Interleukin‐6 limits influenza‐induced inflammation and protects against fatal lung pathology

Balancing the generation of immune responses capable of controlling virus replication with those causing immunopathology is critical for the survival of the host and resolution of influenza‐induced inflammation. Based on the capacity of interleukin‐6 (IL‐6) to govern both optimal T‐cell responses and inflammatory resolution, we hypothesised that IL‐6 plays an important role in maintaining this balance. Comparison of innate and adaptive immune responses in influenza‐infected wild‐type control and IL‐6‐deficient mice revealed striking differences in virus clearance, lung immunopathology and generation of heterosubtypic immunity. Mice lacking IL?6 displayed a profound defect in their ability to mount an anti‐viral T‐cell response. Failure to adequately control virus was further associated with an enhanced infiltration of inflammatory monocytes into the lung and an elevated production of the pro‐inflammatory cytokines, IFN‐α and TNF‐α. These events were associated with severe lung damage, characterised by profound vascular leakage and death. Our data highlight an essential role for IL‐6 in orchestrating anti‐viral immunity through an ability to limit inflammation, promote protective adaptive immune responses and prevent fatal immunopathology.     

The role of hippocampal theta oscillations in working memory impairment in multiple sclerosis

Working memory (WM) problems are frequently present in people with multiple sclerosis (MS). Even though hippocampal damage has been repeatedly shown to play an important role, the underlying neurophysiological mechanisms remain unclear. This study aimed to investigate the neurophysiological underpinnings of WM impairment in MS using magnetoencephalography (MEG) data from a visual‐verbal 2‐back task. We analysed MEG recordings of 79 MS patients and 38 healthy subjects through event‐related fields and theta (4–8 Hz) and alpha (8–13 Hz) oscillatory processes. Data was source reconstructed and parcellated based on previous findings in the healthy subject sample. MS patients showed a smaller maximum theta power increase in the right hippocampus between 0 and 400 ms than healthy subjects (p = .014). This theta power increase value correlated negatively with reaction time on the task in MS (r = −.32, p = .029). Evidence was provided that this relationship could not be explained by a ‘common cause’ confounding relationship with MS‐related neuronal damage. This study provides the first neurophysiological evidence of the influence of hippocampal dysfunction on WM performance in MS.     

Obesity and regional fat distribution in Kenyan populations: Impact of ethnicity and urbanization

Background: Obesity is increasing rapidly in Africa, and may not be associated with the same changes in body composition among different ethnic groups in Africa.

Objective: To assess abdominal visceral and subcutaneous fat thickness, prevalence of obesity, and differences in body composition in rural and urban Kenya.

Subjects and methods: In a cross-sectional study carried out among Luo, Kamba and Maasai in rural and urban Kenya, abdominal visceral and subcutaneous fat thicknesses were measured by ultrasonography. Height and weight, waist, mid-upper arm circumferences, and triceps skinfold thickness were measured. Body mass index (BMI), arm fat area (AFA) and arm muscle area (AMA) were calculated.

Results: Among 1430 individuals (58.3% females) aged 17–68 years, abdominal visceral and subcutaneous fat, BMI, AFA and waist circumference (WC) increased with age, and were highest in the Maasai and in the urban population. AMA was only higher with increasing age among males. The prevalence of overweight (BMI ≥ 25) (39.8% vs. 15.8%) and obesity (BMI ≥ 30) (15.5% vs. 5.1%) was highest in the urban vs. rural population.

Conclusion: Abdominal visceral and subcutaneous fat thickness was higher with urban residency. A high prevalence of overweight and obesity was found. The Maasai had the highest overall fat accumulation.     

Flow cytometry data mining by cytoChain identifies determinants of exhaustion and stemness in TCR-engineered T cells

The phenotype of infused cells is a major determinant of Adoptive T-cell therapy (ACT) efficacy. Yet, the difficulty in deciphering multiparametric cytometry data limited the fine characterization of cellular products. To allow the analysis of dynamic and complex flow cytometry samples, we developed cytoChain, a novel dataset mining tool and a new analytical workflow. CytoChain was challenged to compare state-of-the-art and innovative culture conditions to generate stem-like memory cells (T_SCM) suitable for ACT. Noticeably, the combination of IL-7/15 and superoxides scavenging sustained the emergence of a previously unidentified nonexhausted Fit-T_SCM signature, overlooked by manual gating and endowed with superior expansion potential. CytoChain proficiently traced back this population in independent datasets, and in T-cell receptor engineered lymphocytes. CytoChain flexibility and function were then further validated on a published dataset from circulating T cells in COVID-19 patients. Collectively, our results support the use of cytoChain to identify novel, functionally critical immunophenotypes for ACT and patients immunomonitoring.     

Investigation of the Relationship Between Prostate Cancer and MSMB and NCOA4 Genetic Variants and Protein Expression

Two genome‐wide association studies (GWAS) identified the β‐microseminoprotein (MSMB) promoter SNP, rs10993994:C>T, as significantly associated with prostate cancer (PC) risk. Follow‐up studies demonstrate that the variant allele directly affects expression of the MSMB‐encoded protein, PSP94, and also suggest that it affects mRNA expression levels of an adjacent gene, NCOA4, which is involved in androgen receptor transactivation. In a population‐based study of 1,323 cases and 1,268 age‐matched controls, we found the NCOA4 SNP, rs7350420:T>C, was associated with a 15% reduction in PC risk, but the association was not significant after adjustment for the rs10993994:C>T genotype. Tumor tissue microarrays of 519 radical prostatectomy patients were used to measure PSP94 and NCOA4 protein expression. Taken together, these data confirm that the rs10993994:C>T variant allele is associated with decreased PSP94 expression, and the association is stronger in tumor compared to normal prostate tissue. No association was observed between rs10993994:C>T and NCOA4 expression, and only moderate associations were seen between two NCOA4 SNPs, rs10761618:T>C and rs7085433:G>A, and NCOA4 protein expression. These data indicate that the increase in PC risk associated with rs10993994:C>T is likely mediated by the variant's effect on PSP94 expression; however, this effect does not extend to NCOA4 in the data presented here.     

High prevalence of polymorphisms of angiotensin-converting enzyme (I/D) and endothelial nitric oxide synthase (Glu298Asp) in patients with systemic sclerosis

PURPOSE: Systemic sclerosis is characterized by progressive microvascular occlusion and fibrosis and by an imbalance in the fibrinolytic system. In vivo and in vitro studies suggest that the renin-angiotensin system partly regulates vascular fibrinolytic balance. Angiotensin II increases the production and secretion of plasminogen activator inhibitor-1, while angiotensin-converting enzyme (ACE) contributes to reduced production of tissue plasminogen activator and endothelial nitric oxide synthesis by bradykinin degradation. The aim of our study was to investigate the effects of ACE insertion/deletion (I/D) and endothelial nitric oxide synthase (eNOS) Glu298Asp (G894-->T) and T-786-->C polymorphisms in patients with systemic sclerosis. SUBJECTS AND METHODS: We studied 73 consecutive patients (47 with limited and 26 with diffuse cutaneous systemic sclerosis) and 112 control subjects. ACE I/D and eNOS polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: The ACE I/D and the eNOS G894-->T polymorphisms were more common in patients than in controls (for the ACE D allele: odds ratio [OR] = 3.4; 95% confidence interval [CI]: 1.5 to 7.9; P = 0.003; for the eNOS T allele: OR = 1.9; 95% CI: 1.0 to 3.4; P = 0.04). There was no association between the eNOS T-786-->C polymorphism and systemic sclerosis. CONCLUSIONS: Our findings of an increased risk of systemic sclerosis in ACE D and eNOS 894T allele carriers suggest that these polymorphisms may contribute to the pathogenesis of the disease.     

Increased Antifungal Drug Resistance in Clinical Isolates of Cryptococcus neoformans in Uganda

Cryptococcal antigen screening is recommended among people living with AIDS when entering HIV care with a CD4 count of <100 cells/μl, and preemptive fluconazole monotherapy treatment is recommended for those with subclinical cryptococcal antigenemia. Yet, knowledge is limited of current antimicrobial resistance in Africa. We examined antifungal drug susceptibility in 198 clinical isolates collected from Kampala, Uganda, between 2010 and 2014 using the CLSI broth microdilution assay. In comparison with two previous studies from 1998 to 1999 that reported an MIC₅₀ of 4 μg/ml and an MIC₉₀ of 8 μg/ml prior to widespread human fluconazole and agricultural azole fungicide usage, we report an upward shift in the fluconazole MIC₅₀ to 8 μg/ml and an MIC₉₀ value of 32 μg/ml, with 31% of isolates with a fluconazole MIC of ≥16 μg/ml. We observed an amphotericin B MIC₅₀ of 0.5 μg/ml and an MIC₉₀ of 1 μg/ml, of which 99.5% of isolates (197 of 198 isolates) were still susceptible. No correlation between MIC and clinical outcome was observed in the context of amphotericin B and fluconazole combination induction therapy. We also analyzed Cryptococcus susceptibility to sertraline, with an MIC₅₀ of 4 μg/ml, suggesting that sertraline is a promising oral, low-cost, available, novel medication and a possible alternative to fluconazole. Although the CLSI broth microdilution assay is ideal to standardize results, limit human bias, and increase assay capacity, such assays are often inaccessible in low-income countries. Thus, we also developed and validated an assay that could easily be implemented in a resource-limited setting, with similar susceptibility results (P = 0.52).