Bone Marrow Failure and Immunodeficiency Associated with Human RAD50 Variants.

PURPOSE: The MRE11-RAD50-NBN (MRN) complex plays a key role in recognizing and signaling DNA double-strand breaks. Pathogenic variants in NBN and MRE11 give rise to the autosomal-recessive diseases, Nijmegen breakage syndrome (NBS) and ataxia telangiectasia-like disorder, respectively. The clinical consequences of pathogenic variants in RAD50 are incompletely understood. We aimed to characterize a newly identified RAD50 deficiency/NBS-like disorder (NBSLD) patient with bone marrow failure and immunodeficiency. METHODS: We report on a girl with microcephaly, mental retardation, bird-like face, short stature, bone marrow failure and B-cell immunodeficiency. We searched for candidate gene by whole-exome sequencing and analyzed the cellular phenotype of patient-derived fibroblasts using immunoblotting, radiation sensitivity assays and lentiviral complementation experiments. RESULTS: Compound heterozygosity for two variants in the RAD50 gene (p.Arg83His and p.Glu485Ter) was identified in this patient. The expression of RAD50 protein and MRN complex formation was maintained in the cells derived from this patient. DNA damage-induced activation of the ATM kinase was markedly decreased, which was restored by the expression of wild-type (WT) RAD50. Radiosensitivity appeared inconspicuous in the patient-derived cell line as assessed by colony formation assay. The RAD50R83H missense substitution did not rescue the mitotic defect in complementation experiments using RAD50-deficient fibroblasts, whereas RAD50WT did. The RAD50E485X nonsense variant was associated with in-frame skipping of exon 10 (p.Glu485_545del). CONCLUSION: These findings indicate important roles of RAD50 in human bone marrow and immune cells. RAD50 deficiency/NBSLD can manifest as a distinct inborn error of immunity characterized by bone marrow failure and B-cell immunodeficiency.

Identifying the neuropsychiatric health effects of low-dose lithium interventions: A systematic review.

BACKGROUND: Lithium is widely evidenced for its neuropsychiatric benefits. Advantages of 'sub-therapeutic' doses are increasingly being reported, which is apposite given enduring concerns around adverse effects of 'therapeutic' doses. We aimed to synthesise all available evidence from interventional studies investigating low-dose lithium (LDL) across neuropsychiatric outcomes. METHODS: Electronic databases were systematically searched to include studies where a group of adult humans were treated with LDL (∼serum level ≤0.6 mmol/L), where data describing a neuropsychiatric outcome were reported either before and after treatment, and/or between lithium and a comparator. RESULTS: 18 articles were examined and grouped according to outcome domain (cognition, depression, mania, and related constructs e.g., suicidality). Significant benefits (versus placebo) were identified for attenuating cognitive decline, and potentially as an adjunctive therapy for people with depression/mania. Across studies, LDL was reported to be safe. CONCLUSIONS: Despite the paucity and heterogeneity of studies, LDL's apparent pro-cognitive effects and positive safety profile open promising avenues in the fields of neurodegeneration, and augmentation in affective disorders. We urge future examinations of LDL's potential to prevent cognitive/affective syndromes.

Topographic distribution pattern of morphologically different G cells in the murine antral mucosa.

Gastrin-secreting enteroendocrine cells (G cells) in the antrum play an important role in the regulation of gastric secretion, gastric motility and mucosal cell proliferation. Recently we have uncovered the existence of two subpopulations of G cells with pivotally different morphology and a distinct localization in the antral invaginations; the functional implications of the different G cell types are still elusive. In this study a transgenic mouse line in which EGFP is expressed under the control of a gastrin promoter was used to elucidate the distribution pattern of the two G cell types throughout the different regions of the antrum. The results of immunohistochemical analyses revealed that G cells were not equally distributed along the anterior/posterior axis of the antrum. The "typical" pyramidal- or roundish-shaped G cells, which are located in the basal region of the antral invaginations, were more abundant in the proximal antrum bordering the corpus region but less frequent in the distal antrum bordering the pylorus. In contrast, the "atypical" G cells, which are located in the upper part of the antral invaginations and have a spindle-like contour with long processes, were evenly distributed along the anterior/posterior axis. This characteristic topographic segregation supports the notion that the two G cell types may serve different functions. A comparison of the antrum specific G cells with the two pan-gastrointestinal enteroendocrine cell types, somatostatin-secreting D cells and serotonin-secreting enterochromaffin (EC) cells, revealed a rather similar distribution pattern of G and D cells, but a fundamentally different distribution of EC cells. These observations suggest that distinct mechanisms govern the spatial segregation of enteroendocrine cells in the antrum mucosa.

Financing vaccinations - the South African experience.

South Africa provides a useful country case study for financing vaccinations. It has been an early adopter of new vaccinations and has financed these almost exclusively from domestic resources, largely through general taxation. National vaccination policy is determined by the Department of Health, based on advice from a national advisory group on immunisation. Standard health economic criteria of effectiveness, cost-effectiveness, affordability and burden of disease are used to assess whether new vaccinations should be introduced. Global guidelines and the advice of local and international experts are also helpful in making the determination to introduce new vaccines. In terms of recent decisions to introduce new vaccines against pneumococcal disease and rotavirus diarrhoea in children, the evidence has proved unequivocal. Universal rollout has been implemented even though this has led to a fivefold increase in national spending on vaccines. The total cost to government remains below 1-1.5% of public expenditures for health, which is viewed by the South African authorities as affordable and necessary given the number of lives saved and morbidity averted. To manage the rapid increase in domestic spending, efforts have been made to scale up coverage over several years, give greater attention to negotiating price reductions and, in some cases, obtain initial donations or frontloaded deliveries to facilitate earlier universal rollout. There has been strong support from a wide range of stakeholders for the early introduction of new generation vaccines.