The Measurement of the Stratum Corneum Reservoir. A Predictive Method for In Vivo Percutaneous Absorption Studies: Influence of Application Time

The relation existing in vivo between the reservoir function of the stratum corneum following a 30-mm application time and the total percutaneous absorption of molecules applied for a longer time was studied on hairless rats. One thousand nanomoles of 4 radiolabeled molecules (theophylline, nicotinic acid, acetyl salicylic acid, benzoic acid) were applied on 1 cm2 of back skin for 0.5, 2, 4 and 6 h. The total recovery in excreta and the whole animal body were measured 4 days later in order to determine the level of absorption. A direct proportionality (r = 0.99) between the total percutaneous absorption of these compounds and the duration of their application was observed. This suggests that a constant flux of penetration does exist in vivo. The reservoir function of the stratum corneum was measured by successive stripping of the treated area. Following a 30-mm application, a strict correlation (r = 0.99) between the total amounts of molecules penetrated in 4 days and the amounts found in the reservoir of the horny layer was demonstrated.All together these findings show that the simple knowledge of the reservoir effect of the stratum corneum for a molecule applied for 30 mm allows the predictive assessment of its total penetration resulting from various times of application

RÉGIMES DE RETRAITE, INÉGALITÉS DE REVENU ET REDISTRIBUTION AU MAGHREB

Les systèmes de retraite du Maghreb ont des effets contradictoires sur la répartition des revenus des assurés sociaux. Ils ont tendance à amplifier l’écart entre salariés du public et du privé, mais à l’inverse à resserrer l’éven-tail des revenus à l’intérieur de chaque régime. Ils opèrent une redistribution horizontale au profit des familles par les pensions au profit des survivants. Entre générations, les vieux retraités sont défavorisés par rapport aux jeunes retraités et des dispositifs temporaires de retraite anticipée créent des inéquités. L’inégalité la plus forte oppose les assurés aux non assurés dans la mesure où les systèmes de retraite ne couvrent qu’une fraction minoritaire de la population âgée. Abstract - The North African pension systems have contradictory effects on the income distribution of insured persons. These systems tend to increase the gap between public and private sector employees. Conversely, they tend to narrow the income range within each system. They lead to horizontal redistribution to the benefit of families thanks to pensions paid to survivor. Among pensioners, the older pensioners are at a disadvantage compared with the younger. Moreover, temporary plans of early retirement increase those inequalities. The strongest inequality however is between insured and non-insured persons due to the fact that pension systems cover only a small proportion of the old population.SYSTÈMES DE RETRAITE, INÉGALITÉS DE REVENU, MAGHREB

Prophylaxis after Exposure to Coxiella burnetii

Postexposure prophylaxis may avert Q fever illness and death when the probability of exposure is above the population-specific threshold point

Low Penetrance, Broad Resistance, and Favorable Outcome of Interleukin 12 Receptor β1 Deficiency: Medical and Immunological Implications

The clinical phenotype of interleukin 12 receptor β1 chain (IL-12Rβ1) deficiency and the function of human IL-12 in host defense remain largely unknown, due to the small number of patients reported. We now report 41 patients with complete IL-12Rβ1 deficiency from 17 countries. The only opportunistic infections observed, in 34 patients, were of childhood onset and caused by weakly virulent Salmonella or Mycobacteria (Bacille Calmette-Guérin -BCG- and environmental Mycobacteria). Three patients had clinical tuberculosis, one of whom also had salmonellosis. Unlike salmonellosis, mycobacterial infections did not recur. BCG inoculation and BCG disease were both effective against subsequent environmental mycobacteriosis, but not against salmonellosis. Excluding the probands, seven of the 12 affected siblings have remained free of case-definition opportunistic infection. Finally, only five deaths occurred in childhood, and the remaining 36 patients are alive and well. Thus, a diagnosis of IL-12Rβ1 deficiency should be considered in children with opportunistic mycobacteriosis or salmonellosis; healthy siblings of probands and selected cases of tuberculosis should also be investigated. The overall prognosis is good due to broad resistance to infection and the low penetrance and favorable outcome of infections. Unexpectedly, human IL-12 is redundant in protective immunity against most microorganisms other than Mycobacteria and Salmonella. Moreover, IL-12 is redundant for primary immunity to Mycobacteria and Salmonella in many individuals and for secondary immunity to Mycobacteria but not to Salmonella in most

Specifications of the ACMG/AMP variant curation guidelines for hereditary hemorrhagic telangiectasia genes - ENG and ACVRL1

13 p.-1 fig.-3 tab.The 2015 ACMG/AMP standards and guidelines for interpretation of sequence variants are widely used by laboratories, including for variant curation of the hereditary hemorrhagic telangiectasia (HHT) genes. However, the need for gene- and disease-specific modifications and specifications of these general guidelines to optimize and standardize variant classification was recognized at the time of publication. With this goal, the ClinGen HHT variant curation expert panel was formed. Here, we describe our recommended HHT-specific variant classification criteria and the outcomes from pilot testing of 30 variants of the ENG and ACVRL1 genes. Eight of the original ACMG/AMP rules were determined to not be applicable for ENG- or ACVRL1-related HHT or were previously recommended by ClinGen for removal, two rules were unmodified, and the remaining 18 rules were modified according to HHT specifications or previous ClinGen general recommendations. This study demonstrates the importance of HHT-specific criteria in the optimization and standardization of HHT variant classification and conflicting classification resolution. © 2024 Desiree DeMille et al.The authors would like to acknowledge the support of the ClinGen Sequence Variant Interpretation Working Group and the Hemostasis/Thrombosis Clinical Domain Working Group, especially Kristy Lee. The authors would also like to acknowledge the participation of previous ClinGen HHT VCEP members: Pernille Tørring, Hans Kristian Ploos van Amstel, and Helen Arthur. CLS acknowledges support from the NIHR Imperial Biomedical Research Centre. LJ acknowledges support from Knut and Alice Wallenberg Foundation grant (2018.0042) and Swedish Research Council grant (2020-04936). CB was supported by Consejo Superior de Investigaciones Cientificas (CSIC) of Spain. CC, CO,and AS are funded by the Italian Ministry of University and Research, “Fondo Beneficenza Intesa Sanpaolo,” and Banca d’Italia. ClinGen is primarily funded by the National Human Genome Research Institute (NHGRI) with cofunding from the National Cancer Institute (NCI), through the following grants: Baylor/Stanford (U24HG009649), Broad/Geisinger(U24HG006834), and UNC/Kaiser (U24HG009650).Peer reviewe

Widening of the genetic and clinical spectrum of Lamb-Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency

Purpose Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved. Methods Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types ofSOX5 alterations. Functional consequences of selected substitutions were investigated. Results Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated. Conclusions This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features

Clinical impact of a targeted next-generation sequencing gene panel for autoinflammation and vasculitis.

BACKGROUND: Monogenic autoinflammatory diseases (AID) are a rapidly expanding group of genetically diverse but phenotypically overlapping systemic inflammatory disorders associated with dysregulated innate immunity. They cause significant morbidity, mortality and economic burden. Here, we aimed to develop and evaluate the clinical impact of a NGS targeted gene panel, the "Vasculitis and Inflammation Panel" (VIP) for AID and vasculitis. METHODS: The Agilent SureDesign tool was used to design 2 versions of VIP; VIP1 targeting 113 genes, and a later version, VIP2, targeting 166 genes. Captured and indexed libraries (QXT Target Enrichment System) prepared for 72 patients were sequenced as a multiplex of 16 samples on an Illumina MiSeq sequencer in 150bp paired-end mode. The cohort comprised 22 positive control DNA samples from patients with previously validated mutations in a variety of the genes; and 50 prospective samples from patients with suspected AID in whom previous Sanger based genetic screening had been non-diagnostic. RESULTS: VIP was sensitive and specific at detecting all the different types of known mutations in 22 positive controls, including gene deletion, small INDELS, and somatic mosaicism with allele fraction as low as 3%. Six/50 patients (12%) with unclassified AID had at least one class 5 (clearly pathogenic) variant; and 11/50 (22%) had at least one likely pathogenic variant (class 4). Overall, testing with VIP resulted in a firm or strongly suspected molecular diagnosis in 16/50 patients (32%). CONCLUSIONS: The high diagnostic yield and accuracy of this comprehensive targeted gene panel validate the use of broad NGS-based testing for patients with suspected AID

Deir el-Médina

La mission a débuté plus tard que prévu, car les autorisations de la Sécurité ont été délivrées fin janvier, deux semaines après la date du 15 janvier fixée pour l’ouverture de la mission. Faute de temps, certaines équipes n’ont pas réussi à atteindre leurs objectifs. La mission a poursuivi les travaux engagés en 2018 axés sur l’étude et la restauration des tombes de la nécropole de l’ouest et du mobilier conservé dans les magasins du site. Quatre équipes sont intervenues dans les TT 2, TT 2B..