Drug discovery for Diamond-Blackfan anemia using reprogrammed hematopoietic progenitors.

Diamond-Blackfan anemia (DBA) is a congenital disorder characterized by the failure of erythroid progenitor differentiation, severely curtailing red blood cell production. Because many DBA patients fail to respond to corticosteroid therapy, there is considerable need for therapeutics for this disorder. Identifying therapeutics for DBA requires circumventing the paucity of primary patient blood stem and progenitor cells. To this end, we adopted a reprogramming strategy to generate expandable hematopoietic progenitor cells from induced pluripotent stem cells (iPSCs) from DBA patients. Reprogrammed DBA progenitors recapitulate defects in erythroid differentiation, which were rescued by gene complementation. Unbiased chemical screens identified SMER28, a small-molecule inducer of autophagy, which enhanced erythropoiesis in a range of in vitro and in vivo models of DBA. SMER28 acted through autophagy factor ATG5 to stimulate erythropoiesis and up-regulate expression of globin genes. These findings present an unbiased drug screen for hematological disease using iPSCs and identify autophagy as a therapeutic pathway in DBA.

Reticular dysgenesis-associated AK2 protects hematopoietic stem and progenitor cell development from oxidative stress.

Adenylate kinases (AKs) are phosphotransferases that regulate the cellular adenine nucleotide composition and play a critical role in the energy homeostasis of all tissues. The AK2 isoenzyme is expressed in the mitochondrial intermembrane space and is mutated in reticular dysgenesis (RD), a rare form of severe combined immunodeficiency (SCID) in humans. RD is characterized by a maturation arrest in the myeloid and lymphoid lineages, leading to early onset, recurrent, and overwhelming infections. To gain insight into the pathophysiology of RD, we studied the effects of AK2 deficiency using the zebrafish model and induced pluripotent stem cells (iPSCs) derived from fibroblasts of an RD patient. In zebrafish, Ak2 deficiency affected hematopoietic stem and progenitor cell (HSPC) development with increased oxidative stress and apoptosis. AK2-deficient iPSCs recapitulated the characteristic myeloid maturation arrest at the promyelocyte stage and demonstrated an increased AMP/ADP ratio, indicative of an energy-depleted adenine nucleotide profile. Antioxidant treatment rescued the hematopoietic phenotypes in vivo in ak2 mutant zebrafish and restored differentiation of AK2-deficient iPSCs into mature granulocytes. Our results link hematopoietic cell fate in AK2 deficiency to cellular energy depletion and increased oxidative stress. This points to the potential use of antioxidants as a supportive therapeutic modality for patients with RD.

Meeting the needs of women who use drugs and alcohol in North-east India - a challenge for HIV prevention services.

BACKGROUND: The North-east Indian states of Manipur and Nagaland consistently report relatively high HIV prevalence. The targeted HIV prevention interventions in these two states are mostly delivered by non-government organizations (NGOs), and prevention of HIV transmission by injecting drug use is their main focus. Most injecting drug users (IDUs) are male, and the services are primarily tailored to meet their needs, which are not necessarily the same as those for women. This qualitative study describes the health service needs of women who use drugs and alcohol in Manipur and Nagaland, with the goal of identifying strategies and activities that can be implemented by NGOs wanting to improve their reach among vulnerable women. METHODS: In 2009-10, semi-structured in-depth interviews were conducted with 27 key informants and nine focus group discussions (FGDs) with women who use drugs and alcohol, and two FGDs with male IDUs. The thematic areas covered included: the context of female drug and alcohol use; drug and alcohol use patterns; HIV risk behaviours; barriers and facilitators of service use; perceived health needs; and expressed health service needs. The data were recorded, transcribed, translated and thematically analysed. RESULTS: The most problematic substance for women from Nagaland was alcohol, and for women from Manipur it was heroin. The most commonly identified health problems were primarily related to the women's drug and alcohol use, reproductive health and mental health. Other problems of major concern included social exclusion, violence, children's welfare, and financial difficulties. The expressed service needs of these women were women-only integrated health services, women-only detoxification and rehabilitation services, mental health services, desensitization of mainstream health workers, free access to medicines, assistance to meet basic needs, and a safe place for engaging in sex work. CONCLUSION: The expressed health and other service needs of women who use drugs and alcohol in Manipur and Nagaland do not match the services currently provided by HIV prevention NGOs, and this may, in part, account for the relatively poor uptake of these services by women. Strategies and activities that can be implemented by NGOs to strengthen their reach to vulnerable women are identified. However, many of these women's needs are beyond the scope of services typically offered by HIV prevention NGOs, and require a coordinated multi-sectoral response.

The role of induced pluripotent stem cells in research and therapy of primary immunodeficiencies.

The advent of reprogramming technology has greatly advanced the field of stem cell biology and nurtured our hope to create patient specific renewable stem cell sources. While the number of reports of disease specific induced pluripotent stem cells is continuously rising, the field becomes increasingly more aware that induced pluripotent stem cells are not as similar to embryonic stem cells as initially assumed. Our state of the art understanding of human induced pluripotent stem cells, their capacity, their limitations and their promise as it pertains to the study and treatment of primary immunodeficiencies, is the content of this review.

Mental health promotion for the widows of injecting drug users in north-east India.

The prevalence of HIV is high in the north-east Indian states of Manipur and Nagaland. The major route of HIV transmission is injecting drug use. Most injecting drug users (IDUs) are male and about 40% are married. The widows of IDUs are among the most disadvantaged people. Many are HIV-infected and experiencing poverty, poor health, social isolation and discrimination, all factors likely to compromise their mental health. Some widows are engaging in HIV risk behaviours, including alcohol and drug misuse, sex work and unprotected sex. There is increasing recognition of the links between poverty and mental health status and risk of HIV infection. People with poor mental health are more likely to engage in HIV risk behaviours.