Fabry disease is caused by the deficiency of lysosomal α-galactosidase A (α-gal A) and usually develops clinical manifestations during childhood/adolescence. Adult Fabry model mice have been ...successfully treated by various viral vectors. Here, in order to examine the feasibility of preventive gene therapy, we compared AAV vector-mediated gene transfer into neonatal and adult model mice. AAV serotype 1 vector (AAV1) carrying human α-gal A cDNA driven by the CAG promoter was intravenously injected into adult (12 weeks old) and neonatal (2 days old) Fabry model mice, and were sacrificed for detailed examination 25 weeks after vector injection. AAV1 vector preferentially transduced the liver in male adult and sustained high concentration of α-gal A was detected in the liver, heart and plasma. In contrast, AAV1-mediated gene expression was suppressed in similarly treated female adult mice. When the vector was systemically injected into neonates, moderate increase in plasma α-gal A and cardiac-specific expression of α-gal A were observed independently of mouse sex. The high levels of α-gal A activity in the heart appear to be due to the strong activity of the CAG promoter in the heart. Globotriaosylceramide (Gb3) accumulation was efficiently inhibited in the liver and heart by a single injection into both adult and neonatal animals. The biodistribution of the AAV1 vector and levels of α-gal A expression are markedly different between adult and neonatal mice. Neonatal injection is effective to inhibit Gb3 accumulation and therefore, might help prevent failure of major organs during adulthood.
Membrane electrode assemblies of direct methanol fuel cells (DMFCs) with different catalyst and ionomer loading were prepared. Anode performance and impedance spectra were measured to clarify the ...characteristics of vapor feed DMFCs (VF-DMFCs). The impedance spectra were deconvolved into three semi-circles with different time constants, each showing a different dependence on the anodic polarization. The middle-frequency range arc decreased as the anodic polarization increased, indicating that this process represents the oxidation reaction of methanol. The high-frequency range arc showed little dependence on the anodic polarization, but increased with the thickness of the electrode, indicating that this process might be related to proton conduction through the electrode. The low-frequency range arc was observed only when the methanol concentration was low, in contrast to liquid feed DMFCs (LF-DMFCs), for which the removal of the product gas presents a large resistance. A simpler design can therefore be used for a VF-DMFC, giving it an advantage over an LF-DMFC. A decreasing ionomer to catalyst ratio (
I/
C) caused the interfacial conductivity (
σ
E) to increase, but it intensively decreased when
I/
C was below 0.25. Thus, the connection of the catalysts is important for the anode’s performance.
A case of wear and entrapment of a polyethylene disc observed in a Starr-Edwards (SE) mitral caged-disc valve at 37 years after implantation is reported. A 66-year-old woman who had undergone mitral ...valve replacement with a SE disc valve 37 years previously was admitted to the authors' hospital. Cinefluoroscopy showed the polyethylene disc of the SE valve to have impinged against a calcified mass on the left ventricular posterior wall, causing a tipping motion of the disc during opening. The valve was successfully replaced at surgery. A macroscopic examination of the excised valve revealed wear of the polyethylene disc at sites where the disc abutted the cage struts, and where it impinged on the calcified mass. The long-term durability of the SE caged-disc valves has been favorable; however, when implanted for over 20 years, they should be carefully followed up.
The ubiquitin-proteasome pathway is a major proteolytic system in eukaryotic cells and regulates various cellular processes. The 26 S proteasome, the central enzyme of this pathway, consists of a ...proteolytic core particle and two 19 S regulatory particles (RPs) composed of ATPase (Rpt) and non-ATPase (Rpn) subunits. Growing evidence indicates that proteasome assembly is assisted by a variety of chaperones. In particular, it has been reported recently that Nas2, Nas6, Rpn14, and Hsm3 bind specific Rpt subunits, thereby contributing to the formation of 19 S RP. Rpn14 transiently binds to the C-terminal domain of the Rpt6 subunit (Rpt6-C) during maturation of the ATPase ring of 19 S RP. In this study, we determined the crystal structure of yeast Rpn14 at 2.0 Å resolution, which revealed that this chaperone consists of a unique N-terminal domain with unknown function and a C-terminal domain assuming a canonical seven-bladed β-propeller fold. The Rpt6-binding site on Rpn14 was predicted based on structural comparison with the complex formed between Nas6 and Rpt3-C. The top face of Rpn14 exhibits a highly acidic surface area, whereas the putative interacting surface of Rpt6-C is basic. By inspection of structural data along with genetic and biochemical data, we determined the specific residues of Rpn14 and Rpt6 for complementary charge interactions that are required for 19 S RP assembly.
Case
A 69‐year‐old man was transferred to our hospital because of an aortoduodenal fistula with hematemesis and pre‐shock vital signs. He had a history of alcoholism, malnutrition, and distal ...gastrectomy and Billroth I reconstruction. Endovascular aneurysm repair was successfully carried out; however, the presence of comorbidities affected further radical treatment.
Outcome
The patient survived for 2 months postoperatively.
Conclusion
Endovascular aneurysm repair is a useful first‐line treatment for high‐risk aortoduodenal fistula patients; however, it requires improvement for long‐term outcomes in complicated high‐risk cases.
Our aim was to evaluate the long-term results of implantation of the Carpentier–Edwards pericardial (CEP) valve in the aortic position. Between January 1996 and December 2007, 244 patients who ...underwent aortic valve replacement using the CEP valve were enrolled in this study. A 19-mm valve was used in 39 patients, a 21-mm valve in 94 patients, a 23-mm valve in 81 patients, and a 25-mm valve in 30 patients. The early and the late results were evaluated. Furthermore, echocardiographic examination was performed at follow-up. There were 5 early deaths, with an early mortality rate of 2.0%. Follow-up was performed in 95.4% of the survivors of the operation for a mean period of 4.1 years. Actuarial survival rates at 5, 10, and 12 years were 85.3 ± 2.8, 80.0 ± 3.7 and 70.0 ± 9.8%, respectively. Thromboembolism was observed in 6 patients, endocarditis in 2 patients, reoperation in 4 patients, and structural valve deterioration in 2 patients. Actuarial freedoms from thromboembolism, endocarditis, and reoperation at 10 years were 96.9 ± 0.14, 97.7 ± 0.16, and 97.0 ± 0.16%, respectively. Echocardiographic examination revealed that the pressure gradients across the valve prosthesis for valves of each size were acceptable. Left ventricular mass index decreased significantly in all valve sizes. The long-term results of implantation of the CEP bioprosthesis in the aortic position were satisfactory. The CEP bioprosthesis maintained its hemodynamic performance even as late as 10 years after implantation.
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