Gemcitabine, carboplatin, and Epstein-Barr virus-specific autologous cytotoxic T lymphocytes for recurrent or metastatic nasopharyngeal carcinoma: VANCE, an international randomized phase III trial.

BACKGROUND: Epstein-Barr virus-specific cytotoxic T lymphocyte (EBV-CTL) is an autologous adoptive T-cell immunotherapy generated from the blood of individuals and manufactured without genetic modification. In a previous phase II trial of locally recurrent or metastatic nasopharyngeal carcinoma (R/M NPC) patients, first-line gemcitabine and carboplatin (GC) and EBV-CTL combination demonstrated objective antitumor EBV-CTL activity and a favorable safety profile. The present study explored whether this combined first-line chemo-immunotherapy strategy would produce superior clinical efficacy and better quality of life compared with conventional chemotherapy treatment. PATIENTS AND METHODS: This multicenter, randomized, phase III trial evaluated the efficacy and safety of GC followed by EBV-CTL versus GC alone as first-line treatment of R/M NPC patients. Thirty clinical sites in Singapore, Malaysia, Taiwan, Thailand, and the USA were included. Subjects were randomized to first-line GC (four cycles) and EBV-CTL (six cycles) or GC (six cycles) in a 1 : 1 ratio. The primary outcome was overall survival (OS) and secondary outcomes included progression-free survival, objective response rate, clinical benefit rate, quality of life, and safety. CLINICALTRIALS: gov identifier: NCT02578641. RESULTS: A total of 330 subjects with NPC were enrolled. Most subjects in both treatment arms received four or more cycles of chemotherapy and most subjects in the GC + EBV-CTL group received two or more infusions of EBV-CTL. The central Good Manufacturing Practices (GMP) facility produced sufficient EBV-CTL for 94% of GC + EBV-CTL subjects. The median OS was 25.0 months in the GC + EBV-CTL group and 24.9 months in the GC group (hazard ratio = 1.19; 95% confidence interval 0.91-1.56; P = 0.194). Only one subject experienced a grade 2 serious adverse event related to EBV-CTL. CONCLUSIONS: GC + EBV-CTL in subjects with R/M NPC demonstrated a favorable safety profile but no overall improvement in OS versus chemotherapy. This is the largest adoptive T-cell therapy trial reported in solid tumors to date.

Durvalumab with or without tremelimumab versus the EXTREME regimen as first-line treatment for recurrent or metastatic squamous cell carcinoma of the head and neck: KESTREL, a randomized, open-label, phase III study.

BACKGROUND: Patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) have a poor prognosis. The phase III KESTREL study evaluated the efficacy of durvalumab [programmed death-ligand 1 (PD-L1) antibody] with or without tremelimumab [cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody], versus the EXTREME regimen in patients with R/M HNSCC. PATIENTS AND METHODS: Patients with HNSCC who had not received prior systemic treatment for R/M disease were randomized (2 : 1 : 1) to receive durvalumab 1500 mg every 4 weeks (Q4W) plus tremelimumab 75 mg Q4W (up to four doses), durvalumab monotherapy 1500 mg Q4W, or the EXTREME regimen (platinum, 5-fluorouracil, and cetuximab) until disease progression. Durvalumab efficacy, with or without tremelimumab, versus the EXTREME regimen in patients with PD-L1-high tumors and in all randomized patients was assessed. Safety was also assessed. RESULTS: Durvalumab and durvalumab plus tremelimumab were not superior to EXTREME for overall survival (OS) in patients with PD-L1-high expression [median, 10.9 and 11.2 versus 10.9 months, respectively; hazard ratio (HR) = 0.96; 95% confidence interval (CI) 0.69-1.32; P = 0.787 and HR = 1.05; 95% CI 0.80-1.39, respectively]. Durvalumab and durvalumab plus tremelimumab prolonged duration of response versus EXTREME (49.3% and 48.1% versus 9.8% of patients remaining in response at 12 months), correlating with long-term OS for responding patients; however, median progression-free survival was longer with EXTREME (2.8 and 2.8 versus 5.4 months). Exploratory analyses suggested that subsequent immunotherapy use by 24.3% of patients in the EXTREME regimen arm contributed to the similar OS outcomes between arms. Grade 3/4 treatment-related adverse events (TRAEs) for durvalumab, durvalumab plus tremelimumab, and EXTREME were 8.9%, 19.1%, and 53.1%, respectively. CONCLUSIONS: In patients with PD-L1-high expression, OS was comparable between durvalumab and the EXTREME regimen. Durvalumab alone, and with tremelimumab, demonstrated durable responses and reduced TRAEs versus the EXTREME regimen in R/M HNSCC.

Cryo-FIB preparation of whole cells and tissue for cryo-TEM: use of high-pressure frozen specimens in tubes and planchets.

The desire to study macromolecular complexes within their cellular context requires the ability to produce thin samples suitable for cryo-TEM (cryo-transmission electron microscope) investigations. In this paper, we discuss two similar approaches, which were developed independently in Utrecht (the Netherlands) and Albany (USA). The methods are particularly suitable for both tissue samples and cell suspensions prepared by a high-pressure freezer (HPF). The workflows are explained with particular attention to potential pitfalls, while underlying principles are highlighted ('why to do so'). Although both workflows function with a high success rate, full execution requires considerable experience and remains demanding. In addition, throughput is low. We hope to encourage other research groups worldwide to take on the challenge of improving the HPF- cryo-FIB-SEM - cryo-TEM workflow. We discuss a number of suggestions to this end. LAY DESCRIPTION: Life is ultimately dictated by the interaction of molecules in our bodies. Highly complex equipment is being used and further developed to study these interactions. The present paper describes methods to prepare small, very thin lamellae (area of 5×5 µm2 , thickness 50-300 nm) of a cell to be studied in a cryo-transmission electron microscope (cryo-TEM). Special care must be taken to preserve the natural state of molecules in their natural environment. In the case of cryo-TEM, the samples must be frozen and kept frozen to be compatible with the vacuum conditions in the microscope. The frozen condition imposes technical challenges which are addressed. Two approaches to obtain the thin lamellae are described. Both make use of a focused ion beam (FIB) microscope. The FIB allows removal of material with nanometre precision by focusing a beam of ionised atoms (gallium ions) onto the sample. Careful control of the FIB allows cutting out of the required thin lamellae. In both strategies, the thin lamellae remain attached to the original sample, and the ensemble of sample with section and sample holder is transported from the FIB microscope to the TEM while being kept frozen.

Associations between comorbidity and quality of life outcomes after total joint replacement.

PURPOSE: We examined associations between self-reported and clinician-assessed comorbidity and quality of life (QOL) outcomes after hip and knee replacement. METHODS: This is a cross-sectional, questionnaire-based national survey. Participants aged 45 years or older (n = 409) were recruited from the New Zealand Joint Registry six months after a total hip (THR), total knee (TKR) or unicompartmental knee replacement (UKR). The main outcome QOL was measured using an 8-item short form of the World Health Organisation Quality of Life (WHOQOL-Bref) questionnaire six months following joint replacement surgery. The WHOQOL is a generic and non-health condition specific measure of QOL. RESULTS: Participants were on average 68 years of age, with more men (54%) than women (46%). Number of coexisting conditions and body mass index were correlated with age, pain and function scores, and QOL (p < 0.01), but not with each other. Linear regression analyses showed that comorbidities such as number of comorbid conditions and BMI had moderate associations with QOL outcomes. CONCLUSION: This study showed that general QOL outcomes following hip and knee joint replacement, while generally high, were associated with comorbidity burden and BMI. Future prospective research examining change in QOL before and following surgery would help to advance understandings of the various factors that contribute to patient satisfaction with their joint replacement.

Identification of circulating biomarkers for differentiating patients with papillary thyroid cancers from benign thyroid tumors.

BACKGROUND: This study aimed to identify the potential circulating biomarkers of protein, mRNAs, and long non-coding RNAs (lncRNAs) to differentiate the papillary thyroid cancers from benign thyroid tumors. METHODS: The study population of 100 patients was classified into identification (10 patients with papillary thyroid cancers and 10 patients with benign thyroid tumors) and validation groups (45 patients with papillary thyroid cancers and 35 patients with benign thyroid tumors). The Sengenics Immunome Protein Array-combined data mining approach using the Open Targets Platform was used to identify the putative protein biomarkers, and their expression validated using the enzyme-linked immunosorbent assay. Next-generation sequencing by Illumina HiSeq was used for the detection of dysregulated mRNAs and lncRNAs. The website Timer v2.0 helped identify the putative mRNA biomarkers, which were significantly over-expressed in papillary thyroid cancers than in adjacent normal thyroid tissue. The mRNA and lncRNA biomarker expression was validated by a real-time polymerase chain reaction. RESULTS: Although putative protein and mRNA biomarkers have been identified, their serum expression could not be confirmed in the validation cohorts. In addition, seven lncRNAs (TCONS_00516490, TCONS_00336559, TCONS_00311568, TCONS_00321917, TCONS_00336522, TCONS_00282483, and TCONS_00494326) were identified and validated as significantly downregulated in patients with papillary thyroid cancers compared to those with benign thyroid tumors. These seven lncRNAs showed moderate accuracy based on the area under the curve (AUC = 0.736) of receiver operating characteristic in predicting the occurrence of papillary thyroid cancers. CONCLUSIONS: We identified seven downregulated circulating lncRNAs with the potential for predicting the occurrence of papillary thyroid cancers.

Differential effects of aquatic anaesthetics on the pharmacokinetics of antibiotics: Examples using florfenicol in Nile tilapia (Oreochromis niloticus).

Anaesthetics are commonly applied in pharmacokinetic (PK) studies to assure smooth handling of experimental procedures or to promote animal welfare. However, the influence of anaesthetics on the PK of co-administered drug is generally unknown but assumes ignorable. The goal of the study was to investigate the effect of tricaine methanesulfonate (MS-222), 2-phenoxyethanol (2-PE) and eugenol (EUG) on the PK of florfenicol (FF) in Nile tilapia. Twenty-eight fish were repeatedly exposed to 90 ppm EUG, 300 ppm MS-222 or 900 ppm 2-PE before FF oral administration (15 mg/kg) and each successive blood sampling. The serum concentration-time profiles were analysed by a 2-compartmental model, and the generated parameters in the control (without anaesthetic) and anaesthetic groups were statistically compared. The results demonstrated that the serum concentrations of each anaesthetic were similar at every FF sampling times (70 µg/ml for MS-222; 277 µg/ml for 2-PE; and 61 µg/ml for EUG). In comparison with the control group, the repeated use of MS-222 did not result in a statistical difference in most of the PK parameters. In contrast, the elimination half-lives of the 2-PE and EUG groups were significantly longer whereas the absorption and distribution half-lives of the 2-PE group were significantly shorter than the control, resulting in altered optimal dosages in the simulation modelling. Whether or not the numbers and extent of PK parameters change mitigate subsequent estimations of other PK-derived secondary values such as dosing regimen and withdrawal time remains to be elucidated, but the auxiliary use of anaesthetics in PK studies should not assume uninfluential.

Gaussian Thermal Operations and The Limits of Algorithmic Cooling.

The study of thermal operations allows one to investigate the ultimate possibilities of quantum states and of nanoscale thermal machines. Whilst fairly general, these results typically do not apply to continuous variable systems and do not take into account that, in many practically relevant settings, system-environment interactions are effectively bilinear. Here we tackle these issues by focusing on Gaussian quantum states and channels. We provide a complete characterization of the most general Gaussian thermal operation acting on an arbitrary number of bosonic modes, which turn out to be all embeddable in a Markovian dynamics, and derive necessary and sufficient conditions for state transformations under such operations in the single-mode case, encompassing states with nonzero coherence in the energy eigenbasis (i.e., squeezed states). Our analysis leads to a no-go result for the technologically relevant task of algorithmic cooling: We show that it is impossible to reduce the entropy of a system coupled to a Gaussian environment below its own or the environmental temperature, by means of a sequence of Gaussian thermal operations interspersed by arbitrary (even non-Gaussian) unitaries. These findings establish fundamental constraints on the usefulness of Gaussian resources for quantum thermodynamic processes.

Combination immunosuppressant therapy and lupus nephritis outcome: a hospital-based study.

Lupus nephritis (LN) is the leading cause of mortality in lupus patients. This study aimed to investigate the treatment outcome and renal histological risk factors of LN in a tertiary referral center. Between 2006 and 2017, a retrospective observational study enrolled 148 biopsy-proven LN patients. After propensity score matching, 75 cases were included for further analysis. The classification and scoring of LN were assessed according to the International Society of Nephrology/Renal Pathology Society. Treatment response was evaluated by daily urine protein and urinalysis at two years after commencing induction treatment and the development of end-stage renal disease (ESRD). In total, 50.7% patients achieved complete remission (CR) or partial remission (PR), while 49.3% patients were categorized as nonresponders. Therapeutic responses in terms of CR/PR rates were associated with Systemic Lupus Erythematosus Disease Activity Index scores (odds ratio (OR): 1.34, 95% confidence interval (CI): 1.12-1.60, p = 0.001). Moreover, higher baseline creatinine levels (hazard ratio (HR): 2.10, 95% CI: 1.29-3.40, p = 0.003), higher renal activity index (HR: 1.30, 95% CI: 1.07-1.58, p = 0.008) and chronicity index (HR: 1.40, 95% CI: 1.06-1.85, p = 0.017) predicted ESRD. Among pathological scores, cellular crescents (HR: 4.42, 95% CI: 1.01-19.38, p = 0.049) and fibrous crescents (HR: 5.93, 95% CI: 1.41-24.92, p = 0.015) were independent risk factors for ESRD. In conclusion, higher lupus activity was a good prognostic marker for renal remission. Renal histology was predictive of ESRD. Large-scale prospective studies are required to verify the efficacy of mycophenolate in combination with azathioprine or cyclosporine in LN patients.

A simulation impact evaluation of a cigarette excise tax increase on licit and illicit cigarette consumption and tax revenue in 36 European countries.

OBJECTIVES: To assess the impact of a simulated 10% tax-induced cigarette price increase on licit and illicit consumption and tax revenues in 36 European countries. METHODS: Employing panel data for licit and illicit cigarette consumption, fixed effects regression models were applied for different income clusters. RESULTS: Total cigarette consumption dropped by about 3.1% as a result of the simulated tax-induced price increase. Annual illicit cigarette consumption increased by 1.52%, (95% confidence interval: 0.21, 2.83), while annual licit cigarette consumption decreased by 4.61% (95% confidence interval: -6.51, -2.72) in the observed 36 European countries. With total consumption decreasing by about 8%, the Czech Republic, Latvia, Lithuania, Poland and Slovakia were affected the most by the price hike. More specifically, licit consumption in these countries decreased by 18.43% (95% confidence interval: -19.91, -16.95) while illicit use increased by 10.99% (95% confidence interval: 6.01, 15.96). Moreover, the overall annual tobacco tax revenue increased by US$14.69 billion in the simulation. CONCLUSION: Results of the study suggest that European policy makers continue to implement tobacco taxation policies to control smoking prevalence and national health care expenditures. At the same time, efforts to kerb contraband activities along EU Eastern borders should be intensified.

A real-time prediction model for post-irradiation malignant cervical lymph nodes.

OBJECTIVE: To establish a real-time predictive scoring model based on sonographic characteristics for identifying malignant cervical lymph nodes (LNs) in cancer patients after neck irradiation. METHODS: One-hundred forty-four irradiation-treated patients underwent ultrasonography and ultrasound-guided fine-needle aspirations (USgFNAs), and the resultant data were used to construct a real-time and computerised predictive scoring model. This scoring system was further compared with our previously proposed prediction model. RESULTS: A predictive scoring model, 1.35 × (L axis) + 2.03 × (S axis) + 2.27 × (margin) + 1.48 × (echogenic hilum) + 3.7, was generated by stepwise multivariate logistic regression analysis. Neck LNs were considered to be malignant when the score was ≥ 7, corresponding to a sensitivity of 85.5%, specificity of 79.4%, positive predictive value (PPV) of 82.3%, negative predictive value (NPV) of 83.1%, and overall accuracy of 82.6%. When this new model and the original model were compared, the areas under the receiver operating characteristic curve (c-statistic) were 0.89 and 0.81, respectively (P < .05). CONCLUSIONS: A real-time sonographic predictive scoring model was constructed to provide prompt and reliable guidance for USgFNA biopsies to manage cervical LNs after neck irradiation.

Prognostic impact of pre-treatment neutrophil-to-lymphocyte ratio (NLR) in nasopharyngeal carcinoma: A retrospective study of 180 Taiwanese patients.

OBJECTIVES: Nasopharyngeal cancer (NPC) is an endemic disease in Taiwan. Prognostic factors the anatomical TNM stage are important for its prognostic stratification. An elevated neutrophil-to-lymphocyte ratio (NLR) has been reported to be associated with poor prognosis in various solid tumours. In this study, we analysed the prognostic impact of the NLR in NPC in Taiwan. DESIGN: Single-institution retrospective study. SETTING: Medical centre. PARTICIPANTS: One hundred and eighty patients with NPC treated at the Far Eastern Memorial Hospital, Taiwan, from January 2007 to December 2013. MAIN OUTCOME MEASURES: The association between the clinical or haematological presentations and the prognosis. RESULTS: The majority of the 180 patients included in this study were men (80%) and were <65 years old (91.7%). A neck mass (55.6%) was the most common clinical presentation, followed by nasal (39.4%) and aural (30.6%) symptoms. In addition, the majority (75.4%) of patients had advanced stage (III and IV) disease. Patients with a high NLR (≧3.6) had significantly lower progression-free survival, overall survival and disease-specific survival rates. The association between high NLR and poor prognosis was more pronounced in patients with advanced disease than in those with early-stage NPC. The results of a multivariate analysis revealed that advanced age, clinical symptoms including headache, diplopia and facial numbness, advanced disease stage, and high NLR were independent prognostic factors. CONCLUSION: A high NLR is an independent poor prognostic factor of NPC in Taiwan.

Association of betel nut chewing with exercise performance in a military male cohort: the CHIEF study.

INTRODUCTION: Betel nut chewing may cause obesity, neurohormonal activation and inflammation, possibly impairing exercise performances. METHODS: We examined the cross-sectional association in 4388 military male adults aged 18-50 years from the cardiorespiratory fitness in armed forces study in Taiwan between 2013 and 2014. The status of betel nut chewing was classified as current and former/never based on each participant's response to a questionnaire. Physical fitness was evaluated by three basic exercise tests including 3000 m running, 2 min sit-ups and 2 min push-ups. Multiple logistic regression for the best 10% and the worst 10% performers in each exercise, and linear regression were used to determine the relationship. RESULTS: There were 564 current chewers and 3824 non-current chewers for the analysis. The linear regression shows that current betel nut chewing was positively correlated with 3000 m running duration (r=0.37, p=0.042) after adjusting for age, service specialty, body mass index, exercise frequency and alcohol intake. In addition, the logistic regression shows that as compared with non-current chewers, current chewers had lower odds of being the top 10% performers in 2 min push-ups and higher odds of being the bottom 10% performers in 2 min sit-ups (ORs and 95% CIs: 0.71 (0.50 to 0.99) and 1.32 (1.00 to 1.75), respectively). However, the associations between betel nut chewing and physical fitness were all insignificant after further adjusting for current smoking. CONCLUSIONS: Our findings suggest that the impairment of physical fitness associated with betel nut chewing of military young men might be mainly mediated or moderated by the coexisted cigarette smoking.

Patterns of recurrence after oesophagectomy and postoperative chemoradiotherapy versus surgery alone for oesophageal squamous cell carcinoma.

BACKGROUND: Patterns of recurrence after surgery with postoperative chemoradiotherapy (S-CCRT) or surgery alone in patients with oesophageal squamous cell carcinoma (SCC) may differ. This might influence the nature and timing of subsequent management strategies. METHODS: Patients with SCC who had undergone R0 resection were included. Propensity score matching was used to select matched groups. Survival and recurrence were compared by Kaplan-Meier analysis. Univariable and multivariable Cox regression analyses were used to identify prognostic factors for overall and disease-free survival. RESULTS: A total of 1390 patients were included, of whom 1000 had surgery alone and 390 underwent S-CCRT. Propensity score matching yielded 213 well balanced pairs. The 3-year overall survival rate and median survival time in the S-CCRT group were 0·50 and 36·5 (95 per cent c.i. 25·1 to 52·6) months respectively, compared with 0·38 and 22·8 (18·2 to 29·0) months in the surgery-alone group (P = 0·006). The 3-year disease-free survival rate and median disease-free survival time in the S-CCRT group were 0·46 and 30·6 (22·2 to 39·3) months respectively, compared with 0·36 and 17·6 (11·3 to 23·9) months in the surgery-alone group (P = 0·006). The 2-year freedom from locoregional recurrence rate was 0·87 and 0·77 in the S-CCRT and surgery-alone groups respectively (P = 0·003). In multivariable analysis, independent prognostic factors for disease-free survival included age over 56 years, pT3-4 category, pN category, poor differentiation, tumour length exceeding 4·0 cm, and receiving postoperative chemoradiotherapy (hazard ratio 0·62, 95 per cent c.i. 0·47 to 0·81; P < 0·001). CONCLUSION: Oesophagectomy with postoperative chemoradiotherapy was associated with longer survival and lower recurrence rates, especially at a locoregional level, compared with surgery alone.

Predictive value of nodal maximum standardized uptake value of pretreatment [18F]fluorodeoxyglucose positron emission tomography imaging in patients with esophageal cancer.

We retrospectively reviewed 102 patients with esophageal cancer (97.1% squamous cell carcinoma, 96.1% stage III) received FDG-PET staging and were treated by chemoradiotherapy with or without resection to assess whether the pretreatment [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) maximum standardized uptake value (SUVmax) of the primary tumor and metastatic lymph nodes can predict the prognosis of patients with esophageal cancer. Receiver operating characteristic analysis was performed to find the cutoff values for primary tumor SUVmax and nodal SUVmax. The influence of clinical factors including primary tumor SUVmax and nodal SUVmax on local progression-free survival, nodal progression-free survival (NPFS), distant metastases-free survival (DMFS), and overall survival (OS) were evaluated using univariate and multivariate analyses. A total of 40 patients received esophagectomy after neoadjuvant chemoradiotherapy (trimodality), while 62 patients received definitive chemoradiotherapy (dCRT). The median follow-up was 26.4 months. The SUVmax of primary tumor had no significant predictive value on all outcomes, while the SUVmax of metastatic lymph nodes had predictive value on several outcomes. High nodal SUVmax (≥7) predicted for worse outcomes than low nodal SUVmax (<7) in the patients who received dCRT (two-year DMFS, 17% vs. 92%, P < 0.001; NPFS, 14% vs. 81%, P = 0.001; OS, 21% vs. 50%, P = 0.003), but not in those received trimodality. On multivariate analysis of patients receiving dCRT, nodal SUVmax was the strongest independent predictor on DMFS (hazard ratio [HR] 13.93, P < 0.001), NPFS (HR 3.99, P = 0.026), PFS (HR 2.90, P = 0.003), and OS (HR 3.80, P = 0.001). High pretreatment nodal SUVmax predicts worse treatment outcomes for the patients treated with dCRT.

Rapidly increasing liver progenitor cell numbers in human regenerating liver after portal vein ligation and liver partition.

BACKGROUND: Liver regeneration is dependent on the proliferation of hepatocytes. Hepatic progenitor cells are intra-hepatic precursor cells capable of differentiating into hepatocytes or biliary cells. Although liver progenitor cell proliferation during the regenerative process has been observed in animal models of severe liver injury, it has never been observed in vivo in humans because it is unethical to take multiple biopsy specimens for the purpose of studying the proliferation of liver progenitor cells and the roles they play in liver regeneration. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a staged procedure for inducing remnant liver hypertrophy so that major hepatectomy can be performed safely. This staged procedure allows for liver biopsy specimens to be taken before and after the liver begins to regenerate. CASE PRESENTATION: The liver progenitor cell proliferation is observed in a patient undergoing ALPPS for a metastatic hepatic tumour. Liver biopsy is acquired before and after ALPPS for the calculation of average number of liver progenitor cell under high magnification examination by stain of immunomarkers. This is the first in vivo evidence of growing liver progenitor cells demonstrated in a regenerating human liver.

Periodontal ligament cells as alternative source for cell-based therapy of tendon injuries: in vivo study of full-size Achilles tendon defect in a rat model.

Tendon's natural healing potential is extremely low and inefficient, with significant dysfunction and disability due to hypocellularity and hypovascularity of tendon tissues. The application of stem cells can aid in significantly enhanced repair of tendon rupture; therefore, the main aim of this study is to assess the potential of using periodontal ligament cells (PDL), usually obtained from patients undergoing orthodontic treatment, as a novel cell source for cell-based therapy for tendon injuries in a clinically relevant rat full-size Achilles tendon defect. In addition, the study compares the differences between the healing effects of Achilles tendon-derived cells (AT) versus PDL and, hence, comprises of four experimental groups, native tendon (NT), empty defect (ED), PDL and human AT (hAT). The tendon healing in each group was assessed in the late remodelling phase at 16 weeks after surgery using a combination of methods, including evaluation of gross morphological appearance; various histological and immunohistological stainings; and detailed analyses of cell morphometry. Based on these outcome measures, PDL cell-implanted tendons exhibited not only advanced tissue maturation, less ectopic fibrocartilage formation, more organised collagen fibres, tendon matrix expression corresponding to the final healing stage, and better cell-morphometry parameters when compared with the ED group, but were also very similar to the tendons treated with hAT-derived cells. Taken together, our study clearly demonstrates the feasibility of using PDL cells as a novel cell source for tendon repair and strongly recommends this cell type for the future development of innovative regenerative applications for treatment of different tendon or ligament pathologies.

Designing a stronger interface through graded structures in amorphous/nanocrystalline ZrCu/Cu multilayered films.

Many multilayered nano-structures appear to fail due to brittle matter along the interfaces. In order to toughen them, in this study, the microstructure and interface strength of multilayered thin films consisting of amorphous ZrCu and nanocrystalline Cu (with sharp or graded interfaces) are examined and analyzed. The interface possesses a gradient nature in terms of composition, nanocrystalline phase size and volume fraction. The bending results extracted from the nano-scaled cantilever bending samples demonstrate that multilayered films with graded interfaces would have a much higher interface bending strength/strain/modulus, and an overall improvement upgrade of more than 50%. The simple graded interface design of multilayered thin films with improved mechanical properties can offer much more promising performance in structural and functional applications for MEMS or optical coating.

Herb formula enhances treatment of impotent patients after penile venous stripping: a randomised clinical trials.

Herbs have been regarded as aphrodisiacs in treating impotence for many centuries despite little true scientific evidence. Our latest refined penile venous stripping (PVS) technique is effective in treating impotence, although this procedure remains controversial. A synergic effect of PVS and oral herbs was confirmed in our practice but lacked rigorous scientific proof. The objective of this report was to review our experience with this combination. From August 2010 to May 2014, 263 males underwent PVS. Among these, 67 unsatisfied men chose additional salvage therapy and were randomly assigned to oral herbs (n = 35) or placebo treatment (n = 32) which replaced herb eventually. All were evaluated with the international index of erectile function (IIEF-5) scoring and our dual pharmaco-cavernosography. The pre-op IIEF-5 score for the herb group was 9.7 ± 3.7, post-operative 13.9 ± 3.3 and post-herb 19.6 ± 3.4, while the control group scores were as follows: pre-op 9.3 ± 4.1, post-op 14.5 ± 3.6, post-placebo 15.1 ± 3.5 and post-herb 19.9 ± 3.2. Although there was no significant difference between the two groups pre-operatively, post-operatively and post-herb, a statistically significant difference was found post-salvage therapy (19.6 ± 3.4 versus 15.1 ± 3.6, P < 0.001). It appears that the combination of oral herbs and PVS treatment provides an enhanced outcome to impotent patients refractory to medicine and unsatisfied with PVS monotherapy alone.

Smoking-related changes or brand switching? Smokers' anticipated responses to a large increase in Taiwan's Tobacco Health and Welfare Surcharge.

OBJECTIVES: This study examines the impact on smokers' behaviour of a planned increase in the Health and Welfare Surcharge of Tobacco Products in Taiwan. STUDY DESIGN: This study used a structured questionnaire to perform telephone interviews. Stratified random sampling was applied to interview current smokers aged 18-65 years in Taiwan. METHODS: Based on nationwide survey data of smokers' responses to future increases in cigarette prices, this study used multinomial logistic regression to perform its analyses. RESULTS: After the proposed increase in the Health and Welfare Surcharge of Tobacco Products, subsequent cigarette price increases would motivate nearly 30% of the smokers to adopt smoking-related changes and 10% to change to lower-priced brands. CONCLUSIONS: The study suggests that a large increase in the Health and Welfare Surcharge of Tobacco Products would lead to considerable changes in smoking behaviour, which in turn would increase cessation rate at the population level.

¹8F-FP-(+)-DTBZ positron emission tomography detection of monoaminergic deficient network in patients with carbon monoxide related parkinsonism.

BACKGROUND AND PURPOSE: Although parkinsonism after carbon monoxide (CO) intoxication is well known, neurotransmitter deficient networks that are responsible for the severity of parkinsonism have rarely been systemically evaluated. METHODS: Eighteen patients with CO-related parkinsonism and nine age- and sex-matched controls were enrolled for detailed neurological examinations, three-dimensional T1-weighted images, diffusion tensor imaging and (18)F-9-fluoropropyl-(+)-dihydrotetrabenzazine ((18)F-FP-(+)-DTBZ) positron emission tomography (PET). The structural analysis included voxel-based morphometry to assess grey matter atrophy and tract-based spatial statistics related to white matter involvement. For presynaptic monoaminergic assessment, volume of interest analysis in six subcortical regions and non-parametric voxel-wise comparison were performed on PET images with estimation of registration parameters from magnetic resonance images. All the imaging modalities were compared between the patients and controls. For the patients, a regression model for correlation with cognitive behaviour and Unified Parkinson's Disease Rating Scale (UPDRS) score was used. RESULTS: In the patients, monoaminergic deficit networks were found in the caudate, anterior putamen, anterior insular, thalamus and anterior cingulate cortex. The UPDRS revealed significant correlations with the prefrontal white matter fractional anisotropy values and with the (18)F-FP-(+)-DTBZ uptake values in the caudate nucleus, insular, medial prefrontal and dorsomedial thalamus. The neuropsychiatric inventory score correlated with the (18)F-FP-(+)-DTBZ uptake values in the anterior cingulate cortex and dorsolateral prefrontal cortex. CONCLUSIONS: Our study demonstrated monoaminergic deficits and white matter damage networks in CO-related parkinsonism that determined the severity of parkinsonism or behaviour changes. As the substantia nigra was spared, the monoaminergic topography of involvement suggests a different pathophysiology in CO-related parkinsonism.