Structural elucidation and immunostimulatory activity of a new polysaccharide from Cordyceps militaris.
A new polysaccharide (CMPB90-1) was isolated from cultured Cordyceps militaris by alkaline extraction. The chemical structure of CMPB90-1 was determined by analysis of physicochemical and spectral data. The backbone of CMPB90-1 is composed of (1→6)-linked α-d-glucopyranosyl and (1→3)-linked α-d-glucopyranosyl residues, with branching at O-6, which consists of (1→4)-linked β-d-mannopyranosyl and (1→6)-linked α-d-glucopyranosyl residues, respectively. β-d-Galactopyranosyl residues is the terminal unit. In vitro immunomodulatory assay revealed that CMPB90-1 promoted proliferation of splenic lymphocytes, enhanced cytotoxicity of NK cells and promoted lymphocyte secretion of the cytokine interleukin-2. Besides, CMPB90-1 upregulated T-cell subpopulation, strengthened phagocytosis function of macrophages and induced their M1 polarization. The mechanism of the effects might be due to the activation of TLR2, MAPK and NF-κB pathways. The results proposed that CMPB90-1 can be researched and developed as a new functional food.


Designing for psychological change: individuals' reward and cost valuations in weight management.
Knowledge of the psychological constructs that underlie behavior offers valuable design opportunities for persuasive systems. We use the decision theory, which describes how behavior is underpinned by reward-cost valuations, as a framework for investigating such psychological constructs to deliver design objectives for weight management technologies. We applied a decision theory-based analysis in the domain of weight management to understand the rewards and costs that surround individuals' weight management behaviors, with the aim of uncovering design opportunities for weight management technologies. We conducted qualitative interviews with 15 participants who were or had been trying to lose weight. Thematic analysis was used to extract themes that covered the rewards and costs surrounding weight management behaviors. We supplemented our qualitative study with a quantitative survey of 100 respondents investigating the extent to which they agreed with statements reflecting themes from the qualitative study. The primary obstacles to weight management were the rewards associated with unhealthy choices, such as the pleasures of unhealthy foods and unrestricted consumption in social situations, and the significant efforts required to change habits, plan, and exercise. Psychological constructs that supported positive weight management included feeling good after making healthy choices, being good to oneself, experiencing healthy yet still delicious foods, and receiving social support and encouraging messages (although opinions about encouraging messages was mixed). A rewards-costs driven enquiry revealed a wide range of psychological constructs that contribute to discouraging and supporting weight management. The constructs extracted from our qualitative study were verified by our quantitative survey, in which the majority of respondents also reported similar thoughts and feelings. This understanding of the rewards and costs surrounding weight management offers a range of new opportunities for the design of weight management technologies that enhance the encouraging factors and alleviate the discouraging ones.


Assessing chlorinated ethene degradation in a large scale contaminant plume by dual carbon-chlorine isotope analysis and quantitative PCR.
The fate of chlorinated ethenes in a large contaminant plume originating from a tetrachloroethene (PCE) source in a sandy aquifer in Denmark was investigated using novel methods including compound-specific carbon and chlorine isotope analysis and quantitative real-time polymerase chain reaction (qPCR) methods targeting Dehaloccocoides sp. and vcrA genes. Redox conditions were characterized as well based on concentrations of dissolved redox sensitive compounds and sulfur isotopes in SO(4)(2-). In the first 400 m downgradient of the source, the plume was confined to the upper 20 m of the aquifer. Further downgradient it widened in vertical direction due to diverging groundwater flow reaching a depth of up to 50 m. As the plume dipped downward and moved away from the source, O(2) and NO(3)(-) decreased to below detection levels, while dissolved Fe(2+) and SO(4)(2-) increased above detectable concentrations, likely due to pyrite oxidation as confirmed by the depleted sulfur isotope signature of SO(4)(2-). In the same zone, PCE and trichloroethene (TCE) disappeared and cis-1,2-dichloroethene (cDCE) became the dominant chlorinated ethene. PCE and TCE were likely transformed by reductive dechlorination rather than abiotic reduction by pyrite as indicated by the formation of cDCE and stable carbon isotope data. TCE and cDCE showed carbon isotope trends typical for reductive dechlorination with an initial depletion of (13)C in the daughter products followed by an enrichment of (13)C as degradation proceeded. At 1000 m downgradient of the source, cDCE was the dominant chlorinated ethene and had reached the source δ(13)C value confirming that cDCE was not affected by abiotic or biotic degradation. Further downgradient (up to 1900 m), cDCE became enriched in (13)C by up to 8 ‰ demonstrating its further transformation while vinylchloride (VC) concentrations remained low (<1 μg/L) and ethene was not observed. The correlated shift of carbon and chlorine isotope ratios of cDCE by 8 and 3.9 ‰, respectively, the detection of Dehaloccocides sp genes, and strongly reducing conditions in this zone provide strong evidence for reductive dechlorination of cDCE. The significant enrichment of (13)C in VC indicates that VC was transformed further, although the mechanism could not be determined. The transformation of cDCE was the rate limiting step as no accumulation of VC occurred. In summary, the study demonstrates that carbon-chlorine isotope analysis and qPCR combined with traditional approaches can be used to gain detailed insight into the processes that control the fate of chlorinated ethenes in large scale plumes.


Tetraspanin-6 negatively regulates exosome production.
Exosomes, extracellular vesicles (EVs) of endosomal origin, emerge as master regulators of cell-to-cell signaling in physiology and disease. Exosomes are highly enriched in tetraspanins (TSPNs) and syndecans (SDCs), the latter occurring mainly in proteolytically cleaved form, as membrane-spanning C-terminal fragments of the proteins. While both protein families are membrane scaffolds appreciated for their role in exosome formation, composition, and activity, we currently ignore whether these work together to control exosome biology. Here we show that TSPN6, a poorly characterized tetraspanin, acts as a negative regulator of exosome release, supporting the lysosomal degradation of SDC4 and syntenin. We demonstrate that TSPN6 tightly associates with SDC4, the SDC4-TSPN6 association dictating the association of TSPN6 with syntenin and the TSPN6-dependent lysosomal degradation of SDC4-syntenin. TSPN6 also inhibits the shedding of the SDC4 ectodomain, mimicking the effects of matrix metalloproteinase inhibitors. Taken together, our data identify TSPN6 as a regulator of the trafficking and processing of SDC4 and highlight an important physical and functional interconnection between these membrane scaffolds for the production of exosomes. These findings clarify our understanding of the molecular determinants governing EV formation and have potentially broad impact for EV-related biomedicine.


Young adults' childhood experiences of support when living with a parent with a mental illness.
There are several concerns in relation to children living with a parent suffering from a mental illness. In such circumstances, the health-care professionals need to involve the whole family, offering help to the parents on parenting as well as support for their children. These children are often helped by participating in meetings that provide them with contact with others with similar experiences. The aim of this study was to investigate young adults' childhood experiences of support groups when living with a mentally ill parent. Seven young women were chosen to participate in this study. A qualitative descriptive method was chosen. The main category emerged as 'the influence of life outside the home because of a parent's mental illness' from the two generic categories: 'a different world' and 'an emotion-filled life'. The participants' friends did not know that their parent was ill and they 'always had to…take responsibility for what happened at home'. These young adults appreciated the support group activities they participated in during their childhood, stating that the meetings had influenced their everyday life as young adults. Despite this, they associated their everyday life with feelings of being different. This study highlights the need for support groups for children whose parents suffer from mental illness.


Community Rates of IgG4 Antibodies to Ascaris Haemoglobin Reflect Changes in Community Egg Loads Following Mass Drug Administration.
Conventional diagnostic methods for human ascariasis are based on the detection of Ascaris lumbricoides eggs in stool samples. However, studies of ascariasis in pigs have shown that the prevalence and the number of eggs detected in the stool do not correlate well with exposure of the herd to the parasite. On the other hand, an ELISA test measuring antibodies to Ascaris suum haemoglobin (AsHb) has been shown to be useful for estimating transmission intensity on pig farms. In this study, we further characterized the AsHb antigen and screened samples from a population-based study conducted in an area that is endemic for Ascaris lumbricoides in Indonesia to assess changes in AsHb antibody rates and levels in humans following mass drug administration (MDA). We developed and evaluated an ELISA to detect human IgG4 antibodies to AsHb. We tested 1066 plasma samples collected at different times from 599 subjects who lived in a village in rural Indonesia that was highly endemic for ascariasis. The community received 6 rounds of MDA for lymphatic filariasis with albendazole plus diethylcarbamazine between 2002 and 2007. While the AsHb antibody assay was not sensitive for detecting all individuals with Ascaris eggs in their stools, the percentage of seropositive individuals decreased rapidly following MDA. Reductions in antibody rates reflected decreased mean egg output per person both at the community level and in different age groups. Two years after the last round of MDA the community egg output and antibody prevalence rate were reduced by 81.6% and 78.9% respectively compared to baseline levels. IgG4 antibody levels to AsHb appear to reflect recent exposure to Ascaris. The antibody prevalence rate may be a useful indicator for Ascaris transmission intensity in communities that can be used to assess the impact of control measures on the force of transmission.


Kinetic and mechanistic requirements for helping CD8 T cells.
The requirements for the generation of fully competent long-lived memory CD8 T cells and in particular the role and the mechanisms of help from CD4 T cells remain ill-defined. Memory CD8 T cells generated in the absence of CD4 T cell help often have an impaired recall proliferation and are thus unable to confer protection against certain pathogens. However, the timing and the mechanisms involved in the delivery of help are still unclear and differ between various experimental systems. In this study, we investigated the role of CD4 T help in generating memory CD8 T cells in a defined heterologous prime-boost system, consisting of priming with replication incompetent virus-like particles and challenge with recombinant vaccinia virus, both sharing only a common lymphocytic choriomeningitis virus-derived CD8 T cell epitope. We show in this system that delivery of help is only essential during the challenge phase for recall proliferation of memory CD8 T cells. Furthermore, we show that generation of proliferation-competent memory CD8 T cells is independent of CD40 and CCR5 and that in vivo IL-2 supplementation neither during priming nor during challenge was able to rescue recall proliferation of "unhelped" memory CD8 T cells.


Reactive oxygen species damage drives cardiac and mitochondrial dysfunction following acute nano-titanium dioxide inhalation exposure.
Nanotechnology offers innovation in products from cosmetics to drug delivery, leading to increased engineered nanomaterial (ENM) exposure. Unfortunately, health impacts of ENM are not fully realized. Titanium dioxide (TiO2) is among the most widely produced ENM due to its use in numerous applications. Extrapulmonary effects following pulmonary exposure have been identified and may involve reactive oxygen species (ROS). The goal of this study was to determine the extent of ROS involvement on cardiac function and the mitochondrion following nano-TiO2 exposure. To address this question, we utilized a transgenic mouse model with overexpression of a novel mitochondrially-targeted antioxidant enzyme (phospholipid hydroperoxide glutathione peroxidase; mPHGPx) which provides protection against oxidative stress to lipid membranes. MPHGPx mice and littermate controls were exposed to nano-TiO2 aerosols (Evonik, P25) to provide a calculated pulmonary deposition of 11 µg/mouse. Twenty-four hours following exposure, we observed diastolic dysfunction as evidenced by E/A ratios greater than 2 and increased radial strain during diastole in wild-type mice (p < 0.05 for both), indicative of restrictive filling. Overexpression of mPHGPx mitigated the contractile deficits resulting from nano-TiO2 exposure. To investigate the cellular mechanisms associated with the observed cardiac dysfunction, we focused our attention on the mitochondrion. We observed a significant increase in ROS production (p < 0.05) and decreased mitochondrial respiratory function (p < 0.05) following nano-TiO2 exposure which were attenuated in mPHGPx transgenic mice. In summary, nano-TiO2 inhalation exposure is associated with cardiac diastolic dysfunction and mitochondrial functional alterations, which can be mitigated by the overexpression of mPHGPx, suggesting ROS contribution in the development of contractile and bioenergetic dysfunction.


An automated microfluidic multiplexer for fast delivery of C. elegans populations from multiwells.
Automated biosorter platforms, including recently developed microfluidic devices, enable and accelerate high-throughput and/or high-resolution bioassays on small animal models. However, time-consuming delivery of different organism populations to these systems introduces a major bottleneck to executing large-scale screens. Current population delivery strategies rely on suction from conventional well plates through tubing periodically exposed to air, leading to certain disadvantages: 1) bubble introduction to the sample, interfering with analysis in the downstream system, 2) substantial time drain from added bubble-cleaning steps, and 3) the need for complex mechanical systems to manipulate well plate position. To address these concerns, we developed a multiwell-format microfluidic platform that can deliver multiple distinct animal populations from on-chip wells using multiplexed valve control. This Population Delivery Chip could operate autonomously as part of a relatively simple setup that did not require any of the major mechanical moving parts typical of plate-handling systems to address a given well. We demonstrated automatic serial delivery of 16 distinct C. elegans worm populations to a single outlet without introducing any bubbles to the samples, causing cross-contamination, or damaging the animals. The device achieved delivery of more than 90% of the population preloaded into a given well in 4.7 seconds; an order of magnitude faster than delivery modalities in current use. This platform could potentially handle other similarly sized model organisms, such as zebrafish and drosophila larvae or cellular micro-colonies. The device's architecture and microchannel dimensions allow simple expansion for processing larger numbers of populations.


Are family factors universally related to metabolic outcomes in adolescents with Type 1 diabetes?
To assess the importance of family factors in determining metabolic outcomes in adolescents with Type 1 diabetes in 19 countries. Adolescents with Type 1 diabetes aged 11-18 years, from 21 paediatric diabetes care centres, in 19 countries, and their parents were invited to participate. Questionnaires were administered recording demographic data, details of insulin regimens, severe hypoglycaemic events and number of episodes of diabetic ketoacidosis. Adolescents completed the parental involvement scale from the Diabetes Quality of Life for Youth--Short Form (DQOLY-SF) and the Diabetes Family Responsibility Questionnaire (DFRQ). Parents completed the DFRQ and a Parental Burden of Diabetes score. Glycated haemoglobin (HbA(1c)) was analysed centrally on capillary blood. A total of 2062 adolescents completed a questionnaire, with 2036 providing a blood sample; 1994 parents also completed a questionnaire. Family demographic factors that were associated with metabolic outcomes included: parents living together (t = 4.1; P < 0.001), paternal employment status (F = 7.2; d.f. = 3; P < 0.001), parents perceived to be over-involved in diabetes care (r = 0.11; P < 0.001) and adolescent-parent disagreement on responsibility for diabetes care practices (F = 8.46; d.f. = 2; P < 0.001). Although these factors differed between centres, they did not account for centre differences in metabolic outcomes, but were stronger predictors of metabolic control than age, gender or insulin treatment regimen. Family factors, particularly dynamic and communication factors such as parental over-involvement and adolescent-parent concordance on responsibility for diabetes care appear be important determinants of metabolic outcomes in adolescents with diabetes. However, family dynamic factors do not account for the substantial differences in metabolic outcomes between centres.


Parasympathetic functions in children with sensory processing disorder.
The overall goal of this study was to determine if parasympathetic nervous system (PsNS) activity is a significant biomarker of sensory processing difficulties in children. Several studies have demonstrated that PsNS activity is an important regulator of reactivity in children, and thus, it is of interest to study whether PsNS activity is related to sensory reactivity in children who have a type of condition associated with sensory processing disorders termed sensory modulation dysfunction (SMD). If so, this will have important implications for understanding the mechanisms underlying sensory processing problems of children and for developing intervention strategies to address them. The primary aims of this project were: (1) to evaluate PsNS activity in children with SMD compared to typically developing (TYP) children, and (2) to determine if PsNS activity is a significant predictor of sensory behaviors and adaptive functions among children with SMD. We examine PsNS activity during the Sensory Challenge Protocol; which includes baseline, the administration of eight sequential stimuli in five sensory domains, recovery, and also evaluate response to a prolonged auditory stimulus. As a secondary aim we examined whether subgroups of children with specific physiological and behavioral sensory reactivity profiles can be identified. Results indicate that as a total group the children with severe SMD demonstrated a trend for low baseline PsNS activity, compared to TYP children, suggesting this may be a biomarker for SMD. In addition, children with SMD as a total group demonstrated significantly poorer adaptive behavior in the communication and daily living subdomains and in the overall Adaptive Behavior Composite of the Vineland than TYP children. Using latent class analysis, the subjects were grouped by severity and the severe SMD group had significantly lower PsNS activity at baseline, tones and prolonged auditory. These results provide preliminary evidence that children who demonstrate severe SMD may have physiological activity that is different from children without SMD, and that these physiological and behavioral manifestations of SMD may affect a child's ability to engage in everyday social, communication, and daily living skills.


Ultrasonic scalpel causes greater depth of soft tissue necrosis compared to monopolar electrocautery at standard power level settings in a pig model.
Ultrasonic scalpel (UC) and monopolar electrocautery (ME) are common tools for soft tissue dissection. However, morphological data on the related tissue alteration are discordant. We developed an automatic device for standardized sample excision and compared quality and depth of morphological changes caused by UC and ME in a pig model. 100 tissue samples (5 × 3 cm) of the abdominal wall were excised in 16 pigs. Excisions were randomly performed manually or by using the self-constructed automatic device at standard power levels (60 W cutting in ME, level 5 in UC) for abdominal surgery. Quality of tissue alteration and depth of coagulation necrosis were examined histopathologically. Device (UC vs. ME) and mode (manually vs. automatic) effects were studied by two-way analysis of variance at a significance level of 5%. At the investigated power level settings UC and ME induced qualitatively similar coagulation necroses. Mean depth of necrosis was 450.4 ± 457.8 μm for manual UC and 553.5 ± 326.9 μm for automatic UC versus 149.0 ± 74.3 μm for manual ME and 257.6 ± 119.4 μm for automatic ME. Coagulation necrosis was significantly deeper (p < 0.01) when UC was used compared to ME. The mode of excision (manual versus automatic) did not influence the depth of necrosis (p = 0.85). There was no significant interaction between dissection tool and mode of excision (p = 0.93). Thermal injury caused by UC and ME results in qualitatively similar coagulation necrosis. The depth of necrosis is significantly greater in UC compared to ME at investigated standard power levels.


Identification of stimulatory and inhibitory inputs to the hypothalamic-pituitary-adrenal axis during hypoglycaemia or transport in ewes.
This study used the novel approach of statistical modelling to investigate the control of hypothalamic-pituitary-adrenal (HPA) axis and quantify temporal relationships between hormones. Two experimental paradigms were chosen, insulin-induced hypoglycaemia and 2 h transport, to assess differences in control between noncognitive and cognitive stimuli. Vasopressin and corticotropin-releasing hormone (CRH) were measured in hypophysial portal plasma, and adrenocorticotropin hormone (ACTH) and cortisol in jugular plasma of conscious sheep, and deconvolution analysis was used to calculate secretory rates, before modelling. During hypoglycaemia, the relationship between plasma glucose and vasopressin or CRH was best described by log10 transforming variables (i.e. a positive power-curve relationship). A negative-feedback relationship with log10 cortisol concentration 2 h previously was detected. Analysis of the "transport" stimulus suggested that the strength of the perceived stimulus decreased over time after accounting for cortisol facilitation and negative-feedback. The time course of vasopressin and CRH responses to each stimulus were different However, at the pituitary level, the data suggested that log10 ACTH secretion rate was related to log10 vasopressin and CRH concentrations with very similar regression coefficients and an identical ratio of actions (2.3 : 1) for both stimuli. Similar magnitude negative-feedback effects of log10 cortisol at -110 min (hypoglycaemia) or -40 min (transport) were detected, and both models contained a stimulatory relationship with cortisol at 0 min (facilitation). At adrenal gland level, cortisol secretory rates were related to simultaneously measured untransformed ACTH concentration but the regression coefficient for the hypoglycaemia model was 2.5-fold greater than for transport. No individual sustained maximum cortisol secretion for longer than 20 min during hypoglycaemia and 40 min during transport. These unique models demonstrate that corticosteroid negative-feedback is a significant control mechanism at both the pituitary and hypothalamus. The amplitude of HPA response may be related to stimulus intensity and corticosteroid negative-feedback, while duration depended on feedback alone.


Autophagic Flux Is Regulated by Interaction Between the C-terminal Domain of PATCHED1 and ATG101.
The Hedgehog (Hh) receptor Patched1 (PTCH1) is a well-known tumor suppressor that in its active form represses Smoothened (SMO) activity, inhibits proliferation, and induces apoptosis. The cytoplasmic C-terminal domain (CTD) regulates PTCH1 turnover and nucleates a proapoptotic complex. In this study, it was mechanistically determined that Autophagy-related 101 (ATG101), essential for mammalian autophagy, physically interacts with the CTD of PTCH1 and connects it to the ULK complex, which stimulates the autophagy machinery in response to changes in nutrient availability. This interaction results in a blockade of basal autophagic flux and accumulation of autophagosomes with undegraded cargo. Remarkably, this function of PTCH1 is independent of its repressive activity on SMO, as shown in SMO-deficient cells or in the presence of a SMO inhibitor, but is opposed by Sonic Hedgehog (SHH). These findings reveal a novel noncanonical function of PTCH1 that limits autophagy, mediated by ATG101, which could have therapeutic implications in Hh-dependent cancers.Implications: Loss-of-function of the tumor suppressor Patched1 might promote cancer cell fitness by increasing autophagic flux in response to metabolic or environmental stresses. Mol Cancer Res; 16(5); 909-19. ©2018 AACR.


Chronic neuroleptic-induced mouth movements in the rat: suppression by CCK and selective dopamine D1 and D2 receptor antagonists.
Fluphenazine decanoate (25 mg/kg IM every 3 weeks x 6) resulted in spontaneous vacuous chewing mouth movements and jaw tremor in male Sprague-Dawley rats. These movements could be suppressed by the selective D1 or D2 dopamine antagonists SCH 23390 (0.5 mg/kg) and raclopride (0.5 mg/kg), respectively, and by CCK-8S (50 micrograms/kg). Fluphenazine-induced mouth movements were unaffected by the selective CCK antagonist MK-329, and by a dose of physostigmine (50 micrograms/kg) sufficient to stimulate mouth movements in placebo treated rats. Scopolamine (0.1 mg/kg) suppressed spontaneous mouth movements in placebo-treated rats, but the effect on fluphenazine-induced mouth movements was not significant. A higher dose of scopolamine (0.5 mg/kg) did suppress the neuroleptic-induced mouth movements, but also induced hyperactivity, characterized by increased sniffing and grooming. These findings indicate that mouth movements resulting from the chronic administration of neuroleptics to the rat may serve as a useful pharmacological model of tardive dyskinesia in the human, and suggest that a relative increase of D1 activity as well as impaired CCK function may contribute to the pathogenesis of this disorder.


CFD for wastewater treatment: an overview.
Computational fluid dynamics (CFD) is a rapidly emerging field in wastewater treatment (WWT), with application to almost all unit processes. This paper provides an overview of CFD applied to a wide range of unit processes in water and WWT from hydraulic elements like flow splitting to physical, chemical and biological processes like suspended growth nutrient removal and anaerobic digestion. The paper's focus is on articulating the state of practice and research and development needs. The level of CFD's capability varies between different process units, with a high frequency of application in the areas of final sedimentation, activated sludge basin modelling and disinfection, and greater needs in primary sedimentation and anaerobic digestion. While approaches are comprehensive, generally capable of incorporating non-Newtonian fluids, multiphase systems and biokinetics, they are not broad, and further work should be done to address the diversity of process designs. Many units have not been addressed to date. Further needs are identified throughout, but common requirements include improved particle aggregation and breakup (flocculation), and improved coupling of biology and hydraulics.


Adherence to endoscopic surveillance for advanced lesions and colorectal cancer in inflammatory bowel disease: an AEG and GETECCU collaborative cohort study.
Patients with colonic inflammatory bowel disease (IBD) have a high risk of colorectal cancer (CRC). Current guidelines recommend endoscopic surveillance, yet epidemiological studies show poor compliance. The aims of our study were to analyse adherence to endoscopic surveillance, its impact on advanced colorectal lesions, and risk factors of non-adherence. A retrospective multicentre study of IBD patients with criteria for CRC surveillance, diagnosed between 2005 and 2008 and followed up to 2020, was performed. Following European guidelines, patients were stratified into risk groups and adherence was considered when surveillance was performed according to the recommendations (±1 year). Cox-proportional regression analyses were used to compare the risk of lesions. p-values below 0.05 were considered significant. A total of 1031 patients (732 ulcerative colitis, 259 Crohn's disease and 40 indeterminate colitis; mean age of 36 ± 15 years) were recruited from 25 Spanish centres. Endoscopic screening was performed in 86% of cases. Adherence to guidelines was 27% (95% confidence interval, CI = 24-29). Advanced lesions and CRC were detected in 38 (4%) and 7 (0.7%) patients respectively. Adherence was associated with increased detection of advanced lesions (HR = 3.59; 95% CI = 1.3-10.1; p = 0.016). Risk of delay or non-performance of endoscopic follow-up was higher as risk groups increased (OR = 3.524; 95% CI = 2.462-5.044; p < 0.001 and OR = 4.291; 95%CI = 2.409-7.644; p < 0.001 for intermediate- and high- vs low-risk groups). Adherence to endoscopic surveillance allows earlier detection of advanced lesions but is low. Groups at higher risk of CRC are associated with lower adherence.


Sleep Outcomes for Parents of Children With Neurodevelopmental Disabilities: A Systematic Review.
Parents of children with Neurodevelopmental Disabilities (NDDs) are at risk of sleep loss. No comprehensive systematic reviews examining parental sleep outcomes in caregivers of children with NDDs exist. A systematic search was conducted between June and August 2016 examining sleep quantity, quality, sleepiness, and fatigue outcomes of caregivers of children with NDDs. Of 7,534 citations retrieved, 33 met eligibility criteria. Most studies ( n = 27) were cross-sectional, included a range of NDDs and were of "poor" ( n = 14) or "fair" ( n = 17) quality. Few good quality studies compared objectively measured sleep in parents of children with NDDs with parents with typically developing children. Parents of children with NDDs consistently reported significantly poorer subjective sleep quality. There is a paucity of good quality comparative studies, using well-validated measures, examining parental sleep outcomes. Future research should aim to fill this gap, providing greater insight to parents' experiences, and identifying targets for intervention design and evaluation.


A Survey of Direct Users and Uses of SNOMED CT: 2010 Status.
SNOMED CT is gaining momentum and endorsements as an international clinical terminology. However, many vendors await a clearer business case and clients' demand. We conducted a survey of direct users of SNOMED CT to determine the current profile of users, modes of use, and attitudes towards different aspects of the terminology. A web-base survey, consisting of 43 questions was distributed in January 2010, and 215 responses were elicited. This paper summarizes findings regarding profiles of users and their SNOMED CT use. The results indicate significant use by non-researchers and by industry and government sectors. Many users are relative newcomers with less than 3 years experience with SNOMED CT, and production-related use was reported by 39% of respondents. Most users are satisfied with the level of content coverage. The results indicate that SNOMED CT has a solid footing in production systems, and that SCT is mostly used for concept searches and clinical coding.


The effectiveness of humane teaching methods in veterinary education.
Animal use resulting in harm or death has historically played an integral role in veterinary education, in disciplines such as surgery, physiology, biochemistry, anatomy, pharmacology, and parasitology. However, many non-harmful alternatives now exist, including computer simulations, high quality videos, ''ethically-sourced cadavers'' such as from animals euthanased for medical reasons, preserved specimens, models and surgical simulators, non-invasive self-experimentation, and supervised clinical experiences. Veterinary students seeking to use such methods often face strong opposition from faculty members, who usually cite concerns about their teaching efficacy. Consequently, studies of veterinary students were reviewed comparing learning outcomes generated by non-harmful teaching methods with those achieved by harmful animal use. Of eleven published from 1989 to 2006, nine assessed surgical training--historically the discipline involving greatest harmful animal use. 45.5% (5/11) demonstrated superior learning outcomes using more humane alternatives. Another 45.5% (5/11) demonstrated equivalent learning outcomes, and 9.1% (1/11) demonstrated inferior learning outcomes. Twenty one studies of non-veterinary students in related academic disciplines were also published from 1968 to 2004. 38.1% (8/21) demonstrated superior, 52.4% (11/21) demonstrated equivalent, and 9.5% (2/21) demonstrated inferior learning outcomes using humane alternatives. Twenty nine papers in which comparison with harmful animal use did not occur illustrated additional benefits of humane teaching methods in veterinary education, including: time and cost savings, enhanced potential for customisation and repeatability of the learning exercise, increased student confidence and satisfaction, increased compliance with animal use legislation, elimination of objections to the use of purpose-killed animals, and integration of clinical perspectives and ethics early in the curriculum. The evidence demonstrates that veterinary educators can best serve their students and animals, while minimising financial and time burdens, by introducing well-designed teaching methods not reliant on harmful animal use.


A novel E3 ubiquitin ligase substrate screen identifies Rho guanine dissociation inhibitor as a substrate of gene related to anergy in lymphocytes.
Ubiquitination of eukaryotic proteins regulates a broad range of cellular processes, including regulation of T cell activation and tolerance. We have previously demonstrated that gene related to anergy in lymphocytes (GRAIL), a ring finger ubiquitin E3 ligase, is required for the induction of T cell anergy; however, the substrate(s) for GRAIL E3 ligase activity is/are unknown. In this study, we report a novel prokaryotic system developed to screen for substrates of E3 ligases. Using this screen, Rho guanine dissociation inhibitor (RhoGDI) was identified as a potential substrate of GRAIL. GRAIL was subsequently demonstrated to bind and ubiquitinate RhoGDI, although GRAIL-mediated ubiquitination of RhoGDI did not result in proteosomal degradation. Expression of GRAIL in T cells resulted in specific inhibition of RhoA GTPase activation; activation of Rac1, cdc42, and Ras GTPases were not affected. Interestingly, stable T cell lines expressing dominant-negative RhoA mimicked the GRAIL-mediated IL-2 inhibition phenotype, and T cells expressing constitutively active RhoA were able to overcome GRAIL-mediated inhibition of IL-2 expression. These findings validate our prokaryotic screen as a method of identifying substrates for ubiquitin E3 ligases and suggest a role for Rho effector molecules in T cell anergy.


Release of human platelet factor V activity is induced by both collagen and ADP and is inhibited by aspirin.
Factor V activity in suspensions of human platelets washed by albumin density gradient separation increased in response to stimulation by both collagen and adenosine diphosphate (ADP). The appearance of factor V activity extracellularly had the characteristics of platelet secretion and was partially inhibited by aspirin and by the antimetabolites 2-deoxyglucose and antimycin A. Some increase in factor V activity was also observed in platelet suspensions during the initial response to ADP; this activity was not detected extracellularly, but remained associated with the platelets. Patients with storage pool deficiency (SPD) whose platelets are deficient only in dense granule substances released normal amounts of factor V activity, whereas decreased amounts were released in a patient whose platelets have both dense and alpha granule deficiencies. These findings suggest that a portion of platelet factor V is associated with, and released from, alpha granules.


In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone. An 85-day multicenter trial. COMBIVENT Inhalation Aerosol Study Group.
Combination bronchodilator therapy for chronic obstructive pulmonary disease (COPD) is available widely throughout the world except in North America. Previous studies have yielded conflicting results regarding the advantages of combining anticholinergic therapy with sympathomimetic therapy in COPD. We report the results of a 12-week prospective, double-blind, parallel-group evaluation of the use of the following: albuterol, a beta-adrenergic agent; ipratropium, an anticholinergic agent; or a combination of the two, administered by metered-dose inhaler to patients with moderately severe stable COPD. Following baseline studies, 534 patients were given one of the three test bronchodilator preparations to be used at home four times daily in addition to oral theophylline and corticosteroids as required. The doses of the latter two drugs were kept stable. Subjects were tested on days 1, 29, 57, and 85. Analysis of 1-s forced expiratory volume (FEV1) curves on those test days indicated that the combination was superior to either single agent alone in peak effect, in the effect during the first 4 h after dosing, and in the total area under the curve of the FEV1 response. The mean peak percent increases in FEV1 over baseline on the four test days were 31 to 33 percent for the combination, 24 to 25 percent for ipratropium, and 24 to 27 percent for albuterol. The differences between the combination and its components were statistically significant on all test days. The AUC0-4 means for the combination were 21 to 44 percent greater than the ipratropium means and 30 to 46 percent greater than the albuterol means. Similar changes were noted in the forced vital capacity curves. Symptom scores did not change over time and did not differ among the treatment groups. We conclude that the combination of ipratropium and albuterol, when given by metered-dose inhaler to patients with COPD, is more effective than either of the two agents alone. The advantage of the combination is apparent primarily during the first 4 h after administration. The availability of combination therapy by metered-dose inhaler should help to improve patient compliance.


Design and fabrication of silicon-tessellated structures for monocentric imagers.
Compared with conventional planar optical image sensors, a curved focal plane array can simplify the lens design and improve the field of view. In this paper, we introduce the design and implementation of a segmented, hemispherical, CMOS-compatible silicon image plane for a 10-mm diameter spherical monocentric lens. To conform to the hemispherical focal plane of the lens, we use flexible gores that consist of arrays of spring-connected silicon hexagons. Mechanical functionality is demonstrated by assembling the 20-μm-thick silicon gores into a hemispherical test fixture. We have also fabricated and tested a photodiode array on a silicon-on-insulator substrate for use with the curved imager. Optical testing shows that the fabricated photodiodes achieve good performance; the hemispherical imager enables a compact 160 ° field of view camera with >80% fill factor using a single spherical lens.


Microswitches for the Activation of the Nociceptin Receptor Induced by Cebranopadol: Hints from Microsecond Molecular Dynamics.
Cebranopadol (CBP) is a novel analgesic acting as agonist at the nociceptin (NOP) and μ-opioid (MOP) receptors, exhibiting high potency and efficacy as an antinociceptive and antihypersensitive drug. The binding conformation and the dynamical interactions of CBP with the NOP receptor have been investigated by molecular docking, molecular dynamics (MD) in the microsecond time scale, and hybrid quantum mechanics/molecular mechanics (QM/MM). CBP binds to the NOP receptor as a bidentate ligand of the aspartate D1303,32 by means of both its fluoroindole and dimethyl nitrogens. Starting from the known crystal structure of the inactive state of the receptor, in complex with the antagonist compound-24 (NOP-C24) the comparative analysis of 1 μs MD trajectories of the NOP-C24 complex itself and the NOP_free and NOP-CBP complexes provides new insights on the already known microswitches related to receptor activation, in the frame of the extended ternary complex model. The agonist acts by destabilizing the inactive conformation of the NOP receptor, by inducing a conformational change of M1343,36, which allows W2766,48 to flip around its χ2 dihedral, going in close proximity to the receptor hydrophobic core (T1383,40, P2275,50, F2726,44), which is known to be fundamental for the activation of the opioid receptors. A complete rational picture is also provided for the role of N1333,35 and W2766,48 undergoing critical conformational changes related to an anticooperativity effect, i.e. the well-known role of sodium as negative modulator of agonist binding. Finally, the movement of residue Y3197,53 belonging to the NPxxY motif is also induced by the binding of the agonist in the inactive state, opening a gate for a water channel just as upon receptor activation.


Apically exposed, tight junction-associated beta1-integrins allow binding and YopE-mediated perturbation of epithelial barriers by wild-type Yersinia bacteria.
Using polarized epithelial cells, primarily MDCK-1, we assessed the mode of binding and effects on epithelial cell structure and permeability of Yersinia pseudotuberculosis yadA-deficient mutants. Initially, all bacteria except the invasin-deficient (inv) mutant adhered apically to the tight junction areas. These contact points of adjacent cells displayed beta1-integrins together with tight junction-associated ZO-1 and occludin proteins. Indeed, beta1-integrin expression was maximal in the tight junction area and then gradually decreased along the basolateral membranes. Wild-type bacteria also opened gradually the tight junction to paracellular permeation of different-sized markers, viz., 20-, 40-, and 70-kDa dextrans and 45-kDa ovalbumin, as well as to their own translocation between adjacent cells in intimate contact with beta1-integrins. The effects on the epithelial cells and their barrier properties could primarily be attributed to expression of the Yersinia outer membrane protein YopE, as the yopE mutant bound but caused no cytotoxicity. Moreover, the apical structure of filamentous actin (F-actin) was disturbed and tight junction-associated proteins (ZO-1 and occludin) were dispersed along the basolateral membranes. It is concluded that the Yersinia bacteria attach to beta1-integrins at tight junctions. Via this localized injection of YopE, they perturb the F-actin structure and distribution of proteins forming and regulating tight junctions. Thereby they promote paracellular translocation of bacteria and soluble compounds.


Proteomic analysis of albumin and globulin fractions of pea (Pisum sativum L.) seeds.
Proteomic analysis is emerging as a highly useful tool in food research, including studies of food allergies. Two-dimensional gel electrophoresis involving isoelectric focusing and sodium dodecyl sulfate polyacrylamide gel electrophoresis is the most effective method of separating hundreds or even thousands of proteins. In this study, albumin and globulin tractions of pea seeds cv. Ramrod were subjected to proteomic analysis. Selected potentially alergenic proteins were identified based on their molecular weights and isoelectric points. Pea seeds (Pisum sativum L.) cv. Ramrod harvested over a period of two years (Plant Breeding Station in Piaski-Szelejewo) were used in the experiment. The isolated albumins, globulins and legumin and vicilin fractions of globulins were separated by two-dimensional gel electrophoresis. Proteomic images were analysed in the ImageMaster 2D Platinum program with the use of algorithms from the Melanie application. The relative content, isoelectric points and molecular weights were computed for all identified proteins. Electrophoregrams were analysed by matching spot positions from three independent replications. The proteomes of albumins, globulins and legumin and vicilin fractions of globulins produced up to several hundred spots (proteins). Spots most characteristic of a given fraction were identified by computer analysis and spot matching. The albumin proteome accumulated spots of relatively high intensity over a broad range of pi values of ~4.2-8.1 in 3 molecular weight (MW) ranges: I - high molecular-weight albumins with MW of ~50-110 kDa, II - average molecular-weight albumins with MW of ~20-35 kDa, and III - low molecular-weight albumins with MW of ~13-17 kDa. 2D gel electrophoregrams revealed the presence of 81 characteristic spots, including 24 characteristic of legumin and 14 - of vicilin. Two-dimensional gel electrophoresis proved to be a useful tool for identifying pea proteins. Patterns of spots with similar isoelectric points and different molecular weights or spots with different isoelectric points and similar molecular weights play an important role in proteome analysis. The regions characteristic of albumin, globulin and legumin and vicilin fractions of globulin with typical MW and pi values were identified as the results of performed 2D electrophoretic separations of pea proteins. 2D gel electrophoresis of albumins and the vicilin fraction of globulins revealed the presence of 4 and 2 spots, respectively, representing potentially allergenic proteins. They probably corresponded to vicilin fragments synthesized during post-translational modification of the analysed protein.


OBO-Fused Benzo[fg]tetracene as Acceptor With Potential for Thermally Activated Delayed Fluorescence Emitters.
Six luminophores bearing an OBO-fused benzo[fg]tetracene core as an electron acceptor were designed and synthesized. The molecular structures of three molecules (PXZ-OBO, 5PXZ-OBO, 5DMAC-OBO) were determined by single crystal X-ray diffraction studies and revealed significant torsion between the donor moieties and the OBO acceptor with dihedral angles between 75.5 and 86.2°. Photophysical studies demonstrate that blue and deep blue emission can be realized with photoluminescence maxima (λPL) ranging from 415 to 480 nm in mCP films. The emission energy is modulated by simply varying the strength of the donor heterocycle, the number of donors, and their position relative to the acceptor. Although the DMAC derivatives show negligible delayed emission because of their large singlet-triplet excited state energy difference, ΔE ST, PXZ-based molecules, especially PXZ-OBO with an experimental ΔE ST of 0.25 eV, demonstrate delayed emission in blend mCP films at room temperature, which suggests triplet exciton harvesting occurs in these samples, potentially by thermally activated delayed fluorescence.


N-Acetyl cysteine abrogates silver-induced reactive oxygen species in human cells without altering silver-based antimicrobial activity.
Silver-based antimicrobials are widely used topically to treat infections associated with multi-drug resistant (MDR) pathogens. Expanding this topical use to aerosols to treat lung infections requires understanding and preventing silver toxicity in the respiratory tract. A key mechanism resulting in silver-induced toxicity is the production of reactive oxygen species (ROS). In this study, we have verified ROS generation in silver-treated bronchial epithelial cells prompting evaluation of three antioxidants, N-acetyl cysteine (NAC), ascorbic acid, and melatonin, to identify potential prophylactic agents. Among them, NAC was the only candidate that abrogated the ROS generation in response to silver acetate exposure resulting in the rescue of these cells from silver-associated toxicity. Further, this protective effect directly translated to preservation of metabolic activity, as demonstrated by the normal levels of citric acid cycle metabolites in NAC-pretreated silver acetate-exposed cells. Because the citric acid cycle remained functional, silver-exposed cells pre-incubated with NAC demonstrated significantly higher levels of adenosine triphosphate levels compared with NAC-free controls. Moreover, we found that this prodigious capacity of NAC to rescue silver acetate-exposed cells was due not only to its antioxidant activity, but also to its ability to directly bind silver. Despite binding to silver, NAC did not alter the antimicrobial activity of silver acetate.


A cross-site, comparative effectiveness study of an integrated HIV and substance use treatment program.
Co-occurrence of HIV and substance abuse is associated with poor outcomes for HIV-related health and substance use. Integration of substance use and medical care holds promise for HIV patients, yet few integrated treatment models have been reported. Most of the reported models lack data on treatment outcomes in diverse settings. This study examined the substance use outcomes of an integrated treatment model for patients with both HIV and substance use at three different clinics. Sites differed by type and degree of integration, with one integrated academic medical center, one co-located academic medical center, and one co-located community health center. Participants (n=286) received integrated substance use and HIV treatment for 12 months and were interviewed at 6-month intervals. We used linear generalized estimating equation regression analysis to examine changes in Addiction Severity Index (ASI) alcohol and drug severity scores. To test whether our treatment was differentially effective across sites, we compared a full model including site by time point interaction terms to a reduced model including only site fixed effects. Alcohol severity scores decreased significantly at 6 and 12 months. Drug severity scores decreased significantly at 12 months. Once baseline severity variation was incorporated into the model, there was no evidence of variation in alcohol or drug score changes by site. Substance use outcomes did not differ by age, gender, income, or race. This integrated treatment model offers an option for treating diverse patients with HIV and substance use in a variety of clinic settings. Studies with control groups are needed to confirm these findings.


Herpes simplex virus 1 tegument protein US11 downmodulates the RLR signaling pathway via direct interaction with RIG-I and MDA-5.
The interferon (IFN)-mediated antiviral response is a major defense of the host immune system. In order to complete their life cycle, viruses must modulate host IFN-mediated immune responses. Herpes simplex virus 1 (HSV-1) is a large DNA virus containing more than 80 genes, many of which encode proteins that are involved in virus-host interactions and show immune modulatory capabilities. In this study, we demonstrate that the US11 protein, an RNA binding tegument protein of HSV-1, is a novel antagonist of the beta IFN (IFN-β) pathway. US11 significantly inhibited Sendai virus (SeV)-induced IFN-β production, and its double-stranded RNA (dsRNA) binding domain was indispensable for this inhibition activity. Additionally, wild-type HSV-1 coinfection showed stronger inhibition than US11 mutant HSV-1 in SeV-induced IFN-β production. Coimmunoprecipitation analysis demonstrated that the US11 protein in HSV-1-infected cells interacts with endogenous RIG-I and MDA-5 through its C-terminal RNA-binding domain, which was RNA independent. Expression of US11 in both transfected and HSV-1-infected cells interferes with the interaction between MAVS and RIG-I or MDA-5. Finally, US11 dampens SeV-mediated IRF3 activation. Taken together, the combined data indicate that HSV-1 US11 binds to RIG-I and MDA-5 and inhibits their downstream signaling pathway, preventing the production of IFN-β, which may contribute to the pathogenesis of HSV-1 infection.


Parabiosis Incompletely Reverses Aging-Induced Metabolic Changes and Oxidant Stress in Mouse Red Blood Cells.
Mature red blood cells (RBCs) not only account for ~83% of the total host cells in the human body, but they are also exposed to all body tissues during their circulation in the bloodstream. In addition, RBCs are devoid of de novo protein synthesis capacity and, as such, they represent a perfect model to investigate system-wide alterations of cellular metabolism in the context of aging and age-related oxidant stress without the confounding factor of gene expression. In the present study, we employed ultra-high-pressure liquid chromatography coupled with mass spectrometry (UHPLC-MS)-based metabolomics and proteomics to investigate RBC metabolism across age in male mice (6, 15, and 25 months old). We report that RBCs from aging mice face a progressive decline in the capacity to cope with oxidant stress through the glutathione/NADPH-dependent antioxidant systems. Oxidant stress to tryptophan and purines was accompanied by declines in late glycolysis and methyl-group donors, a potential compensatory mechanism to repair oxidatively damaged proteins. Moreover, heterochronic parabiosis experiments demonstrated that the young environment only partially rescued the alterations in one-carbon metabolism in old mice, although it had minimal to no impact on glutathione homeostasis, the pentose phosphate pathway, and oxidation of purines and tryptophan, which were instead aggravated in old heterochronic parabionts.


Genistein affects parathyroid gland and NaPi 2a cotransporter in an animal model of the andropause.
This study aimed to examine the effects of genistein on the structural and functional changes in parathyroid glands (PTG) and sodium phosphate cotransporter 2a (NaPi 2a) in orchidectomized rats. Sixteen-month-old Wistar rats were divided into sham-operated (SO), orchidectomized (Orx) and genistein-treated orchidectomized (Orx+G) groups. Genistein (30 mg/kg/day) was administered subcutaneously for 3 weeks, while the controls received vehicle alone. PTG was analyzed histomorphometrically, while the expressions of NaPi 2a mRNA/protein levels from kidneys were determined by real time PCR and Western blots. Serum and urine parameters were determined biochemically. The PTG volume in Orx rats was increased by 30% (p<0.05), compared to the SO group. Orx+G treatment increased the PTG volume by 35% and 75% (p<0.05) respectively, comparing to Orx and SO animals. Orchidectomy led to increment of serum PTH by 27% (p<0.05) compared to the SO group, Orx+G decreased it by 18% (p<0.05) comparing to Orx animals. NaPi 2a expression in Orx animals was reduced in regards to its abundance in SO animals, although it was increased in Orx+G group compared to the Orx. Phosphorus urine content of Orx animals was raised by 12% (p<0.05) compared to that for the SO group, while Orx+G induced a 17% reduction (p<0.05) in regards to Orx animals. Our study shows that Orx increases PTG volume and serum PTH level, while protein expression of NaPi 2a is reduced. Application of genistein attenuates the orchidectomy-induced changes in serum PTH level, stimulates the expression of NaPi 2a and reduces urinary Pi excretion, implying potential beneficial effects on andropausal symptoms.


Subjective Social Standing and Conflict Tactics Among Young Kenyan Men.
Efforts to reduce intimate partner violence in sub-Saharan Africa generally approach the issue through the lens of women's empowerment. These efforts include foci on women's relative power in the relationship, educational background, and earning potential. The social status of men has largely been ignored, reducing the potential to involve them in efforts to demote intimate partner violence. In this study we consider whether a man's perceived social status predicts conflict tactics, and whether these tactics are mediated by loneliness and collective self-esteem from a community-based sample in semi-rural Kenya (n = 263). We find that men who reported lower perceived social status also reported significantly more frequent violent conflicts with their intimate partners. This association was significantly, and completely, mediated by lower collective self-esteem and higher loneliness. There was no direct association between subjective social status and negotiation-based conflict tactics, although there was an indirect association. Men with higher perceived social status reported higher collective self-esteem, and men with higher collective self-esteem reported more negotiation-based conflict tactics. These findings inform efforts to reduce intimate partner violence by involving men, showing potential to reduce violence by building self-esteem among men-particularly those with lower perceived social status.


Correlation and reliability of cone-beam computed tomography nasopharyngeal volumetric and area measurements as determined by commercial software against nasopharyngoscopy-supported diagnosis of adenoid hypertrophy.
The aim of this study was to evaluate the diagnostic correlation and reliability of Dolphin Imaging fully automated segmentation (Dolphin Imaging and Management Solutions, Chatsworth, Calif) for assessing adenoid hypertrophy. This was investigated through 3 modes: (1) intraobserver and interobserver agreement of repeated airway auto-segmentation procedures, (2) correlation between auto-segmentation measures of volume and minimal cross-sectional airway against nasopharyngoscopy, and (3) optimum diagnostic cutoff thresholds for volume and minimal cross-sectional airway identified and tested with sensitivity and specificity analyses. Cone-beam computed tomography scans of 38 patients with suspected upper airway obstruction were analyzed. Two calibrated evaluators applied a previously validated method to quantify nasopharyngeal minimal cross-sectional airway and volume using Dolphin Imaging. Assessments were compared against grades of obstruction provided by otolaryngologists' diagnoses. The reliability between the 2 assessments by the same evaluator on the Dolphin automatic segmentation function for volume (ICC, 0.97; 95% CI, 0.95, 0.98) and minimal cross-sectional airway (ICC, 0.84; 95% CI, 0.69, 0.91) was excellent. The interoperator reliability for volume was also excellent (ICC, 0.97; 95% CI, 0.95, 0.98), but only good (ICC, 0.701; 95% CI, 0.44, 0.85) for minimal cross-sectional airway. In contrast, the Spearman rank correlation test demonstrated weak associations between the values of the automatic measurements for both volume (4.9%; ρ = -0.22) and minimal cross-sectional airway (3.7%; ρ = 0.19). Assessments of accuracy via Receiver Operating characteristic analysis, sensitivity, specificity, negative predictive values, positive predictive values, and likelihood ratios demonstrated the poor clinical applicability of volume and minimal cross-sectional airway numbers provided by Dolphin Imaging. The evaluators were reliable at manipulating the selected software, achieving consistent volume and minimal cross-sectional airway measurements, However, Dolphin Imaging volumetric and minimal cross-sectional airway measurements did not correlate well with the nasopharyngoscopy-supported reference standard for adenoid hypertrophy assessment. Under these study conditions, volume and minimal cross-sectional airway used to assess localized adenoid hypertrophy with cone-beam computed tomography imaging based on automated measurements may not yield high-quality clinically relevant information about upper airway constriction related to adenoid hypertrophy.


Pseudoprogression of brain tumors.
This review describes the definition, incidence, clinical implications, and magnetic resonance imaging (MRI) findings of pseudoprogression of brain tumors, in particular, but not limited to, high-grade glioma. Pseudoprogression is an important clinical problem after brain tumor treatment, interfering not only with day-to-day patient care but also the execution and interpretation of clinical trials. Radiologically, pseudoprogression is defined as a new or enlarging area(s) of contrast agent enhancement, in the absence of true tumor growth, which subsides or stabilizes without a change in therapy. The clinical definitions of pseudoprogression have been quite variable, which may explain some of the differences in reported incidences, which range from 9-30%. Conventional structural MRI is insufficient for distinguishing pseudoprogression from true progressive disease, and advanced imaging is needed to obtain higher levels of diagnostic certainty. Perfusion MRI is the most widely used imaging technique to diagnose pseudoprogression and has high reported diagnostic accuracy. Diagnostic performance of MR spectroscopy (MRS) appears to be somewhat higher, but MRS is less suitable for the routine and universal application in brain tumor follow-up. The combination of MRS and diffusion-weighted imaging and/or perfusion MRI seems to be particularly powerful, with diagnostic accuracy reaching up to or even greater than 90%. While diagnostic performance can be high with appropriate implementation and interpretation, even a combination of techniques, however, does not provide 100% accuracy. It should also be noted that most studies to date are small, heterogeneous, and retrospective in nature. Future improvements in diagnostic accuracy can be expected with harmonization of acquisition and postprocessing, quantitative MRI and computer-aided diagnostic technology, and meticulous evaluation with clinical and pathological data. 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018.


Effects of Gradient and Offset Architectures on the Mechanical and Biological Properties of 3-D Melt Electrowritten (MEW) Scaffolds.
This study describes the fabrication and characterization of three-dimensional (3-D) poly(ε-caprolactone) (PCL) scaffolds with defined pore architectures prepared using the melt electrowriting (MEW) technique. Three homogeneous pore-sized (250, 500, and 750 μm) scaffolds, two fiber offset (30/70% and 50/50%), and a three-layered (250 μm bottom-500 μm middle-750 μm top) gradient pore-sized scaffolds were designed and printed with ∼10 μm fibers. The mechanical properties (tensile and compression tests), total surface area, porosity of these scaffolds, and their ability to promote the attachment and proliferation of human osteoblasts were then compared. All scaffolds induced good tensile properties; however, they reacted differently during compressive testing. The offset 30/70 scaffold had the highest surface area to volume ratio which enhanced osteoblast attachment after 3 days of cell culture. While the highest initial level of osteoblast attachment at day 1 was found on the 250 μm homogeneous scaffold, the highest degree of cell proliferation and infiltration at day 30 was observed in the three-layered graded porosity scaffold. In terms of physical and biological properties to support bone cell distribution and migration through the entire structure of the scaffold, our results suggest that melt electrowritten offset and gradient scaffolds are good candidate platforms for cell infiltration and growth compared to homogeneous scaffolds.


In-group rationalizations of risk and indoor tanning: A textual analysis of an online forum.
Unlike other health behaviors, there does not appear to be a strong relationship between perceived skin cancer risk and reduction or cessation of indoor tanning bed use. This study seeks to address this inconsistency by determining how indoor tanning bed users rationalize skin cancer risk with their tanning behavior. Qualitative textual analysis of indoor tanning message board posts (N = 330) revealed varied perceptions of risk, including acknowledging the risk of indoor tanning; denying or downplaying risk, often citing perceived health benefits associated with tanning; blaming outside forces for cancer, such as lotion or genetics; and fatalistic beliefs about cancer. These results highlight the nuanced relationship between perceived skin cancer risk and indoor tanning bed use.


A new proofreading mechanism for lesion bypass by DNA polymerase-λ.
Replicative DNA polymerases (DNA pols) increase their fidelity by removing misincorporated nucleotides with their 3' → 5' exonuclease activity. Exonuclease activity reduces translesion synthesis (TLS) efficiency and TLS DNA pols lack 3' → 5' exonuclease activity. Here we show that physiological concentrations of pyrophosphate (PP(i)) activate the pyrophosphorolytic activity by DNA pol-λ, allowing the preferential excision of the incorrectly incorporated A opposite a 7,8-dihydro-8-oxoguanine lesion, or T opposite a 6-methyl-guanine, with respect to the correct C. This is the first example of an alternative proofreading mechanism used during TLS.


Assessment of surgical resectability of pancreatic adenocarcinomas with multidetector computed tomography: what are the possibilities and problems?
To investigate the accuracy of multidetector computed tomography (MDCT) in preoperatively determining the surgical resectability of pancreatic adenocarcinomas. Multidetector computed tomography, surgery, and pathological results of 274 patients with pancreatic adenocarcinoma were evaluated retrospectively. MDCT findings were compared with surgical and pathological findings to determine the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of MDCT in determining surgical resectability. A total of 124 of 274 (56%) patients (83 males, mean age: 60 years) underwent laparoscopy and/or laparotomy. The sensitivity, specificity, PPV, NPV, and accuracy of MDCT in determining the surgical resectability of pancreatic adenocarcinomas were 100%, 72%, 78%, 100%, and 86%, respectively. Liver metastases in 9 cases, peritoneal metastases in 3 cases, and vascular invasion in 5 cases, which were determined during surgery, were not reported by MDCT. On re-review of the MDCT images of these 17 patients, no metastatic lesions could be seen in 9 patients with liver metastases and in 2 of 3 patients with peritoneal metastases. In 1 patient, a peritoneal implant of a diameter of 8 mm was missed on MDCT. There was no vascular invasion according to Lu criteria on the MDCT images in the 5 cases that had vascular invasion in the surgical exploration. The accuracy of MDCT is high in the preoperative determination of surgical resectability of pancreatic adenocarcinomas, but the detection of small liver and peritoneal metastases and accurate determination of vascular invasion are still major problems. Surgeons should be aware of the limitations of preoperative MDCT.


Room temperature hyperpolarization of nuclear spins in bulk.
Dynamic nuclear polarization (DNP), a means of transferring spin polarization from electrons to nuclei, can enhance the nuclear spin polarization (hence the NMR sensitivity) in bulk materials at most 660 times for (1)H spins, using electron spins in thermal equilibrium as polarizing agents. By using electron spins in photo-excited triplet states instead, DNP can overcome the above limit. We demonstrate a (1)H spin polarization of 34%, which gives an enhancement factor of 250,000 in 0.40 T, while maintaining a bulk sample (∼ 0.6 mg, ∼ 0.7 × 0.7 × 1 mm(3)) containing >10(19) (1)H spins at room temperature. Room temperature hyperpolarization achieved with DNP using photo-excited triplet electrons has potentials to be applied to a wide range of fields, including NMR spectroscopy and MRI as well as fundamental physics.


Association of different types of playing surfaces with bone mass in growing girls.
The aim of this cross-sectional study was to compare bone mass in young female athletes playing ball games on different types of playing surfaces. About 120 girls, 9-13 years of age (10.6 ± 1.5 years old Tanner I-III) were recruited and divided into prepubertal and pubertal groups. The sample represented 3 groups of athletes: soccer (N = 40), basketball (N = 40), and handball (N = 40); and 6 different playing surfaces (soccer - ground, soccer - artificial turf, basketball - synthetic, basketball - parquet, handball - synthetic, and handball - smooth concrete). Total and regional body composition (bone mass, fat mass, and lean mass) were measured by dual-energy X-ray absorptiometry (DXA). The mechanical properties of the surfaces (force reduction, vertical deformation, and energy return) were measured with the Advanced Artificial Athlete (Triple A) method. The degree of sexual development was determined using Tanner test. The pubertal group showed that soccer players on the ground, basketball players on synthetic, and handball players on smooth concrete had higher values of bone mineral content (BMC) and bone mineral density (BMD) (P < 0.05) than the soccer players on the artificial turf, basketball players on parquet, and handball players on synthetic. In conclusion, a hard playing surface, with less vertical deformation and force reduction, and greater energy return, is associated with higher levels of BMD and BMC in growing girls, regardless of the sport they practice.


Recovery During a Congested Schedule and Injury in Professional Football.
To analyze the relationships between the recovery kinetics experienced by professional football players and noncontact injury. A cohort of 46 professional football players (age 24.2 [4.7] y) from the same team (French Ligue 1) was monitored each day between matches when the team played twice a week. The recovery monitoring procedure was implemented after 38 matches and included some questionnaires: duration of sleep, Hooper scale (quality of sleep, level of stress, fatigue, and muscle soreness), perceived recovery status scale, creatine kinase concentrations, a countermovement jump, and an isometric force test. Noncontact injuries were collected during these periods. Noncontact injuries were associated with perceived fatigue and muscle soreness 2 days (relative risk [RR] = 1.89 and 1.48, respectively) and 3 days following the matches (RR = 2.08 and 2.08, respectively). An increase of sleep quantity during the 2 nights following a match was significantly associated with a lower RR (RR = 0.65), as well as a lower decrement score on the isometric force test on each of the 3 days after the matches (RR = 0.97, RR = 0.99, and RR = 0.97, respectively). No other association was reported for the variables sleep quality, stress, perceived recovery, creatine kinase concentrations, countermovement jump, and noncontact injuries. During a congested schedule, implementing a recovery monitoring protocol including questionnaires about fatigue, muscle soreness, quantity of sleep, and a physical test of isometric force could help practitioners prevent injuries.


Structure-activity relationship study reveals ML240 and ML241 as potent and selective inhibitors of p97 ATPase.
To discover more potent p97 inhibitors, we carried out a structure-activity relationship study of the quinazoline scaffold previously identified from our HTS campaigns. Two improved inhibitors, ML240 and ML241, inhibit p97 ATPase with IC(50) values of 100 nM. Both compounds inhibited degradation of a p97-dependent but not a p97-independent proteasome substrate in a dual-reporter cell line. They also impaired the endoplasmic-reticulum-associated degradation (ERAD) pathway. Unexpectedly, ML240 potently stimulated accumulation of LC3-II within minutes, inhibited cancer cell growth, and rapidly mobilized the executioner caspases 3 and 7, whereas ML241 did not. The behavior of ML240 suggests that disruption of the protein homeostasis function of p97 leads to more rapid activation of apoptosis than is observed with a proteasome inhibitor. Further characterization revealed that ML240 has broad antiproliferative activity toward the NCI-60 panel of cancer cell lines, but slightly lower activity toward normal cells. ML240 also synergizes with the proteasome inhibitor MG132 to kill multiple colon cancer cell lines. Meanwhile, both probes have low off-target activity toward a panel of protein kinases and central nervous system targets. Our results nominate ML240 as a promising starting point for the development of a novel agent for the chemotherapy of cancer, and provide a rationale for developing pathway-specific p97 inhibitors.


Virulence Factors Associated with Enterococcus Faecalis Infective Endocarditis: A Mini Review.
The enterococci are accountable for up to 20% of all cases of infective endocarditis, with Enterococcus faecalis being the primary causative isolate. Infective endocarditis is a life-threatening infection of the endocardium that results in the formation of vegetations. Based on a literature review, this paper provides an overview of the virulence factors associated with E. faecalis infective endocarditis. Furthermore, it reports the effects of active or passive immunization against some of these involved factors. Nine virulence factors have in particular been associated with E. faecalis infective endocarditis. Absence of these factors entailed attenuation of strains in both mixed- and mono-bacterial infection endocarditis models as well as in in vitro and ex vivo assays when compared to their virulence factor expressing parental strains. The virulence factors promote a broad spectrum of events that together allow for disease development and progression. The infection is initiated through bacterial binding to ligands present at the site of infection after which the colonization can be accelerated through inter-bacterial attachment and modulation of the host immune response. The formation and growth of the vegetation provide protection and promote growth. Controlled degeneration of the vegetation appears to increase the likelihood of embolization and dissemination, without exposing protected bacteria. In most cases, active and passive immunization against associated virulence factors provided partial protection. There is a need for further evaluation of the known virulence factors. Immunization against two or more virulence factors might be an effective prophylactic tool.


Preoperative chemotherapy for stage IIIa (N2) lung cancer: the Sloan-Kettering experience with 136 patients.
From 1984 to 1991, 136 patients with histologically confirmed non-small cell lung cancer and stage IIIa (N2) disease received two to three cycles of MVP (mitomycin + vindesine or vinblastine + high-dose cisplatin) chemotherapy. All patients had clinical N2 disease, defined as bulky mediastinal lymph node metastases or multiple levels of lymph node involvement in the ipsilateral mediastinum or subcarinal space on chest roentgenograms, computed tomographic scans, or mediastinoscopy. The overall major response rate to chemotherapy was 77% (105/136). Thirteen patients had a complete response and 92 patients had a partial but major response (> 50%). The overall complete resection rate was 65% (89/136) with a complete resection rate of 78% (82/105) in patients with a major response to chemotherapy. There was no histologic evidence of tumor in the resected specimens of 19 patients. The overall survival was 28% at 3 years and 17% at 5 years (median, 19 months). For patients who had complete resection, the median survival was 27 months and the 3-year and 5-year survivals were 41% and 26%, respectively. There were seven treatment-related deaths, five of which were postoperative deaths. To date, 33 patients, all of whom had complete resection, have had no recurrence after treatment. These results demonstrate that (1) preoperative chemotherapy with MVP produces high response rates in stage IIIa (N2) disease, (2) high complete resection rates occur after response to chemotherapy, and (3) survival is longest in patients who have a complete resection after major response to chemotherapy.


Evaluation of the effectiveness of four different inhalers in patients with chronic obstructive pulmonary disease.
The percentage of patients inhaling their medication effectively varies widely, according to methods of assessment and inhalers used. This study was carried out to assess differences among four types of inhalers using inhaler-specific checklists. Inhalation technique was evaluated in adult patients with chronic obstructive pulmonary disease (COPD). Inhalers investigated were either metered dose inhalers (MDIs) or the dry powder inhalers Turbohaler (Turbuhaler), Diskhaler, and Rotahaler. Errors were recorded against inhaler-specific checklists. From these, scores were derived by dividing the number of items correctly completed by the total number of items on the checklist and the result was expressed as a percentage. For every inhaler "essential actions" were identified and scores on these key manoeuvres were calculated. The percentage of patients performing all these essential actions correctly was also calculated. Scores were also compared with adjustment for differences in relevant patient characteristics. Important differences among inhalers were found. Of 152 patients with COPD (mean (SD) age 55.1 (8.7) years), those with MDIs performed worst, especially when only essential items were considered. Patients with a Diskhaler did best, although after correction for patient characteristics the differences tended to diminish. Only 60% of patients were able to perform all essential inhaler actions satisfactorily. Of those using the Diskhaler, 96% did so correctly, while the corresponding figure for those using the MDI was only 24%. Many patients with COPD use their inhaler ineffectively. After adjusting for patient characteristics, differences among inhalers, although less pronounced, persist. Patients using a Diskhaler made fewest errors, while most patients using MDIs made crucial mistakes.


Inhibition of PPAR gamma 2 gene expression by the HIF-1-regulated gene DEC1/Stra13: a mechanism for regulation of adipogenesis by hypoxia.
Cellular differentiation involves transcriptional responses to environmental stimuli. Adipocyte differentiation is inhibited under hypoxic conditions, indicating that oxygen (O(2)) is an important physiological regulator of adipogenesis. Hypoxia inhibits PPAR gamma 2 nuclear hormone receptor transcription, and overexpression of PPAR gamma 2 or C/EBP beta stimulates adipogenesis under hypoxia. Mouse embryonic fibroblasts deficient in hypoxia-inducible transcription factor 1 alpha (HIF-1 alpha) are refractory to hypoxia-mediated inhibition of adipogenesis. The HIF-1-regulated gene DEC1/Stra13, a member of the Drosophila hairy/Enhancer of split transcription repressor family, represses PPAR gamma 2 promoter activation and functions as an effector of hypoxia-mediated inhibition of adipogenesis. These data indicate that an O(2)-sensitive signaling mechanism regulates adipogenesis. Thus, agents that regulate HIF-1 activity or O(2) sensing may be used to inhibit adipogenesis and control obesity.


Interaction of Campylobacter spp. and human probiotics in chicken intestinal mucus.
Campylobacter is the most common cause of bacterial food-borne diarrhoeal disease throughout the world. The principal risk of human contamination is handling and consumption of contaminated poultry meat. To colonize poultry, Campylobacter adheres to and persists in the mucus layer that covers the intestinal epithelium. Inhibiting adhesion to the mucus could prevent colonization of the intestine. The aim of this study was to investigate in vitro the protective effect of defined commercial human probiotic strains on the adhesion of Campylobacter spp. to chicken intestinal mucus, in a search for alternatives to antibiotics to control this food-borne pathogen. The probiotic strains Lactobacillus rhamnosus GG and Propionibacterium freudenreichii ssp. shermanii JS and a starter culture strain Lactococcus lactis ssp. lactis adhered well to chicken intestinal mucus and were able to reduce the binding of Campylobacter spp. when the mucus was colonized with the probiotic strain before contacting the pathogen. Human-intended probiotics could be useful as prophylactics in poultry feeding for controlling Campylobacter spp. colonization.


The effects of monochromatic illumination on early eye development in rhesus monkeys.
Influence of longitudinal chromatic aberration (LCA) on emmetropization during early eye development has not been studied in primates. We investigated the effects of quasi-monochromatic lighting on refractive development and eye growth in rhesus monkeys. Infant rhesus monkeys were raised under one of three lighting conditions for 51 weeks: quasi-monochromatic blue light (peak 455 nm), red light (peak 610 nm), and white light (color temperature 5000 K). All animals underwent biometric measurements using cycloplegic streak retinoscope, keratometry, and A-scan ultrasonography for refraction, corneal power, and axial components, respectively, at designated time points. At the 51st week, the mean difference in refraction of the white light and blue light groups, compared with that of the red light group, reached 1.71 diopters (D) and 1.43 D, respectively (both P < 0.001). Two monkeys in the red light group developed myopia at the 16th week, whereas the other seven remained hyperopic throughout the experiment. No significant difference in mean refraction was observed between the blue light group and white light group. Illumination from long-wavelength light during early life could be a risk factor for the development of myopia in a small proportion of rhesus monkeys that are sensitive to L-cone stimulation.


Genetic disorders of hemoglobin.
The inherited disorders of hemoglobin, the most common monogenic diseases, are now well understood at the molecular and cellular level, knowledge which has led to considerable Improvements in their control and management. Because of their particularly high gene frequencies in sub-Saharan Africa, the Indian subcontinent, and throughout Southeast Asia, the organization of their control and treatment provides a major challenge for the new millennium.


Contingency management is effective in promoting abstinence and retention in treatment among crack cocaine users with a previous history of poor treatment response: a crossover trial.
Crack use has become a severe health problem in Brazil. Contingency management has shown robust evidence of efficacy in the treatment of cocaine use disorder (CUD) in high-income countries; however, it is still unclear how this intervention can impact treatment in low-income countries. To evaluate the efficacy of contingency management in the treatment of CUD among individuals with a previous history of poor treatment response in Brazil. Six months after the end of treatment, 32 participants previously allocated to the usual care condition (UCC) were invited to receive an additional 12 weeks of treatment in a contingency management condition (CMC), and 16 accepted the invitation. We compared data obtained from only the 16 participants (14 male) exposed to both treatment conditions. Participants attended more treatment sessions and were retained in treatment for a longer period during the CMC than during the UCC (p < .01 for both). The proportion of negative cocaine samples submitted, the mean longest duration of cocaine abstinence, and the odds of being abstinent from cocaine during the 12 weeks of treatment were significantly higher during treatment in the CMC when compared to the UCC (p < .05). This study provides further evidence that contingency management is effective in promoting abstinence and retention in treatment among individuals with CUD with a history of poor treatment response. Our findings argue for the incorporation of CM among public treatment services for CUD in Brazil. This study was registered at ClinicalTrials.gov as NCT01815645 on March 21, 2013.


Delivery of antigen using a novel mannosylated dendrimer potentiates immunogenicity in vitro and in vivo.
Antigen mannosylation has been shown to be an effective approach to potentiate antigen immunogenicity, due to the enhanced antigen uptake and presentation by APC. To overcome disadvantages associated with conventional methods used to mannosylate antigens, we have developed a novel mannose-based antigen delivery system that utilizes a polyamidoamine (PAMAM) dendrimer. It is demonstrated that mannosylated dendrimer ovalbumin (MDO) is a potent immune inducer. With a strong binding avidity to DC, MDO potently induced OVA-specific T cell response in vitro. It was found that the immunogenicity of MDO was due not only to enhanced antigen presentation, but also to induction of DC maturation. Mice immunized with MDO generated strong OVA-specific CD4(+)/CD8(+) T cell and antibody responses. MDO also targeted lymph node DC to cross-present OVA, leading to OTI CD8(+) T cell proliferation. Moreover, upon challenge with B16-OVA tumor cells, tumors in mice pre-immunized with MDO either did not grow or displayed a much more delayed onset, and had slower kinetics of growth than those of OVA-immunized mice. This mannose-based antigen delivery system was applied here for the first time to the immunization study. With several advantages and exceptional adjuvanticity, we propose mannosylated dendrimer as a potential vaccine carrier.


Therapeutic use, efficiency and safety of the proteolytic pineapple enzyme Bromelain-POS in children with acute sinusitis in Germany.
The therapeutic efficiency and safety of the proteolytic enzyme bromelaine obtained from pineapple (Bromelain-POS, Ursapharm GmbH, Saarbrücken, Germany) was evaluated in children under the age of 11 years diagnosed with acute sinusitis. Data from 116 patients from 19 centres located across Germany were analysed in a pharmacoepidemiological cohort study. Patient cohorts were either treated with Bromelain-POS (N = 62), in combination with Bromelain-POS and standard therapies (N = 34), or with standard therapies (N = 20). The primary parameter measuring effectiveness of the different treatment groups was the duration of symptoms. The shortest mean period of symptoms was observed in patients treated with Bromelain-POS alone (6.66 days), followed by the standard therapy (7.95 days) and those treated with a combination of Bromelain-POS and the standard therapy (9.06 days). Patients of the Bromelain-POS monotherapy group showed a statistically significant faster recovery from symptoms (p = 0.005) compared to the other treatment groups. One 10-year-old male patient, with a known pineapple allergy, showed a self-limiting mild allergic reaction. No other unwanted side-effects were reported. This trial documents that the proteolytic pineapple enzyme Bromelain-POS is widely used in the treatment of young children diagnosed with acute sinusitis in Germany and that the use of proteolytic enzymes can benefit such patients.


Epileptogenic properties of cocaine in humans.
Ninety-eight of 945 patients admitted to Hennepin County Medical Center with acute medical complications of cocaine intoxication presented with seizures within 90 min of cocaine ingestion. Cocaine-related seizures were most frequently single, generalized convulsions, and these individuals all had normal cranial CT and EEG. Of the 945 patients, 18.4% of the women presented with seizures, compared with only 6.2% of the men. All subjects who presented with new onset focal seizures following cocaine ingestion had acute cocaine-related cerebral strokes or hemorrhages. Individuals with a history of cocaine-unrelated seizures, had their typical convulsions precipitated with "recreational" doses of cocaine. All four subjects with status epilepticus had ingested massive doses of cocaine, were resistant to medical treatment, and had significant morbidity and mortality. We were able to characterize four subgroups of subjects at risk for cocaine-related convulsions. First, individuals who had ingested massive doses of cocaine (2-8 gms) in whom cocaine induced seizures by its direct, dose-related convulsant effects. Second, individuals with a history of epilepsy had their typical seizures precipitated by lowering the seizure threshold. Third, females are at greater risk for cocaine-related compared to males. Fourth, years of chronic, habitual cocaine abuse may result in "chemical" kindling of epilepsy.


Effects of irradiance and spectral quality on leaf structure and function in seedlings of two Southeast Asian Hopea (Dipterocarpaceae) species.
We studied the development of leaf characters in two Southeast Asian dipterocarp forest trees under different photosynthetic photon flux densities (PFD) and spectral qualities (red to far-red, R:FR). The two species, Hopea helferi and H. odorata, are taxonomically closely related but differ in their ecological requirements; H. helferi is more drought tolerant and H. odorata more shade tolerant. Seedlings were grown in replicated shadehouse treatments of differing PFD and R:FR. We measured or calculated (1) leaf and tissue thicknesses; (2) mesophyll parenchyma, air space, and lignified tissue volumes; (3) mesophyll air volumes (V(mes)/A(surf)) and surfaces (A(mes)/A(surf)); (4) palisade cell length and width; (5) chlorophyll/cm and a/b; (6) leaf absorption; and (7) attenuance/absorbance at 652 and 550 nm. These characters varied in response to light conditions in both taxa. Characters were predominantly affected by PFD, and R:FR slightly influenced many characters. Leaf characters of H. odorata were more plastic in response to treatment conditions. Characters were correlated with each other in a complex fashion. Variation in leaf anatomy is most likely a consequence of increasing leaf thickness in both taxa, which may increase mechanical strength and defense against herbivory in more exposed environments. Variation in leaf optical properties was most likely affected by pigment photo-bleaching in treatments of more intense PFD and was not correlated with A(max). The greater plasticity of leaf responses in H. odorata helps explain the acclimation over the range of light conditions encountered by this shade-tolerant taxon. The dense layer of scales on the leaf undersurface and other anatomical characters in H. helferi reduced gas exchange and growth in this drought-tolerant tree.


Performance evaluation of a multinational data platform for critical care in Asia.
Background: The value of medical registries strongly depends on the quality of the data collected. This must be objectively measured before large clinical databases can be promoted for observational research, quality improvement, and clinical trials. We aimed to evaluate the quality of a multinational intensive care unit (ICU) network of registries of critically ill patients established in seven Asian low- and middle-income countries (LMICs). Methods: The Critical Care Asia federated registry platform enables ICUs to collect clinical, outcome and process data for aggregate and unit-level analysis. The evaluation used the standardised criteria of the Directory of Clinical Databases (DoCDat) and a framework for data quality assurance in medical registries. Six reviewers assessed structure, coverage, reliability and validity of the ICU registry data. Case mix and process measures on patient episodes from June to December 2020 were analysed. Results: Data on 20,507 consecutive patient episodes from 97 ICUs in Afghanistan, Bangladesh, India, Malaysia, Nepal, Pakistan and Vietnam were included. The quality level achieved according to the ten prespecified DoCDat criteria was high (average score 3.4 out of 4) as was the structural and organizational performance -- comparable to ICU registries in high-income countries. Identified strengths were types of variables included, reliability of coding, data completeness and validation. Potential improvements included extension of national coverage, optimization of recruitment completeness validation in all centers and the use of interobserver reliability checks. Conclusions: The Critical Care Asia platform evaluates well using standardised frameworks for data quality and equally to registries in resource-rich settings.


Functional magnetic resonance imaging identifies somatotopic organization of nociception in the human spinal cord.
Functional magnetic resonance imaging (fMRI) is a technique that uses blood oxygen-level-dependent (BOLD) signals to elucidate discrete areas of neuronal activity. Despite the significant number of fMRI human brain studies, few researchers have applied fMRI technology to investigating neuronal activity within the human spinal cord. Our study goals were to demonstrate that fMRI could reveal the following: (i) appropriate somatotopic activations in response to noxious stimuli in the deep and superficial dorsal horn of the human cervical spinal cord, and (ii) lateralization of fMRI activations in response to noxious stimulation in the right and left upper extremity. We subjected healthy participants to noxious stimulation during fMRI scans. Using a spiral in-out image sequence and retrospective correction for physiologic noise, we demonstrated that fMRI can create high-resolution, neuronal activation maps of the human cervical spinal cord. During nociceptive stimulation of all 4 sites (left deltoid, right deltoid, left thenar eminence and right thenar eminence), we found ipsilateral dorsal horn activation. Stimulation of the deltoid activated C5, whereas stimulation of the thenar eminence activated C6. Our study contributes to creating an objective analysis of pain transmission; other investigators can use these results to further study central nervous system changes that occur in patients with acute and chronic pain.


Persistent, long-term cerebral white matter changes after sports-related repetitive head impacts.
Repetitive head impacts (RHI) sustained in contact sports are thought to be necessary for the long-term development of chronic traumatic encephalopathy (CTE). Our objectives were to: 1) characterize the magnitude and persistence of RHI-induced white matter (WM) changes; 2) determine their relationship to kinematic measures of RHI; and 3) explore their clinical relevance. Prospective, observational study of 10 Division III college football players and 5 non-athlete controls during the 2011-12 season. All subjects underwent diffusion tensor imaging (DTI), physiologic, cognitive, and balance testing at pre-season (Time 1), post-season (Time 2), and after 6-months of no-contact rest (Time 3). Head impact measures were recorded using helmet-mounted accelerometers. The percentage of whole-brain WM voxels with significant changes in fractional anisotropy (FA) and mean diffusivity (MD) from Time 1 to 2, and Time 1 to 3 was determined for each subject and correlated to head impacts and clinical measures. Total head impacts for the season ranged from 431-1,850. No athlete suffered a clinically evident concussion. Compared to controls, athletes experienced greater changes in FA and MD from Time 1 to 2 as well as Time 1 to 3; most differences at Time 2 persisted to Time 3. Among athletes, the percentage of voxels with decreased FA from Time 1 to 2 was positively correlated with several helmet impact measures. The persistence of WM changes from Time 1 to 3 was also associated with changes in serum ApoA1 and S100B autoantibodies. WM changes were not consistently associated with cognition or balance. A single football season of RHIs without clinically-evident concussion resulted in WM changes that correlated with multiple helmet impact measures and persisted following 6 months of no-contact rest. This lack of WM recovery could potentially contribute to cumulative WM changes with subsequent RHI exposures.


Preclinical evidence implicating corticotropin-releasing factor signaling in ethanol consumption and neuroadaptation.
The results of many studies support the influence of the corticotropin-releasing factor (CRF) system on ethanol (EtOH) consumption and EtOH-induced neuroadaptations that are critical in the addiction process. This review summarizes the preclinical data in this area after first providing an overview of the components of the CRF system. This complex system involves hypothalamic and extra-hypothalamic mechanisms that play a role in the central and peripheral consequences of stressors, including EtOH and other drugs of abuse. In addition, several endogenous ligands and targets make up this system and show differences in their involvement in EtOH drinking and in the effects of chronic or repeated EtOH treatment. In general, genetic and pharmacological approaches paint a consistent picture of the importance of CRF signaling via type 1 CRF receptors (CRF(1)) in EtOH-induced neuroadaptations that result in higher levels of intake, encourage alcohol seeking during abstinence and alter EtOH sensitivity. Furthermore, genetic findings in rodents, non-human primates and humans have provided some evidence of associations of genetic polymorphisms in CRF-related genes with EtOH drinking, although additional data are needed. These results suggest that CRF(1) antagonists have potential as pharmacotherapeutics for alcohol use disorders. However, given the broad and important role of these receptors in adaptation to environmental and other challenges, full antagonist effects may be too profound and consideration should be given to treatments with modulatory effects.