Centella asiatica and its caffeoylquinic acid and triterpene constituents increase dendritic arborization of mouse primary hippocampal neurons and improve age-related locomotion deficits in Drosophila.

Introduction: Centella asiatica (CA) is known in Ayurvedic medicine as a rejuvenating herb with particular benefits in the nervous system. Two groups of specialized metabolites found in CA and purported to contribute to its beneficial effects are triterpenes (TTs) and caffeoylquinic acids (CQAs). In order to evaluate the role and interactions of TTs and CQAs in the effects of CA, we examined the neurotrophic effects of a water extract of CA (CAW) and combinations of its TT and CQA components in mouse primary hippocampal neurons in vitro and in Drosophila melanogaster flies in vivo. Methods: Primary hippocampal neurons were isolated from mouse embryos and exposed in vitro for 5 days to CAW (50 µg/mL), mixtures of TTs, CQAs or TT + CQA components or to 4 TTs or 8 individual CQA compounds of CAW. Dendritic arborization was evaluated using Sholl analysis. Drosophila flies were aged to 28 days and treated for 2 weeks with CAW (10 mg/mL) in the food, mixtures of TTs, CQAs or TT + CQA and individual TT and CQA compounds. TTs and CQAs were tested at concentrations matching their levels in the CAW treatment used. After 2 weeks of treatment, Drosophila aged 42 days were evaluated for phototaxis responses. Results: In mouse primary hippocampal neurons, CAW (50 µg/mL), the TT mix, CQA mix, all individual TTs and most CQAs significantly increased dendritic arborization to greater than control levels. However, the TT + CQA combination significantly decreased dendritic arborization. In Drosophila, a marked age-related decline in fast phototaxis response was observed in both males and females over a 60 days period. However, resilience to this decline was afforded in both male and female flies by treatment from 28 days onwards with CAW (10 mg/mL), or equivalent concentrations of mixed TTs, mixed CQAs and a TT + CQA mix. Of all the individual compounds, only 1,5-diCQA slowed age-related decline in phototaxis in male and female flies. Discussion: This study confirmed the ability of CAW to increase mouse neuronal dendritic arborization, and to provide resilience to age-related neurological decline in Drosophila. The TT and CQA components both contribute to these effects but do not have a synergistic effect. While individual TTs and most individual CQAs increased dendritic arborization at CAW equivalent concentrations, in the Drosophila model, only 1,5-diCQA was able to slow down the age-related decline in phototaxis. This suggests that combinations (or potentially higher concentrations) of the other compounds are needed to provide resilience in this model.

Effectiveness of topical gabapentin in the treatment of vulvodynia: a narrative synthesis.

Vulvodynia is a leading cause of dyspareunia in premenopausal women, causing considerable morbidity and sexual dysfunction. A multimodal approach is used to treat vulvodynia. Alongside psychosocial interventions and physiotherapy, pharmacological treatment such as oral gabapentin are used in the treatment of vulvodynia. Topical formulations of gabapentin have shown promise in animal models and case reports investigating its use in other pain conditions. The topical route also avoids the systemic complications of gabapentin such as somnolence, dizziness, and peripheral edema. This study aimed to perform a narrative synthesis of studies investigating the use of topical gabapentin in the treatment of vulvodynia. The primary outcome was a change in pain score following treatment with topical gabapentin. A broad literature search was performed, which identified four studies for inclusion. The included studies reported improved pain measures following treatment; however, conclusions cannot be made due to methodological heterogeneity and inherent limitations. These include lack of control arms, small sample sizes, lack of patient randomization, and use of combination treatments. Due to the paucity of evidence, this review supports the future implementation of double-blind randomized controlled trials to further investigate the efficacy of topical gabapentin in the treatment of vulvodynia.

A Comparison of Long-Term Outcomes in Patients Managed With Venovenous Extracorporeal Membrane Oxygenation in the First and Second Waves of the COVID-19 Pandemic in the United Kingdom.

OBJECTIVES: Early studies of venovenous extracorporeal membrane oxygenation (ECMO) in COVID-19 have revealed similar outcomes to historical cohorts. Changes in the disease and treatments have led to differences in the patients supported on venovenous ECMO in the first and second waves. We aimed to compare these two groups in both the acute and follow-up phase. DESIGN: Retrospective single-center cohort study comparing mortality at censoring date (November 30, 2021) and decannulation, patient characteristics, complications and lung function and quality of life (QOL-by European Quality of Life 5 Dimensions 3 Level Version) at first follow-up in patients supported on venovenous ECMO between wave 1 and wave 2 of the COVID-19 pandemic. SETTING: Critical care department of a severe acute respiratory failure service. PATIENTS: Patients supported on ECMO for COVID-19 between wave 1 (March 17, 2020, to August 31, 2020) and wave 2 (January 9, 2020, to May 25, 2021). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred twenty-three patients were included in our analysis. Survival at censoring date (χ 2 , 6.35; p = 0.012) and decannulation (90.4% vs 70.0%; p < 0.001) was significantly lower in the second wave, while duration of ECMO run was longer (12.0 d [18.0-30.0 d] vs 29.5 d [15.5-58.3 d]; p = 0.005). Wave 2 patients had longer application of noninvasive ventilation (NIV) prior to ECMO and a higher frequency of barotrauma. Patient age and NIV use were independently associated with increased mortality (odds ratio 1.07 [1.01-1.14]; p = 0.025 and 3.37 [1.12-12.60]; p = 0.043, respectively). QOL and lung function apart from transfer coefficient of carbon monoxide corrected for hemoglobin was similar at follow-up across the waves. CONCLUSIONS: Most patients with COVID-19 supported on ECMO in both waves survived in the short and longer term. At follow-up patients had similar lung function and QOL across the two waves. This suggests that ECMO has an ongoing role in the management of a carefully selected group of patients with COVID-19.

Withania somnifera Extracts Promote Resilience against Age-Related and Stress-Induced Behavioral Phenotypes in Drosophila melanogaster; a Possible Role of Other Compounds besides Withanolides.

Withania somnifera (WS) extracts have been used in traditional medicine for millennia to promote healthy aging and wellbeing. WS is now also widely used in Western countries as a nutritional supplement to extend healthspan and increase resilience against age-related changes, including sleep deficits and depression. Although human trials have supported beneficial effects of WS, the study designs have varied widely. Plant material is intrinsically complex, and extracts vary widely with the origin of the plant material and the extraction method. Commercial supplements can contain various other ingredients, and the characteristics of the study population can also be varied. To perform maximally controlled experiments, we used plant extracts analyzed for their composition and stability. We then tested these extracts in an inbred Drosophila line to minimize effects of the genetic background in a controlled environment. We found that a water extract of WS (WSAq) was most potent in improving physical fitness, while an ethanol extract (WSE) improved sleep in aged flies. Both extracts provided resilience against stress-induced behavioral changes. WSE contained higher levels of withanolides, which have been proposed to be active ingredients, than WSAq. Therefore, withanolides may mediate the sleep improvement, whereas so-far-unknown ingredients enriched in WSAq likely mediate the effects on fitness and stress-related behavior.

Chronic blue light leads to accelerated aging in Drosophila by impairing energy metabolism and neurotransmitter levels.

Blue light (BL) is becoming increasingly prevalent in artificial illumination, raising concerns about its potential health hazard to humans. In fact, there is evidence suggesting that acute BL exposure may lead to oxidative stress and death of retinal cells specialized for photoreception. On the other hand, recent studies in Drosophila melanogaster demonstrated that chronic BL exposure across lifespan leads to accelerated aging manifested in reduced lifespan and brain neurodegeneration even in flies with genetically ablated eyes, suggesting that BL can damage cells and tissues not specialized for light perception. At the physiological level, BL exposure impairs mitochondria function in flies, but the metabolic underpinnings of these effects have not been studied. Here, we investigated effects of chronic BL on metabolic pathways in heads of eyes absent (eya 2 ) mutant flies in order to focus on extra-retinal tissues. We compared metabolomic profiles in flies kept for 10 or 14 days in constant BL or constant darkness, using LC-MS and GC-MS. Data analysis revealed significant alterations in the levels of several metabolites suggesting that critical cellular pathways are impacted in BL-exposed flies. In particular, dramatic metabolic rearrangements are observed in heads of flies kept in BL for 14 days, including highly elevated levels of succinate but reduced levels of pyruvate and citrate, suggesting impairments in energy production. These flies also show onset of neurodegeneration and our analysis detected significantly reduced levels of several neurotransmitters including glutamate and Gamma-aminobutyric acid (GABA), suggesting that BL disrupts brain homeostasis. Taken together, these data provide novel insights into the mechanisms by which BL interferes with vital metabolic pathways that are conserved between fly and human cells.

Age-dependent effects of blue light exposure on lifespan, neurodegeneration, and mitochondria physiology in Drosophila melanogaster.

Blue light is a predominant component of light emitting devices (LEDs), which are increasingly present in our environment. There is already accumulating evidence that blue light exposure causes damage to retinal cells in vitro and in vivo; however, much less is known about potential effects of blue light on non-retinal cells. That blue light may be detrimental at the organismal level independent from retinal effect was recently shown by findings that it reduces lifespan in worms and also in flies with genetically ablated retinas. Here, we investigated the effects of blue light exposure across the fly lifespan and found that susceptibility to blue light stress is strongly age-dependent. The blue light of the same intensity and duration reduced survival and increased neurodegeneration more significantly in old flies than in young flies. These differences appear to be caused, at least in part, by impairments of mitochondrial respiratory function. We report that blue light significantly reduces the activity of Complex II in the electron transport system and decrease the biochemical activity of succinate dehydrogenase in both young and old flies. In addition, complex I and complex IV activities are reduced by age, as are ATP levels. We therefore propose that older flies are more sensitive to blue light because the light-induced mitochondrial damage potentiates the age-related impairments in energy metabolism that occurs even in darkness. Taken together, our results show that damaging effects of blue light at the organismal level are strongly age dependent and are associated with reduced activity of specific components of energy producing pathways in mitochondria.

FTD-associated mutations in Tau result in a combination of dominant and recessive phenotypes.

Although mutations in the microtubules-associated protein Tau have long been connected with several neurodegenerative diseases, the underlying molecular mechanisms causing these tauopathies are still not fully understood. Studies in various models suggested that dominant gain-of-function effects underlie the pathogenicity of these mutants; however, there is also evidence that the loss of normal physiological functions of Tau plays a role in tauopathies. Previous studies on Tau in Drosophila involved expressing the human Tau protein in the background of the endogenous Tau gene in addition to inducing high expression levels. To study Tau pathology in more physiological conditions, we recently created Drosophila knock-in models that express either wildtype human Tau (hTauWT) or disease-associated mutant hTau (hTauV337M and hTauK369I) in place of the endogenous Drosophila Tau (dTau). Analyzing these flies as homozygotes, we could therefore detect recessive effects of the mutations while identifying dominant effects in heterozygotes. Using memory, locomotion and sleep assays, we found that homozygous mutant hTau flies showed deficits already when quite young whereas in heterozygous flies, disease phenotypes developed with aging. Homozygotes also revealed an increase in microtubule diameter, suggesting that changes in the cytoskeleton underlie the axonal degeneration we observed in these flies. In contrast, heterozygous mutant hTau flies showed abnormal axonal targeting and no detectable changes in microtubules. However, we previously showed that heterozygosity for hTauV337M interfered with synaptic homeostasis in central pacemaker neurons and we now show that heterozygous hTauK369I flies have decreased levels of proteins involved in the release of synaptic vesicles. Taken together, our results demonstrate that both mutations induce a combination of dominant and recessive disease-related phenotypes that provide behavioral and molecular insights into the etiology of Tauopathies.

An exercise cum cognitive-behavioral intervention for older adults with chronic pain: A cluster-randomized controlled trial.

OBJECTIVE: To examine the medium-term effects of a group intervention combining exercise and cognitive-behavioral strategies (EC) on older adults with chronic pain. METHOD: One hundred and fifty-two Hong Kong Chinese older adults with chronic pain affecting bones, muscles, and joints were randomized by clinic/social center to receive 10 weekly sessions of EC or pain education (control). The primary (pain intensity) and secondary outcomes (pain disability, pain self-efficacy, pain catastrophizing, pain coping, depressive symptoms, health-related quality of life, and hip and knee strength) were collected at baseline (T1), postintervention (T2), and 3- (T3) and 6-month follow-ups (T4). The trajectories of intervention effects were modeled by EC × time and EC × time2 interaction terms in mixed-effects regression. RESULTS: Significant EC × time and/or EC × time2 interactions were found for pain intensity, pain disability, self-efficacy, and catastrophizing, such that the treatment effect leveled off (pain disability) or diminished (pain intensity and catastrophizing) over time, or continued to increase in a linear fashion (self-efficacy). There was also a treatment main effect on hip/knee muscle strength. Group differences in favor of EC were observed up to 3-month follow-up for pain intensity (d = -0.51) and hip/knee muscle strength (d = 0.38), and up to 6-month follow-up for pain disability (d = -0.60) and self-efficacy (d = 0.52). No group difference was found for catastrophizing at any time point. No treatment effects were found for the other outcomes. CONCLUSION: Older people suffering from chronic pain can benefit from a program incorporating both cognitive-behavioral techniques and physical exercise. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Withania somnifera and Centella asiatica Extracts Ameliorate Behavioral Deficits in an In Vivo Drosophila melanogaster Model of Oxidative Stress.

Due to an increase in the aging population, age-related diseases and age-related changes, such as diminished cognition and sleep disturbances, are an increasing health threat. It has been suggested that an increase in oxidative stress underlies many of these changes. Current treatments for these diseases and changes either have low efficacy or have deleterious side effects preventing long-time use. Therefore, alternative treatments that promote healthy aging and provide resilience against these health threats are needed. The herbs Withania somnifera and Centella asiatica may be two such alternatives because both have been connected with reducing oxidative stress and could therefore ameliorate age-related impairments. To test the effects of these herbs on behavioral phenotypes induced by oxidative stress, we used the Drosophila melanogaster sniffer mutant which has high levels of oxidative stress due to reduced carbonyl reductase activity. Effects on cognition and mobility were assessed using phototaxis assays and both, W. somnifera and C. asiatica water extracts improved phototaxis in sniffer mutants. In addition, W. somnifera improved nighttime sleep in male and female sniffer flies and promoted a less fragmented sleep pattern in male sniffer flies. This suggests that W. somnifera and C. asiatica can ameliorate oxidative stress-related changes in behavior and that by doing so they might promote healthy aging in humans.

Six Month Mortality in Patients with COVID-19 and Non-COVID-19 Viral Pneumonitis Managed with Veno-Venous Extracorporeal Membrane Oxygenation.

A significant proportion of patients with COVID-19 develop acute respiratory distress syndrome (ARDS) with high risk of death. The efficacy of veno-venous extracorporeal membrane oxygenation (VV-ECMO) for COVID-19 on longer-term outcomes, unlike in other viral pneumonias, is unknown. In this study, we aimed to compare the 6 month mortality of patients receiving VV-ECMO support for COVID-19 with a historical viral ARDS cohort. Fifty-three consecutive patients with COVID-19 ARDS admitted for VV-ECMO to the Royal Brompton Hospital between March 17, 2020 and May 30, 2020 were identified. Mortality, patient characteristics, complications, and ECMO parameters were then compared to a historical cohort of patients with non-COVID-19 viral pneumonia. At 6 months survival was significantly higher in the COVID-19 than in the non-COVID-19 viral pneumonia cohort (84.9% vs. 66.0%, p = 0.040). Patients with COVID-19 had an increased Murray score (3.50 vs. 3.25, p = 0.005), a decreased burden of organ dysfunction (sequential organ failure score score [8.76 vs. 10.42, p = 0.004]), an increased incidence of pulmonary embolism (69.8% vs. 24.5%, p < 0.001) and in those who survived to decannulation longer ECMO runs (19 vs. 11 days, p = 0.001). Our results suggest that survival in patients supported with EMCO for COVID-19 are at least as good as those treated for non-COVID-19 viral ARDS.

Typology of pain coping and associations with physical health, mental health, and pain profiles in Hong Kong Chinese older adults.

OBJECTIVES: To identify typology of pain coping in older adults and to see whether the coping types or patterns were associated with pain, physical health, and mental health outcomes. METHODS: Six hundred and fifty six Chinese older adults were recruited on a convenience basis from social centers in Hong Kong. A 14-item Brief Pain Coping Scale (BPCS) was constructed on the basis of the Chronic Pain Coping Inventory. Outcome measures included pain intensity, pain disability, pain-related cognitions, depressive symptoms, health-related quality of life, and health and physical functioning (in terms of chronic illnesses, basic and instrumental activities of daily living, and self-rated health). Coping typology was identified using latent class analysis. RESULTS: A 3-class solution based on BPCS provided the best fit to data. Class 1 used almost all coping strategies on a daily basis, Class 2 used the strategies less frequently, whereas Class 3 adopted few strategies. Yet, Class 3 was basically indistinguishable from Class 1 across the outcome variables, even though the participants had more chronic illnesses and poorer instrumental activities of daily living than those in Class 1. Class 2, however, had the poorest outcome profiles, reporting more pain, disability, depression, and health-related quality of life than the other two classes. The differences in coping could not be explained by the differential effectiveness of coping strategies across groups. CONCLUSION: The way coping was used, and the way it was related to pain, mood, health and functioning outcomes, varied substantially across individuals. Implications for coping skills interventions are discussed.

Disease-Associated Mutant Tau Prevents Circadian Changes in the Cytoskeleton of Central Pacemaker Neurons.

A hallmark feature of Alzheimer's disease (AD) and other Tauopathies, like Frontotemporal Dementia with Parkinsonism linked to chromosome 17 (FTDP-17), is the accumulation of neurofibrillary tangles composed of the microtubule-associated protein Tau. As in AD, symptoms of FTDP-17 include cognitive decline, neuronal degeneration, and disruptions of sleep patterns. However, mechanisms by which Tau may lead to these disturbances in sleep and activity patterns are unknown. To identify such mechanisms, we have generated novel Drosophila Tauopathy models by replacing endogenous fly dTau with normal human Tau (hTau) or the FTDP-17 causing hTauV337M mutation. This mutation is localized in one of the microtubule-binding domains of hTau and has a dominant effect. Analyzing heterozygous flies, we found that aged hTauV337M flies show neuronal degeneration and locomotion deficits when compared to wild type or hTauWT flies. Furthermore, hTauV337M flies are hyperactive and they show a fragmented sleep pattern. These changes in the sleep/activity pattern are accompanied by morphological changes in the projection pattern of the central pacemaker neurons. These neurons show daily fluctuations in their connectivity, whereby synapses are increased during the day and reduced during sleep. Synapse formation requires cytoskeletal changes that can be detected by the accumulation of the end-binding protein 1 (EB1) at the site of synapse formation. Whereas, hTauWT flies show the normal day/night changes in EB1 accumulation, hTauV337M flies do not show this fluctuation. This suggests that hTauV337M disrupts sleep patterns by interfering with the cytoskeletal changes that are required for the synaptic homeostasis of central pacemaker neurons.

Developing a Short Multidimensional Measure of Pain Self-efficacy: The Chronic Pain Self-efficacy Scale-Short Form.

BACKGROUND AND OBJECTIVES: The 22-item Chronic Pain Self-efficacy Scale (CPSS) measures three domains of pain self-efficacy: pain management, physical functioning, and coping with symptoms. This study aims to develop a short form (CPSS-SF) that retains the multidimensional structure of the instrument. RESEARCH DESIGN AND METHODS: Six hundred sixty-four community-dwelling Chinese older adults aged 60-95 years with chronic pain completed a survey. Confirmatory factor analysis (CFA) was conducted on the 22-item CPSS. Regression analyses were performed to examine the items' correlations with criterion variables. After CPSS-SF items were selected, the performance of CPSS-SF subscales in terms of accounting for pain-related outcomes was compared with the full version. RESULTS: CFA supported a modified 3-factor model of the CPSS. On the basis of factor loadings on the 3 dimensions and the items' correlations with pain intensity and pain disability, 11 items were selected for the CPSS-SF, which correlated at .97 with the full version. Regression analyses showed that the associations of the CPSS-SF subscales with pain intensity, pain disability, depressive symptoms, instrumental activities of daily living, and physical and mental health-related quality of life, were indistinguishable from their full-version counterparts. DISCUSSION AND IMPLICATIONS: The CPSS-SF is a valid instrument that can be used in lieu of the full scale. Its availability will facilitate the assessment of pain self-efficacy in research and clinical settings due to its brevity but strong psychometric properties. However, the current evidence is limited to Chinese older adults; more research is needed to ascertain its validity in other age and cultural groups.

Disease-Associated PNPLA6 Mutations Maintain Partial Functions When Analyzed in Drosophila.

Mutations in patatin-like phospholipase domain-containing protein 6 (PNPLA6) have been linked with a number of inherited diseases with clinical symptoms that include spastic paraplegia, ataxia, and chorioretinal dystrophy. PNPLA6 is an evolutionary conserved protein whose ortholog in Drosophila is Swiss-Cheese (SWS). Both proteins are phospholipases hydrolyzing lysophosphatidylcholine (LPC) and phosphatidylcholine (PC). Consequently, loss of SWS/PNPLA6 in flies and mice increases both lipids and leads to locomotion deficits and neurodegeneration. PNPLA6 knock-out mice are embryonic lethal, and a mutation creating an early stop codon in human PNPLA6 has only been identified in compound heterozygote patients. In contrast, disease-causing point mutations are found in homozygous patients, with some localized in the phospholipase domain while others are in a region that contains several cNMP binding sites. To investigate how different mutations affect the function of PNPLA6 in an in vivo model, we expressed them in the Drosophila sws1 null mutant. Expressing wild-type PNPLA6 suppressed the locomotion and degenerative phenotypes in sws 1 and restored lipid levels, confirming that the human protein can replace fly SWS. In contrast, none of the mutant proteins restored lipid levels, although they suppressed the behavioral and degenerative phenotypes, at least in early stages. These results show that these mutant forms of PNPLA6 retain some biological function, indicating that disruption of lipid homeostasis is only part of the pathogenic mechanism. Furthermore, our finding that mutations in the cNMP binding sites prevented the restoration of normal lipid levels supports previous evidence that cNMP regulates the phospholipase activity of PNPLA6.

Daily blue-light exposure shortens lifespan and causes brain neurodegeneration in Drosophila.

Light is necessary for life, but prolonged exposure to artificial light is a matter of increasing health concern. Humans are exposed to increased amounts of light in the blue spectrum produced by light-emitting diodes (LEDs), which can interfere with normal sleep cycles. The LED technologies are relatively new; therefore, the long-term effects of exposure to blue light across the lifespan are not understood. We investigated the effects of light in the model organism, Drosophila melanogaster, and determined that flies maintained in daily cycles of 12-h blue LED and 12-h darkness had significantly reduced longevity compared with flies maintained in constant darkness or in white light with blue wavelengths blocked. Exposure of adult flies to 12 h of blue light per day accelerated aging phenotypes causing damage to retinal cells, brain neurodegeneration, and impaired locomotion. We report that brain damage and locomotor impairments do not depend on the degeneration in the retina, as these phenotypes were evident under blue light in flies with genetically ablated eyes. Blue light induces expression of stress-responsive genes in old flies but not in young, suggesting that cumulative light exposure acts as a stressor during aging. We also determined that several known blue-light-sensitive proteins are not acting in pathways mediating detrimental light effects. Our study reveals the unexpected effects of blue light on fly brain and establishes Drosophila as a model in which to investigate long-term effects of blue light at the cellular and organismal level.

ER responses play a key role in Swiss-Cheese/Neuropathy Target Esterase-associated neurodegeneration.

Swiss Cheese (SWS) is the Drosophila orthologue of Neuropathy Target Esterase (NTE), a phospholipase that when mutated has been shown to cause a spectrum of disorders in humans that range from intellectual disabilities to ataxia. Loss of SWS in Drosophila also causes locomotion deficits, age-dependent neurodegeneration, and an increase in lysophosphatidylcholine (LPC) and phosphatidylcholine (PC). SWS is localized to the Endoplasmic Reticulum (ER), and recently, it has been shown that perturbing the membrane lipid composition of the ER can lead to the activation of ER stress responses through the inhibition of the Sarco/Endoplasmic Reticulum Ca2+ ATPase (SERCA). To investigate whether ER stress induction occurs in NTE-associated disorders, we used the fly sws null mutant as a model. sws flies showed an activated ER stress response as determined by elevated levels of the chaperone GRP78 and by increased splicing of XBP, an ER transcription factor that activates transcriptional ER stress responses. To address whether ER stress plays a role in the degenerative and behavioral phenotypes detected in sws1, we overexpressed XBP1, or treated the flies with tauroursodeoxycholic acid (TUDCA), a chemical known to attenuate ER stress-mediated cell death. Both manipulations suppressed the locomotor deficits and neurodegeneration of sws1. In addition, sws1 flies showed reduced SERCA levels and expressing additional SERCA also suppressed the sws1-related phenotypes. This suggests that the disruption in lipid compositions and its effect on SERCA are inducing ER stress, aimed to ameliorate the deleterious effects of sws1. This includes the effects on lipid composition because XBP1 and SERCA expression also reduced the LPC levels in sws1. Promoting cytoprotective ER stress pathways may therefore provide a therapeutic approach to alleviate the neurodegeneration and motor symptoms seen in NTE-associated disorders.

The Pain Catastrophizing Scale-short form: psychometric properties and threshold for identifying high-risk individuals.

OBJECTIVE: The Pain Catastrophizing Scale (PCS) measures three aspects of catastrophic cognitions about pain-rumination, magnification, and helplessness. To facilitate assessment and clinical application, we aimed to (a) develop a short version on the basis of its factorial structure and the items' correlations with key pain-related outcomes, and (b) identify the threshold on the short form indicative of risk for depression. DESIGN: Cross-sectional survey. SETTING: Social centers for older people. PARTICIPANTS: 664 Chinese older adults with chronic pain. MEASUREMENTS: Besides the PCS, pain intensity, pain disability, and depressive symptoms were assessed. RESULTS: For the full scale, confirmatory factor analysis showed that the hypothesized 3-factor model fit the data moderately well. On the basis of the factor loadings, two items were selected from each of the three dimensions. An additional item significantly associated with pain disability and depressive symptoms, over and above these six items, was identified through regression analyses. A short-PCS composed of seven items was formed, which correlated at r=0.97 with the full scale. Subsequently, receiver operating characteristic (ROC) curves were plotted against clinically significant depressive symptoms, defined as a score of ≥12 on a 10-item version of the Center for Epidemiologic Studies-Depression Scale. This analysis showed a score of ≥7 to be the optimal cutoff for the short-PCS, with sensitivity = 81.6% and specificity = 78.3% when predicting clinically significant depressive symptoms. CONCLUSIONS: The short-PCS may be used in lieu of the full scale and as a brief screen to identify individuals with serious catastrophizing.

Deletion of a specific exon in the voltage-gated calcium channel gene cacophony disrupts locomotion in Drosophila larvae.

TAR DNA-binding protein 43 (TDP-43) is an RNA-binding protein that regulates transcription, translation and alternative splicing of mRNA. We have shown previously that null mutations of the Drosophila ortholog, Tar DNA-binding homolog (tbph), causes severe locomotion defects in larvae that are mediated by a reduction in the expression of a type II voltage-gated calcium channel, cacophony (cac). We also showed that TDP-43 regulates the inclusion of alternatively spliced exons of cacophony; tbph mutants showed significantly increased expression of cacophony isoforms lacking exon 7, a particularly notable finding as only one out of the 15 predicted isoforms lacks exon 7. To investigate the function of exon 7, we generated Drosophila mutant lines with a deletion that eliminates exon 7. This deletion phenocopies many defects in tbph mutants: a reduction in cacophony protein (Dmca1A) expression, locomotion defects in male and female third instar larvae, disrupted larval motor output, and also reduced activity levels in adult male flies. All these defects were rescued by expression of cacophony transcripts containing exon 7. By contrast, expression of a cacophony cDNA lacking exon 7 resulted in reduced cacophony protein levels and failed to rescue larval locomotion.