Sex Differences in Flexibility-Arterial Stiffness Relationship and Its Application for Diagnosis of Arterial Stiffening: A Cross-Sectional Observational Study

Purpose

Arterial stiffness might be related to trunk flexibility in middle-aged and older participants, but it is also affected by age, sex, and blood pressure. This cross-sectional observational study investigated whether trunk flexibility is related to arterial stiffness after considering the major confounding factors of age, sex, and blood pressure. We further investigated whether a simple diagnostic test of flexibility could be helpful to screen for increased arterial stiffening.

Methods

According to age and sex, we assigned 1150 adults (male, n = 536; female, n = 614; age, 18–89 y) to groups with either high- or poor-flexibility based on the sit-and-reach test. Arterial stiffness was assessed by cardio-ankle vascular index.

Results

In all categories of men and in older women, arterial stiffness was higher in poor-flexibility than in high-flexibility (P<0.05). This difference remained significant after normalizing arterial stiffness for confounding factors such as blood pressure, but it was not found among young and middle-aged women. Stepwise multiple-regression analysis also supported the notion of the sex differences in flexibility-arterial stiffness relationship. Receiver operating characteristic curve analysis revealed that cut-off values for sit-and-reach among men and women were 33.2 (area under the curve [AUC], 0.711; 95% confidence interval [CI], 0.666–0.756; sensitivity, 61.7%; specificity, 69.7%) and 39.2 (AUC, 0.639; 95% CI, 0.592–0.686; sensitivity, 61.1%; specificity, 62.0%) cm, respectively.

Conclusion

Our results indicate that flexibility-arterial stiffness relationship is not affected by BP, which is a major confounding factor. In addition, sex differences are observed in this relationship; poor trunk flexibility increases arterial stiffness in young, middle-aged, and older men, whereas the relationship in women is found only in the elderly. Also, the sit-and-reach test can offer a simple method of predicting arterial stiffness at home or elsewhere.     

Novel diphenylalkyl piperazine derivatives with high affinities for the dopamine transporter

The novel diphenyl piperazine derivatives containing the phenyl substituted aminopropanol moiety, including 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(phenylamino)propyl]piperazine 1, which were modified at the connective between the diphenyl and piperazine moieties, have been found to be potent dopamine uptake inhibitors. To study the further structure-activity relationship (SAR) of these compounds, a new series was synthesized, with modifications at the 2-hydroxy-3-phenylaminopropyl moiety of 1. The series was evaluated for dopamine transporter (DAT) binding affinity with [3H]GBR12935 in rat striatal membranes. Most of the compounds showed moderate to high DAT binding affinities and some were approximately equivalent in activity to compound 1 or GBR12909 as a dopamine uptake inhibitor, with IC(50) values of nanomolar range. The SAR suggested that on exhibiting a potent interaction with the DAT, there is probably a steric limitation around the benzene ring of the phenylamino moiety of 1, allowing only small-sized substituents with the exception of basic moieties at the 4-position. In addition, the SAR at the 3-amino-2-propanol moiety of 1 suggested that either the nitrogen atom with an electron donating substituent or the unsubstituted nitrogen atom and also the hydroxy group are desirable for elicitation of a potent DAT binding affinity.     

Imprinting of a small nucleolar RNA gene on mouse chromosome 12

We have identified a novel, maternally expressed imprinted gene encoding a C/D-box small nucleolar RNA (snoRNA) called MBII-343, which may regulate RNA editing or alternative splicing of an as yet unknown target gene. This gene is closely linked to an imprinted gene, Meg3, on mouse distal chromosome 12, which is syntenic to human chromosome 14. The paternal duplication of mouse distal chromosome 12 leads to late embryonal/neonatal lethality, growth promotion, and cardiomyopathy, whereas maternal duplication leads to late embryonal lethality and growth retardation. Human paternal uniparental disomy for chromosome 14 leads to musculoskeletal problems and mental retardation, whereas maternal uniparental disomy leads to intrauterine growth retardation, motor developmental delay, premature puberty, hypotonia, joint laxity, macrocephaly, short statue, neonatal poor sucking, skill with jigsaw puzzles, skin picking, obesity, and maturity onset diabetes of the young.     

Developmental differences in B cell receptor-induced signal transduction

We have compared early signaling events at various stages of B cell differentiation using established mouse cell lines. Clustering of pre-B cell antigen receptor (BCR) or BCR induced the tyrosine phosphorylation of various proteins in all cells, although the phosphorylation pattern differed. In spite of the pre-BCR-induced tyrosine phosphorylation, we could not detect an intracellular Ca(2+) signal in pre-B cells. However, co-clustering of the pre-BCR with CD19 did induce Ca(2+) mobilization. In contrast to the immature and mature B cells, where the B cell linker protein (BLNK) went through inducible tyrosine phosphorylation upon BCR clustering, we observed a constitutive tyrosine phosphorylation of BLNK in pre-B cell lines. Both BLNK and phospholipase C (PLC)gamma were raft associated in unstimulated pre-B cells, and this could not be enhanced by pre-BCR engagement, suggesting a ligand-independent PLC gamma-mediated signaling. Further results indicate that the cell lines representing the immature stage are more sensitive to BCR-, CD19- and type II receptors binding the Fc part of IgG (Fc gamma RIIb)-mediated signals than mature B cells.     

Anti-ovulatory effects of RU486 and trilostane involve impaired cyclooxygenase-2 expression and mitotic activity of follicular granulosa cells in rats

To explore the mechanism for anti-ovulatory effects of blockade of preovulatory synthesis and action of progesterone, we focused on cyclooxygenase (COX)-2 induction and mitotic activity of granulosa cells in gonadotropins-treated rats. Treatment with RU486 (a progesterone receptor antagonist) or trilostane (a 3β-hydroxysteroid dehydrogenase inhibitor) just prior to or 4h after human chorinonic gonadotropin (hCG) (hCG4h) decreased ovulation rates and circulating progesterone level. Human CG induction of immunoreactive COX-2 in the granulosa layer of mature Graafian follicles at hCG8h was reduced by RU486 treatment at hCG0h and trilostane treatment at hCG4h. RU486 treatment further attenuated ovarian prostaglandin E(2) (PGE(2)) level significantly. Cell proliferative activity in mural granulosa layer of the inhibitors-treated follicles was significantly lower than in intact group. Obtained results show that inhibition of synthesis and action of progesterone caused attenuated COX-2/PGE(2) system and dysregulated mitotic response of granulosa cells, resulting in decreased ovulation.     

KL-6 concentration in pulmonary epithelial lining fluid is a useful prognostic indicator in patients with acute respiratory distress syndrome

Background

KL-6 is a mucin-like glycoprotein expressed on the surface of alveolar type II cells. Elevated concentrations of KL-6 in serum and epithelial lining fluid (ELF) in patients with acute respiratory distress syndrome (ARDS) have been previously reported; however, kinetics and prognostic significance of KL-6 have not been extensively studied. This study was conducted to clarify these points in ARDS patients.

Methods

Thirty-two patients with ARDS who received mechanical ventilation under intubation were studied for 28 days. ELF and blood were obtained from each patient at multiple time points after the diagnosis of ARDS. ELF was collected using a bronchoscopic microsampling procedure, and ELF and serum KL-6 concentrations were measured.

Results

KL-6 levels in ELF on days 0 to 3 after ARDS diagnosis were significantly higher in nonsurvivors than in survivors, and thereafter, there was no difference in concentrations between the two groups. Serum KL-6 levels did not show statistically significant differences between nonsurvivors and survivors at any time point. When the highest KL-6 levels in ELF and serum sample from each patient were examined, KL-6 levels in both ELF and serum were significantly higher in nonsurvivors than in survivors. The optimal cut-off values were set at 3453 U/mL for ELF and 530 U/mL for serum by receiver operating characteristic (ROC) curve analyses. Patients with KL-6 concentrations in ELF higher than 3453 U/mL or serum concentrations higher than 530 U/mL had significantly lower survival rates up to 90 days after ARDS diagnosis.

Conclusions

ELF and serum KL-6 concentrations were found to be good indicators of clinical outcome in ARDS patients. Particularly, KL-6 levels in ELF measured during the early period after the diagnosis were useful for predicting prognosis in ARDS patients.     

Effects of phosphatidylethanolamine N-methyltransferase on phospholipid composition, microvillus formation and bile salt resistance in LLC-PK1 cells

Bile salts are potent detergents and can disrupt cellular membranes, which causes cholestasis and hepatocellular injury. However, the mechanism for the resistance of the canalicular membrane against bile salts is not clear. Phosphatidylethanolamine (PE) is converted to phosphatidylcholine (PC) in the liver by phosphatidylethanolamine N-methyltransferase (PEMT). In this study, to investigate the effect of PEMT expression on the resistance to bile salts, we established an LLC-PK1 cell line stably expressing PEMT. By using enzymatic assays, we showed that the expression of PEMT increased the cellular PC content, lowered the PE content, but had no effect on the sphingomyelin content. Consequently, PEMT expression led to reductions in PE/PC and sphingomyelin/PC ratios. Mass spectrometry demonstrated that PEMT expression increased the levels of PC species containing longer acyl chains and almost all ether-linked PC species. PEMT expression enhanced the resistance to duramycin and lysenin, suggesting decreased ratios of PE and sphingomyelin in the apical membrane, respectively. In addition, SEM revealed that PEMT expression increased the diameter of microvilli. The expression of PEMT resulted in reduced resistance to unconjugated bile salts, but surprisingly in increased resistance to conjugated bile salts, which might be attributable to modifications of the phospholipid composition and/or structure in the apical membrane. Because most bile salts exist as conjugated forms in the bile canaliculi, PEMT may be important in the protection of hepatocytes from bile salts and in cholestatic liver injury.     

Toward a brain-based theory of beauty

We wanted to learn whether activity in the same area(s) of the brain correlate with the experience of beauty derived from different sources. 21 subjects took part in a brain-scanning experiment using functional magnetic resonance imaging. Prior to the experiment, they viewed pictures of paintings and listened to musical excerpts, both of which they rated on a scale of 1-9, with 9 being the most beautiful. This allowed us to select three sets of stimuli--beautiful, indifferent and ugly--which subjects viewed and heard in the scanner, and rated at the end of each presentation. The results of a conjunction analysis of brain activity showed that, of the several areas that were active with each type of stimulus, only one cortical area, located in the medial orbito-frontal cortex (mOFC), was active during the experience of musical and visual beauty, with the activity produced by the experience of beauty derived from either source overlapping almost completely within it. The strength of activation in this part of the mOFC was proportional to the strength of the declared intensity of the experience of beauty. We conclude that, as far as activity in the brain is concerned, there is a faculty of beauty that is not dependent on the modality through which it is conveyed but which can be activated by at least two sources--musical and visual--and probably by other sources as well. This has led us to formulate a brain-based theory of beauty.     

Real-time PCR-based analysis of the human bile microRNAome identifies miR-9 as a potential diagnostic biomarker for biliary tract cancer

Biliary tract cancer (BTC) is often difficult to diagnose definitively, even through histological examination. MicroRNAs (miRNAs) regulate a variety of physiological processes. In recent years, it has been suggested that profiles for circulating miRNAs, as well as those for tissue miRNAs, have the potential to be used as diagnostic biomarkers for cancer. The aim of this study was to confirm the existence of miRNAs in human bile and to assess their potential as clinical biomarkers for BTC. We sampled bile from patients who underwent biliary drainage for biliary diseases such as BTC and choledocholithiasis. PCR-based miRNA detection and miRNA cloning were performed to identify bile miRNAs. Using high-throughput real-time PCR-based miRNA microarrays, the expression profiles of 667 miRNAs were compared in patients with malignant disease (n = 9) and age-matched patients with the benign disease choledocholithiasis (n = 9). We subsequently characterized bile miRNAs in terms of stability and localization. Through cloning and using PCR methods, we confirmed that miRNAs exist in bile. Differential analysis of bile miRNAs demonstrated that 10 of the 667 miRNAs were significantly more highly expressed in the malignant group than in the benign group at P<0.0005. Setting the specificity threshold to 100% showed that some miRNAs (miR-9, miR-302c*, miR-199a-3p and miR-222*) had a sensitivity level of 88.9%, and receiver-operating characteristic analysis demonstrated that miR-9 and miR-145* could be useful diagnostic markers for BTC. Moreover, we verified the long-term stability of miRNAs in bile, a characteristic that makes them suitable for diagnostic use in clinical settings. We also confirmed that bile miRNAs are localized to the malignant/benign biliary epithelia. These findings suggest that bile miRNAs could be informative biomarkers for hepatobiliary disease and that some miRNAs, particularly miR-9, may be helpful in the diagnosis and clinical management of BTC.