Regional arterial stiffness in patients with type 2 diabetes and chronic kidney disease

Increased arterial stiffness is an independent predictor of death from cardiovascular disease, and aortic stiffness is more predictive than stiffness of other arterial regions. Because little is known about the effect of chronic kidney disease (CKD) on regional arterial stiffness, pulse wave velocity (PWV) of four different arterial segments was measured in patients who had type 2 diabetes with and without various stages of CKD. A total of 434 patients had type 2 diabetes, and there were 192 healthy control subjects who were comparable in age and gender. GFR was estimated by the abbreviated Modification of Diet in Renal Disease equation. The patients with diabetes were classified into CKD stages by the definition of the Kidney Disease Outcomes Quality Initiative guidelines. PWV was measured in the heart-femoral, heart-carotid, heart-brachial, and femoral-ankle segments simultaneously using an automatic pulse wave analyzer. PWV of each arterial region was increased in patients who had diabetes without kidney damage and was increased further in a stepwise manner with the advanced stages of CKD. The increase in PWV was greater in the heart-femoral and heart-carotid regions than in the heart-brachial and femoral-ankle segments. However, after adjustment for age, BP, and other confounding factors using a multiple regression model, decreased GFR was independently associated with increased PWV of the heart-femoral region but not with PWV of other arterial segments. In type 2 diabetes, CKD was associated with increased stiffness of arteries, particularly of the aorta. The cross-sectional result may explain the increased risk for cardiovascular disease in CKD, although longitudinal studies are needed to confirm it.     

Comparative investigation of inhibitors of extracerebral dopa decarboxylase in man and rats

The decarboxylase inhibitor Ro 4–4602 [N¹-(dl -seryl)-N²-(2,3,4-trihydroxybenzyl)hydrazine] in doses of 3.4–34.0 μmol/kg (1–10mg/kg) progressively enhances the increase of dopa and 3-O-methyldopa and diminishes the rise of phenolcarboxylic acids in human plasma induced by administration of l -dopa. A dose of 3.4 μmol/kg Ro 4–4602 is approximately equipotent to 17.0 μmol/kg MK 485 [β-(3,4-dihydroxyphenyl)-α-hydrazino-α-methyl-dl -propionie acid]. Ro 4–4602, combined with 2 mg/kg l -dopa, causes a higher increase of catecholamines than 20 mg/kg l -dopa alone in the striatum and probably in the hypothalamus of rat brain, whereas in the other brain areas the amine rise is equal after both treatments. MK 485 in doses equimolar to Ro 4–4602 has a less marked effect in all brain areas. Either inhibitor (10–2 μmol/kg) combined with 2 mg/kg l -dopa causes markedly less increase of catecholamines than 20 mg/kg l -dopa alone in the rat heart. Ro 4–4602, in small single doses, used at present in the treatment of Parkinson's syndrome, markedly inhibits the extracerebral decarboxylation of l -dopa in man and rats and is more potent than MK 485.     

Role of rBAT Gene Products in Cystinuria

To investigate whether rBAT gene products function as a crystine transporter component or as a transport activator, we microinjected several C–terminal deletion mutants of rBAT cRNA into Xenopus oocytes, and measured transport activity for arginine, leucine and cystine in the presence and absence of sodium. Wild type rBAT significantly stimulated the uptake of all 3 amino acids 10–20 fold compared to control mutants. On the other hand, no mutant, except a Δ511–685 mutant, stimulated the uptake of these amino acids. However, the Δ511–685 mutant significantly increased the uptake of arginine. In the presence of sodium, the Δ511–685 mutant also increased the uptake of leucine. The Δ511–685 mutant did not stimulate crystine uptake in the presence and absence of sodium. Furthermore, inhibition of L–arginine uptake by L–homoserine was seen only in the presence of sodium. These results suggest that mutant rBAT stimulates the endogenous amino acid transport system y⁺ in oocytes. Finally, rBAT gene products, as the primary cause of cystinuria, may function as activators of the amino acid transport system in renal brush border membrane.     

Expression of CXCR4 indicates poor prognosis in patients with clear cell carcinoma of the ovary

Recent reports have shown that CXCR4 is expressed in various solid tumors and is involved in tumor development and metastasis. We examined the distribution and expression of this molecule in clear cell carcinoma of the ovary to elucidate its clinical significance. Paraffin sections from clear cell carcinoma of the ovary tissues (n = 42) were immunostained with CXCR4 antibody, and the staining intensities were evaluated. The clinicopathologic factors examined were age, FIGO (International Federation of Gynecology and Obstetrics) staging, preoperative value of cancer antigen 125 test, and residual tumor after cytoreductive surgery. Overall survival and progression-free survival were evaluated using the Kaplan-Meier method, and multivariate analysis was completed using Cox proportional hazards analysis. Of the 42 carcinomas, lower level CXCR4 immunoexpression was observed in 21 cases (50.0%) (CXCR4(low) group); and higher level immunoexpression, in 21 cases (50.0%) (CXCR4(high) group). Five-year overall survival was significantly poorer in the CXCR4(high) group than in the CXCR4(low) group (overall survival, CXCR4(low) group [90.2%], CXCR4(high) group [50.3%]; P = .0002). In addition, CXCR4(high) immunoexpression significantly predicted a poorer progression-free survival when compared with lower expression (5-year progression-free survival, CXCR4(low) group [90.5%], CXCR4(high) group [36.2%]; P < .0001). Furthermore, multivariate analyses including the age, preoperative cancer antigen 125 test value, FIGO stage, and CXCR4 expressions revealed that CXCR4(high) expression was an independent prognostic factor for poorer overall survival and progression-free survival of patients with clear cell carcinoma of the ovary (overall survival, P = .0011; progression-free survival, P = .0008, respectively). Our current study suggested that the assessment of CXCR4 immunoreactivity may be a useful prognostic indicator and that CXCR4 may play a critical role in the progression of clear cell carcinoma of the ovary.     

Regional arterial stiffness associated with ischemic heart disease in type 2 diabetes mellitus

Arterial stiffness is increased in type 2 diabetes mellitus, and diabetes preferentially affects arterial stiffness of the central (elastic, capacitive) over peripheral (muscular, conduit) arteries. We hypothesized that arterial stiffness of the central artery may be more closely associated with ischemic heart disease (IHD) than stiffness of peripheral arteries in type 2 diabetes mellitus. The subjects were 595 type 2 diabetes patients including 70 with IHD. Arterial stiffness was measured as pulse wave velocity (PWV) in the heart-carotid, heart-femoral, heart-brachial, and femoral-ankle regions. The PWV values of the four segments correlated with each other in patients without IHD. However, the correlations were less impressive in those with IHD, suggesting unequal stiffening of regional arteries in IHD. As compared with patients without IHD, the IHD group showed significantly higher PWV values of the four arterial segments, particularly of the heart-femoral region. The presence of IHD was significantly associated with higher heart-femoral PWV, and this association remained significant and independent of other factors in a multiple logistic regression analysis. Pulse pressure was more strongly correlated with PWV of the heart-femoral than other arterial regions. Thus, diabetic patients with IHD have increased stiffness of arteries, particularly of the aorta, supporting the concept that central arterial stiffness plays an important role in the development of IHD.     

Novel compound heterozygous ATP6V0A4 mutations in an infant with distal renal tubular acidosis

A Japanese infant presenting with vomiting, failure to thrive, metabolic acidosis, and hyperammonemia was finally diagnosed with autosomal recessive distal renal tubular acidosis (dRTA). Hyperchloremic metabolic acidosis, hypokalemia, a normal serum anion gap, a positive urine anion gap, nephrocalcinosis, and high urine pH despite systemic acidemia were consistent with the cardinal manifestations in dRTA. Mutational analysis of the ATP6V0A4 gene revealed novel compound heterozygous mutations: Ile549fsX580 and Ile557Leu558del. The father was found to be heterozygote for the former mutation, the mother heterozygote for the latter. This is the first case of dRTA with hyperammonemia in which the ATP6V0A4 mutations were identified. dRTA should be considered in the differential diagnosis of children presenting with hyperammonemia. Additionally, in a possible case of autosomal recessive dRTA with normal hearing, mutational analysis of ATP6V0A4 gene may be recommended first to confirm the diagnosis.     

Allergic Potency of Japanese Cedar Pollen Cry j 1 Is Reduced by a Low Concentration of Hypochlorous Acid Generated by Electolysis

BackgroundAlthough Japanese cedar (Cryptomeria japonica) pollinosis has developed into a health problem, few methods eradicate indoor allergens completely. In a recent study, however, the effectiveness of inactivation with sodium hypochlorite (NaOCl) treatment was revealed. Therefore, the present study aimed to elucidate the ability of chlorine bleach (NaOCl) to reduce the immunogenicity of the major allergenic protein of Japanese cedar (Cry j 1).MethodsSodium dodecyl sulfate polyacrylamide gel electrophoresis, Western blotting, enzyme-linked immunosorbant assay, and skin testing were carried out in 7 individuals.ResultsThe allergenic protein was undetectable using sodium dodecyl sulfate polyacrylamide gel electrophoresis and silver staining at a sodium hypochlorite/allergenic protein molar ratio of 457. Western blotting with human sera showed the same dose-dependent efficacy. The immunogenicity of the purified protein and cedar pollen was also demonstrated on enzyme-linked immunosorbant assay to be reduced by sodium hypochlorite treatment in a dose- and time-dependent manner. Moreover, sodium hypochlorite-treatment inhibited the skin test response to the protein in all 7 individuals.ConclusionsHypochlorous acid generated by electrolysis is an effective method for significantly reducing the immunogenicity of Cry j 1.     

Is pancreatectomy with arterial reconstruction a safe and useful procedure for locally advanced pancreatic cancer?

Background/purpose

We often encounter unresectable pancreatic cancer due to invasions of the major vessels. Vascular resection for locally advanced pancreatic cancers has an advantage in en block local resection. There are potential cases in which good outcomes can be achieved by arterial resection.

Methods

Pancreatectomy (including total pancreatectomy in 15 cases, pancreatoduodenectomy in 7 cases and distal pancreatectomy in one case) was performed in 23 cases of invasive ductal carcinoma of the pancreas, in combination with resection and reconstruction of the hepatic artery in 15 cases, the superior mesenteric artery in 12 cases (there are overlaps) and the portal vein in 20 cases.

Results

The median operating time was 686 min (416–1,190 min) and the median blood loss was 2,830 ml (440–19,800 ml). This shows that the surgery was highly-invasive. The operative mortality rate was 4.3%. On the basis of the UICC classification, there were 2 cases of Stage IIa, 4 cases of Stage IIb, 9 cases of Stage III, 8 cases of Stage IV, while there were 18 cases (78.3%) of R0 resection. On the other hand, the final histological findings showed that there were 8 cases (34.8%) of M1 (liver and non-regional lymph node metastases), so it is thought that decisions on operative indications should be not be made slightly. As for the overall survival rate, the 1-year survival rate was 51.2% and the 3-year survival rate was 23.1% while the median survival time (MST) was 12 months. As for 15 cases of M0, the 1-year survival rate was 61.9% and the 4-year survival rate was 38.7% while the MST was 16 months. On the other hand, the MST was poor (10 months) in 8 cases of M1, showing that a statistically significant difference was observed depending upon the degree of metastasis (log-rank P = 0.0409). In 18 cases of R0, the 1-year survival rate was 67.2%, the 4-year survival rate 30.2% and the MST 13 months, respectively, while in 5 cases of R1 and R2, the MST was 6 months, showing that there was a statistically significant difference between R0 cases and R1, R2 cases (log-rank P = 0.0002).

Conclusions

Further discussion is required concerning surgical indications and significance. However, it is thought that resection is useful only when surgery of R0 has taken place for selected locally advanced pancreatic cancer (M0).