Supramolecular Interactions-Assisted Polymorphism and Unique Mechanofluorochromism in 9,10-Bis((E)-4-(trifluoromethyl)styryl)anthracene.

A fluorinated distyrylanthracene (DSA) derivative, 9, 10-bis((E)-4-(trifluoromethyl)styryl)anthracene abbreviated as 4FDSA with two crystalline polymorphs (4FDSA-G (green emission) and 4FDSA-O (orange emission)), showing remarkable aggregation-induced enhanced emission and mechanofluorochromic characteristics, was developed. One of the polymorphs in its crystalline arrangement exhibits the hardly seen F…F interactions. It questions the conventional belief of the non-polarisable nature of fluorine atoms in forming the halogen bond. The twisted molecular conformation facilitated by the various supramolecular interactions resulted in the formation of another intensely emissive bluer nanocrystal (4FDSA-NC) at aggregating conditions. Even though, the both polymorphs show distinct tricolor luminescence switching on the action of mechanical force, fumigation of ground crystals with solvent vapor resulted in the formation of a more thermodynamically favorable 4FDSA-NC form. The work demonstrates the effect of supramolecular interactions assisted conformational changes in tuning the unique mechanofluorochromic characteristics of the polymorphic crystals.

Fermented milk retains beneficial effects on skeletal muscle protein anabolism after processing by centrifugation and supernatant removal.

Lactobacillus-fermented milk can stimulate anabolic effects in skeletal muscle. Fermented milk containing Lactobacillus produces aqueous molecules, such as free AA and lactate. This study aimed to investigate how processing fermented milk by centrifugation and removal of supernatant affects AA absorption and postprandial skeletal muscle protein synthesis (MPS) when mice are fed fermented milk. We gavaged male Sprague-Dawley rats with skim milk (S), fermented milk (F), or processed fermented milk (P), and examined the total AA content in portal vein blood (reflecting AA absorption) and plantaris muscle MPS at 30, 60, and 90 min following administration. Relative to fasted rats, at 30 min the total AA concentration in portal vein blood from rats in the P groups was significantly higher, followed by F and S, respectively. The MPS rates were higher for the F or P groups compared with the S group. Phosphorylation levels of p70S6 kinase in the P and F groups were significantly higher than those for the S group 30 min after administration, although the level of Akt phosphorylation was similar among the groups. These results suggested that fermentation improves AA absorption that in turn enhances postprandial MPS via Akt-independent mechanisms, and that processed fermented milk retains these favorable effects on MPS.

Top Ten Tips Palliative Care Clinicians Should Know about Implementing a Team Wellness Program.

Palliative care (PC) providers often face challenging and emotional cases while operating in the structures that are not ideally resourced. This combination can lead to burnout and further jeopardize resources from turnover, morale, and decreased productivity. Although many wellness efforts have focused on building personal resilience skills for individuals, programmatic approaches to improve a culture wellness are equally important in supporting clinical teams. This article brings together the perspectives of PC leaders with expertise in wellness to collate practical pearls for interventions that impact the culture of well-being in their organizations. In this article, we use a "Top 10" format to highlight the interventions that PC leaders can implement to support the well-being of clinical staff and promote program sustainability.

Effects of Low-Dose Dairy Protein Plus Micronutrient Supplementation during Resistance Exercise on Muscle Mass and Physical Performance in Older Adults: A Randomized, Controlled Trial.

OBJECTIVES: To investigate whether supplementation with low-dose dairy protein plus micronutrients augments the effects of resistance exercise (RE) on muscle mass and physical performance compared with RE alone among older adults. DESIGN: Randomized controlled trial. SETTING: Tokyo, Japan. PARTICIPANTS: Eighty-two community-dwelling older adults (mean age, 73.5 years) were randomly allocated to an RE plus dairy protein and micronutrient supplementation group or an RE only group (n = 41 each). INTERVENTION: The RE plus supplementation group participants ingested supplements with dairy protein (10.5 g/day) and micronutrients (8.0 mg zinc, 12 µg vitamin B12, 200 µg folic acid, 200 IU vitamin D, and others/day). Both groups performed the same twice-weekly RE program for 12 weeks. MEASUREMENTS: Whole-body, appendicular, and leg lean soft-tissue mass (WBLM, ALM, and LLM, respectively) with dual-energy X-ray absorptiometry, physical performance, biochemical characteristics, nutritional intake, and physical activity were measured before and after the intervention. Data were analyzed by using linear mixed-effects models. RESULTS: The groups exhibited similar significant improvements in maximum gait speed, Timed Up-and-Go, and 5-repetition and 30-s chair stand tests. As compared with RE only, RE plus supplementation significantly increased WBLM (0.63 kg, 95% confidence interval [CI]: 0.31-0.95), ALM (0.37 kg, 95% CI: 0.16-0.58), LLM (0.27 kg, 95% CI: 0.10-0.46), and serum concentrations of 25-hydroxyvitamin D (4.7 ng/mL, 95% CI: 1.6-7.9), vitamin B12 (72.4 pg/mL, 95% CI: 12.9-131.9), and folic acid (12.9 ng/mL, 95% CI: 10.3-15.5) (all P < 0.05 for group-by-time interactions). Changes over time in physical activity and nutritional intake excluding the supplemented nutrients were similar between groups. CONCLUSION: Low-dose dairy protein plus micronutrient supplementation during RE significantly increased muscle mass in older adults but did not further improve physical performance.

Eldecalcitol (ED-71), an analog of 1α,25(OH)2D3, inhibits the growth of squamous cell carcinoma (SCC) cells in vitro and in vivo by down-regulating expression of heparin-binding protein 17/fibroblast growth factor-binding protein-1 (HBp17/FGFBP-1) and FGF-2.

Heparin-binding protein 17 (HBp17)/fibroblast growth factor-binding protein-1 (FGFBP-1) was first purified from medium conditioned by A431 cells for its capacity to bind to fibroblast growth factors 1 and 2 (FGF-1 and -2). Among FGF family members, FGF-2 is a potent mitogen for various cell types, including vascular endothelial cells, fibroblasts, and cancer cells such as oral squamous cell carcinoma (OSCC) cells. Besides being well known in bone metabolism, the active form of vitamin D3, i.e., 1α,25(OH)2D3 (1,25D3), was reported to have protective effects for heart disease and cancer. Previously, we reported that 1,25D3 inhibited HBp17/FGFBP-1 expression in OSCC cell lines through NF-κB inhibition (IκBα activation) and resulted in the inactivation of FGF-2. In this study, we examined the potential anti-tumor effect of ED-71, an analog of 1α,25(OH)2D3, for squamous cell carcinoma cells in vitro and in vivo. The cell lines used were OSCC cell lines (NA-HO-1-n-1 and UE-HO-1-u-1), established from oral cancer patients in our laboratory, and an epidermoid carcinoma/SCC cell line (A431). The growth assay in serum-free culture revealed that ED-71 inhibited the growth of the cancer cell lines in a dose-dependent manner. In addition, ED-71 suppressed HBp17/FGFBP-1 expression by inhibiting the NF-κB pathway as did 1,25D3. Furthermore, a luciferase reporter assay revealed that the promoter activity of HBp17/FGFBP-1 (region between -217 and +61) was down-regulated by ED-71. Oral administration of ED-71 significantly inhibited the growth of A431-derived tumors in athymic nude mice. Immunohistochemical analysis revealed that the expression of HBp17/FGFBP-1, FGF-2, CD31, and Ki-67 in the tumors of ED71-treated group was down-regulated in comparison to control. These results suggest that ED-71 possesses potential anti-tumor activity for SCCs both in vitro and in vivo. This compound may act directly on the tumor cells or on endothelial cells by modulating the tumor microenvironment.

Heart rate variability during high-intensity field exercise in female distance runners.

The purposes of this study were to demonstrate the transition of heart rate variability (HRV) during trials in the field and to examine the relationship between peak frequency of high-frequency band (HF) and stride frequency. Ten healthy long-distance college female runners (age 19-21 years) performed a 3000 m realistic time trial. The time-series power spectrum analysis by maximum entropy method was used to evaluate cardiac autonomic nervous activity during the race. Cross-correlation coefficients were calculated to estimate the degree of linear co-ordination between the central peak frequency of HF and stride frequency. Just after starting, the decrease in HF (0.15-1.00 Hz) and a transient increase of low-frequency band (LF)/HF were found. After that, the HF remained at a low level and LF/HF decreased sharply. These findings suggested that the parasympathetic activity was suppressed and sympathetic activity increased just after starting, and the sympathetic activity reached the saturated level according to continuation of high-intensity exercise. In spite of the significant decrease of HRV during trials, peak frequency of HF could be differentiated clearly. The cross-correlation coefficient of peak frequency of HF and stride frequency was from 0.703 to 0.868. This finding indicated that exercise rhythm reflected HRV during high-intensity running in the field.

Effect of nCPAP therapy on heart rate in patients with obstructive sleep apnoea-hypopnoea.

BACKGROUND: Elevated heart rate (HR) is a risk factor for cardiovascular disease. The effects of obstructive sleep apnoea-hypopnoea syndrome (OSAHS) on HR are controversial. AIM: To investigate the effect of nasal continuous positive airway pressure (nCPAP) therapy on HR in OSAHS patients. METHODS: Sixty-two OSAHS patients underwent 24-h electrocardiographic recording, both before and 3 or 4 days after instigation of nCPAP. RESULTS: After nCPAP was started, HR significantly decreased (mean +/- SD 71.8 +/- 10.6 vs. 67.5 +/- 9.4 bpm, p < 0.0001), both in the daytime (0600-2200 h, 76.3 +/- 12.2 vs. 72.2 +/- 10.2 bpm, p < 0.0001) and at night-time (2200-0600 h, 64.5 +/- 9.1 vs. 60.0 +/- 8.9 bpm, p < 0.0001). HR was significantly reduced in both periods in the 44 patients with hypertension and/or diabetes mellitus, but only during the night-time in the 18 with neither condition. Before nCPAP treatment, HR was positively correlated with percentage time of arterial O2 saturation <90% during sleep (p = 0.008) and with the apnoea-hypopnoea index during sleep (p = 0.003). In 15 patients undergoing HR for 2 days before starting nCPAP, the mean HRs for the two periods were similar (p = 0.95). DISCUSSION: nCPAP therapy appears to decrease HR in OSAHS patients, and may thereby reduce their risk of cardiovascular disease.

Dysregulated expression of P1 and P2 promoter-driven hepatocyte nuclear factor-4alpha in the pathogenesis of human cancer.

Hepatocyte nuclear factor-4alpha (HNF4alpha) exists in multiple isoforms that are generated by alternative promoter (P1 and P2) usage and splicing. Here we establish monoclonal antibodies (mAbs) for detecting P1 and P2 promoter-driven HNF4alpha, and evaluate their expression in normal adult human tissues and surgically resected carcinomas of different origins. Using immunohistochemical analysis, we demonstrate that, while P1 promoter-driven HNF4alpha is expressed in hepatocytes, small intestine, colon, kidney and epididymis, P2 promoter-driven HNF4alpha is expressed in bile duct, pancreas, stomach, small intestine, colon and epididymis. Altered expression patterns of P1 and P2 promoter-driven HNF4alpha were observed in gastric, hepatocellular and colorectal carcinomas. HNF4alpha was expressed in lung metastases from renal cell, hepatocellular and colorectal carcinoma but was not observed in lung tumours. The P1 and P2 promoter-driven HNF4alpha expression pattern of tumour metastases correlated with the primary site of origin. P1 promoter-driven HNF4alpha was also found in intestinal metaplasia of the stomach. These data provide evidence for the tissue distribution of P1 and P2 promoter-driven HNF4alpha at the protein level and suggest that HNF4alpha may be a novel diagnostic marker for metastases of unknown primary. We propose that the dysregulation of alternative promoter usage of HNF4alpha is associated with the pathogenesis of certain cancers.

In vivo transfection of a cis element 'decoy' against signal transducers and activators of transcription 6 (STAT6)-binding site ameliorates IgE-mediated late-phase reaction in an atopic dermatitis mouse model.

Signal transducers and activators of transcription 6 (STAT6) play a crucial role in the transactivation of IL-4 and IL-13, which might be involved in the pathogenesis of atopic dermatitis (AD). We herein reported that the IgE-mediated late-phase reaction significantly decreased in STAT6-deficient (STAT6(-/-)) mice in AD model mice induced by intravenous injection of monoclonal anti-dinitrophenyl (DNP)-IgE antibody and subsequent skin testing with dinitrofluorobenzene. We therefore hypothesized that synthetic double-stranded DNA with a high affinity for STAT6 could be introduced in vivo as decoy cis elements to bind the transcriptional factor and block the gene activation contributing to the onset and progression of AD, thus providing effective therapy for AD. Treatment by the transfection of STAT6 decoy oligodeoxynucleotides (ODNs), but not scramble decoy ODN after sensitization by anti-DNP-IgE antibody, had a significant inhibitory effect on not only STAT6 binding to nuclei but also on the late-phase response. A histological analysis revealed that both edema and the infiltration of neutrophils and eosinophils significantly decreased in STAT6 decoy ODN-transfected mice. To examine the mechanism of the in vivo effect of STAT6 decoy ODN, we employed an in vitro mast cells culture system. After IgE receptor engagement, mast cells transfected by STAT6 decoy ODN exhibited normal histamine release, but their cytokine release (TNF-alpha, IL-6) markedly decreased. We herein report the first successful in vivo transfer of STAT6 decoy ODN to reduce the late-phase reaction, thereby providing a new therapeutic strategy for AD.

In vivo transfection of a cis element 'decoy' against signal transducers and activators of the transcription 6 (STAT6) binding site ameliorates the response of contact hypersensitivity.

We herein demonstrate that STAT6 plays an important role in the induction of not only acute contact hypersensitivity (CHS), but also chronic CHS in a mouse model using STAT6-deficient (STAT6(-/-)) mice. We, therefore, determine whether synthetic double-stranded DNA with a high affinity for STAT6 can be introduced in vivo as a decoy cis element to bind the transcriptional factor and block the induction of not only acute CHS but also chronic CHS. Treatment by the transfection of STAT6 decoy oligodeoxynucleotides (ODN), after the induction of 2,4,6-trinitrochlorobenzene or other haptens had a significant inhibitory effect on the induction of both acute CHS and chronic CHS. We thus examined the mechanism of the in vivo effect of the transfection of STAT6 decoy ODN in both acute and chronic CHS. In the histological analysis, the infiltration of eosinophils and degranulated mast cells, and the production of IL-4, IL-6 and eotaxin, but not IFN-gamma in the extracts from challenged skin significantly decreased by the transfection of STAT6 decoy ODN. We herein report the first successful in vivo transfer of STAT6 decoy ODN to inhibit acute and chronic CHS, thus providing a new therapeutic strategy not only for the treatment of CHS but also for atopic dermatitis.

Snail and SIP1 increase cancer invasion by upregulating MMP family in hepatocellular carcinoma cells.

Loss of E-cadherin (E-cad) triggers invasion, metastasis, and dedifferentiation in various epithelial carcinomas. Recently, it has been reported that two transcription factors, Snail and SIP1 (Smad interacting protein 1), directly repress transcription of the E-cad gene by binding E-box on E-cad promoter. Our aim is to solve the molecular mechanism of Snail and SIP1 in hepatocellular carcinoma (HCC). We first showed an inverse correlation between E-cad and Snail/SIP 1 expression among five HCC lines with different phenotypes. The result indicated that undifferentiated, but not differentiated type expressed Snail/SIP1. Then, we established transfectants stably expressing Snail and SIP1 in two differentiated cells with E-cad expression. Suppressed expression of E-cad, morphologic change into fibroblastoid feature, and remarkable acceleration of invasion activity were observed in the transfectants. In reverse transcription-polymerase chain reaction series of genes relating to motility and invasion, we demonstrated striking evidence that matrix metalloproteinase (MMP-1), MMP-2, MMP-7, and MT1-MMP expressions were strongly upregulated by Snail. On the other hand, MMP-1, MMP-2, and MT1-MMP expressions were enhanced by SIP1 transfection, however, the intensity was weaker than that in Snail transfection. In conclusion, Snail or SIP1 expression may be induced during HCC progression, where Snail/SIP1 directly represses E-cad gene transcription and activates cancer invasion via the upregulation of the MMP gene family.

Th2 cytokines, IgE and mast cells play a crucial role in the induction of para-phenylenediamine-induced contact hypersensitivity in mice.

We previously reported the establishment of a mouse model system of contact hypersensitivity (CHS) to paraphenylemediamine (PPD). In order to analyse the functional contribution of Th2 cytokines, IL-4 and IL-5, in PPD induced CHS, STAT6 deficient (STAT6-/-) and wild-type control (WT) mice (C57BL/6) were immunized by the topical application of a PPD solution, and then the subsequent skin reactions were examined. Ear swelling was significantly reduced with a delayed peak response in STAT6-/- mice as compared with that of WT mice. A histological analysis showed the infiltration of both eosinophils and neutrophils in the skin of STAT6-/- mice challenged 24 h previously to significantly decrease in comparison with that in the WT mice. The expression of Th2 cytokines (IL-4, IL-5) by ELISA in the PPD-challenged skin tissue specimens as well as the IgE and IgG1 response after challenge were also profoundly reduced in the STAT6-/- mice. The adoptive transfer of the serum obtained from sensitized WT mice for the putative IgE transfer induced a peak response at 3 h and 24 h after challenge. To further investigate the role of mast cells in the induction of PPD-CHS, mast cell deficient W/Wv mice were sensitized with PPD and then were challenged. Maximal ear swelling was detected from 12 to 24 h and another small peak response was observed at 1 h in+/+mice, whereas only a small peak response at 24 h was detected in W/Wv mice. These data indicate that not only Th2 cytokines and IgE but also mast cells play an essential role in the induction of PPD-CHS.

Mutations in the human homologue of the Drosophila segment polarity gene patched in oral squamous cell carcinoma cell lines.

In the present study, we have analyzed tumor deoxyribonucleic acid from oral squamous cell carcinoma (OSCC) cells for patched mutations using an exon-by-exon single strand conformation polymorphism assay and direct sequencing. We found two missense mutations which affected the conserved residue in the transmembrane domains of the gene product and in the intracellular loop at the C-terminal residue implicated in regulating the smoothened molecule. In addition, we demonstrated that the N-terminal fragment of sonic hedgehog (Shh-N) stimulates the growth of normal epithelial cells, the OSCC cell line, NA, and the salivary gland adenocarcinoma cell lines, HSG and HSY, which have no detectable mutation in patched. On the other hand, Shh has no effect on human SCC cells (UE, KA, KO, NI, A431 cells) that have mutations in patched. These results strongly suggest that an Shh-patched signaling is involved in the cell growth of oral epithelial cells and in the tumorigenesis of OSCCs.

Type A behavior, social support, and sex in Japanese college students.

The relations among self-report scores for Type A behavior with social support and sex were examined in 239 female and 213 male Japanese college students. Scores on Type A behavior were inversely correlated with those for social support for both women and men separately. There were no significant differences in the magnitudes of these coefficients for women and men.

Role of anions on heavy metal sorption of a cellulose modified with poly(glycidyl methacrylate) and polyethyleneimine.

The influence of anions on the equilibrium and kinetic uptake of heavy metals from an aqueous solution by a novel nitrogen-type chelating adsorbent was evaluated. Equilibrium experiments revealed that stoichiometric amounts of metals and anions are adsorbed by the resin. Kinetic studies showed that during the initial stage of adsorption, the anions are adsorbed by the adsorbent prior to the metal ions. This occurred almost simultaneously with an increase in solution pH. At equilibrium, the pH returned towards its initial value. The concentration of anion also fluctuated during the entire equilibration process. Following these observations, mechanisms governing the role of anions on enhancing capacity and rate of metal uptake of this type of chelating adsorbent type were established.

Neurotic perfectionism, perceived stress, and self-esteem among Japanese men: a prospective study.

The present study examined the relationship between self-report scores of neurotic perfectionism and of perceived stress and self-esteem 6 wk. later among 146 Japanese male college students. Hierarchical regression analysis indicated that scores for neurotic perfectionism accounted for statistically significant but functionally small variance (4% and 3%) in scores for perceived stress and self-esteem obtained at Time 2 (6 wk. later), after controlling for the scores for perceived stress and self-esteem at Time 1, respectively.

A prospective clinical study on inhaled nitric oxide therapy for neonates in Japan.

BACKGROUND: This is the first report about a prospective clinical investigation to study the efficacy and safety of nitric oxide (NO) inhalation in infants with persistent pulmonary hypertension of the newborn (PPHN) in Japan. METHODS: Patients in the present study had to meet the following entry criteria: (i) they had to be younger than 7 days of age; (ii) they had to have evidence of PPHN as defined by echocardiograph; (iii) they had to have severe systemic hypoxemia under mechanical ventilation at 100% oxygen supplementation; and (iv) they had to have a failure to respond to conventional therapies. Patients were excluded from this trial if they had any of the following: hypoplastic lung, structural cardiac lesions or severe multiple anomalies. RESULTS: Nitric oxide inhalation therapy was performed in 68 infants who had severe PPHN at 18 hospitals between May 1995 and May 1997. At birth, 21 of 68 infants (31%) weighed less than 1,500 g and 39 infants weighed more than 2,500 g. The diagnoses associated with PPHN were as follows: 27 infants had meconium aspiration syndrome, 15 infants had dry lung syndrome, nine infants had congenital diaphragmatic hernia, six infants had respiratory distress syndrome, three infants had pneumonia and eight infants had other diagnoses. The mean oxygenation index (OI) before NO inhalation therapy in 68 infants was 43.2; 55 infants (81%) had good responses. CONCLUSIONS: These results may be valuable for further randomized controlled and double-blind trials in Japan to evaluate whether NO inhalation therapy is more effective than conventional therapy in infants with severe PPHN.

Congenital diaphragmatic hernia in identical twins.

The authors present a pair of identical twins with congenital diaphragmatic hernia (CDH) diagnosed prenatally, who underwent successful surgical repair. They were diagnosed as having CDH at 32 weeks' gestation and showed respiratory distress soon after cesarean section at 33 weeks' gestation. Both survived after scheduled perinatal management followed by surgery, for which the prenatal diagnosis of CDH was valuable.

Nonconvulsive status epilepticus in a child with congenital bilateral perisylvian syndrome.

A 9-year-old male with congenital bilateral perisylvian syndrome is described. He had pseudobulbar palsy, mental retardation, and intractable epilepsy. Computed tomography and magnetic resonance images of the brain demonstrated bilateral perisylvian malformations and a diffuse pachygyric appearance. At 8 years of age, he had episodes of excessive drooling, fluctuating impairment of consciousness, unsteady sitting, and frequent head drop that lasted several days. The electroencephalogram demonstrated continuous diffuse slow spike and waves. These findings suggested atypical absence status epilepticus. Intravenous administration of diazepam resulted in transient improvement of clinical and electroencephalographic findings. Status epilepticus recurred within several minutes after diazepam administration. Although no patient has been reported to have a history of status epilepticus among those affected by this syndrome, it seems that atypical absence status can occur more frequently than expected, as seen in Lennox-Gastaut syndrome. After recognition and confirmation of nonconvulsive status epilepticus, immediate treatment must be attempted.