Clinically relevant intronic splicing enhancer mutation in myelin proteolipid protein leads to progressive microglia and astrocyte activation in white and gray matter regions of the brain

INTRODUCTION: Mutations in proteolipid protein (PLP), the most abundant myelin protein in the CNS, cause the X-linked dysmyelinating leukodystrophies, Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia type 2 (SPG2). Point mutations, deletion, and duplication of the PLP1 gene cause PMD/SPG2 with varying clinical presentation. Deletion of an intronic splicing enhancer (ISEdel) within intron 3 of the PLP1 gene is associated with a mild form of PMD. Clinical and preclinical studies have indicated that mutations in myelin proteins, including PLP, can induce neuroinflammation, but the temporal and spatial onset of the reactive glia response in a clinically relevant mild form of PMD has not been defined. METHODS: A PLP-ISEdel knockin mouse was used to examine the behavioral and neuroinflammatory consequences of a deletion within intron 3 of the PLP gene, at two time points (two and four months old) early in the pathological progression. Mice were characterized functionally using the open field task, elevated plus maze, and nesting behavior. Quantitative neuropathological analysis was for markers of astrocytes (GFAP), microglia (IBA1, CD68, MHCII) and axons (APP). The Aperio ScanScope was used to generate a digital, high magnification photomicrograph of entire brain sections. These digital slides were used to quantify the immunohistochemical staining in ten different brain regions to assess the regional heterogeneity in the reactive astrocyte and microglial response. RESULTS: The PLP-ISEdel mice exhibited behavioral deficits in the open field and nesting behavior at two months, which did not worsen by four months of age. A marker of axonal injury (APP) increased from two months to four months of age. Striking was the robust reactive astrocyte and microglia response which was also progressive. In the two-month-old mice, the astrocyte and microglia reactivity was most apparent in white matter rich regions of the brain. By four months of age the gliosis had become widespread and included both white as well as gray matter regions of the brain. CONCLUSIONS: Our results indicate, along with other preclinical models of PMD, that an early reactive glia response occurs following mutations in the PLP gene, which may represent a potentially clinically relevant, oligodendrocyte-independent therapeutic target for PMD

Deuteron photo-disintegration with polarised photons in the energy range 30 - 50 MeV

The reaction d(\vec\gamma,np) has been studied using the tagged and polarised LADON gamma ray beam at an energy 30 - 50 MeV to investigate the existence of narrow dibaryonic resonances recently suggested from the experimental measurements in a different laboratory. The beam was obtained by Compton back-scattering of laser light on the electrons of the storage ring ADONE. Photo-neutron yields were measured at five neutron angle \vartheta_n = 22, 55.5, 90, 125 and 157 degrees in the center of mass system.Our results do not support the existence of such resonances.Comment: 16 pages, Latex, 22 figures, 1 table. Nucl. Phys. A to appea

Enhanced Recovery After Surgery (ERAS) protocol in bariatric and metabolic surgery (BMS)-analysis of practices in nutritional aspects from five continents

This study aims to understand the prevalent practices on the nutritional aspects of the enhanced recovery after surgery (ERAS) protocol based on the knowledge and practice of surgeons, nutritionists, and anesthesiologists who work in the bariatric and metabolic surgery (BMS) units worldwide. This cross-sectional study enrolled BMS unit professionals from five continents-Africa, America, Asia, Europe, and Oceania. An electronic questionnaire developed by the researchers was provided to evaluate practices about the three nutritional aspects of ERAS protocol in BMS (Thorel et al. 2016): preoperative fasting, carbohydrate loading, and early postoperative nutrition. Only surgeons, nutritionists, and anesthesiologists were invited to participate. One hundred twenty-five professionals answered the questionnaires: 50.4% from America and 39.2% from Europe. The profile of participating professionals was bariatric surgeons 70.2%, nutritionists 26.4%, and anesthesiologists 3.3%. Approximately 47.9% of professionals work in private services, for about 11 to 20 years (48.7%). In all continents, a large majority were aware of the protocol. Professionals from the African continent reported having implemented the ERAS bariatric protocol 4.0 ± 0 years ago. It is worth mentioning that professionals from the five continents implemented the ERAS protocol based on the published literature (p = 0.012). About preoperative fasting abbreviation protocol, a significant difference was found between continents and consequently between services (p = 0.000). There is no uniformity in the conduct of shortening of fasting in the preoperative period and the immediate postoperative period. Early postoperative (PO) period protein supplementation is not performed in a standard fashion in all units globally. ERAS principles and practices are partial and insufficiently implemented on the five continents despite the prevalent knowledge of professionals based on evidence. Moreover, there is no uniformity in fasting, immediate postoperative diet, and early protein supplementation practices globally.info:eu-repo/semantics/publishedVersio

Collective effects in spin-crossover chains with exchange interaction

The collective properties of spin-crossover chains are studied. Spin-crossover compounds contain ions with a low-spin ground state and low lying high-spin excited states and are of interest for molecular memory applications. Some of them naturally form one-dimensional chains. Elastic interaction and Ising exchange interaction are taken into account. The transfer-matrix approach is used to calculate the partition function, the fraction of ions in the high-spin state, the magnetization, susceptibility, etc., exactly. The high-spin-low-spin degree of freedom leads to collective effects not present in simple spin chains. The ground-state phase diagram is mapped out and compared to the case with Heisenberg exchange interaction. The various phases give rise to characteristic behavior at nonzero temperatures, including sharp crossovers between low- and high-temperature regimes. A Curie-Weiss law for the susceptibility is derived and the paramagnetic Curie temperature is calculated. Possible experiments to determine the exchange coupling are discussed.Comment: 9 pages, 13 color figures, published versio

On isovector meson exchange currents in the Bethe-Salpeter approach

We investigate the nonrelativistic reduction of the Bethe-Salpeter amplitude for the deuteron electrodisintegration near threshold energies. To this end, two assumptions have been used in the calculations: 1) the static approximation and 2) the one iteration approximation. Within these assumptions it is possible to recover the nonrelativistic result including a systematic extension to relativistic corrections. We find that the so-called pair current term can be constructed from the $P$-wave contribution of the deuteron Bethe-Salpeter amplitude. The form factor that enters into the calculation of the pair current is constrained by the manifestly gauge independent matrix elements.Comment: 15 pages, incl. 3 figures, to be published Phys. Rev.

FSH treatment improves sperm DNA damage in men with idiopathic infertility carriers of the FSH receptor p.N680S homozygous N genotype: an interim analysis

Study question: To assess whether in men with idiopathic infertility, the sperm DNA fragmentation (sDF) improves depending on the FSH receptor (FSHR) genotype as assessed by the non-synonymous polymorphisms (SNP) rs6166 (wild type or p.N680S). Summary answer: FSH treatment improves sDF in a subgroup of idiopathic infertile men, although 40% of these men do not show any significant improve- ment. The response of sDF, a surrogate marker of sperm quality, together with the evaluation of FSHR SNP p.N680S might be useful to predict the response to FSH treatment. What is known already: FSH is fundamental for spermatogenesis and is em- pirically used to treat male idiopathic infertility. Several studies suggest that sDF could be a candidate predictor of response to FSH treatment, in terms of probability to conceive. Furthermore, it is widely accepted that the FSHR SNP p.N680S influences ovarian response in women and testicular volume in men. Study design, size, duration: Multicenter, longitudinal, prospective, open-la- bel, two-arms clinical trial. Subjects enrolled were idiopathic infertile men and received 150 IU of recombinant FSH (Gonal f®) every other day for 12 weeks and were then followed-up for further 12 weeks after FSH-withdrawal. Patients were evaluated at baseline and at the end of the two phases. Participants/materials, setting, methods: Eighty-eight men with idiopathic male infertility carrier of the homozygous FSHR p.N680S N or S genotype, FSH 15%, were enrolled. 66 patients completed the sDF analysis. sDF was centrally evaluated by TUNEL/PI assay coupled to flow cy- tometry, resolving two different sperm populations, namely: PIbrighter and PIdimmer. Main results and the role of chance: Thirty-seven men (56%) were carriers of the p.N680S homozygous-N and 29 (44%) of the homozygous-S genotype, respectively. Total sDF (PIbrighter + PIdimmer) was significantly lower at the end of the study in patients carriers of the p.N680S-N allele than patients carri- ers of p.N680S-S allele (p = 0.008). Only in patients carriers of the p.N680S-N allele, total sDF decreased significantly from baseline to the end of the study (p = 0.021) and this decrease was entirely sustained by the sperm population containing vital sperms (i.e., PIbrighter fraction) (p = 0.008). PIdimmer frac- tion, including only non-vital sperms, was significantly higher in patients car- riers of the p.N680S-S allele than in carriers of N allele (p = 0.018). Total sDF was inversely related to total sperm number (p = 0.020) and progressive sperm motility (p = 0.014). Limitations, reason for caution: The statistical power of the results obtained so far is 86.9%, with alpha-error 0.05. This is an interim-analysis. Wider implications of the findings: The study suggests that FSH treatment induces a significant improvement of total sDF in men carriers of the p.N680S homozygous N allele. This sDF decrease awaits confirmation, since the study will be completed by June 2015. Study funding/competing interest(s): Funding by commercial/corporate company(ies) – The study was supported by unrestricted grant by Merck Serono. Trial registration number: EudraCT number 2010-020240-35. Keywords: FSH treatment, male infertility, Sperm-DNA fragmentatio

Consistent Treatment of Relativistic Effects in Electrodisintegration of the Deuteron

The influence of relativistic contributions to deuteron electrodisintegration is systematically studied in various kinematic regions of energy and momentum transfer. As theoretical framework the equation-of-motion and the unitarily equivalent S-matrix approaches are used. In a (p/M)-expansion, all leading order relativistic $\pi$-exchange contributions consistent with the Bonn OBEPQ model are included. In addition, static heavy meson exchange currents including boost terms, $\gamma\pi\rho/\omega$-currents, and $\Delta$-isobar contributions are considered. Sizeable effects from the various relativistic two-body contributions, mainly from $\pi$-exchange, have been found in inclusive form factors and exclusive structure functions for a variety of kinematic regions.Comment: 41 pages revtex including 15 postscript figure