Effect of Ezetimibe on LDL-C Lowering and Atherogenic Lipoprotein Profiles in Type 2 Diabetic Patients Poorly Controlled by Statins.

BACKGROUND: There exists a subpopulation of T2DM in whom first-line doses of statin are insufficient for optimally reducing LDL-C, representing a major risk of CVD. The RESEARCH study focuses on LDL-C reduction in this population along with modifications of the lipid profiles leading to residual risks. METHODS: Lipid changes were assessed in a randomized, multicenter, 12-week, open-label study comparing a high-potency statin (10mg of atorvastatin or 1mg of pitavastatin) plus ezetimibe (EAT: n = 53) with a double dose of statin (20mg of atorvastatin or 2mg of pitavastatin) (DST: n = 56) in DM subjects who had failed to achieve the optimal LDL-C targets. Lipid variables were compared with a primary focus on LDL-C and with secondary focuses on the percentage of patients who reached the LDL-C targets and changes in the levels of RLP-C (remnant like particle cholesterol) and sd-LDL-C, two characteristic atherogenic risks of DM. RESULTS: The reduction of LDL-C (%), the primary endpoint, differed significantly between the two groups (-24.6 in EAT vs. -10.9 in DST). In the analyses of the secondary endpoints, EAT treatment brought about significantly larger reductions in sd-LDL-C (-20.5 vs. -3.7) and RLP-C (-19.7 vs. +5.5). In total, 89.4% of the patients receiving EAT reached the optimized treatment goal compared to 51.0% of the patients receiving DST. The changes in TC (-16.3 vs. -6.3) and non-HDL-C (-20.7 vs. -8.3) differed significantly between the two groups. CONCLUSION: Ezetimibe added to high-potency statin (10 mg of atorvastatin or 1 mg of pitavastatin) was more effective than the intensified-dose statin (20 mg of atorvastatin or 2 mg of pitavastatin) treatment not only in helping T2DM patients attain more LDL-C reduction, but also in improving their atherogenic lipid profiles, including their levels of sd-LDL-C and RLP-C. We thus recommend the addition of ezetimibe to high-potency statin as a first line strategy for T2DM patients with insufficient statin response. TRIAL REGISTRATION: The UMIN Clinical Trials Registry UMIN000002593.

Incretin secretion stimulated by ursodeoxycholic acid in healthy subjects.

Bile acids play an important role in post-prandial glucose metabolism by stimulating release of glucagon-like peptide-1 (GLP-1) via the G-protein-coupled receptor TGR5, which is expressed in intestinal L cells. Thus, bile acid sequestrants are expected to stimulate secretion of endogenous GLP-1 through TGR5. We investigated incretin and insulin secretion after a meal with and without ursodeoxycholic acid (UDCA), a widely used therapeutic agent in liver diseases, in 7 non-diabetic Japanese subjects. We found that UDCA intake resulted in higher GLP-1 secretion (area under the curve [AUC] of 0-60 min after meal without UDCA, 450 ± 162 mmol·min/l; with UDCA, 649 ± 232 mmol·min/l, P = 0.046) and lower blood glucose (AUC of 0-60 min without UDCA, 7191 ± 250 mg·min/dl; with UDCA, 6716 ± 189 mg·min/dl, P = 0.001) , although we did not find statistically significant insulin increase by UDCA intake (AUC of 0-60 min without UDCA, 1551 ± 418 µU·min/ml; with UDCA, 1941 ± 246 µU·min/ml, P = 0.065). These results suggest that UDCA increases bile-induced GLP-1 secretion. Ours is the first report showing increased GLP-1 secretion and decreased blood glucose in response to UDCA.

Isolated adrenocorticotropin deficiency associated with delirium and takotsubo cardiomyopathy.

We report a 65-year-old woman with isolated adrenocorticotropic hormone (ACTH) deficiency. The patient was transported to the emergency outpatient department by ambulance complaining of malaise and nausea. Because her laboratory data revealed hyponatremia, we performed endocrinological examinations and diagnosed isolated ACTH deficiency. After admission, she went into a delirious state and suffered from takotsubo cardiomyopathy due to adrenal insufficiency. Replacement therapy with hydrocortisone sufficiently improved her delirium and cardiomyopathy. We conclude that her unstable mental state and myocardial dysfunction were closely related to adrenal insufficiency and suggest that adrenal crisis may cause delirium and Takotsubo cardiomyopathy.

Association of CYP19 gene polymorphism with vertebral fractures in Japanese postmenopausal women.

This study investigates aromatase gene polymorphism, which might influence bone strength in terms of mineral density and quality. We explored the relationship between CYP19 polymorphisms and vertebral fractures in postmenopausal Japanese women. In addition, we compared estrogen and testosterone levels in Japanese postmenopausal women with and without fractures. Osteoporotic postmenopausal women showed higher incidences of vertebral fractures than osteopenic women or women with normal lumbar bone mineral density (L2-4 BMD). Estrogen concentrations in postmenopausal women were associated with BMD; however, no association was found between sex hormone levels and the presence of fractures. The C allele rs2470152 was significantly associated with increased risk of vertebral fractures (P = 0.04), whereas none of the CYP19 polymorphisms showed differences in sex steroid levels between subjects with and without fractures. Allelic variants of aromatase genes appear to interact to influence the risk of vertebral fractures in postmenopausal Japanese women.

The efficacy of home-based muscle training for the elderly osteoporotic women: the effects of daily muscle training on quality of life (QoL).

There is little evidence that home-based muscle training through exercise improves the muscle strength and QoL of elderly osteoporotic women. The efficacy of home-based daily exercise on muscle strength of the upper and lower extremities and QoL were examined in elderly osteoporotic women by means of a case-controlled study that was designed and conducted between 2005 and 2006. Sixty-three osteoporotic women over 60 years of age were randomly assigned to 12 months of muscle exercise or to no intervention. The outcomes were changes in muscle strength and quality of life (QoL). Ultimately, sixty-two participants completed the 12 months program. Before the start of home-exercise training, the lumbar spine bone mineral density (BMD) and femoral neck BMD values in the intervention group were significantly lower than those in the control group (p<0.05). Grip strength and maximum walking speed increased significantly in the intervention group (p<0.05). In terms of QoL, physical functioning was improved by home-based exercise in the intervention group (p=0.05), while there were no improvements in any of the categories of Short-Form 36 in the control group. Our results suggest that home-based training is effective for elderly osteoporotic women in improving not only muscle strength in upper and lower extremities but also physical functioning in QoL.

[Risk factors for falls in diabetics and measures for prevention].

The reasons of falls for diabetics are low visual acuity, sensory disturbance by neuropathy, dizziness by orthostatic hypotension and low cognition of hyperglycemia or hypoglycemia. In order to prevent diabetics from fractures we should minimize the numbers of these factors. The diabetics who have already complicated with must strictly control blood glucose levels and always take glucose powders if they had hypoglycemia. Additionally diabetics with stroke and myodystrophy must take muscle training of lower extremities and vitamin D supplementation.

Torsade de pointes associated with recurrent ampulla cardiomyopathy in a patient with idiopathic ACTH deficiency.

We describe here a patient with torsade de pointes associated with recurrent ampulla cardiomyopathy, who was later proven to suffer from idiopathic AC TH deficiency. A 70-year-old man was admitted to our hospital for bacterial pneumonia. A cardiac examination performed on admission revealed ampulla cardiomyopathy, which improved spontaneously as the pneumonia was cured. Two months after discharge, he was transferred to our hospital for relapse of the pneumonia. After the second admission, the pneumonia subsided with antibiotic treatment and his general condition ameliorated gradually. However, on the 20(th) hospital day, he was found lying on the floor in a prone position in cardiopulmonary arrest. Cardiac telemetry monitoring showed torsade de pointes worsening to ventricular fibrillation, and immediate cardiac defibrillation was performed. The electrocardiogram after successful defibrillation showed inverted T waves in the chest leads with long QT intervals, and subsequent emergent coronary catherization revealed the recurrence of ampulla cardiomyopathy. Thereafter, endocrinological examinations for the diagnosis of sustained hyponatremia demonstrated secondary adrenal insufficiency caused by idiopathic AC TH deficiency. The cardiomyopathy resolved promptly after steroid hormone replacement without relapse as did the hyponatremia. Patients with ampulla cardiomyopathy or ventricular fibrillation without apparent etiology should be examined for adrenal function. If begun as soon as adrenal insufficiency is diagnosed, immediate steroid replacement therapy can prevent the deterioration and relapse of cardiac involvement.

Implications of measuring soluble receptor activators of nuclear factor-kappaB ligand and osteoprotegerin in bone metabolism of elderly women.

BACKGROUND/AIM: The discovery of a signaling system consisting of a soluble receptor activator of the NF-kappaB ligand (sRANKL) and its decoy receptor osteoprotegerin (OPG) has provided a valuable key to understanding the pathophysiology of the bone microenvironment. We conducted a cross-sectional study of the role of sRANKL and OPG levels as they relate to bone metabolism in elderly postmenopausal women with and without osteoporosis. SUBJECTS AND METHODS: Fifty-one elderly women with or without osteoporosis were enrolled in the study. Bone alkaline phosphatase, osteocalcin, urinary deoxypyridinoline and urinary type I collagen N-terminal telopeptide (NTx) were measured as bone metabolic markers. Serum levels of OPG and sRANKL were measured by sandwich enzyme-linked immunosorbent assay and the lumbar spine bone mineral density (LSBMD) with dual-energy X-ray absorptiometry. Furthermore, we compared the sRANKL and OPG levels in elderly women with and without vertebral fractures (VFs). RESULTS: In elderly postmenopausal women, there was a significant positive association between OPG levels and the T score and Z score of LSBMD (r = 0.345 and p = 0.014 for T score; r = 0.438 and p = 0.001 for Z score). sRANKL levels were not significantly correlated with T score, Z score of LSBMD, or any of the four bone metabolic markers. There were no significant differences in the sRANKL levels among the three groups (normal bone mineral density, osteopenia, and osteoporosis), but a trend toward a higher value in the osteoporosis group. The sRANKL/OPG ratio was negatively correlated with the T score and Z score of LSBMD (r = -0.336, p = 0.017; r = -0.384, p = 0.006, respectively), but not with any of the four bone metabolic markers. OPG levels in elderly women with VFs were lower than in those without VFs (p = 0.05). Multiple regression analysis showed that OPG and NTx are contributing factors to bone loss in elderly women (p = 0.014 and 0.012, respectively). CONCLUSION: The OPG level provides a good predictor of osteoporosis as well as NTx in elderly women; additionally, the findings suggest that OPG might protect elderly women from bone loss or fractures.

Primary aldosteronism due to unilateral adrenal microadenoma in an elderly patient: efficacy of selective adrenal venous sampling.

We encountered a case of drug-resistant hypertension and hypokalemia. Laboratory data suggested primary aldosteronism (PA). Computed tomography imaging appeared normal for a long duration with a left-sided nodule appearing far later; adrenal scintigraphy was first normal, and the second test showed right-sided uptake. However, a repeat selective adrenal venous sampling (SAVS) indicated a left-sided lateralization of the hypersecretion of aldosterone. Left adrenectomy was performed, and his clinical symptoms improved. The histopathological findings demonstrated the aldosterone-producing microadenoma with secondary micronodules. In conclusion, SAVS should be performed to determine the laterality of PA with obscure CT imaging.

[The implementation of personalized treatment for osteoporosis].

AIM: To establish personalized treatment of osteoporosis. METHODS: A T869-->C polymorphism in exon 1 of the transforming growth factor-beta1 gene, which results in a Leu-->Pro substitution at amino acid 10, is reported to be associated with the rate of bone loss as well as the response to active vitamin D treatment. Therefore, we determined this single nucleotide polymorphism (SNP) to estimate the need of active vitamin D treatment. We also determined serum level of 25 hydroxy-vitamin D to evaluate a degree of vitamin D fulfillment. Based on these data, we categorized postmenopausal patients into four groups; C homozygote with vitamin D deficiency patients to whom 1 microg/day active vitamin D was administered, C homozygote without vitamin D deficiency patients or those who bore at least one T-allele with vitamin D deficiency to whom 0.5 microg/day active vitamin D was administered, and patients who bore at least one T-allele without vitamin D deficiency to whom no drug was given. The patients were checked up every 6 months with regard to changes in bone mineral density and occurrence of fresh fractures. RESULTS: The SNP was associated with prevalent vertebral fractures; the frequency of the T allele was significantly greater in patients with vertebral fractures. Furthermore, the serum level of 25 hydroxy-vitamin D was significantly lower in patients with vertebral fractures, which were observed in 17 out of 34 patients who bore at least one T-allele as well as vitamin D deficiency, while only 2 of 15 homozygous C-allele carriers without vitamin D deficiency suffered from fractures. CONCLUSION: These findings suggest that the SNP in combination with the serum level of 25 hydroxy-vitamin D can predict fracture risk in postmenopausal osteoporosis.

Remarkable increase in lumbar spine bone mineral density and amelioration in biochemical markers of bone turnover after parathyroidectomy in elderly patients with primary hyperparathyroidism: a 5-year follow-up study.

We evaluated the efficacy of parathyroidectomy (PTX) on bone mineral density (BMD) and hormonal and biochemical markers of bone metabolism in elderly primary hyperparathyroidism (PHPT) patients, and followed these patients for 5 years after PTX. Eleven PHPT patients were enrolled and were followed for 5 years by measuring lumbar spine BMD (LSBMD), femoral BMD (FBMD), radial BMD (RBMD), parathyroid hormone (PTH), 1,25-dihydroxyvitamin D [1,25(OH)(2)D], serum calcium (SCa), inorganic phosphate (iP), bone-specific alkaline phosphatase (BAP), intact osteocalcin (IOC), urinary excretion of type I collagen cross-linked N-telopeptide (NTx), and urinary deoxypyridinoline (DPD). PTX produced significant increases in LSBMD of 12%, 19%, and 29% as compared with pretreatment levels after 1, 3, and 5 years, respectively (P < 0.01, compared to baseline), whereas there was no significant increase in FBMD and a slight decrease in RBMD. SCa and iP levels remained normal over the five years. PTX also resulted in significant decreases in PTH, 1,25(OH)(2)D, BAP, IOC, NTx, and DPD that continued for at least 3 years after PTX. In conclusion, PTX seemed effective to normalize various markers of bone metabolism in elderly PHPT patients and is recommended to patients with low LSBMD to prevent future fractures. On the other hand, the use of PTX for low FBMD or RBMD patients requires further discussion.

[A case of Plummer disease that appeared in older old age after 10-year course of subclinical hyperthyroidism].

A 81-year-old woman with a thyroid tumor and subclinical hyperthyroidism since ten years ago was admitted to our hospital for palpitations and hyperthyroidism (FT(4) 1.75 ng/dl, FT(3) 5.37 pg/ml, TSH<0.03 microIU/ml). Although thyroid stimulating antibody (TSAb) was transiently and mildly positive, anti-TSH receptor antibody (TRAb), microsome test, and thyroid test were negative. Thyroid echogram showed an isoechoic nodule in the left lobe (33 x 42 x 22 mm) and a small nodule (10 x 15 x 9 mm) in right lobe. Thyroid scintiscan showed a hyperfunctional (hot) nodule in left thyroid lobe with suppressed uptake in the remainder of the gland. The uptake rate of thyroidal radioiodine ((123)I) in 24 hours was within the normal range (7.3%). Based on the above findings, a diagnosis of Plummer disease was made. Since she refused invasive surgical or radioiodine treatment, she was treated with 10 mg thiamazole daily. After treatment with propranolol and thiamazole, the thyrotoxic symptoms disappeared and thyroid function returned to normal level. She had osteoporosis but she had neither atrial fibrillation nor cardiac symptoms. This was a rare case of Plummer disease that appeared in extremely old age after a long course of subclinical hyperthyroidism.

Marked improvement of psychiatric symptoms after parathyroidectomy in elderly primary hyperparathyroidism.

Psychosomatic symptoms in primary hyperparathyroidism (PHPT) are various and include such conditions as obsessive-compulsive disorder, depression, anxiety, and paranoia. In the elderly the clinical features of the disease are often non-specific and difficult to diagnose. To quantify subjective symptoms of patients with hyperparathyroidism in the elderly, we determined whether these clinical manifestations resolved after surgical parathyroidectomy (PTX) in three PHPT patients over eighty years old. They were diagnosed with hypercalcemia, hypophosphatemia, high PTH concentrations, and osteoporosis. A single parathyroid adenoma was confirmed in each patient by Tc-MIBI scintigram, neck ultrasonography and computed tomographic scanning. PTX was performed in these three patients. Assessments of psychologic symptoms, using the Hamilton Rating Scale for Depression (HAM-D), serum calcium, and intact PTH were obtained before and after PTX. Mean weight of the resected adenomas was 438 +/- 138 mg (mean +/- SD). After PTX, serum calcium decreased from 11.1 +/- 0.5 to 9.2 +/- 0.5 mg/dl and intact PTH from 160.0 +/- 25.2 to 45.3 +/- 22.2 pg/ml. Total HAM-D scores in each patient decreased from 45 to 9, 17 to 1 and 15 to 5, respectively. Especially, there were marked improvements in depressive mood, psychomotor inhibition, anxiety and somatic symptoms after PTX. The quality of life in those patients was also improved by PTX. We propose here that PTX in elderly PHPT patients with psychiatric symptoms should be considered instead of oral administration, such as anti-depressants or bisphosphonates.

Postprandial reactive hypoglycemia in an oldest-old patient effectively treated with low-dose acarbose.

We recently encountered a 96-year-old Japanese woman who suffered from frequent hypoglycemia. Endocrinological and imaging data eliminated the possibility of insulinoma, whereas oral glucose tolerance testing revealed impaired glucose tolerance and subsequent reactive hypoglycemia. The patterns between insulin or C-peptide secretions and glucose excursions demonstrated that the discrepancy occurred in the late postprandial stage. Administration of small doses of alpha-glucosidase inhibitor (alpha-GI) dramatically inhibited the rapid rise and subsequent precipitous fall of plasma glucose. Reactive hypoglycemia may be one of the important cause of hypoglycemia in the elderly, and alpha-GI could effectively and safely prevent such hypoglycemic attacks in those patients.

A case of type 2 diabetes mellitus in an elderly patient with rapid attenuation of insulin secretion that resembled fulminant type 1 DM but with incomplete beta cell damage.

We recently encountered a 66-year-old Japanese man who had suffered from acute hyperglycemia following flu-like symptoms during treatment of type 2 diabetes. Despite significantly increased plasma glucose levels, HbA1c was only slightly elevated. The possibility of autoimmune type 1 diabetes was excluded because of negative islet-related autoantibodies. Serum levels of pancreatic exocrine enzymes, amylase, lipase, and elastase-l were elevated. However, the insulin-secreting function of his islets was not severely damaged. This case is particularly notable for two reasons. First, it showed a fulminant type 1 diabetes-like clinical onset, but his beta cell function was fairly preserved. Second, it developed during the treatment of type 2 diabetes in an elderly patient.

Substrate and laser power dependence of surface-enhanced Raman scattering from a silver oxide film.

We report a method to improve the efficiency of surface-enhanced Raman scattering (SERS) from a silver oxide film. A 632.8 nm He-Ne laser beam was focused on silver oxide films deposited on different substrates (silica, TiO2, Si). We found that the substrate material greatly affected the SERS efficiency, and that silica substrate showed the highest efficiency among the materials measured. Scanning electron microscopy observations revealed that silver nanoparticles were generated within the focused laser spot. Computer simulations of the thermal profile based upon data from experimental observations were also carried out. It was found that the temperature of the silver oxide film differed greatly according to the substrate. We infer that substrates that allow higher silver-oxide-film temperatures to be attained are more suitable for efficient SERS.

Diabetes mellitus complicated with rapidly progressive glomerulonephritis in an elderly patient.

An 88-year-old man with a 30-year history of type 2 diabetes and a 3-year history of chronic renal failure was admitted for evaluation of anasarca. On admission, findings of nephrotic syndrome and microscopic hematuria were observed. During the course of therapy, rapid deterioration of renal function occurred with the appearance of pneumonia. Irrespective of the therapy with hemodialysis and antibiotics, he died of respiratory failure. The autopsy showed a rare case of rapidly progressive glomerulonephritis (crescentic glomerulonephritis) superimposed on membranous nephropathy. This experience highlighted the importance of the differential diagnosis of non-diabetic glomerulopathy even in elderly patients with diabetes mellitus.

[Soy protein intake and bone mineral density].

It has been reported that soy protein prevents the bone loss in in vitro and in vivo studies. Isoflavones contained in soy stimulate the protein synthesis and the expression of alkalinephophatases in osteoblasts. Additionally food enriched isoflavones prevented the reduction of bone mineral density (BMD) in ovariectomised rats or mice. We demonstrated the association of soy protein intake with the increase of BMD and the inhibition of urinary deoxypyridinoline. Interventional studies also exhibited the prevention of the reduction of BMD. However double-blind, randomized case-control trial does not support the hypothesis that use of soy protein supplement containing isoflavones improve BMD. We need further to detect the more potent isoflavones on bone metabolism.