Advanced electrophysiologic mapping systems: an evidence-based analysis.
To assess the effectiveness, cost-effectiveness, and demand in Ontario for catheter ablation of complex arrhythmias guided by advanced nonfluoroscopy mapping systems. Particular attention was paid to ablation for atrial fibrillation (AF). Tachycardia Tachycardia refers to a diverse group of arrhythmias characterized by heart rates that are greater than 100 beats per minute. It results from abnormal firing of electrical impulses from heart tissues or abnormal electrical pathways in the heart because of scars. Tachycardia may be asymptomatic, or it may adversely affect quality of life owing to symptoms such as palpitations, headaches, shortness of breath, weakness, dizziness, and syncope. Atrial fibrillation, the most common sustained arrhythmia, affects about 99,000 people in Ontario. It is associated with higher morbidity and mortality because of increased risk of stroke, embolism, and congestive heart failure. In atrial fibrillation, most of the abnormal arrhythmogenic foci are located inside the pulmonary veins, although the atrium may also be responsible for triggering or perpetuating atrial fibrillation. Ventricular tachycardia, often found in patients with ischemic heart disease and a history of myocardial infarction, is often life-threatening; it accounts for about 50% of sudden deaths. Treatment of Tachycardia The first line of treatment for tachycardia is antiarrhythmic drugs; for atrial fibrillation, anticoagulation drugs are also used to prevent stroke. For patients refractory to or unable to tolerate antiarrhythmic drugs, ablation of the arrhythmogenic heart tissues is the only option. Surgical ablation such as the Cox-Maze procedure is more invasive. Catheter ablation, involving the delivery of energy (most commonly radiofrequency) via a percutaneous catheter system guided by X-ray fluoroscopy, has been used in place of surgical ablation for many patients. However, this conventional approach in catheter ablation has not been found to be effective for the treatment of complex arrhythmias such as chronic atrial fibrillation or ventricular tachycardia. Advanced nonfluoroscopic mapping systems have been developed for guiding the ablation of these complex arrhythmias. Four nonfluoroscopic advanced mapping systems have been licensed by Health Canada: CARTO EP mapping System (manufactured by Biosense Webster, CA) uses weak magnetic fields and a special mapping/ablation catheter with a magnetic sensor to locate the catheter and reconstruct a 3-dimensional geometry of the heart superimposed with colour-coded electric potential maps to guide ablation. EnSite System (manufactured by Endocardial Solutions Inc., MN) includes a multi-electrode non-contact catheter that conducts simultaneous mapping. A processing unit uses the electrical data to computes more than 3,000 isopotential electrograms that are displayed on a reconstructed 3-dimensional geometry of the heart chamber. The navigational system, EnSite NavX, can be used separately with most mapping catheters. The LocaLisa Intracardiac System (manufactured by Medtronics Inc, MN) is a navigational system that uses an electrical field to locate the mapping catheter. It reconstructs the location of the electrodes on the mapping catheter in 3-dimensional virtual space, thereby enabling an ablation catheter to be directed to the electrode that identifies abnormal electric potential. Polar Constellation Advanced Mapping Catheter System (manufactured by Boston Scientific, MA) is a multielectrode basket catheter with 64 electrodes on 8 splines. Once deployed, each electrode is automatically traced. The information enables a 3-dimensional model of the basket catheter to be computed. Colour-coded activation maps are reconstructed online and displayed on a monitor. By using this catheter, a precise electrical map of the atrium can be obtained in several heartbeats. A systematic search of Cochrane, MEDLINE and EMBASE was conducted to identify studies that compared ablation guided by any of the advanced systems to fluoroscopy-guided ablation of tachycardia. English-language studies with sample sizes greater than or equal to 20 that were published between 2000 and 2005 were included. Observational studies on safety of advanced mapping systems and fluoroscopy were also included. Outcomes of interest were acute success, defined as termination of arrhythmia immediately following ablation; long-term success, defined as being arrhythmia free at follow-up; total procedure time; fluoroscopy time; radiation dose; number of radiofrequency pulses; complications; cost; and the cost-effectiveness ratio. Quality of the individual studies was assessed using established criteria. Quality of the overall evidence was determined by applying the GRADE evaluation system. (3) Qualitative synthesis of the data was performed. Quantitative analysis using Revman 4.2 was performed when appropriate. Quality of the Studies Thirty-four studies met the inclusion criteria. These comprised 18 studies on CARTO (4 randomized controlled trials [RCTs] and 14 non-RCTs), 3 RCTs on EnSite NavX, 4 studies on LocaLisa Navigational System (1 RCT and 3 non-RCTs), 2 studies on EnSite and CARTO, 1 on Polar Constellation basket catheter, and 7 studies on radiation safety. The quality of the studies ranged from moderate to low. Most of the studies had small sample sizes with selection bias, and there was no blinding of patients or care providers in any of the studies. Duration of follow-up ranged from 6 weeks to 29 months, with most having at least 6 months of follow-up. There was heterogeneity with respect to the approach to ablation, definition of success, and drug management before and after the ablation procedure. Evidence is based on a small number of small RCTS and non-RCTS with methodological flaws.Advanced nonfluoroscopy mapping/navigation systems provided real time 3-dimensional images with integration of anatomic and electrical potential information that enable better visualization of areas of interest for ablationAdvanced nonfluoroscopy mapping/navigation systems appear to be safe; they consistently shortened the fluoroscopy duration and radiation exposure.Evidence suggests that nonfluoroscopy mapping and navigation systems may be used as adjuncts to rather than replacements for fluoroscopy in guiding the ablation of complex arrhythmias.Most studies showed a nonsignificant trend toward lower overall failure rate for advanced mapping-guided ablation compared with fluoroscopy-guided mapping.Pooled analyses of small RCTs and non-RCTs that compared fluoroscopy- with nonfluoroscopy-guided ablation of atrial fibrillation and atrial flutter showed that advanced nonfluoroscopy mapping and navigational systems:Yielded acute success rates of 69% to 100%, not significantly different from fluoroscopy ablation.Had overall failure rates at 3 months to 19 months of 1% to 40% (median 25%).Resulted in a 10% relative reduction in overall failure rate for advanced mapping guided-ablation compared to fluoroscopy guided ablation for the treatment of atrial fibrillation.Yielded added benefit over fluoroscopy in guiding the ablation of complex arrhythmia. The advanced systems were shown to reduce the arrhythmia burden and the need for antiarrhythmic drugs in patients with complex arrhythmia who had failed fluoroscopy-guided ablationBased on predominantly observational studies, circumferential PV ablation guided by a nonfluoroscopy system was shown to do the following:Result in freedom from atrial fibrillation (with or without antiarrhythmic drug) in 75% to 95% of patients (median 79%). This effect was maintained up to 28 months.Result in freedom from atrial fibrillation without antiarrhythmic drugs in 47% to 95% of patients (median 63%).Improve patient survival at 28 months after the procedure as compared with drug therapy.Require special skills; patient outcomes are operator dependent, and there is a significant learning curve effect.Complication rates of pulmonary vein ablation guided by an advanced mapping/navigation system ranged from 0% to 10% with a median of 6% during a follow-up period of 6 months to 29 months.The complication rate of the study with the longest follow-up was 8%.The most common complications of advanced catheter-guided ablation were stroke, transient ischemic attack, cardiac tamponade, myocardial infarction, atrial flutter, congestive heart failure, and pulmonary vein stenosis. A small number of cases with fatal atrial-esophageal fistula had been reported and were attributed to the high radiofrequency energy used rather than to the advanced mapping systems. An Ontario-based economic analysis suggests that the cumulative incremental upfront costs of catheter ablation of atrial fibrillation guided by advanced nonfluoroscopy mapping could be recouped in 4.7 years through cost avoidance arising from less need for antiarrhythmic drugs and fewer hospitalization for stroke and heart failure. Expert Opinion Expert consultants to the Medical Advisory Secretariat noted the following: Nonfluoroscopy mapping is not necessary for simple ablation procedures (e.g., typical flutter). However, it is essential in the ablation of complex arrhythmias including these:Symptomatic, drug-refractory atrial fibrillationArrhythmias in people who have had surgery for congenital heart disease (e.g., macro re-entrant tachycardia in people who have had surgery for congenital heart disease).Ventricular tachycardia due to myocardial infarctionAtypical atrial flutterAdvanced mapping systems represent an enabling technology in the ablation of complex arrhythmias. The ablation of these complex cases would not have been feasible or advisable with fluoroscopy-guided ablation and, therefore, comparative studies would not be feasible or ethical in such cases. (ABSTRACT TRUNCATED)


Genetic evidence that the higher plant Rab-D1 and Rab-D2 GTPases exhibit distinct but overlapping interactions in the early secretory pathway.
GTPases of the Rab1 subclass are essential for membrane traffic between the endoplasmic reticulum (ER) and Golgi complex in animals, fungi and plants. Rab1-related proteins in higher plants are unusual because sequence comparisons divide them into two putative subclasses, Rab-D1 and Rab-D2, that are conserved in monocots and dicots. We tested the hypothesis that the Rab-D1 and Rab-D2 proteins of Arabidopsis represent functionally distinct groups. RAB-D1 and RAB-D2a each targeted fluorescent proteins to the same punctate structures associated with the Golgi stacks and trans-Golgi-network. Dominant-inhibitory N121I mutants of each protein inhibited traffic of diverse cargo proteins at the ER but they appeared to act via distinct biochemical pathways as biosynthetic traffic in cells expressing either of the N121I mutants could be restored by coexpressing the wild-type form of the same subclass but not the other subclass. The same interaction was observed in transgenic seedlings expressing RAB-D1 [N121I]. Insertional mutants confirmed that the three Arabidopsis Rab-D2 genes were extensively redundant and collectively performed an essential function that could not be provided by RAB-D1, which was non-essential. However, plants lacking RAB-D1, RAB-D2b and RAB-D2c were short and bushy with low fertility, indicating that the Rab-D1 and Rab-D2 subclasses have overlapping functions.


International trade and determinants of price differentials of insulin medicine.
Empirical studies on pharmaceutical pricing across countries have found evidence that prices vary according to per capita income. These studies are typically based on survey data from a subset of countries and cover only one year. In this paper, we study the international trade and price of insulin by using detailed trade data for 186 importing countries from 1995 to 2013. With almost 12,000 observations, our study constitutes the largest comparative study on pharmaceutical pricing conducted so far. The large dataset allows us to uncover new determinants of price differentials. Our analysis shows that the international trade of insulin increased substantially over this time period, clearly outpacing the increasing prevalence of diabetes. Using the unit values of imports, we also study the determinants of price differentials between countries. Running various panel regressions, we find that the differences in prices across countries can be explained by the following factors: First, corroborating earlier studies, we find that per capita GDP is positively correlated with the unit price of insulin. Second, the price of insulin drugs originating from Organisation for Economic Co-operation and Development countries tends to be substantially higher than for those imported from developing countries. Third, more intense competition among suppliers leads to lower insulin prices. Fourth, higher out-of-pocket payments for health care are associated with higher prices. Finally, higher volumes and tariffs seem to result in lower unit prices.


Extracellular matrix composition and remodeling in human abdominal aortic aneurysms: a proteomics approach.
Abdominal aortic aneurysms (AAA) are characterized by pathological remodeling of the aortic extracellular matrix (ECM). However, besides the well-characterized elastolysis and collagenolysis little is known about changes in other ECM proteins. Previous proteomics studies on AAA focused on cellular changes without emphasis on the ECM. In the present study, ECM proteins and their degradation products were selectively extracted from aneurysmal and control aortas using a solubility-based subfractionation methodology and analyzed by gel-liquid chromatography-tandem MS and label-free quantitation. The proteomics analysis revealed novel changes in the ECM of AAA, including increased expression as well as degradation of collagen XII, thrombospondin 2, aortic carboxypeptidase-like protein, periostin, fibronectin and tenascin. Proteomics also confirmed the accumulation of macrophage metalloelastase (MMP-12). Incubation of control aortic tissue with recombinant MMP-12 resulted in the extensive fragmentation of these glycoproteins, most of which are novel substrates of MMP-12. In conclusion, our proteomics methodology allowed the first detailed analysis of the ECM in AAA and identified markers of pathological ECM remodeling related to MMP-12 activity.


Effect of the Timing of Fungicide Application on Fusarium Head Blight and Mycotoxin Contamination in Wheat.
Fungicide application to control Fusarium head blight (FHB) and accompanying mycotoxin contamination in wheat is generally performed at anthesis because wheat is most susceptible to FHB around this stage. In this study, we evaluated the effect of the timing of fungicide application on FHB and mycotoxin (deoxynivalenol and nivalenol) accumulation in wheat based on our previous finding that the late period of grain development (beyond 20 days after anthesis [DAA]) is important to determine the final toxin contamination level in wheat. Thiophanate-methyl fungicide was tested under artificial inoculation conditions in which moisture and inoculum spores were provided throughout the testing period. Eight treatments differing in application timing (anthesis, 10, 20, and 30 DAA) and in the number of applications (0 to 2) were tested for 2 years. The results indicated that fungicide application timing differentially affects FHB (disease) and mycotoxin concentration. Fungicide application at 20 DAA reduced mycotoxin concentration in matured grain without reducing FHB severity, whereas application at anthesis was crucial for reducing FHB. These results and our previous findings suggest that around 20 DAA (late milk stage) is a potentially critical timing for mycotoxin control in wheat.


Poor-quality sleep is associated with metabolic syndrome in Korean adults.
Sleep disorder and metabolic syndrome (MetS) are important health-related problems. Recently, sleep duration has decreased among Korean adults. In this study, we examined whether sleep quality is associated with MetS by analyzing 301 subjects, aged 20 years or over, without acute and severe illness who visited three primary care clinics. Sleep duration, sleep quality and the risk of sleep-related breathing disorder (SRBD) were assessed with a standardized sleeping-estimating instrument. MetS was defined according to the modified diagnostic criteria of the National Cholesterol Education Program Adult Treatment Panel-III using the Korean abdominal obesity definition. In the multiple logistic regression analysis, compared with the 7-hour sleep group, the adjusted odds ratios (ORs) of the ≤ 5- and ≥ 9-hour sleep groups for MetS were 4.89 and 5.98, respectively. Compared with the good-sleep quality and low-SRBD risk groups, the adjusted ORs of the poor-quality sleep and high-SRBD risk groups were 3.83 and 1.92, respectively (p < 0.05). In the ≤ 5- and ≥ 9-hour sleep groups, the prevalence of elevated triglyceride and high HOMA-IR was higher (p = 0.069). In the poor-quality sleep group, the prevalence of abdominal obesity, elevated triglyceride, low HDL cholesterol, high fasting insulin and high HOMA-IR were higher. In the high-SRBD risk group, the prevalence of abdominal obesity, obesity and elevated triglyceride were higher (p < 0.05). Overall, the ≤ 5- or ≥ 9-hour sleep duration, poor-quality sleep and high-SRBD risk are related with the high prevalence of MetS, perhaps through elevated insulin-resistance resulting from adiposity.


Time-resolved photoionization spectroscopy of mixed Rydberg-valence states: indole case study.
Time-resolved photoelectron imaging was used to study non-adiabatic relaxation dynamics in gas-phase indole following photo-excitation at 267 nm and 258 nm. Our data analysis was supported by various ab initio calculations using both coupled cluster and density functional methods. The highly differential energy- and angle-resolved information provided by our experimental approach provides extremely subtle details of the complex interactions occurring between several low-lying electronically excited states. In particular, new insight into the role and fate of the mixed Rydberg-valence 3s/πσ* state is revealed. This includes population residing on the excited state surface at large N-H separations for a relatively long period of time (∼1 ps) prior to dissociation and/or internal conversion. Our findings may, in part, be rationalized by considering the rapid evolution of this state's electronic character as the N-H stretching coordinate is extended - as extensively demonstrated in the supporting theory. Overall, our findings highlight a number of important general caveats regarding the nature of mixed Rydberg-valence excited states, their spectral signatures and detection sensitivity in photoionization measurements, and the evaluation of their overall importance in mediating electronic relaxation in a wide range of small model-chromophore systems providing bio-molecular analogues - a topic of considerable interest within the chemical dynamics community over the last decade.


Evidence for an interaction between calcium intake and physical activity on changes in bone mineral density.
Results of trials on the effects of physical activity on bone mineral density (BMD) are conflicting. The current hypothesis was that calcium intake modifies the bone response to physical activity. Published trials on physical activity and bone density were reviewed, and the results of 17 trials are summarized. Physical activity has beneficial effects on BMD at high calcium intakes, with no effect at mean calcium intakes less than a mean of 1000 mg/day. The modifying effect of calcium intake on BMD among exercise groups is more pronounced in the lumbar spine than in the radius. This analysis may explain conflicting results of trials on physical activity and calcium effects on bone. Controlled trials designed to test adequately this hypothesis are needed.


Acute heart failure presentations and outcomes during the fasting month of Ramadan: an observational report from seven Middle Eastern countries.
Fasting during the month of Ramadan is practiced by over 1.5 billion Muslims worldwide. It remains unclear, however, how this change in lifestyle affects heart failure, a condition that has reached epidemic dimensions. This study examined the effects of fasting in patients with acute heart failure (AHF) using data from a large multi-center heart failure registry. Data were derived from Gulf CARE (Gulf aCute heArt failuRe rEgistry), a prospective multi-center study of consecutive patients hospitalized with AHF during February-November 2012. The study included 4,157 patients, of which 306 (7.4%) were hospitalized with AHF in the fasting month of Ramadan, while 3,851 patients (92.6%) were hospitalized in other days. Clinical characteristics, precipitating factors, management, and outcome were compared among the two groups. Patients admitted during Ramadan had significantly lower prevalence of symptoms and signs of volume overload compared to patients hospitalized in other months. Atrial arrhythmias were significantly less frequent and cholesterol levels were significantly lower in Ramadan. Hospitalization in Ramadan was not independently associated with increased immediate or 1-year mortality. The current study represents the largest evaluation of the effects of fasting on AHF. It reports an improved volume status in fasting patients. There were also favorable effects on atrial arrhythmia and total cholesterol and no effects on immediate or long-term outcomes.


Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer.
In KEYNOTE-189, first-line pembrolizumab plus pemetrexed-platinum significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo plus pemetrexed-platinum in patients with metastatic nonsquamous non‒small-cell lung cancer (NSCLC), irrespective of tumor programmed death-ligand 1 (PD-L1) expression. We report an updated analysis from KEYNOTE-189 (ClinicalTrials.gov: NCT02578680). Patients were randomly assigned (2:1) to receive pemetrexed and platinum plus pembrolizumab (n = 410) or placebo (n = 206) every 3 weeks for 4 cycles, then pemetrexed maintenance plus pembrolizumab or placebo for up to a total of 35 cycles. Eligible patients with disease progression in the placebo-combination group could cross over to pembrolizumab monotherapy. Response was assessed per RECIST (version 1.1) by central review. No alpha was assigned to this updated analysis. As of September 21, 2018 (median follow-up, 23.1 months), the updated median (95% CI) OS was 22.0 (19.5 to 25.2) months in the pembrolizumab-combination group versus 10.7 (8.7 to 13.6) months in the placebo-combination group (hazard ratio [HR], 0.56; 95% CI, 0.45 to 0.70]). Median (95% CI) PFS was 9.0 (8.1 to 9.9) months and 4.9 (4.7 to 5.5) months, respectively (HR, 0.48; 95% CI, 0.40 to 0.58). Median (95% CI) time from randomization to objective tumor progression on next-line treatment or death from any cause, whichever occurred first (progression-free-survival-2; PFS-2) was 17.0 (15.1 to 19.4) months and 9.0 (7.6 to 10.4) months, respectively (HR, 0.49; 95% CI, 0.40 to 0.59). OS and PFS benefits with pembrolizumab were observed regardless of PD-L1 expression or presence of liver/brain metastases. Incidence of grade 3-5 adverse events was similar in the pembrolizumab-combination (71.9%) and placebo-combination (66.8%) groups. First-line pembrolizumab plus pemetrexed-platinum continued to demonstrate substantially improved OS and PFS in metastatic nonsquamous NSCLC, regardless of PD-L1 expression or liver/brain metastases, with manageable safety and tolerability.


Envelope determinants of equine lentiviral vaccine protection.
Lentiviral envelope (Env) antigenic variation and associated immune evasion present major obstacles to vaccine development. The concept that Env is a critical determinant for vaccine efficacy is well accepted, however defined correlates of protection associated with Env variation have yet to be determined. We reported an attenuated equine infectious anemia virus (EIAV) vaccine study that directly examined the effect of lentiviral Env sequence variation on vaccine efficacy. The study identified a significant, inverse, linear correlation between vaccine efficacy and increasing divergence of the challenge virus Env gp90 protein compared to the vaccine virus gp90. The report demonstrated approximately 100% protection of immunized ponies from disease after challenge by virus with a homologous gp90 (EV0), and roughly 40% protection against challenge by virus (EV13) with a gp90 13% divergent from the vaccine strain. In the current study we examine whether the protection observed when challenging with the EV0 strain could be conferred to animals via chimeric challenge viruses between the EV0 and EV13 strains, allowing for mapping of protection to specific Env sequences. Viruses containing the EV13 proviral backbone and selected domains of the EV0 gp90 were constructed and in vitro and in vivo infectivity examined. Vaccine efficacy studies indicated that homology between the vaccine strain gp90 and the N-terminus of the challenge strain gp90 was capable of inducing immunity that resulted in significantly lower levels of post-challenge virus and significantly delayed the onset of disease. However, a homologous N-terminal region alone inserted in the EV13 backbone could not impart the 100% protection observed with the EV0 strain. Data presented here denote the complicated and potentially contradictory relationship between in vitro virulence and in vivo pathogenicity. The study highlights the importance of structural conformation for immunogens and emphasizes the need for antibody binding, not neutralizing, assays that correlate with vaccine protection.


Bacterial penetration along different root canal filling materials in the presence or absence of smear layer.
To study the effect of the smear layer on the penetration of bacteria along different root canal filling materials and to examine the dentine/sealer and sealer/core material interfaces for the presence of bacteria. A total of 110 human root segments were instrumented to size 80 under irrigation with 1% sodium hypochlorite. Half of the roots were irrigated with a 5-mL rinse of 17% EDTA. Roots with and without smear layer were filled with gutta-percha (GP) and AH Plus sealer (AH), GP and Apexit sealer (AP), or RealSeal cones and sealer (RS). Following storage in humid conditions at 37 degrees C for 7 days, the specimens were mounted into a bacterial leakage test model for 135 days. Survival analyses were performed to calculate the median time of leakage and log-rank test was used for pairwise comparisons of groups. The level of significance was set at P = 0.05. Selected specimens were longitudinally sectioned and inspected by scanning electron microscopy for the presence of bacteria at the interfaces. In the presence of the smear layer, RS and AP leaked significantly more slowly than in its absence. In the absence of the smear layer, AH leaked significantly more slowly than RS. SEM results indicated a differential pattern of bacterial penetration among the sealers. Removal of the smear layer did not impair bacterial penetration along root canal fillings. A comparison of the sealers revealed no difference except that AH performed better than RS in the absence of the smear layer.


Prevalence of migraines in adolescents with endometriosis.
To determine the prevalence and experience of migraines in adolescents with surgically confirmed endometriosis compared with those without endometriosis. Cross-sectional study conducted within The Women's Health Study: From Adolescence to Adulthood-an ongoing longitudinal cohort. Boston Center for Endometriosis. Adolescent females enrolled November 2012 through November 2016. The case group included adolescents surgically diagnosed with endometriosis. The control group included adolescents without endometriosis, recruited from the local community and clinics. Not available. An extensive online health questionnaire regarding medical history, lifestyle, medication use, anthropometrics, and symptom experience and treatments. Migraine diagnosis was self-reported. Migraine pain and noncyclic pelvic pain severity were rated using an 11-point numerical rating scale. Cyclic pelvic pain was categorized. Adolescents with endometriosis were more likely to experience migraines (69.3%) than those without endometriosis (30.7%) (multivariable odds ratio = 4.77, 95% confidence interval 2.53, 9.02). For each 1-point increase in the migraine numerical rating scale, the odds of endometriosis increased by 22% (multivariable odds ratio = 1.22, 95% confidence interval 1.03, 1.44; Ptrend = .02). Among those with endometriosis, age of menarche was associated inversely with the odds of migraines. Participants with endometriosis and migraines have more dysmenorrhea than those without migraines. Adolescents with endometriosis are more likely to experience migraines than adolescents without endometriosis. A linear relationship exists between migraine pain severity and the odds of endometriosis, suggesting heightened pain sensitivity for adolescents with endometriosis. Due to the strong correlation, patients who present with either condition should be screened for comorbidity to maximize the benefits of care.


Oxidative stress during alcohol withdrawal and its relationship with withdrawal severity.
Oxidative parameters are altered during alcohol withdrawal and are said to contribute towards withdrawal symptoms in alcoholic patients. To study levels of five selected oxidative parameters during alcohol withdrawal state and after treatment of the withdrawal state and to assess the association of the oxidative parameters with the severity of alcohol withdrawal. This was a case-control study done in a De-addiction clinic of a tertiary teaching centre, Southern India. 50 persons having alcohol withdrawal symptoms were included. The oxidative stress parameters malondialdehyde, protein carbonyl, glutathione peroxidase, superoxide dismutase and catalase were assessed in during the withdrawal phase and again after the withdrawal had subsided. The same oxidative stress parameters were measured in the control group. Statistical analysis was done using SPSS version 17.0. One way ANOVA and Pearson correlation test were used for finding the association between the oxidative stress parameters levels and the severity of alcohol withdrawal. Multiple linear regression analysis done to predict variables associated with level of oxidative parameters. During alcohol withdrawal the pro-oxidant malondialdehyde was elevated compared to that in the control group. Among the antioxidant enzymes the superoxide dismutase was higher and catalase was lower than the control group levels. After remission of the alcohol withdrawal both malondialdehyde remained higher and superoxide dismutase lower than in the control group. The levels of oxidative stress parameters not correlated with the severity of alcohol withdrawal. oxidative stress parameters show changes during alcohol withdrawal and during the remission of withdrawal. However, levels of oxidative stress parameters not correlated with the severity of withdrawal.


Catalysis-associated conformational changes revealed by human CD38 complexed with a non-hydrolyzable substrate analog.
Cyclic ADP-ribose (cADPR) is a calcium mobilization messenger important for mediating a wide range of physiological functions. The endogenous levels of cADPR in mammalian tissues are primarily controlled by CD38, a multifunctional enzyme capable of both synthesizing and hydrolyzing cADPR. In this study, a novel non-hydrolyzable analog of cADPR, N1-cIDPR (N1-cyclic inosine diphosphate ribose), was utilized to elucidate the structural determinants involved in the hydrolysis of cADPR. N1-cIDPR inhibits CD38-catalyzed cADPR hydrolysis with an IC(50) of 0.26 mM. N1-cIDPR forms a complex with CD38 or its inactive mutant in which the catalytic residue Glu-226 is mutated. Both complexes have been determined by x-ray crystallography at 1.7 and 1.76 A resolution, respectively. The results show that N1-cIDPR forms two hydrogen bonds (2.61 and 2.64 A) with Glu-226, confirming our previously proposed model for cADPR catalysis. Structural analyses reveal that both the enzyme and substrate cADPR undergo catalysis-associated conformational changes. From the enzyme side, residues Glu-146, Asp-147, and Trp-125 work collaboratively to facilitate the formation of the Michaelis complex. From the substrate side, cADPR is found to change its conformation to fit into the active site until it reaches the catalytic residue. The binary CD38-cADPR model described here represents the most detailed description of the CD38-catalyzed hydrolysis of cADPR at atomic resolution. Our structural model should provide insights into the design of effective cADPR analogs.


Sickle cell anemia as a possible state of enhanced anti-apoptotic tone: survival effect of vascular endothelial growth factor on circulating and unanchored endothelial cells.
The biologic processes of apoptosis and angiogenesis are linked in endothelial biology because some endothelial cell growth factors also exert anti-apoptotic effects. We studied whether apoptosis is occurring in circulating endothelial cells (CEC) that have lost the survival signals derived from anchorage to extracellular matrix. Consistent with this expectation, 64% +/- 16% of CEC from normal donors showed evidence of apoptosis (by morphology and TdT-mediated dUTP nick end labeling [TUNEL] assay). However, only 30% +/- 15% (P <.001 v normal) of CEC from donors with sickle cell anemia were apoptotic. Vascular endothelial growth factor (VEGF) levels were significantly (P =.001) higher in plasma of sickle donors (120.1 +/- 81.4 pg/mL) than that of normal donors (37.6 +/- 34.6 pg/mL), and there was an inverse correlation between VEGF and CEC apoptosis (r =. 612, P =.001). Consistent with stimulation by VEGF, CEC from sickle donors exhibited increased expression of alphavbeta3. In vitro experiments showed that VEGF inhibits apoptosis for cultured endothelial cells that are kept unanchored and not allowed to re-establish attachment to extracellular matrix, thus demonstrating that VEGF provides survival signals independent of its ability to promote matrix reattachment. These data suggest the hypothesis that sickle cell anemia is a state of enhanced anti-apoptotic tone for endothelial cells. If true, this has implications for disease pathobiology, particularly the development of neovascularizing retinopathy.


Role of zinc in the development and treatment of mood disorders.
The present review is a critical examination of the most recent published work on the role of zinc in the development and treatment of mood disorders. Clinical studies and experimental work using animal models have both revealed a link between zinc status and neuropsychological disorders such as depression and anxiety. Not only has zinc deficiency been shown to induce depression-like and anxiety-like behaviors, supplementation has been used as a treatment for major depression. Zinc administration improves the efficacy of antidepressant drugs in depressed patients and may have a particular role to play in treatment-resistant patients. Recent investigations into the molecular mechanisms responsible for these observations suggest a role for zinc in the regulation of neurotransmitter systems, antioxidant mechanisms, neurotrophic factors, and neuronal precursor cells. The data reviewed here not only indicate a role for zinc deficiency in the development of mood disorders, but also show that zinc may also be important in their treatment. Given the prevalence of zinc deficiency in human populations, this work has the potential to influence strategies to prevent and treat these disorders.


Evaluation of umbilical cord serum therapy for persistent corneal epithelial defects.
To evaluate umbilical cord serum therapy as a means of promoting the healing of persistent corneal epithelial defects. Umbilical cord serum or autologous serum drops were used to promote the healing of persistent epithelial defects. The study design was a prospective randomised controlled clinical trial. 60 eyes of 59 patients were divided into two groups, 31 in the cord serum group and 29 in the autologous serum control group. Epithelial defects measuring at least 2 mm in linear dimension resistant to conventional medical management were included. Serial measurements of the size of the epithelial defects-namely, two maximum linear dimensions perpendicular to each other, and the area and perimeter was done at start of therapy and follow up days 3, 7, 14, 21. Rate of healing of the epithelial defects were measured as percentage decrease from the baseline parameter at each subsequent follow up. The data were analysed by the non-parametric Wilcoxon rank sum test using STATA 7.0. The median percentage decrease in the size of the epithelial defect was significantly greater in the cord serum group at days 7, 14 and 21 (p<0.05) when measured in terms of the area and perimeter. A greater number of patients showed complete re-epithelialisation with umbilical cord serum (n = 18) than with autologous serum (n = 11) (Pearson chi = 0.19). None of the patients reported any side effects or discomfort with either treatment. Umbilical cord serum leads to faster healing of the persistent corneal epithelial defects refractory to all medical management compared to autologous serum.


The zebrafish foxj1a transcription factor regulates cilia function in response to injury and epithelial stretch.
Cilia are essential for normal organ function and developmental patterning, but their role in injury and regeneration responses is unknown. To probe the role of cilia in injury, we analyzed the function of foxj1, a transcriptional regulator of cilia genes, in response to tissue damage and renal cyst formation. Zebrafish foxj1a, but not foxj1b, was rapidly induced in response to epithelial distension and stretch, kidney cyst formation, acute kidney injury by gentamicin, and crush injury in spinal cord cells. Obstruction-induced up-regulation of foxj1a was not inhibited by cycloheximide, identifying foxj1a as a primary response gene to epithelial injury. Foxj1 was also dramatically up-regulated in murine cystic kidney disease epithelia [jck/jck (nek8) and Ift88Tg737Rpw(-/-)] as well as in response to kidney ischemia-reperfusion injury. Obstruction of the zebrafish pronephric tubule caused a rapid increase in cilia beat rate that correlated tightly with expanded tubule diameter and epithelial stretch. Zebrafish foxj1a was specifically required for cilia motility. Enhanced foxj1a expression in obstructed tubules induced cilia motility target genes efhc1, tektin-1, and dnahc9. foxj1a-deficient embryos failed to up-regulate efhc1, tektin-1, and dnahc9 and could not maintain enhanced cilia beat rates after obstruction, identifying an essential role for foxj1 in modulating cilia function after injury. These studies reveal that activation of a Foxj1 transcriptional network of ciliogenic genes is an evolutionarily conserved response to multiple forms of tissue damage and highlight enhanced cilia function as a previously uncharacterized component of organ homeostasis.


A remarkably stable TipE gene cluster: evolution of insect Para sodium channel auxiliary subunits.
First identified in fruit flies with temperature-sensitive paralysis phenotypes, the Drosophila melanogaster TipE locus encodes four voltage-gated sodium (NaV) channel auxiliary subunits. This cluster of TipE-like genes on chromosome 3L, and a fifth family member on chromosome 3R, are important for the optional expression and functionality of the Para NaV channel but appear quite distinct from auxiliary subunits in vertebrates. Here, we exploited available arthropod genomic resources to trace the origin of TipE-like genes by mapping their evolutionary histories and examining their genomic architectures. We identified a remarkably conserved synteny block of TipE-like orthologues with well-maintained local gene arrangements from 21 insect species. Homologues in the water flea, Daphnia pulex, suggest an ancestral pancrustacean repertoire of four TipE-like genes; a subsequent gene duplication may have generated functional redundancy allowing gene losses in the silk moth and mosquitoes. Intronic nesting of the insect TipE gene cluster probably occurred following the divergence from crustaceans, but in the flour beetle and silk moth genomes the clusters apparently escaped from nesting. Across Pancrustacea, TipE gene family members have experienced intronic nesting, escape from nesting, retrotransposition, translocation, and gene loss events while generally maintaining their local gene neighbourhoods. D. melanogaster TipE-like genes exhibit coordinated spatial and temporal regulation of expression distinct from their host gene but well-correlated with their regulatory target, the Para NaV channel, suggesting that functional constraints may preserve the TipE gene cluster. We identified homology between TipE-like NaV channel regulators and vertebrate Slo-beta auxiliary subunits of big-conductance calcium-activated potassium (BKCa) channels, which suggests that ion channel regulatory partners have evolved distinct lineage-specific characteristics. TipE-like genes form a remarkably conserved genomic cluster across all examined insect genomes. This study reveals likely structural and functional constraints on the genomic evolution of insect TipE gene family members maintained in synteny over hundreds of millions of years of evolution. The likely common origin of these NaV channel regulators with BKCa auxiliary subunits highlights the evolutionary plasticity of ion channel regulatory mechanisms.


The biphasic dose effect of lychee (Litchi chinensis Sonn.) pulp phenolic extract on alcoholic liver disease in mice.
Lychee (Litchi chinensis Sonn.), a subtropical fruit grown widely in Southeast Asia, has been used as a traditional Chinese medicine for liver protection. Our previous study showed that phenolics from lychee pulp had hepatoprotective activity against restraint stress-induced liver injury. The present study investigated the protective effects of lychee pulp phenolic extract (LPPE) on ethanol-induced liver injury and the mechanism responsible for these effects. Mice were divided into four groups and subjected to either a control liquid diet (control group, CON), a 4% (w/v) ethanol-containing liquid diet (ethanol group, EtOH), a 4% (w/v) ethanol-containing liquid diet supplemented with 0.4 g L-1 LPPE (low dose LPPE-supplemented group, EtOH + L-LPPE), or a 4% (w/v) ethanol-containing liquid diet supplemented with 0.8 g L-1 LPPE (high dose LPPE-supplemented group, EtOH + H-LPPE) for 8 weeks. The ethanol-induced hepatic steatosis and increases of triglyceride levels in the serum and liver were ameliorated by L-LPPE supplementation but aggravated by H-LPPE supplementation. Moreover, L-LPPE supplementation improved the antioxidant status, reduced the nuclear translocation of nuclear erythroid 2-related factor 2 (Nrf2), and reduced the expression of Nrf2 target genes in the liver. H-LPPE supplementation resulted in the improved antioxidant status and reduced the expression of Nrf2 target genes. Furthermore, L-LPPE suppressed the expression of lipid synthesis genes and increased the expression of fatty acid β-oxidation genes. However, H-LPPE increased the expression of genes responsible for lipid synthesis and uptake and reduced the expression of fatty acid β-oxidation genes. Additionally, L-LPPE supplementation effectively decreased the serum endotoxin level and reversed ethanol-induced alterations in the intestinal microbiota composition. Collectively, LPPE showed biphasic effects on ethanol-induced liver injury in mice, indicating that a moderate intake of LPPE or Litchi pulp could be useful for the prevention and control of alcoholic liver disease.


Exposure to cigarette smoke abrogates the beneficial effect of ischemic postconditioning.
Cigarette smoking is one of the risk factors for coronary artery disease. Although conditioning decreases infarct size in hearts from healthy animals, comorbidities may render it ineffective. We investigated the effects of cigarette smoke (CS) exposure on intracellular myocardial signaling, infarct size after ischemia-reperfusion, and the potential interference with ischemic conditioning. Exposure of mice to CS increased blood pressure, caused cardiac hypertrophy, and upregulated the nitric oxide synthatse (NOS)/soluble guanylate cyclase (sGC)/cGMP pathway. To test the effect of CS exposure on the endogenous cardioprotective mechanisms, mice were subjected to regional myocardial ischemia and reperfusion with no further intervention or application of preconditioning (PreC) or postconditioning (PostC). Exposure to CS did not increase the infarction compared with the room air (RA)-exposed group. PreC was beneficial for both CS and RA vs. nonconditioned animals. PostC was effective only in RA animals, while the infarct size-limiting effect was not preserved in the CS group. Differences in oxidative stress markers, Akt, and endothelial NOS phosphorylation and cGMP levels were observed between RA and CS groups subjected to PostC. In conclusion, exposure to CS does not per se increase infarct size. The beneficial effect of ischemic PreC is preserved in mice exposed to CS, as it does not affect the cardioprotective signaling; in contrast, PostC fails to protect CS-exposed mice due to impaired activation of the Akt/eNOS/cGMP axis that occurs in parallel to enhanced oxidative stress.


Associations between obesogenic risk and depressive symptomatology in Australian adolescents: a cross-sectional study.
Depression and obesity are significant health concerns currently facing adolescents worldwide. This paper investigates the associations between obesity and related risk behaviours and depressive symptomatology in an Australian adolescent population. Data from the Australian Capital Territory It's Your Move project, an Australian community-based intervention project were used. In 2012, 800 students (440 females, 360 males) aged 11-14 years (M=13.11 years, SD=0.62 years), from 6 secondary schools were weighed and measured and completed a questionnaire which included physical activity, sedentary behaviour and dietary intake. Weight status was defined by WHO criteria. A cut-off score ≥10 on the Short Mood and Feelings Questionnaire indicated symptomatic depression. Logistic regression was used to test associations. After controlling for potential confounders, results showed significantly higher odds of depressive symptomatology in males (OR=1.22, p<0.05) and females (OR=1.12, p<0.05) who exceeded guidelines for daily screen-time leisure sedentary activities. Higher odds of depressive symptoms were seen in females who consumed greater amounts of sweet drink (OR=1.18, p<0.05), compared to lower female consumers of sweet drinks, and males who were overweight/obese also had greater odds of depressive symptoms (OR=1.83, p<0.05) compared to male normal weight adolescents. This study demonstrates the associations between obesogenic risks and depression in adolescents. Further research should explore the direction of these associations and identify common determinants of obesity and depression. Mental health outcomes need to be included in the rationale and evaluation for diet and activity interventions.


Effect of concurrent chronic exposure of fluoride and aluminum on rat brain.
The present in vivo study was designed to investigate the toxic potential of fluoride alone and in conjugation with aluminum on the rat brain. The region-specific response of both elements was studied in different regions of brain, namely the cerebrum, cerebellum, and medulla oblongata. Following fluoride exposure, oxidative stress increased significantly, estimated by increased lipid peroxidation and a decrease in the activity of the antioxidant enzyme, superoxide dismutase. The neurotransmitter (e.g., dopamine, norepinephrine, and serotonin) content was also altered. However, these aspects were more pronounced in animals given fluoride and aluminum together. Histological evidence showed deprivation of neuronal integrity with higher magnitude in concurrent fluoride and aluminum exposure, as compared to fluoride alone. Thus, it can be concluded that aluminum appears to enhance the neurotoxic hazards caused by fluoride.


Reshaping the gut microbiota: Impact of low calorie sweeteners and the link to insulin resistance?
Disruption in the gut microbiota is now recognized as an active contributor towards the development of obesity and insulin resistance. This review considers one class of dietary additives known to influence the gut microbiota that may predispose susceptible individuals to insulin resistance - the regular, long-term consumption of low-dose, low calorie sweeteners. While the data are controversial, mounting evidence suggests that low calorie sweeteners should not be dismissed as inert in the gut environment. Sucralose, aspartame and saccharin, all widely used to reduce energy content in foods and beverages to promote satiety and encourage weight loss, have been shown to disrupt the balance and diversity of gut microbiota. Fecal transplant experiments, wherein microbiota from low calorie sweetener consuming hosts are transferred into germ-free mice, show that this disruption is transferable and results in impaired glucose tolerance, a well-known risk factor towards the development of a number of metabolic disease states. As our understanding of the importance of the gut microbiota in metabolic health continues to grow, it will be increasingly important to consider the impact of all dietary components, including low calorie sweeteners, on gut microbiota and metabolic health.


Global Climate Change and Children's Health.
Rising global temperatures are causing major physical, chemical, and ecological changes in the planet. There is wide consensus among scientific organizations and climatologists that these broad effects, known as "climate change," are the result of contemporary human activity. Climate change poses threats to human health, safety, and security, and children are uniquely vulnerable to these threats. The effects of climate change on child health include: physical and psychological sequelae of weather disasters; increased heat stress; decreased air quality; altered disease patterns of some climate-sensitive infections; and food, water, and nutrient insecurity in vulnerable regions. The social foundations of children's mental and physical health are threatened by the specter of far-reaching effects of unchecked climate change, including community and global instability, mass migrations, and increased conflict. Given this knowledge, failure to take prompt, substantive action would be an act of injustice to all children. A paradigm shift in production and consumption of energy is both a necessity and an opportunity for major innovation, job creation, and significant, immediate associated health benefits. Pediatricians have a uniquely valuable role to play in the societal response to this global challenge.


Multisession CyberKnife radiosurgery for post-surgical residual and recurrent pituitary adenoma: preliminary result from one center.
To evaluate the efficacy of CyberKnife (Accuray, Inc., Sunnyvale, CA) stereotactic radiosurgery (SRS) for patients with pituitary adenoma. We conducted a retrospective review of all patients treated by image-guided radiosurgery at our institution between August 2007 and June 2009. Twentytwo patients with pituitary adenoma were identified. The median follow-up period from date of treatment was 30.8 + 7.7months. The median patient age was 56 years. The mean tumor volume was 4.1 + 2.8 mL (range, 0.8-16.0 mL), and the prescribed dose was 25 Gy (5 Gy x 5). Tumors were treated with a mean coverage of 95.1 ± 1.3%(range 90.2-99.1%), a mean conformality index of 1.4 ± 0.4 (range, 1.2-1.8), and a mean treatment isodose line of 76.4 ± 3.0%(range70-83%). The primary endpoints were radiographic and endocrinological tumor control. The local radiographic control rate in this series was 100% (22/22). Radiographic evidence of tumor necrosis developed in 3 patients (13.7%). CyberKnife multisession radiosurgery of 25 Gy (5 Gy x 5) provided excellent local control with acceptable adverse effect in patients with pituitary adenoma post-transsphenoidal resection. This preliminary study provides data that supports the belief that the optic nerve and chiasm tolerate the above dosing regimens in perichiasmatic pituitary adenomas, and this dosing regimen may achieve satisfactory radiographic and endocrinological tumor control for post-transsphenoidal resection.


Varicella vaccine uptake in Shandong Province, China.
Varicella vaccine has been licensed in China for decade to be used as single dose in children aged ≥ 12 mo of age in private sector. Little data were available on varicella uptake to date in China yet. A cross-sectional study was conducted in Shandong Province in May 2011 to examine varicella vaccination coverage among children aged 16-40 mo and examine factors associated with varicella vaccine uptake. The overall coverage among children eligible for varicella vaccine was 62% (range 16.7-94.7% by county), much lower than the coverage of the eight vaccines included in the national immunization program (all above 97%). Though proximity to immunization services (< 5 km) was linked with higher vaccine uptake (62.6 vs. 37.4%, p = 0.02), county-level economic development (77.8, 61.0 and 47.1% for developed, sub-developed and developing regions, respectively, p < 0.001) played an even more important role in varicella vaccination. Moreover, there was little variation in coverage of vaccines included in the national immunization program along with county-level economic development. Even though varicella vaccine uptake is relatively high for use on a private basis, the vaccination coverage is not high enough to prevent epidemiology shift to adolescents and adults who are more prone to develop severe outcomes to varicella. Further enhancement on varicella vaccination coverage is necessary and inclusion to national immunization program seems to be a promising option for achieving and maintaining high coverage.


Human handedness and scalp hair-whorl direction develop from a common genetic mechanism.
Theories concerning the cause of right- or left-hand preference in humans vary from purely learned behavior, to solely genetics, to a combination of the two mechanisms. The cause of handedness and its relation to the biologically specified scalp hair-whorl rotation is determined here. The general public, consisting of mostly right-handers (RH), shows counterclockwise whorl rotation infrequently in 8.4% of individuals. Interestingly, non-right-handers (NRH, i.e., left-handers and ambidextrous) display a random mixture of clockwise and counterclockwise swirling patterns. Confirming this finding, in another independent sample of individuals chosen because of their counterclockwise rotation, one-half of them are NRH. These findings of coupling in RH and uncoupling in NRH unequivocally establish that these traits develop from a common genetic mechanism. Another result concerning handedness of the progeny of discordant monozygotic twins suggests that lefties are one gene apart from righties. Together, these results suggest (1) that a single gene controls handedness, whorl orientation, and twin concordance and discordance and (2) that neuronal and visceral (internal organs) forms of bilateral asymmetry are coded by separate sets of genetic pathways. The sociological impact of the study is discussed.


Pica associated with iron deficiency or depletion: clinical and laboratory correlates in 262 non-pregnant adult outpatients.
There are many descriptions of the association of pica with iron deficiency in adults, but there are few reports in which observations available at diagnosis of iron deficiency were analyzed using multivariable techniques to identify significant predictors of pica. We sought to identify clinical and laboratory correlates of pica in adults with iron deficiency or depletion using univariable and stepwise forward logistic regression analyses. We reviewed charts of 262 non-pregnant adult outpatients (ages ≥18 y) who required treatment with intravenous iron dextran. We tabulated their sex, age, race/ethnicity, body mass index, symptoms and causes of iron deficiency or depletion, serum iron and complete blood count measures, and other conditions at diagnosis before intravenous iron dextran was administered. We excluded patients with serum creatinine >133 μmol/L or disorders that could affect erythrocyte or iron measures. Iron deficiency was defined as both SF <45 pmol/L and TS <10%. Iron depletion was defined as serum ferritin (SF) <112 pmol/L. We performed univariable comparisons and stepwise forward logistic regression analyses to identify significant correlates of pica. There were 230 women (184 white, 46 black; ages 19-91 y) and 32 men (31 white, 1 black; ages 24-81 y). 118 patients (45.0%) reported pica; of these, 87.3% reported ice pica (pagophagia). In univariable analyses, patients with pica had lower mean age, black race/ethnicity, and higher prevalences of cardiopulmonary and epithelial manifestations. The prevalence of iron deficiency, with or without anemia, did not differ significantly between patients with and without pica reports. Mean hemoglobin and mean corpuscular volume (MCV) were lower and mean red blood cell distribution width (RDW) and platelet count were higher in patients with pica. Thrombocytosis occurred only in women and was more prevalent in those with pica (20.4% vs. 8.3%; p = 0.0050). Mean total iron-binding capacity was higher and mean serum ferritin was lower in patients with pica. Nineteen patients developed a second episode of iron deficiency or depletion; concordance of recurrent pica (or absence of pica) was 95%. Predictors of pica in logistic regression analyses were age and MCV (negative associations; p = 0.0250 and 0.0018, respectively) and RDW and platelet count (positive associations; p = 0.0009 and 0.02215, respectively); the odds ratios of these predictors were low. In non-pregnant adult patients with iron deficiency or depletion, lower age is a significant predictor of pica. Patients with pica have lower MCV, higher RDW, and higher platelet counts than patients without pica.


Oncogenic BRAFV600E drives expression of MGL ligands in the colorectal cancer cell line HT29 through N-acetylgalactosamine-transferase 3.
Colorectal cancer is the third most common cancer type worldwide. It is characterized by a high expression of aberrantly glycosylated ligands, such as the Tn antigen (GalNAcα1-Ser/Thr), which is a major ligand for the C-type lectin macrophage galactose-type lectin (MGL). We have previously determined that a high level of MGL ligands in colorectal tumors is associated with lower disease-free survival in patients with late stage disease, which we could attribute to the presence of oncogenic BRAFV600E mutations. Here we aimed to elucidate the downstream pathway of BRAFV600E governing high MGL ligand and Tn antigen expression. We focused on glycosylation-related enzymes involved in the synthesis or elongation of Tn antigen, N-acetylgalactosamine-transferases (GALNTs) and C1GalT1/COSMC, respectively. Both the activity and expression of C1GalT1 and COSMC were unrelated to the BRAF mutational status. In contrast, GALNT3, GALNT7 and GALNT12 were increased in colorectal cancer cells harboring the BRAFV600E mutation. Through CRISPR-Cas9 gene knockouts we could establish that GALNT3 increased MGL ligand synthesis in the HT29 cell line, while GALNT7 and GALNT12 appeared to have redundant roles. Together our results highlight a novel mechanistic pathway connecting BRAFV600E to aberrant glycosylation in colorectal cancer through GALNT3.


Young People's, Parents', and Professionals' Views on Required Components of Mobile Apps to Support Self-Management of Juvenile Arthritis: Qualitative Study.
There is growing evidence that supporting self-management of Juvenile Arthritis can benefit both patients and professionals. Young people with Juvenile Arthritis and their healthy peers increasingly use mobile technologies to access information and support in day-to-day life. Therefore, a user-led, rigorously developed and evaluated mobile app could be valuable for facilitating young people's self-management of Juvenile Arthritis. The objective of this study was to seek the views of young people with Juvenile Arthritis, their parents or carers, and health care professionals (HCPs) as to what should be included in a mobile app to facilitate young people's self-management of chronic Juvenile Arthritis. A qualitative approach was adopted with a purposeful sample of 9 young people aged 10-18 years with Juvenile Arthritis, 8 parents or carers, and 8 HCPs involved in their care. Data were gathered through semi-structured focus group and individual interviews with young people and their parents or carers and HCPs. Interview discussion was facilitated through demonstration of four existing health apps to explore participants' views on strengths and limitations of these, barriers and facilitators to mobile app use, preferred designs, functionality, levels of interaction, and data sharing arrangements. Data were analyzed using the framework approach. Analysis revealed three interlinked, overarching themes: (1) purpose, (2) components and content, and (3) social support. Despite some differences in emphasis on essential content, general agreement was found between young people with Juvenile Arthritis their parents or carers, and professionals that a mobile app to aid self-management would be useful. Underpinning the themes was a prerequisite that young people are enabled to feel a sense of ownership and control of the app, and that it be an interactive, engaging resource that offers developmentally appropriate information and reminders, as well as enabling them to monitor their symptoms and access social support. Findings justify and pave the way for a future feasibility study into the production and preliminary testing of such an app. This would consider issues such as compatibility with existing technologies, costs, age, and cross-gender appeal as well as resource implications.


Incidence of first seizures, epilepsy, and seizure mimics in a geographically defined area.
To determine the incidence of first seizures, epilepsy, and seizure mimics in a geographically defined area using the updated 2014 International League Against Epilepsy (ILAE) definition, which allows an epilepsy diagnosis after a single seizure when the risk of further seizures over the next 10 years is ≈60% or greater. This replaced the 1993 definition by which epilepsy was diagnosed when a person had ≥2 seizures separated by 24 hours. Using multiple overlapping methods of case ascertainment followed by individual case classification by an epileptologist, we identified all first seizures, new diagnosis of epilepsy, and seizure mimics occurring in a defined geographic area (population 542,868) from January 1, 2017, to December 31, 2017. Incidence was age standardized to the Standard European Population. We compared incidence rates using the 2014 and 1993 ILAE definitions. When the 2014 ILAE definition of epilepsy was applied, the incidence of new diagnosis of epilepsy was 62 per 100,000 (age standardized 74) compared to 41 per 100,000 (age standardized 48) when the 1993 definition was applied, and the difference was more pronounced at older ages. The incidence of all first seizures and of seizure mimics was 102 per 100,000 (age standardized 123) and 94 per 100,000 (age standardized 111), respectively. The most frequently encountered seizure mimic was syncope. Application of the 2014 ILAE definition of epilepsy resulted in a higher incidence of new diagnosis of epilepsy compared to the 1993 definition. The incidence of seizure mimics almost equals that of all first seizures. Seizures, epilepsy, and seizure mimics represent a significant burden to health care systems.


2D Hexagonal Boron Nitride (2D-hBN) Explored for the Electrochemical Sensing of Dopamine.
Crystalline 2D hexagonal boron nitride (2D-hBN) nanosheets are explored as a potential electrocatalyst toward the electroanalytical sensing of dopamine (DA). The 2D-hBN nanosheets are electrically wired via a drop-casting modification process onto a range of commercially available carbon supporting electrodes, including glassy carbon (GC), boron-doped diamond (BDD), and screen-printed graphitic electrodes (SPEs). 2D-hBN has not previously been explored toward the electrochemical detection/electrochemical sensing of DA. We critically evaluate the potential electrocatalytic performance of 2D-hBN modified electrodes, the effect of supporting carbon electrode platforms, and the effect of "mass coverage" (which is commonly neglected in the 2D material literature) toward the detection of DA. The response of 2D-hBN modified electrodes is found to be largely dependent upon the interaction between 2D-hBN and the underlying supporting electrode material. For example, in the case of SPEs, modification with 2D-hBN (324 ng) improves the electrochemical response, decreasing the electrochemical oxidation potential of DA by ∼90 mV compared to an unmodified SPE. Conversely, modification of a GC electrode with 2D-hBN (324 ng) resulted in an increased oxidation potential of DA by ∼80 mV when compared to the unmodified electrode. We explore the underlying mechanisms of the aforementioned examples and infer that electrode surface interactions and roughness factors are critical considerations. 2D-hBN is utilized toward the sensing of DA in the presence of the common interferents ascorbic acid (AA) and uric acid (UA). 2D-hBN is found to be an effective electrocatalyst in the simultaneous detection of DA and UA at both pH 5.0 and 7.4. The peak separations/resolution between DA and UA increases by ∼70 and 50 mV (at pH 5.0 and 7.4, respectively, when utilizing 108 ng of 2D-hBN) compared to unmodified SPEs, with a particularly favorable response evident in pH 5.0, giving rise to a significant increase in the peak current of DA. The limit of detection (3σ) is found to correspond to 0.65 μM for DA in the presence of UA. However, it is not possible to deconvolute the simultaneous detection of DA and AA. The observed electrocatalytic effect at 2D-hBN has not previously been reported in the literature when supported upon carbon or any other electrode. We provide valuable insights into the modifier-substrate interactions of this material, essential for those designing, fabricating, and consequently performing electrochemical experiments utilizing 2D-hBN and related 2D materials.


Glanzmann thrombasthenia: deficient binding of von Willebrand factor to thrombin-stimulated platelets.
Glanzmann thrombasthenia is an inherited bleeding disorder characterized by the failure of platelets to aggregate in response to almost all stimuli. However, thrombasthenic platelets will aggregate with bovine and porcine von Willebrand factor (vWF) and will show normal ristocetin-induced binding and aggregation in the presence of human vWF. In contrast, we now report that the specific binding of vWF to the thrombin-stimulated platelets was less than 20% of normal in three patients with Glanzmann thrombasthenia. Analysis of binding isotherms was based on the assumption of one class of binding sites for vWF on the platelet membrane. Double-reciprocal plots were used to calculate maximal binding at saturation and apparent dissociation constant (Kd). In nine normals, 2.82 +/- 0.64 micrograms (+/- SD) of vWF bound to 10(8) platelets at saturation, with Kd (+/- SD) = 3.65 +/- 1.23 micrograms/ml. In two patients with thrombasthenia binding was markedly decreased and did not approach saturation. In the third patient, binding at saturation corresponded to 0.21 micrograms per 10(8) platelets, with Kd = 3.93 micrograms/ml. These findings suggest that mechanisms underlying the vWF-platelet interaction are incompletely reflected in ristocetin-dependent assay systems. Moreover, these results, in addition to those previously reported for fibronectin, suggest that the platelet defect in Glanzmann thrombasthenia is not limited to decreased binding of fibrinogen but involves several glycoproteins that are known to interact with platelets.


Brain anatomical abnormalities in high-risk individuals, first-episode, and chronic schizophrenia: an activation likelihood estimation meta-analysis of illness progression.
The present study reviewed voxel-based morphometry (VBM) studies on high-risk individuals with schizophrenia, patients experiencing their first-episode schizophrenia (FES), and those with chronic schizophrenia. We predicted that gray matter abnormalities would show progressive changes, with most extensive abnormalities in the chronic group relative to FES and least in the high-risk group. Forty-one VBM studies were reviewed. Eight high-risk studies, 14 FES studies, and 19 chronic studies were analyzed using anatomical likelihood estimation meta-analysis. Less gray matter in the high-risk group relative to controls was observed in anterior cingulate regions, left amygdala, and right insula. Lower gray matter volumes in FES compared with controls were also found in the anterior cingulate and right insula but not the amygdala. Lower gray matter volumes in the chronic group were most extensive, incorporating similar regions to those found in FES and high-risk groups but extending to superior temporal gyri, thalamus, posterior cingulate, and parahippocampal gryus. Subtraction analysis revealed less frontotemporal, striatal, and cerebellar gray matter in FES than the high-risk group; the high-risk group had less gray matter in left subcallosal gyrus, left amygdala, and left inferior frontal gyrus compared with FES. Subtraction analysis confirmed lower gray matter volumes through ventral-dorsal anterior cingulate, right insula, left amygdala and thalamus in chronic schizophrenia relative to FES. Frontotemporal brain structural abnormalities are evident in nonpsychotic individuals at high risk of developing schizophrenia. The present meta-analysis indicates that these gray matter abnormalities become more extensive through first-episode and chronic illness. Thus, schizophrenia appears to be a progressive cortico-striato-thalamic loop disorder.


E-cadherin mutation-based genetic counseling and hereditary diffuse gastric carcinoma.
The E-cadherin mutation has been identified in a subset of families with multiple cases of diffuse gastric carcinoma. However, the true penetrance of this mutation and its association with other carcinomas in such families remains elusive. We aim to show the importance of DNA-based genetic counseling in hereditary diffuse gastric carcinoma. The proband was self-referred after three of his siblings died of diffuse gastric carcinoma. Medical and pathology records confirmed diagnoses. The family was educated about diffuse gastric carcinoma. Analysis for the 70G-->T mutation was performed by sequencing genomic DNA from lymphocyte pellets. DNA results and genetic counseling were provided individually to those tested. Twenty-four family members were tested for the E-cadherin mutation. Nine were found to be positive and 15 were negative. Three who tested positive and were affected are now deceased. None of the 19 patients counseled wanted results sent to their physicians once they recognized the potential for insurance discrimination. None had undergone endoscopic ultrasound. Three who were positive for the E-cadherin mutation expressed strong interest in prophylactic gastrectomy. The E-cadherin mutation strongly predicts susceptibility to diffuse gastric carcinoma. Emotional stress in at-risk patients, the limited knowledge of the mutation's penetrance, and limitations of available screening mandate patient-centered genetic counseling.


IL-17 and immunologically induced senescence regulate response to injury in osteoarthritis.
Senescent cells (SnCs) are implicated in the pathogenesis of age-related diseases including osteoarthritis (OA), in part via expression of a senescence-associated secretory phenotype (SASP) that includes immunologically relevant factors and cytokines. In a model of posttraumatic OA (PTOA), anterior cruciate ligament transection (ACLT) induced a type 17 immune response in the articular compartment and draining inguinal lymph nodes (LNs) that paralleled expression of the senescence marker p16INK4a (Cdkn2a) and p21 (Cdkn1a). Innate lymphoid cells, γδ+ T cells, and CD4+ T cells contributed to IL-17 expression. Intra-articular injection of IL-17-neutralizing antibody reduced joint degeneration and decreased expression of the senescence marker Cdkn1a. Local and systemic senolysis was required to attenuate tissue damage in aged animals and was associated with decreased IL-17 and increased IL-4 expression in the articular joint and draining LNs. In vitro, we found that Th17 cells induced senescence in fibroblasts and that SnCs skewed naive T cells toward Th17 or Th1, depending on the presence of TGF-β. The SASP profile of the inflammation-induced SnCs included altered Wnt signaling, tissue remodeling, and cell-cycle pathways not previously implicated in senescence. These findings provide molecular targets and mechanisms for senescence induction and therapeutic strategies to support tissue healing in an aged environment.


Contrasting evolution of diversity at two disease-associated chicken genes.
There have been significant evolutionary pressures on the chicken during both its speciation and its subsequent domestication by man. Infectious diseases are expected to have exerted strong selective pressures during these processes. Consequently, it is likely that genes associated with disease susceptibility or resistance have been subject to some form of selection. Two genes involved in the immune response (interferon-gamma and interleukin 1-beta) were selected for sequencing in diverse chicken populations from Pakistan, Sri Lanka, Bangladesh, Kenya, Senegal, Burkina Faso and Botswana, as well as six outgroup samples (grey, green, red and Ceylon jungle fowl and grey francolin and bamboo partridge). Haplotype frequencies, tests of neutrality, summary statistics, coalescent simulations and phylogenetic analysis by maximum likelihood were used to determine the population genetic characteristics of the genes. Networks indicate that these chicken genes are most closely related to the red jungle fowl. Interferon-gamma had lower diversity and considerable coding sequence conservation, which is consistent with its function as a key inflammatory cytokine of the immune response. In contrast, the pleiotropic cytokine interleukin 1-beta had higher diversity and showed signals of balancing selection moderated by recombination, yielding high numbers of diverse alleles, possibly reflecting broader functionality and potential roles in more diseases in different environments.


Role of a Stem-Loop Structure in Helicobacter pylori cagA Transcript Stability.
Helicobacter pylori CagA is a secreted effector protein that contributes to gastric carcinogenesis. Previous studies showed that there is variation among H. pylori strains in the steady-state levels of CagA and that a strain-specific motif downstream of the cagA transcriptional start site (the +59 motif) is associated with both high levels of CagA and premalignant gastric histology. The cagA 5' untranslated region contains a predicted stem-loop-forming structure adjacent to the +59 motif. In the current study, we investigated the effect of the +59 motif and the adjacent stem-loop on cagA transcript levels and cagA mRNA stability. Using site-directed mutagenesis, we found that mutations predicted to disrupt the stem-loop structure resulted in decreased steady-state levels of both the cagA transcript and the CagA protein. Additionally, these mutations resulted in a decreased cagA mRNA half-life. Mutagenesis of the +59 motif without altering the stem-loop structure resulted in reduced steady-state cagA transcript and CagA protein levels but did not affect cagA transcript stability. cagA transcript stability was not affected by increased sodium chloride concentrations, an environmental factor known to augment cagA transcript levels and CagA protein levels. These results indicate that both a predicted stem-loop structure and a strain-specific +59 motif in the cagA 5' untranslated region influence the levels of cagA expression.


Assessing the impact of systematic reviews on future research: two case studies.
To evaluate the impact of systematic reviews on research funded by the Agency for Healthcare Research and Quality (AHRQ) through Evidence-based Practice Centers (EPCs), and to identify barriers to and facilitators for the effects of these documents on future research. Two AHRQ systematic reviews were selected as case studies to evaluate their impact on future research. Key citations generated by these reports were identified through ISI Web of Science and PubMed Central and traced forward to identify effects on subsequent studies through citation analysis from updated systematic reviews on the topics. Requests for applications and program announcements from the NIH Guide for Grants and Contracts website were reviewed and dissemination data were obtained from AHRQ. Finally, interviews were conducted with 13 key informants to help identify short-, medium- and long-term impacts of the EPC reviews. The measurable impact of the two EPC reviews is demonstrably greater on short-term outcomes (greater awareness of the issues) than on medium-term (e.g., the generation of new knowledge) or long-term outcomes (e.g., changes in patient practice or health outcomes). Factors such as the topic and the timing of the report relative to the development of the field may explain the impact of these two AHRQ reports. The degree to which the new research can be directly attributed to the AHRQ reviews remains unclear. Key informants discussed several benefits stemming from the EPC reports, including providing a foundation for the research community on which to build, heightening awareness of the gaps in knowledge, increasing the quality of research and sparking new directions of research. However, the degree to which these reports were influential hinged on several factors including marketing efforts, the very nature of the reports and other influences external to the EPC domain. The findings outlined in this article illustrate the importance of numerous factors influencing future research: the breadth, specificity and readiness of the topic for more research, ongoing developments in the field, availability of funding and active engagement of champions. AHRQ and the EPCs may be able to improve the likelihood of impact by creating more targeted products, planning for and expanding dissemination activities, improving the readability and other attributes of the reports themselves, and actively involving funders early on and throughout the process of creating and publishing the reviews.


Aedes aegypti immature forms distribution according to type of breeding site.
More than 2.5 billion people, in more than 100 countries, are estimated to live in risk areas for the transmission of dengue. We investigated the production of Aedes aegypti immature forms in different types of containers. Larvae and pupae presence were inspected in 747 containers in 300 dwellings in Rio de Janeiro state, Brazil. The statistical significance of the differences of immature forms was calculated for different groups of recipients and classified according to the type of use, volume, and material. Containers used to store water and those classified as garbage enclosed 90.2% of the larvae and 88.9% of the pupae. We concluded that a wider covering of more regular water supply, as well as regular garbage collection, are decisive factors for an effective control of dengue vector.


Priorities, Barriers, and Facilitators towards International Guidelines for the Delivery of Supportive Clinical Care during an Ebola Outbreak: A Cross-Sectional Survey.
During the Ebola outbreak, mortality reduction was attributed to multiple improvements in supportive care delivered in Ebola treatment units (ETUs). We aimed to identify high-priority supportive care measures, as well as perceived barriers and facilitators to their implementation, for patients with Ebola Virus Disease (EVD). We conducted a cross-sectional survey of key stakeholders involved in the response to the 2014⁻2016 West African EVD outbreak. Out of 57 email invitations, 44 responses were received, and 29 respondents completed the survey. The respondents listed insufficient numbers of health workers (23/29, 79%), improper tools for the documentation of clinical data (n = 22/28, 79%), insufficient material resources (n = 22/29, 76%), and unadapted personal protective equipment (n = 20/28, 71%) as the main barriers to the provision of supportive care in ETUs. Facilitators to the provision of supportive care included team camaraderie (n in agreement = 25/28, 89%), ability to speak the local language (22/28, 79%), and having treatment protocols in place (22/28, 79%). This survey highlights a consensus across various stakeholders involved in the response to the 2014⁻2016 EVD outbreak on a limited number of high-priority supportive care interventions for clinical practice guidelines. Identified barriers and facilitators further inform the application of guidelines.


Sacred disease secrets revealed: the genetics of human epilepsy.
Neurons throughout the brain suddenly discharging synchronously and recurrently cause primarily generalized seizures. Discharges localized awhile in one part of the brain cause focal-onset seizures. A genetically determined generalized hyperexcitability had been predicted in primarily generalized seizures, but surprisingly the first epilepsy gene discovered, CHRNA4, was in a focal (frontal lobe)-onset syndrome. Another surprise with CHRNA4 was its encoding of an ion channel present throughout the brain. The reason why CHRNA4 causes focal-onset seizures is unknown. Recently, the second focal (temporal lobe)-onset epilepsy gene, LGI1 (unknown function), was discovered. CHRNA4 led the way to mutation identifications in 15 ion channel genes, most causing primarily generalized epilepsies. Potassium channel mutations cause benign familial neonatal convulsions. Sodium channel mutations cause generalized epilepsy with febrile seizures plus or, if more severe, severe myoclonic epilepsy of infancy. Chloride and calcium channel mutations are found in rare families with the common syndromes childhood absence epilepsy and juvenile myoclonic epilepsy (JME). Mutations in the EFHC1 gene (unknown function) occur in other rare JME families, and yet in other families, associations are present between JME (or other generalized epilepsies) and single nucleotide polymorphisms in the BRD2 gene (unknown function) and the malic enzyme 2 (ME2) gene. Hippocrates predicted the genetic nature of the 'sacred' disease. Genes underlying the 'malevolent' forces seizing 1% of humans have now been revealed. These, however, still account for a mere fraction of the genetic contribution to epilepsy. Exciting years are ahead, in which the genetics of this extremely common, and debilitating, neurological disorder will be solved.


Balancing between a Person-Centred and a Common Staff Approach: Nursing Staff's Experiences of Good Nursing Practice for Patients Who Self-Harm.
The aim of this study was to describe nursing staff's experiences of good nursing practice in psychiatric in-patient care for patients with self-harming behavior. The participants were nine nurses and eight nursing assistants working in two in-patient wards in general psychiatry. Four focus group discussions were held and subjected to qualitative content analysis. The findings showed that good nursing practice balanced a person-centred approach with a common staff approach, allowing people who self-harm and staff to share responsibility for structuring everyday life, keeping to the plan, communicating decisions, and finding individual opportunities for relief. Reflective discussions among the staff concerning prejudice, emotional stress, lack of resources, and shortcomings in care planning could also prevent a stigmatizing culture and organizational deficiencies, which would be beneficial for both the people who self-harm and the staff.


Differential pattern of heart rate variability in patients with schizophrenia.
The cardiac autonomic dysfunction has been reported in patients with schizophrenia. Heart rate variability (HRV) provides non-invasive indices of cardiac autonomic modulation. This study examined whether patients with schizophrenia may show a distinctive pattern of HRV compared to healthy controls. Nine measures of time, frequency and complexity domains were extracted from 5-min resting evaluation of HRV in 30 unmedicated patients with schizophrenia and 30 age- and gender-matched controls. In addition to inferential statistics, a hierarchical clustering (HC) was used to examine difference in the interrelationships among HRV measures between the two groups. Multivariate analysis of variance revealed a significant group effect. Significantly lower sample entropy (SampEn) and a trend towards a higher ratio of low- to high frequency (LF/HF) were observed in the schizophrenia group. In the results of HC using Ward's method, SampEn co-clustered with LF/HF ratio in patients with schizophrenia compared to the separation of LF/HF ratio in healthy controls. In concert with decreased parasympathetic activity, low complexity of heart rate dynamics may reduce adaptability of cardiovascular system to changes in internal or external environment, thus increasing the risk of cardiovascular events. Diverse HRV measures combined in a multivariate fashion appear to be useful in understanding the pattern of neurocardiac modulation in patients with schizophrenia.


Microbiota modulate tumoral immune surveillance in lung through a γδT17 immune cell-dependent mechanism.
Commensal bacteria are crucial to maintain immune homeostasis in mucosal tissues and disturbances in their ecology can affect disease susceptibility. Here, we report evidence that commensal bacteria shape the efficiency of immune surveillance in mucosal tissues. Antibiotic-treated (Abt) mice were more susceptible to development of engrafted B16/F10 melanoma and Lewis lung carcinoma, exhibiting a shortened mean survival time with more numerous and larger tumor foci in the lungs. The defective antitumor response of Abt mice was independent of dehydration caused by antibiotics. Host defenses relied upon intact commensal bacteria with no class specificity. Mechanistic investigations revealed a defective induction of the γδT17 cell response in lungs of Abt mice; here, more aggressive tumor development was observed, possibly related to a reduction in IL6 and IL23 expression there. Adding normal γδT cells or supplementing IL17 restored the impaired immune surveillance phenotype in Abt mice. Overall, our results demonstrated the importance of commensal bacteria in supporting the host immune response against cancer, defined an important role for γδT17 responses in the mechanism, and suggested deleterious effects of antibiotic treatment on cancer susceptibility and progression.


The perspectives of bereaved family carers on dying at home: the study protocol of 'unpacking the home: family carers' reflections on dying at home.
Recent end of life care policy prioritises patient choice over place of care and in particular promotes dying at home. This policy is predicated on the assumption that there are family carers able and willing to provide care for the dying person. Through the accounts of bereaved family members, the 'Unpacking the home' study aims to gain an in-depth understanding of 'home' and the issues faced by family members caring for a dying older person at home; it also aims to examine the way the home is transformed in the process of providing end of life care, and offer a critical analysis of policies that aim to increase home deaths. This paper presents the protocol for this study. A cross-sectional qualitative study has been designed to achieve the study aims. In-depth interviews will be conducted in the north and south of England with 50 bereaved family carers to elicit their accounts of witnessing the dying in the home of an older person (50+ years). All interviews will be subjected to thematic analysis, and narrative analysis will be undertaken on a subset of 30 interview transcripts. A final phase of integration and policy analysis will be conducted towards the end of the study. User involvement is integral to this study, with service users actively engaged at every stage. This study will seek to take a qualitative approach by explicitly recognising that family carers are central to the experience of dying at home for older people, and they have needs that may be amenable to support and anticipatory planning. The strengths of this study, which include its interdisciplinary and participatory approach, and in-depth data collection and analysis methods, will be explored. The limitations and challenges of this research will also be considered. This study seeks to make recommendations that will ensure that family carers receive appropriate and adequate support in caring for their loved ones at the end of life.


Primary adrenal causes of Cushing's syndrome. Diagnosis and surgical management.
Cushing's syndrome is rare with only 20% of patients having a primary adrenal cause of hypercortisolism. We have developed a strategy to evaluate patients with suspected Cushing's syndrome and to localize the pathologic condition responsible for the hypercortisolism. This report reviews the last 11 consecutive patients who had a primary adrenal cause of hypercortisolism. Each patient had elevated 24-hour urine free cortisol and 17-hydroxycorticosteroid excretion consistent with hypercortisolism. All but one patient had undetectable plasma ACTH levels. No patient suppressed urinary steroid levels with high-dose dexamethasone and only one patient increased plasma ACTH or cortisol levels with oCRH, findings that were consistent with a pituitary-independent form of hypercortisolism. No patient had a pituitary tumor detected by computed tomography or magnetic resonance imaging, and eight patients had adrenal tumors accurately imaged. MRI of the adrenal glands correctly diagnosed adenoma in 5 of 6 patients with adenomas, carcinoma in 1 patient, and ACTH-producing pheochromocytoma in 1 patient. One tumor classified as carcinoma by MRI appeared on pathologic examination to be an adenoma. Three patients underwent petrosal sinus sampling for measurement of ACTH before and after oCRH administration, and each had petrosal sinus ACTH levels equal to peripheral levels, consistent with a primary adrenal cause of hypercortisolism. Two of these patients had typical bilateral pigmented micronodular adrenocortical disease and the third patient had macronodular adrenocortical hyperplasia. Each of the 11 patients was cured of hypercortisolism by unilateral or bilateral adrenalectomy and no patient has developed recurrent disease during the 7 to 29 month follow-up period. New modalities including the ovine CRH test, MRI, and petrosal sinus sampling have improved the evaluation of certain patients with Cushing's syndrome.


Cold Hardiness of Winter-Acclimated Drosophila suzukii (Diptera: Drosophilidae) Adults.
Drosophila suzukii Matsumura, often called spotted wing drosophila, is an exotic vinegar fly that is native to Southeast Asia and was first detected in the continental United States in 2008. Previous modeling studies have suggested that D. suzukii might not survive in portions of the northern United States or southern Canada due to the effects of cold. As a result, we measured two aspects of insect cold tolerance, the supercooling point and lower lethal temperature, for D. suzukii summer-morph pupae and adults and winter-morph adults. Supercooling points were compared to adults of Drosophila melanogaster Meigen. The lower lethal temperature of D. suzukii winter-morph adults was significantly colder than that for D. suzukii summer-morph adults, while supercooling points of D. suzukii winter-morph adults were actually warmer than that for D. suzukii summer-morph adults and pupae. D. suzukii summer-morph adult supercooling points were not significantly different than those for D. melanogaster adults. These measures indicate that D. suzukii is a chill intolerant insect, and winter-morph adults are the most cold-tolerant life stage. These results can be used to improve predictions of where D. suzukii might be able to establish overwintering populations and cause extensive damage to spring fruit crops.


The Emerging Social Science Literature on Health Technology Assessment: A Narrative Review.
Social scientists have paid increasing attention to health technology assessment (HTA). This paper provides an overview of existing social scientific literature on HTA, with a focus on sociology and political science and their subfields. Narrative review of key pieces in English. Three broad themes recur in the emerging social science literature on HTA: the drivers of the establishment and concrete institutional designs of HTA bodies; the effects of institutionalized HTA on pricing and reimbursement systems and the broader society; and the social and political influences on HTA decisions. Social scientists bring a focus on institutions and social actors involved in HTA, using primarily small-N research designs and qualitative methods. They provide valuable critical perspectives on HTA, at times challenging its otherwise unquestioned assumptions. However, they often leave aside questions important to the HTA practitioner community, including the role of culture and values. Closer collaboration could be beneficial to tackle new relevant questions pertaining to HTA.


An intervention to stop smoking among patients suspected of TB--evaluation of an integrated approach.
In many low- and middle-income countries, where tobacco use is common, tuberculosis is also a major problem. Tobacco use increases the risk of developing tuberculosis, secondary mortality, poor treatment compliance and relapses. In countries with TB epidemic, even a modest relative risk leads to a significant attributable risk. Treating tobacco dependence, therefore, is likely to have benefits for controlling tuberculosis in addition to reducing the non-communicable disease burden associated with smoking. In poorly resourced health systems which face a dual burden of disease secondary to tuberculosis and tobacco, an integrated approach to tackle tobacco dependence in TB control could be economically desirable. During TB screening, health professionals come across large numbers of patients with respiratory symptoms, a significant proportion of which are likely to be tobacco users. These clinical encounters, considered to be "teachable moments", provide a window of opportunity to offer treatment for tobacco dependence. We aim to develop and trial a complex intervention to reduce tobacco dependence among TB suspects based on the WHO 'five steps to quit' model. This model relies on assessing personal motivation to quit tobacco use and uses it as the basis for assessing suitability for the different therapeutic options for tobacco dependence.We will use the Medical Research Council framework approach for evaluating complex interventions to: (a) design an evidence-based treatment package (likely to consist of training materials for health professionals and education tools for patients); (b) pilot the package to determine the delivery modalities in TB programme (c) assess the incremental cost-effectiveness of the package compared to usual care using a cluster RCT design; (d) to determine barriers and drivers to the provision of treatment of tobacco dependence within TB programmes; and (e) support long term implementation. The main outcomes to assess the effectiveness would be point abstinence at 4 weeks and continuous abstinence up to 6 months. This work will be carried out in Pakistan and is expected to have relevance for other low and middle income countries with high tobacco use and TB incidence. This will enhance our knowledge of the cost-effectiveness of treating tobacco dependence in patients suspected of TB. ISRCTN08829879.


A Mouse Model of Chronic Ocular Hypertension Induced by Circumlimbal Suture.
To develop a chronic ocular hypertension mouse model by inducing intraocular pressure (IOP) elevation using a suture technique previously developed for rats. C57BL/6 mice were given monocular circumlimbal suture (10/0) placement under anesthesia (ketamine/xylazine). The suture was left in place for 12 weeks (n = 10). A control group had the same treatment while it was removed after day 1 (n = 10). Intraocular pressure, electroretinogram (ERG), and optical coherence tomography (OCT) were measured in both groups for 12 weeks. At week 12, animals were euthanized and retina was harvested for histologic assessment. In the group with extended suture placement, IOP spiked from 14.3 ± 0.9 to 48.4 ± 4.8 mm Hg immediately after suture implantation. At day 1, it declined to 33.2 ± 3.7 mm Hg and remained elevated for 12 weeks. In the suture removal group, IOP normalized to baseline within a day following suture removal. In the group with prolonged IOP elevation, the retinal ganglion cell (RGC) mediated ERG responses continued to exacerbate and were significantly reduced by week 12 (P < 0.001). Progressive loss of retinal nerve fiber layer was found and it became significant from week 4 (P < 0.001). At week 12, significant loss of RGCs (P < 0.001) was noted. In the IOP normalization group, no alteration in ERG, OCT, and RGC counting was observed. The circumlimbal suture approach produces a mild chronic IOP elevation in mice. Functional and structural changes under model induction are largely independent of the initial IOP spike.