The Role of Sphingosine Kinase 1/Sphingosine-1-Phosphate Pathway in the Myogenic Tone of Posterior Cerebral Arteries

AIMS: The goal of the current study was to determine whether the sphingosine kinase 1 (SK1)/sphingosine-1-phosphate (S1P) pathway is involved in myogenic vasoconstriction under normal physiological conditions. In the present study, we assessed whether endogenous S1P generated by pressure participates in myogenic vasoconstriction and which signaling pathways are involved in SK1/S1P-induced myogenic response under normal physiological conditions. METHODS AND RESULTS: We measured pressure-induced myogenic response, Ca(2+) concentration, and 20 kDa myosin light chain phosphorylation (MLC(20)) in rabbit posterior cerebral arteries (PCAs). SK1 was expressed and activated by elevated transmural pressure in rabbit PCAs. Translocation of SK1 by pressure elevation was blocked in the absence of external Ca(2+) and in the presence of mechanosensitive ion channel and voltage-sensitive Ca(2+) channel blockers. Pressure-induced myogenic tone was inhibited in rabbit PCAs treated with sphingosine kinase inhibitor (SKI), but was augmented by treatment with NaF, which is an inhibitor of sphingosine-1-phosphate phosphohydrolase. Exogenous S1P further augmented pressure-induced myogenic responses. Pressure induced an increase in Ca(2+) concentration leading to the development of myogenic tone, which was inhibited by SKI. Exogenous S1P further increased the pressure-induced increased Ca(2+) concentration and myogenic tone, but SKI had no effect. Pressure- and exogenous S1P-induced myogenic tone was inhibited by pre-treatment with the Rho kinase inhibitor and NADPH oxidase inhibitors. Pressure- and exogenous S1P-induced myogenic tone were inhibited by pre-treatment with S1P receptor blockers, W146 (S1P1), JTE013 (S1P2), and CAY10444 (S1P3). MLC(20) phosphorylation was increased when the transmural pressure was raised from 40 to 80 mmHg and exogenous S1P further increased MLC(20) phosphorylation. The pressure-induced increase of MLC(20) phosphorylation was inhibited by pre-treatment of arteries with SKI. CONCLUSIONS: Our results suggest that the SK1/S1P pathway may play an important role in pressure-induced myogenic responses in rabbit PCAs under normal physiological conditions

The association of serum irisin with anthropometric, metabolic, and bone parameters in obese children and adolescents

BackgroundIrisin is an adipomyokine secreted by muscle and adipose cells, and it plays a role in glucose, fat, and bone metabolism. This study aimed to determine the correlation of serum irisin levels with anthropometric, metabolic, and bone parameters in obese children and adolescents.MethodsThis single-center study included 103 Korean children and adolescents: 54 (52.4%) obese participants with a body mass index (BMI) ≥95th percentile and 49 (47.6%) healthy controls with BMI within the 15th to 85th percentile. Various parameters were measured, including fasting blood glucose, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), triglyceride and glucose (TyG) index, lipid profile, alkaline phosphatase (ALP), osteocalcin, and 25(OH)-Vitamin D levels. Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry (DEXA) in 33 healthy subjects.ResultsSerum irisin was significantly higher in the obese group than in the control group (mean 18.1 ± 3.5 vs. 16.2 ± 2.0 ng/mL; p = 0.001). Serum irisin level was positively correlated with chronological age (r = 0.28; p = 0.004), height SDS (r = 0.24; p = 0.02), BMI SDS (r = 0.37; p < 0. 001), fasting glucose (r = 0.27; p = 0.007), fasting insulin (r = 0.23; p = 0.03), HOMA-IR (r = 0.21; p = 0.04), osteocalcin (r = 0.27; p = 0.006) and negatively correlated with HDL cholesterol (r = -0.29; p = 0.005). All these correlations were evident in obese subjects but not in healthy subjects. ALP and 25(OH)-Vitamin D were unrelated to irisin levels. Among 33 healthy subjects, total body-less head (TBLH) BMD Z-score was positively correlated with serum irisin (r = 0.39; p = 0.03), osteocalcin (r = 0.40; p = 0.02), fasting insulin (r = 0.39; p = 0.04), and HOMA-IR (r = 0.38; p = 0.047).ConclusionThis study demonstrated an association between irisin levels and glucose, lipid, and bone parameters in children and adolescents. Our findings suggest that irisin has a potential role in metabolic disorders and bone health in obese children and adolescents

Factors affecting height velocity in normal prepubertal children

Purpose To analyze the effects of clinical and laboratory factors, including insulin-like growth factor (IGF) levels, on the height velocity of normal prepubertal children. Methods Ninety-five healthy prepubertal children (33 boys, 62 girls) were enrolled. The mean chronological age was 6.3±1.4 years, with a height standard deviation score (SDS) of -0.88±0.70. IGF-1, IGF binding protein-3 (IGFBP-3), SDS for anthropometric measurements, and changes in SDS for anthropometric measurements were analyzed for 1 year, and their associations with 1-year height velocity were investigated. Results The group of children with a 1-year height velocity of ≥6 cm were chronologically younger than the group with a 1-year height velocity of <6 cm (5.9±1.3 years vs. 6.7±1.3 years, P=0.004), with a lesser increase of SDS for body mass index (BMI) over 1 year (-0.18±0.68 vs. 0.13±0.53, P=0.014). There were no differences between the 2 groups in IGF-1 SDS and IGFBP-3 SDS. Multiple linear regression showed that baseline chronological age (r=0.243, P=0.026) and height SDS (r=0.236, P=0.030) were positively associated with IGF-1 SDS. Binomial logistic regression showed that an older chronologic age at referral (odds ratio [OR], 0.68; 95% confidence interval [CI], 0.47–0.99) and an increase of BMI SDS over 1 year (OR, 0.41; 95% CI, 0.18–0.89) were associated with a decreased growth possibility of an above-average height velocity (≥6 cm/yr). Conclusions Height velocity of normal prepubertal children is affected by an increase of BMI SDS and chronological age. Prepubertal IGF-1 SDS reflects height SDS at the time of measurement but is not associated with subsequent height velocity

Favorable response to doxorubicin combination chemotherapy does not yield good clinical outcome in patients with metastatic breast cancer with triple-negative phenotype

<p>Abstract</p> <p>Background</p> <p>We analyzed the responses to first line treatment and clinical outcomes of metastatic breast cancer patients treated with palliative doxorubicin/cyclophosphamide (AC) according to molecular cancer subtype.</p> <p>Methods</p> <p>A retrospective analysis was performed for 110 metastatic breast cancer patients selected on the basis of palliative AC treatment and the availability of immunohistochemical data for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER-2/neu) status.</p> <p>Results</p> <p>Of the 110 patients analyzed, 71 (64.5%) were hormone receptor positive (HR+), 14 (12.7%) were HER2+, and 25 (22.7%) were triple negative (TN). There were no differences in age, stage at diagnosis, total number of cycles of palliative chemotherapy, incidence of visceral metastasis, and metastatic sites with the exception of liver among breast cancer subtypes. The overall response rates to AC were 55.9% for the HR+ subgroup, 42.9% for the HER2+ subgroup, and 56.5% for the TN subgroup. The progression-free survival (PFS) in patients with HER2+ and TN were significantly shorter than in the HR+ (median PFS, 9.1 <it>vs </it>8.1 <it>vs </it>11.5 months, respectively; p = 0.0002). The overall survival (OS) was 25.4 months in the TN subgroup and 27.3 months in HER2+ subgroup. The median OS for these two groups was significantly shorter than for patients in the HR+ subgroup (median, 38.5 months; 95% CI, 30.1-46.9 months; p < 0.0001).</p> <p>Conclusions</p> <p>The response to palliative AC chemotherapy did not differ among breast cancer subtypes. Despite chemosensitivity for palliative AC, the TN subtype has a shorter overall survival than non-TN subtypes. Innovative treatment strategies should be developed to slow the course of disease.</p

Metabolically-Healthy Obesity and Coronary Artery Calcification

ObjectivesThe purpose of this study was to compare the coronary artery calcium (CAC) scores of metabolically-healthy obese (MHO) and metabolically healthy normal-weight individuals in a large sample of apparently healthy men and women.BackgroundThe risk of cardiovascular disease among obese individuals without obesity-related metabolic abnormalities, referred to as MHO, is controversial.MethodsWe conducted a cross-sectional study of 14,828 metabolically-healthy adults with no known cardiovascular disease who underwent a health checkup examination that included estimation of CAC scores by cardiac tomography. Being metabolically healthy was defined as not having any metabolic syndrome component and having a homeostasis model assessment of insulin resistance <2.5.ResultsMHO individuals had a higher prevalence of coronary calcification than normal weight subjects. In multivariable-adjusted models, the CAC score ratio comparing MHO with normal-weight participants was 2.26 (95% confidence interval: 1.48 to 3.43). In mediation analyses, further adjustment for metabolic risk factors markedly attenuated this association, which was no longer statistically significant (CAC score ratio 1.24; 95% confidence interval: 0.79 to 1.96). These associations did not differ by clinically-relevant subgroups.ConclusionsMHO participants had a higher prevalence of subclinical coronary atherosclerosis than metabolically-healthy normal-weight participants, which supports the idea that MHO is not a harmless condition. This association, however, was mediated by metabolic risk factors at levels below those considered abnormal, which suggests that the label of metabolically healthy for obese subjects may be an artifact of the cutoff levels used in the definition of metabolic health

The strong association of left-side heart anomalies with Kabuki syndrome

PurposeKabuki syndrome is a multiple congenital malformation syndrome, with characteristic facial features, mental retardation, and skeletal and congenital heart anomalies. However, the cardiac anomalies are not well described in the Korean population. We analyzed the cardiac anomalies and clinical features of Kabuki syndrome in a single tertiary center.MethodsA retrospective analysis was conducted for a total of 13 patients with Kabuki syndrome.ResultsThe median age at diagnosis of was 5.9 years (range, 9 days to 11 years and 8 months). All patients showed the characteristic facial dysmorphisms and congenital anomalies in multiple organs, and the diagnosis was delayed by 5.9 years (range, 9 days to 11 years and 5 months) after the first visit. Noncardiac anomalies were found in 84% of patients, and congenital heart diseases were found in 9 patients (69%). All 9 patients exhibited left-side heart anomalies, including hypoplastic left heart syndrome in 3, coarctation of the aorta in 4, aortic valve stenosis in 1, and mitral valve stenosis in 1. None had right-side heart disease or isolated septal defects. Genetic testing in 10 patients revealed 9 novel MLL2 mutations. All 11 patients who were available for follow-up exhibited developmental delays during the median 4 years (range, 9 days to 11 years 11 months) of follow-up. The leading cause of death was hypoplastic left heart syndrome.ConclusionPediatric cardiologist should recognize Kabuki syndrome and the high prevalence of left heart anomalies with Kabuki syndrome. Genetic testing can be helpful for early diagnosis and counseling

A Case of Congenital Central Hypoventilation Syndrome with PHOX2B Gene Mutation in a Korean Neonate

Congenital central hypoventilation syndrome (CCHS) is a life-threatening disorder with apnea and cyanosis during sleep requiring immediate endotracheal intubation during the first day of life. The PHOX2B gene has been identified as the major gene involved in CCHS. This is the first report of a Korean neonate with CCHS confirmed to have a PHOX2B mutation with expanded alleles containing 20 polyalanine repeats that is a relatively small number compared to previous cases. The patient required intermittent ventilator support during sleep only and did not suffer from any other disorders of the autonomic nerve system. He consistently needs ventilator support during sleep and remains alive. Analysis of PHOX2B gene is useful for diagnosis and appropriate therapeutic intervention of CCHS patients

Refractory Duodenal Crohn's Disease Successfully Treated with Infliximab

Crohn's disease (CD) may involve any part of the gastrointestinal tract, from the mouth to the anus. Approximately >90% of cases occur in the small bowel and colon. Upper gastrointestinal involvement, especially duodenal manifestation, is relatively rare. Therefore, adequate medical treatment for duodenal CD has not yet been established. We report a case of CD with duodenal involvement. A 46-year-old man with Crohn's ileocolitis presented to our hospital with right upper quadrant pain. An endoscopy showed a deep excavated ulcer with deformity at the duodenal bulb, and he was initially treated with azathioprine (1 mg/kg), Pentasa (3.0 g/day), and a proton pump inhibitor for 1 year. However, the deep ulcer did not heal. Therefore, infliximab infusion therapy was initiated, and the duodenal lesion completely resolved on follow-up esophagogastroduodenoscopy. We report a case of duodenal CD that completely resolved following infliximab infusion, with a review of the literature