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Background and aimsInternet use has become an important part of daily living. However, for a minority it may become problematic. Moreover, problematic use of the Internet/smartphone (PUIS) has been associated with low physical activity. The present study investigated the temporal associations between three types of PUIS (i.e., problematic smartphone use [PSPU], problematic social media use [PSMU] and problematic gaming [PG]) and physical activity among Taiwanese university students.MethodsA six-month longitudinal survey study comprising three time points for assessments was conducted. From the original 974 participants, a total of 452 completed all three waves of an online survey comprising the International Physical Activity Questionnaire Short Form (IPAQ-SF) assessing physical activity level, Smartphone Application-Based Addiction Scale (SABAS) assessing PSPU, Bergen Social Media Addiction Scale (BSMAS) assessing PSMU, and Internet Gaming Disorder Short Form (IGDS9-SF) assessing PG.ResultsThe linear mixed effects model found positive temporal associations of PSMU and PG with physical activity level (PSMU: B = 85.88, SE = 26.24; P = 0.001; PG: B = 36.81, SE = 15.17; P = 0.02). PSPU was not associated with physical activity level (B = 40.54, SE = 22.99; P = 0.08). Additionally, the prevalence rates were 44.4% for at-risk/PSPU, 24.6% for at-risk/PSMU, and 12.3% for at-risk/PG.Discussion and ConclusionsPSMU and PG unexpectedly demonstrated correlations with higher physical activity level. The nature of these relationships warrants additional investigation into the underlying mechanisms in order to promote healthy lifestyles among university students.

To determine whether combined transoral robotic surgery and postoperative oropharyngeal rehabilitation are effective for reducing the severity of obstructive sleep apnea.A quasi-experimental study enrolled participants without blinding between May 2019 and April 2021.Single-center study at National Cheng Kung University Hospital.Patients with moderate to severe obstructive sleep apnea who were otherwise healthy were recruited from the ear, nose, and throat department at National Cheng Kung University Hospital. The group undergoing transoral robotic surgery with oropharyngeal rehabilitation (n = 18) received a 12-week intervention consisting of home-based rehabilitation exercises following surgery; the transoral robotic surgery group (n = 17) received surgery only; and the control group (n = 15) received conservative treatment, such as continuous positive airway pressure therapy or other oral appliance therapy. Polysomnography data and tongue muscle performance were measured before and after the interventions.The group that underwent transoral robotic surgery with oropharyngeal rehabilitation exhibited significantly improved tongue protrusion strength as compared with the transoral robotic surgery-only group, as well as significantly improved apnea-hypopnea index in the supine position vs the control group.In this study, we demonstrated the synergistic effects of transoral robotic surgery and postoperative oropharyngeal rehabilitation for adult patients with obstructive sleep apnea. Objective records should be used to monitor home-based rehabilitation exercises and examine the lasting synergistic effects.

The aim of the experiment was to investigate the effects of treadmill exercise on postthoracotomy pain and the expression of spinal pro-inflammatory and anti-inflammatory cytokines.Animals were randomly distributed into four groups: (a) sham surgery, (b) rats following 60 min thoracotomy and rib retraction (thoracotomy), (c) thoracotomy rats received treadmill training (thoracotomy+treadmill), and (d) sham surgery rats received treadmill training (sham surgery+treadmill). Treadmill workouts were started on postoperative day 10 (POD10) and lasted for 6 weeks (5 days per week). Rats were examined for cold allodynia using acetone and mechanical allodynia using von Frey hairs (in grams) at the surgical site. Spinal pro-inflammatory and anti-inflammatory cytokines were analyzed on PODs 28 and 49.Both thoracotomy and thoracotomy+treadmill groups exhibited a decrease in mechanical force thresholds (g) and an increase in scratches per min on POD10. Mechanical hypersensitivity and incremental scratches lasted from POD14 and POD49 in the thoracotomy group. Although force thresholds and scratches remained not return to baseline, incremental force thresholds (Mechanical allodynia using von Frey filament testing and cold allodynia by acetone testing were improved in thoracotomy rats after treadmill workouts.. Treadmill exercise restrained excess pro-inflammatory cytokine expression but increased anti-inflammatory cytokine level in a rib retraction model.

This study observed the cutaneous analgesic effect of adrenergic agonists when combined with lidocaine. We aimed at the usefulness of four adrenergic agonists and epinephrine as analgesics or as tools to prolong the effect of local anesthetics using a model of cutaneous trunci muscle reflex (pinprick pain) in rats. We showed that subcutaneous four adrenergic agonists and epinephrine, as well as the local anesthetic bupivacaine and lidocaine, developed a concentration-dependent cutaneous analgesia. The rank order of the efficacy of different compounds (ED

Objectives The purpose of the experiment was to estimate whether intrathecal antimalarial drugs could provoke spinal block, and their comparison with lidocaine. Methods Rats were intrathecally administrated with antimalarial agents (primaquine, chloroquine, hydroxychloroquine and amodiaquine) and lidocaine, and neurobehavioural examinations (nociception, proprioception and motor function) were assessed; n = 8 per group. One-way and two-way analysis of variance were designed to analyse data. Key findings At a concentration of 20 mM, primaquine (0.46 mg/rat) exhibited the longest duration and the most potent effect of nociceptive, proprioceptive and motor blockade (P < 0.01) among five drugs, whereas the other antimalarial drugs displayed a lesser or similar potency of spinal blockade compared with lidocaine (0.29 mg/rat). In dose-dependent studies, primaquine was more potent (P < 0.01) than lidocaine for spinal block. At ED25, ED50 and ED75 equipotent doses, primaquine produced a greater duration of spinal motor, proprioceptive and nociceptive blockade when compared with lidocaine (P < 0.01). Conclusions Primaquine, chloroquine, hydroxychloroquine and amodiaquine produced spinal blockade. Primaquine was more potent and displayed a prolonged life of local anaesthetic effect compared with lidocaine, whereas the other antimalarial drugs displayed a lesser or similar potency compared with lidocaine.

Po-Ching Huang,1 Ching-Hsia Hung,1,2 Guan-Wei Chen,3 Ciaran Cashin,3 Mark D Griffiths,4 Wen-Chi Yang5,6 &ast;, Hsiao-Wen Wang3 &ast;, Chung-Ying Lin1,7– 9&ast;, Nai-Ying Ko10 1Institute of Allied Health Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 2Department of Physical Therapy, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 3Department of Hydraulic and Ocean Engineering, College of Engineering, National Cheng Kung University, Tainan, Taiwan; 4International Gaming Research Unit, Psychology Department, Nottingham Trent University, Nottingham, UK; 5Division of Hematology and Medical Oncology, Department of Internal Medicine, E-DA Hospital, Kaohsiung, Taiwan; 6Faculty of School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan; 7Biostatistics Consulting Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 8Department of Occupational Therapy, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 9Department of Public Health, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 10Department of Nursing, College of Medicine, National Cheng Kung University, Tainan, Taiwan&ast;These authors contributed equally to this workCorrespondence: Chung-Ying Lin, Institute of Allied Health Sciences, College of Medicine, National Cheng Kung University, 1 University Rd, Tainan, 701, Taiwan, Tel +886 6-2353535 ext. 5106, Fax +886 6-2367981, Email cylin36933@gmail.comPurpose: The duties related to COVID-19 control and prevention may have caused psychological stress for the individuals in charge (eg, frontline government workers) and have reportedly led to mental health issues, such as insomnia and post-traumatic stress disorder (PTSD). However, the prevalence of these COVID-19-related disorders and their associated factors remain unclear. Therefore, the purpose of the present study was to investigate the prevalence rates of insomnia, PTSD, COVID-19-related self-stigma, and smartphone addiction, along with the identification of risk factors and protective factors for Taiwan frontline government workers with COVID-19 pandemic control duties.Methods: The survey was carried out with 151 participants between September and October 2021. All participants completed the Fear of COVID-19 Scale (assessing fear of COVID-19), Self-Stigma Scale (assessing self-stigma during the COVID-19 pandemic), Smartphone Application-Based Addiction Scale (assessing the risk of smartphone addiction), Insomnia Severity Index (assessing insomnia), Impacts of Event Scale-6 (assessing PTSD), and a self-designed set of questions assessing trait resilience.Results: The results showed that the prevalence rate was 31.1% for insomnia and 33.8% for PTSD. Furthermore, service duration (adjusted odds ratio [AOR] = 0.93; 95% confidence interval [CI] = 0.86, 0.999) and trait resilience (AOR = 0.19; 95% CI = 0.08, 0.46) were protective factors and fear of COVID-19 (AOR = 1.91; 95% CI = 1.02, 3.57) was a risk factor for insomnia. Fear of COVID-19 (AOR = 2.63; 95% CI = 1.35, 5.14), self-stigma (AOR = 3.62; 95% CI = 1.19, 11.02), and smartphone addiction (AOR = 1.09, 95% CI = 1.001, 1.19) were risk factors, and trait resilience was a protective factor (AOR = 0.58; 95% CI = 0.29, 1.17) for PTSD.Conclusion: The findings demonstrated a high prevalence of insomnia and PTSD. Risk-reducing strategies and protective factor promotion strategies are recommended to help reduce the symptoms of insomnia and PTSD among Taiwan frontline government workers.Keywords: mental health, insomnia, post-traumatic stress disorder, smartphone addiction, village officer

Background Critically compromised by upper airway anatomical impaired properties, obstructive sleep apnea (OSA) can be categorized into different phenotypic traits, mainly including oropharyngeal muscle dysfunction. The upper airway muscle strength training was targeted on oropharyngeal muscle dysfunction by re-educating the oropharyngeal muscles to maintain the upper airway patency. OSA was characterized with multilevel collapsibility of the upper airway; however, the programs are still inconsistent and the effects are unknown. Therefore, the purpose of this study was to investigate the effects of a comprehensive physical therapy on OSA. Methods Fifteen subjects with newly diagnosed moderate or severe OSA (AHI ≥ 15) were randomized into intervention and control groups. The intervention group underwent a 12-week-intervention of hospital based physical therapy, while the control group was kept on waiting for 12 weeks. Polysomnography (PSG) data, oropharyngeal and respiratory muscle performance were measured before and after intervention. Results In intervention group (n = 8), AHI was significantly improved (from 46.96 ± 19.45 to 32.78 ± 10.78 events/h, p = 0.017); in control group (n = 7), AHI was significantly increased (from 35.77 ± 17.49 to 42.96 ± 17.32 events/h, p = 0.043). While the control group remained no change between pre- and post- intervention, the intervention group demonstrated that other PSG outcomes significantly improved, including arousal index (46.04 ± 18.9 versus 32.98 ± 8.35/h), mean SpO2 (92.88 ± 2.1 versus 94.13 ± 1.46%), and oxygen desaturation index (ODI) (31.13 ± 19.48 versus 20.57 ± 7.83/h). Conclusion This comprehensive physical therapy can be prescribed for the significant clinical improvement on sleep apnea for the patients with moderate and severe OSA.

The purpose of the experiment was to study the effect of pulsed ultrasound (PUS) on post-thoracotomy pain and local tissue temperature and to correlate the findings with the alteration in spinal anti-inflammatory and pro-inflammatory cytokines. Mechanical sensitivity, subcutaneous temperature and spinal interleukin-10 (IL-10), IL-6 or tumor necrosis factor-alpha (TNF-α) expression were examined in a rat model of experimental post-thoracotomy pain. Group 1 received a sham surgery where thoracotomy was performed except for rib retraction. Group 2 underwent thoracotomy with rib retraction (TRR). Group 3 received the TRR procedure followed by PUS. Group 4 underwent the TRR procedure followed by only the massage with the ultrasound turned off. Compared with group 1 (sham), groups 2-4 showed a decrease in mechanical withdrawal thresholds on postoperative days (PODs) 10 and 11. On PODs 16, 23 and 30, group 3 (TRR+PUS-1) displayed an increase in mechanical withdrawal thresholds compared with groups 2 and 4. Subcutaneous and body temperatures in group 3 were not prominently different from group 1, group 2 (TRR only) or group 4 (TRR+PUS-0). Compared with group 2, group 3 had an increase in spinal IL-10 level on POD 30 and a decrease in spinal IL-6 or TNF-α expression on PODs 16 and 30. We concluded that mechanical hypersensitivity after TRR is postponed by PUS, and its effect continues for 3 wk. A PUS dose not increase local tissue temperature. The beneficial effect of PUS appears related to upregulation of spinal anti-inflammatory cytokine and downregulation of spinal pro-inflammatory cytokines.

This study sought to assess the cutaneous (peripheral) analgesic effects of antihistamine chlorpheniramine, compared with the long-lasting local anesthetic bupivacaine. After chlorpheniramine and bupivacaine were subcutaneously injected under the dorsal skin of the rats, the cutaneous analgesia effect was quantitatively evaluated by scoring the number to which the animal failed to react (cutaneous trunci muscle reflex). The quality and duration of chlorpheniramine and bupivacaine on infiltrative cutaneous analgesia were compared. We revealed that subcutaneous chlorpheniramine, as well as the local anesthetic bupivacaine elicited cutaneous analgesia in a dosage-dependent manner. Based on their ED50s (50% effective doses), the relative potency was found to be chlorpheniramine [1.13 (1.05–1.22) μmol]

The purpose of the study was to investigate spinal sensory and motor block by antiparkinsonian drugs (pramipexole and selegiline), and the combination of pramipexole and the local anesthetic lidocaine.Using a technique of spinal blockade in rats, the effects of pramipexole, selegiline, and coadministration of pramipexole and lidocaine on spinal blockades of motor and sensory function were investigated.Under a concentration of 100 mM, pramipexole displayed more potent and had a longer duration of nociceptive, proprioceptive, and motor block than selegiline, whereas pramipexole and selegiline were less potent in comparison to lidocaine. Pramipexole produced spinal nociceptive, proprioceptive, and motor blocks in a dose-related manner. On the EDPramipexole and selegiline were less potent than lidocaine to block sensory and motor responses. The duration of the spinal anesthetic effect of pramipexole was longer than lidocaine. At a non-effective dose, pramipexole increased the duration of efficacy of lidocaine.

Objective This study aims to evaluate the effectiveness of neural mobilization (NM) in the management of sensory dysfunction and nerve degeneration related to experimental painful diabetic neuropathy (PDN). Methods This is a pre-clinical animal study performed in the streptozocin-induced diabetic rat model. Three groups were included: a treatment group of rats with PDN receiving NM under anesthesia (PDN-NM, n = 10), a sham treatment group of rats with PDN that received only anesthesia (PDN-Sham, n = 9), and a vehicle control group with nondiabetic animals (Vehicle, n = 10). Rats in the PDN-NM and PDN-Sham groups received 1 treatment session on days 10, 12, and 14 after streptozocin injection, with a 48-hour rest period between sessions. Behavioral tests were performed using von Frey and Plantar tests. Evaluation for peripheral nerve degeneration was performed through measuring protein gene product 9.5-positive intra-epidermal nerve fiber density in hind-paw skin biopsies. All measurements were performed by a blinded investigator. Results The behavioral tests showed that a single NM session could reduce hyperalgesia, which was maintained for 48 hours. The second treatment session further improved this treatment effect, and the third session maintained it. These results suggest that it requires multiple treatment sessions to produce and maintain hypoalgesic effects. Skin biopsy analysis showed that the protein gene product 9.5-positive intra-epidermal nerve fiber density was higher on the experimental side of the PDN-NM group compared with the PDN-Sham group, suggesting NM may mitigate the degeneration of peripheral nerves. Conclusion This study demonstrated that NM may be an effective method to manage experimentally induced PDN, potentially through mitigation of nerve degeneration. Further studies are needed to develop standardized protocols for clinical use. Impact These findings provide neurophysiological evidence for the use of NM in PDN and can form the basis for the development of physical therapy-based programs in clinics.

Vaccination appears to be one of the effective strategies to control the COVID-19 pandemic. However, the challenge of vaccine hesitancy may lower the uptake rate and affect overall vaccine efficacy. Being a low-risk group in terms of serious consequences of infection, university students may possess low motivation to get vaccinated. Therefore, an expanded Protection Motivation Theory (PMT) incorporating perceived knowledge, adaptive response, and maladaptive response was proposed to investigate the COVID-19 vaccination intention among Taiwanese university students. University students (n = 924, 575 males, mean age = 25.29 years) completed an online survey during January to February 2021. The proposed expanded PMT model was examined using structural equation modeling (SEM). The results showed that perceived knowledge was significantly associated with coping appraisal (standardized coefficient (β) = 0.820, p &lt, 0.001), and coping appraisal was significantly associated with adaptive response (β = 0.852, 0.001), maladaptive response (β = 0.300, 0.001) and intention (β = 0.533, p = 0.009). Moreover, maladaptive response (β = −0.173, p = 0.001) but not adaptive response (β = 0.148, p = 0.482) was significantly and negatively associated with intention. The present study’s results demonstrated a positive path between perceived knowledge, coping appraisal, and intention among university students. Therefore, improving knowledge among this population may increase the intention to uptake the vaccine.

Relaxin/insulin-like family peptide receptor 1 (RXFP1) mediates relaxin’s antifibrotic effects and has reduced expression in the lung and skin of patients with fibrotic interstitial lung disease (fILD) including idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc). This may explain the failure of relaxin-based anti-fibrotic treatments in SSc, but the regulatory mechanisms controlling RXFP1 expression remain largely unknown. This study aimed to identify regulatory elements of RXFP1 that may function differentially in fibrotic fibroblasts.We identified and evaluated a distal regulatory region of RXFP1 in lung fibroblasts using a luciferase reporter system. Using serial deletions, an enhancer upregulating pGL3-promoter activity was localized to the distal region between -584 to -242bp from the distal transcription start site (TSS). This enhancer exhibited reduced activity in IPF and SSc lung fibroblasts. Bioinformatic analysis identified two clusters of activator protein 1 (AP-1) transcription factor binding sites within the enhancer. Site-directed mutagenesis of the binding sites confirmed that only one cluster reduced activity (−358 to -353 relative to distal TSS). Co-expression of FOS in lung fibroblasts further increased enhancer activity. In vitro complex formation with a labeled probe spanning the functional AP-1 site using nuclear proteins isolated from lung fibroblasts confirmed a specific DNA/protein complex formation. Application of antibodies against JUN and FOS resulted in the complex alteration, while antibodies to JUNB and FOSL1 did not. Analysis of AP-1 binding in 5 pairs of control and IPF lung fibroblasts detected positive binding more frequently in control fibroblasts. Expression of JUN and FOS was reduced and correlated positively with RXFP1 expression in IPF lungs.In conclusion, we identified a distal enhancer of RXFP1 with differential activity in fibrotic lung fibroblasts involving AP-1 transcription factors. Our study provides insight into RXFP1 downregulation in fILD and may support efforts to reevaluate relaxin-based therapeutics alongside upregulation of RXFP1 transcription.

We postulate that using a simple pulse oximetry monitor (POM) to detect the severity of OSA will help clinical staff confirm the need for early treatment. Hence, we compared the POM-derived oxygen desaturation index (ODI) (events/h) with the polysomnography (PSG)-derived apnea–hypopnea index (AHI) (events/h). Our study is intended to validate the SpO2 measurements and related ODI4% and ODI3% (events/h) calculations from POM associated with AHI and ODI from PSG based on 2007 and 2012 criteria. All 73 participants (mean age: 51.04 ± 13.14 years old) underwent an overnight PSG test and wore wristwatch POMs (PULSOX 300i) to automatically collect POM oxygen saturation (SpO2) data. Pearson correlation and the Bland and Altman method were used to verify the correlation between POM and PSG. We found that the POM SpO2 and the PSG2007 and PSG2012 scores were significantly highly correlated (total record time [TRT] and lowest SpO2, R2 = 0.815 and 0.817; ODI4%, R2 = 0.912 and 0.863 and ODI3%, R2 = 0.930 and 0.914). AHI was significantly correlated with ODI4% and ODI3%, but ODI3% was nonsignificantly higher (ODI4%, r = 0.955–0.929; ODI3%, r = 0.965–0.956). Both the ODI3% and the ODI4% were highly diagnostically sensitive and specific. The ODI3% score with the AHI 15 events/h cutoff was nonsignificantly higher (area under the curve [AUC] = 0.99, AHI 15 events/h; AUC = 0.95, AHI 5 events/h). We conclude that the ODI3% score is a feasible early screening alternative for patients with moderate-to-severe OSA.

The objective of the experiment was to assess the antinociceptive effect of dibucaine, bupivacaine, and epinephrine. To assess the mechanism of action of the interaction between dibucaine and epinephrine, phentolamine, a nonselective α-adrenergic antagonist, was added to the mixture.We assessed sensory blockade with these drugs by injecting 0.6 mL of drug-in-saline in the dorsal thoracolumbar area of rats; pinprick of the "wheal" formed by the injectate was the area targeted for stimulation to elicit a cutaneous trunci muscle reflex. The sensory block of dibucaine was compared with that of bupivacaine or epinephrine. Drug-drug interactions were analyzed by isobologram. Phentolamine was added to investigate the antinociceptive effect of dibucaine coinjected with epinephrine.We demonstrated that dibucaine, epinephrine, and bupivacaine produced dose-dependent skin antinociception. On the median effective dose (ED50) basis, the potency was higher for epinephrine (mean, 0.011 [95% confidence interval {CI}, 0.007-0.015] μmol) than for dibucaine (mean, 0.493 [95% CI, 0.435-0.560] μmol) (P.01), while there were no significant differences between dibucaine and bupivacaine (mean, 0.450 [95% CI, 0.400-0.505] μmol). On the equipotent basis (75% effective dose, median effective dose, and 25% effective dose), sensory block duration provoked by epinephrine was greater (P.01) than that provoked by dibucaine or bupivacaine. Coadministration of dibucaine with epinephrine produced a synergistic nociceptive block, whereas phentolamine blocked that synergistic block.The preclinical data indicated that there is no statistically significant difference between the potency and duration of dibucaine and bupivacaine in this model. Epinephrine synergistically enhances the effects of dibucaine, while phentolamine partially blocked those effects. α-Adrenergic receptors play an important role in controlling synergistic analgesic effect of dibucaine combined with epinephrine.

BackgroundTherapeutic ultrasound (TU) alleviates nerve injury-associated pain, while the molecular mechanisms are less clear. This is an investigator-initiated experimental study to evaluate the mechanisms and effects of ultrasound on prolonged post-thoracotomy pain in a rodent model.MethodsThe rats were randomly separated into four groups (n=8 per group): sham-operation (sham; group 1), thoracotomy and rib retraction (TRR; group 2), and TRR procedure followed by TU (TRR+TU-3; group 3) or TU with the ultrasound power turned off (TRR+TU-0; group 4). TU was delivered daily, beginning on postoperative day 11 (POD 11) for the next 2 weeks. Mechanical sensitivity, subcutaneous tissue temperature, and spinal substance P and interleukin-1 beta (IL-1β) were evaluated on PODs 11 and 23.ResultsGroup 3, which received ultrasound treatment (3 MHz; 1.0 W/cm2) for 5 min each day, demonstrated higher mechanical withdrawal thresholds when compared with the group without ultrasound intervention (group 2) or sham ultrasound (group 4). Ultrasound treatment also inhibited the upregulation of spinal substance P and IL-1β measured from spinal cord dorsal horns extract and increased subcutaneous temperature.ConclusionsThe results of this study suggest an increase in mechanical withdrawal thresholds and subcutaneous temperature, as well as a downregulation of spinal substance P and IL-1β, in the group which received ultrasound treatment. The regulation of spinal substance P and IL-1β may mediate potential effects of this non-invasive treatment.

Background: Cisplatin administration may induce muscle atrophy, thereby reducing the fitness level of patients with head and neck cancer (HNC). To date, only animal studies have been conducted to test the effectiveness of exercise interventions in diminishing side effects of cisplatin. Aim: To determine whether exercise training improves physical fitness and health-related quality of life (HRQoL) in patients receiving chemotherapy for Head &amp, Neck (H&amp, N). Material and methods: This pilot-randomized controlled trial was conducted on 57 participants receiving chemotherapy for HNC. The participants were randomized into an exercise group and a control group. The exercise group received moderate-intensity combined aerobic, resistance and flexibility exercises three times a week for eight weeks during chemotherapy. The control group received no specific information regarding exercise. The outcome measures including body composition, muscle strength, balance, flexibility, cardiovascular fitness and health-related quality of life (HRQoL) were assessed at baseline and eight weeks following baseline. Results: The body composition (body fat percentage, p = 0.002, skeletal muscle percentage, p = 0.008), dynamic balance (p = 0.01), muscle strength (upper extremity, p = 0.037, lower extremity, p = 0.025) and HRQoL (p = 0.001) showed a significant difference between the exercise group and the control group eight weeks following baseline. Significant deteriorations were noted in flexibility, muscle strength, cardiovascular fitness and several domains of HRQoL scale in the control group at eight weeks following baseline. Conclusions: This study found that a combined aerobic, resistance and flexibility exercise program during chemotherapy may improve physical fitness (i.e., muscle strength, balance, flexibility and body composition) and HRQoL and alleviate the deterioration of cardiovascular fitness in patients with HNC. Further research studies with large sample sizes are warranted to investigate the long-term effects of exercise in this population.

Objectives The purpose of this study was to estimate the ability of antimalarial medications to induce local infiltration analgesia. Methods Using a rat model of skin infiltration anaesthesia, the effects of antimalarial medications (primaquine, chloroquine, hydroxychloroquine and amodiaquine) were compared with the application of lidocaine. Key findings At a dose of 3 μmol, primaquine and chloroquine displayed better potency (all P < 0.05) and greater duration (all P < 0.01) of cutaneous analgesia than lidocaine, whereas the other antimalarial medications showed a similar potency and duration of cutaneous analgesia when compared with lidocaine. When a dose of 3 μmol antimalarial medication was used, primaquine was the most potent and had the longest duration of action among four antimalarial medications. The relative potency ranking (ED50, 50% effective dose) has been found to be primaquine [2.10 (1.87 – 2.37) μmol] > lidocaine [6.27 (5.32 –7.39) μmol] (P < 0.01). Infiltration analgesia of skin with primaquine had a greater duration of action than did lidocaine on the equipotent (ED25, ED50, ED75) basis (P < 0.01). Conclusions Primaquine and chloroquine have greater potency and longer lasting skin analgesia when compared with lidocaine, while the other antimalarials display a similar potency in comparison with lidocaine.

BACKGROUND Previous studies have reported that chemotherapy results in substantial long-term risk of heart failure. Exercise ameliorates exercise responses and exercise tolerance in patients receiving chemotherapy. The cardioprotective effect of real-time exercise in breast cancer is still unclear. OBJECTIVES The aim of the present study was to determine the effect of real-time moderate-to-high-intensity exercise training in women with breast cancer undergoing chemotherapy and to follow up on parameters of cardiac function and exercise capacity at different times. We hypothesized that early moderate-to-high-intensity exercise training has beneficial effects on cardiac function in women with breast cancer undergoing chemotherapy. METHODS This was a randomized controlled study that included 32 women randomly allocated into the control or exercise group. Exercise began with the first cycle of chemotherapy, and the training program was maintained during chemotherapy with 2 to 3 sessions per week for 3 months. Patients were instructed to perform moderate-to-high-intensity training with aerobic and resistance training. Outcome measurements were echocardiography and cardiopulmonary exercise test. The primary outcome was the change in left ventricle ejection fraction (LVEF). The secondary outcome was peak oxygen consumption (peak VO2). RESULTS The control group showed lower cardiac systolic function than the exercise group [mean (SD) LVEF 62% (2) and 70% (5), P

The purpose of this study was to investigate the ability of chloroquine and chloroquine in combination with vasoconstrictor epinephrine to act as a local anesthetic in skin analgesia. After subcutaneous injection of drugs in rats, the inhibition of the cutaneous trunci muscle reflex (CTMR) is designed for evaluation of the cutaneous analgesic effect. The analgesic effect of chloroquine was compared with that of bupivacaine or coadministration of chloroquine and epinephrine. Chloroquine produced exactly the same local anesthesia as bupivacaine did in a dose-dependent manner. On the ED50 (50 % effective dose) basis, the analgesic potency was chloroquine (4.81 [4.45–5.20] μmol)

Background Relaxin/relaxin family peptide receptor 1 (RXFP1) signaling is important for both normal physiology and disease. Strong preclinical evidence supports relaxin as a potent antifibrotic molecule. However, relaxin‐based therapy failed in clinical trial in patients with systemic sclerosis. We and others have discovered that aberrant expression of RXFP1 may contribute to the abnormal relaxin/RXFP1 signaling in different diseases. Reduced RXFP1 expression and alternative splicing transcripts with potential functional consequences have been observed in fibrotic tissues. A relative decrease in RXFP1 expression in fibrotic tissues—specifically lung and skin—may explain a potential insensitivity to relaxin. In addition, receptor dimerization also plays important roles in relaxin/RXFP1 signaling. Methods This review describes the tissue specific expression, characteristics of the splicing variants, and homo/heterodimerization of RXFP1 in both normal physiological function and human diseases. We discuss the potential implications of these molecular features for developing therapeutics to restore relaxin/RXFP1 signaling and to harness relaxin's potential antifibrotic effects. Results Relaxin/RXFP1 signaling is important in both normal physiology and in human diseases. Reduced expression of RXFP1 in fibrotic lung and skin tissues surrenders both relaxin/RXFP1 signaling and their responsiveness to exogenous relaxin treatments. Alternative splicing and receptor dimerization are also important in regulating relaxin/RXFP1 signaling. Conclusions Understanding the molecular mechanisms that drive aberrant expression of RXFP1 in disease and the functional roles of alternative splicing and receptor dimerization will provide insight into therapeutic targets that may restore the relaxin responsiveness of fibrotic tissues., The failure of antifibrotic effects in systemic sclerosis patients by relaxin may be the result of reduced expression of its receptor relaxin family peptide receptor 1 (RXFP1) in the fibrotic tissues. Alternative splicing and RXFP1 dimerization with other receptors also play roles in regulating relaxin/RXFP1 signaling. Molecular mechanisms underline the reduced RXFP1 expression and alternative splicing are potential therapeutic targets for restoring relaxin sensitivity in fibrotic diseases.

Emerging evidence has indicated that the perturbed expression of homocysteine (Hcy) may induce mitochondrial dysfunction and disturb bone metabolism. Sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK) are two critical sensors that regulate mitochondrial biogenesis and have been recognized as therapeutic targets in osteoarthritis (OA). This study was designed to test whether Hcy caused pro-osteoarthritic changes through modulation of SIRT1 and AMPK. Our results showed that administration of Hcy reduced the SIRT1/AMPK/PGC-1α signaling in chondrocytes, leading to mitochondrial dysfunction as a result of increased oxidative stress and apoptosis. Moreover, we demonstrated that the expression of NF-κB, COX-2, IL-8, and MMP-13 were elevated subsequent to inhibition of SIRT1/AMPK/PGC-1α/PPAR-γ pathway by homocysteine, thereby causing detrimental effects on chondrocytes. In the animal model of diet-induced hyperhomocysteinemia (HHcy), we observed the similar findings that SIRT1/PGC-1α/PPAR-γ cascades were downregulated with elevated MMP-13 and COX-2. Taken together, data from the current study revealed that the reduced SIRT1 by Hcy may contribute to degradative cartilage process, which provided insight into the etiology of OA., Highlights • Homocysteine-reduced SIRT1 leads to downregulation of phosphorylated AMPK and PGC-1α. • Homocysteine-inhibited SIRT1 results in mitochondrial dysfunction. • Homocysteine-induced oxidative stress is reversed by activation of SIRT1/AMPK/PGC-1α signaling. • Homocysteine-induced pro-apoptosis effect is rescued by overexpression of SIRT1/AMPK/PGC-1α cascades. • Expression levels of pro-inflammatory mediators and MMP13 are elevated subsequent to suppression of PPAR-γ by homocysteine.

We evaluated the interaction of dopamine-proxymetacaine and dopamine- oxybuprocaine antinociception using isobolograms.This experiment uses subcutaneous drug (proxymetacaine, oxybuprocaine, and dopamine) injections under the skin of the rat's back, thus simulating infiltration blocks. The dose-related antinociceptive curves of proxymetacaine and oxybuprocaine alone and in combination with dopamine were constructed, and then the antinociceptive interactions between the local anesthetic and dopamine were analyzed using isobolograms.Subcutaneous proxymetacaine, oxybuprocaine, and dopamine produced a sensory block to local skin pinpricks in a dose-dependent fashion. The rank order of potency was proxymetacaine (0.57 [0.52-0.63] μmol/kg)oxybuprocaine (1.05 [0.96-1.15] μmol/kg)dopamine (165 [154-177] μmol/kg; P.01 for each comparison) based on the 50% effective dose values. On the equianesthetic basis (25% effective dose, 50% effective dose, and 75% effective dose), the nociceptive block duration of proxymetacaine or oxybuprocaine was shorter than that of dopamine (P.01). Oxybuprocaine or proxymetacaine coinjected with dopamine elicited a synergistic antinociceptive effect and extended the duration of action.Oxybuprocaine and proxymetacaine had a higher potency and provoked a shorter duration of sensory block compared with dopamine. The use of dopamine increased the quality and duration of skin antinociception caused by oxybuprocaine and proxymetacaine.

Osteoarthritis (OA) is a degenerative joint disease affecting a large population of people. Although the elevated expression of PKR (double stranded RNA-dependent protein kinase) and MMP-13 (collagenase-3) have been indicated to play pivotal roles in the pathogenesis of OA, the exact mechanism underlying the regulation of MMP-13 by PKR following inflammatory stimulation was relatively unknown. The purpose of this study was to determine the signaling pathway involved in the PKR-mediated induction of MMP-13 after TNF-α-stimulation. In this study, cartilages of knee joint were obtained from OA subjects who underwent arthroplastic knee surgery. Cartilages were used for tissue analysis or for chondrocytes isolation. In results, the upregulated expression of PKR was observed in damaged OA cartilages as well as in TNF-α-stimulated chondrocytes. Phosphorylation of PKC (protein kinase C) was found after TNF-α administration or PKR activation using poly(I:C), indicating PKC was regulated by PKR. The subsequent increased activity of NADPH oxidase led to oxidative stress accumulation and antioxidant capacity downregulation followed by an exaggerated inflammatory response with elevated levels of COX-2 and IL-8 via ERK/NF-κB pathway. Activated ERK pathway also impeded the inhibition of MMP-13 by PPAR-γ. These findings demonstrated that TNF-α-induced PKR activation triggered oxidative stress-mediated inflammation and MMP-13 in human chondrocytes. Unraveling these deregulated signaling cascades will deepen our knowledge of OA pathophysiology and provide aid in the development of novel therapies., Graphical abstract fx1

Objectives The objective of this experiment was to investigate spinal anaesthetic effects of pramoxine and its comparison with bupivacaine, a long-lasting local anaesthetic. Methods After intrathecal injection, three neurobehavioural assessments, which consisted of nociceptive, proprioceptive and motor block, were constructed in rats. The effects of bupivacaine and pramoxine (four doses of each drug) in a dose-related manner were conducted to obtain the ED50 (50% effective dose). Pramoxine potency and duration at provoking spinal nociceptive, proprioceptive and motor block were compared with those of bupivacaine. Key findings We manifested that pramoxine provoked dose-relatedly spinal blockades of nociception, proprioception and motor function. Based on the ED50, the rank potency at producing spinal nociceptive, proprioceptive and motor block was bupivacaine (0.90 (0.82–1.02), 1.00 (0.92–1.08) and 1.16 (1.02–1.34) μmol/kg) greater (P < 0.01 for the differences) than pramoxine (15.47 (14.04–17.05), 16.46 (15.06–17.99), and 17.77 (16.48–19.15) μmol/kg). The spinal block duration created by bupivacaine was not predominantly different (P > 0.05 for the differences) from that created by pramoxine at the equipotent doses (ED75, ED50 and ED25). Conclusions Our preclinical experiment indicated that pramoxine elicited a dose-related spinal block, was less potent than bupivacaine and had a similar duration of spinal block compared with bupivacaine.

Coronary artery disease (CAD) is the primary critical cardiovascular event. Endothelial cell and monocyte dysfunction with subsequent extravagant inflammation are the main causes of vessel damage in CAD. Thus, strategies that repress cell death and manage unsuitable pro-inflammatory responses in CAD are potential therapeutic strategies for improving the clinical prognosis of patients with CAD. SIRT1 (Sirtuin 1) plays an important role in regulating cellular physiological processes. SIRT1 is also thought to protect the cardiovascular system by means of its antioxidant, anti-inflammation and anti-apoptosis activities. In the present study, we found that the SIRT1 expression levels were repressed and the acetylated p53 expression levels were enhanced in the monocytes of patients with CAD. LOX-1/oxidative stress was also up-regulated in the monocytes of patients with CAD, thereby increasing pro-apoptotic events and pro-inflammatory responses. We also demonstrated that monocytes from CAD patients caused endothelial adhesion molecule activation and the adherence of monocytes and endothelial cells. Our findings may explain why CAD patients remain at an increased risk of long-term recurrent ischemic events and provide new knowledge regarding the management of clinical CAD patients., Highlights • SIRT1 expression is repressed in monocytes from CAD subjects. • LOX-1 and oxidative stress were increased in monocytes from CAD subjects. • SIRT1 inhibition causes mitochondrial dysfunction and apoptosis in monocytes from CAD subjects. • Monocytes from CAD patients had an increased adherence to endothelial cells through SIRT1 repression.

Coronary artery disease (CAD) is a critical cardiovascular disease and a cause of high morbidity and mortality in this world. Hyperhomocysteinemia (HHcy) has been suggested as a risk factor for CAD. In addition, SIRT1 (sirtuin 1) has been reported to play a protective role in a variety of diseases, especially in the cardiovascular system. The main purpose of this study was to investigate the effects of exercise training on apoptosis and inflammation in HHcy animals. We also tested whether exercise protected against Hhcy-induced dysfunction of endothelium through modulation of SIRT1. C57BL mice (8 in each group) were fed with or without 1% L-methionine (w/w) in water for 4 months to induce HHcy. We found that Hhcy repressed SIRT1 and AMPK expression and increased NADPH oxidase activity. Plasma MDA, endothelium LOX-1 and p-p38 were up-regulated by Hhcy induction. NF-κB and it downstream molecules were activated under Hhcy situation, thereby promoting pro-inflammatory responses. Moreover, we also reported that Hhcy caused endothelium apoptosis involving Akt inhibition and mitochondria-dependent apoptotic pathways. Exercise training significantly protected against endothelium from Hhcy caused oxidative injuries. In addition, EX527 (SIRT1 inhibitor) reduced the therapeutic effects by exercise. Our results had indicated that exercise training prevent the development of atherosclerosis through SIRT1 activation and oxidative stress inhibition under Hhcy situation., Highlights • Exercise reversed Hyperhomocysteinemia(HHcy)-mitigated expression levels of SIRT1 and AMPK. • Exercise reduced Hyperhomocysteinemia(HHcy)-induced oxidative stress by NADPH oxidase inhibition in the aortic endothelium. • Exercise reduced the HHcy-induced activation of LOX-1 signaling. • Exercise reduces HHcy-induced apoptosis and inflammation in the aortic endothelium.

The goal of the experimental design was to assess the cutaneous analgesic effect of mexiletine by co-injection with clonidine. The effect of nociceptive block was evaluated according to the inhibition of the cutaneous trunci muscle reflex (CTMR) in response to skin pinpricks in rats. The dose-related analgesic effect of mexiletine alone or mexiletine co-administrated with clonidine was constructed after subcutaneous injection. Subcutaneous injections of mexiletine elicited dose-related cutaneous analgesia. Compared with mexiletine (1.8 μmol), adding clonidine to mexiletine (1.8 μmol) solutions for skin nociceptive block potentiated and prolonged the action ( p 0.01). Mexiletine (6 μmol) combined with clonidine extended the duration of cutaneous analgesia when compared with mexiletine (6 μmol) alone ( p 0.01). Co-administration of clonidine increases the potency and extends the duration of cutaneous analgesia by mexiletine, and the minimal dose of clonidine to intensify the analgesic effect is 0.06 μmol.

Osteoarthritis (OA) is one of the most common types of arthritis in the elderly people. It has been known that chondrocyte apoptosis occurs in OA cartilage, however, the detailed molecular mechanism remains unclear. In the current study, we aimed to elucidate the role of double-stranded RNA-dependent protein kinase R (PKR) in the TNF-&alpha, caused apoptosis in chondrocytes. Human articular chondrocytes were digested from cartilages of OA subjects who accepted arthroplastic knee surgery. Our results showed that phosphorylation of p38 MAPK was increased after TNF-&alpha, stimulation or PKR activation using poly (I:C), and TNF-&alpha, induced p38 MAPK upregulation was inhibited by PKR inhibition, suggesting phosphor-p38 MAPK was regulated by PKR. Moreover, we found that PKR participated in the p53-dependent destruction of AKT following activation of p38 MAPK. The inhibition of AKT led to the reduced expression of PGC-1&alpha, which resulted in mitochondrial dysfunction and increased oxidative stress. We showed that the reduction of oxidative stress using antioxidant Mito TEMPO lowered the TNF-&alpha, induced caspase-3 activation and TUNEL-positive apoptotic cells. The diminished apoptotic response was also observed after repression of PKR/p38 MAPK/p53/AKT/PGC-1&alpha, signaling. Taken together, we demonstrated that the aberrant mitochondrial biogenesis and increased oxidative stress in chondrocytes after TNF-&alpha, stimulation were mediated by PKR, which may contribute to the chondrocyte apoptosis and cartilage degeneration in OA.

Obstructive sleep apnea (OSA) is a sleep-related breathing disorder associated with dysfunction of oropharyngeal muscles to maintain upper airway patency during sleep. Oropharyngeal rehabilitation (OPR) was developed to restore, reconstruct, and reeducate oropharyngeal muscle function, but current protocols and effectiveness of OPR have been inconsistent. The purpose of this study was to review (1) indications of OPR, (2) protocols of OPR, and (3) effectiveness of OPR. We searched MEDLINE, EMBASE, and the Cochrane Library and then conducted both meta-synthesis and meta-analysis according to the statement of Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). A total of eight studies with 203 patients were included. By means of meta-synthesis, the patients with middle age, BMI

Patients with obstructive sleep apnea (OSA) (an obstructed airway and intermittent hypoxia) negatively affect their respiratory muscles. We evaluated the effects of a 12-week threshold inspiratory muscle training (TIMT) program on OSA severity, daytime sleepiness, and pulmonary function in newly diagnosed OSA. Sixteen patients with moderate-to-severe OSA were randomly assigned to a TIMT group and 6 to a control group. The home-based TIMT program was 30–45 min/day, 5 days/week, for 12 weeks using a TIMT training device. Their apnea-hypopnea index (AHI), Epworth sleepiness scale (ESS), and forced vital capacity (FVC) scores were evaluated pre- and post-treatment. Polysomnographic (PSG) analysis showed that 9 TIMT-group patients had positively responded (TIMT-responder group: post-treatment AHI pre-treatment). Post-treatment AHI and ESS scores were significantly (both P

Galectin-3, a biomarker linking oxidative stress and inflammation, participates in different mechanisms related to atherothrombosis, such as inflammation, proliferation, or macrophage chemotaxis. Accumulating evidence indicates that galectin-3 may also promote atherogenesis through inducing endothelial dysfunction. Lectin-like oxidized low-density lipoprotein (oxLDL) receptor-1 (LOX-1), a receptor for oxLDL uptake, contributes to oxLDL-induced endothelial dysfunction. Whether galectin-3 induces endothelial dysfunction through modulation of LOX-1-mediated signaling remains unclear. In the present study, we explored the mechanisms underlying galectin-3 enhanced cytotoxicity of oxLDL in human umbilical vein endothelial cells (HUVECs) and the role of LOX-1. Incubation of HUVECs with galectin-3 increased the expression of LOX-1 in RNA and protein levels. In addition, the expression of LOX-1 induced by oxLDL was promoted by galectin-3. However, pretreatment of LOX-1 antibody reduced LOX-1 mRNA expression level in cells with oxLDL plus galectin-3 incubation. Compared to cells treated with oxLDL alone, reactive oxygen species (ROS) generation via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and subsequent activation of p38 mitogen-activated protein kinases followed by nuclear factor kappa B (NF-κB) activation and related inflammatory responses including adhesion molecule expression, adhesiveness of monocytic cells, and IL-8 release were also aggravated in cells treated with galectin-3 combined with oxLDL. Compared to cells treated with galectin-3 plus oxLDL group. We found that LOX-1 antibody mitigated NADPH oxidase activity, p-38 up-regulation, NF-κB activation, and proinflammatory responses in cells treated with galectin-3 combined with oxLDL. We conclude that galectin-3 enhances endothelial LOX-1 expression and propose a new mechanism by which galectin-3 may promote endothelial dysfunction by inducing inflammation via LOX-1/ROS/p38/NF-κB-mediated signaling pathway.