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.

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.

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.

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.

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)).

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.

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.

Helper T cells induced by an immunopurified herpes simplex virus type I (HSV-I) 115 kilodalton glycoprotein (gB) protect mice against HSV-I infection.

Three herpes simplex virus type I (HSV-I) glycoproteins of apparent molecular masses 103, 63, and 115 kD have been purified using virus-specific monoclonal antibodies (mAb) G8D1, C2D2, and T157, respectively. Both G8D1 and C2D2 neutralize HSV-I in vitro and passively protect CBA mice against HSV-I infection in vivo, whereas T157 is neither neutralizing nor passively protective. However, mice given a single subcutaneous injection of 30 micrograms 115 kD glycoprotein in saline were completely protected against lethal challenges of HSV-I administered intraperitoneally or in the footpad 7 d after immunization. In contrast, mice similarly immunized with 103 or 63 kD glycoproteins were only partially protected. The prophylactic immunity was correlated with an early induction of specific antibody, which became even more evident 3 d after virus challenge. There was a remarkable similarity in antibody isotype distribution between the responses to 115 kD glycoprotein and to heat-inactivated intact HSV-I. However, the prechallenge sera from 115 kD glycoprotein hyperimmunized mice were again neither virus-neutralizing nor passively protective. All three glycoproteins induced only low levels of delayed-type hypersensitivity (DTH). Pretreatment of mice with cyclophosphamide significantly enhanced DTH to 115 kD and 103 kD glycoproteins in the absence of antibody, but failed to confer significant immunity, indicating that DTH alone is insufficient for protection. Splenic and lymph node Ig- (B cell-depleted) cells from mice protectively immunized with 115 kD glycoprotein could adoptively transfer effective protection and enhance a virus neutralizing antibody response in normal recipients challenged with a lethal dose of HSV-I. Both the protection and the ability to enhance neutralizing antibody were diminished when the cells were treated with mAb GK 1.5 and complement. These results therefore demonstrate that the 115 kD glycoprotein, though not apparently containing accessible epitopes for the induction of virus-neutralizing antibody, possesses determinants capable of activating helper T cells. These L3T4+ cells confer strong protective immunity by enhancing protective antibody upon challenge infection, probably through associative help.

Protection in simian immunodeficiency virus-vaccinated monkeys correlates with anti-HLA class I antibody response.

Our earlier reports demonstrated that Cynomolgus macaques vaccinated with either inactivated partially purified simian immunodeficiency virus (SIV), fixed SIV-infected C8166 (a human T lymphoblastoid cell line) cells, or fixed uninfected C8166 cells can be protected against a challenge infection with the 32H isolate of SIVmac 251 (grown in C8166) (Stott, E. J., W. L. Chan, K. H. G. Mills, M. Page, F. Taffs, M. Cranage, P. Greenway, and P. Kitchin. 1990. Lancet. 336:1538; Stott, E. J., P. A. Kitchin, M. Page, B. Flanagan, L. F. Taffs, W. L. Chan, K. H. G. Mills, P. Silvera, and A. Rodgers. 1991. Nature [Lond.]. 353:393). Protection is correlated with the levels of antibody response to cellular antigens in the human cells from which the virus immunogen was grown. However, the mechanism of protection is unclear. We report here the analysis of sera from these protected monkeys and demonstrate that there is positive correlation of protection with antibody response to the HLA class I molecule.

Selective expression of a stable cell surface molecule on type 2 but not type 1 helper T cells.

T helper cell type 1 (Th1) and 2 (Th2) are central to immune regulation. However, no stable cell surface marker capable of distinguishing and separating these two subsets of CD4(+) cells has yet been found. Using differential display PCR, we have identified a gene encoding a cell membrane bound molecule, originally designated ST2L, T1, DER4, or Fit, expressed constitutively and stably on the surface of murine Th2s, but not Th1s even after stimulation with a range of immunological stimuli. Antibody against a peptide derived from ST2L strongly and stably labeled the surface of cloned Th2s but not Th1s, and Th2s but not Th1s derived from naive T cells of ovalbumin T cell receptor-alpha/beta transgenic mice. Three-color single cell flow cytometric analysis shows that cell surface ST2L coexpressed with intracellular interleukin (IL)-4, but not with interferon (IFN)-gamma. The antibody selectively lysed Th2s in vitro in a complement-dependent manner. In vivo, it enhanced Th1 responses by increasing IFN-gamma production and decreasing IL-4 and IL-5 synthesis. It induced resistance to Leishmania major infection in BALB/c mice and exacerbated collagen-induced arthritis in DBA/1 mice. Thus, ST2L is a stable marker distinguishing Th2s from Th1s and is also associated with Th2 functions. Hence, it may be a target for therapeutic intervention.

Selective expression and functions of interleukin 18 receptor on T helper (Th) type 1 but not Th2 cells.

Interleukin (IL)-18 induces interferon (IFN)-gamma synthesis and synergizes with IL-12 in T helper type 1 (Th1) but not Th2 cell development. We report here that IL-18 receptor (IL-18R) is selectively expressed on murine Th1 but not Th2 cells. IL-18R mRNA was expressed constitutively and consistently in long-term cultured clones, as well as on newly polarized Th1 but not Th2 cells. IL-18 sustained the expression of IL-12Rbeta2 mRNA, indicating that IL-18R transmits signals that maintain Th1 development through the IL-12R complex. In turn, IL-12 upregulated IL-18R mRNA. Antibody against an IL-18R-derived peptide bound Th1 but not Th2 clones. It also labeled polarized Th1 but not Th2 cells derived from naive ovalbumin-T cell antigen receptor-alphabeta transgenic mice (D011.10). Anti-IL-18R antibody inhibited IL-18- induced IFN-gamma production by Th1 clones in vitro. In vivo, anti-IL-18R antibody reduced local inflammation and lipopolysaccharide-induced mortality in mice. This was accompanied by shifting the balance from Th1 to Th2 responses, manifest as decreased IFN-gamma and proinflammatory cytokine production and increased IL-4 and IL-5 synthesis. Therefore, these data provide a direct mechanism for the selective effect of IL-18 on Th1 but not Th2 cells. They also show that the synergistic effect of IL-12 and IL-18 on Th1 development may be due to the reciprocal upregulation of their receptors. Furthermore, IL-18R is a cell surface marker distinguishing Th1 from Th2 cells and may be a therapeutic target.

Vibrational resonance in neuron populations.

In this paper different topologies of populations of FitzHugh-Nagumo neurons have been introduce to investigate the effect of high-frequency driving on the response of neuron populations to a subthreshold low-frequency signal. We show that optimal amplitude of high-frequency driving enhances the response of neuron populations to a subthreshold low-frequency input and the optimal amplitude dependences on the connection among the neurons. By analyzing several kinds of topology (i.e., random and small world) different behaviors have been observed. Several topologies behave in an optimal way with respect to the range of low-frequency amplitude leading to an improvement in the stimulus response coherence, while others with respect to the maximum values of the performance index. However, the best results in terms of both the suitable amplitude of high-frequency driving and high stimulus response coherence have been obtained when the neurons have been connected in a small-world topology.

Kinetic Monte Carlo simulations compared with continuum models and experimental properties of pattern formation during ion beam sputtering.

Kinetic Monte Carlo simulations model the evolution of surfaces during low energy ion bombardment using atomic level mechanisms of defect formation, recombination and surface diffusion. Because the individual kinetic processes are completely determined, the resulting morphological evolution can be directly compared with continuum models based on the same mechanisms. We present results of simulations based on a curvature-dependent sputtering mechanism and diffusion of mobile surface defects. The results are compared with a continuum linear instability model based on the same physical processes. The model predictions are found to be in good agreement with the simulations for predicting the early-stage morphological evolution and the dependence on processing parameters such as the flux and temperature. This confirms that the continuum model provides a reasonable approximation of the surface evolution from multiple interacting surface defects using this model of sputtering. However, comparison with experiments indicates that there are many features of the surface evolution that do not agree with the continuum model or simulations, suggesting that additional mechanisms are required to explain the observed behavior.

Stress-enhanced pattern formation on surfaces during low energy ion bombardment.

Ion-induced surface patterns (sputter ripples) are observed to grow more rapidly than predicted by current models, suggesting that additional sources of roughening may be involved. Using a linear stability analysis, we consider the contribution of ion-induced stress in the near surface region to the formation rate of ripples. This leads to a simple model that combines the effects of stress-induced roughening with the curvature-dependent erosion model of Bradley and Harper. The enhanced growth rate observed on Cu surfaces appears to be consistent with the magnitude of stress measured from wafer curvature measurements.

Harmonics and intermodulation in subthreshold FitzHugh-Nagumo neuron.

Intermodulation and harmonics are important in frequency analysis of nonlinear systems. In neuron research, most investigations are taken in studying synchronization between the external stimuli and the output of neuron, but harmonics and intermodulation are often ignored. In this paper, harmonics and intermodulation of the subthreshold FitzHugh-Nagumo neuron are investigated and their magnitudes are used to predict frequency response of the neuron. Furthermore, through analyzing the magnitudes of harmonics, the intrinsic frequencies of the neuron could be identified.

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.

A proinflammatory role for IL-18 in rheumatoid arthritis.

IL-18 is a novel cytokine with pleiotropic activities critical to the development of T-helper 1 (Th1) responses. We detected IL-18 mRNA and protein within rheumatoid arthritis (RA) synovial tissues in significantly higher levels than in osteoarthritis controls. Similarly, IL-18 receptor expression was detected on synovial lymphocytes and macrophages. Together with IL-12 or IL-15, IL-18 induced significant IFN-gamma production by synovial tissues in vitro. IL-18 independently promoted GM-CSF and nitric oxide production, and it induced significant TNF-alpha synthesis by CD14(+) macrophages in synovial cultures; the latter effect was potentiated by IL-12 or IL-15. TNF-alpha and IFN-gamma synthesis was suppressed by IL-10 and TGF-beta. IL-18 production in primary synovial cultures and purified synovial fibroblasts was, in turn, upregulated by TNF-alpha and IL-1beta, suggesting that monokine expression can feed back to promote Th1 cell development in synovial membrane. Finally, IL-18 administration to collagen/incomplete Freund's adjuvant-immunized DBA/1 mice facilitated the development of an erosive, inflammatory arthritis, suggesting that IL-18 can be proinflammatory in vivo. Together, these data indicate that synergistic combinations of IL-18, IL-12, and IL-15 may be of importance in sustaining both Th1 responses and monokine production in RA.

Thumb polydactyly: clinical outcome after reconstruction.

PURPOSE: To evaluate clinical and cosmetic outcomes of reconstruction in thumb polydactyly and prognostic value of the Wassel classification. METHODS: Between 1993 and 2000 inclusive, out of the patients with thumb polydactyly (involving 80 thumbs) operated on, 34 patients (36 thumbs) were available for review and underwent clinical and radiological assessment. Outcomes in terms of the Tada score and complications were recorded. RESULTS: The mean age of patients at the time of operation was 2.8 (range, 0.6-47) years. The mean follow-up period was 5 (range, 2.4-10) years. According to the Wassel classification, 12 were type-II thumb polydactyly, 3 type-III, 11 type-IV, 6 type-V, one type-VI, and 3 type-VII. There was no perioperative mortality or wound infection. More than 88% of the patients were satisfied or very satisfied with functional and cosmetic outcomes. Postoperative complications such as scar hypertrophy, pulp atrophy, joint deformity, and instability were common but minor. Ridge nail deformity after the Bilhaut Cloquet procedure was amenable to secondary corrective procedures. All types of operated thumb polydactyly achieved similar mean Tada scores (14.7- 16.6 out of 20). The Wassel classification category, age, and surgical procedures were found to have no prognostic value with regard to the Tada score and presence of complications. CONCLUSION: Surgery on thumb polydactyly is rewarding. The Wassel classification category can be used as a guide for treatment, although it fails to predict the occurrence of postoperative complications or Tada scores. Our patients' results can serve as guidelines of expected outcomes after reconstructive procedures in different sub-types of thumb polydactyly.