Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalacia

The balance between bioactivation and degradation of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] is critical for ensuring appropriate biological effects of vitamin D. Cytochrome P450, family 24-mediated (CYP24-mediated) 24-hydroxylation of 1,25(OH)2D3 is an important step in the catabolism of 1,25(OH)2D3. The enzyme is directly regulated by vitamin D receptor (VDR), and it is expressed mainly in the kidney, where VDR is also abundant. A recent report suggests that activation of steroid and xenobiotic receptor (SXR) also enhances the expression of CYP24, providing a new molecular mechanism of drug-induced osteomalacia. However, here we showed that activation of SXR did not induce CYP24 expression in vitro and in vivo, nor did it transactivate the CYP24 promoter. Instead, SXR inhibited VDR-mediated CYP24 promoter activity, and CYP24 expression was very low in tissues containing high levels of SXR, including the small intestine. Moreover, 1,25(OH)2D3-induced CYP24 expression was enhanced in mice lacking the SXR ortholog pregnane X receptor, and treatment of humans with the SXR agonist rifampicin had no effect on intestinal CYP24 expression, despite demonstration of marked CYP3A4 induction. Combined with our previous findings that CYP3A4, not CYP24, plays the dominant role in hydroxylation of 1,25(OH)2D3 in human liver and intestine, our results indicate that SXR has a dual role in mediating vitamin D catabolism and drug-induced osteomalacia.     

Reprogramming of CTLs into natural killer-like cells in celiac disease

Celiac disease is an intestinal inflammatory disorder induced by dietary gluten in genetically susceptible individuals. The mechanisms underlying the massive expansion of interferon gamma-producing intraepithelial cytotoxic T lymphocytes (CTLs) and the destruction of the epithelial cells lining the small intestine of celiac patients have remained elusive. We report massive oligoclonal expansions of intraepithelial CTLs that exhibit a profound genetic reprogramming of natural killer (NK) functions. These CTLs aberrantly expressed cytolytic NK lineage receptors, such as NKG2C, NKp44, and NKp46, which associate with adaptor molecules bearing immunoreceptor tyrosine-based activation motifs and induce ZAP-70 phosphorylation, cytokine secretion, and proliferation independently of T cell receptor signaling. This NK transformation of CTLs may underlie both the self-perpetuating, gluten-independent tissue damage and the uncontrolled CTL expansion leading to malignant lymphomas in severe forms of celiac disease. Because similar changes were detected in a subset of CTLs from cytomegalovirus-seropositive patients, we suggest that a stepwise transformation of CTLs into NK-like cells may underlie immunopathology in various chronic infectious and inflammatory diseases.     

Modern Dual-Mobility Cups in Revision Total Hip Arthroplasty: A Systematic Review and Meta-Analysis

Background

The purpose of this systematic review is to analyze the outcomes of dual-mobility (DM) cups in revision total hip arthroplasty (THA). Specifically, we evaluated the following: (1) all-cause and aseptic survivorship rates; (2) dislocation rates; (3) complications; and (4) clinical outcomes reported using validated health status measures.

The use of neutrophil-to-lymphocyte ratio (NLR) as a marker for COVID-19 infection in Saudi Arabia: A case-control retrospective multicenter study

Objectives:To assess the neutrophil-to-lymphocyte ratio (NLR) diagnostic and prognostic value in the context of Coronavirus disease-2019 (COVID-19) infection in Saudi Arabia.Methods:A case-control study in which 701 confirmed COVID-19 patients (of which 41 were intensive care unit [ICU]-admitted) and 250 control subjects were enrolled. The study was conducted retrospectively in October on patients admitted to 3 separate hospitals in Saudi Arabia namely: King Abdullah Bin Abdulaziz University Hospital (Riyadh), Ohud Hospital (Madinah), and Nojood Medical Center (Madinah) between May and September 2020. Neutrophil-to-lymphocyte ratio was calculated based on absolute neutrophil and lymphocyte count. Institutional ethical approval was obtained prior to the study.Results:Patients (median age 35 years), of which 54.8% were females, were younger than the control cohort (median age 48 years). Patients had significantly higher NLR compared to the control group. Intensive care unit admitted patients had significantly higher platelet, WBC and neutrophil counts. The ICU patients’ NLR was almost twice as of the non-intensive patients. The NLR value of 5.5 was found to be of high specificity (96.4%) and positive predictive value (91.4%) in diagnosing COVID-19. Furthermore, it had a very good sensitivity (86.4%) in predicting severe forms of disease, such as, ICU admission.Conclusion:Neutrophil-to-lymphocyte ratio is an important tool in determining the COVID-19 clinical status. This study further confirms the prognostic value of NLR in detecting severe infection, and those patients with high NLR should be closely monitored and managed.     

Severe hypercalcemia complicated by acute pancreatitis revealing generalized bone lysis metastasis: Case report and review

Malignant hypercalcemia is a frequent metabolic complication of osteophilic tumors, exceptionally revealing cavitary cancer, but its prognosis remains poor despite early and adequate management. We report the case of a young patient, smoker without any previous history, admitted for the management of a digestive symptoms made of abdominal pain with food vomiting. The patient had an electrocardiogram withchest computed tomography scan and BBC evoking PA on malignant hypercalcemia. An etiological investigation was conducted to confirm the tumoral origin of the hypercalcemia. We put the patient on hyperhydration with corticotherapie and biohosphonates with a good clinical and biological improvement. Malignant hypercalcemia affects about 10%-20% of patients with cancer including nasopharyngeal carcinoma. Its clinical presentation varies according to the extent and speed of onset, responsible for multivisceral involvement including kidney, heart, neuropsychiatric system, which may engage the patient''s vital prognosis. The therapeutic management is based on 4 main principles; hyperhydration, increase of urinary calcium excretion by loop diuretics, decrease of bone resorption by biphosphonates and extrarenal purification which remains the ideal choice in case of life-threatening severe hypercalcemia. Acute hypercalcemic pancreatitis as a mode of revelation of cavum cancer has almost never been described in the literature