Effects of Diclofenac Etalhyaluronate (SI-613/ONO-5704) on Cartilage Degeneration in Arthritic Rats and Inflammatory Cytokine-Stimulated Human Chondrocytes.

OBJECTIVE: Cartilage degeneration is a key feature of osteoarthritis (OA) and rheumatoid arthritis and is thought to negatively impact patients' quality of life. Diclofenac etalhyaluronate (DEH, SI-613/ONO-5704) is a hyaluronic acid (HA) derivative chemically bound to diclofenac (DF) that has been reported to improve OA symptoms; however, its effect on cartilage degeneration remains unknown. In the present study, we investigated the chondroprotective effect of DEH in rats with collagen-induced arthritis and interleukin-1ß-stimulated human chondrocytes. DESIGN: Rats with collagen-induced arthritis were administered DEH and HA intra-articularly, and DF orally. Knee joint swelling, histological scores of articular cartilage, and inflammatory (Il1b) and catabolic (Mmp3 and Mmp13) gene expression in the synovial tissue and cartilage were evaluated. In vitro direct effects of DEH on matrix metalloproteinase (MMP)-3 and MMP-13 expression were examined in interleukin-1ß-stimulated human chondrocytes. RESULTS: In a rat model of collagen-induced arthritis, a single intra-articular dose of DEH inhibited knee joint inflammation and cartilage degeneration. Daily oral administration of DF had similar effects. Conversely, HA administered as a single intra-articular dose had no effect. Only DEH inhibited Mmp3 gene expression in the cartilage, whereas DEH and DF inhibited Mmp3 and Mmp13 mRNA expression in the synovial tissue. In interleukin-1ß-stimulated human chondrocytes, DEH and HA inhibited MMP-3 and MMP-13 production, whereas DF had no effect. CONCLUSIONS: In this study, we demonstrated the chondroprotective effect of DEH in rats with collagen-induced arthritis and in interleukin-1ß-stimulated human chondrocytes. Thus, DEH may suppress cartilage degeneration in patients with musculoskeletal diseases, such as OA.

Constrictive pericarditis after SARS-CoV-2 vaccination: A case report.

Coronavirus disease 2019 (COVID-19) and vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are associated with cardiovascular complications. Here, we report a case of right-sided heart failure caused by constrictive pericarditis that developed after the administration of messenger ribonucleic acid (mRNA) vaccine against SARS-CoV-2. A 70-year-old woman presented with body weight gain, peripheral edema, and dyspnea on effort, which developed over a period of 1 week after the second dose of vaccine. The jugular venous pressure was high with a prominent y descent (Friedreich's sign) and paradoxical increase on inspiration (Kussmaul's sign). The results of IgM and IgG testing specific to SARS-CoV-2 spike and nucleocapsid proteins indicated the presence of mRNA vaccine-induced antibody and were not suggestive of COVID-19 infection. Echocardiography showed pericardial thickening and septal bounce of the interventricular septum. Computed tomography (CT) also showed pericardial thickening compared with the results of the previous CT scan performed 4 months earlier. A diagnosis of right-sided heart failure due to constrictive pericarditis was confirmed on the basis of pressure analysis during cardiac catheterization.

Advances in Understanding the Mechanism of Ophthalmic Viscosurgical Device Retention in the Anterior Chamber or on the Corneal Surface during Ocular Surgery.

Retention durability, especially in the eye, is one of the most important properties of ophthalmic viscosurgical devices (OVDs) during ocular surgery. However, the information on the physical properties of OVDs is insufficient to explain their retention durability. The purpose of this study is to clarify the mechanism of OVD retention to improve understanding of the behavior of OVDs during ocular surgery. To elucidate the mechanism of OVD retention, we have developed a new test method for measuring repulsive force. As a result, the maximum repulsive force of OVDs was positively and well correlated with the retention durability of investigated OVDs. Consequently, we demonstrated that the repulsive force could be used as an index of retention durability on the ocular surface and in the eye. We directly compared the intraocular retention durability of three OVDs (Shellgan, Viscoat, and Opegan-Hi) in ex vivo porcine eyes. Opegan-Hi was immediately removed from the anterior chamber, but Shellgan and Viscoat remained largely in the anterior chamber as determined by fluorescence imaging. These results showed that the intraocular retention behavior of OVDs was similar to their ocular surface behavior in our previous report, suggesting that retention durability is dependent on the OVD itself. The retention durability of Shellgan seemed to be higher than that of Viscoat, and the maximum repulsive force of Shellgan was 1.35-fold higher than that of Viscoat. Therefore, the repulsive force might be a useful index for assessing the difference in the retention durability between OVDs such as Shellgan and Viscoat.

[Residual Property of SI-613, a Novel Drug for Osteoarthritis, in Knee Joint].

Osteoarthritis is the most common joint disorder worldwide and one of the leading causes of disability in the elderly. We have reported that the novel sodium hyaluronate derivative chemically linked with diclofenac (DF), diclofenac etalhyaluronate (SI-613), exerted a potent and long-lasting analgesic effect in experimental arthritis models. In this study, we evaluated the properties of residual SI-613 in the knee joint after an intra-articular (IA) administration. After IA administration of fluorescent labeled SI-613 (FA-SI-613) or fluorescent labeled hyaluronic acid (FA-HA) to rabbits, fluorescence intensities in the synovial membrane and cartilage were higher in the FA-SI-613 group until 7 d after administration than in the FA-HA group. After IA administration of radiolabeled SI-613 (14C-SI-613) to rabbits, the radioactivity remained in the joint cavity and the joint tissues such as synovial membrane and cartilage until 84 d after administration. This residual radioactivity was identified mainly as HA linked with DF, since 14C-SI-613 was labeled at the benzene ring of DF and since more DF-linked HA oligomer was detected on metabolite analysis than free DF in the synovial membrane and synovial lavage fluid up to 28 d after administration. These results suggested that intra-articularly administered SI-613 remained for a longer time in the joint as HA linked with DF than when HA was administered. Therefore, SI-613 was considered to prolong the pharmacological effects of both HA and DF by remaining in the joint as HA linked with DF.

Biocompatibility study of different hyaluronan products for intra-articular treatment of knee osteoarthritis.

BACKGROUND: Intra-articular (IA) injection of hyaluronic acid (HA) (IA-HA) is a well-recognized treatment option for pain associated with symptomatic knee osteoarthritis (OA). IA-HA products differ in their HA content, molecular weight, cross-linking, and source of HA. These differences are assumed to affect the biocompatibility of the IA-HA products once injected inside the knee joint. METHODS: In the present study, we investigated the biocompatibility of three multiple-injection IA-HA products available in the global market. These included SUPARTZ FX™, a medium range molecular weight HA derived from rooster comb (Avian-HA); ORTHOVISC®, a high range molecular weight HA obtained through biological fermentation (Bio-HA); and SYNVISC®, a high molecular weight cross-linked hyaluronan derived from rooster comb (Avian-CL-HA). Rabbit knee joint tissues were histologically and biochemically examined after IA injection of the products. Furthermore, we compared the amounts of impurities in the IA-HA products. RESULTS: IA injection of Avian-CL-HA into rabbit knee joints induced the aggregation of inflammatory cells, infiltration of eosinophils, and an increase in the number of cells in the synovial fluid. However, these effects were not seen in the Avian-HA and Bio-HA groups. The residual protein content and the contaminant levels of bacterial endotoxins were below the limit of quantitation in all HA products. Avian-CL-HA contained relatively a large amount of (1 → 3)-ß-D-glucan, but this was below the lower limit of quantification in the other HA products. CONCLUSIONS: The present results clearly demonstrate that the biocompatibility of Avian-HA is comparable to that of Bio-HA, and they were both considered to have a favorable safety profile for the treatment of symptomatic OA of the knee. However, immunostimulatory activity was observed after injection of Avian-CL-HA: this might be a result of its unique cross-linking structure and/or the considerable amount of (1 → 3)-ß-D-glucan impurity present in the formulation.

Effect of diclofenac etalhyaluronate (SI-613) on the production of high molecular weight sodium hyaluronate in human synoviocytes.

BACKGROUND: We have reported that a single intra-articular injection of diclofenac etalhyaluronate (SI-613) exerted a potent and long-lasting analgesic effect in experimental arthritis models. In the present study, we investigated the effect of SI-613 on the production of high molecular weight hyaluronic acid (HMW-HA) in synoviocytes from osteoarthritis (OA) patients and compared its efficacy with that of hyaluronic acid (HA). METHODS: We compared the effect of SI-613, HA, and diclofenac sodium (DF-Na) on high molecular weight HA production by human synoviocytes. RESULTS: SI-613 and exogenous HA induced the production of high molecular weight HA in synoviocytes from OA patients, whereas DF-Na had no effect. The molecular weight of newly produced HA was about 1000 kDa in the HA-treated synoviocytes and much higher than 2400 kDa in the SI-613-treated cells. The effect of the mixture of HA and DF-Na was similar to that of HA alone in that the molecular weight of newly produced HA was around 1000 kDa. SI-613 significantly suppressed hyaluronidase 2 (HYAL2) mRNA expression and significantly enhanced hyaluronan synthase 2 (HAS2) mRNA expression. HA had no effect on the expression levels of HYAL and HAS. CONCLUSION: The present results clearly demonstrate that SI-613 induces the production of high molecular weight HA in synoviocytes from OA patients, suggesting the long-lasting analgesic and disease modifying effect of SI-613 for OA. Taken together with the anti-inflammatory and analgesic effects we recently reported for the intra-articular administration of SI-613 to experimental animal models, SI-613 holds great promise for the treatment of knee osteoarthritis.

Electrocardiographic changes as a marker of improved subendocardial ischemia in a patient with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) patients sometimes develop subendocardial ischemia without coronary artery stenosis. We report a case of non-obstructive HCM, in which electrocardiographic changes were observed with improvement of subendocardial ischemia. A 76-year-old man presented with chest pain on exertion. The electrocardiogram revealed left ventricular (LV) hypertrophy with repolarization abnormalities. No coronary stenosis was found on computed tomography angiography, but thallium-201 exercise scintigraphy revealed transient LV cavity dilation after exercise, consistent with subendocardial ischemia. His chest symptoms disappeared after starting verapamil. Transient LV cavity dilation improved without a reduction in exercise tolerance, as did electrocardiographic abnormalities without any changes on echocardiography.

Skin autofluorescence is associated with high-sensitive cardiac troponin T, a circulating cardiac biomarker, in Japanese patients with diabetes: A cross-sectional study.

The study aims to evaluate the relationship between skin autofluorescence, a marker of advanced glycated end-products accumulation in tissue, and high-sensitive cardiac troponin T, a cardiovascular biomarker, in Japanese subjects with diabetes. A total of 145 subjects with diabetes and 32 nondiabetic subjects as control attending the outpatient clinic were examined. Skin autofluorescence was measured using the AGE Reader™. Univariate and multivariate regression analyses were used to identify the factors associated with the high-sensitive cardiac troponin T and N-terminal pro-B-type natriuretic peptide values. Skin autofluorescence, high-sensitive cardiac troponin T, and maximum intima-media thickness values were significantly higher in subjects with diabetes than in nondiabetic subjects. Diabetic subjects with skin autofluorescence level⩾2.47 AU (median value) had higher levels of N-terminal pro-B-type natriuretic peptide ( p = 0.006), high-sensitive cardiac troponin T ( p < 0.0001), pentosidine ( p = 0.011) and maximum intima-media thickness ( p = 0.017) compared to those with skin autofluorescence level <2.47 AU. A multivariate regression analysis using variables that were significantly correlated with high-sensitive cardiac troponin T and N-terminal pro-B-type natriuretic peptide, revealed that estimated glomerular filtration rate (ß = -0.364, p < 0.001) and skin autofluorescence (ß = 0.254, p = 0.0022) were independent determinants of high-sensitive cardiac troponin T, but the variables that were significant in the univariate analysis were no longer predictors for N-terminal pro-B-type natriuretic peptide. Skin autofluorescence measured with the AGE Reader™ could be an easy and noninvasive surrogate marker for identifying diabetic subjects at high risk for subclinical cardiac injury.

Pharmacological effects of N-[2-[[2-[2-[(2,6-dichlorophenyl)amino]phenyl]acetyl]oxy]ethyl]hyaluronamide (diclofenac Etalhyaluronate, SI-613), a novel sodium hyaluronate derivative chemically linked with diclofenac.

BACKGROUND: Osteoarthritis (OA) is the most common joint disorder worldwide and one of the leading causes of disability in the elderly. We have investigated the novel sodium hyaluronate derivative chemically linked with diclofenac (DF), diclofenac etalhyaluronate (SI-613), which is a potentially safer and more effective treatment for OA knee pain. In this study, we evaluated the pharmacological effects of SI-613 in experimental arthritis models. METHODS: We compared the analgesic and anti-inflammatory effects of intra-articularly administered SI-613, hyaluronic acid (HA), and of orally administered diclofenac sodium (DF-Na) in rat silver nitrate-induced arthritis model and rabbit antigen-induced arthritis model. RESULTS: A single intra-articular (IA) administration of SI-613 significantly suppressed pain responses in rats in a dose-dependent manner. The analgesic effects were greater than those of HA, a mixture of DF-Na and HA, or an oral once-daily administration of DF-Na. In the rabbit arthritis model, SI-613 significantly reduced knee joint swelling compared with that in the control group on day 1 after a single IA injection. This significant anti-inflammatory effect was observed until day 28. In the pharmacokinetic study, the DF concentration in the synovium after SI-613 administration reached its maximum concentration of 311.6 ng/g on day 1, and gradually declined to 10 ng/g by day 28. It fell below the lower limit of quantification on day 35. Thus, a clear correlation was found between pharmacokinetics and pharmacodynamics. These results demonstrate that SI-613 exerts its long-lasting and potent anti-inflammatory effect by sustainable release of DF in the knee joint tissues. CONCLUSION: A single IA injection of SI-613 was shown to exert analgesic and anti-inflammatory effects for 28 days in non-clinical pharmacological studies, suggesting that SI-613 will be a promising candidate in the treatment of osteoarthritis pain.

Skin Autofluorescence is a Noninvasive Surrogate Marker for Diabetic Microvascular Complications and Carotid Intima-Media Thickness in Japanese Patients with Type 2 Diabetes: A Cross-sectional Study.

INTRODUCTION: Advanced glycation end-products (AGEs) are known to play an important role in the pathogenesis of diabetic complications. Skin autofluorescence (AF), a marker of AGE accumulation in tissue, can be measured noninvasively using a skin AF reader. The present study aimed to evaluate the relationships of skin AF with diabetic microvascular complications and carotid intima-media thickness (IMT), a surrogate marker for atherosclerosis, in Japanese subjects with type 2 diabetes (T2D). METHODS: One hundred sixty-two subjects with T2D and 42 nondiabetic control subjects attending the outpatient clinic were examined. Skin AF and carotid max-IMT were measured using an AGE Reader™ and ultrasonography, respectively. Nephropathy was classified into five stages based on the urinary albumin-to-creatinine ratio (UACR) as follows: (1) pre-nephropathy (stage 1) (UACR < 30 mg/g Cr); (2) incipient nephropathy (stage 2) (30 ≤ UACR < 300 mg/g Cr); (3) overt nephropathy (stage 3) (UACR ≥ 300 mg/g Cr); (4) kidney failure (stage 4) (estimated glomerular filtration rate (eGFR) < 30 ml/min/1.732); and (5) dialysis therapy (stage 5). Patients with kidney failure and those receiving dialysis therapy were excluded because the sample size was too small. Retinopathy was diagnosed as nondiabetic retinopathy (NDR), nonproliferative retinopathy (NPDR), or proliferative retinopathy (PDR). Diabetic peripheral neuropathy (DPN) was diagnosed if two or more of the following were present: neuropathic symptoms (decreased sensation, positive neuropathic sensory symptoms), symmetric decreased distal sensation, and unequivocally decreased or absent ankle reflexes. RESULTS: Skin AF values were significantly higher in subjects with T2D (2.53 ± 0.45 AU) than in nondiabetic subjects (2.19 ± 0.34 AU, p < 0.001). Skin AF significantly increased with the severity of DPN (2.39 ± 0.37 with DPN vs 2.80 ± 0.48 without DPN, p < 0.001), retinopathy (NDR 2.42 ± 0.45, mild and moderate NPDR 2.64 ± 0.42, p = 0.042, severe NPDR and PDR 2.85 ± 0.35, p < 0.001), and nephropathy (pre-nephropathy 2.42 ± 0.44, incipient nephropathy 2.62 ± 0.45, p = 0.049, overt nephropathy 2.59 ± 0.46, p = 0.80). Skin AF was an independent determinant of the presence of DPN (OR 8.49, 95% CI 2.04-44.32, p = 0.006) and retinopathy (OR 3.73, 95% CI 1.20-12.90, p = 0.028) but not of diabetic nephropathy after correcting for confounding factors. In addition, skin AF (ß = 0.170, p = 0.029) was an independent determinant of max-IMT, as was age (ß = 0.436, p < 0.0001), after adjusting for other risk factors. CONCLUSION: Skin AF as measured using an AGE Reader is a noninvasive surrogate marker for diabetic microvascular complications and early-stage atherosclerosis.

The inter-arm difference in systolic blood pressure is a novel risk marker for subclinical atherosclerosis in patients with type 2 diabetes.

Recent studies have suggested that the inter-arm blood pressure difference (IAD) is associated with cardiovascular events and mortality. The aim of this study was to assess whether the IAD could be a marker for subclinical atherosclerosis in patients with type 2 diabetes who are at high risk of cardiovascular disease (CVD). In a cross-sectional retrospective study of 206 Japanese patients with type 2 diabetes aged 49-76 years, we examined the correlation of the IAD with the carotid intima-media thickness (IMT), ankle-brachial index (ABI) or cardio ankle vascular index (CAVI). The IAD was positively correlated with the maximum IMT (r=0.266, P<0.0001), mean IMT (r=0.209, P=0.00726) or CAVI (r=0.240, P=0.0005). The IAD was higher in patients with CVD than in those without (P=0.0020). A multiple linear regression analysis demonstrated that the IAD was an independent determinant of maximum IMT (ß=0.169, P=0.0167), mean IMT (ß=0.178, P=0.0153), ABI (ß=-0.222, P=0.0033) or CAVI (ß=0.213, P=0.0011) after adjusting for known risk factors. The area under the receiver operating characteristic curve (AUC) of the IAD as a predictor of subclinical atherosclerosis was similar to the AUC of the Framingham 10-year coronary heart disease risk score. In conclusion, the IAD could be a novel risk marker for subclinical atherosclerosis in patients with type 2 diabetes.

Efficacy of initial Basal-supported oral therapy with sitagliptin in untreated type 2 diabetes.

INTRODUCTION: The present study assessed the efficacy of initial basal-supported oral therapy (BOT) with sitagliptin for achievement of glycemic control and subsequent switching from BOT to sitagliptin-based oral therapy. METHODS: Nineteen recently diagnosed type 2 diabetic patients who had received no antidiabetic medication in the previous 2 years were sequentially examined for the 24-week study. Patients were initially treated with a combination of insulin glargine and sitagliptin. Sitagliptin was initiated and maintained at a dose of 50 mg/day, and insulin glargine was started at a dose of 4 U at bedtime and adjusted if needed. RESULTS: During the 24-week treatment period, 12 patients (63%) achieved HbA1c levels <7% (mean BOT duration 13.7 ± 5.6 weeks) and switched from BOT to sitagliptin monotherapy or in combination with metformin (achievers). The remaining seven patients (37%) failed to achieve HbA1c levels <7% (non-achievers) and continued on BOT. Both FPG and HbA1c in achievers significantly dropped at 4, 8, 12 and 24 weeks from baseline, while those in non-achievers significantly decreased at 12 and 24 weeks from baseline, but failed to reach target glycemic control. There were statistically significant differences in FPG at 4, 8, 12 and 24 weeks and in HbA1c at 8, 12 and 24 weeks between achievers and non-achievers. Body weight and BMI in achievers were significantly reduced at 12 and 24 weeks, but those in non-achievers did not change significantly. Dosage of concomitant insulin during BOT was significantly lower in achievers compared to non-achievers. Non-achievers had a similar CPI, a measure of insulin secretion capacity, to achievers, but significantly showed an insulin resistance index (value of 20/[fasting CPR × FPG]), in comparison to achievers. CONCLUSION: Initiating BOT with sitagliptin followed by sitagliptin-based oral therapy is a useful option in untreated and poorly controlled patients with type 2 diabetes.

Efficacy of vildagliptin on glucose fluctuation in Japanese type 2 diabetic patients with ongoing sulfonylurea based oral glycemic agent therapy.

AIM: To investigate whether vildagliptin, one of the dipeptidylpeptide-4 (DDP-4) inhibitors, improves not only glycemic control but also glycemic fluctuation when added to ongoing sulfonylurea (SU) based oral hypoglycemic agents (OHA) therapy in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 19 patients with T2DM were recruited from outpatients. Vildagliptin was initiated with a dose of 100mg per day in the patients who had inadequate glycemic control and glycemic fluctuation with ongoing SU based OHA therapy. Glycemic excursion was defined by seven-point self-monitoring blood glucose (SMBG) on three days at baseline and 12 weeks after vildagliptin-combined therapy, as well as HbA1c levels. M-value and J-index were calculated to evaluate glycemic excursion. RESULTS: Addition of vildagliptin to ongoing SU based OHA therapy significantly decreased HbA1c values from 8.2 ± 3.8% at baseline to 7.3 ± 0.8% at 12-week. The average of blood glucose profiles was significant improved. As a result, M-value was significantly corrected from 20.9 ± 14.4 to 12.2 ± 13.5 and J-index from 55.1 ± 25.5 to 39.1 ± 19.8. CONCLUSIONS: Vildagliptin when added to ongoing SU based OHA therapy for 12 weeks significantly improved glycemic fluctuation as well as glycemic control in Japanese patients with T2DM.

Useful application of the Neuropad test for assessment of diabetic polyneuropathy.

OBJECTIVE: Examination of sudomotor function is now recommended to assess peripheral autonomic dysfunction. The aim of this study was to evaluate the clinical usefulness of Neuropad, a simple visual indicator test, for assessment of diabetic polyneuropathy (DPN). METHODS: This study examined 87 diabetic patients with a mean age of 61.1±8.8 years, a mean diabetes duration of 13.0±7.5 years and a mean HbA1c of 8.8±1.7%. Diagnosis of DPN was based on clinical examinations using modified Toronto Clinical Neuropathy Score (mTCNS). The patients also underwent 4-g monofilament test and heart rate variability by coefficient of variation of R-R intervals (CV(R-R)) was determined with the patients at rest. The Neuropad test was applied on the plantar aspect of the great toe and removed after 10 minutes to evaluate the color change as normal (blue to completely pink), patchy (patches of blue and pink) and abnormal (remained blue). RESULTS: Twenty-eight patients showed a normal, 45 patchy and 14 abnormal response to the Neuropad test. Patients with an abnormal response had significantly longer diabetes duration than those with a normal or a patchy response, but HbA1c levels were similar among the three groups. The C(R-R) at rest was significantly lower in patients with an abnormal response than those of normal and patchy response, respectively. Abnormal responders showed significantly higher mTCNS and lower monofilament results as well as higher prevalence of orthostatic hypotension, retinopathy or nephropathy than normal responders. CONCLUSION: The Neuropad test is a useful screening test for detecting DPN.

Acute disseminated encephalomyelitis associated with meningitis due to Mycobacterium intracellulare.

A 73-year-old woman was admitted to our hospital because of persistent fever, headache and fatigue for several weeks. On admission, she was diagnosed as having meningitis due to Mycobacterium intracellulare (M. intracellulare) detected in her cerebrospinal fluid (CSF) by polymerase chain reaction. Even though anti-tuberculous therapy improved her CSF findings, her condition was not restored. Brain MRI showed multifocal and asymmetrical increases in T2 signals involving white matter and cortical gray-white junction of cerebral hemispheres, cerebellum and brainstem. Based on the progression of clinical symptoms and radiological features, we diagnosed her illness as acute disseminated encephalomyelitis (ADEM) associated with meningitis due to M. intracellulare. Steroid therapy dramatically improved her condition. This is the first report of ADEM following meningitis due to M. intracellulare in a non-immunocompromized host.

Thyrotoxicosis complicated with dysphagia.

A 36-year-old man was admitted to our hospital because of general fatigue and dysphagia. He had experienced progression of thyrotoxic symptoms of weight loss, palpitation and sweating for several months. On admission, he showed thyroid storm associated with dysphagia and aspiration pneumonia. Dysphagia was restored completely with 2 months after intensive treatment with anti-thyroid agent, beta-blocker, potassium iodide and glucocorticoid for thyroid storm. Although dysphagia is an uncommon manifestation, we should keep in mind that dysphagia may be one of symptoms of thyrotoxic myopathy.

Helicobacter pylori infection and arterial stiffness in patients with type 2 diabetes mellitus.

Epidemiologic studies have suggested possible atherogenic roles for such pathogens as Chlamydia pneumoniae, Helicobacter pylori (Hp), cytomegalovirus, and herpes simplex virus. The aim of the present study was to examine the relationship between seropositivity of antibodies to Hp (Hp infection) and arterial stiffness determined by pulse wave velocity (PWV) in 130 patients (73 men and 57 women) with type 2 diabetes mellitus without a history of cardiovascular disease. The prevalence of Hp infection in patients with type 2 diabetes mellitus was 53.8%. Age (66.7 +/- 11.3 vs 60.0 +/- 12.2 years, P = .0014) and systolic blood pressure (138 +/- 19 vs 131 +/- 22 mm Hg, P = .0420) were significantly higher in patients with Hp infection than in those without. Serum C-reactive protein was higher in patients with Hp infection than in those without, although it did not reach statistical significance (0.23 +/- 0.27 vs 0.18 +/- 0.20 mg/dL, P = .2205). Pulse wave velocity was significantly higher in patients with Hp infection than in those without (1877 +/- 550 vs 1585 +/- 331 cm/s, P = .0005). Multiple regression analysis demonstrated that age (beta = .388, P < .0001), mean arterial pressure (beta = .289, P = .0006), hypertensive treatment (beta = .185, P = .0282), and presence of Hp infection (beta = .169, P = .0220) were independent determinants of PWV. In conclusion, Hp infection is associated with arterial stiffness determined by PWV in patients with type 2 diabetes mellitus.

Relationship between polymorphisms 804C/A and 252A/G of lymphotoxin-alpha gene and -308G/A of tumor necrosis factor alpha gene and diabetic retinopathy in Japanese patients with type 2 diabetes mellitus.

To clarify whether polymorphisms of the lymphotoxin-alpha (LTA) gene and tumor necrosis factor alpha (TNF-alpha) gene were related to diabetic retinopathy (DR), we performed a case-control study in 251 Japanese patients with type 2 diabetes mellitus participating in a multicenter research protocol. Genetic analyses were performed by using a fluorescent allele-specific DNA primer assay system. Diabetic retinopathy was diagnosed in a masked manner by an independent ophthalmologist using fundus photographs and was classified as nondiabetic retinopathy (NDR), nonproliferative retinopathy (NPDR), and proliferative retinopathy (PDR). The results showed that the genotype frequencies of 804C/A in exon 3 and 252A/G in intron 1 of the LTA gene were not significantly different among patients with NDR, NPDR, and PDR. A allelic frequency of the TNF-alpha gene (-302A/G in promoter) was also identical among NDR, NPDR, and PDR groups. Multivariate logistic regression analyses showed that significant associations with DR were glycosylated hemoglobin level and diabetes duration, but not polymorphisms of the LTA gene or TNF-alpha gene. In conclusion, the present study showed no association between polymorphisms 804C/A and 252A/G of the LTA gene and -302A/G of the TNF-alpha gene and DR in Japanese type 2 diabetic patients.

Angiotensinogen gene polymorphism (Met235Thr) influences visceral obesity and insulin resistance in obese Japanese women.

To investigate the relationship between angiotensinogen (AGT) Met235Thr polymorphism (M235T) and human obesity, because AGT is regarded as one of the cytokines produced from adipocytes and serum AGT concentrations are reported to be positively correlated with body mass index. One hundred and twenty obese Japanese women (age, 58.8+/-9.4 years; body mass index, 32.2+/-4.9 kg/m(2)) were enrolled. Angiotensinogen genotypes were determined with a fluorescent allele-specific DNA primer assay system. Subjects were divided into M/M, M/T, and T/T groups. Control subjects comprised 146 healthy age-matched women. Clinical characteristics and the effects of diet and exercise therapy for 6 months were compared among the 3 genotypes. The genotype frequencies of AGT M235T polymorphism were in accordance with the Hardy-Weinberg equation (obese: M/M, 6.7%; M/T, 27.5%; T/T, 65.8%; control: M/M, 6.8%; M/T, 21.2%; T/T, 71.9%). The frequency of the T allele did not differ between obese and control subjects (0.80 vs 0.83). As the number of obese women with M/M genotype was only 8, comparisons of the characteristics and outcomes of weight reduction therapy were performed only between subjects with M/T genotype and T/T genotype. In the T/T group, % body fat and waist circumference at baseline were significantly greater than in the M/T group (36.3%+/-4.8% vs 33.8%+/-4.7%, P=.0105; 107.9+/-10.9 vs 102.6+/-7.9 cm, P=.0428, respectively). Before the weight reduction therapy, significantly higher insulin and higher homeostasis model assessment (HOMA-R) were demonstrated in the T/T group than in the M/T group (9.1+/-5.5 microU/mL vs 5.9+/-4.4 microU/mL, P=.0056; 2.3+/-1.4 vs 1.6+/-1.3, P=.0252, respectively). Both systolic and diastolic blood pressure at baseline in the T/T group tended to be higher than those in the M/T group, but the differences were not significant. No genotype-dependent difference in energy expenditure or outcome of weight reduction therapy was observed with respect to AGT M235T polymorphism. After the diet and exercise therapy, the blood pressure in the T/T group tended to be higher than that in the M/T group, but the difference was not significant. We demonstrated that the T/T genotype of the AGT M235T gene polymorphism was positively related to visceral obesity and hyperinsulinemia in obese Japanese women. Blood pressure did not show genotype-specific differences before or after the treatment. Further studies of the association between obesity and this gene polymorphism should contribute to understanding and treating obesity-related diseases.

Clinical and genetic characteristics of diabetic patients with high-titer (>10,000 U/ml) of antibodies to glutamic acid decarboxylase.

We investigated the clinical aspects and genetic background of 13 diabetic patients with high-titers (>10,000 U/ml) of anti-glutamic acid decarboxylase antibody (Group A) and compared these 28 middle-aged (35-51 years, Group B) and 13 elderly (66-79 years, Group C) patients with anti-GAD(+) (<1100 U/ml) who were diagnosed initially as having type 2 diabetes. The mean age and mean age at onset of Group A were 70.8 +/- 3.9 years (range, 64-78) and 50.4 +/- 5.4 years (range, 43-61), respectively. In Group A, the prevalence of insulin-deficient patients was significantly lower (30.8%, 4 of 13) than in Group C (96.3%, 27 of 28, P < 0.001). Patients in Group A had a significantly longer interval between the clinical onset of diabetes to initiation insulin therapy (21.8 +/- 2.3 years) compared to patients in both Group B (1.8+/-1.1 years, P < 0.001) and Group C (14.8 +/- 7.1 years, P = 0.049). The frequency of DRB1*0405-DQB1*0401/DRB1*1502-DQB1*0601 or DRB*1501-DQB*0602 heterozygous genotypes in Group A (53.8%, 7 of 13) was significantly higher than in both Group B (3.6%, 1 of 28, P < 0.01) and Group C (7.7%, 1 of 13, P < 0.05). Compared with Group B, Group A had an increased frequency of the TNFA-U01 haplotype and the IL-10 -592 C allele (TNFA-U01; 53.8% versus 30.4%, P = 0.05 and IL-10 -592 C; 57.7% versus 33.9 %, P = 0.042). All sera from Group A reacted with GAD(65) protein on Western blots. We conclude that adult-onset diabetic patients with a high-titer of anti-GDAab differ from patients with latent autoimmune diabetes mellitus in adult (LADA) with respect to beta-cell function, cellular autoimmunity and genetic background. Our study also showed that high-titers of antibodies to glutamic acid decarboxylase (anti-GADab) were not predictive of later development of insulin deficiency in adult and/or elderly patients with type 2 diabetes. Furthermore, our results suggest that HLA-DRB1*1502-DQB1*0601 or DRB1*1501-DQB1*0602/DRB1*0405-DQB1*0401 heterozygous genotypes may be associated with high production of anti-GADab that recognizes the linear epitope(s) on the GAD(65) protein.