Genome-wide linkage and exome analyses identify variants of HMCN1 for splenic epidermoid cyst.

BACKGROUND: Splenic epidermoid cyst is a benign tumor-like lesion affecting the spleen and sometimes occurs in familial form. The causality of such rare diseases remain challenging, however recently, with the emergence of exome re-sequencing, the genetics of many diseases have been unveiled. In the present study, we performed a combinatorial approach of genome-wide parametric linkage and exome analyses for a moderate-sized Japanese family with frequent occurrence of splenic epidermoid cyst to identify the genetic causality of the disease. METHODS: Twelve individuals from the family were subject to SNP typing and exome re-sequencing was done for 8 family members and 4 unrelated patients from Kosovo. Linkage was estimated using multi-point parametric linkage analysis assuming a dominant mode of inheritance. All of the candidate variants from exome analysis were confirmed by direct sequencing. RESULTS: The parametric linkage analysis suggested two loci on 1q and 14q with a maximal LOD score of 2.5 . Exome generated variants were prioritized based on; impact on the protein coding sequence, novelty or rareness in public databases, and position within the linkage loci. This approach identified three variants; variants of HMCN1 and CNTN2 on 1q and a variant of DDHD1 on 14q. The variant of HMCN1 (p.R5205H) showed the best co-segregation in the family after validation with Sanger sequencing. Additionally, rare missense variants (p.A4704V, p.T5004I, and p.H5244Q) were detected in three unrelated Kosovo patients. The identified variants of HMCN1 are on conserved domains, particularly the two variants on calcium-binding epidermal growth factor domain. CONCLUSIONS: The present study, by combining linkage and exome analyses, identified HMCN1 as a genetic causality of splenic epidermoid cyst. Understanding the biology of the disease is a key step toward developing innovative approaches of intervention.

Two weeks administration of tranexamic acid for acute intracerebral hemorrhage: A hospital-based pilot study.

Background: A previous report suggested that functional status does not differ between patients who received tranexamic acid and those who received placebo within the early hours of intracerebral hemorrhage (ICH). Our pilot study tested the hypothesis that 2 weeks administration of tranexamic acid would contribute to functional improvement. Methods: Consecutive patients with ICH were administered 250 mg tranexamic acid 3 times a day continuously for 2 weeks. We also enrolled historical control consecutive patients. We collected clinical data that involved hematoma size, level of consciousness, and Modified Rankin Scale (mRS) scores. Results: Univariate analysis showed that the mRS score on day 90 was better in the administration group (P = 0.0095). The mRS scores on the day of death or discharge suggested a favorable effect of the treatment (P = 0.0678). Multivariable logistic regression analysis also showed that the treatment was associated with good mRS scores on day 90 (odds ratio [OR] = 2.81, 95% confidence interval [CI]: 1.10-7.21, P = 0.0312). In contrast, ICH size was associated with poor mRS scores on day 90 (OR = 0.92, 95% CI: 0.88-0.97, P = 0.0005). After propensity score matching, there was no difference in the outcomes between the two groups. We did not detect mild and serious adverse events. Conclusion: The study could not show the significant effect of 2 weeks administration of tranexamic acid on functional outcomes of ICH patients after the matching; however, suggested that this treatment is at least safe and feasible. A larger and adequately powered trial is needed.

[Reduction of vascular pain due to drop-infusion of oxaliplatin (L-OHP) in peripheral vein with heated infusion route].

PURPOSE: The aim of this study is to investigate the possibility of reducting vascular pain with peripheral vein administration of oxaliplatin (L-OHP)by heating infusion routes during XELOX therapy. METHODS: (1) EXPERIMENT: The temperature of the 5%glucose injection solution was measured at the leading edge of the infusion route when it was heated to 36°Cor 40°C. (2) CASES: Among five patients receving XELOX therapy for colorectal cancer, we examined the occurrence of vascular pain by heating the L-OHP solution to 40°C. RESULTS: (1) EXPERIMENT: The injection temperatures were reduced to 25°C and 31°C while passing through the infusion route when L-OHP solution was heated to 36°C and 40°C, respectively. (2) CASE: vascular pain did not occur in all five patients treated with XELOX therapy completely by heating the L-OHP solution at 40°C, including two patients who could not continue treatment caused by vascular pain without the heating method. CONCLUSION: The method using the heat infusion route of L-OHP at 40°C is useful for reducing vascular pain from L-OHP administered intravenously.

Genetic zygosity of mature ovarian teratomas, struma ovarii, and ovarian carcinoids.

Although ovarian monodermal teratomas, including struma ovarii and carcinoids, are closely associated with mature teratomas, their genetic basis is poorly understood. A series of mature and monodermal ovarian teratomas were analyzed by short tandem repeat genotyping to evaluate their genetic zygosity and its associations. Informative DNA genotyping data were obtained for ten mature teratomas, six struma ovarii, and three carcinoids (one insular, one trabecular, and one mucinous). A homozygous genotype was present in five of the ten (50%) mature teratomas, three of the six (50%) struma ovarii, and one of the three (33%) ovarian carcinoids. There was no significant difference in genetic zygosity between mature and monodermal teratomas. Patients' age was not correlated with the genetic zygosity: the youngest age in the homozygous tumor group of patients was 4 years. It is suggested that an oocyte after meiosis I, which has escaped from meiotic arrest, is a significant cause of these tumors. Although one mature teratoma was a rare case with lactating adenoma-like breast tissue, its genetic zygosity was concordant with that of the surrounding teratomatous tissue. In one ovarian carcinoid, the carcinoid and accompanying teratomatous components showed matching zygosity at all but one locus: the carcinoid was heterozygous but teratoma was homozygous at one pericentromeric locus. This suggests that not all carcinoids are secondary neoplasms arising from a fully developed mature teratoma: some are neoplasms deviating from a developing mature teratoma.

A Pilot Study: The Beneficial Effects of Combined Statin-exercise Therapy on Cognitive Function in Patients with Coronary Artery Disease and Mild Cognitive Decline.

Objective Hypercholesterolemia, a risk factor in cognitive impairment, can be treated with statins. However, cognitive decline associated with "statins" (HMG-CoA reductase inhibitors) is a clinical concern. This pilot study investigated the effects of combining statins and regular exercise on cognitive function in coronary artery disease (CAD) patients with prior mild cognitive decline. Methods We recruited 43 consecutive CAD patients with mild cognitive decline. These patients were treated with a statin and weekly in-hospital aerobic exercise for 5 months. We measured serum lipids, exercise capacity, and cognitive function using the mini mental state examination (MMSE). Results Low-density lipoprotein cholesterol levels were significantly decreased, and maximum exercise capacity (workload) was significantly increased in patients with CAD and mild cognitive decline after treatment compared with before. Combined statin-exercise therapy significantly increased the median (range) MMSE score from 24 (22-25) to 25 (23-27) across the cohort (p<0.01). Changes in body mass index (BMI) were significantly and negatively correlated with changes in the MMSE. After treatment, MMSE scores in the subgroup of patients that showed a decrease in BMI were significantly improved, but not in the BMI-increased subgroup. Furthermore, the patients already on a statin at the beginning of the trial displayed a more significant improvement in MMSE score than statin-naïve patients, implying that exercise might be the beneficial aspect of this intervention as regards cognition. In a multivariate logistic regression analysis adjusted for age >65 years, sex, and presence of diabetes mellitus, a decrease in BMI during statin-exercise therapy was significantly correlated with an increase in the MMSE score (odds ratio: 4.57, 95% confidence interval: 1.05-20.0; p<0.05). Conclusion Statin-exercise therapy may help improve cognitive dysfunction in patients with CAD and pre-existing mild cognitive decline.

Statins combined with exercise are associated with the increased renal function mediated by high-molecular-weight adiponectin in coronary artery disease patients.

BACKGROUND: Statins and exercise therapy are clinically effective in preventing cardiovascular events in patients with coronary artery disease (CAD). The aim of this study was to determine the effects of statins combined with exercise on the renal function of CAD patients. METHODS: We performed a sub-analysis of a clinical trial that determined the 20-week-effects of two statins (rosuvastatin, n=14; atorvastatin, n=14) combined with regular exercise on renal function, as assessed by the estimated glomerular filtration rates (eGFRs) of CAD patients. RESULTS: The combination of statins and exercise therapy increased eGFRs from 61.1±16.6 at baseline to 65.8±16.8ml/min/per 1.73m(2) (p=0.03), increased serum levels of high-molecular-weight (HMW) adiponectin, increased ubiquinol/low-density lipoprotein cholesterol (LDL-C) ratios, and decreased high sensitivity C-reactive protein (hs-CRP). Changes in HMW-adiponectin, ubiquinol/LDL-C ratios and hs-CRP were significantly correlated with changes in eGFR (r=0.597, p=0.001; r=0.437, p=0.02; and r=-0.473, p=0.01, respectively). Treatment-induced increases in HMW-adiponectin independently correlated with the increases in eGFR (ß=0.513, p=0.02) in a multivariate analysis. Both atorvastatin and rosuvastatin combined with regular exercise produced increases in eGFR. The patients treated with rosuvastatin exhibited significant improvements in eGFR. CONCLUSION: Statins combined with exercise significantly increased eGFR in CAD patients, and these improvements in renal function were correlated with increases in HMW-adiponectin levels. The statins-exercise combination treatment may have provided clinical benefits for patients with CAD partly through the improvement in renal function.

Combination treatment of rosuvastatin or atorvastatin, with regular exercise improves arterial wall stiffness in patients with coronary artery disease.

OBJECTIVE: Statin- and exercise-therapy are both clinically beneficial by preventing cardiovascular events in patients with coronary artery disease (CAD). However, there is no information on the vascular effects of the combination of statins and exercise on arterial wall stiffness in CAD patients. METHODS: The present study is a sub-analysis of PRESET study that determined the effects of 20-week treatment with statins (rosuvastatin, n=14, atorvastatin, n=14) combined with regular exercise on arterial wall stiffness assessed by measurement of brachial and ankle pulse wave velocity (baPWV) in CAD patients. RESULTS: The combination of statins and regular exercise significantly improved exercise capacity, lipid profile, including low- and high-density lipoprotein cholesterol, and high-sensitivity C-reactive protein (hs-CRP), baPWV (baseline: 1747 ± 355, at 20 weeks of treatment: 1627 ± 271 cm/s, p=0.008), and basophil count (baseline: 42 ± 32, 20 weeks: 26 ± 15 cells/µL, p=0.007), but had no effect on blood pressure (baseline: 125 ± 22, 20 weeks: 121 ± 16 mmHg). Changes in baPWV correlated significantly with changes in basophil count (r=0.488, p=0.008), but not with age, lipids profile, exercise capacity, or hs-CRP. CONCLUSION: In CAD patients, the combination treatment with statins and exercise resulted in significant amelioration of arterial wall stiffness, at least in part, through reduction of circulating basophils.

Rosuvastatin combined with regular exercise preserves coenzyme Q10 levels associated with a significant increase in high-density lipoprotein cholesterol in patients with coronary artery disease.

BACKGROUND: Coenzyme Q10 levels are low in patients with coronary artery disease (CAD), and increasing or preserving coenzyme Q10 could be a beneficial strategy. Exercise and statins improve high-density lipoprotein cholesterol (HDL-C) levels. However, statins inhibit coenzyme Q10 biosynthesis, and the combination of statins with coenzyme Q10 supplementation increases HDL-C compared to statins alone. We compared the effects of two statins (rosuvastatin and atorvastatin) combined with exercise on coenzyme Q10 and HDL-C levels in CAD patients. METHODS: After randomizing 28 CAD patients to rosuvastatin (n=14) and atorvastatin (n=14) groups, patients performed weekly in-hospital aerobic exercise and daily home exercise for 20 weeks. We measured serum lipids, ubiquinol, and exercise capacity. RESULTS: Both statins equally improved exercise capacity and lowered low-density lipoprotein cholesterol and triglyceride levels. Rosuvastatin significantly increased HDL-C (rosuvastatin, +12 ± 9 mg/dL [+30%], atorvastatin, +5 ± 5 mg/dL [+13%], p=0.014) and apolipoprotein A1 (ApoA1) (rosuvastatin, +28.3 ± 20.7 mg/dL, atorvastatin, +13.4 ± 12.0 mg/dL, p=0.030) compared to atorvastatin. Atorvastatin significantly decreased serum ubiquinol (731 ± 238 to 547 ± 219 nmol/L, p=0.001), but rosuvastatin (680±233 to 668 ± 299 nmol/L, p=0.834) did not. There was a significant positive correlation between changes in ubiquinol and ApoA1 (r=0.518, p=0.005). Multivariate regression analysis showed that changes in ubiquinol correlated significantly with changes in ApoA1 after adjusting for age, sex, body mass index, and smoking (ß=0.502, p=0.008). CONCLUSIONS: Compared to atorvastatin, rosuvastatin combined with exercise significantly preserved ubiquinol levels associated with an increase in HDL-C. Rosuvastatin with regular exercise could be beneficial for CAD patients.