Evidence of causality of low body mass index on risk of adolescent idiopathic scoliosis: a Mendelian randomization study

IntroductionAdolescent idiopathic scoliosis (AIS) is a disorder with a three-dimensional spinal deformity and is a common disease affecting 1-5% of adolescents. AIS is also known as a complex disease involved in environmental and genetic factors. A relation between AIS and body mass index (BMI) has been epidemiologically and genetically suggested. However, the causal relationship between AIS and BMI remains to be elucidated.Material and methodsMendelian randomization (MR) analysis was performed using summary statistics from genome-wide association studies (GWASs) of AIS (Japanese cohort, 5,327 cases, 73,884 controls; US cohort: 1,468 cases, 20,158 controls) and BMI (Biobank Japan: 173430 individual; meta-analysis of genetic investigation of anthropometric traits and UK Biobank: 806334 individuals; European Children cohort: 39620 individuals; Population Architecture using Genomics and Epidemiology: 49335 individuals). In MR analyses evaluating the effect of BMI on AIS, the association between BMI and AIS summary statistics was evaluated using the inverse-variance weighted (IVW) method, weighted median method, and Egger regression (MR-Egger) methods in Japanese.ResultsSignificant causality of genetically decreased BMI on risk of AIS was estimated: IVW method (Estimate (beta) [SE] = -0.56 [0.16], p = 1.8 × 10-3), weighted median method (beta = -0.56 [0.18], p = 8.5 × 10-3) and MR-Egger method (beta = -1.50 [0.43], p = 4.7 × 10-3), respectively. Consistent results were also observed when using the US AIS summary statistic in three MR methods; however, no significant causality was observed when evaluating the effect of AIS on BMI.ConclusionsOur Mendelian randomization analysis using large studies of AIS and GWAS for BMI summary statistics revealed that genetic variants contributing to low BMI have a causal effect on the onset of AIS. This result was consistent with those of epidemiological studies and would contribute to the early detection of AIS

Current therapeutic strategies for acute kidney injury

Abstract Acute kidney injury (AKI) is an emerging public health problem worldwide and is associated with high morbidity and mortality. The high mortality rate can be attributed to the lack of pharmacological therapies to prevent and treat AKI. Renal replacement therapy (RRT) plays a pivotal role in the treatment of patients with severe AKI. However, the mortality rate of patients with AKI requiring RRT exceeds 50%. Although studies on RRT for AKI have begun to resolve some of the associated problems, many issues remain to be addressed. Notably, the optimal timing of the initiation of RRT for AKI is still being debated. Recently, new therapeutic strategies for AKI have been developed. Angiotensin II and recombinant alkaline phosphatase treatment are expected to improve the clinical outcomes of patients with distributive and vasodilatory shock. Moreover, mitochondrial-targeted agents have been developed for the treatment of patients with AKI. This review is focused on the optimal timing of RRT for AKI and the new pharmacological interventions and therapies for AKI

Granulocyte-colony stimulating factor-producing gallbladder carcinoma-include analysis all case reports: A case report

Introduction: It is extremely rare for gallbladder carcinoma to produce granulocyte-colony stimulating factor (G-CSF) and such tumors have a poor prognosis. Presentation of case: A 67-year-old man was admitted with continuous fever. Laboratory tests showed a leukocyte count of 27,980/μL, serum C-reactive protein (CRP) of 9.2 mg/dL and serum G-CSF of 225 pg/mL. Imaging revealed an irregular gallbladder mass about 90 mm in diameter with peripheral enhancement that also involved the liver and transverse colon. G-CSF producing gallbladder carcinoma was diagnosed. We performed cholecystectomy, partial resection of segments 4 and 5 of the liver, partial resection of the transverse colon, and gastrostomy. Histopathological examination showed gallbladder carcinoma (pT3, pN0, M0, G2, and pStage IIIA by the UICC classification, version 7). On immunohistochemical staining, tumor cells were positive for G-CSF. The leukocyte count was normalized postoperatively and fever subsided immediately after surgery. Two months later, the leukocyte count rose to 56,820/μL and metastases to the liver and lymph nodes were detected by CT. Chemotherapy (gemcitabine plus cisplatin) was started and the leukocyte count was normalized after the first course. The patient has continued chemotherapy and has survived for 16 months postoperatively. Discussion: G-CSF producing gallbladder carcinoma has a poor prognosis and most patients die within 12 months of starting therapy. It is rare for patients with recurrence to survive for 16 months after surgery, as in the present case. Conclusion: Multidisciplinary therapy (surgery and chemotherapy) may prolong the survival of patients with G-CSF producing gallbladder carcinoma, especially those with recurrence

Characterization of T cell receptors of Th1 cells infiltrating inflamed skin of a novel murine model of palladium-induced metal allergy.

Metal allergy is categorized as a delayed-type hypersensitivity reaction, and is characterized by the recruitment of lymphocytes into sites of allergic inflammation. Because of the unavailability of suitable animal models for metal allergy, the role of T cells in the pathogenesis of metal allergy has not been explored. Thus, we developed a novel mouse model for metal allergy associated with infiltration of T cells by multiple injections of palladium (Pd) plus lipopolysaccharide into the footpad. Using this model, we characterized footpad-infiltrating T cells in terms of phenotypic markers, T cell receptor (TCR) repertoires and cytokine expression. CD3+ CD4+ T cells accumulated in the allergic footpads 7 days after Pd challenge. The expression levels of CD25, interleukin-2, interferon-γ and tumor necrosis factor, but not interleukin-4 and interleukin-5, increased in the footpads after challenge, suggesting CD4+ T helper 1 (Th1) cells locally expanded in response to Pd. Infiltrated T cells in the footpads frequently expressed AV18-1 and BV8-2 T cell receptor (TCR) chains compared with T cells in the lymph nodes and exhibited oligoclonality. T-cell clones identified from Pd-allergic mouse footpads shared identical CDR3 sequences containing AV18-1 and BV8-2. These results suggest that TCR AV18-1 and BV8-2 play dominant and critical parts in the antigen specificity of Pd-specific Th1 cells

Possible Immune Regulation of Natural Killer T Cells in a Murine Model of Metal Ion-Induced Allergic Contact Dermatitis

Metal often causes delayed-type hypersensitivity reactions, which are possibly mediated by accumulating T cells in the inflamed skin, called irritant or allergic contact dermatitis. However, accumulating T cells during development of a metal allergy are poorly characterized because a suitable animal model is unavailable. We have previously established novel murine models of metal allergy and found accumulation of both metal-specific T cells and natural killer (NK) T cells in the inflamed skin. In our novel models of metal allergy, skin hypersensitivity responses were induced through repeated sensitizations by administration of metal chloride and lipopolysaccharide into the mouse groin followed by metal chloride challenge in the footpad. These models enabled us to investigate the precise mechanisms of the immune responses of metal allergy in the inflamed skin. In this review, we summarize the immune responses in several murine models of metal allergy and describe which antigen-specific responses occur in the inflamed skin during allergic contact dermatitis in terms of the T cell receptor. In addition, we consider the immune regulation of accumulated NK T cells in metal ion–induced allergic contact dermatitis