December 1986 137 000 neonates were tested. There were improvements in the detection rate and accuracy of diagnosis for homozygotes and mixed heterozygotes, mainly associated with the introduction of citrate agarose gel electrophoresis as a follow up procedure on all specimens showing any abnormality on the initial cellulose acetate electrophoresis.We recommend that the programme is continued on a service basis.     

Further studies of the plasma alpha 1 B-glycoprotein polymorphism: two new alleles and allele frequencies in Caucasians and in American blacks

Two new alleles (A1 B*3 and A1 B*4) of human plasma alpha 1 B-glycoprotein (alpha 1 B) were reported. alpha 1 B phenotyping was done by using either a simple method of two-dimensional (2-D) agarose gel-horizontal polyacrylamide gel electrophoresis (PAGE) followed by protein staining or by one-dimensional horizontal PAGE and immunoblotting. Seven different alpha 1 B phenotypes (1-1, 1-2, 1-3, 1-4, 2-2, 2-3 and 3-3) were observed; phenotypes 1-3 and 1-4 were differentiated from each other only by the 2-D method. The respective frequencies Af A1 B*1, A1 B*2, A1 B*3 and A1 B*4 alleles in the studied populations were estimated as follows: American Blacks (New York) 0.732, 0.204, 0.064, 0; American Whites (New York) 0.947, 0.053; Czechs (M?lník) 0.964, 0.034, 0, 0.002; Slovaks (Bratislava and Trencin) 0.977, 0.023, 0, 0. The population of American Blacks showed a much higher degree of alpha 1 B polymorphism (polymorphism information content = 0.37) than the Caucasian populations that have been studied.     

Neurofibromatosis type 2 appears to be a genetically homogeneous disease

Neurofibromatosis type 2 (NF2) is an autosomal dominant syndrome characterized by the development of vestibular schwannomas and other tumors of the nervous system, including cranial and spinal meningiomas, schwannomas, and ependymomas. The presence of bilateral vestibular schwannomas is sufficient for the diagnosis. Skin manifestations are less common than in neurofibromatosis type 1 (NF1; von Recklinghausen disease). The apparent clinical distinction between NF1 and NF2 has been confirmed at the level of the gene locus by linkage studies; the gene for NF1 maps to chromosome 17, whereas the gene for NF2 has been assigned (in a single family) to chromosome 22. To increase the precision of the genetic mapping of NF2 and to determine whether additional susceptibility loci exist, we have performed linkage analysis on 12 families with NF2 by using four polymorphic markers from chromosome 22 and a marker at the NF1 locus on chromosome 17. Our results confirm the assignment of the gene for NF2 to chromosome 22 and do not support the hypothesis of genetic heterogeneity. We believe that chromosome 22 markers can now be used for presymptomatic diagnosis in selected families. The NF2 gene is tightly linked to the D22S32 locus (maximum lod score 4.12; recombination fraction 0). A CA-repeat polymorphism at the CRYB2 locus was the most informative marker in our families (lod score 5.99), but because the observed recombination fraction between NF2 and CRYB2 was 10 cM, predictions using this marker will need to be interpreted with caution.     

Analysis of HLA and Disease Susceptibility: Chromosome 6 Genes and Sex Influence Long-QT Phenotype

The long-QT (LQT) syndrome is a genetically complex disorder that is characterized by syncope and fatal ventricular arrhythmias. LQT syndrome, as defined by a prolonged electrocardiographic QT interval, has a higher incidence in females than in males and does not exhibit Mendelian transmission patterns in all families. Among those families that are nearly consistent with Mendelian transmission, linkage between a locus for LQT syndrome and the H-ras-1 locus on the short arm of chromosome 11 has been reported in some families but not in others. Earlier analyses suggesting that LQT syndrome might be caused by a gene in the HLA region of chromosome 6 were not confirmed by standard linkage analyses. Here, we present an analysis of HLA haplotype sharing among affected pedigree members, showing an excess of haplotype sharing in a previously published Japanese pedigree and possibly also in 15 families of European descent. The haplotypes shared by affected individuals derive from both affected and unaffected parents. In an analysis of independent (unrelated) HLA haplotypes, we also found a nonrandom distribution of HLA-DR genes in LQT syndrome patients compared with controls, suggesting an association between the LQT phenotype and specific HLA-DR genes. Our data indicate that DR2 has a protective effect and, particularly in males, that DR7 may increase susceptibility to the LQT syndrome. Thus, LQT syndrome may be influenced by genes on chromosomes 11 and 6, possibly with a sex-specific effect. These results provide a model for an effect of HLA-region genes inherited from either parent on the expression of an illness that may be determined principally by alleles at loci not linked to HLA.     

Amino Acid Neurotransmitter Receptor Changes in Cerebral Cortex in Alcoholism: Effect of Cirrhosis of the Liver

Gamma-aminobutyric acidA/benzodiazepine receptor binding sites and the N-methyl-D-aspartate subclass of glutamate receptor sites were assessed in synaptic plasma membrane homogenates of cerebral cortex tissue obtained at autopsy from cirrhotic and noncirrhotic alcoholic patients and matched control subjects. The alcoholic patients consumed an average of greater than 80 g of ethanol/day, the control subjects less than 20 g/day. Postmortem delays up to approximately 100 h caused no significant loss of any of the binding sites; the patient and subject groups were closely matched for age. The affinities (KD) of the receptor sites did not differ between the patient and subject groups, nor between cortical regions. Using three different radioligands ([3H]muscimol, [3H]flunitrazepam, and [3H]diazepam), the gamma-aminobutyric acidA/benzodiazepine receptor complex was found to have greater density (Bmax) in superior frontal gyrus in alcoholic patients (which selectively shows morphological change in alcoholic patients), but was unchanged in motor cortex. Alcoholic patients with cirrhosis had much less pronounced changes. The density of the N-methyl-D-aspartate subclass of glutamate receptors, assessed with [3H]MK-801, did not vary across patient and subject groups.