Disruption of spermatogenesis in testicular adult Wistar rats after short-term exposure to high dose of glyphosate based-herbicide: Histopathological and biochemical changes.

Glyphosate is an endocrine disruptor and can act on the activity of certain enzymes of metabolism subsequently altering some functions such as reproduction. The goal of the present study is to evaluate the involvement of glyphosate based-herbicide (GBH) in spermatogenesis disruption and to investigate which cells of the adult Wistar rat testis are most affected by short-term exposure to GBH. Treated groups received a diluted solution of GBH orally for 21 days (D1: 102.5 mg/Kg; D2: 200 mg/Kg; D3: 400 mg/Kg). The control group (C) received water in the same manner. Hormone levels, oxidative stress markers were evaluated, histological and morphometric analysis were performed, AR and p53 expression was conducted. Seminiferious epithelium sloughing associated to erosion of Sertoli and spermatogonia from the basement of the seminiferous tubules, with intraluminal exfoliated cells among with immature spermatids were observed. A significant change in morphometric measurement and significant decrease in AR expression in Sertoli cells were noted for all treated groups. A significant increase in NO level and p53 expression in Leydig cells were showed for animals treated with 200 and 400 mg/kg BW/day. These data demonstrate that short-term exposure to high doses of GBH has led to a disruption of certain parameters that could disturb spermatogenesis. The treatment showed that both Leydig and Sertoli cells are affected in the same manner by GBH, the activation of p53 expression in both Leydig cells and peritubular myloid cells nuclei, and the reduction in AR expression in Sertoli cells, which resulted in important testicular damage.

Atypical hemolytic and uremic syndrome in Algeria: diagnostic difficulties and therapeutic constraints / Syndrome hémolytique et urémique atypique en Algérie : difficultés diagnostiques et contraintes thérapeutiques

Atypical Hemolytic Uremic Syndrome (aHUS) is a systemic disease due to dysregulation of the alternate complement pathway, mortality is estimated at 10% and more than 50% of patients progress to end-stage renal disease. The aim of this study was to summarize the clinical data and biological results as well as the evolution and management of patients with aHUS seen over a period of four years in one specialized department in Algeria. Our study was observational and longitudinal. The inclusion criteria were: the clinical-biological triad of aHUS and age ≤ 16 years. The type of treatment, the presence of complement mutation or anti-complement factor autoantibodies were not eligibility conditions. On inclusion and every six months, demographic data, clinical and biological history and results after treatment were collected prospectively. Our workforce consisted of 21 children with aHUS. Thirteen patients benefited from a complement study; among them, 7 had complement abnormalities. Eleven children had familial HUS; among them 8 died and 6 were less than one year old. Plasma exchanges were performed in two children. Six patients received eculizumab, with an average age of 3.6 years. After the acute phase, 9 children recovered their kidney function, one child had developed a chronic kidney disease (CKD), and 11 died, among them 8 belong to aHUS families. Fifty percent of deaths occurred in the first 3 months. At 2 years of evolution, out of 7 children having reached this stage, five had renal sequelae and four of them had CKD. The severe prognosis of this disease makes early diagnosis and treatment essential.

Le syndrome hémolytique et urémique atypique (SHUa) est une maladie systémique due à une dérégulation de la voie alterne du complément. La mortalité est estimée à 10 % et plus de 50 % des patients évoluent vers l'insuffisance rénale terminale. Le but de la présente étude était de résumer les données cliniques et les résultats biologiques ainsi que l'évolution et la prise en charge des patients atteints de SHUa vus sur une durée de quatre ans dans un service spécialisé en Algérie. Notre étude était observationnelle et longitudinale. Les critères d'inclusion étaient : la triade clinico-biologique du SHUa et l'âge ≤ 16 ans. Le type de traitement, la présence de mutation du complément ou d'auto-anticorps anti-facteur du complément ne constituaient pas des conditions d'éligibilité. À l'inclusion et tous les six mois, les données démographiques, l'histoire clinique, biologique et les résultats après traitement étaient collectés prospectivement. Notre effectif était formé de 21 enfants avec SHUa. Treize patients ont bénéficié d'une étude du complément ; parmi eux sept avaient des anomalies du complément. Onze enfants avaient un SHU familial ; parmi eux huit sont décédés et six avaient moins d'un an. Des échanges plasmatiques ont été réalisés chez deux enfants. Six patients ont bénéficié d'éculizumab, avec un âge moyen de 3,6 ans. Après la phase aiguë, neuf enfants avaient récupéré leur fonction rénale, un enfant avait gardé une insuffisance rénale chronique (IRC), et 11 enfants étaient décédés dont huit appartenaient à des familles de SHUa. Cinquante pourcent des décès étaient survenus durant les trois premiers mois. À deux ans d'évolution, sur sept enfants ayant atteint ce stade, cinq avaient des séquelles rénales et quatre d'entre eux étaient en IRC. Le pronostic sévère de cette maladie rend la précocité du diagnostic et de la prise en charge primordiales.

Lung function data of North-African patients with rheumatoid arthritis: a comparative study between anti-citrullinated peptides antibodies positive and negative patients.

INTRODUCTION: Although lung damages are among the leading causes of death from Rheumatoid Arthritis (RA), few studies have assessed the spirometric and plethysmographic data and profile of patients with RA, particularly those with Anti-Citrullinated Peptides Antibodies Positive (ACPA+). AIM: To compare the spirometric and plethysmographic data and profile of RA patients ACPA+ and ACPA-. METHODS: This comparative pilot study was performed over a two-year period (2018-2019) in Algiers (Algeria). The study included two groups of RA non-smoker patients: 26 ACPA+ and 33 ACPA-.RA was diagnosed according to the ACR/EULAR 2010 RA classification criteria. Spirometry and plethysmography were performed. The following definitions were applied: Obstructive Ventilatory Impairment (OVI): FEV1/FVC z-score < -1.645; Restrictive Ventilatory Impairment (RVI): Total Lung Capacity (TLC) z-score< -1.645; Mixed Ventilatory Impairment (MVI): FEV1/FVC z-score < -1.645 and TLC z-score < -1.645; lung- hyperinflation: residual volume z-score > +1.645; Nonspecific Ventilatory Impairment (NSVI): FEV1z-score < -1.645, FVC z-score < -1.645, FEV1 /FVC z-score ≥ -1.645, and TLC z-score ≥ -1.645. RESULTS: The ACPA-group was older than the ACPA+ one by ~ 10 years (63±13 vs. 53±12 years, p=0.0025; respectively). The ACPA+ and ACPA-groups included comparative percentages of patients having RVI, MVI, and NSVI (23.1 vs. 45.5%, p=0.0745; 3.8 vs. 3.0%, p=0.8654; and 7.7 vs. 6.1%, p=0.8086; respectively). Compared to the ACPA- group, the ACPA+ group included a higher percentage of patients having OVI and lung-hyperinflation (9.1 vs. 38.5%, p=0.0069; 9.1 vs. 42.3%, p=0.0029; respectively). CONCLUSION: Compared to the ACPA-group, the ACPA+ one had more lung-hyperinflation and OVI, and comparative percentages of RVI, MVI, and NSVI.

Clinical, immunological, molecular and therapeutic findings in monogenic immune dysregulation diseases: Middle East and North Africa registry.

Monogenic immune dysregulation diseases (MIDD) are caused by defective immunotolerance. This study was designed to increase knowledge on the prevalence and spectrum of MIDDs, genetic patterns, and outcomes in Middle East and North Africa (MENA). MIDD patients from 11 MENA countries (Iran, Turkey, Kuwait, Oman, Algeria, Egypt, United Arab Emirates, Tunisia, Jordan, Qatar, and Azerbaijan) were retrospectively evaluated. 343 MIDD patients (58% males and 42% female) at a median (IQR) age of 101 (42-192) months were enrolled. The most common defective genes were LRBA (23.9%), LYST (8.2%), and RAB27A (7.9%). The most prevalent initial and overall manifestations were infections (32.2% and 75.1%), autoimmunity (18.6% and 41%), and organomegaly (13.3% and 53.8%), respectively. Treatments included immunoglobulin replacement therapy (53%), hematopoietic stem cell transplantation (HSCT) (14.3%), immunosuppressives (36.7%), and surgery (3.5%). Twenty-nine (59.2%) patients survived HSCT. Along with infectious complications, autoimmunity and organomegaly may be the initial or predominant manifestations of MIDD.

Algerian Registry for Inborn Errors of Immunity in Children: Report of 887 Children (1985-2021).

INTRODUCTION: Inborn errors of immunity (IEI) represent a heterogeneous large group of genetic disorders characterized by susceptibility of affected individuals to recurrent infections, autoimmune/inflammatory diseases, allergy, and malignancy. We aimed to report for the first time the Algerian registry for IEI in children. METHODS: We described the characteristics of IEI in Algerian children from the data collected in the Algerian registry for IEI between 1985 and 2021. RESULTS: Over a period of 37 years, we included 887 children (530 male, 59.6%) with a mean age at diagnosis of 3.23 years and a mean diagnosis delay of 2 years. The prevalence rate was estimated at 1.97/100,000 inhabitants or 5.91/100,000 children. The parental consanguinity was found in 52.6%. The most prevalent category was combined immunodeficiencies (CID) (35.5%), followed by predominantly antibody deficiencies (24.5%) and CID with syndromic features (18.3%). The most predominant diseases were severe CID (134 cases), MHC II deficiency (99 cases), agammaglobulinemia (82 cases), common variable immunodeficiency (78 cases), hyper IgE syndromes (61 patients), ataxia-telangiectasia (46 patients), Wiskott-Aldrich syndrome (40 patients) and chronic granulomatous disease (39 cases). The clinical presentation was dominated by lower respiratory tract infections (69%), failure to thrive (38.3%), and chronic diarrhea (35.2%). Genetic analysis was performed in 156 patients (17.6%). The global mortality rate was 28.4% mainly caused by CID. CONCLUSION: This is the first report of the Algerian registry for IEI in children. Data is globally similar to that of the Middle East and North African (MENA) registries with high consanguinity, predominance of CID, and significant mortality. This registry highlights the weak points that should be improved in order to provide better patient care.

Consensus Middle East and North Africa Registry on Inborn Errors of Immunity.

BACKGROUND: Inborn errors of immunity (IEIs) are a heterogeneous group of genetic defects of immunity, which cause high rates of morbidity and mortality mainly among children due to infectious and non-infectious complications. The IEI burden has been critically underestimated in countries from middle- and low-income regions and the majority of patients with IEI in these regions lack a molecular diagnosis. METHODS: We analyzed the clinical, immunologic, and genetic data of IEI patients from 22 countries in the Middle East and North Africa (MENA) region. The data was collected from national registries and diverse databases such as the Asian Pacific Society for Immunodeficiencies (APSID) registry, African Society for Immunodeficiencies (ASID) registry, Jeffrey Modell Foundation (JMF) registry, J Project centers, and International Consortium on Immune Deficiency (ICID) centers. RESULTS: We identified 17,120 patients with IEI, among which females represented 39.4%. Parental consanguinity was present in 60.5% of cases and 27.3% of the patients were from families with a confirmed previous family history of IEI. The median age of patients at the onset of disease was 36 months and the median delay in diagnosis was 41 months. The rate of registered IEI patients ranges between 0.02 and 7.58 per 100,000 population, and the lowest rates were in countries with the highest rates of disability-adjusted life years (DALY) and death rates for children. Predominantly antibody deficiencies were the most frequent IEI entities diagnosed in 41.2% of the cohort. Among 5871 patients genetically evaluated, the diagnostic yield was 83% with the majority (65.2%) having autosomal recessive defects. The mortality rate was the highest in patients with non-syndromic combined immunodeficiency (51.7%, median age: 3.5 years) and particularly in patients with mutations in specific genes associated with this phenotype (RFXANK, RAG1, and IL2RG). CONCLUSIONS: This comprehensive registry highlights the importance of a detailed investigation of IEI patients in the MENA region. The high yield of genetic diagnosis of IEI in this region has important implications for prevention, prognosis, treatment, and resource allocation.

Diagnostic and Predictive Contribution of Autoantibodies Screening in a Large Series of Patients With Primary Immunodeficiencies.

Objectives: To evaluate the diagnostic and predictive contribution of autoantibodies screening in patients with primary immunodeficiencies (PIDs). Methods: In the present study, PID patients and healthy controls have been screened for 54 different autoantibodies. The results of autoantibodies screening in PID patients were correlated to the presence of autoimmune diseases. Results: A total of 299 PID patients were included in this study with a predominance of antibody deficiencies (27.8%) followed by immunodeficiencies affecting cellular and humoral immunity (26.1%) and complement deficiencies (22.7%). Autoimmune manifestations were present in 82 (27.4%) patients. Autoimmune cytopenia (10.4%) was the most common autoimmune disease followed by gastrointestinal disorders (10.0%), rheumatologic diseases (3.7%), and endocrine disorders (3.3%). Autoantibodies were found in 32.4% of PID patients and 15.8% of healthy controls (P < 0.0005). Anti-nuclear antibodies (ANA) (10.0%), transglutaminase antibody (TGA) (8.4%), RBC antibodies (6.7%), anti-smooth muscle antibody (ASMA) (5.4%), and ASCA (5.0%) were the most common autoantibodies in our series. Sixty-seven out of the 82 patients with autoimmune manifestations (81.7%) were positive for one or more autoantibodies. Eleven out of the 14 patients (78.6%) with immune thrombocytopenia had positive platelet-bound IgM. The frequencies of ASCA and ANCA among patients with IBD were 47.4% and 21.0% respectively. All patients with celiac disease had TGA-IgA, while six out of the 11 patients with rheumatologic diseases had ANA (54.5%). Almost one third of patients (30/97) with positive autoantibodies had no autoimmune manifestations. ANA, rheumatoid factor, ASMA, anti-phospholipid antibodies and ANCA were often detected while specific AID was absent. Despite the low positive predictive value of TGA-IgA and ASCA for celiac disease and inflammatory bowel disease respectively, screening for these antibodies identified undiagnosed disease in four patients with positive TGA-IgA and two others with positive ASCA. Conclusion: The present study provides valuable information about the frequency and the diagnostic/predictive value of a large panel of autoantibodies in PIDs. Given the frequent association of some AIDs with certain PIDs, screening for corresponding autoantibodies would be recommended. However, positivity for autoantibodies should be interpreted with caution in patients with PIDs due to their low positive predictive value.

Severity factors in Algerian patients hospitalized for COVID-19.

INTRODUCTION: Determining the profile of COVID-19 patients with low pulsed hemoglobin saturation in oxygen (SpO2) could help clinicians identify those with a poor prognosis. AIM: To identify and to compare the clinical, biological and radiological data of Algerian patients hospitalized for COVID-19 and divided according to the SpO2 measured at admission, at rest, and in ambient air. METHODS: A prospective study was carried out on Algerian patients hospitalized for COVID-19 during the period from March 9 to April 30, 2020. The general characteristics of the patients and the clinical, biological and radiological data were determined. RESULTS: 86 patients were included in the study [G1: SpO2 >95% (n=51) and G2: SpO2 ≤95% (n=35)]. Compared to G1, G2 was older (48±14 vs. 61±12 years, p=0.0001), included more patients aged ≥ 50 years (37.2 vs. 80.0%, p=0.0001), having an arterial-hypertension (21.6 vs. 45.7%, p=0.0180), a cancer (0.0 vs. 14.3%, p=0.0054), an anemia (25.6 vs. 56.3%, p=0.0069), a leukocytosis (4.7 vs. 21.9%, p=0.0236), a biological inflammatory syndrome (82.5 vs. 100%, p=0.0142), a hyper-uremia (7.0 vs. 37.5%, p=0.0185), a hyper-creatininaemia (4.7 vs. 18.8%, p=0.0356), a tissue damage (41.0 vs. 66.7%, p=0.0341), a diffuse ground-glass opacity (52.0 vs. 71.4%, p=0.0397), band condensations (30.0 vs. 54.3%, p=0.0244), a severe extension (2.0 vs. 25.7%, p=0.0008), and included fewer patients who complained from diarrhea (49.0 vs. 22.9%, p=0.0145), having a nodular ground-glass (66.0 vs. 40.0%, p=0.0177) and a slight extension (78.0 vs. 40.0%, p=0.0004). CONCLUSION: Criteria associated with low SpO2 in hospitalized COVID-19 patients were advanced age, a history of arterial-hypertension and cancer, high frequencies of certain biological abnormalities or radiological signs. The diarrhea symptom, the radiological appearance of nodular ground glass, and a slight extension of the radiological lesions appear as protective elements.

[Association of markers of rheumatoid arthritis in lupus. Is it a rhupus?] / Association des marqueurs de la polyarthrite rhumatoïde chez les lupiques. S'agit-il d'un rhupus?

Anti-citrullinated cyclic peptide antibodies (ACPA) were initially considered very specific for the diagnosis of rheumatoid arthritis (RA), and can predict the prognosis of the disease. However, these antibodies can be detected in other autoimmune diseases, including systemic lupus erythematosus (SLE), the most common manifestation of which is inflammatory arthritis, which is often found in early-stage rheumatoid arthritis. The aim of our study is to evaluate the prevalence of ACPA antibodies and to analyze the profiles of their associations with autoantibodies specific to lupus, in order to look for a possible rhupus overlap syndrome in our patients. This is a retrospective study, carried out at the immunology unit, at Blida University Hospital, Algeria, involving 96 lupus patients, diagnosed according to the criteria of the American college of rheumatology (ACR). ACPA have been identified by the ELISA technique. ACPA was positive in 14,56% of our patients, whereas anti-DNA, anti-Sm and rheumatoid factor (RF) autoantibodies were positive, respectively in 47.09%, 35.41%, and in 26.04% of our patients. In addition, the presence of ACPA with anti DNA was found in 12.5% of patients. Of the 14 with ACPA+, 57.14% had arthritis. Our results confirm that ACPA auto-antibodies do not represent a pathognomonic criterion of RA. This sometimes makes the differential diagnosis with lupus difficult especially at the beginning of the disease.

Profil clinique, biologique et radiologique des patients Algériens hospitalisés pour COVID-19: données préliminaires.

INTRODUCTION: Aucune étude antérieure n'a élaboré le profil des patients Algériens hospitalisés pour COVID-19. L'objectif de cette étude était de déterminer le profil clinique, biologique et tomodensitométrique des patients Algériens hospitalisés pour COVID-19. MÉTHODES: Une étude prospective était menée auprès des patients hospitalisés pour COVID-19 (période: 19 mars-30 avril 2020). Les données cliniques, biologiques et radiologiques, le type de traitement reçu et la durée de l'hospitalisation étaient notés. RÉSULTATS: Le profil clinique des 86 patients atteints de COVID-19 était un homme non-fumeur, âgé de 53 ans, qui était dans 42% des cas en contact avec un cas suspect/confirmé de COVID-19 et ayant une comorbidité dans 70% des cas (hypertension artérielle, diabète sucré, pathologie respiratoire chronique et allergie, cardiopathie). Les plaintes cliniques étaient dominées par la triade «asthénie-fièvre-toux¼ dans plus de 70% des cas. Les anomalies biologiques les plus fréquentes étaient: syndrome inflammatoire biologique (90,1%), basocytémie (70,8%), lymphopénie (53,3%), augmentation de la lactico-deshydrogénase (52,2%), anémie (38,7%), augmentation de la phosphokinase (28,8%) et cytolyse hépatique (27,6%). Les signes tomodensitométriques les plus fréquents étaient: verre dépoli (91,8%), condensations alvéolaires (61,2%), verre dépoli en plage (60,0%), et verre dépoli nodulaire (55,3%). Un traitement à base de «chloroquine, azithromycine, zinc, vitamine C, enoxaparine, double antibiothérapie et ± corticoïdes¼ était prescrit chez 34,9% des patients. La moyenne de la durée d'hospitalisation était de 7±3 jours. CONCLUSION: La connaissance des profils des formes modérées et sévères du COVID-19 contribuerait à faire progresser les stratégies de contrôle de l'infection en Algérie.

Immunodominant IgE Epitopes of Der p 5 Allergen.

BACKGROUND: Der p 5 is an important allergen of Dermatophagoides pteronyssinus that plays a key role in allergic airway diseases. Its three dimensional structure (PDB 3MQ1) consists of three anti-parallel α-helices arranged in a helical bundle. Aggregation of Der p5 can modulate its allergenicity. This study aimed to identify the key residues of IgE binding epitopes of Der p 5. METHODS: IgE binding epitopes of Der p 5 were characterized as follow. An in silico prediction of the epitope was performed with the help of SEPPA program. We also made a mapping of the epitope by using an overlapping library of peptides that encompass the sequence of mature Der p 5. Finally, an alanine scanning mutagenesis allowed us to define the key residues of the allergen involved in its interaction with IgE. The integrity of the structure of the different protein's mutants was assessed by far UV circular dichroism. RESULTS: The presented data indicate that the major epitope sequence of Der p 5 is 90DRLMQRKDLDIFEQYNLEM108. Residues L98, D99, I100, F101, E102 and Y104 appear to be important for IgE binding. CONCLUSION: This study highlighted the residues of Der p 5 essential for IgE binding. The identification of the major residues epitope of Der p 5 allergen may participate in the selection and engineering of new hypoallergens used in immunotherapy.

Functional analysis of splicing mutations and of an exon 2 polymorphic variant of SERPING1/C1NH.

Several sequence changes have been reported in hereditary angioedema patients in intron 2 of the SERPING1/C1NH gene, but their consequences on splicing have not been determined. We examined in cell transfection assays the consequences at the mRNA level of splicing mutations affecting either the +3 or the +5 donor site positions, or the conserved canonical splicing signals of exon 2, using mutant C1 inhibitor minigene constructs. Both intron 2 mutations, c.51+3A>G and c.51+5G>A, resulted in marked exon 2 skipping in these assays, but also yielded a large fraction of normal transcripts. We show that the c.51+3A>G mutation cosegregates with low C1 inhibitor protein levels in one family. Moreover, the second base of exon 2 of the SERPING1/C1NH gene is the site of a polymorphic variant, which has been proposed as a modifier of disease severity. We found that the c.-21C allele at this position yields low but significant levels of exon 2 skipping in transfected Hep G2 or Hep 3B cells, suggesting that this allele may contribute, at the RNA level, to more severe forms of angioedema. Furthermore, we describe a previously not detected alternative splicing of exon 3, found in peripheral blood cell mRNA but not in the liver or in hepatoma cell lines and we show that, in cultured monocytes of a patient carrying the c.51+3A>G mutation, this alternative splicing is shifted from exon 3 exclusion to skipping of both exons 2 and 3. The latter finding suggests that mutations affecting splicing of exon 2 of the SERPING1/C1NH gene may have different consequences in monocytes versus other cell types.