Citations

Growing evidence suggests that pretransplant alpha‐fetoprotein (AFP) predicts outcomes of hepatocellular carcinoma (HCC) patients treated with liver transplantation. We aimed to determine whether pretransplant AFP, Lens culinaris agglutinin‐reactive alpha‐fetoprotein (AFP‐L3), and des‐gamma‐carboxyprothrombin (DCP) predicted HCC recurrence after transplantation. A retrospective cohort study of 313 HCC patients undergoing transplantation between 2000 and 2008 was conducted, and 48 (15.3%) developed recurrence during a median follow‐up of 90.8 months. The 127 patients with available serum drawn before transplantation were included; they included 86 without recurrence and 41 with recurrence. Serum was tested for AFP, AFP‐L3%, and DCP in a blinded fashion with the μTASWako i30 immunoanalyzer. All biomarkers were significantly associated with HCC recurrence. The hazard ratios (HRs) were 3.5 [95% confidence interval (CI), 1.9‐6.7; P < 0.0001] for DCP ≥ 7.5 ng/mL and 2.8 (95% CI, 1.4‐5.4; P = 0.002) for AFP ≥ 250 ng/mL. The HR increased to 5.2 (95% CI, 2.3‐12.0; P < 0.0001) when AFP ≥ 250 ng/mL and DCP ≥7.5 ng/mL were considered together. When they were combined with the Milan criteria, the HR increased from 2.6 (95% CI, 1.4‐4.7; P = 0.003) for outside the Milan criteria to 8.6 (95% CI, 3.0‐24.6; P < 0.0001) for outside the Milan criteria and AFP ≥ 250 ng/mL and to 7.2 (95% CI, 2.8‐18.1; P < 0.0001) for outside the Milan criteria and DCP ≥7.5 ng/mL. Our findings suggest that biomarkers are useful for predicting the risk of HCC recurrence after transplantation. Using both biomarkers and the Milan criteria may be better than using the Milan criteria alone in optimizing the decision of liver transplantation eligibility. Liver Transpl 21:599–606, 2015. © 2015 AASLD.

Background— The prevalence and clinical significance of right ventricular (RV) systolic dysfunction (RVD) in patients with heart failure and preserved ejection fraction (HFpEF) are not well characterized. Methods and Results— Consecutive, prospectively identified HFpEF (Framingham HF criteria, ejection fraction ≥50%) patients (n=562) from Olmsted County, Minnesota, underwent echocardiography at HF diagnosis and follow-up for cause-specific mortality and HF hospitalization. RV function was categorized by tertiles of tricuspid annular plane systolic excursion and by semiquantitative (normal, mild RVD, or moderate to severe RVD) 2-dimensional assessment. Whether RVD was defined by semiquantitative assessment or tricuspid annular plane systolic excursion ≤15 mm, HFpEF patients with RVD were more likely to have atrial fibrillation, pacemakers, and chronic diuretic therapy. At echocardiography, patients with RVD had slightly lower left ventricular ejection fraction, worse diastolic dysfunction, lower blood pressure and cardiac output, higher pulmonary artery systolic pressure, and more severe RV enlargement and tricuspid valve regurgitation. After adjustment for age, sex, pulmonary artery systolic pressure, and comorbidities, the presence of any RVD by semiquantitative assessment was associated with higher all-cause (hazard ratio=1.35; 95% confidence interval, 1.03–1.77; P =0.03) and cardiovascular (hazard ratio=1.85; 95% confidence interval, 1.20–2.80; P =0.006) mortality and higher first (hazard ratio=1.99; 95% confidence interval, 1.35–2.90; P =0.0006) and multiple (hazard ratio=1.81; 95% confidence interval, 1.18–2.78; P =0.007) HF hospitalization rates. RVD defined by tricuspid annular plane systolic excursion values showed similar but weaker associations with mortality and HF hospitalizations. Conclusions— In the community, RVD is common in HFpEF patients, is associated with clinical and echocardiographic evidence of more advanced HF, and is predictive of poorer outcomes.

The kidney of marine teleosts is the major site of Mg2+excretion and produces urine with a high Mg2+concentration. However, the transporters involved in Mg2+excretion are poorly understood. The cyclin M (Cnnm; also known as ancient conserved domain protein) family comprises membrane proteins homologous to the bacterial Mg2+and Co2+efflux protein, CorC. To understand the molecular mechanism of Mg2+homeostasis in marine teleosts, we analyzed the expression of the C nnm family genes in the seawater (SW) pufferfish, torafugu ( Takifugu rubripes), and the closely related euryhaline species, mefugu ( Takifugu obscurus). Database mining and phylogenetic analysis indicated that the Takifugu genome contains six members of the Cnnm family: two orthologs of Cnnm1, one of Cnnm2, one of Cnnm3, and two of Cnnm4. RT-PCR analyses indicated that Cnnm2, Cnnm3, and Cnnm4a are expressed in the kidney, whereas other members are mainly expressed in the brain. Renal expression of Cnnm3 was upregulated in SW mefugu, whereas renal expression of Cnnm2 was upregulated in freshwater (FW) mefugu. No significant difference was observed in renal expression of Cnnm4a between SW and FW mefugu. In situ hybridization and immunohistochemical analyses of the SW mefugu kidney revealed that Cnnm3 is expressed in the proximal tubule, and its product localizes to the lateral membrane. When Cnnm3 was expressed in Xenopus laevis oocytes, whole cellular Mg2+content and free intracellular Mg2+activity significantly decreased. These results suggest that Cnnm3 is involved in body fluid Mg2+homeostasis in marine teleosts.

ABSTRACTBackgroundVariants within the leucine‐rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine‐rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late‐onset sporadic disorders like Parkinson's disease.MethodsThe Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine‐rich repeat kinase 2 gene across 23 different sites in 15 countries.ResultsHerein, we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K‐R1398H‐K1423K) nominated in the original publication. Simple population allele frequencies not only can provide insight into the clinical relevance of specific variants but also can help genetically define patient groups.ConclusionsEstablishing individual patient‐based genomic susceptibility profiles that incorporate both risk factors and protective factors will determine future diagnostic and treatment strategies. © 2013 International Parkinson and Movement Disorder Society

The second most abundant cation in seawater (SW), Mg2+, is present at concentrations of ∼53 mM. Marine teleosts maintain plasma Mg2+concentration at 1–2 mM by excreting Mg2+into the urine. Urine Mg2+concentrations of SW teleosts exceed 70 mM, most of which is secreted by the renal tubular epithelial cells. However, molecular mechanisms of the Mg2+secretion have yet to be clarified. To identify transporters involved in Mg2+secretion, we analyzed the expression of fish homologs of the Slc41 Mg2+transporter family in various tissues of SW pufferfish torafugu ( Takifugu rubripes) and its closely related euryhaline species mefugu ( Takifugu obscurus). Takifugu genome contained five members of Slc41 genes, and only Slc41a1 was highly expressed in the kidney. Renal expression of Slc41a1 was markedly elevated when mefugu were transferred from fresh water (FW) to SW. In situ hybridization analysis and immunohistochemistry at the light and electron microscopic levels revealed that Slc41a1 is localized to vacuoles in the apical cytoplasm of the proximal tubules. These results suggest that pufferfish Slc41a1 is a Mg2+transporter involved in renal tubular transepithelial Mg2+secretion by mediating Mg2+transport from the cytosol to the vacuolar lumen, and support the hypothesis that Mg2+secretion is mediated by exocytosis of Mg2+-rich vacuoles to the lumen.

AbstractBackground and objectiveDespite significant recent progress in the understanding of idiopathic pulmonary fibrosis (IPF), the early phase of the disease is still poorly understood. We studied patients with IPF without pulmonary function impairment in order to determine the clinical features, natural history and key findings for physiological progression.MethodsTwenty‐five patients without pulmonary function impairment were identified from among patients with previously diagnosed IPF who underwent surgical lung biopsies between January 1997 and December 2006 at our institutions. ‘Without pulmonary function impairment’ was defined as both forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLco) >80% predicted. Patients diagnosed with IPF through multidisciplinary discussion based on the new IPF guidelines were the subjects of this study.ResultsSixteen patients had a confirmed diagnosis of IPF. Eleven patients presented with chest X‐ray abnormality found during an annual health examination. Seven patients were asymptomatic. Eleven patients showed physiological disease progression (median time; 19.9 ± 12.3 months) defined by a decline of at least 10% in FVC or at least 15% in DLco. Univariate analysis revealed that both usual interstitial pneumonia pattern and extent of honeycombing on high‐resolution computed tomography (HRCT) were factors associated with disease progression (odds ratio 5.634, 95% confidence interval 1.364–23.278; odds ratio 2.371/5%, 95% confidence interval 1.042–5.395).ConclusionsIPF patients without pulmonary function impairment have a progressive but slow clinical course. The existence and extent of honeycombing on HRCT are predictive of disease progression.

Background Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive. Methods and results We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort. Conclusions Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.

Endothelial NO synthase (eNOS) is an enzyme responsible for the production of a potent vasodilator and a key regulator of vascular tone, NO. In peripheral arteries, expression of a recombinant eNOS gene increases production of NO in the blood vessel wall. This approach appears to be a promising strategy for gene therapy of cerebrovascular disease. The major objective of the present study was to determine whether a recombinant eNOS gene (AdCMVNOS) can be functionally expressed in cerebral arteries. Replication-defective recombinant adenovirus vectors encoding bovine eNOS and Escherichia coli beta-galactosidase (AdCMVLacZ) genes, driven by the cytomegalovirus promoter, were used for ex vivo gene transfer. Rings of canine basilar artery were incubated with increasing titers of the vectors in MEM. Twenty-four or forty-eight hours after gene transfer, expression and function of AdCMVNOS were evaluated by (1) immunohistochemical staining, (2) isometric tension recording, and (3) cGMP radioimmunoassay. Transfection with AdCMVNOS resulted in the expression of recombinant eNOS protein in the vascular adventitia and endothelium, associated with significantly reduced contractile responses to UTP and enhanced endothelium-dependent relaxation to calcium ionophore A23187. Basal production of cGMP was significantly increased in the transfected vessels. The reduced contractions to UTP with increased cGMP production were reversed by a NOS inhibitor, NG-monomethyl-L-arginine. Contractions to UTP or production of cGMP were not affected in arteries transfected with AdCMVLacZ reporter gene. The results of the present study represent the first successful transfer and functional expression of recombinant eNOS gene in cerebral arteries. Our findings suggest that cerebral arterial tone can be modulated by recombinant eNOS expression in the vessel wall. (Circ Res. 1997;80:327-335.)