Erythropoietin and cerebral vascular protection： role of nitric oxide

Cerebral vasospasm after subarachnoid hemorrhage (SAH) is a major clinical problem causing cerebral ischemia and infarction. The pathogenesis of vasospasm is related to a number of pathological processes including endothelial damage and alterations in vasomotor function leading to narrowing of arterial diameter and a subsequent decrease in cerebral blood flow. Discovery of the tissue protective effects of erythropoietin (EPO) stimulated the search for therapeutic application of EPO for the prevention and treatment of cerebrovascular disease. Recent studies have identified the role of EPO in vascular protection mediated by the preservation of endothelial cell integrity and stimulation of angiogenesis. In this review, we discuss the EPO-induced activation of endothelial nitric oxide (NO) synthase and its contribution to the prevention of cerebral vasospasm.     

Diethylnitrosamine and acetoxymethyl methylnitrosamine-induced carcinogenesis in mice and vitamin A deficiency

The modulating influence of vitamin A deficiency on carcinogenesis induced by two potent carcinogens, diethylnitrosamine (DEN) and acetoxymethyl methylnitrosamine (AMMN), was studied in BALB/c mice. DEN was administered intragastrically every 30 days at a total dose of 200 mg/kg body weight, split into four doses. AMMN was applied continuously every 14 days on the tongue, at a dose of 2 mg/kg body weight. AMMN and DEN treated animals fed the vitamin A deficient diet had a significantly higher tumor incidence that mice fed the normal diet (p less than 0.05). Studies on the levels of vitamins A, C, B2 and folic acid in the liver and plasma of mice treated with the two carcinogens revealed that both the carcinogens increased vitamin C in both tissues, decreased folic acid and had no effect on vitamin A, while hepatic vitamin B2 was lowered by treatment with AMMN by not by DEN.     

Early outcome of children with complex atrial isomerism undergoing uni-ventricular cardiac palliation

OBJECTIVE: To review the postoperative intensive care unit (ICU) course and early outcome of children with complex atrial isomeric hearts undergoing cardiac surgery for uni-ventricular heart repair. METHODS: A retrospective review and analysis of ICU course of pediatric patients with atrial isomerism admitted from January 2000 to December 2004 in King Abdul-Aziz Medical City, Riyadh, Kingdom of Saudi Arabia, who underwent uni-ventricular repair. RESULTS: During the study period, 18 (n=18) patients were identified to have complex congenital heart disease (CHD) associated with atrial isomerism. They were in the form of right atrial isomerism (n=12), and left atrial isomerism (n=6). Eight patients did not meet the inclusion criteria of the study and were excluded. Ten of the 18 patients fulfilled the study criteria and underwent first stage uni-ventricular heart repair with 8 survivals (80%). Three of the 8 operated survival cases underwent second stage repair with 2 survivals (66%) and one patient completed Fontan surgery with a good outcome. An uneventful ICU course was noted in 3 of 10 operated patients (30%). Complications were noted in (40%) of cases including sepsis (n=4), tracheostomy (n=1), prolonged mechanical ventilation >7days (n=2). Over 50% of the operated patients required prolonged ICU stay (>2 weeks). CONCLUSION: Atrial isomerism is frequently associated with complex cardiac defects that often present in the neonatal stage and requires multiple staged cardiac surgeries. The surgical repair and peri-operative management of this group of patients can be difficult, challenging, and with potential risk of significant morbidity or mortality. In our setting, we found the outcome of children with atrial isomerism undergoing uni-ventricular palliation comparable to the literature.     

Impact of the COVID‐19 pandemic on HIV prevention and care services among key populations across 15 cities in India: a longitudinal assessment of clinic‐based data

IntroductionThe COVID‐19 pandemic has threatened to diminish gains in HIV epidemic control and impacts are likely most profound among key populations in resource‐limited settings. We aimed to understand the pandemic''s impact on HIV‐related service utilization among men who have sex with men (MSM) and people who inject drugs (PWID) across India.MethodsBeginning in 2013, we established integrated care centres (ICCs) which provide HIV preventive and treatment services to MSM and PWID across 15 Indian sites. We examined utilization patterns for an 18‐month period covering 2 months preceding the pandemic (January–February 2020) and over the first and second COVID‐19 waves in India (March 2020–June 2021). We assessed: (1) unique clients accessing any ICC service, (2) ICC services provided, (3) unique clients tested for HIV and (4) HIV diagnoses and test positivity. Among an established cohort of PWID/MSM living with HIV (PLHIV), we administered a survey on the pandemic''s impact on HIV care and treatment (June–August 2020).ResultsOverall, 13,854 unique clients visited an ICC from January 2020 to June 2021. In January/February 2020, the average monthly number of clients was 3761. Compared to pre‐pandemic levels, the number of clients receiving services declined sharply in March 2020, dropping to 25% of pre‐pandemic levels in April/May 2020 (first wave), followed by a slow rebound until April/May 2021 (second wave), when there was a 57% decline. HIV testing followed a similar trajectory. HIV test positivity changed over time, declining in the first wave and reaching its nadir around July 2020 at ∼50% of pre‐pandemic levels. Positivity then increased steadily, eventually becoming higher than pre‐pandemic periods. The second wave was associated with a decline in positivity for MSM but was relatively unchanged for PWID. Among 1650 PLHIV surveyed, 52% of PWID and 45% of MSM reported the pandemic impacted their ability to see an HIV provider. MSM had barriers accessing sexually transmitted infection testing and partner HIV testing.ConclusionsThe COVID‐19 pandemic led to significant decreases in HIV‐related service utilization among key populations in India. This presents an opportunity for increased transmission and patients presenting with advanced disease among groups already disproportionately impacted by HIV.     

Activation of plasmacytoid dendritic cells promotes AML-cell fratricide

Acute myeloid leukemia (AML) is characterized by the proliferation of immature myeloid blasts and a suppressed immune state. Interferons have been previously shown to aid in the clearance of AML cells. Type I interferons are produced primarily by plasmacytoid dendritic cells (pDCs). However, these cells exist in a quiescent state in AML. Because pDCs express TLR 7–9, we hypothesized that the TLR7/8 agonist R848 would be able to reprogram them toward a more active, IFN-producing phenotype. Consistent with this notion, we found that R848-treated pDCs from patients produced significantly elevated levels of IFNβ. In addition, they showed increased expression of the immune-stimulatory receptor CD40. We next tested whether IFNβ would influence antibody-mediated fratricide among AML cells, as our recent work showed that AML cells could undergo cell-to cell killing in the presence of the CD38 antibody daratumumab. We found that IFNβ treatment led to a significant, IRF9-dependent increase in CD38 expression and a subsequent increase in daratumumab-mediated cytotoxicity and decreased colony formation. These findings suggest that the tolerogenic phenotype of pDCs in AML can be reversed, and also demonstrate a possible means of enhancing endogenous Type I IFN production that would promote daratumumab-mediated clearance of AML cells.