Mutations in the gene ELOVL4 have been shown to cause stargardt-like macular dystrophy. ELOVL4 is part of a family of fatty acid elongases and is yet to have a specific elongase activity assigned to it. We generated Elovl4 Y270X mutant mice and characterized the homozygous mutant as well as homozygous Elovl4 knockout mice in order to better understand the function or role of Elovl4. We found that mice lacking a functional Elovl4 protein died perinatally. The cause of death appears to be from dehydration due to faulty permeability barrier formation in the skin. Further biochemical analysis revealed a significant reduction in free fatty acids longer than C26 in homozygous mutant and knockout mouse skin. These results implicate the importance of these long chain fatty acids in skin barrier development. Furthermore, we suggest that Elovl4 is likely involved in the elongation of C26 and longer fatty acids.

Eighty-seven patients with beta thalassaemia of intermediate severity were investigated in our Unit to determine whether it is possible to consistently predict phenotypic severity from genotypic factors. The subjects were from the following ethnic backgrounds: Asian Indian (35.1%), Middle Eastern (24.3%), Mediterranean (21.6%), Northern European (14.9%) and South-East Asian/Chinese (4.1%). There was a wide spectrum of phenotypic severity; 49 had mild disease, 22 moderate and 16 severe disease. 22/87 patients had inherited only a single copy of a beta-thalassaemia allele, of whom 11 had also co-inherited triplicated alpha genes (alpha alpha alpha/alpha alpha or alpha alpha alpha/alpha alpha alpha) and seven had dominantly inherited beta thalassaemia. In four of the heterozygotes no explanation was found for the thalassaemia-intermedia phenotype. 65/87 patients were homozygous or compound heterozygous for 26 mutations (40 genotypes) which ranged from very mild beta+ to beta0 thalassaemia alleles. All patients with two mild or very mild beta+ thalassaemia alleles had mild to moderate disease. Although concurrent inheritance of extra alpha genes with heterozygous beta thalassaemia results in thalassaemia intermedia, the disease is mild. Co-inheritance of alpha thalassaemia as a modulating factor was not evident in this cohort of patients. Presence of the in-cis Xmn I-Ggamma site was a modulating factor but insufficient to explain the high fetal haemoglobin levels encountered. In conclusion, apart from the two categories of triplicated alpha genes with heterozygous beta thalassaemia and inheritance of mild beta+ thalassaemia alleles, it was not possible to consistently predict phenotype from alpha and beta genotypes alone, due to the influence of modulating factors, some implicated (such as inheritance of HPFH determinants) and others as yet unidentified.

Objective The artificial liver support system (ALSS) is used frequently as a first‐line treatment for hepatitis B virus‐associated acute‐on‐chronic liver failure (HBV‐ACLF). This study aims to compare the therapeutic efficacy of double plasma molecular adsorption system (DPMAS) with sequential half‐dose plasma exchange (PE) (DPMAS+PE) and full‐dose PE in patients with HBV‐ACLF. Methods A total of 131 hospitalized patients who were diagnosed with HBV‐ACLF and underwent DPMAS+PE or PE were retrospectively analyzed. According to the treatment methods used, they were divided into PE group (n = 77) and DPMAS+PE group (n = 54). The main evaluation indexes included the change of liver function and the 28‐days liver transplant‐free survival rates after the different treatments. Results There were no significant differences on severity of illness between PE group and DPMAS+PE group (P > 0.05). The total bilirubin (TBIL) levels immediately after treatment, and at 24 and 72 hours after treatment were markedly decreased in DPMAS+PE group than that in PE group (52.3 ± 9.4% vs 42.3 ± 7.2%, P < 0.05; 24.2 ± 10.0% vs 13.5 ± 13.0%, P < 0.05; 24.8 ± 13.1% vs 14.9 ± 14.9%, P < 0.05; respectively). The 28‐days survival rates was 62.3% and 72.2% in PE and DPMAS+PE groups (P = 0.146). Furthermore, the 28‐days survival rates were significantly higher in DPMAS+PE group than that in PE group (57.4% vs 41.7%, P = 0.043) in the intermediate‐advanced stage patients. Conclusion Compared with PE alone, DPMAS+PE might more effectively improve temporary TBIL in ACLF patients, and improve the 28‐days survival rates in HBV‐ACLF patients with intermediate‐advanced stage. Therefore, DPMAS+PE may be an available ALSS treatment for HBV‐ACLF patients.

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Mildly elevated serum bilirubin levels were reported to be associated with decreased risk of non-alcoholic fatty liver disease (NAFLD). Whether this is a causal relationship remains unclear. We tested the hypothesis that genetically elevated plasma bilirubin levels are causally related to reduce risk of NAFLD. A total of 403 eligible participants were enrolled. NAFLD was determined by liver ultrasonography. The uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene variants (UGT1A1*6 and UGT1A1*28) were genotyped through sequencing. We applied a Mendelian randomization approach to assess the effects of genetically elevated bilirubin levels on NAFLD. NAFLD was diagnosed in 19% of participants in our study (NAFLD = 76; Non-NAFLD = 327). The variants of UGT1A1*28 and UGT1A1*6 were strongly associated with increased total bilirubin (TB), direct bilirubin (DB), and indirect bilirubin (IB) levels (each P < 0.001). These two common variants explain 12.7% (TB), 11.4% (IB), and 10.2% (DB) of the variance in bilirubin levels, respectively. In logistic regression model, after multifactorial adjustment for sex, age, aminotransferase (ALT), white blood count (WBC), and body mass index (BMI), variant UGT1A1*28 (OR = 1.39; 95%CI: 0.614–3.170; P = 0.43) and UGT1A1*6 (OR = 1.64, 95%CI, 0.78–3.44; P = 0.19) genotypes were not significantly associated with the risk of NAFLD. Moreover, the plasma bilirubin level (TB, IB, and DB) were not significantly associated with the risk of NAFLD (P > 0.30). A Mendelian randomization analysis of the UGT1A1 variants suggests that bilirubin is unlikely causally related with the risk of NAFLD.