An immunohistochemical evaluation of C4d deposition in pediatric inflammatory liver diseases

C4d is a marker of the activated complement cascade used to assess the humoral component of rejection, mostly in kidney allograft transplants. The role of C4d deposition has recently been addressed in hepatic allograft but has never been tested in a series of inflammatory liver diseases without previous liver transplantation. The aim of this study was to compare the immunohistochemistry profile of C4d deposition in a pediatric population, between a cohort of patients with autoimmune hepatitis (AIH) and a series of patients with chronic viral hepatitis B or C. Immunohistochemical analysis was performed on 64 liver biopsies. C4d deposition was observed in 25 (83%) of 30 AIH biopsies examined, in 6 (40%) of 15 hepatitis C biopsies, and in 17 (89%) of 19 hepatitis B biopsies. No expression of C4d was observed in 4 noninflammatory liver specimens used as negative controls. In the AIH group, a staining of the periportal sinusoids was often observed, as well as focal periductal reinforcement. Centrolobular vein staining was observed in the 3 hepatitis groups with a higher frequency in viral hepatitis B biopsies. Regardless of the etiology, lymphoid aggregates demonstrated an accentuation of the staining. These results confirm a role for a humoral immune response in pediatric autoimmune as well as in viral hepatitis. The relative ratios of positive cases imply that this immunostaining does not represent a strong diagnostic criterion in the differentiation between viral hepatitis and AIH. However, differences in the pattern of the staining were observed, depending on the etiology of the disease. The high prevalence of C4d reactivity in viral hepatitis strongly suggests that C4d does not represent a useful marker in the differentiation between acute rejection and viral hepatitis relapse in liver transplants.     

A splice donor variant of GAS8 induces structural disorganization of the axoneme in sperm flagella and leads to nonsyndromic male infertility

Motile cilia and flagella are closely related organelles structured around a highly conserved axoneme whose formation and maintenance involve proteins from hundreds of genes. Defects in many of these genes have been described to induce primary ciliary dyskinesia (PCD) mainly characterized by chronic respiratory infections, situs inversus and/or infertility. In men, cilia/flagella-related infertility is usually caused by asthenozoospermia due to multiple morphological abnormalities of the sperm flagella (MMAF). Here, we investigated a cohort of 196 infertile men displaying a typical MMAF phenotype without any other PCD symptoms. Analysis of WES data identified a single case carrying a deleterious homozygous GAS8 variant altering a splice donor consensus site. This gene, also known as DRC4, encodes a subunit of the Nexin-Dynein Regulatory Complex (N-DRC), and has been already associated to male infertility and mild PCD. Confirming the deleterious effect of the candidate variant, GAS8 staining by immunofluorescence did not evidence any signal from the patient's spermatozoa whereas a strong signal was present along the whole flagella length in control cells. Concordant with its role in the N-DRC, transmission electron microscopy evidenced peripheral microtubule doublets misalignments. We confirm here the importance of GAS8 in the N-DRC and observed that its absence induces a typical MMAF phenotype not necessarily accompanied by other PCD symptoms.     

Recurrent Cellulitis Revealing Helicobacter cinaedi in Patient on Ibrutinib Therapy,France

Helicobacter cinaedi bacteremia caused recurring multifocal cellulitis in a patient in France who had chronic lymphocytic leukemia treated with ibrutinib. Diagnosis required extended blood culture incubation and sequencing of the entire 16S ribosomal RNA gene from single bacterial colonies. Clinicians should consider H. cinaedi infection in cases of recurrent cellulitis.     

Inherited Kidney Complement Diseases

In the past 20 years, we have witnessed tremendous advances in our ability to diagnose and treat genetic diseases of the kidney caused by complement dysregulation. Staggering progress was realized toward a better understanding of the genetic underpinnings and pathophysiology of many forms of atypical hemolytic uremic syndrome (aHUS) and C3-dominant glomerulopathies that are driven by complement system abnormalities. Many of these seminal discoveries paved the way for the design and characterization of several innovative therapies, some of which have already radically improved patients’ outcomes. This review offers a broad overview of the exciting developments that have occurred in the recent past, with a particular focus on single-gene (or Mendelian), complement-driven aHUS and C3-dominant glomerulopathies that should be of interest to both nephrologists and kidney researchers. The discussion is restricted to genes with robust associations with both aHUS and C3-dominant glomerulopathies (complement factor H, complement component 3, complement factor H–related proteins) or only aHUS (complement factor B, complement factor I, and membrane cofactor protein). Key questions and challenges are highlighted, along with potential avenues for future directions.     

Current insights in invasive group A streptococcal infections in pediatrics

A rising incidence of invasive group A Streptococcus infections (IGASI) has been noted in children in the past three decades. The relative frequency of the infection types showed marked differences to IGASI in adults, and severity of the disease resulted in a mortality rate usually comprising between 3.6% and 8.3%. The emm1-type group A Streptococcus (GAS) subclone displaying a particular pattern of virulence factors was widely disseminated and prevalent in children with IGASI while the emm3-type GAS subclone appeared as a recent emerging genotype. However, the implication of these hypervirulent clones in the increase of IGASI in children is still controversial. Recent advances in our knowledge on pathogenesis of IGASI underlined that deregulation of virulence factor production, individual susceptibility, as well as exuberant cytokine response are important factors that may account for the severity of the disease in children. Future changes in IGASI epidemiology are awaited from current prospects for a safe and effective vaccine against GAS. IGASI are complex infections associating septic, toxic, and immunological disorders. Treatment has to be effective on both the etiologic agent and its toxins, due to the severity of the disease associated to the spread of highly virulent bacterial clones. More generally, emergence of virulent clones responsible for septic and toxic disease is a matter of concern in pediatric infectiology in the absence of vaccination strategy.     

Respiratory effort during sleep and the rate of prevalent type 2 diabetes in obstructive sleep apnoea

Aim

To determine the association between total sleep time (TST) spent in increased respiratory effort (RE) and the prevalence of type 2 diabetes in a large cohort of individuals with suspected obstructive sleep apnoea (OSA) referred for in-laboratory polysomnography (PSG).

Materials and Methods

We conducted a retrospective cross-sectional study using the clinical data of 1128 patients. Non-invasive measurements of RE were derived from the sleep mandibular jaw movements (MJM) bio-signal. An explainable machine-learning model was built to predict prevalent type 2 diabetes from clinical data, standard PSG indices, and MJM-derived parameters (including the proportion of TST spent with increased respiratory effort [REMOV [%TST]).

Results

Original data were randomly assigned to training (n = 853) and validation (n = 275) subsets. The classification model based on 18 input features including REMOV showed good performance for predicting prevalent type 2 diabetes (sensitivity = 0.81, specificity = 0.89). Post hoc interpretation using the Shapley additive explanation method found that a high value of REMOV was the most important risk factor associated with type 2 diabetes after traditional clinical variables (age, sex, body mass index), and ahead of standard PSG metrics including the apnoea-hypopnea and oxygen desaturation indices.

Conclusions

These findings show for the first time that the proportion of sleep time spent in increased RE (assessed through MJM measurements) is an important predictor of the association with type 2 diabetes in individuals with OSA.