Determination of Arterial Blood Flow by Percutaneously Introduced Flow Sensors in an External Magnetic Field, II. Implementation of the Method In Vivo

Blood flow in a dog's aorta has been measured by percutaneous introduction of a flow sensor. Two types of flow probes have been used in conjunction with an external magnetic field: Loop-shaped probes used as rate of volume-flow meters and L-shaped probes as velometers. Methods of calibration and establishing the base line are discussed, and the performance of the apparatus is illustrated by records of blood flow in the thoracic and abdominal regions of the aorta.     

Chronic graft-versus-host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression

Fifty-two of 175 (30%) survivors of allogeneic marrow transplantation developed chronic graft-versus-hose diseases (GVHD). Five with limited chronic GVHD had an indolent clinical course with involvement of only the skin and liver. Forty-seven with extensive chronic GVHD had an unfavorable multiorgan disorder that resembled several autoimmune diseases. Thirteen patients with extensive disease (group I) were not treated and only 2 survive with Karnofsky scores >- 70%. Mortality resulted from infections and morbidity from sica syndrome, pulmonary and hepatic insufficiency, scleroderma-like skin disease, and contractures. Another 13 (group II) received a median of 8 mo prednisone and/or a brief course of antithymocyte globulin, and 3 survive without disability. The other 21 (group III) were treated with a combination of prednisone (1.0 mg/kg/q.o.d.) and either cyclophosphamide, procarbazine, or azathioprine (all 1.5 mg/kg/day) for a median of 13 mo. Combination therapy was well tolerated with only modest myelotoxicity. Fifteen in group III had a good and 4 a fair response to treatment while 2 with no response died. Azathioprine and prednisone was the most effective regimen. All therapy has been discontinued in 12 group III patients: GVHD returned in 5 (including 2 who died in spite of retreatment) while 7 remain free of GVHD for a median of 11 (range 6-30) mo observation. Only I group III survivor is disabled and 16 of the original 21 are alive 2-4 yr after transplant with Karnofsky scores of 70%-100%. Thus, combination immmunosuppression appears to favorably affect and, in some cases, premanently arrest the adverse natural course of extensive chronic GVHD.     

Mutations in the Ca(2+)-sensing receptor gene cause autosomal dominant and sporadic hypoparathyroidism

Parathyroid hormone secretion is negatively regulated by a 7- transmembrane domain, G-protein coupled Ca(2+)-sensing receptor. We hypothesized that activating mutations in this receptor might cause autosomal dominant hypoparathyroidism (ADHP). Consistent with this hypothesis, we identified, in two families with ADHP, heterozygous missense mutations in the Ca(2+)-sensing receptor gene that cosegregated with the disorder. None of 50 normal controls had either mutation. We also identified a de novo, missense Ca(2+)-sensing receptor mutation in a child with severe sporadic hypoparathyroidism. The amino acid substitution in one ADHP family affected the N-terminal, extracellular domain of the receptor. The other mutations involved the transmembrane region. Unlike patients with acquired hypoparathyroidism, patients with these mutations had hypercalciuria even at low serum calcium concentrations. Their greater hypercalciuria presumably reflected activation of Ca(2+)-sensing receptors in kidney cells, where the receptor negatively regulates calcium reabsorption. This augmented hypercalciuria increases the risk of renal complications and thus has implications for the choice of therapy.      

Cancer‐associated somatic DICER1 hotspot mutations cause defective miRNA processing and reverse‐strand expression bias to predominantly mature 3p strands through loss of 5p strand cleavage

Our group recently described recurrent somatic mutations of the miRNA processing gene DICER1 in non‐epithelial ovarian cancer. Mutations appeared to be clustered around each of four critical metal‐binding residues in the RNase IIIB domain of DICER1. This domain is responsible for cleavage of the 3′ end of the 5p miRNA strand of a pre‐mRNA hairpin. To investigate the effects of these cancer‐associated 'hotspot' mutations, we engineered mouse DICER1‐deficient ES cells to express wild‐type and an allelic series of the mutant DICER1 variants. Global miRNA and mRNA profiles from cells carrying the metal‐binding site mutations were compared to each other and to wild‐type DICER1. The miRNA and mRNA profiles generated through the expression of the hotspot mutations were virtually identical, and the DICER1 hotspot mutation‐carrying cells were distinct from both wild‐type and DICER1‐deficient cells. Further, miRNA profiles showed that mutant DICER1 results in a dramatic loss in processing of mature 5p miRNA strands but were still able to create 3p strand miRNAs. Messenger RNA (mRNA) profile changes were consistent with the loss of 5p strand miRNAs and showed enriched expression for predicted targets of the lost 5p‐derived miRNAs. We therefore conclude that cancer‐associated somatic hotspot mutations of DICER1, affecting any one of four metal‐binding residues in the RNase IIIB domain, are functionally equivalent with respect to miRNA processing and are hypomorphic alleles, yielding a global loss in processing of mature 5p strand miRNA. We further propose that this resulting 3p strand bias in mature miRNA expression likely underpins the oncogenic potential of these hotspot mutations. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Application of the Attitude-Social Influence-Efficacy Model to Condom Use Among African-American STD Clinic Patients: Implications for Tailored Health Communication

The purpose of the current investigation was to apply the attitude-social influence-efficacy (ASE) model to achieve a theory-based understanding of condom use among low income, heterosexually active African-American STD clinic patients. N = 293 participants were recruited from a large, publicly-funded metropolitan STD clinic in the Southeastern United States and surveyed using an ACASI computer program. Results indicated that several ASE variables exhibited meaningful relationships with condom stages of change in univariate analyses, replicating patterns found in previous research. Fewer variables remained significant in multivariate analyses, however. There was also some support for the proposition that early stage movement (e.g., Precontemplation to Contemplation) is based more upon perceptions of condom use (e.g., pros, perceived norms), whereas later stage movement (e.g., Preparation to Action/Maintenance) is based more upon perceived and actual skills acquisition (e.g., condom self-efficacy, negotiation strategies). Results varied with regard to main and casual condom stage of change. Implications for developing tailored HIV prevention interventions with heterosexual African-Americans are discussed.     

Incarceration and Sexual Risk: Examining the Relationship Between Men’s Involvement in the Criminal Justice System and Risky Sexual Behavior

In this study, we used data from Add Health Waves II and III to compare men who had been incarcerated to those who had not, and examined whether incarceration was associated with increased numbers of sexual partners and increased odds of concurrent partnerships. We used multivariate regression and propensity-score matching to compare sexual behavior of Wave III male respondents who had been incarcerated with those who had not, and compared sexual behavior at Wave II to identify differences in sexual behavior prior to incarceration. Incarceration was associated with an increased rate of lifetime sexual partnership, but this was attenuated by substance use. Criminal justice involvement was associated with increased odds of having partners who report concurrent partnerships, but no further increase was seen with incarceration. There were no significant sexual behavior differences prior to incarceration. These results suggest that the criminal justice system and substance use may interact to shape sexual behavior.     

A novel tetrameric gp350 as a potential Epstein–Barr virus vaccine

Infectious mononucleosis and B-cell transformation in response to infection with Epstein–Barr virus (EBV) is dependent upon binding of the EBV envelope glycoprotein gp350 to CD21 on B-cells. Gp350-specific antibody comprises most of the EBV neutralizing activity in the serum of infected patients, making this protein a promising target antigen for a prophylactic EBV vaccine. We describe a novel, tetrameric gp350-based vaccine that exhibits markedly enhanced immunogenicity relative to its monomeric counterpart. Plasmid DNA was constructed for synthesis, within transfected CHO cells, of a tetrameric, truncated (a.a. 1–470) gp350 protein (gp350^1–470). Tetrameric gp350^1–470 induced ∼20-fold higher serum titers of gp350^1–470-specific IgG and >19-fold enhancements in neutralizing titers at the highest dose, and was >25-fold more immunogenic on a per-weight basis than monomeric gp350^1–470. Further, epidermal immunization with plasmid DNA encoding gp350^1–470 tetramer induced 8-fold higher serum titers of gp350^1–470-specific IgG relative to monomer. Tetrameric gp350^1–470 binding to human CD21 was >24-fold more efficient on a per-weight basis than monomer, but neither tetramer nor monomer mediated polyclonal human B-cell activation. Finally, the introduction of strong, universal tetanus toxoid (TT)-specific CD4+ T-cell epitopes into the tetrameric gp350^1–470 had no effect on the gp350^1–470-specific IgG response in naïve mice, and resulted in suppressed gp350^1–470-specific IgG responses in TT-primed mice. Collectively, these data suggest that tetrameric gp350^1–470 is a potentially promising candidate for testing as a prophylactic EBV vaccine, and that protein multimerization, using the approach described herein, is likely to be clinically relevant for enhancing the immunogenicity of other proteins of vaccine interest.     

Tailor‐Made Antimicrobial/Antiviral Star Polymer via ATRP of Cyclodextrin and Guanidine‐Based Macromonomer

Novel star‐like polymers are prepared via atom transfer radical polymerization (ATRP) of polyhexamethylene guanidine hydrochloride (PHMG) macromonomer and acrylamide (AM) using β‐cyclodextrin (CD) with 8‐active and 5‐active sites as a macroinitiator. The resulting star‐like polymers are characterized by gel permeation chromatography (GPC) and ¹H NMR and are used for deactivating bacteria and viruses. It is found that star polymers with comparable amounts of PHMG possess excellent antimicrobial activity, which, however, strongly depends on the topological structure (i.e., the arm number and the monomer ratio) of the composing copolymers. The in vitro antibacterial activities of the synthesized polymers are investigated against Escherichia coli in terms of the minimum inhibitory concentration (MIC), whereas the antiviral activity of star copolymers is assessed via a plaque assay against non‐enveloped adenovirus (ADV). The results show that the highest antimicrobial activity is achieved by the star‐like copolymer with the monomer ratio of 20:3 (AM:PHGM, mol/mol), while the number of functional arms is fixed at 8. The incorporation of PHMG also renders the star copolymer highly antiviral, thus permitting it to be used as an effective antibacterial/antiviral agent for various applications.

     

Sexual and reproductive health: Progress and outstanding needs

We examine progress towards the 1994 International Conference on Population and Development (ICPD) commitment to provide universal access to sexual and reproductive health (SRH) services by 2014, with an emphasis on changes for those living in poor and emerging economies. Accomplishments include a 45% decline in the maternal mortality ratio (MMR) between 1990 and 2013; 11.5% decline in global unmet need for modern contraception; ~21% increase in skilled birth attendance; and declines in both the case fatality rate and rate of abortion. Yet aggregate gains mask stark inequalities, with low coverage of services for the poorest women. Demographic and Health Surveys and Multiple Indicator Cluster Surveys from 80 developing countries highlight persistent disparities in skilled birth attendance by household wealth: in 70 of 80 countries (88%), ≥80% of women in the highest quintile were attended by a skilled provider at last birth; in only 23 of the same countries (29%) was this the case for women in the lowest wealth quintile. While there have been notable declines in HIV incidence and prevalence, women affected by HIV are too often bereft of other SRH services, including family planning. Achieving universal access to SRH will require substantially greater investment in comprehensive and integrated services that reach the poor.