Physical activity and health outcomes in persons with haemophilia B

Regular participation in physical activity helps to prevent damage and maintain joint health in persons with haemophilia. This study describes self‐reported physical activity participation among a sample of people with haemophilia B in the US and measures its association with health‐related quality of life (HRQoL). Data on 135 participants aged 5–64 years were abstracted from Hemophilia Utilization Group Study Part Vb. The International Physical Activity Questionnaire assessed physical activity among participants aged 15–64 years, and the Children's Physical Activity Questionnaire abstracted from the Canadian Community Health Survey was used for participants aged 5–14 years. SF‐12 was used to measure HRQoL and the EuroQol (EQ‐5D‐3L) was used to measure health status for participants older than 18 years of age. PedsQL was used to measure HRQoL in children aged 5–18 years. Sixty‐two percent of participants in the 15–64 year‐old age cohort reported a high level of physical activity, 29% reported moderate activity and 9% reported low activity. For children aged 5–14 years, 79% reported participating in physical activity for at least 4 days over a typical week. Based on the 2008 Physical Activity Guidelines for Americans, 79% of adults achieved the recommended physical activity level. Multivariable regression models indicated that adults who engaged in a high level of physical activity reported EQ‐5D Visual Analogue Scale (VAS) scores that were 11.7 (P = 0.0726) points greater than those who engaged in moderate/low activity, indicating better health outcomes. Among children, no statistically significant differences in health outcomes were found between high and moderate or low activity groups.     

Cytocompatibility of novel extracellular matrix protein analogs of biodegradable polyester polymers derived from α-hydroxy amino acids

One of the challenges in regenerative medicine is the development of novel biodegradable materials to build scaffolds that will support multiple cell types for tissue engineering. Here we describe the preparation, characterization, and cytocompatibility of homo- and hetero-polyesters of α-hydroxy amino acid derivatives with or without lactic acid conjugation. The polymers were prepared by a direct condensation method and characterized using gel permeation chromatography, ¹H-nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, optical activity, and solubility. The surface charge of the polymers was evaluated using zeta potential measurements. The polymers were coated onto glass cover slips followed by characterization using nano-surface profiler, thin film reflectometry, and atomic force microscopy (AFM). Their interaction with endothelial and neuronal cells was assessed using adhesion, proliferation, and differentiation assays. Of the characterized polymers, Poly-HOVal-LA, but not Poly-(D)HOPhe, significantly augmented nerve growth factor (NGF)-induced neuronal differentiation of the PC12 pheochromcytoma cells. In contrast, Poly-HOLeu increased by 20% the adhesion of endothelial cells, but did not affect PC12 cell differentiation. NGF-induced Erk1/2 phosphorylation in PC12 cells grown on the different polymers was similar to the effect observed for cells cultured on collagen type I. While no significant association could be established between charge and the differentiative/proliferative properties of the polymers, AFM analysis indicated augmentation of NGF-induced neuronal differentiation on smooth polymer surfaces. We conclude that overall selective cytocompatibility and bioactivity might render α-hydroxy amino acid polymers useful as extracellular matrix-mimicking materials for tissue engineering.     

CD28 signals the differential control of regulatory T cells and effector T cells

One possible means of driving antigen‐specific immune suppression is to expand or induce antigen‐specific FoxP3‐expressing Treg cells. One way of activating and expanding these specialized cells, both in vitro and in vivo, is by strong costimulation via CD28 with an agonistic anti‐CD28 monoclonal antibody, called anti‐CD28 superagonist (CD28SA). However, CD28SA also strongly activates conventional T (Tconv) cells to secrete proinflammatory cytokines and, under certain conditions, causes serious cytokine release syndrome. In this issue of European Journal of Immunology, Tabares et al. [Eur. J. Immunol. 2014. 44: 1225–1236] address how CD28SA can be used for the differential control of human Treg and Tconv cells to suppress immune responses without serious adverse effects. They show that, depending on the dose of the antibody or by comedication of cortico‐steroid, the selective expansion of Treg cells can be achieved without significantly activating Tconv cells to produce inflammatory cytokines. This difference in CD28 signal sensitivity between the two populations can be exploited for better control of immune responses.     

Biofilm Formation within the Interface of Bovine Root Dentin Treated with Conjugated Chitosan and Sealer Containing Chitosan Nanoparticles

IntroductionThe purpose of this study was to assess biofilm formation within sealer-dentin interfaces of root segments filled with gutta-percha and sealer incorporated with chitosan (CS) nanoparticles with and without canal surface treatment with different formulations of CS.MethodsStandardized canals of 4-mm bovine root segments (N = 35) were filled with gutta-percha and pulp canal sealer incorporated with CS nanoparticles without surface treatment (group CS) or after surface treatment with phosphorylated CS (group PHCS), CS-conjugated rose bengal and photodynamic irradiation (group CSRB), or a combination of both PHCS and CSRB (group RBPH). The control group was filled with gutta-percha and an unmodified sealer. After 7 days of setting, specimens were aged in buffered solution at 37°C for 1 or 4 weeks. Monospecies biofilms of Enterococcus faecalis were grown on specimens for 7 days in a chemostat-based biofilm fermentor. Biofilm formation within the sealer-dentin interface was assessed with confocal laser scanning microscopy.ResultsIn the 4-week–aged specimens only, the mean biofilm areas were significantly smaller than in the control for the CS (P = .008), PHCS (P = .012), and RBPH (P = .034) groups. The percentage of the biofilm-covered interface also was significantly lower than in the control for the CS (P = .024) and PHCS (P = .003) groups. The CS, PHCS, and RBPH groups did not differ significantly.ConclusionsIncorporating CS nanoparticles into the zinc oxide–eugenol sealer inhibited biofilm formation within the sealer-dentin interface. This effect was maintained when canals were treated with phosphorylated CS, and it was moderated by canal treatment with CS-conjugated rose bengal and irradiation.     

Pituitary-directed medical therapy with pasireotide for a corticotroph macroadenoma: pituitary volume reduction and literature review

Hypercortisolism due to an ACTH-secreting pituitary adenoma (Cushing’s disease) is a chronic condition associated with high morbidity and mortality if inadequately managed. Pasireotide is a multireceptor-targeted somatostatin analogue and is the only approved medical therapy for Cushing’s disease that treats the underlying cause of the disorder. This paper reviews the available literature for medical-therapy-induced adenoma volume reduction in patients with Cushing’s disease and reports the experience of a 53-year-old surgically, radiologically and medically naïve (de novo) female with a pituitary macroadenoma who declined surgery. This patient was treated with pasireotide as first-line therapy as part of the largest randomized Phase III study evaluating a medical therapy in patients with Cushing’s disease (SOM230B2305 trial). Subcutaneous pasireotide significantly decreased tumor volume, suppressed cortisol secretion, and improved clinical signs and symptoms of Cushing’s disease in this patient. Based on this experience, first-line pasireotide has the potential to achieve substantial tumor volume reduction in addition to significant improvements in cortisol levels and signs and symptoms in patients with Cushing’s disease for whom surgery is not an option.     

Leishmania donovani polyamine biosynthetic enzyme overproducers as tools to investigate the mode of action of cytotoxic polyamine analogs

A number of anticancer and antiparasitic drugs are postulated to target the polyamine biosynthetic pathway and polyamine function, but the exact mode of action of these compounds is still being elucidated. To establish whether polyamine analogs specifically target enzymes of the polyamine pathway, a model was developed using strains of the protozoan parasite Leishmania donovani that overproduce each of the polyamine biosynthetic enzymes. Promastigotes overexpressing episomal constructs encoding ornithine decarboxylase (ODC), S-adenosylmethionine decarboxylase (ADOMETDC), or spermidine synthase (SPDSYN) revealed robust overproduction of the corresponding polyamine biosynthetic enzyme. Polyamine pools, however, were either unchanged or only marginally affected, implying that regulatory mechanisms must exist. The ODC, ADOMETDC, and SPDSYN overproducer strains exhibited a high level of resistance to difluoromethylornithine, 5'-{[(Z)-4-amino-2-butenyl]methylamino}-5'-deoxyadenosine, and n-butylamine, respectively, confirming previous observations that these agents specifically target polyamine enzymes. Conversely, augmented levels of polyamine biosynthetic enzymes did not affect the sensitivity of L. donovani promastigotes to pentamidine, berenil, and mitoguazone, drugs that were postulated to target the polyamine pathway, implying alternative and/or additional targets for these agents. The sensitivities of wild-type and overproducing parasites to a variety of polyamine analogs were also tested. The polyamine enzyme-overproducing lines offer a rapid cell-based screen for assessing whether synthetic polyamine analogs exert their mechanism of action predominantly on the polyamine biosynthetic pathway in L. donovani. Furthermore, the drug resistance engendered by the amplification of target genes and the overproduction of the encoded protein offers a general strategy for evaluating and developing therapeutic agents that target specific proteins in Leishmania.