Mutant ryanodine receptors in catecholaminergic polymorphic ventricular tachycardia generate delayed afterdepolarizations due to increased propensity to Ca2+ waves.

AIMS: Mutations in cardiac ryanodine receptors (RyR2s) are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT), characterized by risk of polymorphic ventricular tachyarrhythmias and sudden death during exercise. Arrhythmias are caused by gain-of-function defects in RyR2, but cellular arrhythmogenesis remains elusive. METHODS AND RESULTS: We recorded endocardial monophasic action potentials (MAPs) at right ventricular septum in 15 CPVT patients with a RyR2 mutation (P2,328S, Q4,201R, and V4,653F) and in 12 control subjects both at baseline and during epinephrine infusion (0.05 microg/kg/min). At baseline 3 and during epinephrine infusion, four CPVT patients, but none of the control subjects, showed delayed afterdepolarizations (DADs) occasionally coinciding with ventricular premature complexes. In order to study the underlying mechanisms, we expressed two types of mutant RyR2 (P2,328S and V4,653F) causing CPVT as well as wild-type RyR2 in HEK 293 cells. Confocal microscopy of Fluo-3 loaded cells transfected with any of the three RyR2s showed no spontaneous subcellular Ca(2+) release events at baseline. Membrane permeable cAMP analogue (Dioctanoyl-cAMP) triggered subcellular Ca(2+) release events as Ca(2+) sparks and waves. Cells expressing mutant RyR2s showed spontaneous Ca(2+) release events at lower concentrations of cAMP than cells transfected with wild-type RyR2. CONCLUSION: CPVT patients show DADs coinciding with premature action potentials in MAP recordings. Expression studies suggest that DADs are caused by increased propensity of abnormal RyR2s to generate spontaneous Ca(2+) waves in response to cAMP stimulation. Increased sensitivity of mutant RyR2s to cAMP may explain the occurrence of arrhythmias during exercise or emotional stress in CPVT.     

Isolation of silica-dependent protein from rat lung with special reference to development of fibrosis

Silicosis was produced experimentally in rats by single intratracheal injections of various doses of SiO2 dust. The weight of the lungs as well as the contents of total nitrogen, collagen, nucleic acids (especially RNA), and lipids increased in accordance with the dose and the time interval. Fibrogenic stimulation in vitro was shown by the supernatant of the homogenized lung in the incorporation of proline into incubated granulation tissue or lung fibroblasts. The fibrogenic factor-activity depended more on the time interval after the injection than on the SiO2 dose. Electrophoresis of the soluble proteins in the silicotic rat lungs showed a protein of 16,000 Da, which was dependent on the time interval following SiO2 administration as well as on the dose itself, and which originated from macrophages. This protein was purified by repeated gel-filtration chromatography. It stimulated collagen synthesis in granulation-tissue cells at a concentration of about 10(-10) M in a dose-dependent way. It was acidic by amino acid composition but differed from calmodulin which also increased collagen synthesis in granulation-tissue cells in vitro. The ability of non-fractionated macrophage preparations to stimulate the incorporation of proline into collagen correlated inversely with the gross alkaline RNase activity.     

A randomized controlled trial evaluating combination detection of HIV in Malawian sexually transmitted infections clinics

IntroductionHIV diagnosis is the necessary first step towards HIV care initiation, yet many persons living with HIV (PLWH) remain undiagnosed. Employing multiple HIV testing strategies in tandem could increase HIV detection and promote linkage to care. We aimed to assess an intervention to improve HIV detection within socio‐sexual networks of PLWH in two sexually transmitted infections (STI) clinics in Lilongwe, Malawi.MethodsWe conducted a randomized controlled trial to evaluate an intervention combining acute HIV infection (AHI) screening, contract partner notification and social contact referral versus the Malawian standard of care: serial rapid serological HIV tests and passive partner referral. Enrolment occurred between 2015 and 2019. HIV‐seropositive persons (two positive rapid tests) were randomized to the trial arms and HIV‐seronegative (one negative rapid test) and ‐serodiscordant (one positive test followed by a negative confirmatory test) persons were screened for AHI with HIV RNA testing. Those found to have AHI were offered enrolment into the intervention arm. Our primary outcome of interest was the number of new HIV diagnoses made per index participant within participants’ sexual and social networks. We also calculated total persons, sexual partners and PLWH (including those previously diagnosed) referred per index participant.ResultsA total of 1230 HIV‐seropositive persons were randomized to the control arm, and 561 to the intervention arm. Another 12,713 HIV‐seronegative or ‐serodiscordant persons underwent AHI screening, resulting in 136 AHI cases, of whom 94 enrolled into the intervention arm. The intervention increased the number of new HIV diagnoses made per index participant versus the control (ratio: 1.9; 95% confidence interval (CI): 1.2 to 3.1). The intervention also increased the numbers of persons (ratio: 2.5; 95% CI: 2.0 to 3.2), sexual partners (ratio: 1.7; 95% CI: 1.4 to 2.0) and PLWH (ratio: 2.3; 95% CI: 1.7 to 3.2) referred per index participant.ConclusionsCombining three distinct HIV testing and referral strategies increased the detection of previously undiagnosed HIV infections within the socio‐sexual networks of PLWH seeking STI care. Combination HIV detection strategies that leverage AHI screening and socio‐sexual contact networks offer a novel and efficacious approach to increasing HIV status awareness.     

Nutritional Status and Physical Fitness of Tribal Adolescents in Ahmednagar District of Maharashtra

We examined the influence of nutritional status, body fat, and anemia on the physical fitness (PFI) of tribal adolescents. Weight, height, skinfold thickness, PFI, and hemoglobin levels of 147 adolescents (11 to 16 years) were measured. The experience of cycling was recorded. Overall, 31.3% were mildly, 12.9% were moderately, and 10.9% were severely thin. The majority (81.6%) were nonanemic. All had “poor” PFI scores. Hemoglobin levels were significantly associated with PFI scores in boys and girls. Experience of cycling also predicted PFI in girls. Nutritional status, hemoglobin level, and physical activity were associated with the fitness levels of these adolescents.     

Older rehabilitees’ life-course agency in Finnish gerontological rehabilitation

Aims: This study investigates gerontological rehabilitation sessions of Finnish rehabilitees in the framework of life-course agency from the perspectives of temporal orientation and agency. Methods: The research data were obtained by non-participatory observation in 11 individual goal-setting sessions between 11 rehabilitees and their personal counsellors. The data were analysed in accordance with data-driven, qualitative content and narrative analysis, with an emphasis on the life-course agency approach. Results: Four temporal orientations of older rehabilitees were identified in the rehabilitation sessions: (i) timeless, (ii) past, (iii) present, and (iv) life course. For each temporal orientation, the rehabilitees displayed different kinds of agency. Fractured agency was intertwined with the timeless orientation, frozen agency was related to the past orientation, practical agency to the present orientation, and transitional agency emerged in relation to the life-course orientation. Conclusions: The article contributes to the discussion of how older adults’ rehabilitation should be reformed within the Finnish context. The study suggests that a person-centred gerontological rehabilitation process should be conceptualized in terms of an agency-based approach with a personally constructed and temporally embedded life-course perspective. This kind of conceptualizing could promote empowered cooperation and innovative interventions with flexible schedules in the rehabilitation processes of older adults.     

Birth seasons and heights among girls and boys below 12 years of age: lasting effects and catch-up growth among native Amazonians in Bolivia

Background: Seasons affect many social, economic, and biological outcomes, particularly in low-resource settings, and some studies suggest that birth season affects child growth.

Aim: To study a predictor of stunting that has received limited attention: birth season.

Subjects and methods: This study uses cross-sectional data collected during 2008 in a low-resource society of horticulturists-foragers in the Bolivian Amazon, Tsimane’. It estimates the associations between birth months and height-for-age Z-scores (HAZ) for 562 girls and 546 boys separately, from birth until age 11?years or pre-puberty, which in this society occurs ～13–14?years.

Results: Children born during the rainy season (February–May) were shorter, while children born during the end of the dry season and the start of the rainy season (August–November) were taller, both compared with their age–sex peers born during the rest of the year. The correlations of birth season with HAZ were stronger for boys than for girls. Controlling for birth season, there is some evidence of eventual partial catch-up growth, with the HAZ of girls or boys worsening until?～?age 4–5?years, but improving thereafter. By age 6?years, many girls and boys had ceased to be stunted, irrespective of birth season.

Conclusion: The results suggest that redressing stunting will require attention to conditions in utero, infancy and late childhood.     

Alcoholic Liver Damage is Provoked by 4-Methylpyrazole, which Prolongs the Influence of Ethanol but Reduces Acetaldehyde Levels

Rats chronically fed ethanol developed liver injury only if they also received low doses of the alcohol dehydrogenase inhibitor, 4-methylpyrazole, suggesting that the consistency of the influence of ethanol and its metabolism, rather than the level of acetaldehyde or the degree of the metabolic effects, contributes to the pathogenesis of alcoholic liver damage.