Molecular pathogenesis of acquired aplastic anemia

The application of next‐generation sequencing (NGS) has enhanced our understanding of the genetic landscape in acquired aplastic anemia (AA). Parallel progress has been in addressing aspects underlying immune dysregulation in disease pathogenesis. Novel insights into the molecular and biologic mechanisms have led to a shift in the paradigm of AA, from a solely autoimmune pathogenic concept toward its recognition as a multifaceted pathophysiology characterized by cytogenetic abnormalities, recurrent somatic mutations, telomere attrition, and immune dysregulation. The detection of recurrent driver mutations disrupting myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)‐associated genes has suggested a pathophysiologic link between clonal hematopoiesis in AA and the later development of these clonal disorders. Further, certain AA‐related somatic genetic alterations may have clinical implications on treatment response, disease progression, and survival following immunosuppressive therapy. Going forward, wider validation of these genetic abnormalities will allow for their incorporation into a more informative risk stratification system that does not rely solely on clinical factors.     

Out of Pocket Expenditure for Sick Newborn Care in Referral Hospitals of Nepal

Background

Almost all preventable neonatal deaths take place in low- and middle-income countries and affect the poorest who have the least access to high quality health services. Cost of health care is one of the factors preventing access to quality health services and universal health coverage. In Nepal, the majority of expenses related to newborn care are borne by the caregiver, regardless of socioeconomic status. We conducted a study to assess the out of pocket expenditure (OOPE) for sick newborn care in hospitals in Nepal.

Methods

This cross-sectional study of hospital care for newborns was conducted in 11 hospitals in Nepal and explored OOPE incurred by caregivers for sick newborn care. Data were collected from the caregivers of the sick newborn on the topics of cost of travel, accommodation, treatment (drugs, diagnosis) and documented on a sick newborn case record form.

Results

Data were collected from 814 caregivers. Cost of caregivers’ stay accounted for more than 40% of the OOPE for sick newborn care, followed by cost of travel, and the baby’s stay and treatment. The overall OOPE ranged from 13.6 to 226.1 US dollars (USD). The median OOPE was highest for preterm complications ($33.2 USD; CI 14.0–226.1), followed by hyperbilirubinemia ($31.9 USD; CI 14.0–60.7), respiratory distress syndrome ($26.9 USD; 15.3–121.5), neonatal sepsis ($ 25.8 USD; CI 13.6–139.8) and hypoxic ischemic encephalopathy ($23.4 USD; CI 13.6–97.7).

Discussion for practice

In Nepal, OOPE for sick newborn care in hospitals varied by neonatal morbidity and duration of stay. The largest proportion of OOPE were for accommodation and travel. Affordable and accessible health care will substantially reduce the OOPE for sick newborn care in hospitals.

     

Prognostic Factors in the Era of Targeted Therapies in CLL

Purpose of Review

Chronic lymphocytic leukemia is heterogeneous disease characterized by a variable clinical course that is greatly influenced by various patient and disease characteristics. Over the last two decades, advent of new diagnostic methodologies has led to the identification of several factors of prognostic and predictive relevance. Furthermore, recent advances in next-generation sequencing techniques has identified recurrent novel mutations in NOTCH1, SF3B1, BIRC3, and ATM genes whose role as prognostic and predictive markers is currently being investigated. These biologic markers carry new prognostic information and their incorporation into prognostic scoring systems will likely lead to refined multi-parameter risk models.

Recent Findings

While the prognostic impact of many of the most commonly used markers on clinical outcomes in patients treated with chemo-immunotherapy is well documented, it is important to review their predictive and prognostic role in the era of novel targeted therapies.

Summary

This article will discuss the currently available information on the clinical relevance of prognostic markers in patients treated with novel targeted therapies.

     

Novel consequences of voltage-dependence to G-protein-coupled P2Y1 receptors

BACKGROUND AND PURPOSE: Emerging evidence suggests that activation of G-protein-coupled receptors (GPCRs) can be directly regulated by membrane voltage. However, the physiological and pharmacological relevance of this effect remains unclear. We have further examined this phenomenon for P2Y1 receptors in the non-excitable megakaryocyte using a range of agonists and antagonists. EXPERIMENTAL APPROACH: Simultaneous whole-cell patch clamp and fura-2 fluorescence recordings of rat megakaryocytes, which lack voltage-gated Ca2+ influx, were used to examine the voltage-dependence of P2Y1 receptor-evoked IP3-dependent Ca2+ mobilization. RESULTS: Depolarization transiently and repeatedly enhanced P2Y1 receptor-evoked Ca2+ mobilization across a wide concentration range of both weak, partial and full, potent agonists. Moreover, the amplitude of the depolarization-evoked [Ca2+]i increase displayed an inverse relationship with agonist concentration, such that the greatest potentiating effect of voltage was observed at near-threshold levels of agonist. Unexpectedly, depolarization also stimulated an [Ca2+]i increase in the absence of agonist during exposure to the competitive antagonists A3P5PS and MRS2179, or the allosteric enhancer 2,2'-pyridylisatogen tosylate. A further effect of some antagonists, particularly suramin, was to enhance the depolarization-evoked Ca2+ responses during co-application of an agonist. Of several P2Y1 receptor inhibitors, only SCH202676, which has a proposed allosteric mechanism of action, could block ADP-induced voltage-dependent Ca2+ release. CONCLUSIONS AND IMPLICATIONS: The ability of depolarization to potentiate GPCRs at near-threshold agonist concentrations represents a novel mechanism for coincidence detection. Furthermore, the induction and enhancement of voltage-dependent GPCR responses by antagonists has implications for the design of therapeutic compounds.