Minimal residual disease prior to stem cell transplant for childhood acute lymphoblastic leukaemia

Allogeneic stem cell transplantation (SCT) is a highly effective therapy for childhood acute lymphoblastic leukaemia (ALL). Concerns about unnecessary toxicity and expense mean that SCT is currently largely reserved for children who cannot be cured with chemotherapy. Not surprisingly, many such children also fail SCT. Retrospective studies have shown that a single analysis of minimal residual disease (MRD) pre-SCT identified those at highest risk of relapse. It is now appropriate to call for the universal incorporation of standardized MRD testing into SCT protocols as the next step to maximize the clinical impact of this technology in ALL.     

Characterization of hyaluronan synthase expression and hyaluronan synthesis in bone marrow mesenchymal progenitor cells: predominant expression of HAS1 mRNA and up-regulated hyaluronan synthesis in bone marrow cells derived from multiple myeloma patients

Interaction of hemoglobin S polymers with the red blood cell (RBC) membrane induces a reversible increase in permeability ("P(sickle)") to (at least) Na(+), K(+), Ca(2+), and Mg(2+). Resulting changes in [Ca(2+)] and [H(+)] in susceptible cells activate 2 transporters involved in sickle cell dehydration, the Ca(2+)-sensitive K(+) ("Gardos") channel (K(Ca)) and the acid- and volume-sensitive K:Cl cotransport. We investigated the distribution of P(sickle) expression among deoxygenated sickle cell anemia (SS) RBCs using new experimental designs in which the RBC Ca(2+) pumps were partially inhibited by vanadate, and the cells' dehydration rates were detected as progressive changes in the profiles of osmotic fragility curves and correlated with flow cytometric measurements. The results exposed marked variations in (sickling plus Ca(2+))-induced dehydration rates within populations of deoxygenated SS cells, with complex distributions, reflecting a broad heterogeneity of their P(sickle) values. P(sickle)-mediated dehydration was inhibited by clotrimazole, verifying the role of K(Ca), and also by elevated [Ca(2+)](o), above 2 mM. Very high P(sickle) values occurred with some SS discocytes, which had a wide initial density (osmotic resistance) distribution. Together with its previously shown stochastic nature, the irregular distribution of P(sickle) documented here in discocytes is consistent with a mechanism involving low-probability, reversible interactions between sickle polymers and membrane or cytoskeletal components, affecting only a fraction of the RBCs during each deoxygenation event and a small number of activated pathways per RBC. A higher participation of SS reticulocytes in P(sickle)-triggered dehydration suggests that they form these pathways more efficiently than discocytes despite their lower cell hemoglobin concentrations.     

Mutations associated with hemophilia A in the 558-565 loop of the factor VIIIa A2 subunit alter the catalytic activity of the factor Xase complex

The 558-565 loop region in the A2 subunit of factor (F) VIIIa forms a direct interface with FIXa. We have expressed and purified B-domainless FVIII (FVIII(WT)) and B-domainless FVIII containing the hemophilia A-associated mutations Ser558Phe, Val559Ala, Asp560Ala, Gln565Arg, and the activated protein C cleavage site mutant Arg562Ala. Titration of FVIIIa in FXa generation assays showed that the mutant and wild-type proteins had similar functional affinities for FIXa (dissociation constant [K(d)] values approximately 5 nM-20 nM and approximately 100 nM-250 nM in the presence and absence of phospholipid, respectively). The catalytic activities of the factor Xase complex composed of the hemophilia A-associated FVIII species were markedly reduced both in the presence and absence of phospholipid. FVIII(WT) and FVIII(Arg562Ala) showed catalytic rate constant (k(cat)) values of approximately 60 minute(-1) in the presence of phospholipid, whereas the hemophilia A-associated mutants showed k(cat) values ranging from 3.3 minute(-1) to 7.5 minute(-1). In the absence of phospholipid, all k(cat) values were reduced but FVIII(WT) and FVIII(Arg562Ala) retained higher activities as compared with the hemophilic mutant FVIII forms. Fluorescence anisotropy experiments using fluorescein-modified FIXa confirmed that all FVIII forms interacted with FIXa. However, the presence of factor X yielded minimal increases in anisotropy observed with the mutant factor VIII forms, consistent with their reduced activity. These results show that residues within the 558-565 loop are critical in modulating FIXa enzymatic activity but do not contribute significantly to the affinity of FVIIIa for FIXa.     

National Comparison of Literally Homeless Male and Female VA Service Users: Entry Characteristics,Clinical Needs,and Service Patterns

BackgroundAlthough there are growing numbers of homeless female U.S. veterans, the U.S. Department of Veterans Affairs (VA) has traditionally served a predominantly male population; thus, it is important to examine differences between homeless female and male veterans in their service needs and the current provision of VA homeless services.MethodsA national registry of 119,947 users of VA homeless services from 2011 to 2012 was used to 1) estimate the proportion of female veterans among VA homeless service users, 2) examine the proportion of VA homeless service users who are literally homeless by gender, and 3) report differences between female and male VA homeless service users who are literally homeless on sociodemographic and clinical characteristics, as well as on outreach, referral, and admission patterns for an array of specialized VA services.FindingsOf VA homeless service users, 8% were female compared with 7% among all homeless veterans, 6% among all VA service users, and 7% among all veterans. Of female VA homeless service users, 54% were literally homeless, slightly fewer than the 59% of male VA homeless service users. Comparing literally homeless VA service users, females were younger, 21% more had dependent children, 8% more were diagnosed with non–military-related posttraumatic stress disorder, and 19% to 20% more were referred and admitted to VA's supported housing program than males.ConclusionsFemale veterans use VA homeless services at a rate similar to their use of general VA services and they have unique needs, especially for child care, which may require additional specialized resources.     

A qualitative assessment of health seeking practices among and provision practices for men who have sex with men in Malawi

Background

In the context of a generalized epidemic and criminalization of homosexuality, men who have sex with men (MSM) in Malawi have a disproportionate burden of HIV compared to other adults. Past research has documented low uptake of HIV prevention and health services among MSM, self-reported fear of seeking health services, and concerns of disclosure of sexual orientation and discrimination in health settings. Qualitative research was conducted among MSM and health service providers in Blantyre, Malawi to understand underlying factors related to disclosure and health seeking behaviors and inform the development of a community-based comprehensive HIV prevention intervention.

Methods

Using peer recruitment, eight MSM participants representing a range of ages, orientations, and social and behavioral characteristics were enrolled for in-depth interviews. Five service providers were recruited from the district hospital, local health and STI clinics, and a HIV prevention service organization. We use the Health Belief Model as a framework to interpret the influential factors on 1) health seeking and uptake among MSM, and 2) influences on provision of services by healthcare providers for MSM.

Results

Results highlight disclosure fears among MSM and, among providers, a lack of awareness and self-efficacy to provide care in the face of limited information and political support. Service providers reported concerns of adverse repercussions related to the provision of services to men in same sex sexual relationships. Some MSM demonstrated awareness of HIV risk but believed that within the wider MSM community, there was a general lack of HIV information for MSM, low awareness of appropriate prevention, and low perception of risks related to HIV infection.

Conclusions

Qualitative research highlights the need for appropriate information on both HIV risks and acceptable, effective HIV prevention options for MSM. Information and educational opportunities should be available to the wider MSM community and the health sector. Health sector interventions may serve to increase cultural and clinical competency to address health problems experienced by MSM. To ensure availability and use of services in light of the criminalization and stigmatization of same sex practices, there is need to increase the safety of uptake and provision of these services for MSM.