CTLA4 Autoimmunity-Associated Genotype Contributes to Severe Pulmonary Tuberculosis in an African Population

The gene of Cytotoxic T Lymphocyte-associated Antigen 4 (CTLA4), a negative regulator of T lymphocytes, contains a single-nucleotide polymorphism (SNP) at position +6230A->G (ct60A->G), which has been found associated with several autoimmune diseases and appears to reduce T-cell inhibitory activity. In Ghana, West Africa, we compared the frequencies of CTLA4 +6230 A/G and 6 haplotype-tagging SNPs in 2010 smear-positive, HIV-negative patients with pulmonary tuberculosis (TB) and 2346 controls matched for age, gender and ethnicity. We found no difference in allele frequencies between cases and controls. However, +6230A and a distinct CTLA4 haplotype and a diplotype comprising the +6230A allele were significantly less frequent among cases with large opacities in chest radiographs compared to those with small ones (P_{corrected [cor]} = 0.002, P_cor = 0.00045, P = 0.0005, respectively). This finding suggests that an increased T-cell activity associated with the CTLA4 +6230G allele contributes to pathology rather than to protection in pulmonary TB.     

Skeletal muscle creatine kinase MB alterations in women marathon runners

Total creatine kinase (CK) and CK MB activities were determined in gastrocnemius muscle and serum obtained from 14 female marathon runners. The level of CK MB in muscle increased significantly (p less than 0.05) after chronic exercise training from 5.3% to 10.5% of the total CK activity, but not after acute exercise (post-marathon 8.9%). No significant differences in total CK activities were detected. However, the total CK activity in the muscles were significantly (p less than 0.05) less than those previously reported from the muscle of men runners (1800 U/g, 3000 U/g respectively). No significant correlation existed between fiber type and muscle CK MB activity. Additionally, trace amounts of mitochondrial CK and CK BB were present in muscle homogenates. A significant correlation was observed in the increase in mean serum total CK (597 UL-1) and CK MB (23 UL-1) activities 24 h after the race (r = 0.97, p less than 0.05). These results suggest that gastrocnemius muscle in women adapts to training with increased CK MB activities and imply that skeletal muscle is the major source of elevated serum CK MB activities in women marathon runners.     

The value of decreasing the duration of the infectious period of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection

Finding medications or vaccines that may decrease the infectious period of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could potentially reduce transmission in the broader population. We developed a computational model of the U.S. simulating the spread of SARS-CoV-2 and the potential clinical and economic impact of reducing the infectious period duration. Simulation experiments found that reducing the average infectious period duration could avert a median of 442,852 [treating 25% of symptomatic cases, reducing by 0.5 days, reproductive number (R₀) 3.5, and starting treatment when 15% of the population has been exposed] to 44.4 million SARS-CoV-2 cases (treating 75% of all infected cases, reducing by 3.5 days, R₀ 2.0). With R₀ 2.5, reducing the average infectious period duration by 0.5 days for 25% of symptomatic cases averted 1.4 million cases and 99,398 hospitalizations; increasing to 75% of symptomatic cases averted 2.8 million cases. At $500/person, treating 25% of symptomatic cases saved $209.5 billion (societal perspective). Further reducing the average infectious period duration by 3.5 days averted 7.4 million cases (treating 25% of symptomatic cases). Expanding treatment to 75% of all infected cases, including asymptomatic infections (R₀ 2.5), averted 35.9 million cases and 4 million hospitalizations, saving $48.8 billion (societal perspective and starting treatment after 5% of the population has been exposed). Our study quantifies the potential effects of reducing the SARS-CoV-2 infectious period duration.     

Describing Ordinal Odds Ratios for Stratified r × c Tables

For an r × ctable with ordinal responses, odds ratios are commonly used to describe the relationship between the row and column variables. This article shows two types of ordinal odds ratios where local‐global odds ratios are used to compare several groups on a c‐category ordinal response and a global odds ratio is used to measure the global association between a pair of ordinal responses. When there is a stratification factor, we consider Mantel‐Haenszel (MH) type estimators of these odds ratios to summarize the association from several strata. Like the ordinary MH estimator of the common odds ratio for several 2 × 2 contingency tables, the estimators are used when the association is not expected to vary drastically among the strata. Also, the estimators are consistent under the ordinary asymptotic framework in which the number of strata is fixed and also under sparse asymptotics in which the number of strata grows with the sample size. Compared to the maximum likelihood estimators, simulations find that the MH type estimators perform better especially when each stratum has few observations. This article provides variances and covariances formulae for the local‐global odds ratios estimators and applies the bootstrap method to obtain a standard error for the global odds ratio estimator. At the end, we discuss possible ways of testing the homogeneity assumption.     

Suppression of defective-sporulation phenotypes by mutations in the major sigma factor gene (rpoD) of Bacillus subtilis

Summary Mutations (crsA47 and crsA4) in the major sigma factor gene (rpoD) of Bacillus subtilis RNA polymerase have been found to be powerful intergenic suppressors of spoOB, spoOE, spoOF, spoOK and spoIIG mutations. The crsA47 suppressor restores sporulation of spoOE, spoOF, spoOK and spoIIG mutants to levels near those of wild type bacteria and substantially improves the sporulation of a spoOB strain. The crsA mutations are shown to prevent the induction by aliphatic alcohols of SpoO phenocopies in wild type B. subtilis cells.     

Adrenalectomy of Rats Results in Hypomyelination of the Central Nervous System

The effect of adrenalectomy on CNS myelin accumulation was investigated to determine whether glucocorticoids play a role in regulating myelination. When 14-day-old rats were adrenalectomized and sacrificed 7-8 days later, the amount of bulk-isolated myelin in whole brain, as expressed per gram wet weight of brain or per milligram DNA-phosphate, was reduced to about 75% that of sham-operated controls. Both brain weight and DNA content were unchanged by adrenalectomy. Examination of individual brain regions also revealed decreased amounts of myelin in adrenalectomized animals. Brain glycerol 3-phosphate dehydrogenase specific activity was reduced in adrenalectomized animals to 40-60% that of controls, and serum corticosterone levels were less than 0.6% of control levels. The amount of cerebral myelin in animals adrenalectomized on day 21 and sacrificed 9 days later was not significantly reduced. This suggests a possible role of glucocorticoids during the early period of rapid myelination.     

Organization of the ribosomal ribonucleic acid genes in various wild-type strains and wild-collected strains of Neurospora

Summary The organization of the ribosomal DNA (rDNA) repcat unit in the standard wild-type strain of Neurospora crassa, 74-OR23-1A, and in 30 other wild-type strains and wild-collected strains of N. crassa, N. tetrasperma, N. sitophila, N. intermedia, and N. discreta isolated from nature, was investigated by restriction enzyme digestion of genomic DNA, and probing of the Southern-blotted DNA fragments with specific cloned pieces of the rDNA unit from 74-OR23-1A. The size of the rDNA unit in 74-OR23-1A was shown to be 9.20 kilobase pairs (kb) from blotting data, and the average for all strains was 9.11+0.21 kb; standard error=0.038; coefficient of variation (C.V.)=2.34%. These data indicate that the rDNA repeat unit size has been highly conserved among the Neurospora strains investigated. However, while all strains have a conserved HindIII site near the 5 end of the 25 S rDNA coding sequence, a polymorphism in the number and/or position of HindIII sites in the nontranscribed spacer region was found between strains. The 74-OR23-1A strain has two HindIII sites in the spacer, while others have from 0 to at least 3. This restriction site polymorphism is strain-specific and not species-specific. It was confirmed for some strains by restriction analysis of clones containing most of the rDNA repeat unit. The current restriction map of the 74-OR23-1A rDNA repeat unit is presented.     

Deoxycytidine Transport and Metabolism in the Central Nervous System

Abstract: The mechanisms by which deoxycytidine enters and leaves brain, choroid plexus, and CSF were investigated by injecting [³H]deoxycytidine intraarterially, intravenously, and intraventricularly. After intracarotid injection of deoxycytidine (1.0 μM) into rats, deoxycytidine did not pass through the blood-brain barrier at a faster rate than sucrose. [³H]Deoxycytidine, either alone or together with unlabeled deoxycytidine, was infused at a constant rate into conscious adult rabbits. At 130 min, [³H]deoxycytidine readily entered CSF, choroid plexus, and brain. In brain, approx. 60% of the nonvolatile radioactivity was attributable to [³H]deoxycytidine phosphates. The addition of 0.22 mmol/kg unlabeled deoxycytidine to the infusion syringe decreased the phosphorylation of [³H]deoxycytidine in brain by approx. 50%; the addition of 2.2 mmol/kg of unlabeled deoxycytidine to the infusion syringe decreased the relative entry of [³H]deoxycytidine into CSF and brain by approx. 50 and 75%, respectively. Two hours after the intraventricular injection of [³H]deoxycytidine, [³H]deoxycytidine was rapidly cleared from CSF, in part, to brain, where approx. 65% of the [³H]deoxycytidine was converted to [³H]deoxycytidine phosphates. The intraventricular injection of unlabeled deoxycytidine with the [³H]deoxycytidine decreased the phosphorylation of [³H]deoxycytidine in the brain significantly and also decreased the clearance of [³H]deoxycytidine from the CSF. These results were interpreted as showing that the entry of deoxycytidine from blood into CSF occurs by a saturable transport system within the choroid plexus. Once within the CSF, the deoxycytidine can enter brain, undergo phosphorylation to deoxycytidine phosphates, and subsequently be incorporated into DNA.     

Muscle morphological and biochemical adaptations to training in obese Zucker rats

The purposes of the present study were to characterize the histochemical and enzymatic profiles of various hindlimb skeletal muscles, as well as to determine maximal O2 consumption (VO2max) and respiratory exchange ratios (R) during steady-state exercise in the obese Zucker rat. The changes that occurred in these parameters in response to a 6-wk training program were then assessed. Obese rats were randomly assigned to a sedentary or training group. Lean littermates served as a second control. Training consisted of treadmill running at 18 m/min up an 8% grade, 1.5 h/day, 5 day/wk for 6 wk. During week 6, VO2max and R during a steady-state run (74% max) were determined. After 2 days of inactivity, hindlimb muscles were excised, stained for fiber type and capillaries, and assayed for hexokinase, citrate synthase, cytochrome oxidase, and beta-hydroxyacetyl-CoA dehydrogenase. The obese sedentary rats demonstrated greater oxidative enzyme activities per gram of muscle tissue than their lean littermates, greater R values during submaximal exercise of the same relative intensity, and greater absolute VO2max values. Training resulted in a 20-56% increase in oxidative enzymes, a 10% increase in VO2max, and an increase in capillary density in the soleus and plantaris. There was no alteration in R values during exercise at 74% VO2max or in fiber type composition in response to exercise training. Results suggest that the muscle of the obese Zucker rat manifests a greater oxidative capacity than the muscle of its lean littermates. The apparent inability of the obese rat to increase its use of fat during submaximal exercise of the same relative intensity in response to training remains to be elucidated.