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Physical activity brings significant health benefits to middle-aged adults, although the research to date has been focused on late adulthood. This study aims to examine how ageing affects the self-reported and accelerometer-derived measures of physical activity levels in middle-aged adults. We employed the data recorded in the UK Biobank and analysed the physical activity levels of 2,998 participants (1381 men and 1617 women), based on self-completion questionnaire and accelerometry measurement of physical activity. We also assessed the musculoskeletal health of the participants using the dual-energy X-ray absorptiometry (DXA) measurements provided by the UK Biobank. Participants were categorised into three groups according to their age: group I younger middle-aged (40 to 49 years), group II older middle-aged (50 to 59 years), and group III oldest middle-aged (60 to 69 years). Self-reported physical activity level increased with age and was the highest in group III, followed by group II and I (P

The desmosome is a type of intercellular junction found in epithelial cells, cardiomyocytes and other specialized cell types. Composed of a network of transmembranous cadherins and intracellular armadillo, plakin and other proteins, desmosomes contribute to cell-cell adhesion, signalling, development and differentiation. Mutations in genes encoding desmosomal proteins result in a spectrum of erosive skin and mucosal phenotypes that also may affect hair or heart. This review summarizes the molecular pathology and phenotypes associated with desmosomal dysfunction with a focus on inherited disorders that involve the skin/hair, as well as associated extracutaneous pathologies. We reviewed the relevant literature to collate studies of pathogenic human mutations in desmosomes that have been reported over the last 25 years. Mutations in 12 different desmosome genes have been documented, with mutations in nine genes affecting the skin/mucous membranes (DSG1, DSG3, DSC2, DSC3, JUP, PKP1, DSP, CDSN, PERP) and eight resulting in hair abnormalities (DSG4, DSC2, DSC3, JUP, PKP1, DSP, CDSN, PERP). Mutations in three genes can result in cardiocutaneous syndromes (DSC2, JUP, DSP), although mutations have been described in five genes in inherited heart disorders that may lack any dermatological manifestations (DSG2, DSC2, JUP, PKP2, DSP). Understanding the diverse nature of these clinical phenotypes, as well as the desmosome gene mutation(s), has clinical value in managing and counselling patients, as well as demonstrating the biological role and activity of specific components of desmosomes in skin and other tissues.

Introduction Peroxisome proliferator-activated receptor γ (PPARγ) plays a key role in glucose, which is a ligand-mediated transcription factor. The lipid homeostasis often serves as a pharmacological target for new drug discovery and development. Materials and methods In the research, we synthesized a series of piperine derivatives and then used a fluorescence polarization-based PPARγ ligand screening assay to evaluate the agonistic activity of PPARγ. Then, we cultured human normal hepatocytes, which were treated with 100μM compounds 2a, 2t or 3d. Then, the levels of PPARγ gene were determined so as to show whether the compounds could activate or inhibit the expression of PPARγ. Results A total of 30 piperine derivatives were synthesized and evaluated. Compound 2a was identified as a potential PPARγ agonist with IC50 at 2.43 μM, which is 2 times more potent than the positive control rosiglitazone with IC50 at 5.61μM. The human hepatocytes cells were cultured and treated with compounds 2a, 2t or 3d as described in the "Materials and Methods" section. We found that compounds 2a, 2t and 3d could activate PPARγ by 11.8, 1.9 and 7.0 times compared with the "blank", with compound 2a activation being the most significant. Molecular docking studies indicated that the piperine derivative 2a stably interacts with the amino acid residues of the PPARγ complex active site, which is consistent with the results of the in vitro PPARγ ligand screening assay.

Background. We compared the outcomes of laparoscopic-assisted (LA) and robotic-assisted (RA) gastrectomies performed for gastric adenocarcinoma in the National Cancer Database. Methods. The National Cancer Database was queried for patients 18 years old with stages I to III gastric adenocarcinoma who underwent LA or RA gastrectomy. Propensity matching was performed between the 2 groups with regard to clinical staging, adjuvant treatment, demographics, and the extent of surgery. Results. A cohort of 1893 (1262 = LA, 631 = RA) patients was identified in a 2:1 propensity matching. The groups were well matched. The rate of negative margin as well as 30- and 90-day mortality were similar between the 2 cohorts. Long-term survival was similar between the 2 groups (median survival 49.2 months in LA vs 56.2 months for RA, P = .405). However, the average number of lymph nodes (LNs) sampled was significantly higher in the RA group compared with the LA group (19.6 vs 17.4, P < .001). Similarly, the percentage of surgeries in which ≥15 LNs were sampled was also greater in the RA group compared with the LA group (63.9% vs 57.6%, P = .010). On multivariable analysis, having 15 LNs or more examined was associated with better survival (hazard ratio = 0.72, 95% confidence interval = 0.60-0.87, P < .001). Advanced age, nodal positivity, and advanced clinical stages were significantly associated with worse survival. Conclusions. RA gastrectomy may allow a greater harvest of LNs, and thus more accurate staging, without increasing short-term adverse outcomes compared with LA gastrectomy. Short-term and long-term outcomes in this well-matched cohort appear comparable for both approaches.

Background Opioids have been prescribed to reduce suffering from pain and to enhance quality of life. Due to the addictive potential and the lack of other effective alternatives to treat severe acute and chronic pains, opioids remain a serious public health issue. While, opioids directly influence the drug-seeking behavior, tolerance and withdrawal processes, through neuroadaptation, the brain's endogenous opioid system also adapts in the presence of chronic pain and could contribute to the difficulty of treatment. Despite the seemingly obvious interaction between the presence of pain and opioid-abuse, little is known about the underlying mechanisms in the brain. Purpose To review the current understanding of the interaction mechanisms of neurotransmitter circuitries in pain modulation and reward in the brain and the effects of L-tetrahydropalmatine (L-THP) and its metabolites in pain management and opioid use disorder and gain a better insight on the pharmacological profile and in vivo effects of L-THP and its metabolites. Method A detailed literature search on available (preclinical and clinical) studies about the effects of L-THP and its metabolites against drug addiction and chronic pain has been performed. The data was collected using various search engines such as PubMed, ScienceDirect, Google scholar and articles in English up to December 2020 were included in this review. Results L-THP and its metabolites demonstrated analgesic and anti-addiction effects. Due to their dual pharmacological properties (D1 partial agonist and D2 antagonist) these compounds could be used as molecular tools to provide a better understanding of the interactions between pain and addiction. Conclusion The available data confirms the potential of L-THP and its metabolites to treat both chronic pain and drug addiction. However, further clinical trials are needed to establish safety and efficacy.

Opioid abuse and misuse have led to an epidemic which is currently spreading worldwide. Since the number of opioid overdoses is still increasing, it is becoming obvious that current rather unsystematic approaches to tackle this health problem are not effective. This review suggests that fighting the opioid epidemic requires a structured public health approach. Therefore, it is important to consider not only scientific and biomedical perspectives, but societal implications and the lived experience of groups at risk as well. Hence, this review evaluates the risk factors associated with opioid overdoses and investigates the rates of chronic opioid misuse, particularly in the context of chronic pain as well as post-surgery treatments, as the entrance of opioids in people’s lives. Linking pharmaceutical biology to narrative analysis is essential to understand the modulations of the usual themes of addiction and abuse present in the opioid crisis. This paper shows that patient narratives can be an important resource in understanding the complexity of opioid abuse and addiction. In particular, the relationship between chronic pain and social inequality must be considered. The main goal of this review is to demonstrate how a deeper transdisciplinary-enriched understanding can lead to more precise strategies of prevention or treatment of opioid abuse.

The widespread use of opioids to treat chronic pain led to a nation-wide crisis in the United States. Tens of thousands of deaths annually occur mainly due to respiratory depression, the most dangerous side effect of opioids. Non-opioid drugs and non-pharmacological treatments without addictive potential are urgently required. Traditional Chinese medicine (TCM) is based on a completely different medical theory than academic Western medicine. The scientific basis of acupuncture and herbal treatments as main TCM practices has been considerably improved during the past two decades, and large meta-analyses with thousands of patients provide evidence for their efficacy. Furthermore, opinion leaders in the United States favor non-pharmacological techniques including TCM for pain management to fight the opioid crisis. We advocate TCM as therapeutic option without addictive potential and without life-threatening side effects (e.g., respiratory depression) to treat chronic pain patients suffering from opioid misuse. The evidence suggests that: (1) opioid misuse cannot be satisfactorily managed with standard medication; (2) opinion leaders in the United States favor to consider non-opioid and non-pharmacological treatment strategies including those from TCM to treat acute and chronic pain conditions; (3) large meta-analyses provide scientific evidence for the clinical activity of acupuncture and herbal TCM remedies in the treatment of chronic pain. Future clinical trials should demonstrate the safety of TCM treatments if combined with Western medical practices to exclude negative interactions between both modalities.

Pueraria lobata is one of the most important medicinal herbs used traditionally in China. According to Shanghan Lun (Treatise on Exogenous Febrile Disease), it has been used traditionally to relieve body heat, eye soring, dry mouth, headache associated with high blood pressure, and stiff neck problems. Modern studies in the 1970s revealed that isoflavonoids extracted from P. lobata were the bioactive components of an herbal remedy namely Yufeng Ningxin Tablets for the treatment of patients after stroke. This article reviews recent application of P. lobota in the treatment of diabetics and in reducing alcohol drinking. In view of its low toxicity profile, P. lobota stands an excellent chance to be developed as a phytomedicine for treating human diseases.

ObjectivesTo investigate spinal kinematics, tibial and sacral impacts during fast bowling, among bowlers with a history of low back pain (LBP) (retrospective) and bowlers who developed LBP in the follow-up season (prospective).Methods35 elite male fast bowlers; senior (n=14; age=24.1±4.3 years; height=1.89±0.05 m; weight=89.2±4.6 kg) and junior (n=21; age=16.9±0.7; height=1.81±0.05; weight=73.0±9.2 kg) were recruited from professional county cricket clubs. LBP history was gathered by questionnaire and development of LBP was monitored for the follow-up season. Spinal kinematics, tibial and sacral impacts were captured using inertial measurement units placed over S1, L1, T1 and anteromedial tibia. Bonferroni corrected pairwise comparisons and effect sizes were calculated to investigate differences in retrospective and prospective LBP groups.ResultsApproximately 38% of juniors (n=8) and 57% of seniors (n=8) reported a history of LBP. No differences were evident in spinal kinematics or impacts between those with LBP history and those without for seniors and juniors. Large effect sizes suggest greater rotation during wind-up (d=1.3) and faster time-to-peak tibial impacts (d=1.5) in those with no history of LBP. One junior (5%) and four (29%) seniors developed LBP. No differences were evident in spinal kinematics or impacts between those who developed LBP and those who did not for seniors. In seniors, those who developed LBP had lower tibial impacts (d=1.3) and greater lumbar extension (d=1.9) during delivery.ConclusionRetrospective analysis displayed non-significant differences in kinematics and impacts. It is unclear if these are adaptive or impairments. Prospective analysis demonstrated large effect sizes for lumbar extension during bowling suggesting a target for future coaching interventions.

Background Throughout the 5000-year history of China, more than 300 epidemics were recorded. Traditional Chinese herbal medicine (TCM) has been used effectively to combat each of these epidemics’ infections, and saved many lives. To date, there are hundreds of herbal TCM formulae developed for the purpose of prevention and treatment during epidemic infections. When COVID-19 ravaged the Wuhan district in China in early January 2020, without a deep understanding about the nature of COVID-19, patients admitted to the TCM Hospital in Wuhan were immediately treated with TCM and reported later with >90% efficacy. Approach We conducted conduct a systematic survey of various TCM herbal preparations used in Wuhan and to review their efficacy, according to the published clinical data; and, secondly, to find the most popular herbs used in these preparations and look into the opportunity of future research in the isolation and identification of bioactive natural products for fighting COVID-19. Results Although bioactive natural products in these herbal preparations may have direct antiviral activities, TCM employed for fighting epidemic infections was primarily based on the TCM theory of restoring the balance of the human immune system, thereby defeating the viral infection indirectly. In addition, certain TCM teachings relevant to the meridian system deserve better attention. For instance, many TCM herbal preparations target the lung meridian, which connects the lung and large intestine. This interconnection between the lung, including the upper respiratory system, and the intestine, may explain why certain TCM formulae showed excellent relief of lung congestion and diarrhea, two characteristics of COVID-19 infection. Conclusion There is good reason for us to learn from ancient wisdom and accumulated clinical experience, in combination with cutting edge science and technologies, to fight with the devastating COVID-19 pandemic now and emerging new coronaviruses in the future.

Dermatofibromas are common benign skin lesions, the etiology of which is poorly understood. We identified two unrelated pedigrees in which there was autosomal dominant transmission of multiple dermatofibromas. Whole exome sequencing revealed a rare shared heterozygous missense variant in the F13A1 gene encoding factor XIII subunit A (FXIII-A), a transglutaminase involved in hemostasis, wound healing, tumor growth, and apoptosis. The variant (p.Lys679Met) has an allele frequency of 0.0002 and is predicted to be a damaging mutation. Recombinant human Lys679Met FXIII-A demonstrated reduced fibrin crosslinking activity in vitro. Of note, the treatment of fibroblasts with media containing Lys679Met FXIII-A led to enhanced adhesion, proliferation, and type I collagen synthesis. Immunostaining revealed co-localization between FXIII-A and α4β1 integrins, more prominently for Lys679Met FXIII-A than the wild type. In addition, both the α4β1 inhibitors and the mutation of the FXIII-A Isoleucine-Leucine-Aspartate-Threonine (ILDT) motif prevented Lys679Met FXIII-A-dependent proliferation and collagen synthesis of fibroblasts. Our data suggest that the Lys679Met mutation may lead to a conformational change in the FXIII-A protein that enhances α4-integrin binding and provides insight into an unexpected role for FXIII-A in the pathobiology of familial dermatofibroma.

Deriving from the Greek word λeιχήν for "tree moss" and the Latin word planus for "planar," lichen planus is a relatively uncommon and heterogeneous cutaneous disorder that typically develops in middle-aged adults. Despite the significant clinical burden associated with the disorder, little well-conducted molecular research has been undertaken, possibly because of heterogeneity impeding consistent and confident phenotyping. The multiple variants of lichenoid disease bear overlapping clinical and pathologic features despite manifesting as distinct clinical disorders. The first article in this 2-part continuing medical education series provides a comprehensive overview of the clinical and pathologic characteristics of cutaneous lichenoid dermatoses and links these manifestations to recent advances in our understanding of the underlying pathobiology of such diseases.

Background - Fast bowlers display a high risk of lower back injury and pain. Studies report factors that may increase this risk, however exact mechanisms remain unclear. Objective - To provide a contemporary analysis of literature, up to April 2016, regarding fast bowling, spinal kinematics, ground reaction force (GRF), lower back pain (LBP) and pathology. Method - Key terms including biomechanics, bowling, spine and injury were searched within MEDLINE, Google Scholar, SPORTDiscuss, Science Citation Index, OAIster, CINAHL, Academic Search Complete, Science Direct and Scopus. Following application of inclusion criteria, 56 studies (reduced from 140) were appraised for quality and pooled for further analysis. Results - Twelve times greater risk of lumbar injury was reported in bowlers displaying excessive shoulder counter-rotation (SCR), however SCR is a surrogate measure which may not describe actual spinal movement. Little is known about LBP specifically. Weighted averages of 5.8 ± 1.3 times body weight (BW) vertically and 3.2 ± 1.1 BW horizontally were calculated for peak GRF during fast bowling. No quantitative synthesis of kinematic data was possible due to heterogeneity of reported results. Conclusions - Fast bowling is highly injurious especially with excessive SCR. Studies adopted similar methodologies, constrained to laboratory settings. Future studies should focus on methods to determine biomechanics during live play.

Purpose: This study examined the activation patterns of the cervical and thoracic muscles in people with and without chronic neck pain during functional activities and their associations with pain intensity and functional disability.Methods: Thirty-four adults with chronic neck pain and 34 asymptomatic adults were recruited. They were requested to perform active cervical movements and an upper limb lifting task. Electromyographic activation patterns (EMG) of bilateral upper trapezius, cervical erector spinae, sternocleidomastoid, and thoracic erector spinae were recorded during these tasks. Correlation and multiple regression analysis were used to examine the associations between EMG variables and severity of pain and functional disability.Results: When performing the cervical movements, the neck pain group displayed lower EMG activity levels, especially in the cervical and thoracic extensors. In addition, significantly prolonged activation was observed in seven of the ten muscles during the upper limb lifting task. The changes in EMG amplitude and activation duration were found to be significantly correlated with severity of pain (R2 = 0.716) and functional disability (R2 = 0.623).Conclusions: Significant differences in the activation patterns of multiple cervical and thoracic muscles were found in individuals with neck pain compared with those without neck pain. These were significantly associated with their degree of pain and functional limitation. The findings of this study highlight the importance of assessing and optimising the neuromuscular activation of these muscles in the rehabilitation of those suffering from chronic neck pain.

Background The bioactive alkaloids identified from Cortex Phellodendri (CP) were highly effective in treating rats with benign prostatic hyperplasia (BPH). Specifically, lipoxygenase-5 (LOX-5) and cyclooxygenase-2 (COX-2) were identified as two primary targets for alleviating inflammation in BPH rats. However, it remains unknown whether the alkaloid components in CP can interact with the two target proteins. Purpose To further identify bioactive alkaloids targeting LOX/COX pathways. Methods An affinity-ultrafiltration mass spectrometry approach was employed to screen dual-target LOX-5/COX-2 ligands from alkaloid extract. The structures of bioactive alkaloids were characterized by high-resolution Fourier transform ion cyclotron resonance mass spectrometry. To understand the molecular mechanisms underlying the effects of bioactive alkaloids, the expression levels of LOX-5 and COX-2 in BPH model rats were investigated at both protein and mRNA levels. The LOX-5/COX-2 enzymes activity experiments and molecular docking analysis were performed to fully evaluate the interactions between bioactive alkaloids and LOX-5/COX-2. Results After comprehensive analysis, the results showed that bioactive alkaloids could suppress the expression of LOX-5 and COX-2 simultaneously to exert an anti-inflammatory effect on the progression of BPH. In addition, the screened protoberberine, demethyleneberberine was found to exhibit prominent inhibitory activities against both LOX-5 and COX-2 enzymes, palmatine and berberine with moderate inhibitory activities. Molecular docking analysis confirmed that demethyleneberberine could interact well with LOX-5/COX-2. Conclusion This study is the first to explore the inhibitory effects of bioactive alkaloids from CP on LOX-5 and COX-2 activities in BPH rats. Our findings demonstrate that the bioactive alkaloids from CP can ameliorate BPH via dual LOX-5/COX-2 pathways, which serves as an efficient approach for the discovery of novel drug leads from natural products with reduced side effects.

This study aims to investigate the dysfunction and recovery of the lumbopelvic movement and motor control of people with chronic nonspecific low back pain after a structured rehabilitation which emphasizes on re-education and training of movement and motor control. The lumbopelvic movement and motor control pattern of 30 adults (15 with chronic low back pain, 15 healthy controls) were assessed using 3D motion and electromyographic analysis during the repeated forward bending test, in additional to the clinical outcome measures. Regional kinematics and muscle recruitment pattern of the symptomatic group was analysed before and after the 6-week rehabilitation, and compared to healthy controls. Significant improvement in back pain, functional capacity and self-efficacy of the symptomatic group was found after the rehabilitation. Patients with chronic nonspecific low back pain were capable to recover to a comparable level of the healthy controls in terms of their lumbopelvic movement and motor control pattern upon completion of a 6-week rehabilitation program, despite their dysfunction displayed at baseline. Phase specific motor control reorganization in which more profound and positive changes shown during the flexion phase. Our findings indicate that the recovery of the movement and motor control pattern in patients with chronic low back pain achieved to a comparable level of the healthy able-bodies. The improvement of both the physical outcome measures suggest that specific rehabilitation program which emphasizes on optimizing motor control during movements would help promoting the functional recovery of this specific low back pain subgroup.

Introduction: Ectodermal dysplasia refers to the abnormal development of two or more embryological elements that give rise to skin, hair, teeth, and sweat glands. Clinically, ectodermal dysplasia c...

Background: fractures occur more commonly in the thoracic than in the lumbar spine. Physical activity complemented with pharmacological interventions has been advocated as a preventive measure for osteoporosis. However, walking has been shown to produce only a small improvement in spinal bone mineral density. The characteristics of vibration transmission during walking at the lumbar and thoracic spines may be different, and this may help explain the relative incidence of fractures in the two spine regions. Objective: to determine how mechanical vibration is transmitted in the lumbar and thoracic spines in older adults with and without osteoporosis. Methods: 16 young healthy adults, 19 older adults without osteoporosis and 41 adults with osteoporosis were recruited. Inertial sensors were attached to the skin over the lumbar and thoracic spines for recording the vibration transmitted during level walking. Vibration characteristics were compared across lumbar and thoracic spines and across groups. Results: the lumbar spine generally amplified the vibration transmitted during walking, whereas the thoracic spine exhibited a much smaller amplification effect, except at the lowest frequency. The magnitude of vibration was generally reduced in the older spines. Osteoporosis had minimal effects on vibration transmission. Conclusions: the larger amplification of vibration in the lumbar spine may explain the lower incidence of vertebral fractures in this region when compared to the thoracic spine. Ageing alters the transmission of vibration in the spine while osteoporosis has minimal effects. Future research should determine the characteristics of vibration transmitted through the thoracic spine during other physical activities.

l-Isocorypalmine is a newly identified metabolite of l-tetrahydropalmatine with a unique dual pharmacological profile as a partial dopamine receptor 1 agonist and dopamine receptor 2 antagonist properties for treating cocaine use disorder. The purpose of this study was to explore the pharmacokinetic profiles, tissue distribution, and excretion of l-isocorypalmine in Sprague-Dawley rats. A sensitive and reliable ultra high performance liquid chromatography with tandem mass spectrometry method was developed and validated for determination of l-isocorypalmine in biological samples. The biological samples were extracted by liquid-liquid extraction and separated on a Bonshell ASB C18 column (2.1 × 100 mm, 2.7 μm, Agela) with gradient mobile phase at the flow rate of 0.2 mL/min. The detection was performed by positive electrospray ionization with multiple reaction monitoring mode. Satisfactory linearity, precision, accuracy, extraction recovery, and acceptable matrix effect were achieved. The quantitative method was successfully applied to the pharmacokinetics, tissue distribution, and excretion study of l-isocorypalmine. The results showed that l-isocorypalmine was rapidly distributed, and eliminated from rat plasma and manifested linear dynamics in a dose range of 7.5-15 mg/kg. In addition, the results would be helpful for further clinical reference of l-isocorypalmine as a potential candidate drug for the treatment of cocaine addiction.

Obesity and osteoporotic‐related fractures are two common public health problems, although it is unclear how obesity affects the risk of vertebral fractures. The purpose of this study was to examine the association between different measures of obesity and the risk of vertebral fracture, and to establish the various clinical factors that can predict such risk. We analyzed data obtained from 502,543 participants in the UK Biobank (229,138 men and 273,405 women), aged 40 to 69 years. Imaging information was available in a subset of this cohort (5189 participants: 2473 men and 2716 women). We further examined how BMD and geometry of the vertebrae were related to body fat measures. It was shown that a larger waist circumference (WC), but not BMI, was associated with an increase in fracture risk in men, but in women, neither BMI nor WC affected the risk. Trunk fat mass, visceral adipose tissue (VAT) mass, and limb fat mass were negatively associated with vertebral body BMD and geometry in men and women. BMD and geometry are related to vertebral strength, but may not be directly related to the risk of fractures, which is also influenced by other factors. The binary logistic regression equation established in this study may be useful to clinicians for the prediction of vertebral fracture risks, and may provide further information to supplement the fracture risk assessment tool, which assesses general fracture risks. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Background - Dance has shown to be beneficial for people with Parkinson’s. However, there is a lack of research on ballet for this population. The present study aimed to determine the effect of weekly ballet classes on gait variability and balance confidence for people with Parkinson’s.Methods - The study follows a non-randomized, controlled project evaluation design. A group of 19 people with Parkinson’s who were already involved in weekly ballet classes volunteered for this research. A control group of 13 people with Parkinson’s were asked to not participate in dance classes across the duration of the study. Results - The study did not demonstrate significant effects of weekly ballet classes on gait variability or balance confidence. Conclusions - These findings differ from recent studies that suggest dancing can improve balance and gait for this population. There is a need to examine the optimal ballet class frequency required to elicit any potential positive change.

First described in 1978, Griscelli syndrome (GS) is a rare autosomal recessive disorder featuring pigmentary dilution of hair and skin.1 GS is caused by mutations in any of three genes encoding a tripartite protein complex essential for melanosome transport.2 GS1 (MIM214450) presents as hypomelanosis with primary neurological defects and is caused by mutations in MYO5A,3 and which also may be the same entity as Elejalde syndrome (MIM256710).4 This article is protected by copyright. All rights reserved.

Mutations in ceramide biosynthesis pathways have been implicated in a few Mendelian disorders of keratinization although ceramides are known to have key roles in several biological processes in skin and other tissues. Using whole-exome sequencing in four probands with undiagnosed skin hyperkeratosis/ichthyosis, we identified compound heterozygosity for mutations in KDSR, encoding an enzyme in the de novo synthesis pathway of ceramides. Two individuals had hyperkeratosis confined to palms and soles as well as anogenital skin, whereas the other two had more severe, generalized harlequin ichthyosis-like skin. Of note, thrombocytopenia was present in all cases. The mutations in KDSR were associated with reduced ceramide levels in skin and impaired platelet function. KDSR enzymatic activity was variably reduced in all cases resulting in defective acylceramide synthesis. Mutations in KDSR have recently been reported in inherited recessive forms of progressive symmetric erythrokeratoderma, but our study demonstrates that biallelic mutations in KDSR are implicated in an extended spectrum of disorders of keratinization in which thrombocytopenia is also part of the phenotype. Mutations in KDSR cause defective ceramide biosynthesis, underscoring the importance of ceramide and sphingosine synthesis pathways in skin and platelet biology.

Background Previous study has found that people with chronic neck pain moved with a consistently compromised acceleration/deceleration at their cervical and thoracic spines. This study examined the strength of the association between the electromyographic activities and the acceleration/deceleration of the cervical and thoracic spine, and its correlation with the functional disabilities in individuals with neck pain. Methods Time history of the cervical and thoracic acceleration/deceleration and EMG activity was acquired in thirty-four subjects with chronic neck pain and thirty-four age- and gender-matched asymptomatic subjects during active neck movements. The strength of the association between the electromyographic activity of spinal muscles and the cervical and thoracic acceleration/deceleration was determined using cross-correlation method. Relationship between the strength of this association and the severity of the functional disabilities in neck pain group was examined using correlation analysis. Findings The strength of the association between cervical and thoracic acceleration/deceleration and electromyographic activities was significantly lower in neck pain group. Significant negative correlations were found between the functional disability level and the strength of this defined association in the symptomatic group. Interpretation The compromised capability of the spinal muscles to produce acceleration/deceleration in the neck pain group may imply an impaired electromechanical coupling of these spinal muscles when performing neck movements. Significant negative correlation of the degree of functional disabilities suggests that the present approach can be used as an objective and specific evaluation of the dynamic performance of the spinal muscles and its relationship with the functional disabilities in neck pain subjects.

BACKGROUND Antrodia camphorata is proven to probably inhibit the neurotoxicity of amyloid β-peptide (Aβ), known as a risk factor toward the development of Alzheimer's disease. Deep ocean water (DOW), drawn from an ocean depth of more than 200 m, has proven to stimulate the growth and metabolite biosynthesis of fungi owing to its rich minerals and trace elements. Based on these advantages of DOW, this study used statistical response surface methodology (RSM) to investigate the effects of DOW on the growth and anti-Aβ-induced neurocytotoxicity ability of A. camphorata. RESULTS The results showed that DOW was useful for increasing the biomass of A. camphorata and enhancing its neuroprotective capability. The anti-Aβ40-induced neurocytotoxicity ability of filtrate was increased via raising the mycelium-secreted components. Furthermore, the anti-Aβ40-induced neurocytotoxicity ability of mycelium was also increased by the DOW-stimulated intracellular antioxidants. Using 80% DOW concentration, initial pH 3.3 and 20% inoculum size as the optimal culture conditions of A. camphorata significantly stimulated the biomass and mycelium-mediated Aβ40-induced cell viability from 302 ± 14 mg per 100 mL and 49.2 ± 2.2% to 452 ± 33 mg per 100 mL and 65.0 ± 7.4% respectively. CONCLUSION This study indicated that DOW could be used as a promising supplementary for the production of A. camphorata secondary metabolites with strong antioxidant activity to protect neuron cells from damage based on Aβ stimulation cytotoxicity. © 2016 Society of Chemical Industry

Background: People with Parkinson’s often move the trunk in a more in-phase pattern with reduced range of motion. No studies to date have assessed changes to trunk coordination after a dance intervention. The present study aimed to determine the effect of weekly ballet classes on trunk coordination and range of motion during gait for people with Parkinson’s. Methods: The study follows a non-randomized, controlled project evaluation design. Two inertial sensors were used to record angular displacement of the pelvis and thorax during a 10 m walk for 19 experimental participants and 13 control participants. Coordination was assessed using cross-correlation of the angular displacement of the two body regions. Results: No significant changes in trunk coordination and range of motion were found across time for both dancing and control groups (p > 0.01). There were also no significant differences between groups on all measures at different time intervals (p > 0.01). Conclusions: The present study did not demonstrate significant effects of a weekly ballet class on trunk coordination and range of motion during gait for people with Parkinson’s. There is a need to determine optimal dance class frequency and appropriate levels of overload to allow for potential physiological improvements.

Background\ud It has been found that alterations in passive muscle properties may be associated with low back pain, and these may be responsible for the altered gait parameters often observed in subjects with back pain. The purpose of the present study was to assess total hip and passive hip extensor moments in people with or without low back pain during the hip flexion component of walking.\ud Methods\ud 52 subjects volunteered for this study (low back pain group, n = 25 (male n = 13, female n = 12), control group, n = 27 (male n = 15, female n = 12)). Passive hip moments were calculated using an adapted force transducer during supine testing. A biomechanical model and predictive equation were used to calculate passive hip moments during walking. Total hip moments were calculated with the use of a 9 camera, 3-D motion-capture system.\ud Findings\ud Independent samples t-tests demonstrated no significant differences between groups for gait parameters or hip or knee angles. Results of the ANOVAs demonstrated significant differences in passive hip flexor moments during the second half of hip flexion ( P

Psychostimulant reinforcement is mediated by stimulation of both dopamine (DA) D1-like and D2-like receptors, suggesting that pharmacotherapy agents with a dual DA receptor mechanism may be useful for managing psychostimulant abuse. (-)-Stepholidine (L-SPD) is a Chinese herbal extract that functions as a D1-like receptor agonist and D2-like receptor antagonist. L-SPD has been shown to attenuate the reinforcing effects of heroin; however, its effects on the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV) have not been examined. The current study determined the effects of L-SPD on reinstatement of MDPV-seeking behavior in the drug intravenous self-administration (IVSA) and conditioned place preference (CPP) paradigms. To determine whether the effects of L-SPD were specific to psychostimulant reinforcement, we also examined its effects on sucrose-seeking behavior. Using a locomotor activity assay, we tested the locomotor effects of L-SPD, as well as its effects on MDPV-induced hyperactivity. The results of a battery of in vitro binding and functional assays confirmed that L-SPD functioned as a D1-like receptor agonist and D2-like receptor antagonist. In behavioral experiments, L-SPD dose-dependently attenuated cue plus MDPV-primed reinstatement of MDPV-seeking behavior in the IVSA model. The highest dose of L-SPD also attenuated MDPV-primed reinstatement of MDPV CPP, as well as cue-induced reinstatement of sucrose-seeking. L-SPD had no significant locomotor effects, and did not modulate the robust hyperactivity induced by MDPV. The current findings show for the first time a robust reinstatement effect with MDPV, which can be reduced by L-SPD. These results establish a role for DA receptors in drug-seeking behavior for MDPV.

\ud Purpose\ud \ud This study aimed at investigating whether association between physical activity, and bone density and muscle strength depends on daily activity pattern.\ud \ud Methods\ud \ud Loading dose of moderate-to-vigorous physical activity (MVPA) was measured using accelerometer on 54 men (Mage = 54.1 years) and 59 women (Mage = 52.1 years). Pattern of MVPA was quantified as number and length of MVPA bouts, and the length of break bouts between MVPA bouts. Knee extension torque (KET) and broadband ultrasound attenuation (BUA) of the calcaneus were also measured. Regression analysis was employed to examine the moderation effect of MVPA pattern.\ud \ud Results\ud \ud Loading dose had a larger effect on BUA (b = .002, p = .035) and KET (b = .004, p = .01) with the increase of median length of MVPA bout, but had a smaller effect on KET with the increase of maximal length of break bout (b = − .015, p = .024).\ud \ud Conclusions\ud \ud This study suggests that pattern of physical activity can influence its efficacy on muscle and bone health.

The synthesis of a new series of C-2-alkyl-2-methoxymethyl-salvinorin ethers and their binding affinities at κ-, μ-, and δ-opioid receptors are presented. We have developed a synthesis that enables installation of alkyl-substituents at C-2 while maintaining the integrity of the C-2 methoxymethyl ether and retaining κ-opioid receptor binding activity. Among these new compounds, 2-methyl-2-methoxymethyl-salvinorin ether (9a) is a potent full agonist at the κ receptor and shows comparable potency in Ki and EC50 with salvinorin A and U50488H. These C2-alkylated analogs have been identified as full κ agonists.

This study aimed to investigate the relationship between shoulder counter-rotation (SCR), hip shoulder separation (HSS) and three-dimensional spinal kinematics during fast bowling in cricket. Thirty five elite male fast bowlers were analysed using three-dimensional inertial sensors on the spine. Lumbar, thoracic and thoracolumbar kinematics were determined during the delivery stride. Spearman's pairwise correlations displayed significant associations between SCR, thoracic and thoracolumbar lateral flexion between the back foot impact and max contralateral rotation phase of the delivery stride (rs = -.462 and -.460). HSS and thoracolumbar lateral flexion displayed a significant correlation between back foot impact and max contralateral rotation (rs = -.552). No other significant correlations were observed. These results suggest SCR and HSS are modestly related to lateral flexion, leaving a large component of SCR and HSS unrelated to specific three-dimensional spinal kinematics. It is possible that this represents changes in whole spinal orientation and not resultant spinal motion. Despite this, SCR remains the only metric currently related to injury and therefore is important; however it is only a very modest proxy for more traditional descriptions of spinal motion.

Cenderitide is a novel designer natriuretic peptide (NP) composed of C-type natriuretic peptide (CNP) fused to the C-terminus of Dendroaspis natriuretic peptide (DNP). Cenderitide was engineered to coactivate the two NP receptors, particulate guanylyl cyclase (pGC)-A and -B. The rationale for its design was to achieve the renal-enhancing and antifibrotic properties of dual receptor activation, but without clinically significant hypotension. Here we report the first clinical trial on the safety, tolerability, and cyclic guanosine monophosphate (cGMP) activating properties of Cenderitide in subjects with stable heart failure (HF). Four-hour infusion of Cenderitide was safe, well-tolerated, and significantly increased plasma cGMP levels and urinary cGMP excretion without adverse effects with no change in blood pressure. Thus, Cenderitide has a favorable safety profile and expected pharmacological effects in stable human HF. Our results support further investigations of Cenderitide in HF as a potential future cGMP-enhancing therapeutic strategy.

Background - Impaired lumbo-pelvic movement in people with low back pain during bending task has been reported previously. However, the regional mobility and the pattern of the lumbo-pelvic movement were found to vary across studies. The inconsistency of the findings may partly be related to variations in the speed at which the task was executed. This study examined the effects of bending speeds on the kinematics and the coordination lumbo-pelvic movement during forward bending, and to compare the performance of individuals with and without low back pain.Methods - The angular displacement, velocity and acceleration of the lumbo-pelvic movement during the repeated forward bending executed at five selected speeds were acquired using the three dimensional motion tracking system in seventeen males with low back pain and eighteen males who were asymptomatic. The regional kinematics and the degree of coordination of the lumbo-pelvic movement during bending was compared and analysed between two groups.Results - Significantly compromised performance in velocity and acceleration of the lumbar spine and hip joint during bending task at various speed levels was shown in back pain group (p Conclusions - The present findings show that bending speed imposes different levels of demand on the kinematics and pattern of the lumbo-pelvic movement. The ability to regulate the lumbo-pelvic movement pattern during the bending task that executed at various speed levels was shown only in pain-free individuals but not in those with low back pain. Individuals with low back pain moved with a stereotyped strategy at their lumbar spine and hip joints. This specific aberrant lumbo-pelvic movement pattern may have a crucial role in the maintenance of the chronicity in back pain.

Nor Najwatul Akmal Ab Rahman,1 Devinder Kaur Ajit Singh,1 Raymond Lee2 1Physiotherapy Programme, School of Rehabilitation Sciences, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur, Malaysia; 2School of Applied Sciences, London South Bank University, London, UK Abstract: Aging is associated with alterations in thoracolumbar curvatures and respiratory function. Research information regarding the correlation between thoracolumbar curvatures and a comprehensive examination of respiratory function parameters in older adults is limited. The aim of the present study was to examine the correlation between thoracolumbar curvatures and respiratory function in community-dwelling older adults. Thoracolumbar curvatures (thoracic and lumbar) were measured using a motion tracker. Respiratory function parameters such as lung function, respiratory rate, respiratory muscle strength and respiratory muscle thickness (diaphragm and intercostal) were measured using a spirometer, triaxial accelerometer, respiratory pressure meter and ultrasound imaging, respectively. Sixty-eight community-dwelling older males and females from Kuala Lumpur, Malaysia, with mean (standard deviation) age of 66.63 (5.16) years participated in this cross-sectional study. The results showed that mean (standard deviation) thoracic curvature angle and lumbar curvature angles were -46.30° (14.66°) and 14.10° (10.58°), respectively. There was a significant negative correlation between thoracic curvature angle and lung function (forced expiratory volume in 1 second: r=-0.23, P

14 Background: ICOS is a costimulatory molecule upregulated on activated T cells. Vopra is an investigational ICOS agonist antibody that results in activation and proliferation of primed CD4 T effector cells. Vopra was assessed in heavily pretreated patients with advanced solid tumors as monotherapy (mono) or in combination with nivolumab (nivo) in the Phase 1/2 ICONIC trial (NCT02904226). Emergence of a distinct ICOS high (hi) population of peripheral CD4 T effector cells, not seen with PD-1 inhibitors alone, was associated with improved ORR, PFS and OS with vopra mono and combo therapy (AACR 2019). Baseline tumor and blood biomarkers were assessed for ability to predict ICOS hi CD4 T cell emergence and clinical outcomes. Methods: Fresh pre-treatment tumor biopsies were assessed by RS, a gene signature describing immune cell infiltration, and other biomarkers, including PD-L1 TPS by IHC. Pts were classified as RS1 and RS2 based on medium and high cutoffs. Associations between potential predictive biomarkers, ICOS hi CD4 T cell emergence and clinical outcomes were evaluated. Results: Baseline RS is significantly higher in patients with emergence of ICOS hi CD4 T cells. High RS was associated with increased emergence of ICOS hi CD4 T cells, accompanied by improved RECIST response, PFS, and OS. In contrast, no association was noted with PD-L1 IHC. Clinical trial information: NCT02904226. Conclusions: In this retrospective subset analysis, the RS score, but not PD-L1, in baseline tumor biopsies was predictive of emergence of an ICOS hi CD4 T cell population and improved RECIST response, PFS, and OS in patients treated with vopra alone and in combination with nivo. Clinical evaluation of vopra and investigational PD-1 inhibitor JTX-4014 in cancer patients with RS selection is planned. [Table: see text]

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The purpose of this study was to examine the muscular activities and kinetics of the trunk during unstable sitting in healthy and LBP subjects. Thirty-one healthy subjects and twenty-three LBP subjects were recruited. They were sat on a custom-made chair mounted on a force plate. Each subject was asked to regain balance after the chair was tilted backward at 20°, and then released. The motions of the trunk and trunk muscle activity were examined. The internal muscle moment and power at the hip and lumbar spine joints were calculated using the force plate and motion data. No significant differences were found in muscle moment and power between healthy and LBP subjects (. p>. 0.05). The duration of contraction of various trunk muscles and co-contraction were significantly longer in the LBP subjects (. p

Novel psychoactive substances (NPS) are becoming increasingly popular worldwide in recent years, some of which have been reported to cause considerable harm and even fatalities. Currently, simultaneous screening for a comprehensive panel of conventional and novel drugs of abuse is not widely available in most clinical laboratories. The aim of this study was to establish a chromatography/mass spectrometry-based analytical system for the simultaneous detection of conventional drugs of abuse and NPS in urine. Sample preparation entails enzyme digestion and solid phase extraction; analytes were then detected by liquid-chromatography tandem mass spectrometry (LC-MS/MS) with multiple reaction monitoring. Forty-seven conventional drugs (28 parent drugs, 19 metabolites) and 46 NPS analytes (44 parent drugs, two metabolites) are covered by the established method, which has been validated according to international guidelines. The method was then applied to 964 urine samples collected from drug abusers and the results revealed the presence of two NPS - TFMPP and methcathinone - as well as conventional drugs of abuse. To conclude, an LC-MS/MS method has been established that allows the simultaneous detection of over 90 conventional as well as novel psychoactive substances and metabolites in urine samples. The method was successfully applied to authentic specimens revealing the presence of conventional as well as novel drugs of abuse in the local population.

The aim of the current study was to investigate the association between loading dose of physical activity, muscle strength and bone density in middle-aged women. Thirty four healthy women (mean age = 49.8 ± 7.5. years) were recruited. They were requested to wear an accelerometer for a period of 10. h (from 9 am to 7 pm) on a day to record the acceleration. On a separate day their knee extension torque (KET) was measured using an isokinetic dynamometer and broadband ultrasound attenuation (BUA) at the heel by an ultrasound bone scanner. The loading dose of physical activity was calculated at four intensity categories - very light, light, moderate, and vigorous (intensities of < 5. BW/s, 5-10. BW/s, 10-15. BW/s and >. 15. BW/s) and for three frequency bands - 0.1-2. Hz, 2-4. Hz, and 4-6. Hz. Correlation analysis was used to examine the association between loading dose and age, KET, and BUA. With the increase of age, there tended to be a decrease in the loading dose of vigorous activity in 2-4 and 4-6. Hz frequency bands (Kendall's tau. = -. .22, p. < .1). The increase of loading dose in all three frequency bands in moderate or vigorous activity was associated with higher BUA (Kendall's tau = .27-.41, p. < .05). The increase of loading dose in all frequency bands in light, moderate, or vigorous activity was associated with higher KET (Kendall's tau = .30-.45, p. < .05). It is concluded that physical activity, especially that at high intensity level and high frequency range, may have beneficial effect on muscle strength and bone density in middle-aged women.

Huo Luo Xiao Ling Dan (HLXLD), a Chinese herbal formula composed of 11 different herbs, has been used traditionally for the treatment of arthritis and other chronic inflammatory diseases. However, the pharmacokinetic profile of its anti-inflammatory bioactive compounds has not been elucidated. Boswellic acids are the bioactive compounds with potent anti-inflammatory activity isolated from Boswellia serrate which is one of the 11 herbs of HLXLD. The objective of the study was to compare the pharmacokinetics of the two bioactive bowsellic acids: 11-keto-β-boswellic acid and 3-O-acetyl-11-keto-β-boswellic following oral administration of HLXLD or Boswellia serrata extract alone in normal and arthritic rats. An LC-MS method was developed and validated for the determination of 11-keto-β-boswellic acid and 3-O-acetyl-11-keto-β-boswellic in the comparative pharmacokinetic study. The results showed that there were significant differences in pharmacokinetic parameters between normal and arthritic groups. Interestingly, the absorptions of two boswellic acids were significantly higher in HLXLD than Boswellia serrata extract alone, indicating the synergistic effect of other herbal ingredients in HLXLD. This comparative pharmacokinetic study provided direct evidence supporting the notion that the efficacy of a complex mixture such as HLXLD is better than that of single components in treating human diseases.

STUDY DESIGN Cross-sectional study. OBJECTIVE To evaluate the dynamic stability and kinematics of the trunk during unstable sitting, and to determine the differences in these biomechanical parameters between healthy participants and participants with low back pain (LBP). SUMMARY OF BACKGROUND DATA Patients with LBP exhibited alterations in trunk kinematics while performing different dynamic tasks and in static posture as a result of pain. It is not clear if changing in trunk motion may reduce postural control and the ability to perform a balancing task. METHODS Twenty-three participants with LBP and 31 healthy participants were requested to sit on a custom-made swinging chair and to regain the balance after tilting the chair backward for 10° and 20°. Lumbar spine, pelvis, and chair motions were recorded using FASTRAK sensors. The thoracolumbar curvature of all participants was also evaluated in the standing position. The angular displacement of the chair was fitted in an equation describing the underdamped second-order response to a step input. RESULTS Kinematic analysis showed that the hip range of motion increased whereas spine range of motion angle decreased in participants with LBP for both tilt angles (P < 0.05). There were no significant differences between the 2 subject groups in the time required to regain balance, and the natural frequency and damping ratio of the kinematic equation. Lumbar lordosis significantly decreased in LBP group. CONCLUSION Participants with LBP showed trunk postural and movement adaptations that seems to be compensatory strategies to decrease the risk of further injuries and aggravation of the symptoms, but their ability to regain the balance was not affected by LBP. Clinicians should encourage patients with LBP to remain active while they are experiencing pain.

We previously reported isolation of l-isocorypalmine (l-ICP), a mono-demethylated analog of l-tetrahydropalmatine (l-THP), from the plant Corydalis yanhusuo. Here we characterized its in vitro pharmacological properties and examined its effects on cocaine-induced behaviors in mice.Receptor binding, cAMP and [(35)S]GTPγS assays were used to examine pharmacological actions of l-ICP in vitro. Effects of l-ICP on cocaine-induced locomotor hyperactivity and sensitization and conditioned place preference (CPP) in mice were investigated. HPLC was employed to analyze metabolites of l-ICP in mouse serum.Among more than 40 targets screened, l-ICP and l-THP bound only to dopamine (DA) receptors. l-ICP was a high-affinity partial agonist of D1 and D5 receptors and a moderate-affinity antagonist of D2, D3 and D4 receptors, whereas l-THP bound to only D1 and D5 receptors, with lower affinities than l-ICP. At 10mg/kg (i.p.), l-ICP inhibited spontaneous locomotor activity for a shorter time than l-THP. Pretreatment with l-ICP reduced cocaine-induced locomotor hyperactivities. Administration of l-ICP before cocaine once a day for 5 days reduced cocaine-induced locomotor sensitization on days 5 and 13 after 7 days of withdrawal. Pretreatment with l-ICP before cocaine daily for 6 days blocked cocaine-induced CPP, while l-ICP itself did not cause preference or aversion. HPLC analysis showed that l-ICP was the main compound in mouse serum following i.p. injection of l-ICP.l-ICP likely acts as a D1 partial agonist and a D2 antagonist to produce its in vivo effects and may be a promising agent for treatment of cocaine addiction.

Bleomycin (BLM), a family of anti-tumor drugs, was reported to exhibit severe side effects limiting its usage in clinical treatment. Therefore, finding adjuvants that enhance the anti-tumor effect and reduce the detrimental effect of BLM is a prerequisite. Chrysanthemum indicum, an edible flower, possesses abundant bioactivities; the supercritical-carbon dioxide fluid extract from flowers and buds of C. indicum (CISCFE) have strong anti-inflammatory, anti-oxidant, and lung protective effects. However, the role of CISCFE combined with BLM treatment on tumor-bearing mice remains unclear. The present study aimed to investigate the potential synergistic effect and the underlying mechanism of CISCFE combined with BLM in the treatment of hepatoma 22 (H22) tumor-bearing mice. The results suggested that the oral administration of CISCFE combined with BLM could markedly prolong the life span, attenuate the BLM-induced pulmonary fibrosis, suppress the production of pro-inflammatory cytokines (interleukin-6), tumor necrosis factor-α, activities of myeloperoxidase, and malondiadehyde. Moreover, CISCFE combined with BLM promoted the ascites cell apoptosis, the activities of caspases 3 and 8, and up-regulated the protein expression of p53 and down-regulated the transforming growth factor-β1 by activating the gene expression of miR-29b. Taken together, these results indicated that CISCFE could enhance the anti-cancer activity of BLM and reduce the BLM-induced pulmonary injury in H22 tumor-bearing mice, rendering it as a potential adjuvant drug with chemotherapy after further investigation in the future.