Search

Previous studies had showed that indigenous clones of Salmonella Typhi and S. Paratyphi were originally imported from other countries in Taiwan. We presented the clinical manifestations and laboratory findings of indigenous and imported enteric fever cases in Taiwan in the current decade. We retrospectively reviewed typhoid and paratyphoid fever cases in two medical centers of Chang Gung Memorial Hospitals in 2010-2020. A total of 37 enteric fever cases including 24 typhoid fever and 13 paratyphoid fever were recorded. There were 20 indigenous cases, 16 imported cases, and one indetermined case. Splenomegaly and hepatitis were more frequent in typhoid fever than in paratyphoid fever (P 0.05). Imported cases had more ciprofloxacin non-susceptibility rate (8/16, 50.0%) than indigenous cases (2/20, 10%). Indigenous ciprofloxacin non-susceptible S. Typhi isolates were found in 2018. One indigenous S. Paratyphi B isolate was multi-drug resistant (MDR) to chloramphenicol, ampicillin, and trimethoprim/sulfamethoxazole.

Background/purpose Morbidity and mortality from typhoid and paratyphoid fever remain an important problem for public health authorities in developing countries. In countries with lower incidences, most cases occur in travelers who visit regions in which typhoid and paratyphoid fever are highly endemic. The aim was to evaluate the source and transmission dynamics of typhoid and paratyphoid fever in Taiwan by using genomic analysis. Methods During 2012–2019, 15 clinical isolates of Salmonella Typhi and S. Paratyphi A were collected. Demographic and clinical information of the infections were analyzed. We performed whole genome sequencing and evolutionary analysis on these isolates. Results Clinical and microbiological data from 7 S. Typhi and 8 S. Paratyphi A isolates in Taiwan showed epidemiological and bacterial genomic link to the infection in South and Southeast Asia. The Taiwanese typhoidal isolates also share highly similar genomes with those collected from UK, indicating global circulation of the typhoidal clones. Local transmission of the imported but indigenized international clones was observed. Mutations occurring at gyrA 83 aa, including S83Y and S83F, were identified in the ciprofloxacin-resistant strains. Conclusion Due to the advance of global transportation and communication, the transmission mode of infectious disease has been modified. Domestic typhoid and paratyphoid fever caused by international resistant clones can occur in low-incidence countries. Genome analysis showed that the indigenous clone originally imported from other countries has been circulating in Taiwan for over a decade.

Antimicrobial resistance of nontyphoidal Salmonella (NTS) is a threat to public health worldwide.A study on longitudinally collected NTS isolates from a medical center in Taiwan from 2011 to 2019 was undertaken. The multidrug resistance (MDR) and extensively drug resistance (XDR) phenotypes were determined according to internationally used definitions. Molecular serotyping was performed on the resistant NTS.Notably 16.1% (870/5412) of the isolates were MDR, while XDR accounted for 2.1% (111/5412). Both MDR and XDR NTS have increased significantly from 2011 to 2019, especially from 2015 to 2017 (MDR from 9.6% in 2015 to 23.1% 2017; XDR from 1.4% in 2016 to 4.7% in 2017). S. Anatum was the commonest NTS serotype expressing MDR and XDR, in 256/559 (45.8%) and 81/111 (73.0%) of the isolates, respectively, followed by S. Typhimurium and S. Goldcoast. Children 18 years old contributed to 69.0% of all MDR cases and 64.0% of all XDR cases; majority of them aged less than 5 years.Increasing MDR and XDR NTS is a threat to public health. MDR and XDR NTS usually caused gastroenteritis in children 5 years old. Multiple NTS serotypes expressing MDR and XDR indicate multiple food vehicles involved in the transmission. Proper food hygiene practice should never be over-reinforced.

Background Severe illness can occur in young children infected with certain types of enteroviruses including echovirus 11 (Echo11) and coxsackievirus B5 (CoxB5). The manifestations and outcomes of Echo11 and CoxB5 diseases across all ages of children remained not comprehensively characterized in Taiwan. Methods Culture-confirmed Echo11 (60 patients) or CoxB5 (65 patients) infections were identified in a hospital from 2010 to 2018. The demographics, clinical presentations, laboratory data and outcomes were abstracted and compared between the two viruses infections. Results Echo11 and CoxB5 was respectively identified in 7 (77.8%) and 2 (22.2%) of 9 calendar years. The median age of all patients was 15 months (range, 1 day–14.5 years). For infants ≤3 months old, Echo11 (23 cases) was associated with higher incidence of aseptic meningitis (35% versus 0%, P = 0.003), and a lower rate of upper respiratory tract infections (URI) (22% versus 65%, P = 0.004) compared to CoxB5 (20 cases) infections. For patients >3 months old, URI was the cardinal diagnosis (60%) for both viruses. Aseptic meningitis was also more commonly identified in elder children with Echo11 infections (27% versus 11%), though with marginal significance (P = 0.07). Acute liver failure was identified in four young infants with Echo11 infections including one neonate dying of severe sepsis and myocarditis. All patients with CoxB5 infections recovered uneventfully. Conclusion Aseptic meningitis, sepsis-like illness and acute liver failure were more commonly identified in children with Echo11 than those with CoxB5 infections, suggesting greater neurological tropism and virulence toward Echo11.

Background: Craniopharyngiomas are benign tumors of embryologic origin located in the sellar region. Patients have both neurological and endocrinological symptoms. Symptoms may be subtle in the early clinical course, which leads to delayed diagnosis. This study evaluated the clinical and endocrinological manifestations of childhood-onset craniopharyngioma. Methods: We retrospectively reviewed medical records of 45 children diagnosed as having craniopharyngioma between 1995 and 2019. We collected data on clinical symptoms and signs, height, weight, biochemical and hormone data, images, operation records, and pathology reports. A three-graded classification system was applied to define the degree of hypothalamic damage (HD). We analyzed clinical and endocrinological manifestations among patients with and without obesity, with short and normal stature, and with differing degrees of HD. Results: Clinical endocrinologic manifestations included adrenocortical insufficiency (42%), central hypothyroidism (37%), short stature (31%), obesity (20%), weight

Mitochondria dysfunction is implicated in the pathogenesis of cardiovascular diseases (CVD). Exercise training is potentially an effective non-pharmacological strategy to restore mitochondrial health in CVD. However, how exercise modifies mitochondrial functionality is inconclusive. We conducted a systematic review using the PubMed; Scopus and Web of Science databases to investigate the effect of exercise training on mitochondrial function in CVD patients. Search terms included “mitochondria”, “exercise”, “aerobic capacity”, and “cardiovascular disease” in varied combination. The search yielded 821 records for abstract screening, of which 20 articles met the inclusion criteria. We summarized the effect of exercise training on mitochondrial morphology, biogenesis, dynamics, oxidative capacity, antioxidant capacity, and quality. Amongst these parameters, only oxidative capacity was suitable for a meta-analysis, which demonstrated a significant effect size of exercise in improving mitochondrial oxidative capacity in CVD patients (SMD = 4.78; CI = 2.99 to 6.57; p < 0.01), but with high heterogeneity among the studies (I2 = 75%, p = 0.003). Notably, aerobic exercise enhanced succinate-involved oxidative phosphorylation. The majority of the results suggested that exercise improves morphology and biogenesis, whereas findings on dynamic, antioxidant capacity, and quality, were inadequate or inconclusive. A further randomized controlled trial is clearly required to explain how exercise modifies the pathway of mitochondrial quantity and quality in CVD patients.

Background/Purpose Post-stroke dysphagia is a frequent complication. Although most patients with dysphagia recover after the acute phase, some patients require long-term enteral feeding, either through a nasogastric (NG) or gastrostomy tube; the effectiveness of using either tube is still under debate. This study elucidated the natural course of NG tube installation and removal and examined the predictors and associating factors based on clinical and brain imaging data. Methods This retrospective cohort study with medical record reviews recruited patients received NG tube installation after their acute stroke events between January 1, 2016, and December 31, 2016. Inclusion criteria were subjects above 20 years of age and with a diagnosis of a newly onset stroke except SAH whose comprehensive clinical and imaging data were available. Survival analysis was performed for the right-censored data because some patients were lost to follow-up after discharge or transferal. Results In total we recruited 135 patients. Among these patients, the timing of their NG tube removal reached a plateau at 12–16 weeks after stroke. The modified Rankin score on discharge, representing the overall subacute disease status, was the most significant factor. Other clinical variables could be divided into 2 categories: baseline patient characteristics and stroke event severity. Moreover, semi-quantitative brain imaging scores corresponding to the aforementioned 3 categories were correlated significantly. Conclusion In Taiwan, the NG tube removal rate reached a plateau at around 12–16 weeks after stroke onset. Variables related to long-term NG tube use were divided into baseline characteristics of patient and stroke event severity.

Cantharidic acid (CA) is the hydrolysis product of the acid anhydride cantharidin, which is a natural toxin secreted by several species of blister beetles. Several studies have indicated that as an inhibitor of protein phosphatase 2 (PP2A), CA induces apoptosis in various human cancer cells. However, the effect of CA on human nasopharyngeal carcinoma (NPC) cells and the underlying pathways have not been addressed. In our current study, we tested the hypothesis that CA treatment reduces the viability of human NPC cells (HONE-1, NPC-39, and NPC-BM) by inducing apoptosis. Results indicated that CA markedly reduced cell viability, which was revealed by the upregulation of caspase activation in extrinsic and intrinsic apoptosis pathways as well as the upregulation of extracellular-signal-regulated kinase 1/2 (ERK1/2), p38, and c-Jun N-terminal kinase 1/2 (JNK1/2) pathways. Coadministration of a p38 inhibitor (SB203580) with CA abolished the activation of caspase proteins. These findings indicated that CA treatment leads to apoptosis in human NPC cells through the upregulation of caspase activation, mediated particularly by the p38 pathway. Hence, CA is a promising therapeutic agent for human NPC.

This study investigated fatigue-related modulation of common neural inputs to motor units (MUs) under 5 Hz, which determines force precision control. Twenty-seven adults performed a sequence of fatiguing contractions. The participants were assessed with a static isometric index abduction at 20% maximal voluntary contraction in the pre-test and post-test. Discharge characteristics of MUs of the first dorsal interosseous muscle were analyzed with decomposed EMG signals. Along with increases in the mean (58.40 ± 11.76 ms → 62.55 ± 10.83 ms, P = 0.029) and coefficient of variation (0.204 ± .014 → 0.215 ± 0.017, P = 0.002) in inter-spike intervals, the fatiguing contraction caused reductions in the mean frequency (16.84 ± 3.31 Hz → 15.59 ± 3.21 Hz, P = 0.027) and spectral dispersions (67.54 ± 4.49 → 62.64 ± 6.76 Hz, P = 0.007) of common neural drive, as estimated with smoothed cumulative motor unit spike trains (SCMUSTs). Stabilogram diffusion analysis of SCMUSTs revealed significant fatigue-related reductions in the long-term effective diffusion coefficient (1.91 ± 0.77 Hz2/s → 1.61 ± 0.61 Hz2/s, P = 0.020) and long-term scaling exponent (0.480 ± 0.013 Hz2/s → 0.471 ± 0.017 Hz2/s, P = 0.014). After fatiguing contraction, mutual information of force fluctuations and SCMUSTs was augmented roughly by 12.95% (P = 0.041). Muscular fatigue could compress and shift the low-frequency common drive to MUs toward lower spectral bands, thereby enhancing transmission of twitch forces through the muscle–tendon complex with a low-pass filter property. The fatigue-induced changes involve increased closed-loop control of the common modulation of MU discharge rates.

Introduction The failure of immune checkpoint inhibitor (ICPi) on glioblastoma (GBM) treatment underscores the need for improving therapeutic strategy. We aimed to change tumor associated macrophage (TAM) from M2 type (anti-inflammatory) to M1 (pro-inflammatory) type to increase the therapeutic response of ICPi. We proposed that combined rapamycin (R) and hydroxychloroquine (Q) preferentially induce M2 cells death, as fatty acid oxidation was their major source of energy. Methods Macrophage polarization was characterized on mice and human macrophage cell lines by specific cytokines stimulation with or without RQ treatment under single culture or co-culture with GBM cell lines. Tumor sizes were evaluated on subcutaneous and intracranial GL261 mice models with or without RQ, anti-PD1 mAb treatment. Tumor volumes assessed by MRI scan and proportions of tumor infiltrating immune cells analyzed by flow cytometry were compared. Results In vitro RQ treatment decreased the macrophages polarization of M2, increased the phagocytic ability, and increased the lipid droplets accumulation. RQ treatment decreased the expression levels of CD47 and SIRPα on tumor cells and macrophage cells in co-culture experiments. The combination of RQ and anti-PD1 treatment was synergistic in action. Enhanced the intra-tumoral M1/M2 ratio, the CD8/CD4 ratio in the intracranial GL261 tumor model after RQ treatment were evident. Conclusion We provide a rationale for manipulating the macrophage phenotype and increased the therapeutic effect of ICPi. To re-educate and re-empower the TAM/microglia opens an interesting avenue for GBM treatment. Graphic Abstract

This study contrasted the stochastic force component between young and older adults, who performed pursuit tracking/compensatory tracking by exerting in-phase/antiphase forces to match a sinusoidal target. Tracking force was decomposed into the force component containing the target frequency and the nontarget force fluctuations (stochastic component). Older adults with inferior task performance had higher complexity (entropy across time; p = .005) in total force. For older adults, task errors were negatively correlated with force fluctuation complexity (pursuit tracking: r = −.527 to −.551; compensatory tracking: r = −.626 to −.750). Notwithstanding an age-related increase in total force complexity (p = .004), older adults exhibited lower complexity of the stochastic force component than young adults did (low frequency: p = .017; high frequency: p = .035). Those older adults with a higher complexity of stochastic force had better task performance due to the underlying use of a richer gradation strategy to compensate for impaired oscillatory control.

Acinetobacter baumannii emerged as one of the most important pathogens that causes nosocomial infections due to its increased multidrug resistance. Identifying capsular epidemiology in A. baumannii can aid in the development of effective treatments and preventive measures against this emerging pathogen. Here we established a wzc-based method, and combined it with wzy-PCR to determine capsular types of A. baumannii causing nosocomial bacteraemia collected at two medical centres in Taiwan from 2015 to 2017. Among the 237 patients with A. baumannii bacteraemia, 98 (41.4%) isolates were resistant to carbapenems. Four prevalent capsular types (KL2, KL10, KL22, and KL52) accounted for 84.7% of carbapenem-resistant A. baumannii (CRAB) and 12.2% of non-CRAB. The rate of pneumonia, intensive care unit admission, APACHE II score, and Pitt bacteraemia score were higher in patients with KL2/10/22/52 infection than in those with non-KL2/10/22/52 infection. Patients with KL2/10/22/52 infection and patients with CRAB infection have a higher cumulative incidence of attributable and all-cause in-hospital 30-day mortality. On multivariate analysis, appropriate empirical antimicrobial therapy within 24 h was associated with a lower risk of 30-day attributable mortality in the KL2/10/22/52 isolates (odds ratio = 0.19, 95% CI: 0.06–0.66, p = 0.008) but not in non-KL2/10/22/52 isolates. Early recognition of carbapenem resistance-associated capsular types may help clinicians to promptly implement appropriate antimicrobial therapy for improving the outcomes in patients with CRAB bacteraemia.

The apelin receptor (APJ), a receptor for apelin and elabela/apela, induces vasodilation and vasoconstriction in blood vessels. However, the prolonged effects of increased APJ-mediated signalling, involving vasoconstriction, in smooth muscle cells have not been fully characterized. Here, we investigated the vasoactive effects of APJ gain of function under the control of the smooth muscle actin (SMA) gene promoter in mice. Transgenic overexpression of APJ (SMA-APJ) conferred sensitivity to blood pressure and vascular contraction induced by apelin administration in vivo. Interestingly, ex vivo experiments showed that apelin markedly increased the vasoconstriction of isolated aorta induced by noradrenaline (NA), an agonist for α- and β-adrenergic receptors, or phenylephrine, a specific agonist for α1-adrenergic receptor (α1-AR). In addition, intracellular calcium influx was augmented by apelin with NA in HEK293T cells expressing APJ and α1A-AR. To examine the cooperative action of APJ and α1A-AR in the regulation of vasoconstriction, we developed α1A-AR deficient mice using a genome-editing technique, and then established SMA-APJ/α1A-AR-KO mice. In the latter mouse line, aortic vasoconstriction induced by a specific agonist for α1A-AR, A-61603, were significantly less than in SMA-APJ mice. These results suggest that the APJ-enhanced response requires α1A-AR to contract vessels coordinately.

Patients with severe carpal tunnel syndrome (CTS) undergo carpal tunnel release (CTR) surgery to alleviate pressure in the carpal tunnel. However, the subsequent lack of the transverse carpal ligament (TCL) causes the bowstring phenomenon of the flexor tendons and increases the potential incidence of trigger finger.This study aimed to investigate the effects of various compressive forces on the flexor tendon and identify the appropriate force needed to mitigate the bowstring effect of those flexors.Cross-sectional repeated measures comparison.Thirteen CTS patients who underwent CTR surgery were asked to flex the middle finger while applying different external compressive forces, just contact, 4N, and 8N force, over the carpal tunnel. Images of the flexor tendon within the carpal tunnel and at the metacarpal phalangeal (MCP) joint were recorded via ultrasound.Results show that the compression force limited the volar migration of the flexor tendon under maximal voluntary contraction (MVC) conditions. Entrance angles between the flexor tendon and metacarpal bone also decreased as the external compressive force increased.Findings of this study may indicate that applying compression force on the carpal tunnel is useful for CTS patients and can inhibit the volar shift of the flexor digitorum superficialis (FDS) tendon after surgery, which may further prevent trigger finger.

Atrial enlargement in response to pathological stimuli (e.g., hypertension, mitral valve disease) and physiological stimuli (exercise, pregnancy) can be comparable in magnitude, but the diseased enlarged atria is associated with complications such as atrial fibrillation (AF), whereas physiological atrial enlargement is not. Pathological atrial enlargement and AF is also observed in a small percentage of athletes undergoing extreme/intense endurance sport and pregnant women with preeclampsia. Differences between physiological and pathological atrial enlargement and underlying mechanisms are poorly understood. This review describes human and animal studies characterizing atrial enlargement under physiological and pathological conditions and highlights key knowledge gaps and clinical challenges, including: 1) the limited ability of atria to reverse remodel; and 2) distinguishing physiological and pathological enlargement via imaging/biomarkers. Finally, this review discusses how targeting distinct molecular mechanisms underlying physiological and pathological atrial enlargement could provide new therapeutic and diagnostic strategies for preventing or reversing atrial enlargement and AF.

Background Mycoplasma pneumoniae is a major pathogen for community-acquired pneumonia and frequently causes outbreaks in children. M. pneumoniae-specific antibody response is detected upon acute infection and the serology is widely used in the clinical setting. Nevertheless, the cellular basis for antigen-specific antibody response to acute M. pneumoniae infection is largely undetermined in children. Methods Hospitalized children with community-acquired pneumonia were enrolled and the infection with M. pneumoniae was confirmed with positive PCR result and negative findings for other pathogens. The M. pneumoniae P1-specific antibody-secreting B cell (ASC) response was examined with the ex vivo enzyme-linked immunosorbent spot assay and the relationships between the ASC frequency and serological level and clinical parameters within M. pneumoniae patients were studied. Results A robust M. pneumoniae P1-specific ASC response was detected in the peripheral blood among M. pneumoniae-positive patients. By contrast, no M. pneumoniae-specific ASCs were detected among M. pneumoniae-negative patients. The IgM-secreting B cells are the predominant class and account for over 60% of total circulating M. pneumoniae-specific ASCs in the acute phase of illness. The M. pneumoniae P1-specific ASC frequency significantly correlated with the fever duration, and the IgG ASC frequency significantly correlated with serological titer among patients. Conclusion A rapid and potent elicitation of peripheral M. pneumoniae-specific ASC response to acute infection provides the cellular basis of antigen-specific humoral response and indicates the potential of cell-based diagnostic tool for acute M. pneumoniae infection. Our findings warrant further investigations into functional and molecular aspects of antibody immunity to M. pneumoniae.

Background/purpose Superspreading events (SSEs) are pivotal in the spread of SARS-CoV-2. This study aimed to investigate an SSE of COVID-19 in a hospital and explore the transmission dynamics and heterogeneity of SSE. Methods We performed contact tracing for all close contacts in a cluster. We did nasopharyngeal or throat swabbing for SARS-CoV-2 by real-time RT-PCR. Environmental survey was performed. The epidemiological and clinical characteristics of the SSE were studied. Results Patient 1 with congestive heart failure and cellulitis, who had onset of COVID-19 two weeks after hospitalization, was the index case. Patient 1 led to 8 confirmed cases, including four health care workers (HCW). Persons tested positive for SARS-CoV-2 were HCW (n = 4), patient 1's family (n = 2), an accompanying person of an un-infected in-patient (n = 1), and an in-patient admitted before the SSE (n = 1). The attack rate among the HCW was 3.2 % (4/127). Environmental survey confirmed contamination at the bed rails, mattresses, and sink in the room patient 1 stayed, suggesting fomite transmission. The index case's sputum remained positive on illness day 35. Except one asymptomatic patient, at least three patients acquired the infection from the index case at the pre-symptomatic period. The effective reproduction number (Rt) was 0.9 (8/9). Conclusion The host factor (heart failure, longer viral shedding), transmissibility of SARS-CoV-2 (Rt, pre-symptomatic transmission), and possible multiple modes of transmission altogether contributed to the SSE. Rapid response and advance deployment of multi-level protection in hospitals could mitigate COVID-19 transmission to one generation, thereby reducing its impact on the healthcare system.

Female carriers with X-linked chronic granulomatous disease (XL-CGD) who have 10% reactive oxygen species (ROS) production due to profound X-chromosome inactivation (XCI or lyonization) are more susceptible to infections. We assessed ROS production in Taiwanese female carriers with XL-CGD to investigate whether the level of ROS correlated to their clinical features of infection, autoimmunity, and autoinflammation.Clinical course, ROS production, flavocytochrome b558 (Cyto b558) expression, and genetic analysis in carriers were investigated after identifying their index cases between 2004 and 2019.A total of 19 mothers (median 27 years; range 25-60 years) and three of four girls (range 4-6 years) relative to 22 male index XL-CGD cases from 19 unrelated families were enrolled. Approximately half (8/19, 42%) of the mothers had novel one-allele mutations. Twenty-two of the 23 females were carriers. One carrier with de novo [Arg290X]CYBB who suffered from refractory salmonella sepsis and chorioretinitis as an XL-CGD phenotype had extreme XCI, absent Cyto b558 expression, and only 8% ROS production. The remaining carriers had bimodal patterns of Cyto b558 expressions (median 40.2%, 26.8-52.4%) and ROS production (38.3%, range 28.2-54.2%) sufficient to prevent significant infections, although neck lymphadenitis recurred in one mother and sister who had ROS expressions of 28.2% and 38.0%, respectively. However, none of the carriers had manifestations of autoimmunity or autoinflammation (e.g., photosensitivity, aphthous stomatitis, or joint disorders), of which each was seen in approximately one-third of XL-CGD carriers from the Western world.One carrier had undetectable Cyto b558 expression and an extremely low ROS production, and consequently presented with an XL-CGD phenotype. One mother and her daughter experienced recurrent neck lymphadenitis despite having sufficient ROS production. Significant autoimmunity/autoinflammation did not develop in any of the carriers. Studies with a longer follow-up period are needed to validate our findings.

Proximal tibiofibular joint (PTFJ) instability is uncommon, resulting from violent twisting motions of the flexed knee during sport activities. No known image variables functionally relate the degrees of PTFJ instability.This study used ultrasound imaging to quantify the discrimination threshold for PTFJ instability and relevant functional significances.Twenty patients (mean age: 42.7 (21-59) years) with chronic PTFJ instability participated in this study. Along with the Knee Injury and Osteoarthritis Outcome Score (KOOS),the tibiofibular distances of the affected and unaffected knees were estimated with ultrasonography in the four standardized conditions at 90° of flexion of the hip and knee, including neutrally relaxed position, passive internal rotation, passive external rotation, and forceful flexion of the knee joint.During forceful knee flexion, the absolute tibiofibular distance in the affected leg (28.1 ± 4.0 mm) was greater than the unaffected leg (25.1 ± 3.7 mm). Relative changes in tibiofibular distance (RTFD) were different for both legs (affected leg:3.9 ± 2.7 mm; unaffected leg:1.0 ± 1.4 mm) (P 0.001). The area under the receiver operator characteristic curve for the RTFD was a potent predictor of PTFJ instability (84.5%) with specificity of 95% and sensitivity of 65%. Patients with RTFD greater than 2.95 mm exhibited higher scores on the KOOS subscales of pain (P = 0.043) and quality of life (P = 0.009).Ultrasonic measurement of the tibiofibular distance under forceful knee flexion is clinically valuable for diagnosing PTFJ instability with functional significance.

During radiotherapy for head and neck tumours, the oral cavity and cheek area would be inevitably exposed to high energy radiation; thus, the material surface of the teeth, dental restorations with high atomic number, or alloy prosthodontics would generate backscatter electrons that cause the buccal mucosa adjacent to these materials to receive localized high dose enhancement, which primarily leads to side effects or oral mucositis. Based on the size of the adult oral cavity, this study aimed to use acrylic resin to create an oral phantom with two grooves on the left and right sides for placement of three molars. Moreover, the distance between the inner cheek and the side surface of the teeth could be accurately adjusted every 1 mm from 0 to 5 mm. This enhanced the dose in the buccal mucosa during head and neck radiotherapy and made the distribution measurement of the radiation dose simple and feasible at different depths (0-5 mm). Meanwhile, the study employed the film type optically stimulated luminescent dosimeter with a thickness of 0.3 mm to measure the absorbed dose inside the buccal mucosa to reduce the dose interference from radiotherapy. The study fixed three real molars in a row located at the left side of the phantom and employed 6 MV photons and intensity-modulated radiotherapy (IMRT) to treat and simulate oral cancer and measure the attenuation of the molar's backscatter dose from 0 to 5 mm in an up beam direction. The result showed that, in every 3 mm, the phantom had attenuated the enhancement of backscatter dose

Although force steadiness varies with visuospatial information, accountable motor unit (MU) behaviors are not fully understood. This study investigated the modulation of MU discharges and force–discharge relation due to variations in the spatial resolution of visual feedback, with a particular focus on discharge variability among MUs. Fourteen young adults produced isometric force at 10% of maximal voluntary contraction (MVC) through index abduction, under the conditions of force trajectory displayed with low visual gain (LVG) and high visual gain (HVG). Together with smaller and more complex force fluctuations, HVG resulted in greater variabilities of the mean interspike interval and discharge irregularity among MUs than LVG did. Estimated via smoothening of a cumulative spike train of all MUs, global discharge rate was tuned to visual gain, with a more complex global discharge rate and a lower force–discharge relation in the HVG condition. These higher discharge variabilities were linked to larger variance of the common drive received by MUs for regulation of muscle force with higher visuospatial information. In summary, higher visuospatial information improves force steadiness with more complex force fluctuations, underlying joint effects of low-pass filter property of the musculotendon complex and central modulation of discharge variability among MUs.

The emergence and spread of a novel coronavirus (SARS-CoV-2) from Wuhan, China, have become a Public Health Emergency of International Concern, designated by World Health Organization. As of February 26, 2020, the National Health Commission of the People's Republic of China has received a total of 77,663 confirmed cases from across China. As of February 26, 126 confirmed cases were reported from Hong Kong (HK), Macao, and Taiwan, and 1804 from 37 countries worldwide. During the previous outbreaks of Severe Acute Respiratory Syndrome (SARS) in HK and Middle East Respiratory Syndrome (MERS) in South Korean, very few pediatric patients were reported, respectively. Despite a high mortality rate of SARS and MERS in the adults, there were no fatalities in the pediatric patients. Children appeared to have a milder form of the disease caused by the coronaviruses, including SARS-CoV-2.

This study investigated age-related changes in behavioral and neural complexity for a polyrhythmic movement, which appeared to be an exception to the loss of complexity hypothesis. Young (n = 15; age = 24.2 years) and older (15; 68.1 years) adults performed low-level force-tracking with isometric index abduction to couple a compound sinusoidal target. Multiscale entropy (MSE) of tracking force and inter-spike interval (ISI) of motor unit (MU) in the first dorsal interosseus muscle were assessed. The MSE area of tracking force at shorter time scales of older adults was greater (more complex) than that of young adults, whereas an opposite trend (less complex for the elders) was noted at longer time scales. The MSE area of force fluctuations (the stochastic component of the tracking force) were generally smaller (less complex) for older adults. Along with greater mean and coefficient of ISI, the MSE area of the cumulative discharge rate of elders tended to be lower (less complex) than that of young adults. In conclusion, age-related complexity changes in polyrhythmic force-tracking depended on the time scale. The adaptive behavioral consequences could be multifactorial origins of the age-related impairment in rate coding, increased discharge noises, and lower discharge complexity of pooled MUs.

Background Post-surgical prognosis is usually poor for combined hepatocellular cholangiocarcinoma (CHCC-CC), a rare primary liver cancer. Although midkine (MK) is a prognostic biomarker for several known cancers, it is not known whether it can be used as such in resectable CHCC-CC. This study examined whether MK expression can predict recurrence and survival in patients with resectable CHCC-CC. Methods We retrospectively enrolled 52 patients with resectable CHCC-CC who had received curative hepatic resections. MK expression was assessed in post-surgical immunohistochemical studies of specimens in paraffin blocks. Clinical outcomes were analyzed from medical records. Results Two-year disease-free and three-year overall survival rates were 42.1% and 44.6%. MK was expressed in 30 patients. Univariate analysis showed patients positively expressing MK had a significantly poorer 2-year disease free and three-year overall survival. Multivariate analysis found positive MK expression independently predicted recurrence. Conclusions Positive expression of MK predicts poor prognosis in patients with resectable CHCC-CC.

Visual feedback that provides error information is critical to task quality and motor adjustments. This study investigated how the size of perceived errors via visual feedback affected rate control and force gradation strategy of a designate force task. Fourteen young adults coupled force exertions to a compound sinusoidal signal (0.2 Hz and 0.5 Hz) that fluctuated around a mean level of 30% of maximal voluntary contraction, when the size of execution errors were differently scaled with the error amplification factors. In the low (LAF) and high (HAF) amplification factor conditions, the execution errors in the visual display half and double of the real errors, respectively. The visualized error was the real errors in the medium amplification factor (MAF) condition. In addition to a phase-lead of force output, the LAF condition that virtually reduced the size of error feedback associated with a poorer task accuracy than the MAF and HAF conditions. Virtual increase in error size of visual feedback selectively suppressed the fast target force at 0.5 Hz. In addition, complexity and high-frequency components (>0.75 Hz) of force outputs multiplied progressively with increasing error size. Error-enhancing feedback suppressed fast target force, accentuating the use of error information to tune force output, whereas error-reducing feedback enhanced fast target force in favor of predictive force control.

Oxidative stress-induced lymphocyte apoptosis is linked to hypoxemic individuals suffering from cardiopulmonary disorders or exposed to hypoxic environments. What kind of the exercise strategy under hypoxic condition improves exercise performance and simultaneously minimizes lymphocyte dysfunction caused by oxidative stress has not yet been established. This study elucidates how various exercises regimens with/without hypoxia affect lymphocyte apoptosis induced by oxidative stress. A total of 60 sedentary males were randomly divided into five groups. Each group (n = 12) received one of the five interventions: hypoxic-absolute exercise (HAT, 50%Wmax under 15%O2), hypoxic-relative exercise (HRT, 50% heart rate reserve under 15%O2), normoxic exercise (NT, 50%Wmax under 21%O2), hypoxic control (HC, resting under 15%O2), or normoxic control (NC, resting under 21%O2) for 30 min/day, 5 days/week for 4 weeks. Before the intervention, the graded exercise test (GXT, progressive exercise up to VO2max) decreased the surface thiol level on lymphocytes and subsequently augmented the extents of H2O2-induced mitochondria transmembrane potential (MTP) diminishing, caspase 3/8/9 activations, and phosphotidyl serine (PS) exposure in lymphocytes. However, 4 weeks of NT, HRT, or HAT reduced the extents of surface thiol decreasing on lymphocytes and H2O2-induced MTP diminishing, caspase 3/8/9 activations, and PS exposure in lymphocytes following GXT. Moreover, the HAT group exhibited greater improvements in pulmonary ventilation and VO2max than either NT or HRT group did. Exercise training with/without hypoxic exposure effectively alleviates lymphocyte apoptosis induced by oxidative stress following strenuous exercise. However, the HAT is superior to the NT or HRT for enhancing aerobic capacity.

Background The most severe form of pneumococcal disease is invasive pneumococcal disease (IPD), including empyema, sepsis and meningitis. Thomsen-Friedenreich antigen (TA; Galβ1-3GalNAc) activation is known to be a predictor of Streptococcus pneumoniae-associated hemolytic uremic syndrome (Sp-HUS). There have been limited data to correlate TA activation and overall disease severity of IPD in children. The study aimed to prove the positive correlation between TA activation and disease severity and to demonstrate the trend of TA level during the disease course. Methods We retrospectively reviewed the medical records from 38 pediatric patients aged from 0 to 18 years with microbiologically-confirmed IPD between 2010 and 2015 at a medical center in Taiwan. All cases underwent TA activation testing by the fluorescence-labeled peanut lectin agglutination method. Medical information including demographic data, laboratory findings, co-morbidities, and outcome was collected and reviewed. We compared the clinical manifestations and associated co-morbidities between TA-positive and TA-negative patients. Results Among the 38 patients, 25 (66%) showed TA activation. Compared to TA-negative patients, patients with TA activation had a statistically higher rate of prolonged anemia, thrombocytopenia, and acute kidney injury. TA-positive patients also had a longer intensive care unit stay and overall hospitalization days. The TA levels usually peaked 5–10 days after disease onset. Twenty-one pneumococcal isolates were recovered from the patients and serotyping was determined in 11 isolates: 10 serotype 19A and 1 serotype 3. Conclusions TA determination not only helps to diagnose Sp-HUS but also is a predictor for IPD severity. Among hospitalized patients with severe pneumococcal disease, the peak of TA level usually appeared 5–10 days after disease onset.

Objectives Mycoplasma pneumoniae is currently the most commonly detected bacterial cause of childhood community-acquired pneumonia in several countries. Of note, clonal expansion of macrolide-resistant ST3 occurred in Japan and South Korea. An alarming surge in macrolide resistance complicates the treatment of pneumonia. We aimed to evaluate the clinical manifestation and clonal relatedness of M. pneumoniae circulating among children in Taiwan. Methods We prospectively enrolled 626 children with radiologically confirmed pneumonia between 2017 and 2019. An M. pneumoniae infection was suspected on clinical grounds, and tested by real-time PCR and oropharyngeal swab cultures. We used multilocus sequence typing and whole-genome sequencing to characterize the genetic features of M. pneumoniae. Results A total of 226 children with M. pneumoniae pneumonia were enrolled. Macrolide resistance was found in 77% (174/226) of patients. Multi-locus sequence typing revealed that ST3 (n = 93) and its single-locus variant ST17 (n = 84) were the predominant clones among macrolide-resistant strains. ST17 presented clinical characteristics comparable to its ancestor ST3. On multivariate analysis, macrolide resistance (OR 3.5; 95% CI 1.4–8.5; p 0.007) was independently associated with fever >72 hours after macrolide treatment. By whole-genome sequencing, prediction analysis of recombination sites revealed one recombination site in ST3 and ST17 compared with M29 (a macrolide-sensitive ST3 strain isolated from China in 2005) containing cytadhesin MgpC-like protein, RepMP4 and RepMP5. ST17 had another recombination site containing an adhesin and RepMP2/3. Conclusions In addition to macrolide resistance, ST3 and its ST17 variant might evolve through recombination between repetitive sequences and non-P1 cytadhesins for persistent circulation in Taiwan.

Background Nitrous oxide (N2O) is a commonly used inhaled anesthetic in outpatient dental procedures. However, the increasing recreational use of N2O may result in vitamin B12 deficiency-related neurologic and psychiatric symptoms. The aim of this study was to demonstrate the clinical features of chronic N2O abuse in pediatric patients. Methods Patients under 20 years of age who were diagnosed with N2O-induced subacute combined degeneration of the spinal cord from 2012 to 2018 were enrolled in this study. Clinical presentations, laboratory, imaging, ancillary studies, treatments and outcomes were analyzed. Results Nine patients were included, all of whom presented with symptoms of myeloneuropathy including limb numbness, limb weakness or unsteady gait. Six patients had low or low-normal vitamin B12 (cyanocobalamin) levels. Eight patients had evidence of subacute combined degeneration of the spinal cord via neuroimaging studies. All of the patients received vitamin B12 supplementation as treatment. All had full recovery of muscle power within 2 months. Five patients had persistent sensory deficits. Conclusion Chronic N2O abuse can cause permanent neurological damage if not treated promptly. Clinical staff should be aware of the various presentations of neurotoxicity related to N2O abuse.

Background The natural killer cell line, NK-92MI, is cytotoxic against various types of cancer. The aim of this study was to develop chimeric antigen receptor-modified (CAR) NK-92MI cells targeting carcinoembryonic antigen-expressing (CEA) tumours and increase killing efficacy by pharmacologically modifying CEA-expression. Result We generated anti-CEA-CAR NK-92MI cells by retroviral vector transduction. This genetically-modified cell line recognised and lysed high CEA-expressing tumour cell lines (LS174T) at 47.54 ± 12.60% and moderate CEA-expressing tumour cell lines (WiDr) at 31.14 ± 16.92% at a 5:1 effector: target (E/T) ratio. The cell line did not lyse low CEA-expressing tumour cells (HCT116) as they did their parental cells (NK-92MI cells). The histone deacetylase-inhibitor (HDAC) sodium butyrate (NaB) and the methylation-inhibitor 5-azacytidine (5-AZA), as epigenetic modifiers, induced CEA-expression in HCT116 and WiDr cells. Although the IC50 of 5 fluorouracil (5-FU) increased, both cell lines showed collateral sensitivity to anti-CEA-CAR NK-92MI cells. The cytolytic function of anti-CEA-CAR NK-92MI cells was increased from 22.99 ± 2.04% of lysis background to 69.20 ± 11.92% after NaB treatment, and 69.70 ± 9.93% after 5-AZA treatment, at a 10:1 E/T ratio in HCT116 cells. The WiDr cells showed similar trend, from 22.99 ± 4.01% of lysis background to 70.69 ± 10.19% after NaB treatment, and 59.44 ± 10.92% after 5-AZA treatment, at a 10:1 E/T ratio. Conclusions This data indicates that the effector-ability of anti-CEA-CAR NK-92MI increased in a CEA-dependent manner. The combination of epigenetic-modifiers like HDAC-inhibitors, methylation-inhibitors, and adoptive-transfer of ex vivo-expanded allogeneic-NK cells may be clinically applicable to patients with in 5-FU resistant condition.

Peritoneal dissemination of tumor has high mortality and is associated with the loss of epithelial features, acquisition of motile mesenchymal morphology characteristics, and invasive properties by tumor cells. Melatonin is an endogenously produced molecule in all plant species that is known to exert antitumor activity, but to date, its underlying mechanisms and antiperitoneal metastasis efficacy is not well defined. This study determined the antiperitoneal dissemination potential of melatonin in vivo and assessed its association with the inhibition of epithelial-to-mesenchymal transition (EMT) signaling mechanism by endoplasmic reticulum (ER) stress, which may be a major molecular mechanism of melatonin against cancer. The results demonstrate that melatonin inhibited peritoneal metastasis in vivo and activated ER stress in Cignal ERSE Reporter Assay, organelle structure in transmission electron microscopy images, calpain activity, and protein biomarkers like p-elf2α. Moreover, the overexpression of transcription factor C/EBPβ in gastric cancer interacted with NFκB and further regulates COX-2 expression. These were dissociated and downregulated by melatonin, as proven by immunofluorescence imaging, immunoprecipitation, EMSA, and ChIP assay. Melatonin or gene silencing of C/EBPβ decreased the EMT protein markers (E-cadherin, Snail, and Slug) and Wnt/beta-catenin activity by Topflash activity, and increased ER stress markers. In an animal study, the results of melatonin therapy were consistent with those of in vitro findings and attenuated systemic proangiogenesis factor production. In conclusion, C/EBPβ and NFκB inhibition by melatonin may impede both gastric tumor growth and peritoneal dissemination by inducing ER stress and inhibiting EMT.

Cholecystokinin and gastrin receptors are upregulated in many human digestive malignancies; however, the correlation of their expressions with severity of colon carcinoma remains sketchy. Here, we determined the expression of cholecystokinin-1 and cholecystokinin-2 receptor, CCK1R and CCK2R, in colon carcinomas and investigated their correlations with clinicopathological characteristics and 1-year survival rate. Expression of CCK1R and CCK2R was determined by immunohistochemical assay in tissue samples obtained from 97 surgical specimens. Clinicopathological character analysis revealed that higher expression of cytoplasmic CCK1R and CCK2R was significantly associated with several variables including the depth of tumor invasion (P = 0.001), venous invasion (P = 0.023), and progression stage (P = 0.013). In addition, immunohistochemical staining revealed statistically significant associations of nuclear CCK1R expression with higher lymphatic invasion (P = 0.042), progression stage (P = 0.025), and unfavorable survival (P = 0.025). Interestingly, we found no link between nuclear CCK2R expression and all the clinicopathological characteristics examined. Taken these, our findings indicate that nuclear CCK1R represents a potential biomarker for poor prognosis, and CCK1R may play a role differing from CCK2R in colon carcinogenesis.

Phagocytosis and oxidative burst are essential mechanisms of innate immunity by which neutrophils eliminate invading pathogens. Afterwards, phagocytic neutrophils are dissipated by facilitating apoptosis to control inflammation. This study investigates how exercise training with or without hypoxic exposure affects the bactericidal activity and subsequent apoptosis of neutrophils following strenuous exercise. A total of 60 healthy, sedentary men were randomly divided into four groups (n = 15 in each group), who were exposed to 21% O2 [normoxic control (NC)] or 15% O2 [hypoxic control (HC)] at rest or were trained at 50% of peak work rate at 21% O2 [normoxic training (NT)] or 15% O2 [hypoxic training (HT)] for 30 min/day, 5 days/week for 4 weeks. Before the intervention, acute strenuous exercise (SE) enhanced the phagocytosis of Escherichia coli (E. coli) by neutrophils and the release of neutrophil oxidant products in response to E. coli, accompanied by increases in the expression of adhesion molecules (CD62L, CD11b, and CD11a), an opsonic receptor (FcγIIIBR), and complement receptors (C1qRp and CD5aR) on neutrophils. Subsequently, the SE facilitated caspase-3 activation and phosphatidylserine exposure in E. coli-stimulated neutrophils. Furthermore, 4 weeks of HT promoted the expressions of adhesion molecules and opsonic/complement receptors on neutrophils, and it also augmented the bactericidal and apoptotic activities of neutrophils at rest or after SE. However, NT, HC, and NC did not influence these neutrophil-related immune responses to strenuous exercise. Therefore, we conclude that the HT regimen effectively promotes the bactericidal capacity of neutrophils, and facilitates their subsequent apoptosis both at rest and following SE.

Acute hypoxic exposure increases vascular thrombotic risk. The release of procoagulant-rich microparticles from neutrophils accelerates the pathogenesis of inflammatory thrombosis. The present study explicates the manner in which interval and continuous exercise regimens affect neutrophil-derived microparticle (NDMP) formation and neutrophil/NDMP-mediated thrombin generation (TG) under hypoxic condition. A total of 60 sedentary males were randomized to perform either aerobic interval training [AIT; 3-min intervals at 40% and 80% V̇O2max (maximal O2 consumption)] or moderate continuous training (MCT; sustained 60% V̇O2max) for 30 min/day, 5 days/week for 5 weeks, or to a control (CTL) group who did not receive any form of training. At rest and immediately after hypoxic exercise test (HE, 100 W under 12% O2 for 30 min), the NDMP characteristics and dynamic TG were measured by flow cytometry and thrombinography respectively. Before the intervention, HE (i) elevated coagulant factor VIII/fibrinogen concentrations and shortened activated partial thromboplastin time (aPTT), (ii) increased total and tissue factor (TF)-rich/phosphatidylserine (PS)-exposed NDMP counts and (iii) enhanced the peak height and rate of TG promoted by neutrophils/NDMPs. Following the 5-week intervention, AIT exhibited higher enhancement of V̇O2max than did MCT. Notably, both MCT and AIT attenuated the extents of HE-induced coagulant factor VIII/fibrinogen elevations and aPTT shortening. Furthermore, the two exercise regimens significantly decreased TF-rich/PS-exposed NDMP formation and depressed neutrophil/NDMP-mediated dynamic TG at rest and following HE. Hence, we conclude that AIT is superior to MCT for enhancing aerobic capacity. Moreover, either AIT or MCT effectively ameliorates neutrophil/NDMP-promoted TG by down-regulating expression of procoagulant factors during HE, which may reduce thrombotic risk evoked by hypoxia. Moreover, either AIT or MCT effectively ameliorates neutrophil/NDMP-promoted TG by down-regulating expression of procoagulant factors during HE, which may reduce thrombotic risk evoked by hypoxia.

Objectives The purpose of this study is to target career women with metabolic syndrome (Mets) risk factors and investigate the effectiveness of using a health management platform (HMP) to improve health behavior and reduce Mets risk factors. Methods This study adopted the structure of a randomized control trial, and targeted full-time career women aged ≥ 20 years, who possessed Mets risk factors. Intervention was performed via an Internet-based HMP, and changes in health behavior 1.5 months and 3 months after intervention and Mets risk factors 3 months after intervention were analyzed. Results A total of 66 career women participated in this study. At 3 months, the HMP group displayed better results than the control group in terms of waist circumference, fasting glucose, and the mean number of Mets components. In terms of the group and time interaction analysis on health behavior, the HMP group only displayed significantly better results in exercise scores than the control group at 1.5 months. Conclusion The application of an Internet-based tailored HMP can facilitate an effective improvement in Mets components of career women with Mets risk factors.

HS (high shear) stress associated with artery stenosis facilitates TG (thrombin generation) by increasing the release of procoagulant PDMPs (platelet-derived microparticles). Physical exercise and hypoxia may paradoxically modulate vascular thrombotic risks. The aim of the present study was to investigate how exercise training with/without hypoxia affected TG mediated by PDMPs under physio-pathological shear flows. A total of 75 sedentary males were randomly divided into five groups (n=15 in each group): 21% O2 [NC (normoxic control)] or 15% O2 [HC (hypoxic control)] at rest or were trained at 50% of peak work rate under 21% O2 [NT (normoxic training)] or 15% O2 [HAT (hypoxic-absolute training)], or 50% of HR (heart rate) reserve under 15% O2 [HRT (hypoxic-relative training)] for 30 min/day, 5 days/week for 4 weeks. The PDMP characteristics and dynamic TG were measured by flow cytometry and thrombinography respectively. Before the intervention, strenuous exercise markedly increased the PDMP count (14.8%) and TG rate (19.5%) in PDMP-rich plasma at 100 dynes/cm2 of shear stress (P

A novel aqueous solvent-based dispersive liquid-liquid microextraction (AS-DLLME) method was combined with narrow-bore liquid chromatography and fluorescence detection for the determination of hydrophilic compounds. A remover (non-polar solvent) and extractant (aqueous solution) were introduced into the derivatization system (acetonitrile) to obtain a water-in-oil emulsion state that increased the mass transfer of analytes. As a proof of concept, three quaternary ammonium substances, including butyrobetaine, l -carnitine and acetyl- l -carnitine, were also used as analytes and determined in pharmaceuticals, personal care products, food and human plasma. The analytes were derivatized with 4-bromomethylbiphenyl for fluorescence detection and improved retention in the column. The linear response was 10–2000 nM for l -carnitine and acetyl- l -carnitine with a good determination coefficient (r2 > 0.998) in the standard solution. The detection limit for l -carnitine and acetyl- l -carnitine was 4.5 fmol. The method was also successfully applied to a 1 μL sample of human plasma. In the linearity calculations for determining butyrobetaine, l -carnitine and acetyl- l -carnitine in human plasma, the determination coefficients ranged from 0.996 to 0.999. Linear regression exhibited good reproducibility and a relative standard deviation better than 7.50% for the slope and 9.06% for the intercept. To characterize highly hydrophilic compounds in various samples, the proposed method provides good sensitivity for a small sample volume with a low consumption of toxic solvents.

Objective The objective of this study was to demonstrate the diversity of urodynamic findings and temporal effects on bladder dysfunction in diabetes as well as to evaluate the predisposing factors that attenuate the storage and voiding function of diabetic women. Material and Methods In this prospective study, 181 women with type 2 diabetes mellitus (DM) and lower urinary tract dysfunction underwent complete urogynecological evaluations and urodynamic studies. The patients' histories of DM and the treatment agents used were documented from chart records and interviews. The urodynamic diagnoses were recategorized into two groups for comparison, namely overactive detrusor (detrusor overactivity and/or increased bladder sensation as well as mixed incontinence) and voiding dysfunction (detrusor hyperactivity with insufficient contractility and detrusor underactivity with poor voiding efficiency) in order to evaluate the temporal effect of DM on diabetic bladder dysfunction. Results The development of bladder dysfunction showed a trend involving time-dependent progression, beginning with storage problems (i.e. advancing from urodynamic stress incontinence to detrusor overactivity and/or increased bladder sensation) and eventually led to impaired voiding function. The duration of DM relative to the urodynamic diagnoses of these women was longer in women with voiding dysfunction (6.8 ± 2.8 years with urodynamic stress incontinence, 7.3 ± 6.5 years with detrusor overactivity and/or increased bladder sensation, and 10.4 ± 8.3 years with women with voiding dysfunction). Notwithstanding these findings, stepwise logistic regression analysis indicated that age and recurrent urinary tract infections were the two independent factors associated with developing voiding dysfunction. Conclusion The urodynamic study revealed a temporal effect on bladder function, and women with diabetic voiding dysfunction were found to have had a longer duration of DM than women with an overactive detrusor. However, aging and recurrent urinary tract infections are the two independent factors that contribute to impaired voiding function and diabetic bladder dysfunction.

Purpose: The study was undertaken to investigate the contralateral overflow effect on physiological tremors in pianists and nonmusicians. Group differences in cross modulation on underlying finger fractionated movement were characterized. Methods: Physiological tremors of the right index, middle, ring, and little fingers were recorded in 12 right-handed pianists and 12 matched nonmusician controls; meanwhile, two contralateral resistance protocols (unilateral handgrip using the left hand at slight and maximal efforts) were randomly conducted. Results: Digit tremors of the control and pianist groups were differentially modulated with the resistance protocols. An increase in gripping force led to cross excitations over 8-12 Hz digit tremors and interdigit tremor coupling for the nonmusicians. An opposite cross effect was noted for the pianists, who exhibited significant tremor suppression and the release of interdigit tremor coupling. Further analysis of tremor dynamics revealed that contralateral gripping reduced the complexity of digit tremors of the pianists but added to the tremor complexity of the nonmusicians. Conclusions: Cross modulation on digit tremors suggests that pianists could centrally suppress unintended motor excitation across the midline. When the opposite hand is active, pianists have superior finger independence that allows them to achieve artistic aspects of musical performance.

Physiological tremors within a limb are coupled, whereas between-limb tremors are thought to oscillate independently for a healthy subject. This study was undertaken to reinvestigate bilateral tremor relations and intra-limb tremor dynamics for a two-limb task after exhausting a single joint. Fifteen volunteers conducted prolonged tracking with the left (target) shoulder. Neuromuscular functions were monitored before and after the exercise-fatiguing intervention, including tracking displacement, muscle activity of the deltoid, and physiological tremors in the bilateral upper limbs. Localized fatiguing contraction degraded tracking accuracy and movement smoothness, accompanied by an increase in deltoid activation. Segment tremors in the bilateral limbs and inter-limb tremor coherences in 8-12 Hz increased, though coherence peaks in 5-8 Hz waned with fatigue response. Intra-limb tremor relations in the target and non-target limbs were also reorganized with unilateral fatiguing contraction. Tremor coupling in the arm-C7 complexes was enhanced, associated with tremor uncoupling in the forearm-arm and hand-forearm complexes. Tracking error in the pre- fatigue and post-fatigue conditions was predicted by different principal components that had high communalities with tremors of distal and proximal segments of the target limb, respectively. The adaptive changes in tremor dynamics were attributable to fatigue-induced enhancement of common central drive and decline in neural inputs of long-looped reflexes that diverge to contralateral segments.

Previously, we have shown that bortezomib overcame TRAIL resistance in hepatocellular carcinoma (HCC) cells via the inhibition of Akt. Here, we report that bortezomib sensitizes these TRAIL-resistant cells, including Huh-7, Hep3B, and Sk-Hep1, to CS-1008, a humanized agonistic antihuman death receptor 5 antibody. Cancerous inhibitor of protein phosphatase 2A (CIP2A) mediated the sensitizing effect of bortezomib to CS-1008 through inhibiting protein phosphatase 2A (PP2A) activity. Combination treatment of bortezomib and CS-1008 downregulated CIP2A in a concentration- and time-dependent manner, and increased PP2A activity in HCC cells. Importantly, ectopic expression of CIP2A decreased Akt-related PP2A activity, indicating that CIP2A negatively regulates Akt-related PP2A activity in HCC cells. Moreover, silencing CIP2A by short interfering RNA enhanced CS-1008–induced apoptosis in HCC cells and ectopic expression of CIP2A in HCC cells abolished CS-1008–induced apoptosis, indicating that CIP2A plays an important role in the sensitizing effect of bortezomib to CS-1008. Finally, our in vivo data showed that CS-1008 and bortezomib combination treatment decreased tumor growth significantly. In conclusion, bortezomib sensitized HCC cells to CS-1008 through the inhibition of CIP2A. Mol Cancer Ther; 10(5); 892–901. ©2011 AACR.

The positive inotropic effect of cardiac glycosides lies in their reversible inhibition on the membrane-bound Na(+)/K(+)-ATPase in human myocardium. Steroid-like compounds containing a core structure similar to cardiac glycosides are found in many Chinese medicines conventionally used for promoting blood circulation. Some of them are demonstrated to be Na(+)/K(+)-ATPase inhibitors and thus putatively responsible for their therapeutic effects via the same molecular mechanism as cardiac glycosides. On the other hand, magnesium lithospermate B of danshen is also proposed to exert its cardiac therapeutic effect by effectively inhibiting Na(+)/K(+)-ATPase. Theoretical modeling suggests that the number of hydrogen bonds and the strength of hydrophobic interaction between the effective ingredients of various medicines and residues around the binding pocket of Na(+)/K(+)-ATPase are crucial for the inhibitory potency of these active ingredients. Ginsenosides, the active ingredients in ginseng and sanqi, substantially inhibit Na(+)/K(+)-ATPase when sugar moieties are attached only to the C-3 position of their steroid-like structure, equivalent to the sugar position in cardiac glycosides. Their inhibitory potency is abolished, however, when sugar moieties are linked to C-6 or C-20 position of the steroid nucleus; presumably, these sugar attachments lead to steric hindrance for the entrance of ginsenosides into the binding pocket of Na(+)/K(+)-ATPase. Neuroprotective effects of cardiac glycosides, several steroid-like compounds, and magnesium lithospermate B against ischemic stroke have been accordingly observed in a cortical brain slice-based assay model, and cumulative data support that effective inhibitors of Na(+)/K(+)-ATPase in the brain could be potential drugs for the treatment of ischemic stroke.

Summary Objective The aim of the present study is to evaluate the effect of a hospital-based therapeutic lifestyle program on women with metabolic syndrome (MetS). Materials and Methods We conducted a therapeutic lifestyle program for women with MetS. They all received a low calorie, balanced diet and participated in a regular aerobic exercise program for 8 weeks. Anthropometric indices, blood pressure, and biochemical data were collected. A paired t test was used for statistical analysis. A p value of less than 0.05 was considered statistically significant. Results Forty-four women took part in the program. All the components of MetS had decreased significantly by the end of the program and 25% of women no longer had MetS at the end of the program. Conclusion The therapeutic lifestyle program with diet control and regular exercise improves most markers of MetS except for levels of high density lipoprotein cholesterol. Therapeutic lifestyle intervention may be the best way of reducing the risk of cardiovascular disease in women with MetS.

To examine if magnesium lithospermate B (MLB), a potent inhibitor of Na(+)/K(+)-ATPase, leads to the elevation of intracellular Ca(2+) level as observed in cells treated with cardiac glycosides.Viability of SH-SY5Y neuroblastoma cells treated with various concentrations of ouabain or MLB was measured. Intracellular Ca(2+) levels were visualized using Fluo4-AM (fluorescent dye) when cells were treated with ouabain or MLB in the presence or absence of KB-R7943 (Na(+)/Ca(2+) exchanger inhibitor) and 2-APB (IP(3) receptor antagonist). Molecular modeling was conducted for the docking of ouabain or MLB to Na(+)/K(+)-ATPase. Changes of cell body and dendrite morphology were monitored under a microscope.severe toxicity was observed in cells treated with ouabain of concentration higher than 1 micromol/L for 24 h while no apparent toxicity was observed in those treated with MLB. Intracellular Ca(2+) levels were substantially elevated by MLB (1 micromol/L) and ouabain (1 micromol/L) in similar patterns, and significantly reduced in the presence of KB-R7943 (10 micromol/L) or 2-APB (100 micromol/L). Equivalent interaction with the binding cavity of Na(+)/K(+)-ATPase was simulated for ouabain and MLB by forming five hydrogen bonds, respectively. Treatment of ouabain (1 micromol/L), but not MLB (1 mumol/L), induced dendritic shrink of SH-SY5Y cells.Comparable to ouabain, MLB leads to the elevation of intracellular Ca(2+) level presumably via the same mechanism by inhibiting Na(+)/K(+)-ATPase. The elevated Ca(2+) levels seem to be supplied by Ca(2+) influx through the reversed mode of the Na(+)/Ca(2+) exchanger and intracellular release from endoplasmic reticulum.

Background: Spinal muscular atrophy (SMA) is a degenerative motor neuron disease caused by homozygous mutations of the survival motor neuron 1 (SMN1) gene. Effective treatment for SMA is unavailable at present. The aim of this study was to investigate the effect of hydroxyurea (HU) in SMA cells and patients. Materials and methods: Fifteen SMA lymphoid and three fibroblast cell lines, 2 from SMA patients and 1 control, were treated with HU at different concentrations, and 33 patients (types II, III) randomized into three groups on different HU dosage, 20, 30, 40 mg/kg/day, were treated for 8 weeks and followed up for another drug-free 8 weeks. The effect of HU on SMN2 gene expression and clinical manifestations was evaluated. Results: After treatment, in vitro, full-length mRNA level and gems number increased significantly, and hnRNP A1 protein decreased. In vivo, there were slight increases in muscle strength scores at 4 weeks and full-length SMN mRNA at 8 weeks in 30 mg/kg/day subgroup. Conclusions: Treating with HU enhanced SMN2 gene expression in SMA cells and showed slight trend towards improvement in some clinical outcome measures in SMA patients which suggests HU may be safe to use in SMA patients but larger randomized, placebocontrolled, double-blind trials are needed to further investigate its efficacy. © 2007 Elsevier B.V. All rights reserved.

The objective of this study was to examine the changes in H reflex sensitivity after neuromuscular fatigue associated with fluctuations of the M wave. In the maximal and submaximal voluntary contraction (MVC and SMVC) paradigms, subjects performed voluntary plantarflexion at 100% MVC and 40% MVC respectively until the limit of torque maintenance was reached. In the submaximal electrical stimulation (SMES) paradigm, the tricep surae was exhausted with sustained electrical stimulation of 40% of the maximal tolerable intensity at a 40-Hz stimulus rate. The H reflexes and maximal M waves (M(max)) of the soleus were recorded before and after the three fatigue paradigms, and the H reflex was standardized with M(max) to minimize possible bias due to fatigue-induced M wave fluctuation. The results showed a significant increase in the standardized H reflex due to the SMES paradigm in spite of M(max) potentiation. The SMVC paradigm led to a reduction in size of the standardized H reflex without modification of M(max), whereas the standardized H reflex was not mediated by the MVC paradigm, which contributed to a noticeable M(max) potentiation. The present study underscored the fact that the H reflex sensitivity and M wave amplitude were not necessarily suppressed consequent to neuromuscular fatigue, but varied with the activation history of a muscle for size-dependent efficacy of the Ia transmission pathways and postactivation potentiation.

Aim: To examine if magnesium lithospermate B (MLB) extracted from Danshen, the dried roots of Salvia miltiorrhiza , may act as an active component responsible for the cardiac therapeutic effect of this traditional Chinese herb via the same molecular mechanism triggered by cardiac glycosides, such as ouabain and digoxin. Moreover, we wanted to test if MLB may provide neuroprotection against ischemic stroke as observed for cardiac glycosides. Methods: Similarity in the chemical structure and molecular configuration between MLB and ouabain was analyzed. The inhibition potency of MLB and ouabain on Na + ,K + -ATPase activity of a commercial product, as well as in purified membrane fractions from rat brain and heart tissues, was examined and compared. Neuroprotective effect of MLB against ischemic stroke was also evaluated using a cortical brain slice-based assay model. Results: Dose-dependent inhibition on the commercial Na + ,K + - ATPase equivalent to that for ouabain was observed for MLB of approximately half dosage by weight. This relative potency of ouabain and MLB was also observed for their inhibition on Na + ,K + -ATPase activity of plasma membrane purified from rat tissues, although these 2 inhibitors exhibited somewhat lower competence in these crude extracts. In ischemic gerbil brains, post-treatment with MLB significantly reduced the infarct size, visualized by 2,3,5-triphenyltetrazolium chloride staining, by approximately 55% when compared with the control group. Conclusion: These results evidently suggest that the cardiac therapeutic effect of Danshen should be at least partly attributed to the effective inhibition of Na + ,K + - ATPase by MLB, and that MLB provides anti-ischemic neuroprotection in gerbils subjected to focal ischemia and reperfusion.

This qualitative study explores the traumas of Chinese heroin users. The results showed that the Chinese experience traumas during (childhood, later in life but prior to heroin-use onset, and throughout their heroin-use career. Themes related to the traumas include the historical economic transition, the value of family orientation, an emphasis on scholarly pursuits, the shame orientation, and a scarcity of resources conducive to recovery. This article provides a framework to understand the traumas experienced by Chinese people and offers insights on how macrofactors may impact the trauma and its treatment in different societies.