Trypanosoma cruzi I genotypes in different geographical regions and transmission cycles based on a microsatellite motif of the intergenic spacer of spliced-leader genes

The intergenic region of spliced-leader (SL-IR) genes from 105 Trypanosoma cruzi I (Tc I) infected biological samples, culture isolates and stocks from 11 endemic countries, from Argentina to the USA were characterised, allowing identification of 76 genotypes with 54 polymorphic sites from 123 aligned sequences. On the basis of the microsatellite motif proposed by Herrera et al. (2007) to define four haplotypes in Colombia, we could classify these genotypes into four distinct Tc I SL-IR groups, three corresponding to the former haplotypes Ia (11 genotypes), Ib (11 genotypes) and Id (35 genotypes); and one novel group, Ie (19 genotypes). Genotypes harbouring the Tc Ic motif were not detected in our study. Tc Ia was associated with domestic cycles in southern and northern South America and sylvatic cycles in Central and North America. Tc Ib was found in all transmission cycles from Colombia. Tc Id was identified in all transmission cycles from Argentina and Colombia, including Chagas cardiomyopathy patients, sylvatic Brazilian samples and human cases from French Guiana, Panama and Venezuela. Tc Ie gathered five samples from domestic Triatoma infestans from northern Argentina, nine samples from wild Mepraia spinolai and Mepraia gajardoi and two chagasic patients from Chile and one from a Bolivian patient with chagasic reactivation. Mixed infections by Tc Ia + Tc Id, Tc Ia + Tc Ie and Tc Id + Tc Ie were detected in vector faeces and isolates from human and vector samples. In addition, Tc Ia and Tc Id were identified in different tissues from a heart transplanted Chagas cardiomyopathy patient with reactivation, denoting histotropism. Trypanosoma cruzi I SL-IR genotypes from parasites infecting Triatoma gerstaeckeri and Didelphis virginiana from USA, T. infestans from Paraguay, Rhodnius nasutus and Rhodnius neglectus from Brazil and M. spinolai and M. gajardoi from Chile are to our knowledge described for the first time.     

Role of plasma phosphorylated neurofilament heavy chain (pNfH) in amyotrophic lateral sclerosis

The phosphorylated neurofilament heavy chain (pNfH) is a promising biomarker in amyotrophic lateral sclerosis (ALS). We examined plasma pNfH concentrations in order to corroborate its role as a diagnostic and prognostic biomarker in ALS. Incident ALS cases enrolled in a population‐based registry were retrospectively selected and matched by sex and age with a cohort of healthy volunteers. Plasma pNfH levels were measured by an ELISA kit and correlated with clinical parameters. Discrimination ability of pNfH was tested using receiving operating characteristic (ROC) curves. Kaplan–Meier (KM) analysis and Cox proportional hazard models were used for survival analysis. Plasma pNfH was significantly higher in patients compared to controls. An optimal cut‐off of 39.74 pg/ml discriminated cases from controls with an elevated sensitivity and specificity. Bulbar‐onset cases had higher plasma pNfH compared to spinal onset (p = 0.0033). Furthermore, plasma pNfH positively correlated with disease progression rate (r = 0.19, p = 0.031). Baseline plasma pNfH did not influence survival in our cohort. Our findings confirmed the potential utility of plasma pNfH as a diagnostic biomarker in ALS. However, further studies with longitudinal data are needed to corroborate its prognostic value.     

Successful Treatment of Human Visceral Leishmaniasis Restores Antigen-Specific IFN-γ, but not IL-10 Production

One of the key immunological characteristics of active visceral leishmaniasis (VL) is a profound immunosuppression and impaired production of Interferon-γ (IFN-γ). However, recent studies from Bihar in India showed using a whole blood assay, that whole blood cells have maintained the capacity to produce IFN-γ. Here we tested the hypothesis that a population of low-density granulocytes (LDG) might contribute to T cell responses hyporesponsiveness via the release of arginase. Our results show that this population is affected by the anticoagulant used to collect blood: the frequency of LDGs is significantly lower when the blood is collected with heparin as compared to EDTA; however, the anticoagulant does not impact on the levels of arginase released. Next, we assessed the capacity of whole blood cells from patients with active VL to produce IFN-γ and IL-10 in response to antigen-specific and polyclonal activation. Our results show that whole blood cells produce low or levels below detection limit of IFN-γ and IL-10, however, after successful treatment of VL patients, these cells gradually regain their capacity to produce IFN-γ, but not IL-10, in response to activation. These results suggest that in contrast to VL patients from Bihar, India, whole blood cells from VL patients from Gondar, Ethiopia, have lost their ability to produce IFN-γ during active VL and that active disease is not associated with sustained levels of IL-10 production following stimulation.     

Ion Migration‐Induced Amorphization and Phase Segregation as a Degradation Mechanism in Planar Perovskite Solar Cells

The operation of halide perovskite optoelectronic devices, including solar cells and LEDs, is strongly influenced by the mobility of ions comprising the crystal structure. This peculiarity is particularly true when considering the long‐term stability of devices. A detailed understanding of the ion migration‐driven degradation pathways is critical to design effective stabilization strategies. Nonetheless, despite substantial research in this first decade of perovskite photovoltaics, the long‐term effects of ion migration remain elusive due to the complex chemistry of lead halide perovskites. By linking materials chemistry to device optoelectronics, this study highlights that electrical bias‐induced perovskite amorphization and phase segregation is a crucial degradation mechanism in planar mixed halide perovskite solar cells. Depending on the biasing potential and the injected charge, halide segregation occurs, forming crystalline iodide‐rich domains, which govern light emission and participate in light absorption and photocurrent generation. Additionally, the loss of crystallinity limits charge collection efficiency and eventually degrades the device performance.     

A Randomized,Non-Inferiority Study Comparing Efficacy and Safety of a Single Dose of Pegfilgrastim versus Daily Filgrastim in Pediatric Patients after Autologous Peripheral Blood Stem Cell Transplant

Purpose

To assess the non-inferiority of pegfilgrastim versus filgrastim in speeding the recovery of polymorphonuclear cells (PMN) in pediatric patients who underwent autologous peripheral blood stem cell transplant (PBSCT).

Methods

The sample size of this randomized, multicenter, phase III study, was calculated assuming that a single dose of pegfilgrastim of 100 ug/kg was not inferior to 9 doses of filgrastim of 5 ug/kg/day. Randomization was performed by a computer-generated list and stored by sequentially numbered sealed envelopes.

Results

Sixty-one patients, with a median age of 11.5 years, were recruited: 29 in the filgrastim arm and 32 in the pegfilgrastim arm. Twenty percent were affected by lymphoma/leukaemia and eighty percent by solid tumors. The mean time to PMN engraftment was 10.48 days (standard deviation [SD] 1.57) and 10.44 days (SD 2.44) in the filgrastim and pegfilgrastim arms, respectively. Having fixed a non-inferiority margin Delta of 3, the primary endpoint of non-inferiority was reached. No differences were observed for other secondary endpoints: platelet engraftment, mean time to platelet recovery (28 days vs. 33 days), fever of unknown origin (79% vs. 78%), proven infection (34% vs. 28%), mucositis (76% vs. 59%). After a median follow-up of 2.3 years (95% C.I.: 1.5, 3.3), 20 deaths were observed due to disease progression.

Conclusions

We conclude that pegfilgrastim was not inferior to daily filgrastim in pediatric patients who underwent PBSCT.

EU Clinical Trial Register Number

2007-001430-14     

Investigation of σ receptors agonist/antagonist activity through N-(6-methoxytetralin-1-yl)- and N-(6-methoxynaphthalen-1-yl)alkyl derivatives of polymethylpiperidines

A series of polymethyl-substituted piperidines linked to either a 6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl or a 6-methoxynaphthalen-1-yl moiety was generated with the aim of verifying a previously generated hypothesis: tetralin and naphthalene nuclei confer opposite activity at the σ₁ receptor. Compounds 6, 9 and 10 displayed appreciable affinity at both σ subtypes, but none of the novel compounds displayed significant antiproliferative activity in MCF7wt and MCF7σ1 cell lines. The effect on bradikynin-triggered Ca²⁺ mobilization was studied as a methodology to suggest σ receptors mediated activity.     

Effects of indomethacin on postural hypotension in Parkinsonism.

A study was conducted to evaluate the effect of indomethacin on orthostatic hypotension in Parkinsonism. Twelve elderly patients participated and the drug was given in two-ways--as an intravenous infusion of 50 mg over 30 minutes and by mouth 50 mg thrice daily for six days. Results were assessed by measuring the degree of hypotension on standing, response to the cold pressor test, and forearm blood flow (by strain-gauge plethysmography). Indomethacin significantly reduced the fall in blood pressure on standing (P less than 0:001) and lessened or reversed orthostatic symptoms. Furthermore, there was an enhanced response to the cold pressor test and a reduction in forearm blood flow. These findings suggest that indomethacin has a positive effect on systemic vascular resistance.     

Relationship of Anterior and Posterior Subcutaneous Abdominal Fat to Insulin Sensitivity in Nondiabetic Men

Recent studies from our group reveal that adipose tissue (AT) in the subcutaneous abdominal region is the most important determinant of peripheral and hepatic insulin sensitivity. Because of different anatomic and physiologic characteristics of anterior and posterior subcutaneous abdominal AT, we investigated the relationship of the masses of each compartment, as determined by magnetic resonance imaging, to insulin sensitivity (using euglycemic hyperinsulinemic glucose clamp technique), and other anthropometric variables. Thirty-four healthy men with varying ranges of obesity were recruited for the study. The mass of posterior subcutaneous abdominal AT was ～1.6 times more than that of the anterior compartment, and these masses accounted for 12.9% and 8.2% of the total body fat mass, respectively. All anthropometric variables, including body mass index (BMI), waist-to-hip circumference ratio (WHR), skinfold thicknesses, and intraperitoneal AT mass were more significantly related to the posterior than the anterior subcutaneous abdominal AT mass. Compared to the anterior compartment mass, the posterior compartment mass displayed stronger relationship with insulin-mediated glucose disposal (Rd) (r=-0.44, p=0.009, and r=-0.76, p=0.0001, respectively) as well as with residual hepatic glucose output during the 40 mU.^?2.min-¹ insulin infusion (r=0.39, p=0.02, and r=0.53, p=0.001, respectively). After adjusting for total body fat, the Rd values showed a significant partial correlation with the posterior subcutaneous abdominal AT mass (r=-0.52, p=0.002). To conclude, posterior subcutaneous abdominal AT mass is a more important determinant of peripheral and hepatic insulin sensitivity than the anterior subcutaneous abdominal AT.