A phase 2 study of the safety, tolerability, and pharmacodynamics of FBS0701, a novel oral iron chelator, in transfusional iron overload

This was a 24-week, multicenter phase-2 study designed to assess safety, tolerability, and pharmacodynamics of FBS0701, a novel oral chelator, in adults with transfusional iron overload. Fifty-one patients, stratified by transfusional iron intake, were randomized to FBS0701 at either 14.5 or 29 mg/kg/d (16 and 32 mg/kg/d salt form). FBS0701 was generally well tolerated at both doses. Forty-nine patients (96%) completed the study. There were no drug-related serious adverse events. No adverse events (AEs) showed dose-dependency in frequency or severity. Treatment-related nausea, vomiting, abdominal pain, and diarrhea were each noted in < 5% of patients. Mean serum creatinine did not change significantly from Baseline or between dose groups. Transaminases wer increased in 8 (16%), three of whom acquired HCV on-study from a single blood bank while five had an abnormal baseline ALT. The 24 week mean change in liver iron concentration (ΔLIC) at 14.5 mg/kg/d was +3.1 mg/g (dw); 29% achieved a decrease in LIC. Mean ΔLIC at 29 mg/kg/d was -0.3 mg/g (dw); 44% achieved a decrease in LIC (P < .03 for ΔLIC between doses). The safety and tolerability profile at therapeutic doses compare favorably to other oral chelators.     

The effect of tobacco control policies on smoking prevalence and smoking-attributable deaths. Findings from the Netherlands SimSmoke Tobacco Control Policy Simulation Model

Aim To develop a simulation model projecting the effect of tobacco control policies in the Netherlands on smoking prevalence and smoking‐attributable deaths. Design, setting and participants Netherlands SimSmoke—an adapted version of the SimSmoke simulation model of tobacco control policy—uses population, smoking rates and tobacco control policy data for the Netherlands to predict the effect of seven types of policies: taxes, smoke‐free legislation, mass media, advertising bans, health warnings, cessation treatment and youth access policies. Measurements Outcome measures were smoking prevalence and smoking‐attributable deaths. Findings With a comprehensive set of policies, as recommended by MPOWER, smoking prevalence can be decreased by as much as 21% in the first year, increasing to a 35% reduction in the next 20 years and almost 40% by 30 years. By 2040, 7706 deaths can be averted in that year alone with the stronger set of policies. Without effective tobacco control policies, almost a million lives will be lost to tobacco‐related diseases between 2011 and 2040. Of those, 145 000 can be saved with a comprehensive tobacco control package. Conclusions Smoking prevalence and smoking‐attributable deaths in the Netherlands can be reduced substantially through tax increases, smoke‐free legislation, high‐intensity media campaigns, stronger advertising bans and health warnings, comprehensive cessation treatment and youth access laws. The implementation of these FCTC/MPOWER recommended policies could be expected to show similar or even larger relative reductions in smoking prevalence in other countries which currently have weak policies.     

Prospective phase 1/2 study of rituximab in childhood and adolescent chronic immune thrombocytopenic purpura

We assessed safety and efficacy of rituximab in a prospective study of 36 patients, age 2.6 to 18.3 years, with severe chronic immune thrombocytopenic purpura (ITP). The primary outcome of sustained platelets above 50 x 10(9)/L (50,000/mm3) during 4 consecutive weeks, starting in weeks 9 to 12, was achieved by 11 of 36 patients (31%, confidence interval [CI], 16% to 48%). Median response time was 1 week (range, 1 to 7 weeks). Attainment of the primary outcome was not associated with age, prior pharmacologic responses, prior splenectomy, ITP duration, screening platelet count, refractoriness, or IgM reduction. First-dose, infusion-related toxicity was common (47%) despite premedication. Significant drug-related toxicities included third-dose hypotension (n = 1) and serum sickness (n = 2). Peripheral B cells were depleted in all subjects. IgM decreased 3.4% per week, but IgG did not significantly decrease. Rituximab was well tolerated, with manageable infusion-related side effects, but 6% of subjects developed serum sickness. Rituximab is beneficial for some pediatric patients with severe, chronic ITP.     

Aptamer-based endocytosis of a lysosomal enzyme

Enzyme replacement therapy for lysosomal storage diseases is currently based on endocytosis of lysosomal enzymes via the mannose or mannose 6-phosphate receptors. We are developing a technology for endocytosis of lysosomal enzymes that depends on generic, chemically conjugated reagents. These reagents are aptamers (single-stranded nucleic acid molecules) selected to bind to the extracellular domain of the mouse transferrin receptor. After selection, an RNA aptamer and a DNA aptamer were modified with biotin and linked to dye-labeled streptavidin for detection by confocal microscopy. Aptamer-streptavidin conjugates showed saturable uptake into mouse fibroblasts (Ltk(-) cells), which could be inhibited by an excess of free aptamer but not by tRNA, calf thymus DNA, or transferrin. The RNA aptamer-streptavidin conjugate was mouse-specific, as human cells (293T) did not take it up unless first transfected with the mouse transferrin receptor. Some streptavidin separated from the recycling pathway of transferrin and colocalized with lysosomes. After characterization in the model system, the DNA aptamer was conjugated to a lysosomal enzyme, alpha-l-iduronidase, from which mannose 6-phosphate had been removed. The aptamer had been modified by attachment of terminal glycerol for oxidation by periodate and reaction of the resulting aldehyde with amino groups on the protein. Dephospho-alpha-L-iduronidase-aptamer conjugate was taken up in saturable manner by alpha-L-iduronidase-deficient mouse fibroblasts, with half-maximal uptake estimated as 1.6 nM. Endocytosed enzyme-aptamer conjugate corrected glycosaminoglycan accumulation, indicating that it reached lysosomes and was functional in those organelles. Both uptake and correction were inhibited by unconjugated aptamer, confirming the role of the aptamer in receptor-mediated endocytosis.     

What do we know about older adults and HIV? A review of social and behavioral literature

The fastest growing segment of the United States HIV population is people aged 50 and older. This heterogeneous group includes people with diverse pathways into HIV positive status in later life, including aging with the disease as well as later life-acquired infections. As people with HIV live into older ages, solving problems of successful secondary prevention and ongoing treatment requires more specific knowledge of the particular aging-related contextual sociocultural, psychosocial, and personal factors salient to the situations of persons living with HIV. Greater knowledge of these factors will help solve challenges to reducing psychological burden and promoting health maintenance for people with HIV. Yet, the current literature on aging and HIV remains nascent. To assess the state of knowledge of the sociocultural and behavioral factors associated with aging with HIV, we conducted a systematic critical content review of peer-reviewed social and behavioral research on aging and HIV to answer the question, "How have older age, and social, cultural, and behavioral aspects of the intersection of HIV and age been addressed in the literature?" We searched First Search, Proquest, Psych Info, Pub Med, Wilson Select Plus, and World Cat and identified 1549 articles. We then reviewed these to select peer-reviewed articles reporting results of research on the social and behavioral aspects of living with HIV at age 50 and older. Fifty-eight publications were identified that met study inclusion criteria. While few publications reported clear age-related differences, there were significant ethnic differences in living with HIV in later life and also differences among older people when groups were defined by mode of transmission. Findings are discussed in light of constructs from gerontology which may contribute to clarifying how later life, life course stage, and psychological development intersect with, influence, and are influenced by HIV disease and long-term anti-retroviral therapy use.     

The population impact of smoke-free workplace and hospitality industry legislation on smoking behaviour. Findings from a national population survey

Aims To study the impact of implementing smoke‐free workplace and hospitality industry legislation on smoking behaviour. Design, setting and participants A cross‐sectional population survey from 2001 to 2008 (n ≈ 18 000 per year) was used to assess trends and seasonal patterns in smoking and quitting, and to examine whether changes could be observed after the workplace smoking ban in the Netherlands in 2004 and the hospitality industry ban in 2008. Measurements Outcome measures were smoking prevalence, quit attempts and successful quit attempts. Interactions with educational level (socio‐economic status) and bar visiting (exposure to the hospitality industry ban) were tested. Findings The workplace ban was followed by a decrease in smoking prevalence (OR = 0.91, P < 0.001), but the hospitality industry ban was not (OR = 0.96, P = 0.127). Both bans, especially the workplace ban, were followed by an increase in quit attempts and successful quit attempts: workplace ban, OR = 1.31, P < 0.001; OR = 1.49, P < 0.001; hospitality industry ban, OR = 1.13, P = 0.013; OR = 1.44, P < 0.001. The workplace ban had a larger effect on successful quitting among higher‐educated (OR = 0.35, P < 0.001) than on lower‐educated respondents (OR = 0.74, P = 0.052). The hospitality industry ban had a larger effect on quit attempts among frequent bar visitors (OR = 1.48, P = 0.003) than on non‐bar visitors (OR = 0.71, P = 0.014). Conclusions A workplace smoking ban in the Netherlands was followed by more changes in smoking and quitting than a hospitality industry ban. The hospitality industry ban only appeared to have an impact on quit attempts, and not on smoking prevalence.     

Severe hemorrhage in children with newly diagnosed immune thrombocytopenic purpura

Controversy exists regarding management of children newly diagnosed with immune thrombocytopenic purpura (ITP). Drug treatment is usually administered to prevent severe hemorrhage, although the definition and frequency of severe bleeding are poorly characterized. Accordingly, the Intercontinental Childhood ITP Study Group (ICIS) conducted a prospective registry defining severe hemorrhage at diagnosis and during the following 28 days in children with ITP. Of 1106 ITP patients enrolled, 863 were eligible and evaluable for bleeding severity assessment at diagnosis and during the subsequent 4 weeks. Twenty-five children (2.9%) had severe bleeding at diagnosis. Among 505 patients with a platelet count less than or equal to 20 000/mm(3) and no or mild bleeding at diagnosis, 3 (0.6%), had new severe hemorrhagic events during the ensuing 28 days. Subsequent development of severe hemorrhage was unrelated to initial management (P = .82). These results show that severe bleeding is uncommon at diagnosis in children with ITP and rare during the next 4 weeks irrespective of treatment given. We conclude that it would be difficult to design an adequately powered therapeutic trial aimed at demonstrating prevention of severe bleeding during the first 4 weeks after diagnosis. This finding suggests that future studies of ITP management should emphasize other outcomes.     

Multiple anomalous venous systemic connections in a case of atrial septal defect associated with right aortic arch and spine defromities

Multiple anomalies of persistent left superior vena cava and left hepatic vein emptying into the left atrium associated with atrial septal defect, right aortic arch and multiple skeletal malformations are presented. The anatomy and the embryology of these anomalous venous connections are briefly reviewed. Clinical, hemodynamic and surgical implications of these anomalies are discussed.     

Juxtaposition of atrial appendages: angiocardiographic observations

The angiographic features of four cases of left-sided juxtaposition and one case of right-sided juxtaposition of the atrial appendages are described. The anomalous appendage was cephalad and dorsal to the normal position of the left atrial appendage and was larger than normal during atrial diastole; the appendage located on the anatomically correct side was caudad and its diastolic size was less than normal. The four cases of left-sided juxtaposition were all associated with transposition of the great vessels. Right-sided juxtaposition was detected inadvertently in a patient with a congenital obstructive lesion of the mitral valve. Left-sided juxtaposition can be demonstrated angiocardiographically by opacification of the right atrium, whereas right-sided juxtaposition can be seen by contrast injection into any cardiac chamber but the left ventricle, with certain exceptions.