Biomedical subjects

Toshio Ogihara

Publications and source records attributed to Toshio Ogihara.

At least 73 records · Page 4Linked to original sources

PubMed2005

Lys418Asn polymorphism of the alpha2-adrenoceptor gene relates to serum uric acid levels but not to insulin sensitivity.

Hyperuricemia is associated with cardiovascular risk. The present study examines the association between serum uric acid (UA) elevation and the alpha2-, beta2-, and beta3-adrenoceptor polymorphisms. In 219 nonobese, normotensive, normouricemic (serum UA <6.5 mg/dL at entry) men, serum UA, plasma norepinephrine (NE), the homeostasis model assessment of insulin resistance (HOMA-IR), body mass index, total body fat mass, the alpha2A(Lys418Asn)-, beta2(Arg16Gly, Gln27Glu)-, and beta3(Trp64Arg)-adrenoceptor polymorphisms were measured annually over 5 years. Hyperuricemia was defined as a serum UA level of > or =mean+1 SD of 5.0 mg/dL in the participants. At entry, there were 36 subjects who had hyperuricemia and 183 who had normal UA levels. A significant UA elevation for 5 years was defined as an increase in > or =10% in UA levels. There were 82 subjects who had significant UA elevations. The subjects who had hyperuricemia at entry in addition to the subjects who had significant UA elevations over the 5-year period carried a significantly higher frequency of the Asn418 allele of Lys418Asn. Additionally, subjects carrying the Asn418 allele had higher UA and plasma NE and greater elevations in UA over the study period, but HOMA-IR was similar. Insulin resistance at entry and during the study was associated with Arg16Gly polymorphisms but not with Lys418Asn polymorphisms. In conclusion, the Asn418 allele of Lys418Asn is associated with either established hyperuricemia or the progressive elevation of UA over time. This polymorphism was not associated with insulin resistance in nonobese, normotensive individuals. Although hyperuricemia is of known relevance to insulin resistance, it appears to have different genetic determinants from insulin resistance in terms of adrenoceptor polymorphisms.

Adult↗

PubMed2005

Evidence for Cd101 but not Fcgr1 as candidate for type 1 diabetes locus, Idd10.

Among polygenes conferring susceptibility to type 1 diabetes in the NOD mouse, Idd10 on distal chromosome 3 has been shown to be important for disease susceptibility. In this study, we investigated the candidacy of Fcgr1 and Cd101 for Idd10, by congenic mapping and candidate gene sequencing. Among seven NOD-related strains studied, the IIS mouse was found to possess a recombinant Idd10 interval with the same sequence at Fcgr1 as the NOD mouse, but a different sequence at Cd101 from that in the NOD mouse with 10 amino acid substitutions. The frequency of type 1 diabetes in NOD mice congenic for IIS Idd10 (NOD.IISIdd10) was significantly reduced as compared to that in the NOD mouse, despite the presence of the identical Fcgr1 sequence. These data indicate that IIS mice possess a resistant allele at Idd10, and suggest that Cd101, but not Fcgr1, is responsible for the Idd10 effect.

Animals↗

PubMed2005

Association of hypoadiponectinemia with smoking habit in men.

Adiponectin is emerging as an important molecule in obesity, the metabolic syndrome, and cardiovascular disease. On the other hand, smoking habit is well known to be related to cardiovascular disease and hypertension. To examine the association between adiponectin concentration and smoking habit, we performed an epidemiological survey and an acute exposure test in humans and an experiment in adipocytes to elucidate the mechanism underlying the association between adiponectin and smoking. In the epidemiological study, we enrolled a total of 331 male subjects to examine chronic smoking exposure. Plasma adiponectin was significantly lower (P=0.01) in current smokers (5.3+/-0.3 microg/mL) than in never-smokers (6.5+/-0.4 microg/mL). A significant association between smoking and low adiponectin level was also confirmed in multiple regression analysis including age, body mass index, hypertension, diabetes, hyperlipidemia, and creatinine clearance (never-smokers 6.5+/-0.4 microg/mL; past smokers 5.6+/-0.3 microg/mL; current smokers 5.2+/-0.4 microg/mL; F=4.52; P=0.01). To examine the acute effect of smoking on adiponectin concentration for 12 hours, we measured plasma adiponectin level in 5 male never-smokers before smoking and 3, 6, and 12 hours after smoking, with the result that adiponectin showed a significant decrease after smoking (12 hours; -14.5+/-0.6%; P<0.01). In cultured mouse 3T3-L1 adipocytes, H2O2 and nicotine reduced the mRNA expression and secretion of adiponectin in a dose-dependent manner. Smoking habit is associated with adiponectin concentration in men, and its suppressive effect is mediated in part through direct inhibition of smoking on adiponectin expression in adipocytes.

3T3 Cells↗

PubMed2005

Does gene therapy become pharmacotherapy?

Recent progress in molecular and cellular biology has led to the development of numerous effective cardiovascular drugs. However, there are still a number of diseases for which no known effective therapy exists, such as peripheral arterial disease, ischaemic heart disease, restenosis after angioplasty, and vascular bypass graft occlusion. Currently, gene therapy is emerging as a potential strategy for the treatment of cardiovascular disease despite its limitations. The first human trial in gene therapy for cardiovascular disease was started at 1994 to treat peripheral vascular disease using vascular endothelial growth factor (VEGF). Then, many different potent angiogenic growth factors were tested in clinical trials to treat peripheral arterial disease and ischaemic heart disease. Improvement of clinical symptoms in peripheral arterial disease and ischaemic heart disease has been reported. This review focuses on the future potential of gene therapy for the treatment of cardiovascular disease. In the future, gene therapy might become a real pharmacotherapy to treat cardiovascular disease.

Animals↗

PubMed2005

Susceptibility to streptozotocin-induced diabetes is mapped to mouse chromosome 11.

To study the contribution of beta-cell vulnerability to susceptibility to diabetes, we studied beta-cell vulnerability to a single high dose of streptozotocin (STZ) in an animal model of type 2 diabetes, the NSY mouse, a sister strain of the STZ-sensitive NOD mouse, in comparison with the STZ-resistant C3H mouse. NSY mice were found to be extremely sensitive to STZ. Introgression of a single Chr 11, where STZ-sensitivity was mapped in the NOD mouse, from NSY mice converted STZ-resistant C3H mice to STZ-sensitive. Two nucleotide substitutions were identified in the nucleoredoxin gene, a positional and functional candidate gene for STZ-induced diabetes on Chr 11. These data, together with the co-localization of type 1 (Idd4) and type 2 (Nidd1n) susceptibility genes on Chr 11, suggest that the intrinsic vulnerability of pancreatic beta cells is determined by a gene or genes on Chr 11, which may also contribute to susceptibility to spontaneous diabetes.

Animals↗

PubMed2005

Detection of embolic particles with the Doppler guide wire during coronary intervention in patients with acute myocardial infarction: efficacy of distal protection device.

OBJECTIVES: We investigated whether embolic particles could be detected as high-intensity transient signals (HITS) with a Doppler guide wire during percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI) We also assessed whether these signals could be reduced using a distal protection (DP) device. BACKGROUND: Embolization of thrombi and plaque components to the microcirculation is a major complication of PCI in patients with AMI. Embolic particles running in the cerebral artery are detected as HITS by transcranial Doppler ultrasound. METHODS: We prospectively studied 16 consecutive patients with AMI who underwent direct PCI within 24 h after the onset of symptoms. A PercuSurge GuardWire (MedtronicAVE, Santa Rosa, California) was used as the DP device. Eight patients were randomly assigned to the non-DP group, and the remaining eight were assigned to the DP group. Coronary flow velocity was recorded continuously from before the first balloon inflation to after balloon deflation. RESULTS: All patients in the non-DP group had HITS detected (12 +/- 9 counts) within five consecutive beats (4 +/- 1 beat) after balloon deflation, but none were detected in any of the patients in the DP group. CONCLUSIONS: The Doppler guide wire can be used to visually detect and count emboli as HITS, and the DP device is effective for prevention of distal embolization.

Aged↗

PubMed2005

An efficient gene transfer method mediated by ultrasound and microbubbles into the kidney.

BACKGROUND: Safety issues are of paramount importance in clinical human gene therapy. From this point of view, it would be better to develop a novel non-viral efficient gene transfer method. Recently, it was reported that ultrasound exposure could induce cell membrane permeabilization and enhance gene expression. METHODS: In this study, we examined the potential of ultrasound for gene transfer into the kidney. First, we transfected rat left kidney with luciferase plasmid mixed with microbubbles, Optison, to optimize the conditions (duration of ultrasound and concentration of Optison). Then, 4, 7, 14 and 21 days after gene transfer, luciferase activity was measured. Next, localization of gene expression was assessed by measuring luciferase activity and green fluorescent protein (GFP) expression. Expression of GFP plasmid was examined under a fluorescence microscope at 4 and 14 days after gene transfer. Finally, to examine the side effects of this gene transfer method, biochemical assays for aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN) and creatinine (Cre) were performed. RESULTS: Optison and/or ultrasound significantly enhanced the efficiency of gene transfer and expression in the kidney. Especially, 70-80% of total glomeruli could be transfected. Also, a significant dose-dependent effect of Optison was observed as assessed by luciferase assay (Optison 25%: 12.5 x 10(5) relative light units (RLU)/g tissue; 50%: 31.3 x 10(5) RLU/g tissue; 100%: 57.9 x 10(5) RLU/g tissue). GFP expression could be observed in glomeruli, tubules and interstitial area. Results of blood tests did not change significantly after gene transfer. CONCLUSIONS: Overall, an ultrasound-mediated gene transfer method with Optison enhanced the efficiency of gene transfer and expression in the rat kidney. This novel non-viral method may be useful for gene therapy for renal disease.

Alanine Transaminase↗

PubMed2005

Gene transfer into adult rat spinal cord using naked plasmid DNA and ultrasound microbubbles.

BACKGROUND: Although gene therapy might become a promising approach to treat spinal cord injury, the safety issue is a serious consideration in human gene therapy. Plasmid DNA transfer is safer than viral vectors, but the transfection efficiency is quite low. To overcome the problem, we applied the ultrasound microbubbles-mediated transfection method to the spinal cord in adult rats, since ultrasound microbubbles have been reported to be efficient to increase transfection efficiency in various tissues. METHODS: After exposing T9-10 spinal cord with a laminectomy, we injected a mixture of naked plasmid DNA and microbubbles into cerebrospinal fluid by lumbar puncture. Then, the T9-10 spinal cord was exposed to ultrasound. CONCLUSIONS: An ultrasound intensity of 0.4-0.5 W/cm2 significantly increased luciferase expression up to approximately 15-60-fold at the insonated level as compared to naked plasmid DNA alone. Luciferase activity could be detected at least up to 7 days after transfection, while the expression level was almost returned to undetectable level at 14 days after transfection. The transfected cells were mainly meningeal cells in the surface of insonated spinal cord. There was no obvious evidence of worsening of neurological deficits as compared to rats transfected with naked plasmid DNA alone or untransfected rats. Similarly, successful gene transfer was also achieved in the insonated T9-10 spinal cord after spinal cord injury. Overall, the present study demonstrated the feasibility of ultrasound microbubbles-mediated plasmid DNA transfer into the target level of the spinal cord.

Animals↗

PubMed2005

The metabolic syndrome in the asian population.

With the rapid emergence of obesity in Asia, the metabolic syndrome is becoming a clinically important issue. The studies on migrants from Asian countries to Western countries indicate that Asian populations may be more susceptible to the Western diet and lifestyle than whites in developing the metabolic syndrome. The World Health Organization (WHO) Expert Consultation recently reported that the cut-off point for observed risk in Asian populations may be smaller than that for non-Asian populations, varying from 22 kg/m(2) to 25 kg/m(2). This variant susceptibility may be caused by gene-environmental interactions and low birth weight in Asian populations.

Asia↗

PubMed2005

Combination of half doses of angiotensin type 1 receptor antagonist and angiotensin-converting enzyme inhibitor in diabetic nephropathy.

BACKGROUND: To investigate the renoprotective effect of combination therapy with an angiotensin I converting enzyme inhibitor and an angiotensin type I receptor blocker (ARB) on diabetic kidney disease, half doses of each monotherapy were given to type 2 diabetic patients with albuminuria. METHODS: Urinary albumin index (UAI) and blood pressure (BP) were measured in a total of 27 outpatients with type 2 diabetes mellitus receiving 10 mg imidapril or 8 mg candesartan per day. Either agent was then substituted with a combination of 5 mg imidapril and 4 mg candesartan. After 3 months of combination therapy, UAI and BP were measured. Changes in the parameters were assessed by paired t test. RESULTS: Although BP was not significantly different prior to and at the end of combination therapy, log-transformed UAI was significantly reduced (P = 0.003) from an initial UAI (mean log-transformed UAI +/- SD) of 79.4 (27.4-231)mg/g Cre to 52.5 (17.1-161)mg/g Cre at the end of combination therapy. The reduction was not associated with the initial UAI, initial BP, decrease in BP, pretreatment medication or other concomitant antihypertensive agents. CONCLUSIONS: In patients with type 2 diabetes and nephropathy, dual blockade of the renin system with an angiotensin-converting enzyme inhibitor and angiotensin receptor blocker significantly reduces albuminuria and, thus, may be renoprotective even when the doses of the agents are reduced by one half.

Aged↗

PubMed2005

Acute hyperinsulinemia reduces plasma leptin levels in insulin-sensitive Japanese men.

BACKGROUND: Elevated plasma leptin levels have been demonstrated in obesity and hypertension. These conditions are documented as insulin-resistant states with sympathetic overactivity. However, the relation between plasma insulin, leptin levels, and sympathetic nerve activity, especially after meals, has not been established. METHODS: To evaluate the impact of insulin sensitivity and obesity on the response of plasma leptin to acute physiologic insulin elevation, we studied 31 nonobese (body mass index [BMI] < 25 kg/m(2)) and 38 overweight or obese (obese; BMI >/= 25 kg/m(2)) normotensive men. Using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), the subjects were subdivided into insulin-sensitive (HOMA-IR <2.5) and insulin-resistant (HOMA-IR >/=2.5) groups. There were 11 nonobese and 28 obese men who were insulin-resistant. Blood pressure (BP), plasma glucose, insulin, leptin, and norepinephrine (NE) levels were measured before and after 75-g oral glucose loading every 30 min for 120 min. RESULTS: In nonobese subjects, fasting plasma insulin and leptin levels and areas-under-the-curves (AUC) for insulin and leptin were significantly lower in the insulin-sensitive group than in the insulin-resistant group. In the insulin-sensitive group regardless of BMI, plasma leptin levels decreased after glucose loading. Plasma glucose, insulin, NE, and BP levels increased in nonobese insulin-sensitive subjects after glucose loading, whereas in obese insulin-sensitive subjects, plasma NE and BP did not change in response to glucose. In insulin-resistant subjects regardless of BMI, marked elevations in plasma insulin did not cause any change in plasma leptin, NE, and BP levels. CONCLUSION: These results demonstrate that insulin sensitivity and adiposity affect the response of leptin and sympathetic nerve activity to acute postprandial hyperinsulinemia.

Acute Disease↗

PubMed2005

Beta2-adrenoceptor polymorphisms relate to insulin resistance and sympathetic overactivity as early markers of metabolic disease in nonobese, normotensive individuals.

BACKGROUND: The genes responsible for insulin resistance are also candidate genes for insulin resistance-related diseases, such as obesity and hypertension. Functional polymorphisms in the beta2- and beta3-adrenergic receptors have been reported to be associated with diabetes, hypertension, and obesity. To clarify the relevance of the beta-adrenergic receptor polymorphisms to insulin resistance, we studied their association with polymorphisms of beta2 (Arg16Gly, Gln27Glu) and beta3 (Trp64Arg) adrenoceptor genes. METHODS: We studied 155 young, nonobese Japanese men using the homeostasis model assessment of insulin resistance (HOMA-IR) to divide individuals into insulin-sensitive and insulin-resistant groups. Insulin resistance in the participants was defined as HOMA-IR equal to or greater than the average plus 1 SD of 3.1. There were 69 men who were insulin resistant and 86 men who were insulin sensitive. Body mass index (BMI), blood pressure (BP), plasma glucose, insulin, leptin, norepinephrine (NE) levels, and the polymorphisms of Arg16Gly and Gln27Glu of the beta2- and Trp64Arg of the beta3-adrenoceptor polymorphisms were measured in all participants. RESULTS: The insulin-resistant group had higher frequency of the Gly16 allele of Arg16Gly compared with the insulin-sensitive group, whereas the frequencies of genotypes or alleles of Gln27Glu and Trp64Arg were similar. The insulin-resistant group had a higher mean HOMA-IR, fasting insulin, NE, and total fat mass compared with levels in the insulin-sensitive group, but the BMI and leptin levels were similar. The subjects carrying the Gly16 allele of the beta2-adrenoceptor gene had a higher mean HOMA-IR, fasting insulin, NE, body fat mass, and BP than those without the Gly16 allele. CONCLUSIONS: The Gly16 mutation of the beta2-adrenoceptor gene is associated with increased insulin resistance, adiposity, and BP accompanied by higher plasma NE levels early in the metabolic disease in developing obesity. These findings show an important role of beta2-adrenoceptor gene polymorphisms in the association of insulin resistance in hypertension and obesity.

Adult↗

PubMed2005

Serum interleukin-15 concentration in patients with essential hypertension.

BACKGROUND: Interleukin (IL)-15 is one of the cytokines produced by neutrophils and monocytes/macrophages, and its expression is found immunohistochemically in inflammatory cells adjacent to vulnerable atherosclerotic plaques. However, the influence of systemic IL-15 on cardiovascular disease is still unclear. Therefore, we designed clinical investigations to clarify the relationship between cardiovascular complications and serum IL-15 levels. METHODS AND RESULTS: Three hundred ninety-nine patients with essential hypertension were analyzed. We divided the study subjects into the following three groups according to the modified World Health Organization-International Society of Hypertension classification of 1999: patients with no organ damage (n = 213), patients with mild organ damage (n = 128), and patients with severe organ damage (n = 58). We measured serum IL-15, highly sensitive C reactive protein, IL-6, soluble intercellular adhesion molecule, and soluble vascular cell adhesion molecule levels. Serum IL-15 concentration in patients with severe organ damage was significantly higher than that in those with no organ damage (P < .01) and those with mild organ damage (P < .01). Serum IL-15 concentration in patients with coronary artery disease or peripheral artery disease was significantly higher than that in those without coronary artery disease or peripheral artery disease. Moreover, serum IL-15 concentration in patients with lacunar infarction was significantly higher than that in those without lacunar infarction (P < .005). By multiple linear logistic regression analysis, serum IL-15 concentration was independently correlated with cardiovascular disease. CONCLUSIONS: These data suggest that a systemic inflammatory response involving IL-15 might be involved in the occurrence of cardiovascular disease in patients with essential hypertension.

Aged↗

PubMed2005

Rebound weight gain as associated with high plasma norepinephrine levels that are mediated through polymorphisms in the beta2-adrenoceptor.

BACKGROUND: A successful weight loss program is essential treatment for obesity-related diseases, but it is well known that the majority of individuals do not succeed in weight loss maintenance. The present study evaluates hormonal mechanisms and the relationship of beta2-adrenoceptor polymorphisms involved in individuals who regain weight after initially successful weight loss. METHODS: Overweight Japanese men (n = 154) were enrolled in a 24-month weight loss program. Body mass index (BMI), total body fat mass, plasma norepinephrine (NE) and leptin levels, and beta2-adrenoceptor polymorphisms (Arg16Gly, Gln27Glu) were measured every 6 months for the 24-month period. Maintenance of weight loss was defined as significant weight loss (>or=10% reduction) from entry weight at 6 months and maintenance of the weight loss for an additional 18 months. Rebound weight gain was defined as significant weight loss at 6 months but subsequent regain of body weight during the next 18 months. RESULTS: The results showed that 37 subjects maintained weight loss during 24 months, whereas 36 subjects had rebound weight gain. The BMI at entry and calorie intake and physical activity at each period were similar between the two groups. Subjects who maintained weight loss had at entry a significantly lower fat mass and plasma NE levels compared to those with rebound weight gain. Body fat mass, NE, and leptin levels at entry predicted the degree of change in body weight during the 24-month study period. Subjects with rebound weight gain had a significantly higher frequency of the Gly16 allele for the beta2-adrenoceptor polymorphism compared to subjects who had a 24-month maintenance of weight loss. Subjects carrying the Gly16 allele also had significantly higher plasma NE, leptin, and body fat mass levels and a greater waist-to-hip ratio both at entry and throughout the study. CONCLUSIONS: A high initial degree of body fat mass and high plasma NE levels as determined by the Gly16 allele for the beta2-adrenoceptor polymorphisms predict those individuals who will have rebound weight gain after their initial successful weight loss.

Adult↗

PubMed2005

Effect of two alpha-glucosidase inhibitors, voglibose and acarbose, on postprandial hyperglycemia correlates with subjective abdominal symptoms.

To assess the possible difference in effectiveness of 2 alpha-glucosidase inhibitors, voglibose and acarbose, the relationship between postprandial hyperglycemia and subjective abdominal symptoms was investigated. A total of 21 inpatients with type 2 diabetes were recruited to a single-center, 2-period, crossover trial. The subjects were given acarbose (150 mg/d) or voglibose (0.9 mg/d) under an isocaloric diet, and the postprandial (2 hours) increment in blood glucose level, M value which is a marker for fluctuation of blood glucose levels, and subjective abdominal symptom score were monitored. There was no significant difference between the 2 agents in postprandial increment in blood glucose level, M value, and subjective symptom score. When patients were divided according to subjective symptoms, however, the sum postprandial glucose increments were significantly different according to the agent (P = .03), with favorable efficacy in patients in whom the alpha-glucosidase inhibitor caused abdominal symptoms, demonstrating a significant interaction (P = .04) between treatment and symptomatic grouping. The results demonstrated that 50 mg acarbose and 0.3 mg voglibose had similar overall effects on postprandial hyperglycemia as well as subjective symptoms, but marked interindividual variation existed. Subjective symptoms may be a predictor of the divergent clinical response to each agent.

Acarbose↗

PubMed2005

Improvement of liver function parameters in patients with type 2 diabetes treated with thiazolidinediones.

To increase our understanding of the effect of thiazolidinediones, a new class of antidiabetic drugs, on liver function as well as glycemic control, we investigated liver function before, during, and after treatment with troglitazone and pioglitazone. A total of 32 patients with type 2 diabetes were studied. Glycemic control and liver function were measured before, during, and after 4 to 12 weeks of treatment with troglitazone or pioglitazone. Glycemic control was assessed by fasting levels of plasma glucose, hemoglobin A 1c , and serum insulin, and liver function was assessed by asparatate aminotransferase (AST), alanine aminotransferase (ALT), and gamma -glutamyl transpeptidase ( gamma-GTP). Homeostasis model assessment for insulin resistance was used as an index of insulin resistance. During treatment with troglitazone, fasting plasma glucose and hemoglobin A 1c levels and homeostasis model assessment for insulin resistance were significantly decreased. Serum AST, ALT, and gamma-GTP levels were significantly decreased during treatment (AST, -17.4%; ALT, -27.2%; gamma-GTP, -47.9%) and returned to pretreatment levels after 4 weeks of withdrawal of the drug. A similar tendency was observed during treatment with pioglitazone (AST, -4.7%; ALT, -16.4%; gamma-GTP, -30.8%). These data suggest that, in contrast to the deterioration of liver function reported in a small subset of patients treated with troglitazone, treatment with thiazolidinediones was associated with a decrease in serum transaminases in most patients. The improvement in liver function parameters known to be associated with fatty liver in the present study, together with an improvement in fatty liver reported for another class of insulin sensitizers, biguanides, suggests that thiazolidinediones may have a beneficial effect on fatty liver.

Alanine Transaminase↗

PubMed2005

Functional polymorphism in Z-DNA-forming motif of promoter of SLC11A1 gene and type 1 diabetes in Japanese subjects: association study and meta-analysis.

The association of the polymorphism of the Z-DNA-forming repeats in the promoter region of SLC11A1 (solute carrier family 11 member 1), formerly designated NRAMP1 (natural resistance associated macrophage protein 1), with type 1 diabetes was studied in a total of 244 Japanese subjects. Three alleles were detected in Japanese subjects. In diabetic patients, allele 2 was less frequent and allele 3 was more frequent, albeit not significantly, than in control subjects. Allele 2 was significantly ( P < .024) less frequent whereas allele 3 was more, albeit not significantly, frequent in the younger onset group than in the control subjects. In patients with a susceptible HLA allele, DRB1*0405 or DRB1*0901 , the frequency of allele 2 was significantly ( P < .013) lower and that of allele 3 tended to be higher than that in patients without either DRB1*0405 or DRB1*0901 . The protective effect of allele 2 against type 1 diabetes and other autoimmune diseases was confirmed by meta-analysis (summary odds ratio, 0.71, 95% confidence interval, 0.53-0.96). Because allele 2 was shown to be associated with low expression of SLC11A1 and protection against another autoimmune disease, rheumatoid arthritis, the negative association of allele 2 with autoimmune type 1 diabetes in the present study suggests that a less active immune system in subjects with allele 2 may protect individuals from autoimmune diseases.

Adolescent↗

PubMed2005

Development of novel method of non-viral efficient gene transfer into neonatal cardiac myocytes.

To establish new treatment for cardiovascular disease, the development of safe and highly efficient vectors is necessary. Especially, non-viral vectors are considered to be ideal for human gene therapy, since recent adverse events with retroviral or adenoviral vectors have highlighted the issue of safety. Although we previously reported safety and high efficiency of HVJ-liposome method, we have modified the envelope of HVJ (Sendai virus). In this novel non-viral vector, the envelope of HVJ alone was utilized as a carrier to deliver proteins, genes and oligodeoxynucleotides (ODN). Thus, we optimized the transfection efficiency of HVJ-envelope vector into neonatal cardiac myocytes in this study, since cardiac myocytes is one of the most difficult cells to be transfected. HVJ-envelope, obtained after complete destruction of HVJ genome, containing FITC-labeled ODN or luciferase plasmid was incubated with cardiac myocytes. In addition, the concentration of protamine sulfate was modified (0-700 microg/ml) to increase transfection efficacy. Without HVJ-envelope vector, few cells showed fluorescence, whereas most cells demonstrated fluorescence with HVJ-envelope vector. Consistent with the high transfection efficiency of ODN, high luciferase activity was also detected using HVJ-envelope vector. Moreover, the transfection efficiency varied according to the concentration of protamine sulfate. No obvious cytotoxicity was observed in cells transfected with HVJ-envelope vector. The present study demonstrated the development of a highly efficient novel non-viral vector for cardiac myocytes, suggesting that further development may provide a new useful tool for research and clinical gene therapy in the field of cardiovascular disease.

Animals↗