STAG2 mutations reshape the cohesin-structured spatial chromatin architecture to drive gene regulation in acute myeloid leukemia.

Cohesin shapes the chromatin architecture, including enhancer-promoter interactions. Its components, especially STAG2, but not its paralog STAG1, are frequently mutated in myeloid malignancies. To elucidate the underlying mechanisms of leukemogenesis, we comprehensively characterized genetic, transcriptional, and chromatin conformational changes in acute myeloid leukemia (AML) patient samples. Specific loci displayed altered cohesin occupancy, gene expression, and local chromatin activation, which were not compensated by the remaining STAG1-cohesin. These changes could be linked to disrupted spatial chromatin looping in cohesin-mutated AMLs. Complementary depletion of STAG2 or STAG1 in primary human hematopoietic progenitors (HSPCs) revealed effects resembling STAG2-mutant AML-specific changes following STAG2 knockdown, not invoked by the depletion of STAG1. STAG2-deficient HSPCs displayed impaired differentiation capacity and maintained HSPC-like gene expression. This work establishes STAG2 as a key regulator of chromatin contacts, gene expression, and differentiation in the hematopoietic system and identifies candidate target genes that may be implicated in human leukemogenesis.

The effect of an integrated multisector model for achieving the Millennium Development Goals and improving child survival in rural sub-Saharan Africa: a non-randomised controlled assessment.

BACKGROUND: Simultaneously addressing multiple Millennium Development Goals (MDGs) has the potential to complement essential health interventions to accelerate gains in child survival. The Millennium Villages project is an integrated multisector approach to rural development operating across diverse sub-Saharan African sites. Our aim was to assess the effects of the project on MDG-related outcomes including child mortality 3 years after implementation and compare these changes to local comparison data. METHODS: Village sites averaging 35,000 people were selected from rural areas across diverse agroecological zones with high baseline levels of poverty and undernutrition. Starting in 2006, simultaneous investments were made in agriculture, the environment, business development, education, infrastructure, and health in partnership with communities and local governments at an annual projected cost of US$120 per person. We assessed MDG-related progress by monitoring changes 3 years after implementation across Millenium Village sites in nine countries. The primary outcome was the mortality rate of children younger than 5 years of age. To assess plausibility and attribution, we compared changes to reference data gathered from matched randomly selected comparison sites for the mortality rate of children younger than 5 years of age. Analyses were done on a per-protocol basis. This trial is registered with ClinicalTrials.gov, number NCT01125618. FINDINGS: Baseline levels of MDG-related spending averaged $27 per head, increasing to $116 by year 3 of which $25 was spent on health. After 3 years, reductions in poverty, food insecurity, stunting, and malaria parasitaemia were reported across nine Millennium Village sites. Access to improved water and sanitation increased, along with coverage for many maternal-child health interventions. Mortality rates in children younger than 5 years of age decreased by 22% in Millennium Village sites relative to baseline (absolute decrease 25 deaths per 1000 livebirths, p=0·015) and 32% relative to matched comparison sites (30 deaths per 1000 livebirths, p=0·033). INTERPRETATION: An integrated multisector approach for addressing the MDGs can produce rapid declines in child mortality in the first 3 years of a long-term effort in rural sub-Saharan Africa. FUNDING: UN Human Security Trust Fund, the Lenfest Foundation, Bill & Melinda Gates Foundation, and Becton Dickinson.

[Acute generalized peritonitis due to uterine perforation following abortion: case study observation]. / Péritonite aigue généralisée par perforation utérine post abortum à propos d'une observation.

UNLABELLED: Clandestine abortion is known to be a major contributor to maternal mortality. We report a case of a 25-year old patient in her 12th week of amenorrhea with peritonitis due to uterine perforation following abortion, admitted with abdomen and pelvis pain, vomiting and diarrhea. Clinical examination on admission showed asthenic peritonitis. Surgical exploration showed widespread acute peritonitis secondary to a perforation of the uterine dome, with collection of 1500 cc of purulent material, dilated bowel loops and multiple false membranes. SURGERY: pus aspiration, peritoneal lavage; uterine suture, drainage. The postoperative course was uneventful, the patient was discharged after 15 days.

The African Millennium Villages.

We describe the concept, strategy, and initial results of the Millennium Villages Project and implications regarding sustainability and scalability. Our underlying hypothesis is that the interacting crises of agriculture, health, and infrastructure in rural Africa can be overcome through targeted public-sector investments to raise rural productivity and, thereby, to increased private-sector saving and investments. This is carried out by empowering impoverished communities with science-based interventions. Seventy-eight Millennium Villages have been initiated in 12 sites in 10 African countries, each representing a major agro-ecological zone. In early results, the research villages in Kenya, Ethiopia, and Malawi have reduced malaria prevalence, met caloric requirements, generated crop surpluses, enabled school feeding programs, and provided cash earnings for farm families.