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Abstract The pathophysiologies of metabolic syndrome (MS) and overactive bladder (OAB) might overlap. Using fructose-fed rats (FFRs) as a rodent model of MS we investigated the effects of tadalafil (a phosphodiesterase type 5 inhibitor) on the dysregulated insulin signalling in the bladder mucosa and bladder overactivity. Micturition behaviour was evaluated. Concentration–response curves on detrusor relaxation to insulin stimulation were examined. Expression and phosphorylation of proteins in the insulin signalling pathway were evaluated by Western blotting. Levels of detrusor cGMP and urinary nitrite and nitrate (NOx) were measured. We observed FFRs exhibited metabolic traits of MS, bladder overactivity, and impaired insulin-activated detrusor relaxation in organ bath study. A high-fructose diet also impeded insulin signalling, reflected by overexpression of IRS1/pIRS1Ser307 and pIRS2Ser731 and downregulation of PI3K/pPI3KTyr508, AKT/pAKTSer473, and eNOS/peNOSSer1177 in the bladder mucosa, alongside decreased urinary NOx and detrusor cGMP levels. Tadalafil treatment restored the reduced level of mucosal peNOS, urinary NOx, and detrusor cGMP, improved the insulin-activated detrusor relaxation, and ameliorated bladder overactivity in FFRs. These results suggest tadalafil may ameliorate MS-associated bladder overactivity by restoring insulin-activated detrusor relaxation via molecular mechanisms that are associated with preservation of IR/IRS/PI3K/AKT/eNOS pathway in the bladder mucosa and cGMP production in the bladder detrusor.

Reduction of bicyclo[3.3.0]octane-3,7-dione yields a mixture of the endo-3,endo-7-diol and endo-3, exo-7-diol (C8H14O2) isomers (5 and 6). These form (5)2·(6) co-crystals in the monoclinic P21/n space group (with Z = 6, Z′ = 1.5) rather than undergoing separation by means of fractional recrystallization or column chromatography. The molecule of 5 occupies a general position, whereas the molecule of 6 is disordered over two orientations across a centre of symmetry with occupancies of 0.463 (2) and 0.037 (2). Individual diol hydroxy groups associate around a pseudo-threefold screw axis by means of hydrogen bonding. The second hydroxy group of each diol behaves in a similar manner, generating a three-dimensional hydrogen-bonded network structure. This hydrogen-bond connectivity is identical to that present in three known helical tubuland diol–hydroquinone co-crystals, and the new crystal structure is even more similar to two homologous aliphatic diol co-crystals.

Abstract Background Tissue oxidative stress, sympathetic activation and nutrient sensing signals are closely related to adult hypertension of fetal origin, although their interactions in hypertension programming remain unclear. Based on a maternal high-fructose diet (HFD) model of programmed hypertension, we tested the hypothesis that dysfunction of AMP-activated protein kinase (AMPK)-regulated angiotensin type 1 receptor (AT1R) expression and sirtuin1 (SIRT1)-dependent mitochondrial biogenesis contribute to tissue oxidative stress and sympathoexcitation in programmed hypertension of young offspring. Methods Pregnant female rats were randomly assigned to receive normal diet (ND) or HFD (60% fructose) chow during pregnancy and lactation. Both ND and HFD offspring returned to ND chow after weaning, and blood pressure (BP) was monitored from age 6 to 12 weeks. At age of 8 weeks, ND and HFD offspring received oral administration of simvastatin or metformin; or brain microinfusion of losartan. BP was monitored under conscious condition by the tail-cuff method. Nutrient sensing molecules, AT1R, subunits of NADPH oxidase, mitochondrial biogenesis markers in rostral ventrolateral medulla (RVLM) were measured by Western blot analyses. RVLM oxidative stress was measured by fluorescent probe dihydroethidium and lipid peroxidation by malondialdehyde assay. Mitochondrial DNA copy number was determined by quantitative real-time polymerase chain reaction. Results Increased systolic BP, plasma norepinephrine level and sympathetic vasomotor activity were exhibited by young HFD offspring. Reactive oxygen species (ROS) level was also elevated in RVLM where sympathetic premotor neurons reside, alongside augmented protein expressions of AT1R and pg91phox subunit of NADPH oxidase, decrease in superoxide dismutase 2; and suppression of transcription factors for mitochondrial biogenesis, peroxisome proliferator-activated receptor γ co-activator α (PGC-1α) and mitochondrial transcription factor A (TFAM). Maternal HFD also attenuated AMPK phosphorylation and protein expression of SIRT1 in RVLM of young offspring. Oral administration of a HMG-CoA reductase inhibitor, simvastatin, or an AMPK activator, metformin, to young HFD offspring reversed maternal HFD-programmed increase in AT1R and decreases in SIRT1, PGC-1α and TFAM; alleviated ROS production in RVLM, and attenuated sympathoexcitation and hypertension. Conclusion Dysfunction of AMPK-regulated AT1R expression and SIRT1-mediated mitochondrial biogenesis may contribute to tissue oxidative stress in RVLM, which in turn primes increases of sympathetic vasomotor activity and BP in young offspring programmed by excessive maternal fructose consumption.

Whereas neuroimmune crosstalk between the sympathetic nervous system (SNS) and immune cells in the pathophysiology of hypertension is recognized, the exact effect of SNS on T-lymphocyte in hypertension remains controversial. This study assessed the hypothesis that excitation of the SNS activates splenic T-lymphocytes through redox signaling, leading to the production of pro-inflammatory cytokines and the development of hypertension. Status of T-lymphocyte activation, reactive oxygen species (ROS) production and pro-inflammatory cytokines expression in the spleen were examined in a rodent model of hypertension programmed by maternal high fructose diet (HFD) exposure. Maternal HFD exposure enhanced SNS activity and activated both CD4+ and CD8+ T-lymphocytes in the spleen of young offspring, compared to age-matched offspring exposed to maternal normal diet (ND). Maternal HFD exposure also induced tissue oxidative stress and expression of pro-inflammatory cytokines in the spleen of HFD offspring. All those cellular and molecular events were ameliorated following splenic nerve denervation (SND) by thermoablation. In contrast, activation of splenic sympathetic nerve by nicotine treatment resulted in the enhancement of tissue ROS level and activation of CD4+ and CD8+ T-cells in the spleen of ND offspring; these molecular events were attenuated by treatment with a ROS scavenger, tempol. Finally, the increase in systolic blood pressure (SBP) programmed in adult offspring by maternal HFD exposure was diminished by SND, whereas activation of splenic sympathetic nerve increased basal SBP in young ND offspring. These findings suggest that excitation of the SNS may activate splenic T-lymphocytes, leading to hypertension programming in adult offspring induced by maternal HFD exposure. Moreover, tissue oxidative stress induced by the splenic sympathetic overactivation may serve as a mediator that couples the neuroimmune crosstalk to prime programmed hypertension in HFD offspring.

Abstract Background Postgraduate vocational training in family medicine (FM) is essential for physicians to build capacity and develop quality primary care. Inadequate standards in training and curriculum development can contribute to poor recruitment and retention of doctors in primary care. This study aimed to investigate: 1) the satisfaction level of doctors regarding vocational training in family medicine and associated demographics; and 2) the satisfaction level of doctors regarding their family medicine career and associated factors. Method This is a cross sectional study of all family medicine physicians across all government-funded primary care clinics (GOPCs). The study questionnaire consisted of items from a standardized and validated physician survey named the Physician Worklife Survey (PWS) (Konrad et al., Med Care, 1999). We selected three scales (7 items) relating to global job satisfaction, global career satisfaction and global specialty (family medicine) satisfaction with additional items on training and demographics. All significant variables in bivariate analyses were further examined using stepwise logistic regression. Results Out of 424 eligible family medicine physicians, 368 physicians successfully completed the questionnaire. The response rate was 86.8%. Most participants were male (52.6%), were aged between 35 and 44 years (55.5%), were FM specialists (42.4%), graduated locally (86.2%), and had postgraduate qualifications. Eighty-two percent (82%) of participants were satisfied with their training. Having autonomy and protected time for training were associated with satisfaction with FM training. Satisfaction with family medicine as a career was correlated with physicians’ satisfaction with their current job. Doctors who did not enroll in training (p

This study aims to investigate whether tissue oxidative stress in the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons reside, plays an active role in age-dependent susceptibility to hypertension in response to nitric oxide (NO) deficiency induced by systemic l-NAME treatment, and to decipher the underlying molecular mechanisms. Systolic blood pressure (SBP) and heart rate (HR) in conscious rats were recorded, along with measurements of plasma and RVLM level of NO and reactive oxygen species (ROS), and expression of mRNA and protein involved in ROS production and clearance, in both young and adult rats subjected to intraperitoneal (i.p.) infusion of l-NAME. Pharmacological treatments were administered by oral gavage or intracisternal infusion. Gene silencing of target mRNA was made by bilateral microinjection into RVLM of lentivirus that encodes a short hairpin RNA (shRNA) to knock down gene expression of NADPH oxidase activator 1 (Noxa1). We found that i.p. infusion of l-NAME resulted in increases in SBP, sympathetic neurogenic vasomotor activity, and plasma norepinephrine levels in an age-dependent manner. Systemic l-NAME also evoked oxidative stress in RVLM of adult, but not young rats, accompanied by augmented enzyme activity of NADPH oxidase and reduced mitochondrial electron transport enzyme activities. Treatment with L-arginine via oral gavage or infusion into the cistern magna (i.c.), but not i.c. tempol or mitoQ10, significantly offset the l-NAME-induced hypertension in young rats. On the other hand, all treatments appreciably reduced l-NAME-induced hypertension in adult rats. The mRNA microarray analysis revealed that four genes involved in ROS production and clearance were differentially expressed in RVLM in an age-related manner. Of them, Noxa1, and GPx2 were upregulated and Duox2 and Ucp3 were downregulated. Systemic l-NAME treatment caused greater upregulation of Noxa1, but not Ucp3, mRNA expression in RVLM of adult rats. Gene silencing of Noxa1 in RVLM effectively alleviated oxidative stress and protected adult rats against l-NAME-induced hypertension. These data together suggest that hypertension induced by systemic l-NAME treatment in young rats is mediated primarily by NO deficiency that occurs both in vascular smooth muscle cells and RVLM. On the other hand, enhanced augmentation of oxidative stress in RVLM may contribute to the heightened susceptibility of adult rats to hypertension induced by systemic l-NAME treatment.

Abstract Background Hereditary polyglucosan inclusion body myopathy of the internal anal sphincter is a rare cause of proctalgia fugax and constipation. Treatment options are explored. Case presentation A 61 year-old Caucasian woman presented with an 18-year history of severe anal pain and constipation. She had no response to medical treatment which included amitriptyline and topically administered diltiazem. Endoscopy revealed no abnormalities, whereas endoanal ultrasound showed an abnormally thick internal anal sphincter (> 5 mm) and anal manometry showed intermittent episodes of very high resting pressures in excess of 200 mmHg that resolved spontaneously after 2 minutes. She had no relief of her symptoms after receiving an injection of botulinum toxin to the internal anal sphincter. She subsequently underwent a lateral internal anal sphincterotomy which led to complete resolution of her symptoms. Conclusions Hereditary polyglucosan inclusion body myopathy of the internal anal sphincter should be considered in the differential diagnosis of a patient presenting with severe anal pain and constipation in the absence of an anal fissure or sepsis. If medical therapy with calcium antagonists fails to provide symptom relief, lateral internal sphincterotomy should be considered rather than botulinum toxin injection.

The current known two-dimensional topological insulators with small band gaps limit the potential for room temperature applications. Here, Chen et al. observe a sizable gap of 129 meV in a 1T'-WSe2 single layer grown on bilayer graphene with in-gap edge state near the layer boundary.

Abstract Background Few studies have examined the relationship between the amounts of heavy metal and stroke incidence. The aim of this study was to explore the relationship between levels of heavy metals, including Pb, Hg, As, and Cd, in patients with acute ischemic stroke (AIS). Methods We selected patients with first-ever AIS onset within 1 week as our study group. Healthy controls were participants without a history of stroke or chronic disease, except hypertension. The serum levels of Pb, Hg, As, and Cd in participants in the experimental and control groups were determined. All participants received a 1-g infusion of edetate calcium disodium (EDTA). Urine specimens were collected for 24 h after EDTA infusion and measured for heavy metal levels. Results In total, 33 patients with AIS and 39 healthy controls were enrolled in this study. The major findings were as follows: (1) The stroke group had a significantly lower level of serum Hg (6.4 ± 4.3 μg/L vs. 9.8 ± 7.0 μg/L, P = 0.032, OR = 0.90, 95% CI = 0.81–0.99) and a lower level of urine Hg (0.7 ± 0.7 μg/L vs. 1.2 ± 0.6 μg/L, P = 0.006, OR = 0.27, 95% CI = 0.11–0.68) than the control group. (2) No significant difference in serum Pb (S-Pb), As (S-As), and Cd (S-Cd) levels and urine Pb (U-Pb), As (U-As) and Cd (U-Cd) levels was observed in either group. Conclusions Our study found low levels of serum and urine Hg in first-ever patients with AIS, providing new evidence of dysregulated heavy metals in patients with AIS.

Due to reduced dimensionality, the properties of 2D materials are often different from their 3D counterparts. Here, the authors identify the emergence of a unique charge density wave (CDW) order in monolayer TiTe2 that challenges the current understanding of CDW formation.

Consumption of food high in fructose and salt is associated with the epidemic of hypertension. Hypertension can originate from early life. Melatonin, a pleiotropic hormone, regulates blood pressure. We examined whether maternal melatonin therapy can prevent maternal high-fructose combined with post-weaning high-salt diet-induced programmed hypertension in adult offspring. Pregnant Sprague-Dawley rats received either a normal diet (ND) or a 60% fructose diet (HF) during pregnancy and the lactation period. Male offspring were on either the ND or a high-salt diet (HS, 1% NaCl) from weaning to 12 weeks of age and were assigned to five groups (n = 8/group): ND/ND, HF/ND, ND/HS, HF/HS, and HF/HS+melatonin. Melatonin (0.01% in drinking water) was administered during pregnancy and lactation. We observed that maternal HF combined with post-weaning HS diets induced hypertension in male adult offspring, which was attenuated by maternal melatonin therapy. The beneficial effects of maternal melatonin therapy on HF/HS-induced hypertension related to regulating several nutrient-sensing signals, including Sirt1, Sirt4, Prkaa2, Prkab2, Pparg, and Ppargc1a. Additionally, melatonin increased protein levels of mammalian targets of rapamycin (mTOR), decreased plasma asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine levels, and increased the l-arginine-to-ADMA ratio. The reprogramming effects by which maternal melatonin therapy protects against hypertension of developmental origin awaits further elucidation.

PPARγ receptor plays an important role in oxidative stress response. Its agonists can influence vascular contractility in experimental hypertension. Our study was focused on the effects of a PPARγ agonist pioglitazone (PIO) on blood pressure regulation, vasoactivity of vessels, and redox-sensitive signaling at the central (brainstem, BS) and peripheral (left ventricle, LV) levels in young prehypertensive rats. 5-week-old SHR were treated either with PIO (10 mg/kg/day, 2 weeks) or with saline using gastric gavage. Administration of PIO significantly slowed down blood pressure increase and improved lipid profile and aortic relaxation after insulin stimulation. A significant increase in PPARγ expression was found only in BS, not in LV. PIO treatment did not influence NOS changes, but had tissue-dependent effect on SOD regulation and increased SOD activity, observed in LV. The treatment with PIO differentially affected also the levels of other intracellular signaling components: Akt kinase increased in the the BS, while β-catenin level was down-regulated in the BS and up-regulated in the LV. We found that the lowering of blood pressure in young SHR can be connected with insulin sensitivity of vessels and that β-catenin and SOD levels are important agents mediating PIO effects in the BS and LV.

BACKGROUND: Status epilepticus (SE) is an acute, prolonged epileptic crisis with a mortality rate of 20-30%; the underlying mechanism is not completely understood. We assessed the hypothesis that brain stem cardiovascular dysregulation occurs during SE because of oxidative stress in rostral ventrolateral medulla (RVLM), a key nucleus of the baroreflex loop; to be ameliorated by brain-derived neurotrophic factor (BDNF) via an antioxidant action. METHODOLOGY/PRINCIPAL FINDINGS: In a clinically relevant experimental model of temporal lobe SE (TLSE) using Sprague-Dawley rats, sustained hippocampal seizure activity was accompanied by progressive hypotension that was preceded by a reduction in baroreflex-mediated sympathetic vasomotor tone; heart rate and baroreflex-mediated cardiac responses remained unaltered. Biochemical experiments further showed concurrent augmentation of superoxide anion, phosphorylated p47(phox) subunit of NADPH oxidase and mRNA or protein levels of BDNF, tropomyosin receptor kinase B (TrkB), angiotensin AT1 receptor subtype (AT1R), nitric oxide synthase II (NOS II) or peroxynitrite in RVLM. Whereas pretreatment by microinjection bilaterally into RVLM of a superoxide dismutase mimetic (tempol), a specific antagonist of NADPH oxidase (apocynin) or an AT1R antagonist (losartan) blunted significantly the augmented superoxide anion or phosphorylated p47(phox) subunit in RVLM, hypotension and the reduced baroreflex-mediated sympathetic vasomotor tone during experimental TLSE, pretreatment with a recombinant human TrkB-Fc fusion protein or an antisense bdnf oligonucleotide significantly potentiated all those events, alongside peroxynitrite. However, none of the pretreatments affected the insignificant changes in heart rate and baroreflex-mediated cardiac responses. CONCLUSIONS/SIGNIFICANCE: We conclude that formation of peroxynitrite by a reaction between superoxide anion generated by NADPH oxidase in RVLM on activation by AT1R and NOS II-derived NO leads to a reduction in baroreflex-mediated sympathetic vasomotor tone during experimental TLSE; to be ameliorated by the upregulated BDNF/TrkB signaling via inhibition of p47(phox) phosphorylation. This information offers a new vista in devising therapeutic strategy towards minimizing mortality associated with TLSE.

One aspect of brain death is cardiovascular deregulation because asystole invariably occurs shortly after its diagnosis. A suitable neural substrate for mechanistic delineation of this aspect of brain death resides in the rostral ventrolateral medulla (RVLM). RVLM is the origin of a life-and-death signal that our laboratory detected from blood pressure of comatose patients that disappears before brain death ensues. At the same time, transcriptional upregulation of heme oxygenase-1 in RVLM by hypoxia-inducible factor-1α (HIF-1α) plays a pro-life role in experimental brain death, and HIF-1α is subject to sumoylation activated by transient cerebral ischemia. It follows that sumoylation of HIF-1α in RVLM in response to hypoxia may play a modulatory role on brain stem cardiovascular regulation during experimental brain death.A clinically relevant animal model that employed mevinphos as the experimental insult in Sprague-Dawley rat was used. Biochemical changes in RVLM during distinct phenotypes in systemic arterial pressure spectrum that reflect maintained or defunct brain stem cardiovascular regulation were studied. Western blot analysis, EMSA, ELISA, confocal microscopy and immunoprecipitation demonstrated that drastic tissue hypoxia, elevated levels of proteins conjugated by small ubiquitin-related modifier-1 (SUMO-1), Ubc9 (the only known conjugating enzyme for the sumoylation pathway) or HIF-1α, augmented sumoylation of HIF-1α, nucleus-bound translocation and enhanced transcriptional activity of HIF-1α in RVLM neurons took place preferentially during the pro-life phase of experimental brain death. Furthermore, loss-of-function manipulations by immunoneutralization of SUMO-1, Ubc9 or HIF-1α in RVLM blunted the upregulated nitric oxide synthase I/protein kinase G signaling cascade, which sustains the brain stem cardiovascular regulatory machinery during the pro-life phase.We conclude that sumoylation of HIF-1α in RVLM ameliorates brain stem cardiovascular regulatory failure during experimental brain death via upregulation of nitric oxide synthase I/protein kinase G signaling. This information should offer new therapeutic initiatives against this fatal eventuality.

BACKGROUND: Brain stem cardiovascular regulatory dysfunction during brain death is underpinned by an upregulation of nitric oxide synthase II (NOS II) in rostral ventrolateral medulla (RVLM), the origin of a life-and-death signal detected from blood pressure of comatose patients that disappears before brain death ensues. Furthermore, the ubiquitin-proteasome system (UPS) may be involved in the synthesis and degradation of NOS II. We assessed the hypothesis that the UPS participates in brain stem cardiovascular regulation during brain death by engaging in both synthesis and degradation of NOS II in RVLM. METHODOLOGY/PRINCIPAL FINDINGS: In a clinically relevant experimental model of brain death using Sprague-Dawley rats, pretreatment by microinjection into the bilateral RVLM of proteasome inhibitors (lactacystin or proteasome inhibitor II) antagonized the hypotension and reduction in the life-and-death signal elicited by intravenous administration of Escherichia coli lipopolysaccharide (LPS). On the other hand, pretreatment with an inhibitor of ubiquitin-recycling (ubiquitin aldehyde) or ubiquitin C-terminal hydrolase isozyme L1 (UCH-L1) potentiated the elicited hypotension and blunted the prevalence of the life-and-death signal. Real-time polymerase chain reaction, Western blot, electrophoresis mobility shift assay, chromatin immunoprecipitation and co-immunoprecipitation experiments further showed that the proteasome inhibitors antagonized the augmented nuclear presence of NF-κB or binding between NF-κB and nos II promoter and blunted the reduced cytosolic presence of phosphorylated IκB. The already impeded NOS II protein expression by proteasome inhibitor II was further reduced after gene-knockdown of NF-κB in RVLM. In animals pretreated with UCH-L1 inhibitor and died before significant increase in nos II mRNA occurred, NOS II protein expression in RVLM was considerably elevated. CONCLUSIONS/SIGNIFICANCE: We conclude that UPS participates in the defunct and maintained brain stem cardiovascular regulation during experimental brain death by engaging in both synthesis and degradation of NOS II at RVLM. Our results provide information on new therapeutic initiatives against this fatal eventuality.

BACKGROUND:Spontaneous circulation returns to less than half of adult cardiac arrest victims who received in-hospital resuscitation. One clue for this disheartening outcome arises from the prognosis that asystole invariably takes place, after a time lag, on diagnosis of brain stem death. The designation of brain stem death as the point of no return further suggests that permanent impairment of the brain stem cardiovascular regulatory machinery precedes death. It follows that a crucial determinant for successful revival of an arrested heart is that spontaneous circulation must resume before brain stem death commences. Here, we evaluated the hypothesis that maintained functional integrity of the rostral ventrolateral medulla (RVLM), a neural substrate that is intimately related to brain stem death and central circulatory regulation, holds the key to the vital time-window between cardiac arrest and resumption of spontaneous circulation. METHODOLOGY/PRINCIPAL FINDINGS:An animal model of brain stem death employing the pesticide mevinphos as the experimental insult in Sprague-Dawley rats was used. Intravenous administration of lethal doses of mevinphos elicited an abrupt cardiac arrest, accompanied by elevated systemic arterial pressure and anoxia, augmented neuronal excitability and enhanced microvascular perfusion in RVLM. This period represents the vital time-window between cardiac arrest and resumption of spontaneous circulation in our experimental model. Animals with restored spontaneous circulation exhibited maintained neuronal functionality in RVLM beyond this critical time-window, alongside resumption of baseline tissue oxygen and enhancement of local blood flow. Intriguingly, animals that subsequently died manifested sustained anoxia, diminished local blood flow, depressed mitochondrial electron transport activities and reduced ATP production, leading to necrotic cell death in RVLM. That amelioration of mitochondrial dysfunction and bioenergetic failure in RVLM by coenzyme Q10, the mobile electron carrier in mitochondrial respiratory chain, or oxygenation restored spontaneous circulation further established a causal relationship between functionality of RVLM and resumed spontaneous circulation after cardiac arrest. CONCLUSIONS/SIGNIFICANCE:We conclude that whereas necrotic cell death because of bioenergetic failure triggered by anoxia in RVLM, which precipitates brain stem death, negates resuscitation of an arrested heart, maintained functional integrity of this neural substrate holds the key to resumption of spontaneous circulation after cardiac arrest in rats.

In the racemic title compound, C34H22Br2N2S·CDCl3, pairs of diquinoline host molecules form centrosymmetric brick-like dimers utilizing three different aryl edge-to-face interactions (EF1–3). The dimeric (EF)6 (i.e. 2 × EF1–3) building blocks pack with the deuterochloroform guest molecules positioned near each of their corners. The Cl atoms of the latter are disordered over two sets of sites in a 0.53 (2):0.47 (2) ratio.

The title compound, C14H20O2, crystallizes with homochiral chains of molecules hydrogen bonded together along the b axis. Adjacent chains in the ab plane contain molecules of the same chirality, leading to a chiral segregation of the molecules into layers.

This is the first checklist of ascidians for the South China Sea and surrounding regions of Southeast Asian nations. Some 381 species of ascidians from 17 families (Clavelinidae, Diazonidae, Didemnidae, Holozoidae, Polycitoridae, Polyclinidae, Pseudodistomidae, Stomozoidae, Ascidiidae, Cionidae, Ciallusiidae, Corellidae, Perophoridae, Plurellidae, Molgulidae, Pyuridae and Styelidae) and 68 genera are documented in this paper. Only 155 species were recorded specifically from the South China Sea but the ascidian fauna of this area is poorly known. Records from the Philippines and Indonesia are somewhat better and are included. The ascidian fauna of major coastlines that border the South China Sea such as those of China, Vietnam and East and West Malaysia Peninsula are poorly studied and published data are lacking. A total of 13 new records of ascidians collected during the 2013 Singapore Straits Expedition are also listed, bringing the number of ascidian records for Singapore to a total of 50. [ABSTRACT FROM AUTHOR]

Objective: Studies on serum vitamin D in smokers showed conflicting results. We examined the association of smoking status with serum vitamin D in older Chinese men, taking advantage of a community-based sample with natural exposure to vitamin D. Design: Cross-sectional study based on the Guangzhou Biobank Cohort Study (GBCS). Setting: Community-based sample from the Guangzhou Biobank Cohort Study. Participants: 612 male participants aged 50+years recruited from 2009 to 2011. Results: The mean (SD) of vitamin D concentration was 58.3 (17.2), 57.0 (15.0) and 54.7 (15.4) nmol/L for never, former and current smokers, respectively. Adjusted for multiple confounders, vitamin D decreased from never to former, then to current smokers (P for trend 0.02). Compared to never smokers, current smokers had lower serum concentrations of vitamin D, and the concentrations decreased with the increasing number of cigarettes per day (-3.11 (95% CI -9.05 to 2.82), -3.29 (-8.3 to 1.72) and -4.61 (-8.89 to -0.33) for 1-9, 10-19 and 20+cigarettes per day, respectively; p for trend 0.01), duration of smoking (-1.39 (-6.09 to 3.30) and -5.39 (-9.42 to -1.35) for 1-39 and 40+years, respectively; p for trend 0.008) as well as pack-years (-2.89 (-6.78 to 1.01) and -5.58 (-10.48 to -0.67) for 1-39 and 40+pack-years, respectively; p for trend 0.009). Longer duration of quitting smoking was associated with higher vitamin D than was current smoking (P for trend 0.04). Conclusions: Current smokers had lower vitamin D than never smokers, and the association showed a dose-response pattern. [ABSTRACT FROM AUTHOR]

3,7-Diphenylbicyclo[3.3.0]octane-endo-3,endo-7-diol 2was identified as a very simple achiral molecule that was likely to pack with difficulty in the solid state just by itself. Such substances are expected to be susceptible to inclusion of a second type of molecule in their crystals in order to achieve lower energy through more efficient packing. In accord with this prediction, four different crystal forms have been prepared and their structures determined using X-ray crystallography: the solvent-free (apohost) structure, two lattice inclusion compounds (2)2·(benzene) and (2)·(o-xylene), and the hydrogen bonded cocrystalline material (2)·(methanol). Further evidence of the packing difficulties of 2was obtained. Three of the four crystal forms contain two crystallographically independent diol molecules, and two of these structures also contain independent guests. Further, the adopted apohost structure forces the achiral molecule 2to crystallise in a chiral space group. These results show that simple, but awkward, molecules likely to exhibit inclusion behaviour can be identified successfully and predictions made. [ABSTRACT FROM AUTHOR]

The very simple alicyclic compounds 3,7-dimethylbicyclo[3.3.0]octane-endo-3,endo-7-diol 3and 2,6-dimethylbicyclo[3.3.0]octane-endo-2,endo-6-diol 5were selected for study in the knowledge that these are awkwardly shaped molecules that are likely to pack in the solid state with some difficulty. The design philosophy behind the choice of these particular test molecules is explained. We expected that these isomeric diols would probably yield more than one crystal form if crystallized from a range of different solvents. Dialcohol 3was found to give three (benzene clathrate, hemihydrate, and hydrate), and dialcohol 5to give two (racemic and kryptoracemate/false conglomerate), crystal forms. The X-ray structures of these five very different crystalline solids (formed by two very similar model compounds) are described and contrasted. Our findings demonstrate that awkward molecules can be identified and indicate that the formation of alternative crystal forms is likely to be a comparatively frequent occurrence under ambient conditions. [ABSTRACT FROM AUTHOR]

Each of the three racemic C2-symmetric endo,endo-bicyclo[3.3.1]nonane-2,6-diols 6–8shows a dominant, but different, mode of crystallisation across a wide range of solvents. These outcomes depend on the type of supramolecular synthon employed and the resulting degree of enantiomer separation that takes place. Diol 6utilises the centrosymmetric hydrogen bonded (O–H)6cycle and forms racemic crystals containing an intimate mix of the two enantiomers. In contrast, diol 7uses (O–H)4cycles with concomitant formation of homochiral layers, but racemic crystals still result since adjacent layers have opposite handedness. Diol 8forms a hydrogen bonded network by using cross-linked (O–H)8repeat helices and self-resolution yields a mixture of pure (+)- and pure (−)-crystals (a conglomerate). Since conglomerates may be separated into their pure enantiomers, the latter discovery offers a new preparative approach for obtaining chirally pure bicyclo[3.3.1]nonane compounds of value in organic synthesis. [ABSTRACT FROM AUTHOR]

The simple dialcohol endo-4,endo-8-dimethylbicyclo[3.3.1]nonane-endo-2,endo-6-diol 2yields inclusion compounds (diol)3.(guest) from nearly all recrystallisation experiments. These crystals have a hydrogen bonded network structure in cubic space group Ia3, in which the disordered guest molecule occupies a spherical cage enclosed by eight (O–H)6cycles positioned at the corners of a cube. Comparison of this structure with the inclusion crystals formed by Dianin's compound 1, and the β-form of hydroquinone 3, reveals familial supramolecular behaviour between the three cases. The nodal relationship of their (O–H)6cycles or aromatic rings creates allied crystal engineering assemblies despite their dissimilar molecular structures. [ABSTRACT FROM AUTHOR]

Atom probe tomography (APT) has been increasingly used to investigate hydrogen embrittlement in metals due to its unique capacity for direct imaging of H atoms interacting with microstructural features. The quantitativeness of hydrogen measurements by APT is yet to be established in views of erroneous compositional measurements of bulk hydrides and the influence of spurious hydrogen, e.g. residual gas inside the analysis chamber. Here, we analyzed titanium deuteride (approx. 65.0 at%–66.6 at% D) in lieu of hydride to minimize the overlap with residual gas, both with laser pulsing and high-voltage (HV) pulsing. Strategies were deployed to prevent H pick-up during specimen fabrication, including preparing specimens at cryogenic temperature. The measured composition of deuterium by APT with laser pulsing decreases significantly with the applied laser pulse energy, which is interpreted with regards to the strength of the corresponding surface electrostatic field, as assessed by the evolution of charge-state ratio. In contrast, compositional analyses with HV pulsing are roughly independent of the applied experimental parameters, although approx. 15 at%–20 at% off the nominal composition. Aided by plotting paired mass-to-charge correlations, the mechanisms of composition bias in both pulsing modes are discussed. A special emphasis is placed on the local variations of the measured composition as a function of the local electric field across the specimen’s surface, which is not uniform due to asymmetric heat distribution related to the localized laser absorption and the faceted nature of surface caused by the crystallographic structure. Our investigations demonstrate the challenges of quantitative analysis of solute deuterium by APT but nevertheless provide insight to achieving the best possible experimental protocol.

Introduction: Escherichia coli (EC) is one of the most common bloodstream infections and carries a significant mortality rate. International studies have shown that age, antibiotic resistance and choice of empirical antibiotics affect the prognosis of patients with EC bacteremia. However, there is scarce local data to evaluate on the prognostic factors for EC bacteremia in Hong Kong. Our study aimed to evaluate the clinical predictors and outcomes of EC bacteremia in critically ill patients admitted to Intensive Care Unit (ICU) in a regional hospital in Hong Kong. Methods: The study is a retrospective analysis of patients with EC bacteremia admitted to the Department of ICU of Pamela Youde Nethersole Eastern Hospital (PYNEH), from 1/1/2009 to 30/12/2017 (8 years). Patients' demographics, past medical histories, clinical parameters, microbiological data, drug prescriptions, and supportive treatments were analyzed. Results: Among 380 patients, 30-day non-survivors were older (p=0.016), more likely to present with respiratory sepsis (p 0.001) and require renal replacement therapy and mechanical ventilation during ICU stay (p 100 (HR=6.129; 95% CI=3.271-11.485; p=0.001), respiratory sepsis (HR=4.366; 95% CI=2.147- 8.878; p=1.3 (HR=3.007; 95% CI=1.685-5.365; p=70 (HR=2.999; 95% CI=1.597-5.632; p=0.001), liver cirrhosis (HR=2.632, CI=1.051-6.591, p=0.039), albumin 24g/L (HR=2.291; 95% CI=1.229-4.270; p=0.009) and interventional radiological (IR) procedures or operative interventions (HR=0.358; 95% CI=0.188-0.679; p=0.002) were independent risk factors for 30-day mortality. Conclusion: Disease severity, respiratory sepsis, use of steroid, age and liver cirrhosis are important predictors for 30-day mortality in critically ill patients with EC bacteremia, while IR procedures or operative interventions is associated with lower 30-day mortality. [ABSTRACT FROM AUTHOR]

Objective Coeliac disease (CD) diagnosis generally depends on histological examination of duodenal biopsies. We present the first study analysing the concordance in examination of duodenal biopsies using digitised whole-slide images (WSIs). We further investigate whether the inclusion of immunoglobulin A tissue transglutaminase (IgA tTG) and haemoglobin (Hb) data improves the interobserver agreement of diagnosis.Design We undertook a large study of the concordance in histological examination of duodenal biopsies using digitised WSIs in an entirely virtual reporting setting. Our study was organised in two phases: in phase 1, 13 pathologists independently classified 100 duodenal biopsies (40 normal; 40 CD; 20 indeterminate enteropathy) in the absence of any clinical or laboratory data. In phase 2, the same pathologists examined the (re-anonymised) WSIs with the inclusion of IgA tTG and Hb data.Results We found the mean probability of two observers agreeing in the absence of additional data to be 0.73 (±0.08) with a corresponding Cohen’s kappa of 0.59 (±0.11). We further showed that the inclusion of additional data increased the concordance to 0.80 (±0.06) with a Cohen’s kappa coefficient of 0.67 (±0.09).Conclusion We showed that the addition of serological data significantly improves the quality of CD diagnosis. However, the limited interobserver agreement in CD diagnosis using digitised WSIs, even after the inclusion of IgA tTG and Hb data, indicates the importance of interpreting duodenal biopsy in the appropriate clinical context. It further highlights the unmet need for an objective means of reproducible duodenal biopsy diagnosis, such as the automated analysis of WSIs using artificial intelligence.

Introduction We aimed to study predictive factors for burnout (BO) among healthcare workers in a tertiary hospital in Singapore. Objectives We hypothesized that burnout would be assoiciated with singles, females, and foreign born staff recently moved into this country, unaccompanied by family members. We further hypothesised that BO would be associated with those scoring less on resilience. Recognising that social support mitigated against stress and burnout, we hypothesized that those who perceived less support would be more prone to BO. Methods The study questionnaire was sent via corporate email to all staff with email access. We stressed that data would be fully anonymised. No financial rewards were given for participation which was carried out on a voluntary basis. The following instruments were used, viz. F-SozU K-6, a brief form of the perceived social support questionnaire; Connor Davidson Resilience Scale; Oldenburg Burnout Inventory; Patient Health Questionnaire-4 item; Demand Control Support Questionnaire and Leisure Time Satisfaction Scale. Ethics approval for the study was sought from the SingHealth Centralised Institutional Review Board, which granted exemption of participant consent. Analyses were performed using Stata version 17.0 (StataCorp. 2021), with statistical significance set as 2-sided 5% (p0.05). Multivariate analyses showed that younger workers displayed higher burnout scores (p < 0.001).The psychological demand sub-score was positively associated with burnout [ 0.61 (95% CI 0.45 to 0.77), p < 0.001)]. Conversely, decision latitude [-0.33 (95% CI -0.44 to -0.21), p < 0.001)] and support [-0.47 (95% CI -0.60 to -0.35), p < 0.001] were negatively associated with BO. Those who experienced anxiety or depressive symptoms were respectively more likely to experience burnout [0.30 (95% CI 0.02 to 0.58), p = 0.035 and 0.72 (95% CI 0.41 to 1.02), p < 0.001], with a clear association between higher PHQ-4 scores and risk for burnout (r = 0.619). Moreover, satisfaction with utilisation of leisure time was inversely related to BO [-0.55 (95% CI -0.68 to –0.41; p < 0.001)]. We could not find any association between number of years worked, profession, marital status and perceived social support and BO, on multivariate anbalysis (p>0.05). Conclusions Strress reduction interventions should be made available for all staff, especially addressing those at highest risk for burnout. Disclosure of Interest None Declared

Abstract Background We previously reported that miR-195 exerts neuroprotection by inhibiting Sema3A and cerebral miR-195 levels decreased with age, both of which urged us to explore the role of miR-195 and miR-195-regulated Sema3 family members in age-associated dementia. Methods miR-195a KO mice were used to assess the effect of miR-195 on aging and cognitive functions. Sema3D was predicted as a miR-195 target by TargetScan and then verified by luciferase reporter assay, while effects of Sema3D and miR-195 on neural senescence were assessed by beta-galactosidase and dendritic spine density. Cerebral Sema3D was over-expressed by lentivirus and suppressed by si-RNA, and effects of over-expression of Sema3D and knockdown of miR-195 on cognitive functions were assessed by Morris Water Maze, Y-maze, and open field test. The effect of Sema3D on lifespan was assessed in Drosophila. Sema3D inhibitor was developed using homology modeling and virtual screening. One-way and two-way repeated measures ANOVA were applied to assess longitudinal data on mouse cognitive tests. Results Cognitive impairment and reduced density of dendritic spine were observed in miR-195a knockout mice. Sema3D was identified to be a direct target of miR-195 and a possible contributor to age-associated neurodegeneration as Sema3D levels showed age-dependent increase in rodent brains. Injection of Sema3D-expressing lentivirus caused significant memory deficits while silencing hippocampal Sema3D improved cognition. Repeated injections of Sema3D-expressing lentivirus to elevate cerebral Sema3D for 10 weeks revealed a time-dependent decline of working memory. More importantly, analysis of the data on the Gene Expression Omnibus database showed that Sema3D levels were significantly higher in dementia patients than normal controls (p

Low dietary calcium intake has been demonstrated to be a risk factor for hip and vertebral fractures in studies conducted among Hong Kong Chinese. Few studies have demonstrated the effect of milk supplementation in bone accretion in Chinese children. The aim was to examine the effects of milk powder supplementation in enhancing bone accretion in Chinese children. Three hundred and forty-four children, aged 9?10 years old, were randomized to receive milk powder equivalent to 1300 mg and 650 mg calcium, and to a control group, respectively. Bone mineral density (BMD) at the proximal femur, lumbar spine and total body were measured at 6 months, 12 months and 18 months. The treatment effects were modeled using linear mixed effect models and compared using linear contrast F-tests, by intention-to-treat. Subjects randomized to milk powder equivalent to 1300 mg calcium had significantly higher increase in BMD at both the total hip (7.4±0.4% in treatment group versus 6.3±0.4% in the control) and the spine (8.4±0.5% in the treatment group versus 7.0±0.5% in the control group). Subjects randomized to milk powder equivalent to 650 mg calcium had smaller increases in BMD at the total hip and spine, although the increase in BMD at the total body was significantly higher (3.1±0.3% in treatment group versus 2.4±0.2% in controls). It is concluded that supplementing the diet of Chinese children with milk powder was effective in enhancing bone accretion. [ABSTRACT FROM AUTHOR]

Adolescent idiopathic scoliosis (AIS) disrupts spinal alignment and increases the intrinsic demand for active stabilization to maintain postural stability. Understanding the paraspinal muscle fatigability and its effects on spinal alignment and kinematics informs the importance of paraspinal muscle endurance for postural stability. This study aims to investigate the effects of fatigue of thoracic erector spinae on the spinal muscle activity and spinal kinematics in individuals with scoliosis. Spinal muscle activity, posture and mobility measured by electromyography and surface tomography were compared between 15 participants with scoliosis and 15 age- and gender-matched healthy controls during unilateral shoulder flexion and abduction with and without holding a 2-kg weight and performed before and after a fatigue task (prone isometric chest raise). No between-groups difference was found for the spinal extensor endurance. Erector spinae activity at the convex side of AIS group was significantly higher than that at their concave side and than that of healthy controls during shoulder elevations, regardless of the fatigue status. Significant decreases in translational and rotational mobility were found at convex side of AIS group during weighted abduction tasks after fatigue. In contrast, a significant increase in rotational mobility was demonstrated at convex side of AIS participants during weighted flexion tasks after fatigue. Our results revealed a comparable level of spinal extensor endurance between individuals with or without AIS. The increase in muscle activation post-fatigue provides no additional active postural stability but may increase the risk of back pain over the convex side in individuals with scoliosis. Findings highlight imbalances in muscles and the potential implications in optimising neuromuscular activation and endurance capacity in the rehabilitation for AIS patients. Future research is needed to investigate if endurance training of the convex-sided back extensors could optimize the impaired neuromuscular control in the AIS patients.

Preterm birth is a major challenge in pregnancy worldwide. Prematurity is the leading cause of death in infants and may result in severe complications. Nearly half of preterm births are spontaneous, but do not have recognizable causes. This study investigated whether the maternal gut microbiome and associated functional pathways might play a key role in spontaneous preterm birth (sPTB). Two hundred eleven women carrying singleton pregnancies were enrolled in this mother-child cohort study. Fecal samples were freshly collected at 24–28 weeks of gestation before delivery, and the 16S ribosomal RNA gene was sequenced. Microbial diversity and composition, core microbiome, and associated functional pathways were then statistically analyzed. Demographic characteristics were collected using records from the Medical Birth Registry and questionnaires. The result showed that the gut microbiome of mothers with over-weight (BMI ≥ 24) before pregnancy have lower alpha diversity than those with normal BMI before pregnancy. A higher abundance of Actinomyces spp. was filtered out from the Linear discriminant analysis (LDA) effect size (LEfSe), Spearman correlation, and random forest model, and was inversely correlated with gestational age in sPTB. The multivariate regression model showed that the odds ratio of premature delivery was 3.274 [95% confidence interval (CI): 1.349; p = 0.010] in the group with over-weight before pregnancy with a cutoff Hit% > 0.022 for Actinomyces spp. The enrichment of Actinomyces spp. was negatively correlated with glycan biosynthesis and metabolism in sPTB by prediction from the Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) platform. Maternal gut microbiota showing a lower alpha diversity, increased abundance of Actinomyces spp., and dysregulated glycan metabolism may be associated with sPTB risk.

We show that laser-assisted hopping of hard-core bosons in a square optical lattice can be described by an antiferromagnetic J _1 – J _2 XY model with a tunable ratio of J _2 / J _1 . We numerically investigated the phase diagram of the J _1 – J _2 XY model using both the tensor network algorithm for infinite systems and the exact diagonalization for small clusters and found strong evidence that in the intermediate region around J _2 / J _1 ∼ 0.5, there is a spin liquid phase with vanishing magnetization and valence bond orders, which interconnects the Néel state on the J _2 ≪ J _1 side and the stripe antiferromagnetic phase on the J _2 ≫ J _1 side. This finding opens up the possibility of studying the exotic spin liquid phase in a realistic experimental system using ultracold atoms in an optical lattice.