Inactivation of glutathione peroxidase activity contributes to UV-induced squamous cell carcinoma formation

Cutaneous squamous cell carcinomas (CSCC) are a common malignancy of keratinocytes that arise in sites of the skin exposed to excessive UV radiation. In the present study, we show that human SCC cell lines, preneoplastic solar keratoses (SK), and CSCC are associated with perturbations in glutathione peroxidase (GPX) activity and peroxide levels. Specifically, we found that two of three SKs and four of five CSCCs, in vivo, were associated with decreased GPX activity and all SKs and CSCCs were associated with an elevated peroxide burden. Given the association of decreased GPX activity with CSCC, we examined the basis for the GPX deficiency in the CSCCs. Our data indicated that GPX was inactivated by a post-translational mechanism and that GPX could be inactivated by increases in intracellular peroxide levels. We next tested whether the decreased peroxidase activity coupled with an elevated peroxidative burden might contribute to CSCC formation in vivo. This was tested in Gpx1(-/-) and Gpx2(-/-) mice exposed to solar-simulated UV radiation. These studies showed that Gpx2 deficiency predisposed mice to UV-induced CSCC formation. These results suggest that inactivation of GPX2 in human skin may be an early event in UV-induced SCC formation.     

High levels of SIVmnd-1 replication in chronically infected Mandrillus sphinx

Viral loads were investigated in SIVmnd-1 chronically infected mandrills and the results were compared with those previously observed in other nonpathogenic natural SIV infections. Four naturally and 11 experimentally SIVmnd-1-infected mandrills from a semi-free-ranging colony were studied during the chronic phase of infection. Four SIVmnd-1-infected wild mandrills were also included for comparison. Twelve uninfected mandrills were used as controls. Viral loads in all chronically infected mandrills ranged from 10(5) to 9 x 10(5) copies/ml and antibody titers ranged from 200 to 14,400 and 200 to 12,800 for anti-V3 and anti-gp36, respectively. There were no differences between groups of wild and captive mandrills. Both parameters were stable during the follow-up, and no clinical signs of immune suppression were observed. Chronic SIVmnd-1-infected mandrills presented slight increases in CD20+ and CD28+/CD8+ cell counts, and a slight decrease in CD4+/CD3+ cell counts. A slight CD4+/CD3+ cell depletion was also observed in old uninfected controls. Similar to other nonpathogenic models of lentiviral infection, these results show a persistent high level of SIVmnd-1 replication during chronic infection of mandrills, with minimal effects on T cell subpopulations.     

Diagnostic performance of visible severe wasting for identifying severe acute malnutrition in children admitted to hospital in Kenya

Objective

To determine the diagnostic value of visible severe wasting in identifying severe acute malnutrition at two public hospitals in Kenya.

Methods

This was a cross-sectional study of children aged 6 to 59.9 months admitted to one rural and one urban hospital. On admission, mid-upper arm circumference (MUAC), weight and height were measured and the presence of visible severe wasting was assessed. The diagnostic performance of visible severe wasting was evaluated against anthropometric criteria.

Findings

Of 11 166 children admitted, 563 (5%) had kwashiorkor and 1406 (12.5%) were severely wasted (MUAC < 11.5 cm). The combined sensitivity and specificity of visible severe wasting at the two hospitals, as assessed against a MUAC < 11.5 cm, were 54% (95% confidence interval, CI: 51–56) and 96% (95% CI: 96–97), respectively; at one hospital, its sensitivity and specificity against a weight-for-height z-score below −3 were 44.7% (95% CI: 42–48) and 96.5% (95% CI: 96–97), respectively. Severely wasted children who were correctly identified by visible severe wasting were consistently older, more severely wasted, more often having kwashiorkor, more often positive to the human immunodeficiency virus, ill for a longer period and at greater risk of death. Visible severe wasting had lower sensitivity for determining the risk of death than the anthropometric measures. There was no evidence to support measuring both MUAC and weight-for-height z-score.

Conclusion

Visible severe wasting failed to detect approximately half of the children admitted to hospital with severe acute malnutrition diagnosed anthropometrically. Routine screening by MUAC is quick, simple and inexpensive and should be part of the standard assessment of all paediatric hospital admissions in the study setting.     

The dominant <Emphasis Type="Italic">Hc.Sdh</Emphasis><Superscript>R</Superscript> carboxin-resistance gene of the ectomycorrhizal fungus <Emphasis Type="Italic">Hebeloma cylindrosporum</Emphasis> as a selectable marker for transformation

In an attempt to get a marker gene suitable for genetical transformation of the ectomycorrhizal fungus Hebeloma cylindrosporum, the gene Hc.Sdh ^R that confers carboxin-resistance was isolated from a UV mutant of this fungus. It encodes a mutant allele of the Fe–S subunit of the succinate dehydrogenase gene that carries a single amino acid substitution known to confer carboxin-resistance. This gene was successfully used as the selective marker to transform, via Agrobacterium tumefaciens, monokaryotic and dikaryotic strains of H. cylindrosporum. We also successfully transformed hygromycin-resistant insertional mutants. Transformation yielded mitotically stable carboxin-resistant mycelia. This procedure produced transformants, the growth of which was not affected by 2 μg l⁻¹ carboxin, whereas wild-type strains were unable to grow in the presence of 0.1 μg l⁻¹ of this fungicide. This makes the carboxin-resistance cassette much more discriminating than the hygromycin-resistance one. PCR amplification and Southern blot hybridisation indicated that more than 90% of the tested carboxin-resistant mycelia contained the Hc.Sdh ^R cassette, usually as a single copy. The AGL-1 strain of A. tumefaciens was a much less efficient donor than LBA 1126; the former yielded ca. 0–30% transformation frequency, depending on fungal strain and resistance cassette used, whereas the latter yielded ca. 60–95%. The authors Chrisse Ngari and Jean-Philippe Combier contributed equally to this work.     

Atopy,asthma, and antibodies to Ascaris among rural and urban children in Kenya

OBJECTIVE: The purpose of this study was to evaluate differences in the relationship between asthma and immune responses to allergens in children living in rural and urban areas of Kenya. STUDY DESIGN: Children (mean age, 11 years) from Kabati (n = 136), a rural village, and Thika (n = 129), a small town, were studied by skin testing and serum immunoglobulin E (IgE) and immunoglobulin G (IgG) antibody measurement. Asthma was evaluated by symptoms, as well as spirometry before and after vigorous exercise to test for exercised-induced bronchospasm (EIB). School children from a study performed in Atlanta, Georgia, were used for comparison of anthropometric and immunologic results. RESULTS: Compared with the urban area of Kenya, children living in the rural area had a lower percentage of body fat, smaller and fewer skin test responses to allergens, a higher prevalence of IgE antibodies to Ascaris (67% vs 26%) and 10-fold higher total IgE. In the urban area of Kenya, there was a strong correlation between EIB and atopy determined both by IgE antibodies (P =.02) and skin tests (P =.002). By contrast, in the rural area, none of the 13 children with EIB were skin-test positive (vs 13/109 of children without EIB). CONCLUSIONS: Among the rural children, there was no association between immune responses to allergens and airway-related symptoms or reactivity. The association between asthma and atopy seen in the town of Thika may represent an important step in the increase in asthma seen both in urban Africa and in the West.     

Phenotype is sustained during hospital readmissions following treatment for complicated severe malnutrition among Kenyan children: A retrospective cohort study

Hospital readmission is common among children with complicated severe acute malnutrition (cSAM) but not well‐characterised. Two distinct cSAM phenotypes, marasmus and kwashiorkor, exist, but their pathophysiology and whether the same phenotype persists at relapse are unclear. We aimed to test the association between cSAM phenotype at index admission and readmission following recovery. We performed secondary data analysis from a multicentre randomised trial in Kenya with 1‐year active follow‐up. The main outcome was cSAM phenotype upon hospital readmission. Among 1,704 HIV‐negative children with cSAM discharged in the trial, 177 children contributed a total of 246 readmissions with cSAM. cSAM readmission was associated with age<12 months (p = .005), but not site, sex, season, nor cSAM phenotype. Of these, 42 children contributed 44 readmissions with cSAM that occurred after a monthly visit when SAM was confirmed absent (cSAM relapse). cSAM phenotype was sustained during cSAM relapse. The adjusted odds ratio for presenting with kwashiorkor during readmission after kwashiorkor at index admission was 39.3 [95% confidence interval (95% CI) [2.69, 1,326]; p = .01); and for presenting with marasmus during readmission after kwashiorkor at index admission was 0.02 (95% CI [0.001, 0.037]; p = .01). To validate this finding, we examined readmissions to Kilifi County Hospital, Kenya occurring at least 2 months after an admission with cSAM. Among 2,412 children with cSAM discharged alive, there were 206 readmissions with cSAM. Their phenotype at readmission was significantly influenced by their phenotype at index admission (p < .001). This is the first report describing the phenotype and rate of cSAM recurrence.     

Children concurrently wasted and stunted: A meta‐analysis of prevalence data of children 6–59 months from 84 countries

Children can be stunted and wasted at the same time. Having both deficits greatly elevates risk of mortality. The analysis aimed to estimate the prevalence and burden of children aged 6–59 months concurrently wasted and stunted. Data from demographic and health survey and Multi‐indicator Cluster Surveys datasets from 84 countries were analysed. Overall prevalence for being wasted, stunted, and concurrently wasted and stunted among children 6 to 59 months was calculated. A pooled prevalence of concurrence was estimated and reported by gender, age, United Nations regions, and contextual categories. Burden was calculated using population figures from the global joint estimates database. The pooled prevalence of concurrence in the 84 countries was 3.0%, 95% CI [2.97, 3.06], ranging from 0% to 8.0%. Nine countries reported a concurrence prevalence greater than 5%. The estimated burden was 5,963,940 children. Prevalence of concurrence was highest in the 12‐ to 24‐month age group 4.2%, 95% CI [4.1, 4.3], and was significantly higher among boys 3.54%, 95% CI [3.47, 3.61], compared to girls; 2.46%, 95% CI [2.41, 2.52]. Fragile and conflict‐affected states reported significantly higher concurrence 3.6%, 95% CI [3.5, 3.6], than those defined as stable 2.24%, 95% CI [2.18, 2.30]. This analysis represents the first multiple country estimation of the prevalence and burden of children concurrently wasted and stunted. Given the high risk of mortality associated with concurrence, the findings indicate a need to report on this condition as well as investigate whether these children are being reached through existing programmes.     

High Rate of Simian Immunodeficiency Virus (SIV) Infections in Wild Chimpanzees in Northeastern Gabon

The emergence of HIV-1 groups M, N, O, and P is the result of four independent cross-species transmissions between chimpanzees (cpz) and gorillas (gor) from central/south Cameroon and humans respectively. Although the first two SIVcpz were identified in wild-born captive chimpanzees in Gabon in 1989, no study has been conducted so far in wild chimpanzees in Gabon. To document the SIVcpz infection rate, genetic diversity, and routes of virus transmission, we analyzed 1458 faecal samples collected in 16 different locations across the country, and we conducted follow-up missions in two of them. We found 380 SIV antibody positive samples in 6 different locations in the north and northeast. We determined the number of individuals collected by microsatellite analysis and obtained an adjusted SIV prevalence of 39.45%. We performed parental analysis to investigate viral spread between and within communities and found that SIVs were epidemiologically linked and were transmitted by both horizontal and vertical routes. We amplified pol and gp41 fragments and obtained 57 new SIVcpzPtt strains from three sites. All strains, but one, clustered together within a specific phylogeographic clade. Given that these SIV positive samples have been collected nearby villages and that humans continue to encroach in ape’s territories, the emergence of a new HIV in this area needs to be considered.