Specific ion effects on the enzymatic activity of alcohol dehydrogenase from Saccharomyces cerevisiae.
The enzymatic activity of alcohol dehydrogenase (ADH) in the presence of a range of electrolytes is investigated. In the presence of 150 and 200 mM cations a substantial increase in activity following the series GnCl < CsCl < KCl ∼ NaCl < LiCl was observed with a 69% increase in the presence of KCl 200 mM with respect to the salt-free solution. In the presence of 150 and 200 mM anions the increase in activity followed an ion specific trend NaF ∼ NaCl ∼ NaBr > no salt > NaClO4 > NaSCN with a peak in activity increase of 75% in the presence of NaBr. The values of the Michaelis-Menten constant (Km) did not show any significant ion specific effect, while the maximum rate (Vmax) of ethanol oxidation to acetaldehyde was strongly ion specific. The changes in specific activity and Vmax in the presence of anions likely arises from ion specific interactions with charged residues in the active site of ADH. The data indicate that the enzymatic activity of alcohol dehydrogenase can be modulated by the nature of electrolytes at physiological concentration.


Long working hours and all-cause mortality in China: A 26-year follow-up study.
The relationship between long working hours and the risk of mortality has been debated in various countries. This study aimed to investigate the association between long working hours and all-cause mortality in a large population-based cohort in China. This retrospective cohort study (N=10 269) used a large, nationally representative data set [the China Health and Nutrition Surveys (CHNS)] from 1989 to 2015. Long working hours (≥55 hours per week) were compared to standard working hours (35-40 hours per week). The outcome measure was all-cause mortality. Hazard ratio (HR) for all-cause mortality was calculated from Cox proportional hazards regression models, with stratified analyses to assess differences in mortality risk among subgroups. Among the participants, 411 deaths (3.52 per 1000 person-years) occurred during a median follow-up of 11.0 (range 4.0-18.0) years. After adjusting for covariates, long working hours were associated with a significantly increased risk of all-cause mortality [HR 1.49, 95% confidence intervals (CI) 1.02-2.18]. Stratified analyses revealed that this association was present only among men (HR 1.78, 95% CI 1.15-2.75) and smoking participants (HR 1.57, 95% CI 1.05-2.57). This study provides evidence of an association between long working hours and all-cause mortality, which is specifically observed among men and smokers. Targeted interventions should be implemented to reduce excessive working hours and identify individuals at elevated risk, with support from labor organizations, policymakers, and employers.


Assessment of apparent ileal digestibility of amino acids and nitrogen in cottonseed and soyabean meals fed to pigs determined using ileal dissection under halothane anaesthesia or following carbon dioxide-stunning.
Two experiments were conducted to determine apparent ileal digestibility of amino acids (AIDAA) and nitrogen (AIDN) in cottonseed meal (CSM) and soyabean meal (SBM) fed to growing pigs. In the first experiment, twenty-four male pigs (37.3 (SE 2.7) kg) were individually penned and randomized to either CSM or SBM diets. The diets contained 40% of the protein meal (either CSM or SBM) in a wheat starch-sucrose (1:1, w/w) base containing vitamins and minerals, and Cr2O3 as an indigestible marker. Pigs were acclimated to the experimental diets over a 3 d period and on day 4 through to day 14 were offered 1800 g/d of the diet. Diets were offered in three meals/d from day 4 to day 11 and in eight meals/d from day 12 to day 13. After the eighth hourly-meal on day 14, twelve pigs were anaesthetized with halothane while the remaining twelve pigs were CO2-stunned and processed using commercial slaughter procedures. Ileal digesta were collected from a 1500 mm portion of the terminal ileum of each pig and subsequently analysed for amino acids, N, organic matter and Cr. Results indicated that AIDAA of CSM and SBM were lower when digesta were collected following CO2-stunning than when digesta were obtained under halothane anaesthesia. Consistently, AIDN in CSM (0.51 v. 0.56) and SBM (0.55 v. 0.71) were lower (P < 0.05) in CO2-stunned pigs than in halothane-anaesthetized pigs. Furthermore, when digesta collection was conducted under halothane anaesthesia, AIDN of CSM was lower (P < 0.001) than that of SBM. In the second experiment, six male pigs (45 (SE 2.6) kg) were fitted with T-piece cannulas implanted in the terminal ileum, housed individually in metabolism cages, and randomly allocated to either CSM or SBM diets in a single reversal arrangement. Ileal digesta were collected for AIDAA and AIDN determination. Although statistical comparisons could not be made between the two experiments, the AIDAA and AIDN data obtained via cannulated pigs were similar to those values obtained using the halothane-anaesthesia method. Overall, the CO2-stunning method is not recommended for studies of amino acid or nitrogen ileal digestibilities, but may be useful for the study of other dietary constituents.


Y chromosome diversity in a linguistic isolate (Mirandese, NE Portugal).
The purpose of this study was to genetically characterize the male lineages of people who speak Mirandese, an interesting case of a linguistic relict that can still be found in the municipality of Miranda do Douro, NE Portugal. This region lies within the area of the Leonese dialects, which are remnants of the Romance dialects spoken in the Kingdom of Leon currently grouped in the Astur-Leonese linguistic continuum. We intended to disclose affinities with surrounding populations, namely from Spain where the Astur-Leonese is also spoken. Eighty-eight unrelated males (58 from Miranda and 30 from Bragança, the broad Portuguese region where Miranda is located) were genotyped with the combined use of 17 Y chromosome short tandem repeats (Y-STRs) and a high resolution Y chromosome single nucleotide polymorphism (Y-SNPs) strategy. Moreover, 236 males from Miranda and neighboring regions, previously classified as R-M269, were also genotyped. R-P312 was the most frequent haplogroup in the Mirandese, followed by J-12f2.1 and T-M70. The male lineages J-12f2.1 and T-M70 were also well represented, and both were shared with descendants of Sephardic Jews. No signs of diversity reduction were detected. Mirandese speakers display a Y chromosome gene pool that shows a subtle differentiation from neighboring populations, mainly attributable to the assimilation of lineages ascribed to be of Jewish ancestry. Although not revealing signs of geographic/linguistic isolation, no clear affinities with other Astur-Leonese populations were detected. The results suggest that in Miranda language sharing is not accompanied by significant gene flow between populations from both sides of the political border. Am. J. Hum. Biol. 28:671-680, 2016. © 2016 Wiley Periodicals, Inc.


HER2-specific immunoligands engaging NKp30 or NKp80 trigger NK-cell-mediated lysis of tumor cells and enhance antibody-dependent cell-mediated cytotoxicity.
NK cells detect tumors through activating surface receptors, which bind self-antigens that are frequently expressed upon malignant transformation. To increase the recognition of tumor cells, the extracellular domains of ligands of the activating NK cell receptors NKp30, NKp80 and DNAM-1 (i.e. B7-H6, AICL and PVR, respectively) were fused to a single-chain fragment variable (scFv) targeting the human epidermal growth factor receptor 2 (HER2), which is displayed by various solid tumors. The resulting immunoligands, designated B7-H6:HER2-scFv, AICL:HER2-scFv, and PVR:HER2-scFv, respectively, bound HER2 and the addressed NK cell receptor. However, whereas B7-H6:HER2-scFv and AICL:HER2-scFv triggered NK cells to kill HER2-positive breast cancer cells at nanomolar concentrations, PVR:HER2-scFv was not efficacious. Moreover, NK cell cytotoxicity was enhanced synergistically when B7-H6:HER2-scFv or AICL:HER2-scFv were applied in combination with another HER2-specific immunoligand engaging the stimulatory receptor NKG2D. In contrast, no improvements were achieved by combining B7-H6:HER2-scFv with AICL:HER2-scFv. Additionally, B7-H6:HER2-scFv and AICL:HER2-scFv enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) by the therapeutic antibodies trastuzumab and cetuximab synergistically, with B7-H6:HER2-scFv exhibiting a higher efficacy. In summary, antibody-derived proteins engaging NKp30 or NKp80 may represent attractive biologics to further enhance anti-tumor NK cell responses and may provide an innovative approach to sensitize tumor cells for antibody-based immunotherapy.


Quality management tools: facilitating clinical research data integrity by utilizing specialized reports with electronic case report forms.
Data collected throughout the course of a clinical research trial must be reviewed for accuracy and completeness continually. The Oracle Clinical (OC) data management application utilized to capture clinical data facilitates data integrity through pre-programmed validations, edit and range checks, and discrepancy management modules. These functions were not enough. Coupled with the use of specially created reports in Oracle Discoverer and Integrated Review, both ad-hoc query and reporting tools, research staff have enhanced their ability to clean, analyze and report more accurate data captured within and among Case Report Forms (eCRFs) by individual study or across multiple studies.


Biomarker clustering in autosomal dominant Alzheimer's disease.
As the number of biomarkers used to study Alzheimer's disease (AD) continues to increase, it is important to understand the utility of any given biomarker, as well as what additional information a biomarker provides when compared to others. We used hierarchical clustering to group 19 cross-sectional biomarkers in autosomal dominant AD. Feature selection identified biomarkers that were the strongest predictors of mutation status and estimated years from symptom onset (EYO). Biomarkers identified included clinical assessments, neuroimaging, cerebrospinal fluid amyloid, and tau, and emerging biomarkers of neuronal integrity and inflammation. Three primary clusters were identified: neurodegeneration, amyloid/tau, and emerging biomarkers. Feature selection identified amyloid and tau measures as the primary predictors of mutation status and EYO. Emerging biomarkers of neuronal integrity and inflammation were relatively weak predictors. These results provide novel insight into our understanding of the relationships among biomarkers and the staging of biomarkers based on disease progression.


The psychodynamic treatment of a disturbed adolescent: a Vygotskian perspective.
From the vantage point of the interplay between action and language, the author traces the mental transformation of a disturbed adolescent during the course of treatment. Conceptually, this account superimposes the work of Vygotsky on a psychoanalytic understanding of the clinical process. Through systematic observations of the patient's behavior and speech, as well as of interventions aimed primarily at fostering the reemergence of intense affects, the author describes four cycles of communicative complexity. The beginning of self-reflection in a withdrawn, impulsive, hostile teenager, within the arena of an intensive psychodynamic treatment, reinforces Vygotsky's position that crucial changes in the relationship between speech and action can occur in a short period of time.


Interview: interview with P Jeffrey Conn. Interview by Hannah Coaker.
Dr Conn is the Lee E Limbird Professor of Pharmacology at Vanderbilt University and Director of the Vanderbilt Center for Neuroscience Drug Discovery (VCNDD). Dr Conn received a PhD in Pharmacology from Vanderbilt in 1986 and pursued postdoctoral studies at Yale University. He served as a professor of Pharmacology at Emory University from 1988 to 2000, before moving to Merck and Co. (PA, USA) as head of the Department of Neuroscience. Dr Conn moved to Vanderbilt University in 2003 where he is the founding director of the VCNDD, with a primary mission of facilitating translation of recent advances in basic science to novel therapeutics. The VCNDD consists of approximately 100 full-time scientists and has advanced novel molecules from four major programs as development candidates for clinical testing with industry partners. Dr Conn has served in editorial positions with multiple international journals and has served the scientific advisory boards of multiple foundations and companies. He has received numerous awards based on the impact of his basic and translational research. Dr Conn's current research is focused on development of novel treatment strategies for schizophrenia, Parkinson's disease and other serious brain disorders. Interview conducted by Hannah Coaker, Assistant Commissioning Editor.


Cannabis Constituents and Acetylcholinesterase Interaction: Molecular Docking, In Vitro Studies and Association with CNR1 rs806368 and ACHE rs17228602.
The study documented here was aimed to find the molecular interactions of some of the cannabinoid constituents of cannabis with acetylcholinesterase (AChE). Molecular docking and LogP determination were performed to predict the AChE inhibitory effect and lipophilicity. AChE enzyme activity was measured in the blood of cannabis addicted human subjects. Further, genetic predisposition to cannabis addiction was investigated by association analysis of cannabinoid receptor 1 (CNR1) single nucleotide polymorphism (SNP) rs806368 and ACHE rs17228602 using restriction fragment length polymorphism (RFLP) method. All the understudied cannabis constituents showed promising binding affinities with AChE and are lipophilic in nature. The AChE activity was observed to be indifferent in cannabis addicted and non-addicted healthy controls. There was no significant association with CNR1 SNP rs806368 and ACHE rs17228602. The study concludes that in silico prediction for individual biomolecules of cannabis is different from in vivo physiological action in human subjects when all are present together. However, for a deeper mechanistic insight into these interactions and association, multi-population studies are suggested. Further studies to explore the inhibitory potential of different cannabis constituents for intended AChE inhibitor-based drug are warranted.


[Pathomorphology of pneumococcal infection in children].
Clinical and pathological data on 10 children who died of pneumococcal infection were analyzed. The disease started as primary pneumococcal meningitis in 4 cases, secondary to otitis media meningitis in 1 and pneumococcal pneumonia in 5 cases. The latter complicated with secondary pneumococcal meningitis in 3 cases, pneumococcemia with hemolytico-uremic syndrome in 1 case. 9 patients died of infectious-toxic shock and 1 patient of massive bleeding from acute gastric and duodenal ulcers. The results suggest that a grave course of pneumococcal infection is due to development of the infectious-toxic shock. Emergence of metastatic suppurative focuses was indicative of sepsis. A fulminant form of pneumococcal sepsis--pneumococcemia--has no large or evident primary focus. Neuraminidase produced by pneumococci is responsible for development of hemolytico-uremic syndrome.


Female-biased dispersal in a bat with a female-defence mating strategy.
The ultimate causes for predominant male-biased dispersal (MBD) in mammals and female-biased dispersal (FBD) in birds are still subject to much debate. Studying exceptions to general patterns of dispersal, for example, FBD in mammals, provides a valuable opportunity to test the validity of proposed evolutionary pressures. We used long-term behavioural and genetic data on individually banded Proboscis bats (Rhynchonycteris naso) to show that this species is one of the rare mammalian exceptions with FBD. Our results suggest that all females disperse from their natal colonies prior to first reproduction and that a substantial proportion of males are philopatric and reproduce in their natal colonies, although male immigration has also been detected. The age of females at first conception falls below the tenure of males, suggesting that females disperse to avoid father-daughter inbreeding. Male philopatry in this species is intriguing because Proboscis bats do not share the usual mammalian correlates (i.e. resource-defence polygyny and/or kin cooperation) of male philopatry. They have a mating strategy based on female defence, where local mate competition between male kin is supposedly severe and should prevent the evolution of male philopatry. However, in contrast to immigrant males, philopatric males may profit from acquaintance with the natal foraging grounds and may be able to attain dominance easier and/or earlier in life. Our results on Proboscis bats lent additional support to the importance of inbreeding avoidance in shaping sex-biased dispersal patterns and suggest that resource defence by males or kin cooperation cannot fully explain the evolution of male philopatry in mammals.


Reciprocity in the intercultural conference space to improve Aboriginal oral health: A qualitative study.
Despite high rates of oral disease in Indigenous communities globally, progress is slow in implementing policies and practices so the depth of inequity is addressed and oral health outcomes improve. Indigenous communities are often poorly consulted in the process. This paper responds to this inequity by seeking to create a respectful intercultural space at international dental conferences where Aboriginal health practitioners and dental public health researchers can discuss ways forward for oral health in Indigenous communities. Participatory action research informed by Indigenist methodologies guided this research. Two roundtable discussions between Australian Aboriginal and non-Aboriginal participants were recorded, transcribed and analysed for themes related to problems and potential solutions to dental disease in Indigenous communities. Follow-up discussions on participants' reflections engaging in this intercultural space were recorded and analysed. Two Aboriginal health practitioners and five non-Aboriginal international dental public health researchers identified the importance of inclusion where intercultural engagement and collaboration with Indigenous Peoples were integral to conducting research in this context and improving oral health outcomes. Creating a safe, respectful space between Aboriginal health practitioners and non-Aboriginal dental public health researchers at an international conference fostered dialogue to better understand barriers and enablers to good oral health outcomes. Intercultural engagement and discussion is a step towards mutual understanding of oral health perspectives and experiences that can foster equity and enable more collaborative responses to improve oral health outcomes.


Genetic analysis of Boletus edulis suggests that intra-specific competition may reduce local genetic diversity as a woodland ages.
Ectomycorrhizal fungi are key players in terrestrial ecosystems yet their mating systems and population dynamics remain poorly understood. We investigated the fine-scale relatedness structure and genetic diversity of Boletus edulis, one of the world's most commercially important wild mushrooms. Microsatellite genotyping of fruiting bodies from 14 different sites around Bielefeld in Germany revealed little in the way of population structure over a geographic scale of several kilometres. However, on a more local scale we found evidence for elevated relatedness as well as inbreeding. We also observed a significant negative association between the genetic diversity of fruit and the age of the trees under which they were sampled. Taken together, our results suggest that as genets mature, they compete and potentially create conditions under which further spores struggle to become established. By implication, even though this species is widely picked, propagules remain common enough to create strong competition when new habitats become available.


Incidence and Influencing Factors of Chronic Postthoracotomy Pain in Lung Tumor Patients.
To estimate the incidence of chronic postthoracotomy pain (CPTP) in lung tumor patients and to explore the influencing factors of the intensity of CPTP. Lung tumor patients who underwent video-assisted thoracoscopic surgery (VATS) or thoracotomy were consecutively recruited from October 2016 to December 2017 at Yunnan Cancer Hospital. All the eligible patients were interviewed via telephone at the end of the third month after surgeries to identify the presence of CPTP. The potential influencing factors of CPTP, including pre-, intra-, and postoperative variables, were collected from medical records. A cumulative logit regression model was used to identify the independent influencing factors of the intensity of CPTP. Three hundred and forty-three patients completed a telephone interview. The estimated overall incidence of CPTP was 67.6% (95% of confidence interval, 95% CI: 62.4%, 72.6%) in lung tumor patients; 70.8% (95% CI: 63.8%, 77.1%) in benign patients and 63.5% (95% CI: 55.2%, 71.3%) in malignant patients; and 78.1% (95% CI: 66.0%, 87.5%) in open chest and 65.2% (95% CI: 59.3%, 70.8%) in VATS. Cumulative logit regression models (intensity order, NRS, 0 ⟶ 1-3 ⟶ 4-) revealed independent influencing factors of CPTP to be patients with diabetes (OR = 0.32; 95% CI: 0.14, 0.76), usage of VATS (OR = 0.47; 95% CI: 027, 0.82), and the amount of intraoperative blood loss (OR = 1.09; 95% CI: 1.00, 1.19). A high incidence of CPTP is detected in lung tumor patients following the thoracic operation. Patients with diabetes and using VATS are the independent protective factors of the intensity of CPTP, and the increasing amount of intraoperative blood loss is an independent risk factor of the intensity of CPTP.


The influence of physical training modalities on basal metabolic rate and leptin on obese adolescent boys.
The aim of this study was to investigate the effects of physical training modalities on basal metabolic rate, cardiovascular fitness and serum leptin level in obese adolescent boys. Sixteen obese adolescent boys (age: 16.81 +- 0.91 years) were randomly assigned to either resistance (RTG) (n=8) or endurance (ETG) (n=8) training and followed the respective training programmes for six months (3 days/wk, 60 min/day). Leptin, basal metabolism rate (BMR), and maximum oxygen consumption (VO2max) were evaluated at the beginning and end of the intervention. After the training period, Leptin was decreased and VO2max was increased in both groups (p<0.05), whereas BMR was statistically increased only in ETG (p<0.05). These results indicated that both types of exercises had positive effects on cardiovascular fitness and hormonal control of fat metabolism in obese male adolescents. Resistance exercises should be considered as an alternative or supplementation to endurance exercises in youth obesity management.


Transient PP2A inhibition alleviates normal tissue stem cell susceptibility to cell death during radiotherapy.
Unintended outcomes of cancer therapy include ionizing radiation (IR)-induced stem cell depletion, diminished regenerative capacity, and accelerated aging. Stem cells exhibit attenuated DNA damage response (DDR) and are hypersensitive to IR, as compared to differentiated non-stem cells. We performed genomic discovery research to compare stem cells to differentiated cells, which revealed Phosphoprotein phosphatase 2A (PP2A) as a potential contributor to susceptibility in stem cells. PP2A dephosphorylates pATM, γH2AX, pAkt etc. and is believed to play dual role in regulating DDR and apoptosis. Although studied widely in cancer cells, the role of PP2A in normal stem cell radiosensitivity is unknown. Here we demonstrate that constitutively high expression and radiation induction of PP2A in stem cells plays a role in promoting susceptibility to irradiation. Transient inhibition of PP2A markedly restores DNA repair, inhibits apoptosis, and enhances survival of stem cells, without affecting differentiated non-stem and cancer cells. PP2Ai-mediated stem cell radioprotection was demonstrated in murine embryonic, adult neural, intestinal, and hematopoietic stem cells.


Knockdown of long noncoding RNA linc-ITGB1 suppresses migration, invasion of hepatocellular carcinoma via regulating ZEB1.
This research focuses on the influence of linc-ITGB1 on the metastasis of hepatocellular carcinoma and further explores its underlying mechanism. A total of 70 hepatocellular carcinoma patients were chosen for our study. RT-qPCR was used for detecting the expression level of linc-ITGB1 in their cancer tissues. Moreover, the expression level of linc-ITGB1 was also detected in hepatocellular carcinoma cell lines. Furthermore, whether linc-ITGB1 could affect the migrated and invaded ability of hepatocellular carcinoma cells was determined by wound healing assay and transwell assay. We further explored the potential mechanism by RT-qPCR and Western blot assay. Linc-ITGB1 expression level in hepatocellular carcinoma tissues was remarkably higher than that in adjacent tissues. Moreover, migrated and invaded ability of hepatocellular carcinoma cells was inhibited through knockdown of linc-ITGB1. Further study revealed that silenced linc-ITGB1 inhibited the expression of ZEB1 and then suppressed epithelial to mesenchymal transition (EMT), which was important during the metastasis of hepatocellular carcinoma. Moreover, the inhibition of cell invasion by silenced linc-ITGB1 could be rescued through overexpression of ZEB1 in hepatocellular carcinoma. The results indicate that linc-ITGB1, a novel oncogene in tumorigenesis, could promote the metastasis and EMT via ZEB1, which may offer a possible therapeutic target in hepatocellular carcinoma.


A modelling approach to the detection of subcutaneous tumours by haematoporphyrin-derivative fluorescence.
The possibility of subcutaneous tumour detection by haematoporphyrin-derivative (HPD) and light has been studied by calculations on a model. The tumour model consists of a skin layer and a (subcutaneous) tumour layer. The Kubelka-Munk theory has been applied to estimate the HPD fluorescence intensities from the two layers. Literature values have been used for the optical parameters of the tissues. The results are that the depth at which a subcutaneous tumour can be detected is almost independent of the excitation wavelength and the tumour thickness. Only superficial tumours (less than 2.3 mm subcutaneously) can be detected as HPD fluorescence from the overlying skin tends to become more intense than from the tumour.


Primary malignant rhabdoid tumor of the central nervous system.
Since the initial description of malignant rhabdoid tumor (MRT) of the kidney by Beckwith in 1978, MRTs have been established as a distinct clinicopathologic entity lacking nephrogenic and myogenic differentiation. MRTs are highly aggressive neoplasms with characteristic histopathologic, immunocytochemical, and ultrastructural features. Many reports have appeared documenting primary extrarenal rhabdoid tumors (ERRTs) occurring at diverse sites, including infratentorial and supratentorial compartments of the central nervous system (CNS). The authors report 2 cases of primary CNS-MRT in young male children (6.5 and 7 years of age) and review the literature on CNS-MRTs. Neuroimaging studies showed an inhomogeneous parasagittal mass in the left anterior parietal region involving the motor strip and attached to the lateral aspect of the superior sagittal sinus in one case, and a right parietal parasagittal tumor with a cystic component in the other case. Metastatic workup, including abdominal CT, was negative in both cases. Histologic examination of the resected tumors showed irregular clusters and nests of cells with variable desmoplasia in both cases. Large areas of tumor necrosis and apoptotic tumor cells were present. Prominent eosinophilic cytoplasmic inclusions and eccentric, indented nuclei with conspicuous nucleoli characterized many of the tumor cells. Diffuse strong vimentin reactivity and focal strong reaction for epithelial membrane antigen (EMA) were demonstrated. Cytogenetic analyses reported a normal male karyotype in one case and an abnormal male karyotype with loss of both normal copies of chromosome 22 and gain of one structurally rearranged chromosome 22 in the other case. Ultrastructural examination displayed tumor cells with avoid to indented nuclei, marginated chromatin, and prominent nucleoli. Intercellular junctions were not found. Masses of cytoplasmic intermediate filaments in a characteristic whorled configuration were present. CNS-MRTs are consistently vimentin positive (100%) and usually EMA positive (90%). Glial fibrillary acidic protein, neuron-specific enolase, and S-100 protein are variably expressed. Markers for myogenous differentiation are invariably absent. Ultrastructural characteristics include aggregates of intermediate filaments. Monosomy 22 occurs in some CNS rhabdoid tumors, while most renal rhabdoid tumors are cytogenetically normal with only isolated cases having del(13q), del(11p), del(22)(q11), and unbalanced reciprocal translocation involving chromosomes 8 and 22. The prognosis for CNS rhabdoid tumors is dismal and almost two-thirds of patients are dead of disease shortly after diagnosis; one-third have been reported to be alive with disease, but have been followed for only short periods; and a single patient is reported to be free of disease at 5 years.


[Epidemiology of falls and fall-related injuries in the aged].
Approximately one third of elderly persons over the age of 65 who live in the community fall each year. About 5% of falls result in a fracture, and 5 to 10% of them result in other serious injuries requiring medical care. Even in the absence of serious physical injury, falls may have severe psychological consequences leading to an accelerated decline in functional capacities. Several epidemiological studies have identified the main intrinsic risk factors for fall. These include advanced age, female sex, impaired balance, gait abnormalities, reduced muscular strength, cognitive deficiencies, impaired visual acuity and use of sedative-hypnotic medications. The results of recent epidemiological studies comparing falls with serious physical injuries to falls without injuries suggest that, besides bone mass, the speed and effectiveness of protective reflexes may greatly influence the risk of trauma after a fall. Contrary to what may be believed, the frequency of falls and fall-related trauma is also high in active and healthy subjects. However, the cause of falls are clearly different for persons of varying age, health status and level of mobility. Several authors have tried to define different types of falls according to the predominance of intrinsic or extrinsic factors in fall aetiology. This approach may allow to identify different risk factors or combinations of risk factors according to the type of falls or to the characteristics of fallers.


The effects of psychotherapies for depression on response, remission, reliable change, and deterioration: A meta-analysis.
Meta-analyses of psychotherapies usually report effects sizes, while clinicians and patients need to know the proportion of patients who benefit from therapy. We conducted a meta-analysis of therapies for depression reporting the rates of response (50% symptom reduction), remission (HAM-D <7), clinical significant deterioration for psychotherapy, and control conditions (CAU, waitlist, and pill placebo), as well as the relative risk of these outcomes and the numbers-needed-to-be-treated (NNTs). We searched bibliographic databases and included 228 randomized trials comparing psychotherapy for depression against control conditions (75 with low risk of bias). Only therapies with at least 10 trials were included. We extracted outcomes from the studies, and for those studies not reporting the outcomes, we used a validated method to estimate the rates. The overall response rate in psychotherapies at 2 (±1) months after baseline was 41% (95% CI: 38~43), 17% (15~20) for usual care (CAU), and 16% (95% CI: 14~18) for waitlist. No significant differences between types of therapy were found. The NNT for therapy versus CAU was 5.3 and versus waitlist 3.9. About one third of patients remitted after therapy compared with 7%-13% in control conditions. The rates of deterioration were 5% versus 12%-13%, respectively. Most sensitivity analyses supported the general findings. Psychotherapies for depression may be effective compared with control conditions, but more than half of patients receiving therapy do not respond and only one third remitted. More effective treatments and treatment strategies such as sequencing and combining treatments are clearly needed.


Affecting the Global Burden of Surgical Disease: Incorporating Surgical Training into International Missions: A Systematic Review.
The global burden of surgical disease is immense. Increasingly in the past several decades, international humanitarian medical missions have become more popular as a method of managing the sheer volume of patients requiring medical care worldwide. Medical education programmes have also had an increase in interest amongst medical students and surgical residents to participate in missions during training. The current review was planned to present the current body of literature on international experiences in residency training programmes. It comprised relevant literatur obtained from Medline (ubMed) using Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) guidelines. A total of 15 publications were reviewed with each falling into one of the threeidentified categories:programme design (goals/objectives), ethics, and post-experience analysis. The benefits of providing international missions opportunities for surgical trainees cannot be understated.


Modelling for risk and biosecurity related to forest health.
Modelling the invasion and emergence of forest pests and pathogens (PnPs) is necessary to quantify the risk levels for forest health and provide key information for policy makers. Here, we make a short review of the models used to quantify the invasion risk of exotic species and the emergence risk of native species. Regarding the invasion process, models tackle each invasion phase, e.g. pathway models to describe the risk of entry, species distribution models to describe potential establishment, and dispersal models to describe (human-assisted) spread. Concerning the emergence process, models tackle each process: spread or outbreak. Only a few spread models describe jointly dispersal, growth, and establishment capabilities of native species while some mechanistic models describe the population temporal dynamics and inference models describe the probability of outbreak. We also discuss the ways to quantify uncertainty and the role of machine learning. Overall, promising directions are to increase the models' genericity by parameterization based on meta-analysis techniques to combine the effect of species traits and various environmental drivers. Further perspectives consist in considering the models' interconnection, including the assessment of the economic impact and risk mitigation options, as well as the possibility of having multi-risks and the reduction in uncertainty by collecting larger fit-for-purpose datasets.


Reporting of the estimated glomerular filtration rate decreased creatinine clearance testing.
The Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines suggest that clinicians use the estimated glomerular filtration rate (eGFR) measurements and minimize the use of timed urine creatinine clearance collection. The intent of this change was to improve recognition of chronic kidney disease. Here we used time-series modeling and intervention analyses to determine the effect of publication of the K/DOQI guidelines and the introduction of widespread eGFR reporting with prompts on physician ordering of 24-h urine collection for creatinine clearance. In this setting, clinical practice guidelines did not influence creatinine clearance testing; however, the direct introduction of eGFR reporting with prompts into physician workflow resulted in a sudden and significant 23.5% decrease in creatinine clearance collection over the 43 months analyzed. Thus, eGFR reporting with prompts may have produced a clinical practice change because it is integrated directly into physician workflow. Changing physician practice patterns may require more than publishing guidelines; rather it is more likely to occur through educational and structural changes to practice.


Zinc Inhibits Amyloid beta Production from Alzheimer's Amyloid Precursor Protein in SH-SY5Y Cells.
Zinc released from excited glutamatergic neurons accelerates amyloid beta (Abeta) aggregation, underscoring the therapeutic potential of zinc chelation for the treatment of Alzheimer's disease (AD). Zinc can also alter Abeta concentration by affecting its degradation. In order to elucidate the possible role of zinc influx in secretase-processed Abeta production, SH-SY5Y cells stably expressing amyloid precursor protein (APP) were treated with pyrrolidine dithiocarbamate (PDTC), a zinc ionophore, and the resultant changes in APP processing were examined. PDTC decreased Abeta40 and Abeta42 concentrations in culture media bathing APP-expressing SH-SY5Y cells. Measuring the levels of a series of C-terminal APP fragments generated by enzymatic cutting at different APP-cleavage sites showed that both beta- and alpha-cleavage of APP were inhibited by zinc influx. PDTC also interfered with the maturation of APP. PDTC, however, paradoxically increased the intracellular levels of Abeta40. These results indicate that inhibition of secretase-mediated APP cleavage accounts -at least in part- for zinc inhibition of Abeta secretion.


Effect of Exposure to Chlorhexidine Residues at "During Use" Concentrations on Antimicrobial Susceptibility Profile, Efflux, Conjugative Plasmid Transfer, and Metabolism of Escherichia coli.
There is no standardized protocol to predict the concentration levels of microbicides that are left on surfaces as a result of the use of these products, and there is no standardized method to predict the potential risk that such levels pose to emerging antibacterial resistance. The ability to distinguish between selection and adaption processes for antimicrobial resistance in bacteria and the impact of different concentrations of microbicide exposure have not been fully investigated to date. This study considers the effect of exposure to a low concentration of chlorhexidine digluconate (CHX) on selected phenotypes of Escherichia coli and relates the findings to the risk of emerging antimicrobial resistance. A concentration of 0.006 mg/ml CHX is a realistic "during use" exposure concentration measured on surfaces. At this concentration, it was possible for CHX-susceptible bacteria to survive, adapt through metabolic alterations, exhibit a transient decrease in antimicrobial susceptibility, and express stable clinical cross-resistance to front-line antibiotics. Efflux activity was present naturally in tested isolates, and it increased in the presence of 0.00005 mg/ml CHX but ceased with 0.002 mg/ml CHX. Phenotypic microarray assays highlighted a difference in metabolic regulation at 0.00005 mg/ml and 0.002 mg/ml CHX; more changes occurred after growth with the latter concentration. Metabolic phenotype changes were observed for substrates involved with the metabolism of some amino acids, cofactors, and secondary metabolites. It was possible for one isolate to continue transferring ampicillin resistance in the presence of 0.00005 mg/ml CHX, whilst 0.002 mg/ml CHX prevented conjugative transfer. In conclusion, E. coli phenotype responses to CHX exposure are concentration dependent, with realistic residual CHX concentrations resulting in stable clinical cross-resistance to antibiotics.


Circadian rhythms and time course of adaptive sodium and potassium excretion in rats after uninephrectomy.
The relationship between renal circadian cyclic excretion and renal compensatory adaptation after uninephrectomy for K, Na, and water was studied. Rats in a 12:12-h light-dark environment were given a liquid diet, and urine was collected for 16 days with consecutive 90-min periods. Days 1-4 were control, 5-10 followed a sham operation, and 11-16 followed uninephrectomy. The major findings were 1) the circadian cycles in excretion were virtually unchanged after sham and uninephrectomy; 2) an adaptive increase in excretion of Na, K, and water by the remaining kidney occurred within 90 min after uninephrectomy; 3) after uninephrectomy the distribution of the 24-h increment in excretion for the remaining kidney closely followed the preexisting pattern of circadian excretion for Na but was evenly distributed between light and dark phases for K; and 4) after uninephrectomy the ratio of excretion to intake was unchanged. This is the first study to document the time course of adaptation to uninephrectomy using consecutive brief collections over several days in unanesthetized and undisturbed rats. Adaptation after uninephrectomy occurred essentially immediately; was maintained unchanged; and preserved Na, K, and water homeostasis. Uninephrectomy did not alter the circadian control of excretion.


[Multiple organ resections in surgery of the colon and rectum].
Colorectal cancer patients with regional invasion or metastatic disease present low life expectancy. Radical surgical treatment is the only potentially curative procedure, with significant good results being reported. Thirty two patients with either regional invasion or metastatic disease were submitted to surgery with good survival rate.


Shell engineering in soft alginate-based capsules for culturing liver spheroids.
Functional interaction between cancer cells and the surrounding microenvironment is still not sufficiently understood, which motivates the tremendous interest for the development of numerous in vitro tumor models. Diverse parameters, for example, transport of nutrients and metabolites, availability of space in the confinement, etc. make an impact on the size, shape, and metabolism of the tumoroids. We demonstrate the fluidics-based low-cost methodology to reproducibly generate the alginate and alginate-chitosan microcapsules and apply it to grow human hepatoma (HepG2) spheroids of different dimensions and geometries. Focusing specifically on the composition and thickness of the hydrogel shell, permeability of the microcapsules was selectively tuned. The diffusion of the selected benchmark molecules through the shell has been systematically investigated using both, experiments and simulations, which is essential to ensure efficient mass transfer and/or filtering of the biochemical species. Metabolic activity of spheroids in microcapsules was confirmed by tracking the turnover of testosterone to androstenedione with chromatography studies in a metabolic assay. Depending on available space, phenotypically different 3D cell assemblies have been observed inside the capsules, varying in the tightness of cell aggregations and their shapes. Conclusively, we believe that our system with the facile tuning of the shell thickness and permeability, represents a promising platform for studying the formation of cancer spheroids and their functional interaction with the surrounding microenvironment.


Health Promotion and Preventive Care Intervention for Older Community-Dwelling People: Long-Term Effects of a Randomised Controlled Trial (RCT) within the LUCAS Cohort.
An RCT of a health promotion and preventive care intervention was done in 2001-2002. Here, long-term analyses based on 12 years of follow-up of survival and of change in functional competence between intervention and control group are presented. Positive 1-year results (significantly higher use of preventive services and better health behaviour) were presented earlier. Parallel group randomised controlled trial (RCT) with 878 participants in the intervention and 1,702 participants in the control group. The study took place in Hamburg, Germany and made use of health care structures and professionals of a geriatrics centre. Study participants were initially community-dwelling, aged 60 years and older and without B-ADL-restrictions, cognitive impairment, or need of nursing care, with sufficient command of the German language. Health promotion and preventive care interventions relied on an extensive health questionnaire and the subsequent offer to participate in multi-topic personal reinforcement performed in small group sessions or at preventive home visits. Primary outcome: Survival time; in some analyses, adjustments were made for gender, age and self-perceived health. Secondary outcome: Functional competence (LUCAS Functional Ability Index) based on responses to self-administered questionnaires at 1-year follow-up and 12 years after 1-year follow-up (2013/2014). Mean time under observation was 10.3 years. 38.3% (987/2,580) of the participants died; intervention group (IG): 35.7% (313/878), control group (CG): 39.6% (674/1,702); HR=0.89; p=0.09. Functional competence at 1-year follow-up: IG: ROBUST 67.4% (391/580), FRAIL 11.9% (69/580) vs. CG: ROBUST 62.9% (861/1,368), FRAIL 14.8% (203/1,368); p=0.12. 12-years after 1-year follow-up: IG: ROBUST 50.0% (160/320), FRAIL 30.9% (99/320) vs. CG: ROBUST 48.9% (307/628), FRAIL 34.1% (214/628); p=0.56. Insignificant but consistent effects on survival and the dynamics of functional competence suggest effectivity of the complex intervention. We plan to take a closer look at the effect of each reinforcement separately.


The use of databases, data mining and immunoinformatics in vaccinology: where are we?
Vaccinology has evolved from a sub-discipline focussed on simplistic vaccine development based on antibody-mediated protection to a separate discipline involving epidemiology, host and pathogen biology, immunology, genomics, proteomics, structure biology, protein engineering, chemical biology, and delivery systems. Data mining in combination with bioinformatics has provided a scaffold linking all these disciplines to the design of vaccines and vaccine adjuvants. Areas covered: This review provides background knowledge on immunological aspects which have been exploited with informatics for the in silico analysis of immune responses and the design of vaccine antigens. Furthermore, the article presents various databases and bioinformatics tools, and discusses B and T cell epitope predictions, antigen design, adjuvant research and systems immunology, highlighting some important examples, and challenges for the future. Expert opinion: Informatics and data mining have not only reduced the time required for experimental immunology, but also contributed to the identification and design of novel vaccine candidates and the determination of biomarkers and pathways of vaccine response. However, more experimental data is required for benchmarking immunoinformatic tools. Nevertheless, developments in immunoinformatics and reverse vaccinology, which are nascent fields, are likely to hasten vaccine discovery, although the path to regulatory approval is likely to remain a necessary impediment.


A Drosera-bioinspired hydrogel for catching and killing cancer cells.
A variety of bioinspired materials have been successfully synthesized to mimic the sophisticated structures or functions of biological systems. However, it is still challenging to develop materials with multiple functions that can be performed synergistically or sequentially. The purpose of this work was to demonstrate a novel bioinspired hydrogel that can interact with cancer cells, functionally similar to Drosera in catching and killing prey. This hydrogel had two layers with the top one functionalized with oligonucleotide aptamers and the bottom one functionalized with double-stranded DNA. The results show that the top hydrogel layer was able to catch target cells with high efficiency and specificity, and that the bottom hydrogel layer could sequester doxorubicin (Dox) for sustained drug release. Importantly, the released Dox could kill 90% of the cells after 1-h residence of the cells on the hydrogel. After the cell release, this bifunctional hydrogel could be regenerated for continuous cell catching and killing. Therefore, the data presented in this study has successfully demonstrated the potential of developing a material system with the functions of attracting, catching and killing diseased cells (e.g., circulating tumor cells) or even invading microorganisms (e.g., bacteria).


Virulence attenuation and live vaccine potential of aroA, crp cdt cya, and plasmid-cured mutants of Salmonella enterica serovar Abortusovis in mice and sheep.
Three live vaccine candidates of Salmonella enterica subspecies I serotype Abortusovis (aroA, cya crp cdt, and plasmid-cured strains) have been developed, and their efficacies in inducing humoral antibodies and protecting against abortion after challenge with wild-type strain SS44 were evaluated in sheep. Following estrus synchronization, animals were immunized 3 weeks after fertilization and boosted once 3 weeks later. Following challenge with wild-type SS44, pregnancy failure of vaccinated ewes was reduced compared to that of nonimmunized controls. Attenuation of each vaccine was also assessed in challenge experiments with nonimmunized pregnant ewes and in BALB/c mice. All three vaccine candidates appear to be safe for use in sheep and provide a model for the development of live vaccine candidates against naturally occurring ovine salmonellosis.


Human induced pluripotent stem cells ameliorate hyperoxia-induced lung injury in a mouse model.
Hyperoxia-induced lung injury occurs in neonates on oxygen support due to premature birth, often leading to the development of bronchopulmonary dysplasia. Current treatment options have limited effect. The aim of this study was to determine if human induced pluripotent stem cells (iPSCs) and those differentiated to an alveolar-like phenotype (diPSCs) could repair hyperoxia-induced lung damage in a mouse model. Neonatal C57BL6/J mice were separated into two groups and exposed to 75% oxygen over 6 or 14 days. Cell treatments were instilled intra-orally following removal. Controls included hyperoxia, normoxia, and a vehicle. 7 and 14 days post treatment, lungs were extracted and histomorphometric analysis performed. Gene expression of markers mediating inflammation (Tgfβ1, Nfkb1, and Il-6) were investigated. In addition, exosomes from each cell type were isolated and administered as a cell free alternative. There was a significant difference between the mean linear intercept (MLI) in hyperoxic vs. normoxic lungs prior to treatment. No difference existed between the MLI in iPSC-treated lungs vs. normoxic lungs after 6 and 14 days of hyperoxia. For mice exposed to 6 days of hyperoxia, gene expression in iPSC-treated lungs returned to normal 14 days later. At the same time points, diPSCs were not as effective. Exosomes were also not as effective in reversing hyperoxic lung damage as their cellular counterparts. This study highlights the potential benefit of using iPSCs to repair damaged lung tissue through possible modulation of the inflammatory response, leading to novel therapies for acute hyperoxia-induced lung injury and the prevention of bronchopulmonary dysplasia.


Genetic predictors of recovery in low back and lumbar radicular pain.
Previous data suggest that persistent back pain may be associated with genetic variability. In this study, we assessed the correlation between 8 genetic polymorphisms (VDR, COL11, MMP1, MMP9, IL-1α, IL-1RN, OPRM1, COMT) and pain recovery in patients with low back pain (LBP) and lumbar radicular pain (LRP). In total, 296 patients with LBP or LRP were followed for 5 years. The patients underwent standardized clinical examination and completed pain and function questionnaires. Univariate linear regression associations with P values <0.1 were included in the multivariable analysis, adjusting for pain intensity at baseline, age, sex, smoking, body mass index, and LBP or LRP. Pain intensity at 5-year follow-up was associated with VDR rs731236 (B = -0.5, 95% confidence interval [CI] -0.9 to -0.1, P = 0.017), MMP9 rs17576 (B = 0.5, 95% CI 0.1-0.9, P = 0.022), and OPRM1 rs1799971 (B = -0.8, 95% CI -1.4 to -0.2, P = 0.006) in the univariate analyses. MMP9 rs17576 and OPRM1 rs1799971 remained significant (B = 0.4, 95% CI 0.05-0.8, P = 0.026 and B = -0.8, 95% CI -1.3 to -0.2, P = 0.007) in the multivariable model. Thus, the data demonstrated that the rare allele of MMP9 rs17576 was associated with poor pain recovery, whereas the rare allele of OPRM1 rs1799971 was associated with better pain recovery at 5-year follow-up in the LBP and LRP patients. In particular, the present study suggested that the OPRM1 rs179971 A>G in men was associated with better long-term pain recovery. In men, the OPRM1 rs1799971 explained 4.7% of the variance of pain intensity. We conclude that the MMP9 rs17576 and OPRM1 rs1799971 genotypes may affect 5-year recovery in patients with LBP and LRP.


Coulometric sodium chloride removal system with Nafion membrane for seawater sample treatment.
Seawater analysis is one of the most challenging in the field of environmental monitoring, mainly due to disparate concentration levels between the analyte and the salt matrix causing interferences in a variety of analytical techniques. We propose here a miniature electrochemical sample pretreatment system for a rapid removal of NaCl utilizing the coaxial arrangement of an electrode and a tubular Nafion membrane. Upon electrolysis, chloride is deposited at the Ag electrode as AgCl and the sodium counterions are transported across the membrane. This cell was found to work efficiently at potentials higher than 400 mV in both stationary and flow injection mode. Substantial residual currents observed during electrolysis were found to be a result of NaCl back diffusion from the outer side of the membrane due to insufficient permselectivity of the Nafion membrane. It was demonstrated that the residual current can be significantly reduced by adjusting the concentration of the outer solution. On the basis of ion chromatography results, it was found that the designed cell used in flow injection electrolysis mode reduced the NaCl concentration from 0.6 M to 3 mM. This attempt is very important in view of nutrient analysis in seawater where NaCl is a major interfering agent. We demonstrate that the pretreatment of artificial seawater samples does not reduce the content of nitrite or nitrate ions upon electrolysis. A simple diffusion/extraction steady state model is proposed for the optimization of the electrolysis cell characteristics.


Microglial NLRP3 Inflammasome Activation upon TLR2 and TLR5 Ligation by Distinct α-Synuclein Assemblies.
Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder and is characterized by the formation of cellular inclusions inside neurons that are rich in an abnormal form of the protein α-synuclein (α-syn). Microglia are the CNS resident immune cells that react to misfolded proteins through pattern recognition receptor ligation and activation of signaling transduction pathways. Here, we studied activation of primary microglia isolated from wild-type mouse by distinct α-syn forms and their clearance. Internalization of α-syn monomers and oligomers efficiently activated the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome via TLR2 and TLR5 ligation, thereby acting on different signaling checkpoints. We found that primary microglia effectively engulf α-syn but hesitate in its degradation. NLRP3 inhibition by the selective inhibitor CRID3 sodium salt and NLRP3 deficiency improved the overall clearance of α-syn oligomers. Together, these data show that distinct α-syn forms exert different microglial NLRP3 inflammasome activation properties, thereby compromising its degradation, which can be prevented by NLRP3 inhibition.


Pathogenic NOTCH3 Variants Are Frequent Among the Korean General Population.
This study aimed to determine the frequency of pathogenic NOTCH3 variants among Koreans. In this cross-sectional study, we queried for pathogenic NOTCH3 variants in 2 Korean public genome databases: the Korean Reference Genome Database (KRGDB) and the Korean Genome Project (Korea1K). In addition, we screened the 3 most common pathogenic NOTCH3 variants (p.Arg75Pro, p.Arg544Cys, and p.Arg578Cys) for 1,000 individuals on Jeju Island, where the largest number of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) have been reported in Korea. The pathogenic NOTCH3 variant (p.Arg544Cys) was found in 0.12% of sequences in the KRGDB, and 3 pathogenic variants (p.Arg75Pro, p.Arg182Cys, and p.Arg544Cys) were present in 0.44% of the Korea1K database. Of the 1,000 individuals on Jeju Island, we found 2 cysteine-altering NOTCH3 variants (p.Arg544Cys variant in 9 and p.Arg578Cys in 1 individual) in 1.00% of the participants (95% confidence interval: 0.48%-1.83%). The presence of cysteine-altering NOTCH3 variants was significantly associated with a history of stroke (p < 0.001). Pathogenic NOTCH3 variants are frequently found in the general Korean population. Such a high prevalence of pathogenic variants could threaten the brain health of tens of thousands to hundreds of thousands of older adults in Korea.


HEALTH TECHNOLOGY ASSESSMENT METHODS GUIDELINES FOR MEDICAL DEVICES: HOW CAN WE ADDRESS THE GAPS? THE INTERNATIONAL FEDERATION OF MEDICAL AND BIOLOGICAL ENGINEERING PERSPECTIVE.
Current health technology assessment (HTA) methods guidelines for medical devices may benefit from contributions by biomedical and clinical engineers. Our study aims to: (i) review and identify gaps in the current HTA guidelines on medical devices, (ii) propose recommendations to optimize the impact of HTA for medical devices, and (iii) reach a consensus among biomedical engineers on these recommendations. A gray literature search of HTA agency Web sites for assessment methods guidelines on devices was conducted. The International Federation of Medical and Biological Engineers (IFMBE) then convened a structured focus group, with experts from different fields, to identify potential gaps in the current HTA guidelines, and to develop recommendations to fill these perceived gaps. The thirty recommendations generated from the focus group were circulated in a Delphi survey to eighty-five biomedical and clinical engineers. Thirty-two panelists, from seventeen countries, participated in the Delphi survey. The responses showed a strong agreement on twenty-seven of thirty recommendations. Some uncertainties remain about the methods to accurately assess the effectiveness and safety, and interoperability of a medical device with other devices or within the clinical setting. As medical devices differ from drug therapies, current HTA methods may not accurately reflect the conclusions of their assessment. Recommendations informed by the focus group discussions and Delphi survey responses aimed to address the perceived gaps, and to provide a more integrated approach in medical device assessments in combining engineering with other perspectives, such as clinical, economic, patient, human factors, ethical, and environmental.


Prognostic Significance of Periadnexal Extension in Cutaneous Melanoma and its Implications for Pathologic Reporting and Staging.
Tumor thickness is the strongest predictor of outcome for clinically localized melanoma. Therefore, accurate assessment is critical for appropriate staging, reliable estimation of prognosis, and management. When melanoma extends alongside skin adnexal structures more deeply than the main tumor mass (periadnexal extension), it is currently unknown whether the prognosis is more accurately reflected by the deepest point of periadnexal tumor extension or the main tumor mass. This study sought to address this question. Survival outcomes of 257 primary cutaneous melanoma patients with periadnexal extension diagnosed between 2005 and 2015 and managed at Melanoma Institute Australia were identified and compared with a control cohort of 514 patients who were matched for tumor thickness, sex, age, mitotic rate, ulceration status, and year of diagnosis but lacked periadnexal extension. The incidence of periadnexal extension at Melanoma Institute Australia was 1.5% (257/16,692 cutaneous melanomas diagnosed between 2005 and 2015). The patient characteristics between the 2 groups were otherwise very similar; median Breslow thickness was 0.9 mm for the periadnexal group and 1.0 mm for the control group. The median extension beyond the Breslow thickness in the tumors with periadnexal extension was 0.45 mm (mean, 0.4 mm). Median follow-up was 46 months for the periadnexal group and 44 months for the control group. Measures of clinical outcomes all showed trends for improved survival in the periadnexal extension group; these were melanoma-specific survival (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.44, 1.38), overall survival (HR, 0.91; 95% CI, 0.59, 1.41), disease-free survival (HR, 0.68; 95% CI, 0.45, 1.03), and distant disease-free survival (HR, 0.69; 95% CI, 0.4, 1.17), although none were statistically significant. There was a higher rate of sentinel lymph node (SLN) metastasis in the periadnexal group versus the control group in patients whose tumors were >1 mm thick (24/100=24% vs. 23/187=12.3%). Periadnexal extension was significantly associated with SLN metastasis on univariate logistic regression analysis (odds ratio [95% CI], 2.25 [1.20, 4.24], P=0.01). If the periadnexal extension had been included in the measurement of tumor thickness, 42.8% of patients would have been upstaged to a higher American Joint Committee on Cancer T category. The findings of this study indicate that periadnexal involvement that extends more deeply than the thickness of the main tumor mass increases the risk of SLN metastasis in tumours >1 mm thick, however, does not worsen clinical outcomes overall, and tumor thickness measurements should not include deeper foci of periadnexal tumor.


Community characteristics associated with where urgent care centers are located: a cross-sectional analysis.
To determine the community characteristics associated with non-hospital-based urgent care centres wherever they are located. National cross-sectional study evaluating the association between non-hospital-based urgent care centers, and their demographic characteristics in a community, using descriptive statistics and multivariate logistic regressions. Communities in the USA with non-hospital-based urgent care centers, as identified using a 2014 national database from the Urgent Care Association of America. 31,022 communities encompassing 6898 urgent care centers across the USA. Presence of a non-hospital-based urgent care center within a community. Communities with non-hospital-based urgent care centers are urban (75.7% with vs 22.2% without; p<0.001 across rural urban commuting area levels), and are located in areas with higher income levels (38.6% in highest quartile with vs 22.3% without; p<0.001 across quartiles) and higher levels of private insurance (29.6% in highest quartile with vs 23.9% without; p<0.001 across quartiles). While the growth of the urgent care industry may have other promising implications, policymakers should recognise that it may exacerbate disparities in access to acute care faced by poorer, uninsured patients, and may also have financial implications for providers that are providing overlapping services, such as emergency departments and primary care practices.


Hamsters fed diets high in saturated fat have increased cholesterol accumulation and cytokine production in the aortic arch compared with cholesterol-fed hamsters with moderately elevated plasma non-HDL cholesterol concentrations.
There is growing evidence that dietary fatty acids and/or dietary cholesterol could have a direct role on inflammatory diseases such as atherosclerosis. F(1)B Golden Syrian hamsters (Mesocricetus auratus), in 2 groups of 72, were fed for 10 wk a semipurified diet containing either 20 g/100 g hydrogenated coconut oil without cholesterol or cocoa butter (20 g/100 g) with cholesterol (0.15 g/100 g). After the 10-wk treatment period, plasma was collected from food-deprived hamsters (16 h) for plasma lipid measurements. Hamsters were then ranked according to their plasma VLDL and LDL cholesterol (non-HDL-C) concentrations with 1.86 mmol/L as the cut-off point between low (Low; n = 36) and medium (Med; n = 36) concentrations for each treatment. Hamsters in the Low and Medium groups fed cholesterol (Low-chol) had significantly lower plasma total cholesterol (TC) concentrations than hamsters in the Low group fed coconut oil (Low-CO). However, this difference for the Medium group was reflected in significantly lower plasma HDL cholesterol (HDL-C) concentrations. Hamsters in the Low-CO group had significantly higher aortic total and esterified cholesterol concentrations than hamsters in the Low-chol group. Hamsters in the Low-chol group had significantly higher aortic tumor necrosis factor-alpha concentrations than hamsters in the Low-CO group. Hamsters in the Med-CO group had significantly higher aortic interleukin-1beta concentrations than hamsters in the Med-chol group. In conclusion, the present study suggests that dietary cholesterol and saturated fatty acids could have an effect on atherosclerosis not only beyond their role in affecting plasma lipoproteins but also through increased production of inflammatory cytokines in the arterial wall.


JAM-L-mediated leukocyte adhesion to endothelial cells is regulated in cis by alpha4beta1 integrin activation.
Junctional adhesion molecules (JAMs) are endothelial and epithelial adhesion molecules involved in the recruitment of circulating leukocytes to inflammatory sites. We show here that JAM-L, a protein related to the JAM family, is restricted to leukocytes and promotes their adhesion to endothelial cells. Cis dimerization of JAM-L is required to engage in heterophilic interactions with its cognate counter-receptor CAR (coxsackie and adenovirus receptor). Interestingly, JAM-L expressed on neutrophils binds CAR independently of integrin activation. However, on resting monocytes and T lymphocytes, which express the integrin VLA-4, JAM-L molecules engage in complexes with VLA-4 and mainly accumulate in their monomeric form. Integrin activation is required for the dissociation of JAM-L-VLA-4 complexes and the accumulation of functional JAM-L dimers, which indicates that the leukocyte integrin VLA-4 controls JAM-L function in cis by controlling its dimerization state. This provides a mechanism through which VLA-4 and JAM-L functions are coordinately regulated, allowing JAM-L to strengthen integrin-dependent adhesion of leukocytes to endothelial cells.


A novel missense mutation in the AVPR2 gene of a Japanese infant with nephrogenic diabetes insipidus.
We describe an infant with nephrogenic diabetes insipidus (NDI) with a novel mutation in the arginine vasopressin receptor 2 (AVPR2) gene. A 1-month-old infant showed failure to thrive and hypernatremia. The water deprivation test revealed elevated serum osmolality and low urine osmolality. The patient showed a slight but not significant response to intramuscular injection of arginine vasopressin (AVP). DNA analysis revealed a novel missense mutation involving substitution of proline for leucine at position 173 (P173L), which was reported to be important for stabilizing the hydrogen bond between tyrosine at position 205 and leucine at position 169. This mutation was not detected in 116 ethnic-matched controls. This case, with clinical data including the water deprivation test and P173L mutation, will facilitate understanding the structure and function of the A VPR2.


OctaDist: a tool for calculating distortion parameters in spin crossover and coordination complexes.
OctaDist is an interactive and visual program for determination of structural distortion in octahedral coordination complexes such as spin crossover complexes, single-ion magnets, perovskites or metal-organic frameworks. OctaDist computes the octahedral distortion parameters initially designed in the context of the spin-crossover phenomenon and denoted ζ, Σ, and Θ from standard structural files. The program also provides additional tools for molecular analyses and visualization. It emphasizes performance, flexibility, ease of use, application programming interface (API) consistency, and clear documentation. The modules and classes in OctaDist can be easily customized to include new algorithms or analytical tools. OctaDist is cross-platform supported for modern operating systems and is available as open-source distributed under the GNU General Public License version 3.


[Role of blood rheological disorders in the pathogenesis of acute venous thrombosis].
The study of rheological properties of the blood in 115 patients with acute venous thrombosis showed that in 73% of cases haemorheological disorders participate in the pathogenesis of the thrombus formation, in 27% the disease runs a course with the normal rheological characteristics of the blood. The increase of the blood viscosity in venous thrombosis has a multifactorial character and depends on the degree of aggregation of the erythrocytes the cell Z-potential, dys- and hyperproteinaemia. In this respect it is essential to approach the problem differentially to correct haemorheological disturbances and disorders of the coagulation system of the blood in patients with venous thrombosis.


Localization and characterization of melatonin receptors in rodent brain by in vitro autoradiography.
Little is known of the neural sites of action for the pineal hormone, melatonin. Thus, we developed an in vitro autoradiographic method using 125I-labeled melatonin (I-MEL) to study putative melatonin receptors in rodent brain. We first determined optimal in vitro labeling conditions for autoradiographic detection of I-MEL binding sites in rat median eminence, the most intensely labeled area in the rat brain. We then assessed the pharmacologic and kinetic properties of I-MEL binding sites in rat median eminence by quantitative autoradiography. These sites have high affinity for I-MEL (equilibrium dissociation constant = 43 pM). I-MEL binding was inhibited by nanomolar concentrations of melatonin or 6-chloromelatonin, but was not inhibited by serotonin, dopamine, or norepinephrine (100 microM). These results suggest that I-MEL binding sites identified by in vitro autoradiography represent specific, high-affinity melatonin receptors. Studies of the distribution of I-MEL binding in rat, Syrian hamster, and Djungarian hamster brain confirm that the median eminence and suprachiasmatic nucleus are major sites of I-MEL binding in rodent brain; other brain areas labeled in one or more of these species were the thalamus (paraventricular, anteroventral, and reuniens nuclei, nucleus of the stria medullaris, and medial part of the lateral habenular nucleus), hypothalamus (dorsomedial nucleus), subiculum, and area postrema. The presence of putative melatonin receptors in the suprachiasmatic nuclei and median eminence of these rodent species suggests that these brain regions are important loci for melatonin effects on circadian rhythms and reproduction.


Alkaline inorganic pyrophosphatase activity of mammalian-cell alkaline phosphatase.
Alkaline phosphatase prepared from mammalian cell cultures was found to have alkaline inorganic pyrophosphatase activity. Both of these activities appear to be associated with a single protein, as demonstrated by: (1) concomitant purification of alkaline phosphatase and alkaline inorganic pyrophosphatase; (2) proportional precipitation of alkaline phosphatase and inorganic pyrophosphatase activities by titrating constant amounts of an enzyme preparation with increasing concentration of antibody; (3) immune electrophoresis, which showed that precipitin bands that have alkaline phosphatase activity also have pyrophosphatase activity; (4) inhibition of pyrophosphatase activity by cysteine, an inhibitor of alkaline phosphatase activity; (5) similar subcellular localization of the two enzyme activities as demonstrated by histochemical methods; (6) hormonal and substrate induction of alkaline phosphatase activity in mammalian cell cultures, which produced a nearly parallel rise in inorganic pyrophosphatase activity.


[Adrenocortical tumors with neuroendocrine differentiation].
18 adrenocortical tumours and 5 pheochromocytomas were studied immunohistochemically. Expression of synaptophysin and chromogranin A was found in cells of cortical adenomas, "frontier" neoplasms and in 20-75% of carcinoma cells, this ultramicroscopically was confirmed by observation of typical neuroendocrine granules. Some groups of cells of cortico-medullary tumours also expressed proteins of neural differentiation (protein S-100).


Multilevel orthopaedic surgery in group IV spastic hemiplegia.
Most children with spastic hemiplegia have high levels of function and independence but fixed deformities and gait abnormalities are common. The classification proposed by Winters et al is widely used to interpret hemiplegic gait patterns and plan intervention. However, this classification is based on sagittal kinematics and fails to consider important abnormalities in the transverse plane. Using three-dimensional gait analysis, we studied the incidence of transverse-plane deformity and gait abnormality in 17 children with group IV hemiplegia according to Winters et al before and after multilevel orthopaedic surgery. We found that internal rotation of the hip and pelvic retraction were consistent abnormalities of gait in group-IV hemiplegia. A programme of multilevel surgery resulted in predictable improvement in gait and posture, including pelvic retraction. In group IV hemiplegia pelvic retraction appeared in part to be a compensating mechanism to control foot progression in the presence of medial femoral torsion. Correction of this torsion can improve gait symmetry and function.


Morphometric analysis of human gingival elastic fibres degradation by human leukocyte elastase protective effect of avocado and soybean unsaponifiables (ASU).
Degradation of preelastic fibres (oxytalan and elaunin) and mature elastic fibres by human leukocyte elastase (HLE) was investigated using automated image analysis. Specimens from two young healthy adults were used. Although HLE hydrolyzed both fibre types, mature elastic fibres exhibited greater susceptibility to this effect than preelastic fibres. Avocado and soybean unsaponifiables are widely prescribed in rheumatology and parodontology and have also been the focus of ex vivo experiments aimed at determining whether they protect elastic fibres against degradation by HLE. Findings from the present study indicate that avocado and soybean unsaponifiables protect all types of gingival elastic fibres from degradation by HLE. Avocado and soybean unsaponifiables may be beneficial in patients with gingival inflammation and parodontitis, since HLE plays a major role in these disease states.


The experience of head and neck cancer survivorship (including laryngectomy): an integrated biopsychosocial model.
The head and neck cancer (HNC) survivorship experience is unique among cancer populations. This review seeks to explore the HNC survivor experience associated with altered upper aerodigestive tract (UADT) function using principles of survivorship. HNC survivors experience complex physical, functional, and psychosocial challenges related to UADT dysfunction. Interventions need to address all of these dimensions being mindful of the survivor experience. Studies reveal related unmet needs of both HNC survivors and their family members. An expose of the HNC survivorship experience is timely since 2016/2017 contains the release of landmark position papers and guidelines in the field. These address the unique challenges faced by the HNC population, their management, and the triad psychosocial, functional, and physical survivor burden. Such developments will drive future care. The head and neck survivorship experience is characterized by complex changes with broad impact when examined in an experiential framework. HNC survivor care demands clinical excellence from multiple disciplines that are positioned to enact recent HNC guidelines and adopt survivorship principles. Future research in this population that explores experiential aspects of altered UADT function would be valuable in informing clinical practice. A biopsychosocial framework is presented for conceptualizing the HNC survivorship experience.


pH/Reduction Dual-Responsive Oxidized Alginate-Doxorubicin (mPEG-OAL-DOX/Cys) Prodrug Nanohydrogels: Effect of Complexation with Cyclodextrins.
Novel biocompatible and biodegradable pH/reduction dual-responsive oxidized alginate-doxorubicin (mPEG-OAL-DOX/Cys) prodrug nanohydrogels were designed for tumor-specific intracellular triggered release of anticancer drug DOX by conjugating DOX via acid-labile Schiff base linkage into the PEGylated oxidized alginate (mPEG-OAL) cross-linked with bioreducible disulfide bond. The effect of the complexation with cyclodextrins (α-CD and β-CD) before or after the cross-linking of the mPEG-OAL on the DOX content and controlled release performance was investigated. It was found that the cyclodextrin inclusion complex prodrug nanohydrogels mPEG(CD)-OAL-DOX/Cys, prepared by cross-linking of the mPEG-OAL after complexation with cyclodextrins, exhibited better pH/reduction dual-responsive controlled release performance than the mPEG-OAL-DOX/Cys(CD) ones prepared by cross-linking of the mPEG-OAL before complexation with cyclodextrins, owing to the supramolecular cross-linking of the adjacent pseudopolyrotaxanes. Especially for the cyclodextrin inclusion complex prodrug nanohydrogels mPEG(α-CD)-OAL-DOX/Cys, DOX was released rapidly under lower pH media mimicking the tumor microenvironment and completely released within 48 h, while the premature leakage under the simulated physiological condition was ∼40%, without burst release in both cases. The cellular toxicity and uptake results demonstrated that the mPEG(α-CD)-OAL-DOX/Cys prodrug nanohydrogels possessed similar inhibition against cancer cell growth in comparison with the free DOX and enhanced drug intracellular accumulation.


Molecular aetiology of primary hyperoxaluria type 1.
Primary hyperoxaluria type 1 (PH1) is a rare autosomal-recessive disorder, caused by a deficiency of the liver-specific intermediary-metabolic enzyme alanine:glyoxylate aminotransferase (AGT). AGT deficiency results in increased synthesis and excretion of the metabolic end-product oxalate and the deposition of insoluble calcium oxalate in the kidney and urinary tract. Numerous mutations and polymorphisms have been identified in the gene (AGXT) that encodes AGT, some of which interact synergistically to cause a variety of complex enzyme phenotypes, including AGT intraperoxisomal aggregation, accelerated degradation, and peroxisome-to-mitochondrion mistargeting. The latter is the single most common cause of PH1 and results from the functional interaction between a common Pro11Leu polymorphism and a disease-specific Gly170Arg mutation. The recent solution of the crystal structure of AGT has enabled the effects of several mutations and polymorphisms to be rationalised in terms of their likely effects on AGT conformation. Increased understanding of the molecular aetiology of PH1 has led to significant improvements in all aspects of the clinical management of the disorder, including diagnosis (by enzyme assay of percutaneous needle liver biopsies), prenatal diagnosis (by DNA analysis of chorionic villus samples) and treatment (by liver transplantation as a form of enzyme replacement therapy).


Challenges for Adoption of Integrated Pest Management (IPM): the Soybean Example.
Soybean is considered one of today's most important crops. Planted on millions of hectares worldwide, the management of soybean pests usually requires large amounts of chemicals. However, a key component to meet the increasing demand for food due to the rapidly growing global population is protecting crops from pests while maintaining environmental quality through ecologically and economically sound integrated pest management (IPM) practices. Not only can IPM result in more profitable agriculture due to the reduction of pest control costs but also assures equitable, secure, sufficient, and stable flows of both food and ecosystem services. Despite those ecological and economic benefits, the vast areas of cultivated soybean as well as the convenience of spraying insecticides are encouraging the adoption of prophylactic pest control as a relatively inexpensive safeguard compared to IPM practices. Thus, in this forum, we discuss the reasons for soybean IPM not reaching its potential. We give examples of how we can revive this once successful pest management program with a focus on experiences in Brazil and the USA. We analyze IPM case studies to illustrate the need for growers to have easy and fast access to IPM information on its medium- and long-term benefits. Overall, this forum highlights the importance of IPM for agricultural sustainability including ecological and financial benefits.


Pemphigus and pemphigoid antigens are expressed in human amnion epithelium.
The sera of patients with pemphigus vulgaris (PV) and bullous pemphigoid (BP) contain autoantibodies which react with antigens present in a variety of mammalian squamous epithelia. The biologic role of these epithelial antigens is unknown; however, they do appear to be markers of epithelial differentiation. We have examined many human tissues that may be used as sources of large amounts of BP and PV antigens, including the human amnion, which is composed of the amnion reflectum and placentum (epithelial monolayers) and amnion cord (stratified epithelium). Human amnion was obtained from normal term deliveries and specimens of each area of the amnion were processed for light and electron microscopy. Samples of amnion were snap-frozen in liquid nitrogen and 4-micron sections were used as a substrate for BP and PV antibodies by indirect immunofluorescence (IF) techniques. Well-characterized BP serum (indirect IF titer 1:2560), PV serum (indirect IF titer 1:160), and normal human serum (negative indirect IF) were utilized as sources of BP and PV autoantibodies and a negative control, respectively. Linear staining of the BMZ was produced by BP antibodies in 8/8 specimens of amnion reflectum, 8/8 specimens of amnion placentum, and 3/3 specimens of amnion cord. Staining of the epithelial intercellular spaces was produced by PV antibodies of 2/3 specimens of amnion cord and none of the amnion reflectum (0/8) or amnion placentum (0/8) tested. Normal human serum produced no specific staining of the amnion. The light and the ultrastructural features of human amnion basement membrane zone and intercellular spaces resembles closely their epidermal counterparts. The restricted distribution of BP antigen in amnion epithelial basal cells (amnion reflectum, placentum, and cord) and PV antigen in stratified amnion epithelium (amnion cord) reinforces their relationship with epithelial differentiation. The abundance and availability of these tissues facilitate extraction and characterization of BP and PV antigens.


Case-control study of a multistate equine herpesvirus myeloencephalopathy outbreak.
A large multistate outbreak of equine herpesvirus myeloencephalopathy (EHM) occurred in May 2011 among horses that participated in a competitive event. To identify EHM risk factors among horses with a common exposure venue. A total of 123 horses: 19 horses with EHM, 14 equine herpesvirus-1 cases with no reported neurologic signs, and 90 control horses. EHM case survey data were compared with data from EHV-1 cases with no neurologic signs and healthy controls using univariable and multivariable methods. Significant factors associated with higher risk for EHM compared with EHV-1 cases with no neurologic signs were (1) greater number of biosecurity risks at the event, (2) female sex, (3) increasing number of classes competed in at the event, and (4) an interaction between sex and number of classes competed in. In the EHM versus controls comparison, in addition to sex and biosecurity risks, factors associated with higher EHM risk included EHV-1 vaccination in the 5 weeks before the event and increasing number of events attended in April 2011; zinc dietary supplementation was associated with decreased risk. An interaction between sex and the number of events attended in April 2011 also was significant. Findings from this study suggest that dietary zinc supplementation may be associated with decreased risk of EHM. Several factors were associated with increased risk of EHM. Additional investigations of factors associated with risk of EHM are warranted to evaluate the importance of these factors in this complex disease of horses.


Fish vision and the detection of planktonic prey.
Planktivorous sunfish of various sizes were studied to ascertain whether growth-related changes in the retina are related to the ability to capture small planktonic crustaceans. Behaviorally, the larger fish detected and captured crustaceans that subtended smaller visual angles. Histological examination of the retinas revealed that the distance between cones, measured in minutes of visual angle, decreased as the animals grew, suggesting that the larger retinas could resolve smaller objects. These correlated behavioral and anatomical results suggest that improved visual resolution contributes to improved predation. This finding provides a selective advantage for the continuous retinal growth noted in many fish.


Localization of nuclear subunits of cyclic AMP-dependent protein kinase by the immunocolloidal gold method.
An immunocolloidal gold electron microscopy method is described allowing the ultrastructural localization and quantitation of the regulatory subunits RI and RII and the catalytic subunit C of cAMP-dependent protein kinase. Using a postembedding indirect immunogold labeling procedure that employs specific antisera, the catalytic and regulatory subunits were localized in electron-dense regions of the nucleus and in cytoplasmic areas with a minimum of nonspecific staining. Antigenic domains were localized in regions of the heterochromatin, nucleolus, interchromatin granules, and in the endoplasmic reticulum of different cell types, such as rat hepatocytes, ovarian granulosa cells, and spermatogonia, as well as cultured H4IIE hepatoma cells. Morphometric quantitation of the relative staining density of nuclear antigens indicated a marked modulation of the number of subunits per unit area under various physiologic conditions. For instance, following partial hepatectomy in rats, the staining density of the nuclear RI and C subunits was markedly increased 16 h after surgery. Glucagon treatment of rats increased the staining density of only the nuclear catalytic subunit. Dibutyryl cAMP treatment of H4IIE hepatoma cells led to a marked increase in the nuclear staining density of all three subunits of cAMP-dependent protein kinase. These studies demonstrate that specific antisera against cAMP-dependent protein kinase subunits may be used in combination with immunogold electron microscopy to identify the ultrastructural location of the subunits and to provide a semi-quantitative estimate of their relative cellular density.


Conceptualizing patient empowerment in cancer follow-up by combining theory and qualitative data.
Patient empowerment (PE) may be defined as the opportunity for patients to master issues important to their own health. The aim of this study was to conceptualize PE and how the concept manifests itself for cancer patients attending follow-up, in order to develop a relevant and sensitive questionnaire for this population. A theoretical model of PE was made, based on Zimmerman's theory of psychological empowerment. Patients who were in follow-up after first line treatment for their cancer (n = 16) were interviewed about their experiences with follow-up. A deductive thematic analysis was conducted to contextualize the theory and find concrete manifestations of empowerment. Data were analyzed to find situations that expressed empowerment or lack of empowerment. We then analyzed what abilities these situations called for and we further analyzed how these abilities fitted Zimmerman's theory. In all, 16 patients from two different hospitals participated in the interviews. PE in cancer follow-up was conceptualized as: (1) the perception that one had the possibility of mastering treatment and care (e.g. the possibility of 'saying no' to treatment and getting in contact with health care when needed); (2) having knowledge and skills regarding, for example treatment, care, plan of treatment and care, normal reactions and late effects, although knowledge and information was not always considered positively; and (3) being able to make the health care system address one's concerns and needs and, for some patients, also being able to monitor one's treatment, tests and care. We conceptualized PE based on Zimmerman's theory and empirical data to contextualize the concept in cancer follow-up. When developing a patient reported outcome measure measuring PE for this group of patients, one needs to be attentive to differences in wishes regarding mastery.


A multidisciplinary approach to the diagnosis and treatment of gastrointestinal stromal tumor.
Management of patients with gastrointestinal stromal tumor (GIST) typically involves a combination of surgical, pathologic, and pharmacologic interventions. Gastroenterologists are often the first specialists to encounter patients presenting with GIST and are therefore responsible for facilitating early intervention strategies. Although patients with gastric or small-bowel GISTs typically present with symptoms, a diagnosis of GIST should be considered whenever a submucosal lesion is seen endoscopically. Visualization by standard endoscopy often can determine tumor location and size, although endoscopic ultrasound (EUS) is the most accurate imaging technique for submucosal lesions. Biopsy techniques that yield sufficient tumor samples for diagnostic studies, such as EUS-guided fine needle aspiration, are essential, although other approaches such as EUS-guided core needle biopsy may increase diagnostic yield for subepithelial lesions. Pathology assessment should include immunohistochemical staining for KIT and possibly DOG1 expression, and mutational analysis can have prognostic and predictive value for certain patients. R0 resection is the goal for patients with localized or potentially resectable tumors, which often can be accomplished by laparoscopic resection, even for larger tumors. Medical oncologists play a key role in assessing risk of recurrence after resection and optimizing tyrosine kinase inhibitor therapy in the adjuvant or metastatic setting. Cytoreductive surgery may have value for patients with recurrent or metastatic GIST who exhibit stable disease or respond to tyrosine kinase inhibitor therapy. A coordinated multidisciplinary approach over the course of the disease will serve to enhance communication among GIST team members, reduce risk of progression, and optimize outcomes.


Detecting Gene-Gene Interactions Associated with Multiple Complex Traits with U-Statistics.
Many complex diseases, such as psychiatric and behavioral disorders, are commonly characterized through various measurements that reflect physical, behavioral and psychological aspects of diseases. While it remains a great challenge to find a unified measurement to characterize a disease, the available multiple phenotypes can be analyzed jointly in the genetic association study. Simultaneously testing these phenotypes has many advantages, including considering different aspects of the disease in the analysis, and utilizing correlated phenotypes to improve the power of detecting disease-associated variants. Furthermore, complex diseases are likely caused by the interplay of multiple genetic variants through complicated mechanisms. Considering gene-gene interactions in the joint association analysis of complex diseases could further increase our ability to discover genetic variants involving complex disease pathways. In this article, we propose a stepwise U-test for joint association analysis of multiple loci and multiple phenotypes. Through simulations, we demonstrated that testing multiple phenotypes simultaneously could attain higher power than testing one single phenotype at a time, especially when there are shared genes contributing to multiple phenotypes. We also illustrated the proposed method with an application to Nicotine Dependence (ND), using datasets from the Study of Addition, Genetics and Environment (SAGE). The joint analysis of three ND phenotypes identified two SNPs, rs10508649 and rs2491397, and reached a nominal P-value of 3.79e-13. The association was further replicated in two independent datasets with P-values of 2.37e-05 and 7.46e-05.


Blood-brain barrier pathology in Alzheimer's and Parkinson's disease: implications for drug therapy.
The blood-brain barrier (BBB) is a tightly regulated barrier in the central nervous system. Though the BBB is thought to be intact during neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's disease (PD), recent evidence argues otherwise. Dysfunction of the BBB may be involved in disease progression, eliciting of peripheral immune response, and, most importantly, altered drug efficacy. In this review, we will give a brief overview of the BBB, its components, and their functions. We will critically evaluate the current literature in AD and PD BBB pathology resulting from insult, neuroinflammation, and neurodegeneration. Specifically, we will discuss alterations in tight junction, transport and endothelial cell surface proteins, and vascular density changes, all of which result in altered permeability. Finally, we will discuss the implications of BBB dysfunction in current and future therapeutics. Developing a better appreciation of BBB dysfunction in AD and PD may not only provide novel strategies in treatment, but will prove an interesting milestone in understanding neurodegenerative disease etiology and progression.


Benefits, key protocol components, and considerations for successful implementation of extracorporeal cardiopulmonary resuscitation: a review of the recent literature.
The application of venoarterial extracorporeal membrane oxygenation (ECMO) in patients unresponsive to conventional cardiopulmonary resuscitation (CPR) has significantly increased in recent years. To date, three published randomized trials have investigated the use of extracorporeal CPR (ECPR) in adults with refractory out-of-hospital cardiac arrest. Although these trials reported inconsistent results, they suggest that ECPR may have a significant survival benefit over conventional CPR in selected patients only when performed with strict protocol adherence in experienced emergency medical services-hospital systems. Several studies suggest that identifying suitable ECPR candidates and reducing the time from cardiac arrest to ECMO initiation are key to successful outcomes. Prehospital ECPR or the rendezvous approach may allow more patients to receive ECPR within acceptable timeframes than ECPR initiation on arrival at a capable hospital. ECPR is only one part of the system of care for resuscitation of cardiac arrest victims. Optimizing the chain of survival is critical to improving outcomes of patients receiving ECPR. Further studies are needed to find the optimal strategy for the use of ECPR.


Diagnosis and screening for obesity-related conditions among children and teens receiving Medicaid--Maryland, 2005-2010.
The prevalence of obesity among children and adolescents in the United States tripled during 1980-2008 and plateaued during 2008-2010. This rise in obesity was associated with a rise in chronic conditions previously observed mostly in adults, including hypertension, hypercholesterolemia, and type 2 diabetes. In 2007, the American Academy of Pediatrics published Expert Committee recommendations for universal screening for overweight and targeted laboratory screening for metabolic disorders among children and adolescents with a body mass index (BMI) at or above the 85th percentile based on age or presence of certain risk factors. To assess the prevalence of overweight and obesity among children and teens enrolled in Maryland Medicaid or the Maryland Children's Health Program (MCHP) and whether or not the children were being screened for obesity-related conditions according to the Expert Committee recommendations, investigators from the Maryland Department of Health and Mental Hygiene computed BMI percentiles for age and sex on a random sample of persons aged 2-19 years enrolled in Maryland Medicaid or MCHP whose height and weight were measured during a well-child visit. Encounter records were used to identify obesity-related conditions and screening laboratory tests received. This study found that 16.5% of participants were overweight (BMI in the 85th-94th percentiles) and 21.4% were obese (BMI at or above the 95th percentile). Obesity was highest among those aged 12-19 years (25.6%) and among Hispanics (28.1%). The diagnosis of obesity-related conditions increased significantly with increasing BMI, with 33.5% of obese participants diagnosed with asthma, 7.9% diagnosed with dyslipidemia, and 7.2% diagnosed with depression. Only 29.9% of overweight and 40.2% of obese participants received a lipid panel test. The results of this investigation were communicated to pediatric, public health, and managed-care leaders. Efforts to communicate the need to increase obesity screening and laboratory testing among this population should continue.