Complications of beta-thalassemia major in North America

Treatment of patients with beta-thalassemia major has improved dramatically during the past 40 years; however, the current clinical status of these patients remains poorly characterized. We performed a cross-sectional study of 342 patients in the Registry of the National Institutes of Health-sponsored Thalassemia Clinical Research Network. Evidence of hepatitis C exposure was present in 35% of tested patients, was associated with age, and had a rate of spontaneous viral clearance of 33%. Ferritin levels ranged from 147 to 11 010 ng/mL (median, 1696 ng/mL). Median hepatic iron content was 7.8 mg/g dry weight and 23% of patients had values of 15 mg/g dry weight or higher. No patients 15 years or younger and 5% of patients aged 16 to 24 years had heart disease requiring medication. Ten percent had cirrhosis on biopsy. Endocrinologic complications were common among adults. Seventy-four (22%) patients had recent implantable central venous access devices (CVADs) placed. Among 80 episodes of bacteremia in 38 patients, 90% were attributable to the CVAD. Among 330 patients who had received deferoxamine chelation therapy, 224 (68%) reported no complications. We conclude that hepatitis C, iron-related organ dysfunction, and complications of iron chelation therapy are strongly age-dependent in North American patients with beta-thalassemia.     

Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5alpha-reductase inhibitor

Dihydrotestosterone (DHT) is the primary metabolite of testosterone in the prostate and skin. Testosterone is converted to DHT by 5alpha-reductase, which exists in two isoenzyme forms (types 1 and 2). DHT is associated with development of benign prostatic hyperplasia (BPH), and reduction in its level with 5alpha-reductase inhibitors improves the symptoms associated with BPH and reduces the risk of acute urinary retention and prostate surgery. A selective inhibitor of the type 2 isoenzyme (finasteride) has been shown to decrease serum DHT by about 70%. We hypothesized that inhibition of both isoenzymes with the dual inhibitor dutasteride would more effectively suppress serum DHT levels than selective inhibition of only the type 2 isoenzyme. A total of 399 patients with BPH were randomized to receive once-daily dosing for 24 wk of dutasteride (0.01, 0.05, 0.5, 2.5, or 5.0 mg), 5 mg finasteride, or placebo. The mean percent decrease in DHT was 98.4 +/- 1.2% with 5.0 mg dutasteride and 94.7 +/- 3.3% with 0.5 mg dutasteride, significantly lower (P < 0.001) and with less variability than the 70.8 +/- 18.3% suppression observed with 5 mg finasteride. Mean testosterone levels increased but remained in the normal range for all treatment groups. Dutasteride appeared to be well tolerated with an adverse event profile similar to placebo.     

Intravenous Ethanol Self-administration in C57BL/6J and DBA/2J Mice

Two strains of mice, C57BL/6J (B6) and DBA/2J (D2) were allowed to self-administer intravenous (iv) ethanol. These two strains were selected because they differ greatly in their preference for drinking ethanol solutions: 86 mice are preferrers, whereas D2 mice are avoiders of ethanol. Of interest was whether these strains would also differ in self-administration of iv ethanol when taste factors presumably do not influence consumption. Mice were trained with either 60, 75, or 90 mg/kg per infusion. Mice from both strains acquired nosepoking for all of these doses on an FR-3 schedule of reinforcement during 2-hr daily sessions. Additionally, mice in both strains acquired an equal preference for nosepoking on the side resulting in ethanol infusions, compared with the side that had no scheduled consequence, although B6 mice took somewhat more ethanol early in training than did D2 mice. Mice in both strains achieved equal levels of responding at the conclusion of training, when response rates had stabilized. A subset of animals were then tested at doses of ethanol ranging from 25 to 125 mg/kg per infusion. Although their responding tended to decrease over time regardless of changes in the unit dose of ethanol, these mice showed lower response rates for higher doses of ethanol, and less responding for saline than for ethanol. Together, these findings imply that iv ethanol has reinforcing properties in both these strains, despite the strain difference in preference for oral ethanol. Self-administration of iv ethanol in mice may prove a valuable addition to existing animal models for the study of ethanol reward.     

Isolation and point of action of a factor from Escherichia coli required to reconstruct translation.

To study the mechanism of translation we have attempted to reconstruct the process from purified components. Protein synthesis was programmed by the RNAs of wild-type or amber mutants of bacteriophages f2 or MS2. Translation programmed by MS2 or f2am3 RNA does not occur using ribosomes, precharged aminoacyl-tRNAs, and the sum of the purified proteins involved in initiation (initiation factors; IF-1, IF-2, and IF-3), propagation (elongation factors; EF-Tu, EF-Ts, and EF-G) and termination (release factors; RF-1 or RF-2) of protein synthesis. The requirement for a protein called W was demonstrated. Protein W was purified free of all translation factors, activating enzymes, and other proteins such as the RR, "rescue," and EF-P implicated in translation. The stimulation of propagation by W depended on the position of the amino acid residue to be added in the synthesis of the NH2-terminal hexapeptide of the coat protein. In the reconstructed system, with the sum of all translation factors but in the absence of W, only dipeptides and smaller quantities of tripeptides were synthesized under the direction of f2am3 RNA. W stimulated the synthesis of the hexapeptide, fMet-Ala-Ser-AspNH2-Phe-Thr directed by this RNA. In addition, W stimulated ejection of non-cognate tRNAs that bind to ribosomal particles.     

Women's empowerment and child nutritional status in South Asia: a synthesis of the literature

Women's disempowerment is hypothesised to contribute to high rates of undernutrition among South Asian children. However, evidence for this relationship has not been systematically reviewed. This review of empirical studies aims to: (1) synthesise the evidence linking women's empowerment and child nutritional status in South Asia and (2) suggest directions for future research. We systematically searched Global Health, Embase (classic and Ovid), MEDLINE, Campbell Collaboration, Popline, Eldis, Web of Science, EconLit and Scopus. We generated 1661 studies for abstract and title screening. We full‐text screened 44 of these, plus 10 additional studies the authors were aware of. Only 12 studies fulfilled our inclusion criteria. We included English materials published between 1990 and 2012 that examined the relationship(s) of at least one women's empowerment domain and nutritional status among South Asian children. Data were extracted and synthesised within three domains of empowerment: control of resources and autonomy, workload and time, and social support. The results showed women's empowerment to be generally associated with child anthropometry, but the findings are mixed. Inter‐study differences in population characteristics, settings or methods/conceptualisations of women's empowerment, and the specific domains studied, likely contributed to these inconsistencies. This review also highlights that different women's empowerment domains may relate differently to child nutritional status. Future research should aim to harmonise definitions of women's empowerment, which key domains it should include, and how it is measured. Rigorous evaluation work is also needed to establish which policies and programmes facilitate women's empowerment and in turn, foster child nutritional well‐being.     

Mapping the lethal factor and edema factor binding sites on oligomeric anthrax protective antigen

Assembly of anthrax toxin complexes at the mammalian cell surface involves competitive binding of the edema factor (EF) and lethal factor (LF) to heptameric oligomers and lower order intermediates of PA(63), the activated carboxyl-terminal 63-kDa fragment of protective antigen (PA). We used sequence differences between PA(63) and homologous PA-like proteins to delineate a region within domain 1' of PA that may represent the binding site for these ligands. Substitution of alanine for any of seven residues in or near this region (R178, K197, R200, P205, I207, I210, and K214) strongly inhibited ligand binding. Selected mutations from this set were introduced into two oligomerization-deficient PA mutants, and the mutants were used in various combinations to map the single ligand site within dimeric PA(63). The site was found to span the interface between two adjacent subunits, explaining the dependence of ligand binding on PA oligomerization. The locations of residues comprising the site suggest that a single ligand molecule sterically occludes two adjacent sites, consistent with the finding that the PA(63) heptamer binds a maximum of three ligand molecules. These results elucidate the process by which the components of anthrax toxin, and perhaps other binary bacterial toxins, assemble into toxic complexes.     

Disparities in HIV treatment and physician attitudes about delaying protease inhibitors for nonadherent patients

BACKGROUND: Current HIV treatment guidelines recommend delaying antiretroviral therapy for nonadherent patients, which some fear may disproportionately affect certain populations and contribute to disparities in care. OBJECTIVES: To examine the relationship of physician's attitude toward prescribing protease inhibitors (PIs) to nonadherent patients with disparities in PI use and with health outcomes. DESIGN: Prospective cohort study. PATIENTS AND SETTING: A national probability sample of HIV-infected adults in the United States and their health care providers was surveyed between January 1996 and January 1998. We analyzed data on 1717 patients eligible for PI treatment and the 367 providers who cared for them. MEASUREMENTS: Providers' attitude toward prescribing PIs to nonadherent patients, time until patients' first receipt of PIs, mortality, and physical health status. MAIN RESULTS: Eighty-nine percent of providers agreed that patient adherence is important in their decision to prescribe PIs (Selective) while 11% disagreed (Nonselective). Patients who had a Selective provider received PIs later than those with a Nonselective provider (P =.05). Adjusting for patient demographics and health characteristics and provider demographics, HIV knowledge, and experience, Latinos, women, and poor patients received PIs later if their provider had a Selective attitude but as soon as others if their provider had a Nonselective attitude. African-American patients received PIs later than whites, irrespective of their providers' prescribing attitude. Patients with Selective providers had similar odds of mortality than those with Nonselective providers (odds ratio, 1.1; 95% confidence interval, 0.6 to 2.0), but had slightly worse adjusted physical health status at follow-up (49.1 vs 50.4, respectively; P =.04), after controlling for baseline physical health status and other patient and provider covariates. CONCLUSIONS: Most providers consider patient adherence an important factor in their decision to prescribe PIs. This attitude appears to account for the relatively later use of PI treatment among Latinos, women, and the poor. Given the rising HIV infection rates among minorities, women, and the poor, further investigation of this treatment strategy and its impact on HIV resistance and outcomes is warranted.     

Knee pain and radiographic osteoarthritis interact in the prediction of levels of self‐reported disability

Objective

To determine predictors of disability depending on whether joint deformity and pain reporting exist independently or concurrently.

Methods

Subjects were 154 volunteers for an osteoarthritis screening examination. Eligible subjects completed questionnaires for physical function, pain, and depressive symptoms; underwent evoked pain testing for tenderness assessment; and had anteroposterior and lateral radiographs taken of both knees. Two blinded rheumatologists scored the images using Kellgren‐Lawrence criteria to determine presence of deformity.

Results

Subjects were divided into 3 subgroups based on radiographic evidence of deformity and self‐reported pain. Disability was greatest when pain and deformity occurred together (F[2,151] = 18.8, P < 0.0001). Self‐reported disability in the absence of deformity was predicted by body mass index, pain threshold, and anxiety symptoms; disability was predicted by the number of osteophytes and depressive symptoms when pain and deformity occurred together.

Conclusion

Self‐reported disability in osteoarthritis of the knee is greatest with concurrent pain and joint deformity. When pain and deformity do not cooccur, disability appears to be related to separate factors, including anxiety and pain threshold (e.g., tenderness).

     

The predominant form of the amyloid beta-protein precursor in human brain is protease nexin 2.

The amyloid beta protein and the amyloid beta-protein precursor (APP) are major constituents of senile plaques and cerebrovascular deposits in patients with Alzheimer disease and Down syndrome. Most human tissues contain mRNA that encodes forms of APP that contain the Kunitz protease inhibitor (KPI+) domain. A major 120-kDa protein corresponding to this KPI+ mRNA is also found in these tissues. This protein is identical to the protease inhibitor protease nexin 2. Brain contains an additional mRNA species that encodes a form of APP that lacks the KPI domain (KPI-). This latter mRNA has been suggested to encode a 105-kDa KPI- form of APP protein also found in brain. Using protease inhibitory functional assays, we show that both the 105-kDa and 120-kDa APP proteins in normal and Alzheimer disease brain contain the KPI domain. Moreover, KPI domain-specific precipitation assays reveal that KPI- forms of APP protein represent less than 14% of total brain APP. Lastly, an enriched fraction from total brain homogenate contains proteolytic activity that can process the purified 120-kDa KPI+ form of APP into a 105-kDa form, resulting in a high-molecular-mass doublet identical to that seen in brain. These findings indicate that although KPI- APP mRNA is abundant in brain, little corresponding protein is present. Thus, KPI+ APP protein (equivalent to protease nexin 2) is the predominant form of APP in human brain.