Post-treatment Lyme disease symptoms score: Developing a new tool for research.

Some patients have residual non-specific symptoms after therapy for Lyme disease, referred to as post-treatment Lyme disease symptoms or syndrome, depending on whether there is functional impairment. A standardized test battery was used to characterize a diverse group of Lyme disease patients with and without residual symptoms. There was a strong correlation between sleep disturbance and certain other symptoms such as fatigue, pain, anxiety, and cognitive complaints. Results were subjected to a Logistic Regression model using the Neuro-QoL Fatigue t-score together with Short Form-36 Physical Functioning scale and Mental Health component scores; and to a Decision Tree model using only the QoL Fatigue t-score. The Logistic Regression model had an accuracy of 97% and Decision Tree model had an accuracy of 93%, when compared with clinical categorization. The Logistic Regression and Decision Tree models were then applied to a separate cohort. Both models performed with high sensitivity (90%), but moderate specificity (62%). The overall accuracy was 74%. Agreement between 2 time points, separated by a mean of 4 months, was 89% using the Decision Tree model and 87% with the Logistic Regression model. These models are simple and can help to quantitate the level of symptom severity in post-treatment Lyme disease symptoms. More research is needed to increase the specificity of the models, exploring additional approaches that could potentially strengthen an operational definition for post-treatment Lyme disease symptoms. Evaluation of how sleep disturbance, fatigue, pain and cognitive complains interrelate can potentially lead to new interventions that will improve the overall health of these patients.

Association of endothelin-1 and matrix metallopeptidase-9 with metabolic syndrome in middle-aged and older adults.

BACKGROUND: Metabolic syndrome (MetS) contains a cluster of cardiovascular risk factors. People with MetS are more susceptible to cardiovascular disease, diabetes mellitus, and cancer. Endothelin-1 (ET-1) and matrix metallopeptidase-9 (MMP-9) have been implicated in the development of cardiovascular diseases, diabetes mellitus and cancers. This cross-sectional study aimed to examine the association of ET-1 and MMP-9 with MetS in middle-aged and older Hong Kong Chinese adults. METHODS: 149 adults aged 50 to 92 (n = 75 for non-MetS group and n = 74 for MetS group) were examined. All subjects were screened for MetS according to the diagnostic guideline of the United States National Cholesterol Education Program (NCEP) Expert Panel Adult Treatment Panel (ATP) III criteria. Serum levels of ET-1 and MMP-9 were measured. Independent t test was used to detect differences between non-MetS and MetS groups and between subjects with or without certain metabolic abnormality. The association of the serum concentration of MMP-9 and ET-1 with MetS parameters were examined by Pearson's correlation analysis. RESULTS: Serum level of ET-1 is higher in MetS-positive subjects and in subjects with high blood pressure, elevated fasting blood glucose, and central obesity. The serum concentration of MMP-9 is higher in subjects positively diagnosed with MetS and subjects with high blood pressure, elevated fasting blood glucose, low blood high-density lipoprotein-cholesterol (HDL-C), high blood triglycerides, and central obesity. Correlation analyses revealed that serum concentration of ET-1 is positively correlated to systolic blood pressure, waist circumference, fasting blood glucose, and age whereas it is negatively correlated to HDL-C. MMP-9 is positively correlated to systolic blood pressure, waist circumference, fasting blood glucose, and age whereas it is negatively correlated to HDL-C. CONCLUSION: Serum ET-1 is higher in subjects with hypertension, hyperglycemia, central obesity or MetS. Serum MMP-9 is higher in subjects diagnosed with MetS or having either one of the MetS parameters. Both circulating levels of ET-1 and MMP-9 are correlated to systolic blood pressure, waist circumference, fasting blood glucose, HDL-C, and age. Further research is needed to fully dissect the role of ET-1 and MMP-9 in the development of cancers, diabetes and cardiovascular disease in relation to MetS.

Differential effects of low-magnitude high-frequency vibration on reloading hind-limb soleus and gastrocnemius medialis muscles in 28-day tail-suspended rats.

OBJECTIVES: Low-magnitude high-frequency vibration (LMHFV) was reported beneficial to muscle contractile functions in clinical and preclinical studies. This study aims to investigate the effects of LMHFV on myofibers, myogenic cells and functional properties of disused soleus (Sol) and gastrocnemius medialis (GM) during reloading. METHODS: Sprague Dawley rats were hind-limb unloaded for 28 days and assigned to reloading control (Ctrl) or LMHFV group (Vib). Sol and GM of both groups were harvested for fiber typing, proliferating myogenic cell counting and in vitro functional assessment. RESULTS: Myogenic cells proliferation was promoted by LMHFV in both Sol and GM (p<0.001 and p<0.05 respectively). Force generating capacity was not much affected (Vib=Ctrl, p>0.05) but fast-fiber favorable changes in fiber type switching (more type IIA but lower type I in Vib; p<0.05 and 0.01 respectively) and fiber hypertrophy (type I, Vib

Distinct E-cadherin-based complexes regulate cell behaviour through miRNA processing or Src and p120 catenin activity.

E-cadherin and p120 catenin (p120) are essential for epithelial homeostasis, but can also exert pro-tumorigenic activities. Here, we resolve this apparent paradox by identifying two spatially and functionally distinct junctional complexes in non-transformed polarized epithelial cells: one growth suppressing at the apical zonula adherens (ZA), defined by the p120 partner PLEKHA7 and a non-nuclear subset of the core microprocessor components DROSHA and DGCR8, and one growth promoting at basolateral areas of cell-cell contact containing tyrosine-phosphorylated p120 and active Src. Recruitment of DROSHA and DGCR8 to the ZA is PLEKHA7 dependent. The PLEKHA7-microprocessor complex co-precipitates with primary microRNAs (pri-miRNAs) and possesses pri-miRNA processing activity. PLEKHA7 regulates the levels of select miRNAs, in particular processing of miR-30b, to suppress expression of cell transforming markers promoted by the basolateral complex, including SNAI1, MYC and CCND1. Our work identifies a mechanism through which adhesion complexes regulate cellular behaviour and reveals their surprising association with the microprocessor.

Autophagic adaptation is associated with exercise-induced fibre-type shifting in skeletal muscle.

AIM: Acute exercise is known to activate autophagy in skeletal muscle. However, little is known about how basal autophagy in skeletal muscle adapts to chronic exercise. In the current study we aim to, firstly, examine whether long-term habitual exercise alters the basal autophagic signalling in plantaris muscle and, secondly, examine the association between autophagy and fibre-type shifting. METHODS: Adult female Sprague-Dawley rats aged 2 months were randomly assigned to control and exercise groups. Animals in exercise group were kept in cages equipped with free access running wheels to perform habitual exercise for 5 months. Animals in the control group were caged in the absence of running wheels. Animals were sacrificed after the 5-month experimental period. Plantaris muscle tissues were harvested for analysis. RESULTS: We showed that long-term habitual exercise enhanced basal autophagy, but without altering expressions of autophagy proteins in plantaris muscle. Interestingly, sirtuin protein, a possible regulator of autophagy, was upregulated in plantaris muscle. Furthermore, we suspected that different types of muscle fibre adapted to chronic exercise in different ways. Long-term habitual exercise resulted in fibre-type shifting from type IIX to IIA in both gastrocnemius muscle and plantaris muscle. Intriguingly, our analysis demonstrated that LC3-II protein abundance is positively correlated with the proportion of type IIA fibre whereas it was negatively correlated with the proportion of type IIX fibre in plantaris muscle. PGC-1α protein abundance was positively associated with the proportion of type IIA fibre and LC3-II in plantaris muscle. CONCLUSION: These results suggest that basal autophagy is enhanced in plantaris muscle after long-term habitual exercise and associated with fibre-type shifting.

Autophagic Adaptations to Long-term Habitual Exercise in Cardiac Muscle.

Autophagy has been shown to be responsive to physical exercise. However, the effects of prolonged habitual exercise on autophagy in cardiac muscle remain unknown. The present study aimed to examine whether long-term habitual exercise alters the basal autophagic signalling in cardiac muscle. Female Sprague-Dawley rats aged 2 months were randomly assigned to control and exercise groups. Animals in exercise group were kept in cages with free access exercise wheels to perform habitual exercise for 5 months. Animals in the control group were placed in cages without exercise wheels. Ventricular muscle tissues were harvested for analysis after 5 months. Phosphorylation statuses of upstream autophagic regulatory proteins and protein expressions of downstream autophagic facts remained unchanged in the cardiac muscle of exercise animals when compared to control animals. Intriguingly, the protein abundance of microtubule-associated protein-1 light chain -3 II (LC3-II), heat shock protein 72 (HSP72) and peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α) were significantly increased in cardiac muscle of exercise rats relative to control rats. 5 months of habitual exercise causes the adaptive increase in LC3-II reserve without altering autophagic flux, which probably contributes to the elevation of cellular autophagic capacity and efficiency of cardiac muscle.

Long noncoding RNA EWSAT1-mediated gene repression facilitates Ewing sarcoma oncogenesis.

Chromosomal translocation that results in fusion of the genes encoding RNA-binding protein EWS and transcription factor FLI1 (EWS-FLI1) is pathognomonic for Ewing sarcoma. EWS-FLI1 alters gene expression through mechanisms that are not completely understood. We performed RNA sequencing (RNAseq) analysis on primary pediatric human mesenchymal progenitor cells (pMPCs) expressing EWS-FLI1 in order to identify gene targets of this oncoprotein. We determined that long noncoding RNA-277 (Ewing sarcoma-associated transcript 1 [EWSAT1]) is upregulated by EWS-FLI1 in pMPCs. Inhibition of EWSAT1 expression diminished the ability of Ewing sarcoma cell lines to proliferate and form colonies in soft agar, whereas EWSAT1 inhibition had no effect on other cell types tested. Expression of EWS-FLI1 and EWSAT1 repressed gene expression, and a substantial fraction of targets that were repressed by EWS-FLI1 were also repressed by EWSAT1. Analysis of RNAseq data from primary human Ewing sarcoma further supported a role for EWSAT1 in mediating gene repression. We identified heterogeneous nuclear ribonucleoprotein (HNRNPK) as an RNA-binding protein that interacts with EWSAT1 and found a marked overlap in HNRNPK-repressed genes and those repressed by EWS-FLI1 and EWSAT1, suggesting that HNRNPK participates in EWSAT1-mediated gene repression. Together, our data reveal that EWSAT1 is a downstream target of EWS-FLI1 that facilitates the development of Ewing sarcoma via the repression of target genes.

Establishment of epithelial polarity--GEF who's minding the GAP?

Cell polarization is a fundamental process that underlies epithelial morphogenesis, cell motility, cell division and organogenesis. Loss of polarity predisposes tissues to developmental disorders and contributes to cancer progression. The formation and establishment of epithelial cell polarity is mediated by the cooperation of polarity protein complexes, namely the Crumbs, partitioning defective (Par) and Scribble complexes, with Rho family GTPases, including RhoA, Rac1 and Cdc42. The activation of different GTPases triggers distinct downstream signaling pathways to modulate protein-protein interactions and cytoskeletal remodeling. The spatio-temporal activation and inactivation of these small GTPases is tightly controlled by a complex interconnected network of different regulatory proteins, including guanine-nucleotide-exchange factors (GEFs), GTPase-activating proteins (GAPs), and guanine-nucleotide-dissociation inhibitors (GDIs). In this Commentary, we focus on current understanding on how polarity complexes interact with GEFs and GAPs to control the precise location and activation of Rho GTPases (Crumbs for RhoA, Par for Rac1, and Scribble for Cdc42) to promote apical-basal polarization in mammalian epithelial cells. The mutual exclusion of GTPase activities, especially that of RhoA and Rac1, which is well established, provides a mechanism through which polarity complexes that act through distinct Rho GTPases function as cellular rheostats to fine-tune specific downstream pathways to differentiate and preserve the apical and basolateral domains. This article is part of a Minifocus on Establishing polarity.

Acylated and unacylated ghrelin inhibit doxorubicin-induced apoptosis in skeletal muscle.

AIM: Doxorubicin, a potent chemotherapeutic drug, has been demonstrated previously as an inducer of apoptosis in muscle cells. Extensive induction of apoptosis may cause excessive loss of muscle cells and subsequent functional decline in skeletal muscle. This study examined the effects of acylated ghrelin, a potential agent for treating cancer cachexia, on inhibiting apoptotic signalling in doxorubicin-treated skeletal muscle. Unacylated ghrelin, a form of ghrelin that does not bind to GHSR-1a, is also employed in this study to examine the GHSR-1a signalling dependency of the effects of ghrelin. METHODS: Adult C57BL/6 mice were randomly assigned to saline control (CON), doxorubicin (DOX), doxorubicin with treatment of acylated ghrelin (DOX+Acylated Ghrelin) and doxorubicin with treatment of unacylated ghrelin (DOX+Unacylated Ghrelin). Mice in all groups that involved DOX were intraperitoneally injected with 15 mg of doxorubicin per kg body weight, whereas mice in CON group received saline as placebo. Gastrocnemius muscle tissues were harvested after the experimental period for analysis. RESULTS: The elevation of apoptotic DNA fragmentation and number of TUNEL-positive nuclei were accompanied with the upregulation of Bax in muscle after exposure to doxorubicin, but all these changes were neither seen in the muscle treated with acylated ghrelin nor unacylated ghrelin after doxorubicin exposure. Protein abundances of autophagic markers including LC3 II-to-LC3 I ratio, Atg12-5 complex, Atg5 and Beclin-1 were not altered by doxorubicin but were upregulated by the treatment of either acylated or unacyated ghrelin. Histological analysis revealed that the amount of centronucleated myofibres was elevated in doxorubicin-treated muscle while muscle of others groups showed normal histology. CONCLUSIONS: Collectively, our data demonstrated that acylated ghrelin administration suppresses the doxorubicin-induced activation of apoptosis and enhances the cellular signalling of autophagy. The treatment of unacylated ghrelin has similar effects as acylated ghrelin on apoptotic and autophagic signalling, suggesting that the effects of ghrelin are probably mediated through a signalling pathway that is independent of GHSR-1a. These findings were consistent with the hypothesis that acylated ghrelin inhibits doxorubicin-induced upregulation of apoptosis in skeletal muscle while treatment of unacylated ghrelin can achieve similar effects as the treatment of acylated ghrelin. The inhibition of apoptosis and enhancement of autophagy induced by acylated and unacylated ghrelin might exert myoprotective effects on doxorubicin-induced toxicity in skeletal muscle.

The Rho guanine nucleotide exchange factor Syx regulates the balance of dia and ROCK activities to promote polarized-cancer-cell migration.

The role of RhoA in promoting directed cell migration has been complicated by studies showing that it is activated both in the front and the rear of migrating cells. We report here that the RhoA-specific guanine nucleotide exchange factor Syx is required for the polarity of actively migrating brain and breast tumor cells. This function of Syx is mediated by the selective activation of the RhoA downstream effector Dia1, the subsequent reorganization of microtubules, and the downregulation of focal adhesions and actin stress fibers. The data argue that directed cell migration requires the precise spatiotemporal regulation of Dia1 and ROCK activities in the cell. The recruitment of Syx to the cell membrane and the subsequent selective activation of Dia1 signaling, coupled with the suppression of ROCK and activation of cofilin-mediated actin reorganization, plays a key role in establishing cell polarity during directed cell migration.

Sustained elevation of systemic oxidative stress and inflammation in exacerbation and remission of asthma.

Oxidative stress has been implicated in the pathogenesis of asthma. We aimed at investigating the biomarkers of oxidative stress, inflammation, and tissue damage in patients with asthma in acute exacerbation and remission. We recruited 18 asthmatics admitted to hospital with acute exacerbation and 18 healthy nonsmoking controls matched for age. We evaluated plasma levels of 8-isoprostane, C-reactive protein (CRP) and total matrix metalloproteinase- (MMP-) 9 by ELISA, and MMP-9 activity by zymographic analysis. Plasma levels of 8-isoprostane and CRP were significantly elevated in acute exacerbation and decreased in remission but remained significantly higher compared to healthy controls. The activities of pro-MMP-9 were also significantly higher in acute exacerbation and decreased in remission but remained significantly higher compared to healthy controls in parallel to plasma levels of total MMP-9. These data suggest that overproduction of MMP-9 along with highly elevated levels of oxidative stress and inflammation is implicated in asthma exacerbation and that measurements of these biomarkers can be a valid index in its management.

TEM4 is a junctional Rho GEF required for cell-cell adhesion, monolayer integrity and barrier function.

Signaling events mediated by Rho family GTPases orchestrate cytoskeletal dynamics and cell junction formation. The activation of Rho GTPases is tightly regulated by guanine-nucleotide-exchange factors (GEFs). In this study, we identified a novel Rho-specific GEF called TEM4 (tumor endothelial marker 4) that associates with multiple members of the cadherin-catenin complex and with several cytoskeleton-associated proteins. Depending on confluence, TEM4 localized to either actin stress fibers or areas of cell-cell contact. The junctional localization of TEM4 was independent of actin binding. Depletion of endogenous TEM4 by shRNAs impaired Madin-Darby canine kidney (MDCK) and human umbilical vein endothelial cell (HUVEC) cell junctions, disrupted MDCK acini formation in 3D culture and negatively affected endothelial barrier function. Taken together, our findings implicate TEM4 as a novel and crucial junctional Rho GEF that regulates cell junction integrity and epithelial and endothelial cell function.

p120 catenin: an essential regulator of cadherin stability, adhesion-induced signaling, and cancer progression.

p120 catenin is the best studied member of a subfamily of proteins that associate with the cadherin juxtamembrane domain to suppress cadherin endocytosis. p120 also recruits the minus ends of microtubules to the cadherin complex, leading to junction maturation. In addition, p120 regulates the activity of Rho family GTPases through multiple interactions with Rho GEFs, GAPs, Rho GTPases, and their effectors. Nuclear signaling is affected by the interaction of p120 with Kaiso, a transcription factor regulating Wnt-responsive genes as well as transcriptionally repressing methylated promoters. Multiple alternatively spliced p120 isoforms and complex phosphorylation events affect these p120 functions. In cancer, reduced p120 expression correlates with reduced E-cadherin function and with tumor progression. In contrast, in tumor cells that have lost E-cadherin expression, p120 promotes cell invasion and anchorage-independent growth. Furthermore, p120 is required for Src-induced oncogenic transformation and provides a potential target for future therapeutic interventions.

Phosphorylation-mediated 14-3-3 protein binding regulates the function of the rho-specific guanine nucleotide exchange factor (RhoGEF) Syx.

Syx is a Rho-specific guanine nucleotide exchange factor (GEF) that localizes at cell-cell junctions and promotes junction stability by activating RhoA and the downstream effector Diaphanous homolog 1 (Dia1). Previously, we identified several molecules, including 14-3-3 proteins, as Syx-interacting partners. In the present study, we show that 14-3-3 isoforms interact with Syx at both its N- and C-terminal regions in a phosphorylation-dependent manner. We identify the protein kinase D-mediated phosphorylation of serine 92 on Syx, and additional phosphorylation at serine 938, as critical sites for 14-3-3 association. Our data indicate that the binding of 14-3-3 proteins inhibits the GEF activity of Syx. Furthermore, we show that phosphorylation-deficient, 14-3-3-uncoupled Syx exhibits increased junctional targeting and increased GEF activity, resulting in the strengthening of the circumferential junctional actin ring in Madin-Darby canine kidney cells. These findings reveal a novel means of regulating junctional Syx localization and function by phosphorylation-induced 14-3-3 binding and further support the importance of Syx function in maintaining stable cell-cell contacts.

Rho GEFs in endothelial junctions: Effector selectivity and signaling integration determine junctional response.

Rho GTPases are cytoskeleton-regulating proteins that mediate the formation of intercellular junctions. Their localized activation by Rho GEFs (guanine-nucleotide exchange factors) and the selective activation of downstream effectors have emerged as areas of active research in the cell adhesion field. We reported recently that the Rho-specific GEFs Syx (Synectin-binding RhoA exchange factor) and TEM4 (Tumor Endothelial Marker 4) are both essential for endothelial junction maturation and barrier function. Syx is recruited to cell contacts via its C-terminal PDZ binding motif and it's interaction with Mupp1 and the Crumbs polarity complex, while the junctional localization of TEM4 requires it's N-terminal domain and interaction with the cadherin-catenin complex. Our findings support multiple roles for RhoA in junction formation and maintenance. They also suggest that selective coupling of RhoA activation to Dia1 and/or ROCK signaling is critical for determining endothelial junction integrity.

VEGF and Angiopoietin-1 exert opposing effects on cell junctions by regulating the Rho GEF Syx.

Vascular endothelial growth factor (VEGF) and Ang1 (Angiopoietin-1) have opposing effects on vascular permeability, but the molecular basis of these effects is not fully known. We report in this paper that VEGF and Ang1 regulate endothelial cell (EC) junctions by determining the localization of the RhoA-specific guanine nucleotide exchange factor Syx. Syx was recruited to junctions by members of the Crumbs polarity complex and promoted junction integrity by activating Diaphanous. VEGF caused translocation of Syx from cell junctions, promoting junction disassembly, whereas Ang1 maintained Syx at the junctions, inducing junction stabilization. The VEGF-induced translocation of Syx from EC junctions was caused by PKD1 (protein kinase D1)-mediated phosphorylation of Syx at Ser(806), which reduced Syx association to its junctional anchors. In support of the pivotal role of Syx in regulating EC junctions, syx(-/-) mice had defective junctions, resulting in vascular leakiness, edema, and impaired heart function.

Residual sleep disturbances in patients remitted from major depressive disorder: a 4-year naturalistic follow-up study.

STUDY OBJECTIVES: To investigate the prevalence and clinical, psychosocial, and functional correlates of residual sleep disturbances in remitted depressed outpatients. DESIGN: A 4-yr prospective observational study in a cohort of psychiatric outpatients with major depressive disorder was conducted with a standardized diagnostic psychiatric interview and a packet of questionnaires, including a sleep questionnaire, Hospital Anxiety and Depression Scale, NEO personality inventory, and Short Form-12 Health Survey. SETTINGS: A university-affiliated psychiatric outpatient clinic. INTERVENTIONS: N/A MEASUREMENTS AND RESULTS: Four hundred twenty-one depressed outpatients were recruited at baseline, and 371 patients (mean age 44.6 ± 10.4 yr, female 81.8%; response rate 88.1%) completed the reassessments, in which 41% were classified as remitted cases. One year prevalence of frequent insomnia at baseline and follow-up in remitted patients was 38.0% and 19.3%, respectively. One year prevalence of frequent nightmares at baseline and follow-up was 24.0% and 9.3%, respectively. Remitted patients with residual insomnia were more likely to be divorced (P < 0.05) and scored higher on the anxiety subscale (P < 0.05). Remitted patients with residual nightmares were younger (P < 0.05) and scored higher on neuroticism (P < 0.05) and anxiety subscales (P < 0.01). Residual insomnia and nightmares were associated with various aspects of impaired quality of life. Residual nightmares was associated with suicidal ideation (odds ratio = 8.40; 95% confidence interval 1.79-39.33). CONCLUSIONS: Residual sleep disturbances, including insomnia and nightmares, were commonly reported in remitted depressed patients with impaired quality of life and suicidal ideation. A constellation of psychosocial and personality factors, baseline sleep disturbances, and comorbid anxiety symptoms may account for the residual sleep disturbances. Routine assessment and management of sleep symptoms are indicated in the integrated management of depression.

Opposing responses of apoptosis and autophagy to moderate compression in skeletal muscle.

AIM: The molecular mechanism that contributes to the pathogenesis of deep pressure ulcer remains to be elucidated. This study tested the hypotheses that: (1) apoptosis and autophagy are activated in compression-induced muscle pathology and (2) apoptotic and autophagic changes precede pathohistological changes in skeletal muscle in response to prolonged moderate compression. METHODS: Adult Sprague-Dawley rats were subjected to an experimental model of pressure-induced deep tissue injury. Static pressure of 100 mmHg was applied to an area of 1.5 cm(2) over the mid-tibialis region of right limb of rats for one single session of 6-h compression (1D) or two sessions of 6-h compression over two consecutive days with rats sacrificed one day (2D) or immediately after (2D-IM) the compression. The left uncompressed limb served as the intra-animal control. Muscle tissues underneath compression region were collected for analysis. RESULTS: Our histological analysis indicated that pathohistological characteristics including rounding contour of myofibres and massive nuclei accumulation were apparently demonstrated in muscles of 2D and 2D-IM. In contrast, these pathohistological changes were generally not found in muscle following 1D. Apoptotic DNA fragmentation, terminal dUTP nick-end labelling index and caspase-3 protease activity were significantly elevated in compressed muscles of all groups. Caspase-9 enzymatic activity was found to be significantly increased in compressed muscles of 2D and 2D-IM whereas increase in caspase-8 activity was exclusively found in compressed muscle of 1D. According to our immunoblot analysis, FoxO3 was significantly reduced in compressed muscles of all groups whereas Beclin-1 was decreased only in 2D. LC3-I was significantly reduced in compressed muscles of all groups while LC3-II was decreased in 2D and 1D. No significant differences were found in the protein abundance of Akt and phospho-Akt in muscles among all groups. CONCLUSION: These data demonstrate the opposing responses of apoptosis and autophagy to moderate compression in muscle. Moreover, our findings suggest that cellular changes in apoptosis and autophagy have already taken place in the very early stage in which apparent histopathology has yet to develop in the process of compression-induced muscle pathology.

Nocturnal sleep disturbances as a predictor of suicide attempts among psychiatric outpatients: a clinical, epidemiologic, prospective study.

OBJECTIVE: Nocturnal sleep disturbances, including insomnia and recurrent nightmares, represent common distressing sleep complaints that might have important prognostic and therapeutic implications in psychiatric patients. The present study aimed at investigating nocturnal sleep disturbances in relation to the risk of suicide attempts in a consecutive cohort of psychiatric outpatients. METHOD: Participants attending a psychiatric outpatient clinic in Hong Kong were recruited into the study with a detailed sleep questionnaire assessment. The questionnaire was distributed between May and June 2006. Relevant clinical information, with a comprehensive clinical history of patients since their attendance at psychiatric services and 1 year after completion of their questionnaires, was reviewed. RESULTS: The final study population consisted of 1,231 psychiatric outpatients with a mean age of 42.5 years (SD = 11.3; range, 18-65). Both frequent insomnia and recurrent nightmares were significantly and independently associated with an increased incidence of suicide attempts 1 year after questionnaire assessment (insomnia: OR = 6.96; 95% CI, 1.21-39.97; recurrent nightmares: OR = 8.17; 95% CI, 1.06-63.13) and an increase in lifetime prevalence of suicide attempts (insomnia: OR = 1.55; 95% CI, 1.06-2.25; recurrent nightmares: OR = 2.43; 95% CI, 1.51-3.91). Comorbid insomnia and nightmares had increased odds of lifetime prevalence (OR = 2.43; 95% CI, 1.53-3.85) and 1-year incidence of suicidal risk (OR = 17.08; 95% CI, 2.64-110.40). Antidepressants, particularly selective serotonin reuptake inhibitors (OR = 1.52; 95% CI, 1.02-2.25), serotonin-norepinephrine reuptake inhibitors (OR = 2.10; 95% CI, 1.15-3.83), heterocyclics (OR = 2.78; 95% CI, 1.21-6.42), and non-benzodiazepine hypnotics (OR = 1.54; 95% CI, 1.02-2.33) were independently associated with recurrent nightmares after adjustment for confounding variables. CONCLUSIONS: Nocturnal sleep disturbances, particularly frequent insomnia and recurrent nightmares, were independently associated with enhanced suicidal risk among psychiatric patients. Future studies are warranted to investigate the underlying pathophysiologic mechanism and interventional responses.