Metabolic syndrome is not a predictor for cardiovascular events in Japanese patients with diabetes mellitus asymptomatic for coronary artery disease: A retrospective analysis of the J-ACCESS-2 study

Purpose

Patients with metabolic syndrome (MetS) have potentially higher risk for cardiovascular events. The aim of this study was to evaluate the effect of MetS on cardiac events in type-2 diabetic patients asymptomatic for coronary artery disease (CAD) in a Japanese population.

Methods

A total of 485 patients from a J-ACCESS-2 investigation with stress-gated myocardial perfusion imaging (MPI) and quantitative-gated MPI analysis were examined. Cardiovascular hard events (cardiac death and acute coronary syndrome) and total events during a 3-year follow-up were analyzed.

Results

The MetS group (n = 229) had higher incidence of hypertension, dyslipidemia, and ventricular dilatation than the non-MetS group (n = 256). The hard events were 8 and 12 for the MetS and non-MetS groups (P = n.s.), and total events were 31 and 31 for each of these groups, respectively (P = n.s.). Significant variables related to total cardiovascular events included age, current smoking, insulin use, total cholesterol, ejection fraction, summed stress score ≥ 9, and summed difference score ≥ 2. Cox proportional hazard analysis and Kaplan-Meier survival analysis showed that only the summed stress score was related to total events (P = .01), and the presence and the number of items for MetS criteria were not.

Conclusion

In patients with type 2 diabetes asymptomatic for CAD, cardiovascular events and ischemia are as common in diabetic patients without MetS as in those with MetS. A high MPI defect score is related to total events including cardiac and cerebrovascular events.     

Comparison of the Central Adrenal Vein and the Common Trunk of the Left Adrenal Vein for Adrenal Venous Sampling

PurposeTo compare left adrenal venous sampling (AVS) in two locations: the central adrenal vein and the common trunk.Materials and MethodsA total of 22 patients (12 men and 10 women; mean age, 50 y; range, 26–65 y) who were suspected of having primary aldosteronism (PA) and underwent successful AVS with cortisol concentration measurement and/or venography between November 2010 and August 2011 were retrospectively analyzed. In regard to the left adrenal vein, collections were done at two locations: at the common trunk below the confluence of the inferior phrenic vein and at the central adrenal vein, which was above the confluence. The effects of the inflow from the inferior phrenic vein on plasma aldosterone and cortisol levels were analyzed.ResultsEight patients had bilateral hypersecreting lesions and 13 had a unilateral lesion. One was diagnosed as having secondary hypertension other than PA. The median cortisol levels below and above the confluence were 129 μg/dL (range, 21–400 μg/dL) and 215 μg/dL (range, 21–690 μg/dL), respectively. The median aldosterone levels were 2,120 pg/mL (range, 164–42,700 pg/mL) and 4,275 pg/mL (range, 119–59,000 pg/mL), respectively. The median aldosterone/cortisol (A/C) ratios were 244 (range, 34–2,401) and 278 (range, 25–2,251), respectively. Cortisol and aldosterone levels were significantly higher above the confluence (P = .0050 and P = .0003, respectively), whereas the A/C ratio showed no significant difference (P = .12).ConclusionsAlthough higher levels of cortisol and aldosterone were obtained upstream, A/C ratio was not significantly different between the central adrenal vein and the common trunk.     

Respiratory-gated F-FDG PET/CT for the diagnosis of liver metastasis

Purpose

To ascertain the role of respiratory-gated PET/CT with ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) for accurate diagnosis of liver metastasis.

Materials and methods

Forty patients with suspected liver metastasis underwent conventional whole-body PET/CT scan initially, followed by respiratory-gated PET/CT scan covering the liver. Visual detectability (using a 5-point confidence scale), maximum standardized uptake value (SUVmax) and metabolic tumor volume (MTV) of hepatic metastatic lesions were assessed for three data sets including ordinary whole-body (WB) scan, and non-respiratory-gated (nRG) and respiratory-gated (RG) scans. Results of enhanced CT and/or MRI, or clinical and radiological follow-up were used for reference.

Results

Sixteen of the patients were found to have 53 metastatic lesions in the liver. Patient-based accuracy of WB, nRG, and RG was 92.5%, 95.0%, and 97.5%, respectively, with a lesion-based detection rate of 67.9%, 73.6%, and 73.6%, respectively. The average SUVmax of 34 liver metastatic lesions for WB, nRG, and RG was 6.60 ± 2.34, 7.19 ± 2.66, and 8.08 ± 3.24, respectively. SUVmax for RG was significantly higher than that for WB (p = 0.0069). The average MTV of these 40 lesions for the three protocols was 5.32 ± 4.78 cm³, 5.07 ± 4.73 cm³, and 4.73 ± 4.67 cm³, respectively. Among the three protocols, RG showed the best visual and quantitative evaluation for diagnosis of liver metastasis.

Conclusion

Respiratory-gated PET/CT allows more accurate identification of liver metastases than non-respiratory-gated PET/CT.     

Changes in bone turnover markers during 14-day 6° head-down bed rest

Osteoporosis caused by exposure to microgravity represents a serious clinical concern, but the mechanisms have yet to be fully elucidated. The present research aimed to elucidate the effects of microgravity environments on bone turnover, with a specific focus on changes in bone resorption markers such as type I collagen cross-linked N-telopeptides (NTx) and deoxypyridinoline (Dpyr), for which scant data are available regarding detailed time course. Methods using 6° head-down bed rest were utilized to simulate a microgravity environment. Eleven adult male volunteers underwent 6° head-down bed rest for 14 days; measurements were made of serum and urine Ca concentrations, in addition to osteocalcin (OC), bone alkaline phosphatase (ALP), NTx, and Dpyr as bone turnover markers. By the end of bed rest, concentrations of bone ALP had significantly increased, but OC displayed a tendency toward decrease. Concentrations of Dpyr significantly increased from day 6, remaining elevated until the end of bed rest. Concentrations of NTx significantly increased on day 13 and at the end of bed rest. Serum and urinary concentrations of Ca increased significantly at the end of bed rest. Bone ALP represents a relatively early marker of osteoblast differentiation at the matrix maturation phase and OC is a late marker in osteoblast differentiation at the calcification phase. The present results therefore suggest an absolute increase in bone resorption and normal or reduced bone formation, together causing prominent uncoupling and rapid bone loss after simulated microgravity. Moreover, the present results suggest that bone resorption is enhanced at an early stage of exposure to microgravity environments.     

Interim evidence of the renoprotective effect of the angiotensin II receptor antagonist losartan versus the calcium channel blocker amlodipine in patients with chronic kidney disease and hypertension: a report of the Japanese Losartan Therapy Intended for Global Renal Protection in Hypertensive Patients (JLIGHT) Study

Background. Insufficiency of renal function and high blood pressure influence each other and eventually result in life-threatening endstage renal disease. It has been proposed that proteinuria per se is a determinant of the progression of chronic kidney disease (CKD). The therapeutic strategy for patients with proteinuric CKD and hypertension should therefore be targeted with a view not merely toward blood pressure reduction but also toward renoprotection. Methods. We examined the effect of the angiotensin (AT)₁ receptor antagonist losartan and the calcium channel blocker amlodipine, throughout a period of 12 months, on reduction of blood pressure and renoprotection. This was done by assessing amounts of urinary protein excretion, serum creatinine (SCr), and creatinine clearance (CCr) in patients with hypertension (systolic blood pressure [SBP] 140mmHg or diastolic blood pressure [DBP] 90mmHg) and CKD (male, body weight [BW] 60kg: 1.5 SCr < 3.0mg/dl; female or male BW < 60kg: 1.3 SCr < 3.0mg/dl), manifesting proteinuria of 0.5g or more/day. Losartan was administered once daily at doses of 25 to 100mg/day, and amlodipine was given once daily at 2.5 to 5mg/day. No antihypertensive combination therapy was allowed during the first 3-month period. Results. A 3-month interim analysis revealed that, despite there being no difference in blood pressure between the two groups, there was a significant reduction in 24-h urinary protein excretion in the losartan group (n = 43), but there was no change in the amlodipine group (n = 43). Analysis of stratified subgroups with proteinuria of 2g or more/day and less than 2g/day showed that losartan lowered proteinuria by approximately 24% in both subgroups, while amlodipine lowered proteinuria by 10%, but only in the subgroup of less than 2g/day (NS). SCr and CCr did not change throughout the period of 3 months in either group. No severe or fatal adverse event was experienced in either group during the study period. Conclusions. Losartan appeared to be efficacious for renoprotection in patients with proteinuric CKD and hypertension, with the mechanism being independent of its antihypertensive action.     

NPHS2 mutations in sporadic steroid-resistant nephrotic syndrome in Japanese children

Podocin is an integral membrane protein encoded by NPHS2, which is mapped to 1q25-31 and is exclusively expressed in glomerular podocytes. NPHS2 mutations are responsible for autosomal recessive familial steroid-resistant nephrotic syndrome (SRNS) with minor glomerular abnormalities or focal segmental glomerulosclerosis (FSGS), which is characterized by early childhood onset (age less than 6 years) and rapid progression to chronic renal insufficiency. This gene mutation is also responsible for an adolescent/adult onset form of autosomal recessive familial FSGS with heavy proteinuria. It has been demonstrated that sporadic SRNS and heavy proteinuria are also due to NPHS2 gene mutations. We isolated genomic DNA from 36 Japanese children with chronic renal insufficiency caused by SRNS or heavy proteinuria, and analyzed all eight exons and exon-intron boundaries of NPHS2 using the polymerase chain reaction and direct sequencing. The age at onset of disease was 3.9+/-0.5 years. There were 29 patients with SRNS and 7 with heavy proteinuria without nephrotic syndrome at the onset, but all patients developed chronic renal insufficiency 4.6+/-0.8 years after the onset. A new homozygous missense variant of NPHS2, G34E (G101A) in exon 1, was detected in 1 of 36 patients. However, this homozygous variant was also found in 1 of 44 normal controls, suggesting that the mutation is a polymorphism. Two silent variants (T954C and A1038G) in exon 8 of this gene were also identified in some of the patients and normal controls, indicating that the silent variants are also polymorphisms. There was no significant difference in the genotypic and allelic frequencies of T954C and A1038G polymorphisms between the patients and normal controls. In conclusion, NPHS2 gene mutations are not a major cause of chronic renal insufficiency caused by sporadic SRNS or heavy proteinuria in Japanese children.     

Induction of apoptosis of articular chondrocytes and suppression of articular cartilage proteoglycan synthesis by heat shock

We investigated cellular and matrix responses of articular cartilage to heat shock. Rat articular cartilage was pretreated at 37 degrees C for 24 h before being exposed to 48 degrees C for 10 min and subsequently incubated at 37 degrees C for 1, 2, 4, 7, 10, and 14 days. Following heat shock, a terminal deoxynucleotidyl transferase nick end labeling assay showed that articular chondrocyte apoptosis appeared at day 1, peaked at day 7, and declined by day 14. Analysis by transmission electron microscopy confirmed that the chondrocytes had characteristic morphological features of apoptosis; immunohistochemical staining revealed that caspase-3 activity in chondrocytes increased, 3-B-3-positive articular chondrocytes decreased in number, and the expression of 3-B-3 native epitope in articular chondrocytes was reduced. Safranin-O staining revealed that depletion of proteoglycans in the matrix was not found in any group. Morphological and biochemical evidence from this study suggested that heat shock at 48 degrees C induced articular chondrocyte apoptosis and suppressed proteoglycan synthesis of articular cartilage in vitro. This study thus provides evidence of the onset of osteoarthritis induced by heat shock and a basis for choosing a temperature at which malignant bone tumor cells can be killed with minimal damage to articular cartilage.     

Clinical impact of the callosal angle in the diagnosis of idiopathic normal pressure hydrocephalus

The utility of measuring the corpus callosal angle (CA) for the diagnosis of idiopathic normal pressure hydrocephalus (INPH) was investigated. Three-dimensional magnetic resonance imaging (MRI) was performed in 34 INPH patients, 34 Alzheimer’s disease (AD) patients, and 34 normal control (NC) subjects. Measurement of the CA on the coronal MR images of the posterior commissure perpendicular to the anteroposterior commissure plane was performed for all subjects. The CA of the INPH group (mean ± SD, 66 ± 14°) was significantly smaller than those of the AD (104 ± 15°) and NC (112 ± 11°) groups. When using the threshold of the mean − 2SD value of the NC group (= 90°), an accuracy of 93%, sensitivity of 97%, and specificity of 88% were observed for discrimination of INPH from AD patients. Measuring the CA helps in differentiating INPH patients from AD and normally aged subjects.     

Intercellular adhesion molecule-1-deficient mice are resistant against renal injury after induction of diabetes

Diabetic nephropathy is a leading cause of end-stage renal failure. Several mechanisms, including activation of protein kinase C, advanced glycation end products, and overexpression of transforming growth factor (TGF)-beta, are believed to be involved in the pathogenesis of diabetic nephropathy. However, the significance of inflammatory processes in the pathogenesis of diabetic microvascular complications is poorly understood. Accumulation of macrophages and overexpression of leukocyte adhesion molecules and chemokines are prominent in diabetic human kidney tissues. We previously demonstrated that intercellular adhesion molecule (ICAM)-1 mediates macrophage infiltration into the diabetic kidney. In the present study, to investigate the role of ICAM-1 in diabetic nephropathy, we induced diabetes in ICAM-1-deficient (ICAM-1(-/-)) mice and ICAM-1(+/+) mice with streptozotocin and examined the renal pathology over a period of 6 months. The infiltration of macrophages was markedly suppressed in diabetic ICAM-1(-/-) mice compared with that of ICAM-1(+/+) mice. Urinary albumin excretion, glomerular hypertrophy, and mesangial matrix expansion were significantly lower in diabetic ICAM-1(-/-) mice than in diabetic ICAM-1(+/+) mice. Moreover, expressions of TGF-beta and type IV collagen in glomeruli were also suppressed in diabetic ICAM-1(-/-) mice. These results suggest that ICAM-1 is critically involved in the pathogenesis of diabetic nephropathy.     

Retroportal Hepaticojejunostomy for Extended Resection of Hilar Bile Ducts

High hepatic duct resection sometimes is unavoidable in achieving curative resection of hilar cholangiocarcinoma, as tumor cells can extend further than expected along the bile ducts from the macroscopically evident cancer. In patients undergoing left hemihepatectomy with caudate lobectomy whose bile duct must be severed at the subsegmental bile duct levels, the orifices of the posterior bile ducts would lie behind the right portal vein. Conventional hepaticojejunostomy would be risky in such cases because an anastomosis performed in the usual manner would be subjected to strain. Instead, between 2002 and 2004, three patients underwent retroportal hepaticojejunostomy using a jejunal limb mobilized and positioned behind the hepatoduodenal ligament. Primary tumors were classified as type IV in the Bismuth–Corlette classification. Tension-free hepaticojejunal anastomosis was performed successfully in all three patients; insufficiency of the hepaticojejunostomy did not develop. Neither early nor late complications directly related to this method occurred. Retroportal hepaticojejunostomy, thus, permits more peripheral resection of the hepatic duct while providing a sufficient operative field for safe, tension-free anastomosis. This technique is very useful for patients undergoing left hemihepatectomy requiring high hilar resection of the bile duct.