An assessment of the relative influence of pain coping, negative thoughts about pain, and pain acceptance on health-related quality of life among people with hemophilia

Many people with hemophilia are affected by chronic arthritic joint pain as well as acute bleeding pain. In this cross-sectional study, 209 men with hemophilia A or B completed the Hemophilia Pain Coping Questionnaire (HPCQ), the Chronic Pain Acceptance Questionnaire (CPAQ), and the RAND 36-item Health Survey (SF-36), a measure of health-related quality of life. Multiple regression was used to test the influence of active pain coping, passive adherence coping, and negative thoughts about pain (HPCQ scales), and activity engagement and pain willingness (CPAQ scales), on physical and mental components of quality of life (SF-36 PCS and MCS scales), taking account of age, hemophilia severity, use of clotting factor, and pain intensity. Pain intensity had the main influence on physical quality of life and negative thoughts had the main influence on mental quality of life. Activity engagement and pain willingness had small but significant influences on physical and mental quality of life. Pain willingness also moderated and partly mediated the influence of pain intensity on physical quality of life, and activity engagement and pain willingness mediated the influence of negative thoughts on mental quality of life. Negative thoughts moderated and partly mediated the influence of pain intensity on mental quality of life. There was no evidence that active pain coping influenced quality of life. The findings suggest that quality of life in hemophilia could potentially be improved by interventions to increase pain acceptance and reduce negative thoughts about pain.     

The Invisible Men: finding and engaging with the male partners of street sex workers

Men, in general, remain less likely than women to seek medical care, and are only half as likely as women to undertake preventive health visits and/or screening tests. There is a great need to increase men's health awareness and reduce this significant gender disparity. Furthermore, marginalised and socially excluded men rarely access health services, even though the reasons for their social exclusion, particularly drug and alcohol dependency, invariably mean that their need for health interventions is greater than in the normal population.The Open Doors Sexual Health Service has been working with female street sex workers (SSWs) in the London Borough of Hackney since 2006, in order to help them address their physical, psychological and social needs. Open Doors is based in, and partly funded by, City and Hackney Primary Care Trust. As Open Doors’ staff's relationships with the women grew and the team developed an understanding of the lives of the women and their networks, it became clear that their relationships with the men in their lives (historically characterised as “pimps”) were more significant and enduring than had previously been assumed, and that working with couples had the potential to be of greater benefit than working with the women only.In July 2008, a male worker joined the Open Doors team, in order to work exclusively with the male partners of women using the service, and to develop access to clinical and social services for this shadowy group. During the first 12 months, the male partners’ coordinator (MPC) engaged with 23 men, each one of whom has needed intensive case management, as illustrated by a Case Study. The MPC's contract has been renewed for a further year, and the scope of the post widened to include other marginalised men, such as street drinkers, squatters and undocumented migrants, achieved by close collaboration with key services, especially the TB service, the Department of Sexual Health (DoSH) and the Specialist Addictions Unit (SAU) in Hackney's local hospital, the Homerton.This paper will describe the work done by the MPC during the first 12 months of his tenure.     

Cyclodextrin-derived host molecules as reversal agents for the neuromuscular blocker rocuronium bromide: synthesis and structure-activity relationships

A series of mono- and per-6-substituted cyclodextrin derivatives were synthesized as synthetic receptors (or host molecules) of rocuronium bromide, the most widely used neuromuscular blocker in anaesthesia. By forming host-guest complexes with rocuronium, these cyclodextrin derivatives reverse the muscle relaxation induced by rocuronium in vitro and in vivo and therefore can be used as reversal agents of the neuromuscular blocker to assist rapid recovery of patients after surgery. Because this supramolecular mechanism of action does not involve direct interaction with the cholinergic system, the reversal by these compounds, e.g., compound 14 (Org 25969), is not accompanied by cardiovascular side effects usually attendant with acetylcholinesterase inhibitors such as neostigmine. The structure-activity relationships are consistent with this supramolecular mechanism of action and are discussed herein. These include the effects of binding cavity size and hydrophobic and electrostatic interaction on the reversal activities of these compounds.     

Blood letting in high-ferritin type 2 diabetes: effects on insulin sensitivity and beta-cell function

Iron-related insulin-resistance is improved by iron depletion or treatment with iron chelators. The aim of this study was to evaluate insulin sensitivity and insulin secretion after blood letting in patients who had high-ferritin type 2 diabetes and were randomized to blood letting (three phlebotomies [500 ml of blood] at 2-week intervals, group 1) or to observation (group 2). Insulin secretion and sensitivity were tested at baseline and 4 and 12 months thereafter. The two groups were matched for age, BMI, pharmacologic treatment, and chronic diabetic complications. All patients were negative for C282Y mutation of hereditary hemochromatosis. Baseline glycated hemoglobin (6.27 +/- 0.9% vs. 6.39 +/- 1.2%), insulin sensitivity (2.75 +/- 1.8 vs. 3.2 +/- 2.1 mg.dl(-1).min(-1)), and area under the curve for C-peptide (AUC(C-peptide); 38.7 +/- 11.6 vs. 37.6 +/- 14.1 ng.ml(-1).min(-1)) were not significantly different between the two groups of patients. Body weight, blood pressure, blood hematocrit levels, and drug treatment remained essentially unchanged during the study period. As expected, serum ferritin, transferrin saturation index, and blood hemoglobin decreased significantly at 4 months only in patients who received blood letting. In parallel to this changes, blood HbA(1c) decreased significantly only in group 1 subjects (mean differences, -0.61; 95% CI, -0.17 to -1.048; P = 0.01). AUC(C-peptide) decreased by -10.2 +/- 6.3% after blood letting. In contrast, a 10.4 +/- 6.4% increase in AUC(C-peptide) was noted in group 2 subjects at 4 months (P = 0.032). At 12 months, AUC(C-peptide) returned to values not significantly different from baseline in the two groups of subjects. At 4 months, the change in insulin sensitivity from baseline was significantly different between the two groups (80.6 +/- 43.2% vs. -8.6 +/- 9.9% in groups 1 and 2, respectively, P = 0.049). At 12 months, the differences between the two groups were even more marked (55.5 +/- 24.8% vs. -26.8 +/- 9.9%; P = 0.005). When the analysis was restricted to those subjects who completed the follow-up until 12 months, results did not show differences compared with the changes observed at 4 months, except for insulin sensitivity. A statistically significant increase in insulin sensitivity was observed in the blood-letting group (from 2.30 +/- 1.81 to 3.08 +/- 2.55 mg.dl(-1).min(-1) at 4 months, to 3.16 +/- 1.85 mg.dl(-1).min(-1) at 12 months; P = 0,045) in contrast with group 2 subjects (from 3.24 +/- 1.9 to 3.26 +/- 2.05 mg.dl(-1).min(-1) at 4 months, to 2.31 +/- 1.35 mg.dl(-1).min(-1) at 12 months). In summary, blood letting led simultaneously to decreased blood HbA(1c) levels and to changes in insulin secretion and insulin resistance that were significantly different from those observed in a matched observational group of subjects with high-ferritin type 2 diabetes. The mechanisms for improvement in peripheral insulin sensitivity after blood letting should be investigated further.     

Emergency contraception in Mexico City: knowledge,attitudes, and practices among providers and potential clients after a 3-year introduction effort

Emergency contraception (EC) has the potential to reduce unwanted pregnancy significantly, in Mexico as elsewhere. Recent years have seen tremendous growth in programs and research devoted to expanding access to emergency methods worldwide. In Mexico City, we conducted a pre-intervention/post-intervention research study of one way to introduce EC. Following a baseline survey of family planning providers and clients in 1997, we organized and implemented a three-year program of training for health care providers and a multi-faceted information campaign for the general public, including a national toll-free hotline and website. In 2000, we again surveyed family planning clinic providers and clients, using instruments similar to those employed in the baseline study. EC awareness increased significantly from 13% of clients to 32%, and support jumped from 73% to 83%. Providers at study clinics improved method recognition from 88% to 100%.     

Synaptic glutamate receptor clustering in mice lacking the SH3 and GK domains of SAP97

Postsynaptic targeting of the Drosophila tumour suppressor discs-large (Dlg) critically depends on its SH3 and GK domains. Here, we asked whether these domains are also involved in subcellular targeting of the mammalian Dlg homolog SAP97 and its interacting partners in CNS cortical neurons by analysing a recently described mouse mutant lacking the SH3 and GK domains of SAP97. Both wildtype and truncated SAP97 were predominantly expressed in perinuclear regions, in a pattern suggesting association with the endoplasmic reticulum. Weaker immunoreactivity was found in neurites colocalizing with both dendritic and axonal markers. As SAP97 has been implicated in the early intracellular processing of the glutamate receptor GluR1, we studied biochemical maturation and subcellular localization of GluR1 in the mutants. Both the glycosylation pattern and synaptic clustering of GluR1 were indistinguishable from wildtype mice. Synaptic clustering of the guanylate kinase domain interacting protein GKAP was also intact. Our data demonstrate that truncation of the SH3 and GK domains of SAP97 in mice does neither change its subcellular distribution nor does it disrupt synaptic structure or protein clustering, as opposed to severe missorting of the respective mutant Dlg protein in Drosophila.     

Constitutive overexpression of cyclin D1 but not cyclin E confers acute resistance to antiestrogens in T-47D breast cancer cells

Cyclin D1 and cyclin E are overexpressed in approximately 45% and 30% of breast cancers, respectively, and adverse associations with patient outcome have been reported. The potential roles of cyclin D1 and cyclin E expression as markers of therapeutic responsiveness to the pure steroidal antiestrogen ICI 182780 were investigated using T-47D breast cancer cell lines constitutively overexpressing cyclin D1 or cyclin E. Measurement of S phase fraction, phosphorylation states of the retinoblastoma protein, and cyclin E-cyclin-dependent kinase (Cdk) 2 activity demonstrated that overexpression of cyclin D1 decreased sensitivity to antiestrogen inhibition at 24 and 48 h. Overexpression of cyclin E produced a less pronounced early cell cycle effect indicating only partial resistance to antiestrogen inhibition in the short-term. In ICI 182780-treated cyclin D1-overexpressing cells, sufficient Cdk activity was retained to allow retinoblastoma protein phosphorylation and cell proliferation, despite an increase in the association of p21 and p27 with cyclin D1-Cdk4/6 and cyclin E-Cdk2 complexes. After longer-term (>7 days) treatment, antiestrogens inhibited colony growth in cyclin D1- or cyclin E-overexpressing breast cancer cells, but with an approximately 2-2.5-fold decrease in dose sensitivity. This was associated with a fall in cyclin D1 levels, a reduction in the half-life of cyclin D1 protein and a decline in cyclin E-Cdk2 activity in cyclin D1-overexpressing cells, and the maintenance of cyclin E-p27 association in the cyclin E-overexpressing cells. These data confirm that cyclin D1 expression and cyclin E-p27 association play important roles in antiestrogen action, and suggest that cyclin D1 or cyclin E overexpression has subtle effects on antiestrogen sensitivity. Additional studies to elucidate the contribution of alterations in cyclin D1 stability to antiestrogen action and to assess the relationship between antiestrogen sensitivity and expression of cyclin D1, cyclin E, or p27 in a clinical setting are required.