Homozygous mutation in the prokineticin-receptor2 gene (Val274Asp) presenting as reversible Kallmann syndrome and persistent oligozoospermia: case report.

Prokineticin 2 (Prok2) or prokineticin-receptor2 (Prok-R2) gene mutations are associated with Kallmann syndrome (KS). We describe a new homozygous mutation of Prok-R2 gene in a man displaying KS with an apparent reversal of hypogonadism. The proband, offspring of consanguineous parents, presented at age 19 years with absent puberty, no sense of smell, low testosterone and gonadotrophin levels. Magnetic resonance imaging showed olfactory bulb absence. The patient achieved virilization and spermatogenesis with gonadotrophin administration. Two years after discontinuing hormonal therapy, he maintained moderate oligozoospermia and normal testosterone levels. Prok2 and Prok- R2 gene sequence analyses were performed. The proband had a homozygous mutation in Prok-R2 exon 2 that harbours the c.T820>A base substitution, causing the introduction of an aspartic acid in place of valine at position 274 (Val274Asp). His mother had the same mutation in heterozygous state. This report describes a novel homozygous mutation of Prok-R2 gene in a man with variant KS, underlying the role of Prok-R2 gene in the olfactory and reproductive system development in humans. Present findings indicate that markedly delayed activation of gonadotrophin secretion may occur in some KS cases with definite gene defects, and that oligozoospermia might result from a variant form of reversible hypogonadotrophic hypogonadism

La traduction dans une perspective de genre. Enjeux politiques, éditoriaux et professionnels

Cet ouvrage s’inscrit dans le cadre théorique de la traduction conçue dans une perspective de genre, un contexte qui sous-tend que la langue n’est jamais neutre, et que tout acte de langage a une dimension politique et des retombées du point de vue culturel et social. Les essais qu’il propose abordent quelques sujets majeurs dans ce domaine. Le livre s’ouvre avec une réflexion de nature générale sur la circulation difficile au niveau transnational de la terminologie et de certains concepts des études de genre ainsi que sur les problèmes posés par leur traduction. Dans le cadre d’une réflexion attentive à la dimension professionnelle, l’expérience de Barbara Bray, médiatrice interculturelle pour la BBC, est ensuite présentée comme un acte politique d’engagement d’une traductrice d’exception. La question du “gender bias” dans la traduction automatique, un enjeu qu’il est désormais indispensable d’affronter, fait l’objet d’une analyse visant à en cerner les causes et à suggérer des solutions possibles. Ces essais sont suivis d’études qui se penchent sur l’édition de textes littéraires traduits et s’intéressent en particulier aux enjeux de la traduction du langage non binaire, ainsi qu’aux politiques éditoriales de diverses maisons d’édition de littérature jeunesse. Ces deux domaines, qui n’ont été abordés par les études de genre que très récemment, ouvrent des perspectives de recherche nouvelles et fécondes

Brain Plasticity in Charcot-Marie-Tooth Type 1A Patients? A Combined Structural and Diffusion MRI Study

Central nervous system involvement has been described in peripheral neuropathies, including different forms of Charcot-Marie-Tooth (CMT) disease. The aim of our study was to systematically investigate possible brain structural modifications in CMT1A patients, using volumetric MRI, and diffusion tensor imaging (DTI). In this prospective cross-sectional study, from May 2017 to May 2019, we acquired 3T MRI brain scans of genetically confirmed CMT1A patients and age- and sex-comparable healthy controls. Patients also underwent clinical and electrophysiological examinations assessing motor and sensory domains. Voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) analyses were performed using a non-parametric approach based on permutations, including age and sex (and total intracranial volume for VBM) as nuisance covariates. When between-group differences emerged at VBM or TBSS analyses, the first eigenvariate was extracted from the cluster and its age- and sex-adjusted standardized residuals tested for correlation with clinical and electrophysiological variables. Twenty CMT1A patients (34.5 ± 11.1 years; M/F:11/9) were enrolled, along with 20 healthy controls (30.1 ± 10.2 years; M/F:11/9). The VBM analysis revealed clusters of significantly increased GM volume in CMT1A patients compared to healthy controls, encompassing the bilateral cerebellar lobules III-VI and the left hippocampus (all ps = 0.04), with no differences in terms of DTI metrics at the TBSS analysis. A negative correlation (r = −0.502, p = 0.03) emerged between ulnar compound motor action potential and the z-scores corresponding to the right cerebellar cluster of augmented GM volume. Our data show evidence of structural reorganization in the brain of CMT1A patients, possibly reflecting neural plasticity mechanisms in response to peripheral nerve pathology and modulating the effect of axonal degeneration on functional impairment

FRI0153 ULTRA HIGH-RESOLUTION ULTRASOUND (UHFUS) OF LABIAL SALIVARY GLANDS: POTENTIAL APPLICATIONS IN PRIMARY SJÖGREN'S SYNDROME

Background:Major salivary gland ultrasonography has an established role in diagnosis and assessment of pSS. Nowadays, however, interest is also growing in last-generation ultra high resolution ultrasound (UHFUS) transducers, which can produce frequencies up to 70 MHz and achieve tissue resolution up to 30 μm, opening up new possibilities for the study labial salivary glands (LSG).Objectives:To investigate the usefulness of UHFUS in LSG ultrasound-guided biopsy and preoperative planning.Methods:Consecutive patients undergoing a LSG for clinically suspected pSS were included in this study from January 2018 to December 2019. UHFUS of LSG was performed by using VEVO MD, equipped with a 70 MHz probe, scanning first the central compartment of the inferior lip, and then both peripheral compartments. The following parameters were evaluated: distribution of the glands, parenchymal inhomogeneity (score 0-3, from normal to evident), and fibrosis. UHFUS imaging was used to help locate the LSG for the US-guided biopsy. The same expert pathologist calculated the surface area of gland sections examined, the LSG focus score (FS), the number of foci and evaluated the presence of ectopic germinal centers (GCs). Consecutive patients that had undergone a traditional LSG biopsy from December 2016 to December 2017 were included as controls.Results:We included a total of 249 patients with suspected pSS: 137 undergoing the UHFUS-guided LSGs and 112 the traditional LSG biopsy procedure. No demographic differences were observed between the two groups. No differences were also observed in the distribution of the final diagnosis. A diagnosis of pSS according the ACR 2016 criteria was made in 60/137 (43.8%) and 36/112 (32.1%) patients, respectively whereas a diagnosis of no-SS sicca was made in 44/137 (32.1%) and in 43/112 (38.4%) patients; the remaining diagnosis included secondary SS (4/137, 3% and 9/112, 8%) and undifferentiated connective tissue disease (UCTD) (29/137, 21.2%, and 24/112, 21.4%). With respect to no-SS sicca controls and UCTD patients, pSS patients presented higher UHFUS inhomogeneity scores in both central and peripheral labial compartments (p=0.001). There were no complications from the HUFUS-guided LSG biopsy. The mean glandular surface area obtained was significantly higher than the area obtained by traditional LSG biopsy procedure (7.4 ±4.0 mm2vs 6.3±3.7 mm2, p=0.02) thus facilitating the assessment of the FS. Interestingly, the latter showed a good correlation with the UHFUS inhomogeneity (r=0.509**, p=0.000).Conclusion:UHFUS of LSG appeared feasible and sensitive in pSS, potentially offering unique advantages in LSG ultrasound-guided biopsy.Disclosure of Interests:None declare

Translational development of an ADAMTS-5 antibody for osteoarthritis disease modification

SummaryObjective/MethodAggrecanase activity, most notably ADAMTS-5, is implicated in pathogenic cartilage degradation. Selective monoclonal antibodies (mAbs) to both ADAMTS-5 and ADAMTS-4 were generated and in vitro, ex vivo and in vivo systems were utilized to assess target engagement, aggrecanase inhibition and modulation of disease-related endpoints with the intent of selecting a candidate for clinical development in osteoarthritis (OA).ResultsStructural mapping predicts the most potent mAbs employ a unique mode of inhibition by cross-linking the catalytic and disintegrin domains. In a surgical mouse model of OA, both ADAMTS-5 and ADAMTS-4-specific mAbs penetrate cartilage following systemic administration, demonstrating access to the anticipated site of action. Structural disease modification and associated alleviation of pain-related behavior were observed with ADAMTS-5 mAb treatment. Treatment of human OA cartilage demonstrated a preferential role for ADAMTS-5 inhibition over ADAMTS-4, as measured by ARGS neoepitope release in explant cultures. ADAMTS-5 mAb activity was most evident in a subset of patient-derived tissues and suppression of ARGS neoepitope release was sustained for weeks after a single treatment in human explants and in cynomolgus monkeys, consistent with high affinity target engagement and slow ADAMTS-5 turnover.ConclusionThis data supports a hypothesis set forth from knockout mouse studies that ADAMTS-5 is the major aggrecanase involved in cartilage degradation and provides a link between a biological pathway and pharmacology which translates to human tissues, non-human primate models and points to a target OA patient population. Therefore, a humanized ADAMTS-5-selective monoclonal antibody (GSK2394002) was progressed as a potential OA disease modifying therapeutic

Determinants of Deep Gray Matter Atrophy in Multiple Sclerosis: A Multimodal MRI Study

Deep gray matter involvement is a consistent feature in multiple sclerosis. The aim of this study was to evaluate the relationship between different deep gray matter alterations and the development of subcortical atrophy, as well as to investigate the possible different substrates of volume loss between phenotypes. Seventy-seven patients with MS (52 with relapsing-remitting and 25 with progressive MS) and 41 healthy controls were enrolled in this cross-sectional study. MR imaging investigation included volumetric, DTI, PWI and Quantitative Susceptibility Mapping analyses. Deep gray matter structures were automatically segmented to obtain volumes and mean values for each MR imaging metric in the thalamus, caudate, putamen, and globus pallidus. Between-group differences were probed by ANCOVA analyses, while the contribution of different MR imaging metrics to deep gray matter atrophy was investigated via hierarchic multiple linear regression models. Patients with MS showed a multifaceted involvement of the thalamus and basal ganglia, with significant atrophy of all deep gray matter structures (P.001). In the relapsing-remitting MS group,WMlesion burden proved to be the main contributor to volume loss for all deep gray matter structures (P .006), with a minor role of local microstructural damage, which, in turn, was the main determinant of deep gray matter atrophy in patients with progressive MS (P .01), coupled with thalamic susceptibility changes (P .05). Our study confirms the diffuse involvement of deep gray matter in MS, demonstrating a different behavior between MS phenotypes, with subcortical GM atrophy mainly determined by global WM lesion burden in patients with relapsing-remitting MS, while local microstructural damage and susceptibility changes mainly accounted for the development of deep gray matter volume loss in patients with progressive MS

ps8 161 the disease burden in patients with longstanding systemic lupus erythematosus focus on health resource use and costs

Introduction As a consequence of increased SLE patients survival, patients with long disease duration represent a significant proportion of our cohorts. This study aims to evaluate health resource use and the 6 months costs in patients with SLE with long disease duration. Methods The economic evaluation was performed in terms of cost-of-illness analysis as part of a larger study enrolling SLE patients with at least 15 years of disease duration regularly followed at our unit. At enrollment, the following information were collected: disease activity (SLEDAI), organ damage (SLICC-DI score), comorbidities, treatment patterns; in addition to clinical data, patients were required to complete an ad-hoc questionnaire for the collection of facts relevant for the estimation of the economic dimension and covering the previous six-months. Such a time frame was considered to be appropriate as recall period. Direct health (drugs, hospitalizations, emergency visits, specialists visits, laboratory tests and instrumental examination) and non-health costs (transportation and accommodation) as well as indirect costs because of productivity loss were estimated. Results 51 adult patients with long disease duration were recruited (98% female, mean age 49±11 years, median disease duration 17 years, IQR 15–23). Median (IQR) SLEDAI score was 2 (0–4), median SLICC-DI was 1 (0–2). The median (IQR) direct health costs per patients over the previous 6 months resulted 410€ (201–1687); indirect costs because of productivity lost were 130€ (0–356). The median overall cost to the Society was 473€ (327–2148); the presence of comorbid conditions resulted associated with higher overall cost for the Society (552€ [327–1807] vs 264€ [94–1164] p=0.046); disease activity and damage at enrollment were not associated with costs increase in this cohort. Conclusions This cohort of patients with long lasting disease is characterised by low disease activity and mild organ damage; in this setting, the disease burden on the single patient and family is significant and the costs to the Society are influenced by the presence of comorbidities

Broadband detection of methane and nitrous oxide using a distributed-feedback quantum cascade laser array and quartz-enhanced photoacoustic sensing

Here we report on the broadband detection of nitrous oxide (N2O) and methane (CH4) mixtures in dry nitrogen by using a quartz-enhanced photoacoustic (QEPAS) sensor exploiting an array of 32 distributed-feedback quantum cascade lasers, within a spectral emission range of 1190−1340 cm−1 as the excitation source. Methane detection down to a minimum detection limit of 200 ppb at 10 s lock-in integration time was achieved. The sensor demonstrated a linear response in the range of 200−1000 ppm. Three different mixtures of N2O and CH4 in nitrogen at atmospheric pressure have been analyzed. The capability of the developed QEPAS sensor to selectively determine the N2O and CH4 concentrations was demonstrated, in spite of significant overlap in their respective absorption spectra in the investigated spectral range

Walk your talk: Real-world adherence to guidelines on the use of MRI in multiple sclerosis

(1) Although guidelines about the use of MRI sequences for Multiple Sclerosis (MS) diagnosis and follow-up are available, variability in acquisition protocols is not uncommon in everyday clinical practice. The aim of this study was to evaluate the real-world application of MS imaging guidelines in different settings to clarify the level of adherence to these guidelines. (2) Via an on-line anonymous survey, neuroradiologists (NR) were asked about MRI protocols and parameters routinely acquired when MS patients are evaluated in their center, both at diagnosis and followup. Furthermore, data about report content and personal opinions about emerging neuroimaging markers were also retrieved. (3) A total of 46 participants were included, mostly working in a hospital or university hospital (80.4%) and with more than 10 years of experience (47.9%). We found a relatively good adherence to the suggested MRI protocols regarding the use of T2-weighted sequences, although almost 10% of the participants routinely acquired 2D sequences with a slice thickness superior to 3 mm. On the other hand, a wider degree of heterogeneity was found regarding gadolinium administration, almost routinely performed at follow-up examination (87.0% of cases) in contrast with the current guidelines, as well as a low use of a standardized reporting system (17.4% of cases). (4) Although the MS community is getting closer to a standardization of MRI protocols, there is still a relatively wide heterogeneity among NR, with particular reference to contrast administration, which must be overcome to guarantee an adequate quality of patients’ care in MS