Targeting TGF-ß signaling, oxidative stress, and cellular senescence rescues osteoporosis in gerodermia osteodysplastica.

GORAB is a key regulator of Golgi vesicle transport and protein glycanation. Loss of GORAB function in gerodermia osteodysplastica (GO) causes shortening of glycosaminoglycan chains, leading to extracellular matrix disorganization that results in wrinkled skin, osteoporosis and elevated TGF-ß signaling. In this study, we investigated the role of TGF-ß-signaling, oxidative stress, and resulting cellular senescence in the osteoporosis phenotype of GO. Treatment of GorabPrx1 conditional knockouts with the TGF-ß neutralizing antibody 1D11 rescued the trabecular bone loss, indicating that TGF-ß overactivation causes osteoporosis in GO. Using an inducible knockout system, we demonstrated that TGF-ß dysregulation was not a cell-intrinsic effect of GORAB inactivation, but a consequence of a disorganized extracellular matrix. Enhanced TGF-ß signaling caused elevated Nox4 expression in GorabPrx1 mutants and in GO patients' fibroblasts, resulting in overproduction of mitochondrial superoxide. The resulting oxidative stress was detected in GORAB null cells and also in wildtype bystander cells. The same effect was observed in zebrafish after TALEN-mediated gorab inactivation, indicating that the pathway is evolutionarily conserved. Treating GorabPrx1 mutants with the antioxidant N-acetylcysteine ameliorated the osteoporosis phenotype. TGF-ß induced oxidative stress coincided with accumulation of DNA damage and elevated expression of senescence markers. Inactivation of Cdkn2a in the GorabPrx1 rescued the osteoporosis phenotype. Reduced colony formation and altered subpopulations of bone marrow stromal cells were normalized upon inactivation of Cdkn2a, thus further demonstrating the relevance of cellular senescence in the pathogenesis. Our results shed light on the causative role of a TGF-ß-Nox4-senescence axis and therapeutic strategies for GO.

Gastric Cancer - From Aetiology to Management: Differences Between the East and the West.

Gastric cancers are highly prevalent in both the East and the West, although they differ in aetiology and prognostic outcome. Management of gastric cancer from screening to definitive treatment varies substantially between Eastern and Western countries and regions, owing to numerous factors, including government incentives to carry out population-wide screening programmes to detect early disease, differences in clinical and biological tumour behaviours and responsiveness to treatment, patient accessibility to effective treatment, etc. This review highlights and contrasts the differences in tumour aetiology and histology, as well as the management approaches between the East and the West, which gives important insights and inspirations on future international multicentre research collaboration to combat this dreadful malignancy.

Atypical periprosthetic femoral fracture: a case report.

We report an 82-year-old woman who underwent fixation with a long-spanning cable-plate for a bisphosphonate-induced Vancouver B1 periprosthetic femoral fracture. Non-union and breakage of the plate occurred at 16 months and necessitated revision surgery using a long-stem femoral prosthesis augmented with a cable-plate construct. Bone union was achieved eventually after 10 months.

Post-radiation Plasma Epstein-Barr Virus DNA and Local Clinical Remission After Radical Intensity-modulated Radiation Therapy for Nasopharyngeal Carcinoma.

AIMS: We studied if post-radiation plasma Epstein-Barr virus (EBV) DNA predicted local clinical remission after radical intensity-modulated radiation therapy (IMRT) for nasopharyngeal carcinoma. MATERIALS AND METHODS: Patients with non-metastatic nasopharyngeal carcinoma with baseline and serial plasma EBV DNA were treated with radical IMRT ± adjunct chemotherapy. Eight weeks after IMRT, they had plasma EBV DNA and routine six-site random nasopharyngeal biopsies on the same day. A repeat biopsy was carried out every 2 weeks if residual tumours were noted in previous biopsies until 12 weeks after IMRT when local persistence was defined. Correlation of undetectable plasma EBV DNA with local clinical remission was carried out. RESULTS: Two hundred and sixty patients with serial plasma EBV DNA completed IMRT, after a median follow-up of 3.1 years. Only one (0.4%) suffered from local persistence. Area under the curve values of receiver operating characteristics of undetectable plasma EBV DNA for negative biopsy at 8 weeks and local persistence were 0.642 and 0.439, respectively. They increased to 0.856 (P = 0.007) and 0.952 (P = 0.119), respectively, when combined with age <65 years and T1/T2 stage. CONCLUSIONS: Post-treatment plasma EBV DNA was not useful to predict local clinical remission in this study, probably because of excellent local control after IMRT. However, it may serve as a reference for high-risk patients treated with older radiation techniques.

Efficacy and safety of hylan G-F 20 injection in treatment of knee osteoarthritis in Chinese patients: results of a prospective, multicentre, longitudinal study.

OBJECTIVE: To study the efficacy and safety of single intra-articular injection of 6-mL hylan G-F 20 in Chinese patients with symptomatic knee osteoarthritis. DESIGN: Prospective case series. SETTING: Six government hospitals in Hong Kong. PATIENTS: Patients with primary knee osteoarthritis were recruited from six government hospitals from 1 October 2010 to 31 May 2012. All patients received 6-mL intra-articular injection of hylan G-F 20. MAIN OUTCOME MEASURES: Pain visual analogue scale, functional visual analogue scale, and 5-point Likert scale on change of pain and function were assessed. Adverse events were checked. Radiographs were taken pre-injection and at 3 months and 1 year. RESULTS: A total of 110 knees of 95 patients with primary knee osteoarthritis were treated. The mean age of the patients was 62 (standard deviation, 9.8) years. All patients completed 1 year of follow-up. The mean pain visual analogue scale, functional visual analogue scale, and Likert value for pain and function showed statistically significant improvements at 6 weeks, 3 months, 6 months, and 1 year compared with the pre-injection values. No significant correlations were found between changes in visual analogue scale and age, body mass index, pre-injection radiological osteoarthritis severity, serum erythrocyte sedimentation rate, or C-reactive protein. Serial radiographs did not show any changes in the radiological severity of knee osteoarthritis. Overall, 16.4% of the patients experienced mild and self-limiting adverse events. CONCLUSION: Hylan G-F 20 is a safe and effective therapy to relieve pain and improve function for up to 1 year in Chinese patients with knee osteoarthritis.

Involvement of RARRES3 in the regulation of Wnt proteins acylation and signaling activities in human breast cancer cells.

The Wnt/ß-catenin signaling pathway has emerged as a key regulator of complex biological processes, such as embryonic development, cell proliferation, cell fate decision and tumorigenesis. Recent studies have shown that the deregulation of Wnt/ß-catenin signaling is frequently observed and leads to abnormal cell growth in human breast cancer cells. In this study, we identified a novel regulatory mechanism of Wnt/ß-catenin signaling through RARRES3 that targets and modulates the acylation status of Wnt proteins and co-receptor low-density lipoprotein receptor-related protein 6, resulting in the suppression of epithelial-mesenchymal transition and cancer stem cell properties. Mutation of the conserved active site residues of RARRES3 indicates that RARRES3 serves as an acyl protein thioesterase that tethers its target proteins and modulates their acylation status. Furthermore, the functions of p53 in cell proliferation and Wnt/ß-catenin signaling are significantly associated with the induction of RARRES3. Thus our findings provide a new insight into the molecular link between p53, protein acylation and Wnt/ß-catenin signaling whereby RARRES3 plays a pivotal role in modulating the acylation status of signaling proteins.

A combined method to estimate parameters of the thalamocortical model from a heavily noise-corrupted time series of action potential.

A combined method composing of the unscented Kalman filter (UKF) and the synchronization-based method is proposed for estimating electrophysiological variables and parameters of a thalamocortical (TC) neuron model, which is commonly used for studying Parkinson's disease for its relay role of connecting the basal ganglia and the cortex. In this work, we take into account the condition when only the time series of action potential with heavy noise are available. Numerical results demonstrate that not only this method can estimate model parameters from the extracted time series of action potential successfully but also the effect of its estimation is much better than the only use of the UKF or synchronization-based method, with a higher accuracy and a better robustness against noise, especially under the severe noise conditions. Considering the rather important role of TC neuron in the normal and pathological brain functions, the exploration of the method to estimate the critical parameters could have important implications for the study of its nonlinear dynamics and further treatment of Parkinson's disease.

Patients with nonalcoholic fatty liver disease have higher risk of colorectal adenoma after negative baseline colonoscopy.

AIM: The study aimed to determine whether nonalcoholic fatty liver disease (NAFLD) is an independent risk factor of adenoma after negative baseline colonoscopy. METHOD: A retrospective cohort study was conducted on 1522 health-check individuals who underwent two consecutive colonoscopies at Taipei Veterans General Hospital between 2003 and 2010. Those developing an adenoma after an initial negative baseline colonoscopy (adenoma group) were compared with those in whom the second colonoscopy was negative (nonadenoma group). Anthropometric measurements, biochemical tests and the presence of NAFLD were compared between the two groups. RESULTS: The adenoma group had a higher prevalence of NAFLD than the nonadenoma group (55.6% vs 38.8%; P < 0.05). On multivariate logistic regression analysis, NAFLD was an independent risk factor (OR = 1.45, 95% CI: 1.07-1.98) for adenoma formation after a negative baseline colonoscopy. The risk of colorectal adenoma increased when NAFLD patients had other morbidities including metabolic syndrome, hypertension or smoking (OR = 2.85, 4.03 and 4.17). CONCLUSION: NAFLD is an independent risk factor for colorectal adenoma formation after a negative baseline colonoscopy. The risk is higher in individuals with NAFLD and other comorbidities, such as hypertension, smoking or metabolic syndrome.

Herpes simplex virus infection and erectile dysfunction: a nationwide population-based study.

Both erectile dysfunction (ED) and herpes simplex virus (HSV) infections are related to cardiovascular events. However, the relationship between ED and HSV infections remains undetermined. The aim of our study was to investigate the possible influence of HSV infections on the development of ED using the Taiwan National Health Insurance database. We identified patients with HSV type 1 or type 2 infections from the 1 000 000 sampling cohort data set. Male patients of age 18 years or older who had been diagnosed as cases of HSV infection since January 1, 2001 were enroled. Patients with previous history of stroke, spinal cord injury or malignancy were excluded. A control group was selected, comprising male patients without HSV infection, stroke, spinal cord injury or malignancy. The age, time of enrolment and comorbidities were matched in the two groups. A total of 1 717 HSV subjects (mean age 43.29 ± 15.97 years) and 6 864 control subjects were enroled. During an average of 3.91 ± 1.93 years' follow-up, HSV-infected subjects experienced a higher incidence of ED than control subjects (1.7% vs. 0.7%, respectively). The log-rank test showed that patients with HSV infections had a significantly higher incidence of ED than those without HSV infections (p < 0.001). After Cox proportional hazard regression model analysis, HSV infections were independently associated with the increased risk of ED (hazard ratio, 2.90; 95% CI, 1.82-4.63, p < 0.001). In conclusion, HSV infections were associated with risk of ED in this cohort.

Hyaluronic acid instillation following arthroscopic anterior cruciate ligament reconstruction: a double-blinded, randomised controlled study.

PURPOSE: To assess the effect of hyaluronic acid instillation after arthroscopic anterior cruciate ligament (ACL) reconstruction for improving pain, range of movement, and function of the knee. METHODS: 28 men and 4 women underwent arthroscopic ACL reconstruction for isolated ACL rupture (partial or complete) and instability after recreational sports injury 2 to 120 months earlier. They were randomised to undergo arthroscopic ACL reconstruction followed by intra-articular viscoseal instillation (13 men and 3 women) or arthroscopic ACL reconstruction alone (15 men and 1 woman). The knee injury osteoarthritis outcome score (for pain, symptoms, activities of daily living, sport and recreation function, and quality of life), range of movement, knee circumference, and analgesic use were assessed on days -1, 1, and 2, and weeks 2, 6 and 12. RESULTS: Patient demographics were similar at baseline. At postoperative days 1 and 2, all subscales of the knee injury osteoarthritis outcome score (except for quality of life) were significantly higher in the viscoseal group. At weeks 2, 6, and 12, improvement in both groups equalised. Knee swelling (change in knee circumference) was significantly less in the viscoseal group at days 1 and 2 (p=0.009 and p=0.038, respectively, Mann-Whitney U test). Only one patient in the viscoseal group had a limited range of movement. No patient developed any adverse reaction. CONCLUSION: Intra-articular viscoseal instillation improved pain control and swelling 2 days after arthroscopic ACL reconstruction.

Updated thresholds for serum alanine aminotransferase level in a large-scale population study composed of 34 346 subjects.

BACKGROUND: The sensitivity of current upper limit of normal (ULN) of serum alanine aminotransferase (ALT) levels for detecting chronic liver disease has been challenged recently. AIM: To identify modulating factors for serum ALT levels and to refine its ULN threshold. METHODS: We enrolled 34 346 consecutive subjects who completed the health check-up at Taipei Veterans General Hospital from 2002 to 2009. ULN was set for healthy ALT level to the 95th percentile of the reference healthy population. RESULTS: A group of 21 282 subjects were used as a training set to define an ULN with the highest sensitivity; afterwards, this ULN was validated in another set of 13 064 subjects. A reference healthy population was selected from the training set after excluding subjects with any abnormalities in independent risk factors associated with elevated serum ALT level (>40 IU/L) by multivariate analysis like body mass index, waist circumference, glucose, cholesterol, high-density lipoprotein-cholesterol, triglyceride, hepatitis B virus surface antigen, anti-hepatitis C virus antibody and fatty liver. The new ULN of serum ALT level defined as the 95% percentile in the healthy population were 21 IU/L and 17 IU/L for men and women respectively. These cut-off values had the highest Youden's index and areas under the corresponding receiver operating curves among four widely applied thresholds in both the training and validation sets. CONCLUSIONS: The suggested threshold of upper limit of normal provides better discrimination between healthy and unhealthy status. Viral hepatitis, metabolic syndrome and fatty liver are the major risk factors of elevated serum alanine aminotransferase levels.

Cirrhotic patients at increased risk of peptic ulcer bleeding: a nationwide population-based cohort study.

BACKGROUND: Few large population-based studies have compared the occurrence of peptic ulcer bleeding (PUB) in cirrhotic and noncirrhotic patients. AIMS: To investigate if cirrhotic patients have higher risk of PUB than the general population and to identify possible risk factors of PUB in cirrhotic patients. METHODS: Using the National Health Insurance Research Database, a nationwide population-based dataset in Taiwan and matching age, gender, comorbidities and ulcerogenic medication by propensity score, 4013 cirrhotic patients, 8013 chronic hepatitis patients and 7793 normal controls were compared. The log-rank test was used to analyse differences in accumulated PUB-free survival rates between the groups. Cox proportional hazard regressions were performed to evaluate independent risk factors for PUB in all patients and identified risk factors of PUB in cirrhotic patients. RESULTS: During the 7-year follow-up, cirrhotic patients had significantly higher incidences of PUB than chronic hepatitis patients and controls, respectively (P < 0.001 by log-rank test). By Cox proportional hazard regression analysis, cirrhosis was independently associated with increased risk of PUB (hazard ratio: 4.22; 95% CI 3.37-5.29, P < 0.001) after adjusting for age, gender, economic status, underlying comorbidities and ulcerogenic medication. Age, male, diabetes, chronic renal disease, history of gastro-oesophageal variceal bleeding and use of nonsteroidal anti-inflammatory drugs were risk factors for PUB in cirrhotic patients. CONCLUSION: Cirrhotic patients have a significantly higher risk of peptic ulcer bleeding after adjustments for possible confounding factors like age, gender, economic status, underlying comorbidities and ulcerogenic medication.

Direct mapping of hot-electron relaxation and multiplication dynamics in PbSe quantum dots.

How hot electrons relax in semiconductor quantum dots is of critical importance to many potential applications, such as solar energy conversion, light emission, and photon detection. A quantitative answer to this question has not been possible due in part to limitations of current experimental techniques in probing hot electron populations. Here we use femtosecond time-resolved two-photon photoemission spectroscopy to carry out a complete mapping in time- and energy-domains of hot electron relaxation and multiexciton generation (MEG) dynamics in lead selenide quantum dots functionalized with 1,2-ethanedithiols. We find a linear scaling law between the hot electron relaxation rate and its energy above the conduction band minimum. There is no evidence of MEG from intraband hot electron relaxation for excitation photon energy as high as three times the bandgap (3E(g)). Rather, MEG occurs in this system only from interband hot electron transitions at sufficiently high photon energies (~4E(g)).

Chronic obstructive pulmonary disease: an independent risk factor for peptic ulcer bleeding: a nationwide population-based study.

BACKGROUND: Peptic ulcer bleeding remains a major healthcare problem despite decreasing prevalence of peptic ulcer disease. The role of chronic obstructive pulmonary disease (COPD) in the risk of peptic ulcer bleeding has not yet been established. AIM: To determine if COPD patients have a higher risk of peptic ulcer bleeding than the general population and to identify the risk factors of peptic ulcer bleeding in COPD patients. METHODS: From Taiwan's National Health Insurance research database, 62,876 patients, including 32,682 COPD and 30,194 age-gender-matched non-COPD controls, were recruited. Cox proportional hazard regression was performed to evaluate independent risk factors for ulcer bleeding in all patients and to identify risk factors in COPD patients. RESULTS: During the 8-year follow-up, COPD patients had a significant higher rate of peptic ulcer bleeding than the control group (P < 0.001, by log-rank test). By Cox proportional hazard regression analysis, COPD [hazard ratio (HR) 1.93, 95% CI 1.73-2.17] was an independent risk factor after adjusting for age, gender, underlying comorbidities and ulcerogenic medication. Age > 65 years, male, comorbidities of hypertension, diabetes, heart failure, history of peptic ulcer disease, and chronic renal disease and use of nonsteroidal anti-inflammatory drugs were risk factors of ulcer bleeding in COPD patients. CONCLUSION: Patients with chronic obstructive pulmonary disease have a higher risk of peptic ulcer bleeding after adjustments for possible confounding factors like underlying comorbidities and ulcerogenic medication.

Chaotic phase synchronization in small-world networks of bursting neurons.

We investigate the chaotic phase synchronization in a system of coupled bursting neurons in small-world networks. A transition to mutual phase synchronization takes place on the bursting time scale of coupled oscillators, while on the spiking time scale, they behave asynchronously. It is shown that phase synchronization is largely facilitated by a large fraction of shortcuts, but saturates when it exceeds a critical value. We also study the external chaotic phase synchronization of bursting oscillators in the small-world network by a periodic driving signal applied to a single neuron. It is demonstrated that there exists an optimal small-world topology, resulting in the largest peak value of frequency locking interval in the parameter plane, where bursting synchronization is maintained, even with the external driving. The width of this interval increases with the driving amplitude, but decrease rapidly with the network size. We infer that the externally applied driving parameters outside the frequency locking region can effectively suppress pathologically synchronized rhythms of bursting neurons in the brain.

Evaluation of chronic disease self-management programme (CDSMP) for older adults in Hong Kong.

OBJECTIVES: To evaluate the locally-adapted CDSMP for older adults with chronic diseases in Hong Kong in the primary care setting. DESIGN: A longitudinal, quasi-experimental study. SETTING: Community-based and primary care setting. PARTICIPANTS: Seven hundred and seventy-two participants aged 55 or above with at least one chronic disease and were living in the community. INTERVENTION: The 6-weeks programme consisted of 6 group sessions, with each session lasting for 2.5 hours. Trained professional and elder lay leaders facilitated participants to gain essential self-management knowledge and skills for the effective management of chronic diseases. MEASUREMENTS: At baseline and 6 months, four categories of outcome measures were documented, covering self-management behaviours, self-efficacy, health status, and health care utilization. RESULTS: 302 and 298 participants in the intervention and control groups completed 6 months follow-up respectively. Participants in the intervention group reported significant improvements in all self-management behaviours and self-efficacy measures, and 5 health status measures (social role limitation, depressive symptoms, health distress, symptoms of pain and discomfort, and self-rated health) when compared with those in the control group. CONCLUSIONS: The locally-adapted CDSMP may improve self-management behaviours, self-efficacy and health status among older adults with chronic diseases in Hong Kong. CDSMP may be integrated into primary care services for older adults.

Experience of a screening centre for influenza A/H1N1: the first 50 days.

BACKGROUND: The authors' emergency department (ED) served as Singapore's screening centre for influenza H1N1 cases. The aims of the study were to describe their screening experience and to compare clinical and laboratory features of H1N1 versus seasonal flu cases. METHODOLOGY: The authors conducted a prospective observational study on consecutive patients aged 16 years and above presenting to a busy, urban ED for H1N1 screening over 50 days. Clinical, laboratory, radiological and PCR data were collected from the hospital electronic databases. Primary outcomes were proportions of confirmed H1N1 cases and their distribution of clinical, laboratory and radiological features. Secondary outcomes were comparison of clinical and laboratory features of H1N1 versus seasonal flu cases. Data were analysed using descriptive statistics and univariate analysis was used to compare factors between the two groups. A p value <0.05 was considered statistically significant. RESULTS: 1205 patients were screened. 31 (2.6%) and 133 (11%) of them had H1N1 and seasonal flu infections, respectively. The two groups had similar symptoms. There were six clinical and two laboratory features with statistically significant differences between H1N1 and seasonal flu cases. Clinical factors were travel or contact history, median age, respiratory rate, diastolic blood pressure and length of hospital stay. Laboratory factors were median platelet and lymphocyte counts. CONCLUSIONS: The authors report their experience as the nation's H1N1 screening centre. They identified factors that were different between H1N1 and seasonal flu cases. Future research is needed to elucidate if and how this information can be used as a screening tool for H1N1.