Novel PGM3 compound heterozygous variants with IgE-related dermatitis, lymphopenia, without syndromic features.

BACKGROUND: Phosphoglucomutase-3 (PGM3) deficiency is a congenital disorder of glycosylation (CDG) with hyperimmunoglobulin IgE, atopy, and a variable immunological phenotype; most reported patients display dysmorphic features. The aim of the study was to characterize the genotype and phenotype of individuals with newly identified compound heterozygous variants in the phosphate-binding domain of PGM3 in order to better understand phenotypic differences between these patients and published cases. METHODS: We analyzed PGM3 protein expression, PGM3 enzymatic activity, the presence of other gene variants within the N-glycosylation pathway, and the clinical and immunological manifestations of two affected siblings. RESULTS: Patients belonged to a non-consanguineous family, presenting with atopic dermatitis, elevated levels of IgE, and CD4+ lymphopenia (a more severe phenotype was observed in Patient 2), but lacked dysmorphic features or neurocognitive impairment. Compound heterozygous PGM3 variants were identified, located in the phosphate-binding domain of the enzyme. PGM3 expression was comparable to healthy donors, but L-PHA binding in naïve-CD4+ cells was decreased. Examination of exome sequence identified the presence of one additional candidate variant of unknown significance (VUS) in the N-glycosylation pathway in Patient 2: a variant predicted to have moderate-to-high impact in ALG12. CONCLUSIONS: Our analysis revealed that L-PHA binding is reduced in naïve-CD4+ cells, which is consistent with decreased residual PGM3 enzymatic activity. Other gene variants in the N-glycosylation pathway may modify patient phenotypes in PGM3 deficiency. This study expands the clinical criteria for when PGM3 deficiency should be considered among individuals with hyper-IgE.

Human macrophages chronically exposed to LPS can be reactivated by stimulation with MDP to acquire an antimicrobial phenotype.

Macrophages are important in host defense and can differentiate into functionally distinct subsets named classically (M1) or alternatively (M2) activated. In several inflammatory disorders, macrophages become tolerized to prevent deleterious consequences. This tolerization reduces the ability of macrophages to respond to bacterial components (e.g., LPS) maintaining a low level of inflammation but compromising the ability of macrophages to mount an effective immune response during subsequent pathogen encounters. In this study, we aimed to reactivate human monocyte-derived macrophages chronically exposed to LPS by re-stimulation with muramyl dipeptide (MDP). We observed an undefined profile of cell surface marker expression during endotoxin tolerance and absence of TNFα production. Stimulating macrophages chronically exposed to LPS with LPS+MDP restored TNFα, production together with an increased production of IL1, IL6, IFNγ, IL4, IL5 and IL10. These results suggest that macrophages chronically exposed to LPS possess a mixed M1-M2 phenotype with sufficient antimicrobial and homeostatic potential.

Physiological Network Is Disrupted in Severe COVID-19.

The human body is a complex system maintained in homeostasis thanks to the interactions between multiple physiological regulation systems. When faced with physical or biological perturbations, this system must react by keeping a balance between adaptability and robustness. The SARS-COV-2 virus infection poses an immune system challenge that tests the organism's homeostatic response. Notably, the elderly and men are particularly vulnerable to severe disease, poor outcomes, and death. Mexico seems to have more infected young men than anywhere else. The goal of this study is to determine the differences in the relationships that link physiological variables that characterize the elderly and men, and those that characterize fatal outcomes in young men. To accomplish this, we examined a database of patients with moderate to severe COVID-19 (471 men and 277 women) registered at the "Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán" in March 2020. The sample was stratified by outcome, age, and sex. Physiological networks were built using 67 physiological variables (vital signs, anthropometric, hematic, biochemical, and tomographic variables) recorded upon hospital admission. Individual variables and system behavior were examined by descriptive statistics, differences between groups, principal component analysis, and network analysis. We show how topological network properties, particularly clustering coefficient, become disrupted in disease. Finally, anthropometric, metabolic, inflammatory, and pulmonary cluster interaction characterize the deceased young male group.

[Epidemiology of varicella in spain pre-and post-vaccination periods]. / Epidemiología de la varicela en España en los períodos pre y post vacunación.

BACKGROUND: Varicella virus can cause two different diseases: chickenpox and herpes zoster. In 2005 varicella vaccine has been introduced in the Spanish national vaccination schedule for 10-14 years old non-immune people, in order to reduce the severity of the disease. In 2007 a new surveillance protocol with aggregate data for chickenpox and herpes zoster was approved in order to detect any change in age distribution, severity and complications of the chickenpox and herpes zoster cases. The aim of this study is to know the burden of diseases (in the last ten years). METHODS: Number of cases, hospitalization and incidence for chickenpox and herpes zoster were study for two periods 1997-2003 and 2005-2007. Analysis for 1996-2007 fatal cases was done too. We decided to remove year 2004 because the extremely high chickenpox incidence registered. SOURCES OF DATA: RENAVE (Spanish Surveillance Network), Spanish hospital surveillance system (CMBD), and mortality registries. RESULTS: Chickenpox incidence decreased since 2005, but an increasing trend was detected in hospitalisation with an average of 1,311 hospitalizations every year. For the 32%-36% of hospitalized cases, the main diagnosis was not chickenpox. 4-14 deaths per year have been detected; 80% of them were older than 14 years. Annual rate of herpes zoster hospitalization was 2.5 per 100,000 inhabitants, similar in both sexes. Case fatality rate per year was 0.31 per million inhabitants. No significant changes were detected in age and sex in complicated cases between the two periods. 88% of chickenpox cases were younger than 15 years old and 64% of herpes zoster older than 50 years in 2007. CONCLUSIONS: Chickenpox has been decreasing during 2005-2007 in Spain. The impact of vaccination is difficult to asses, because of a peak registered in 2004 but also because the lack of vaccination coverage information for this period and the case-data information is available only for the last year.