Burden of asthma among children in a developing megacity: childhood asthma study,Pakistan

Objectives: Global burden of childhood asthma has increased in the past few decades, particularly in low-income countries. In Pakistan, there is a lack of community-based epidemiological studies estimating the burden of asthma among children. This study determined the prevalence and predictors of asthma among children 3–17 years of age in Karachi, Pakistan. Methods: A two-stage community-based representative cross-sectional survey was conducted in Karachi from March 2012 to April 2013 comprising 1046 children aged 3–17 years. Of 7500 clusters, 80 were randomly selected, and of these, 15 children per cluster were enrolled randomly. A translated and pre-tested version of International Study of Asthma and Allergies in Children questionnaire was administered. Results: The overall prevalence of asthma among study participants was 10.2% (95% CI: 8.4–12.0). Asthma was more likely to occur among boys (adj. OR: 2.5, 95% CI: 1.6–4.0), children in the younger age group (3–7 years) (adj. OR: 2.9, 95% CI: 1.7–4.8), those living in households with ill-ventilated kitchens (adj. OR: 1.8, 95% CI: 1.1–3.1), having family history of asthma (adj. OR: 2.3, 95% CI: 1.3–3.9) and those of the Sindhi ethnicity (adj. OR: 2.2, 95% CI: 1.1–4.4). Conclusion: This study is the first robust evidence regarding asthma among children in Pakistan, reporting a high burden in this group. Family history, male gender, Sindhi ethnicity and ill-ventilated kitchen were identified as important predictors of asthma. Targeted preventive measures and intervention studies are required to better understand and reduce the burden of asthma among children in Pakistan.     

COVID-19 and the heart: An update for clinicians

SARS-CoV-2, the cause of the COVID-19 pandemic has significantly impacted cardiovascular healthcare. Patients with pre-existing cardiovascular disease are at higher risk of morbidity and mortality. The virus may affect the heart directly and indirectly with clinical syndromes of acute myocardial injury, myocarditis, acute coronary syndromes, heart failure, arrhythmias, and venous thromboembolism. Some therapeutics under investigation for COVID-19 may also have adverse cardiac effects. The involvement of the RAAS system in viral entry makes it pertinent to consider the effects of medications that modulate the system. Comprehensive knowledge of peculiar cardiovascular manifestations of COVID-19 and the role of RAAS in the prognosis of COVID-19 disease is needed for optimal patient management.     

Interneuron precursor transplants in adult hippocampus reverse psychosis-relevant features in a mouse model of hippocampal disinhibition

GABAergic interneuron hypofunction is hypothesized to underlie hippocampal dysfunction in schizophrenia. Here, we use the cyclin D2 knockout (Ccnd2^−/−) mouse model to test potential links between hippocampal interneuron deficits and psychosis-relevant neurobehavioral phenotypes. Ccnd2^−/− mice show cortical PV⁺ interneuron reductions, prominently in hippocampus, associated with deficits in synaptic inhibition, increased in vivo spike activity of projection neurons, and increased in vivo basal metabolic activity (assessed with fMRI) in hippocampus. Ccnd2^−/− mice show several neurophysiological and behavioral phenotypes that would be predicted to be produced by hippocampal disinhibition, including increased ventral tegmental area dopamine neuron population activity, behavioral hyperresponsiveness to amphetamine, and impairments in hippocampus-dependent cognition. Remarkably, transplantation of cells from the embryonic medial ganglionic eminence (the major origin of cerebral cortical interneurons) into the adult Ccnd2^−/− caudoventral hippocampus reverses these psychosis-relevant phenotypes. Surviving neurons from these transplants are 97% GABAergic and widely distributed within the hippocampus. Up to 6 mo after the transplants, in vivo hippocampal metabolic activity is lowered, context-dependent learning and memory is improved, and dopamine neuron activity and the behavioral response to amphetamine are normalized. These findings establish functional links between hippocampal GABA interneuron deficits and psychosis-relevant dopaminergic and cognitive phenotypes, and support a rationale for targeting limbic cortical interneuron function in the prevention and treatment of schizophrenia.Precursors of most γ-aminobutyric acid (GABA)-releasing interneurons of the cerebral cortex and the hippocampus originate in the embryonic medial ganglionic eminence (MGE) (1–3). A subpopulation of MGE-derived cells differentiates into fast-spiking, parvalbumin-expressing (PV⁺) interneurons that tightly regulate the activity and synchronization of cortical projection neurons (2, 4). Structural and functional deficits in PV⁺ interneurons are hypothesized as a pathophysiological mechanism in schizophrenia and psychotic disorders (4–6).Although psychotic disorders are clearly heterogeneous in etiology, disinhibition within temporolimbic cortical circuits is postulated as a core pathophysiology underlying positive symptoms (e.g., delusions and hallucinations) and a subset of cognitive disturbances that manifest with psychosis (4, 5, 7). Postmortem studies of brains from individuals with psychotic disorders show reduced molecular markers of the number and/or function of PV⁺ interneurons in the hippocampus (6, 8). Consistent with these observations, basal metabolic activity in the hippocampus, as measured with functional magnetic resonance imaging (fMRI), is increased in schizophrenia, a phenotype that predicts psychosis and positive symptom severity (5, 7). This abnormal resting activity is postulated to underlie abnormal recruitment of hippocampal circuits during cognitive performance (5, 9). Striatal dopamine (DA) release capacity is also increased and correlated with positive symptoms in schizophrenia and its risk states (10, 11). Importantly, hippocampal hyperactivity may contribute to DA dysregulation (12), because rodent studies show that caudoventral hippocampal (in the primate, anterior hippocampal) efferents regulate the activity of DA neurons and medial striatal DA release (13, 14).Thus, converging evidence implicates hippocampal disinhibition in the abnormal striatal DA transmission and cognitive impairment in schizophrenia. However, the role of hippocampal inhibitory interneurons in psychosis-relevant circuitry remains to be established. To this end, we used the cyclin D2 (Ccnd2) knockout mouse model (15), which displays a relatively selective deficit in cortical PV⁺ interneurons, and transplantation of interneuron precursors from the MGE to elucidate relationships between reduced hippocampal GABA interneuron function and multiple psychosis-relevant phenotypes, and to explore a novel treatment strategy for psychosis.     

The importance of caregivers in the outcome of pediatric HIV management,Mombasa, Kenya

We assessed programmatic gaps that prevent the optimal treatment of pediatric HIV infection despite free antiretroviral care in Kenya. Of 626 HIV-infected Kenyan children, the median age was five years, 54% were male and the mortality rate was 3.2 per 100 person-years. A total of 380 (61%) children initiated antiretroviral therapy (ART) during the study period. Among the 246 children who never started ART, 129 (52%) met the criteria for ART initiation. Immunologic failure occurred in 20% of children who received ART for >24 weeks. In multivariate analysis, immunological failure was associated with having nonimmediate relative or unrelated caregivers accompanying the child to clinic (AOR = 69.16, p = 0.008). Having ≥3 types of accompanying caregivers was also associated with virologic failure in multivariate analysis (AOR = 3.84, p = 0.03). The lost to follow-up rate was 8.7/100 persons-years for the entire cohort, and significantly higher (17.7/100 persons-years) among children not on ART (p < 0.001). Among children who do initiate ART, those with the best treatment outcomes were those who had a limited number of close relatives as caregivers and good adherence to ART. Focus on early ART initiation and education of the right caregiver will likely improve retention and quality of pediatric HIV care in Kenya.