Suicidal ideation and attempts in Norwegian police.
Studies on suicide among police show inconsistent results, thereby contributing to considerable speculation regarding why police officers commit suicide. The present paper is the first nationwide study on suicidal ideation and attempts among police. 3,272 Norwegian police completed Paykel's Suicidal Feelings in the General Population questionnaire. Lifetime prevalence of specific questionnaire items ranged from 24% for the feeling that life was not worth living, 6.4% for having seriously considered suicide, and 0.7% for attempted suicide. Independent predictors of serious suicidal ideation were marital status, subjective health complaints, reality weakness, anxiety, and depression. Serious suicidal ideation was mainly attributed to personal and family problems.


The biomimetic immunoassay based on molecularly imprinted polymer: a comprehensive review of recent progress and future prospects.
Immunoassay, based on a selective affinity of the biological antibody for its antigen, is one of the most usual analytical methods in food safety and environmental chemistry. However, it presents several drawbacks because of the nature of the antibody. Molecular imprinting technique, due to its high selectivity and stability, ease of preparation and low cost, has shown great potential in producing artificial antibodies in biomimetic immunoassays. This article focuses on the recent states, advantages, current problems and outlooks of molecularly imprinted radio, fluoro, enzyme-linked and chemiluminescent immunoassays, and biomimetic immunosensor, with special emphasis on the challenges in developing biomimetic enzyme-linked immunosorbent assays (BELISAs). The biomimetic immunoassay method will provide an important new analysis platform in food safety, although the sensitivity and specificity is relatively low. As a new simple analysis method, the biomimetic immunoassay has attractive prospect, although some limitations were existed in real-sample assay. In this critical review, some promising solutions for overcoming its drawbacks were put forward, which may promote the more quick development and extensive application of this method in food safety.


Quantifying cell-generated forces: Poisson's ratio matters.
Quantifying mechanical forces generated by cellular systems has led to key insights into a broad range of biological phenomena from cell adhesion to immune cell activation. Traction force microscopy (TFM), the most widely employed force measurement methodology, fundamentally relies on knowledge of the force-displacement relationship and mechanical properties of the substrate. Together with the elastic modulus, the Poisson's ratio is a basic material property that to date has largely been overlooked in TFM. Here, we evaluate the sensitivity of TFM to Poisson's ratio by employing a series of computer simulations and experimental data analysis. We demonstrate how applying the correct Poisson's ratio is important for accurate force reconstruction and develop a framework for the determination of error levels resulting from the misestimation of the Poisson's ratio. In addition, we provide experimental estimation of the Poisson's ratios of elastic substrates commonly applied in TFM. Our work thus highlights the role of Poisson's ratio underpinning cellular force quantification studied across many biological systems.


Assessing aesthetic outcomes after trigonocephaly correction.
This study analysed the aesthetic outcome assessments after trigonocephaly correction using different assessor groups. Twenty-four patients (9 males, 15 females) with a surgical age between 8 and 10 months were included. Standardised photographs showing different facial views of the patients between ages 3 and 6 years were evaluated in terms of aesthetics by three study groups: surgeons, medical students, and lay persons. Each photograph was scored as follows: 1 (normal), 2 (acceptable, no need for revision), or 3 (unacceptable, needs revision). The mean surgical age was 9.1 ±0.4 months. Based on the en-face images, the mean scores assigned by the surgeon, student, and lay groups were 1.4 ±0.49, 1.25 ±0.44, and 1.13 ±0.34, respectively. Based on the patients' profiles, the mean scores assigned by the surgeon, student, and lay groups were 1.37 ±0.49, 1.16 ±0.37, and 1.09 ±0.29, respectively. The scores of the hemi-profile evaluation were 1.14 ±0.35, 1.07 ±0.26, and 1.09 ±0.31, respectively. The scores of the frontal region were 1.47 ±0.54, 1.33 ±0.49, and 1.39 ±0.49, respectively. Within the orbital area, the surgeon, student, and lay groups assigned mean scores of 1.53 ±0.56, 1.29 ±0.46, and 1.15 ±0.36, respectively. The midface analysis showed mean scores of 1.8 ±0.66, 1.63 ±0.52, and 1.46 ±0.5, respectively. In all areas, there were significant differences (P < 0.05) among the assessor groups. The expectations regarding aesthetic outcome differ considerably between experts and non-experts. The need for correction did not concern the reshaped bone but rather the soft tissue epicanthal area.


Daptomycin-induced eosinophilic pneumonia - a systematic review.
Eosinophilic pneumonia comprises a group of lung diseases in which eosinophils appear in increased numbers in the lungs and sometimes in the bloodstream. Several case reports link daptomycin use to this phenomenon. We performed a systematic literature review to identify cases of eosinophilic pneumonia associated with daptomycin use. Relevant studies were identified by searching Pubmed/Medline, EMBASE, Google Scholar, Cochrane Database of Systematic Reviews, and Clin-Alert from inception to May 2016, and manual searches of reference lists. All case reports that include information regarding patient age, indication, clinical and objective findings, treatment and outcome were evaluated. Abstracts from conference proceedings as well as case reports not in English were excluded. Descriptive statistics were used to analyze the data. Thirty-five patient-cases were included in the final analysis. Patients most likely to be identified with daptomycin-induced eosinophilic pneumonia were male (83%) and elderly (mean age 65.4 ± 15 years). The dose for daptomycin ranged from 4 to 10 mg/kg/day, but included a large number of patients with renal dysfunction. The average duration of daptomycin therapy upon onset of EP symptoms was 2.8 ± 1.6 weeks. Majority of patients presented with dyspnea (94%), fever (57%) and were also found to have peripheral eosinophilia (77%) and infiltrates/opacities of CT/CXR (86%). Symptom improvement was seen after daptomycin discontinuation (24 h to 1 week). The majority of patients were also prescribed treatment with corticosteroids (66%). Clinicians should be aware of daptomycin-induced eosinophilic pneumonia and its symptoms along with its presentation and treatment.


Melt-electrospun polycaprolactone strontium-substituted bioactive glass scaffolds for bone regeneration.
Polycaprolactone (PCL) is a resorbable polymer used extensively in bone tissue engineering owing to good structural properties and processability. Strontium-substituted bioactive glass (SrBG) has the ability to promote osteogenesis and may be incorporated into scaffolds intended for bone repair. Here, we describe for the first time, the development of a PCL-SrBG composite scaffold incorporating 10% (weight) of SrBG particles into PCL bulk, produced by the technique of melt electrospinning. We show that we are able to reproducibly manufacture composite scaffolds with an interconnected porous structure and, furthermore, these scaffolds were demonstrated to be noncytotoxic in vitro. Ions present in the SrBG component were shown to dissolve into cell culture media and promoted precipitation of a calcium phosphate layer on the scaffold surface which in turn led to noticeably enhanced alkaline phosphatase activity in MC3T3-E1 cells compared to PLC-only scaffolds. These results suggest that melt-electrospun PCL-SrBG composite scaffolds show potential to become effective bone graft substitutes.


Inhibition of the PI3K pathway suppresses hormonal secretion and limits growth in pheochromocytoma cells.
Operative resection is the only curative treatment for pheochromocytomas. Inhibition of the phosphatidylinositol-3 kinase (PI3K)-Akt pathway has been shown to be an effective treatment of neuroendocrine (NE) tumors in vitro. We hypothesized that inhibition of the PI3K-Akt pathway would be a viable strategy to inhibit growth and hormonal secretion in pheochromocytoma cells. Sixteen pheochromocytomas were analyzed for expression of phosphorylated Akt and the NE marker achaete scute complex-like 1 (ASCL1). Pheochromocytoma PC-12 cells were treated with up to 100 microM of the PI3K-specific inhibitor LY294002 for 48 h. Western blot analysis was used to measure phosphorylated Akt, total Akt, ASCL1, chromogranin A (CgA), and markers of apoptosis. Growth was assessed by a methylthiazolyldiphenyl-tetrazolium (MTT) bromide cellular proliferation assay for six days. Human pheochromocytomas expressed significant amounts of phosphorylated Akt, and there was a significant correlation between malignant pheochromocytomas and the amount of expressed ASCL1. LY294002 significantly inhibited the PI3K-Akt pathway. Treatment led to a dose-dependent decrease in both ASCL1 and CgA, indicating an alteration in the NE phenotype and hormonal suppression. Treatment decreased cellular proliferation, and cleavage of the apoptotic markers caspase-3 and PARP was observed. Human pheochromocytoma tumor samples express high levels of phosphorylated Akt. LY294002 effectively inhibits the PI3K-Akt pathway, suppresses NE tumor markers, and decreases cellular proliferation via apoptosis in vitro. Inhibition of the PI3K pathway may represent a new strategy in the treatment of pheochromocytomas.


Determinants of new-onset diabetes among 19,257 hypertensive patients randomized in the Anglo-Scandinavian Cardiac Outcomes Trial--Blood Pressure Lowering Arm and the relative influence of antihypertensive medication.
The purpose of this study was to determine the baseline predictors of new-onset diabetes (NOD) in hypertensive patients and to develop a risk score to identify those at high risk of NOD. Among 19,257 hypertensive patients in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) who were randomly assigned to receive one of two antihypertensive regimens (atenolol +/- thiazide or amlodipine +/- perindopril), 14,120 were at risk of developing diabetes at baseline. Of these, 1,366 (9.7%) subsequently developed NOD during median follow-up of 5.5 years. A multivariate Cox model was developed to identify the independent predictors of NOD and individual risk scores. NOD was significantly associated with an increase in baseline fasting plasma glucose (FPG), BMI, serum triglycerides, and systolic blood pressure. In contrast, amlodipine +/- perindopril in comparison with atenolol +/- thiazide treatment (hazard ratio 0.66 [95% CI 0.59-0.74]), high HDL cholesterol, alcohol use, and age >55 years were found to be significantly protective factors. FPG was the most powerful predictor with risk increasing by 5.8 times (95% CI 5.23-6.43) for each millimole per liter rise >5 mmol/l. The risk of NOD increased steadily with increasing quartile of risk score, with a 19-fold increase (95% CI 14.3-25.4) among those in the highest compared with those in the lowest quartile. The model showed excellent internal validity and discriminative ability. Baseline FPG >5 mmol/l, BMI, and use of an atenolol +/- diuretic regimen were among the major determinants of NOD in hypertensive patients. The model developed from these data allows accurate prediction of NOD among hypertensive subjects.


Use of genomic data in risk assessment case study: II. Evaluation of the dibutyl phthalate toxicogenomic data set.
An evaluation of the toxicogenomic data set for dibutyl phthalate (DBP) and male reproductive developmental effects was performed as part of a larger case study to test an approach for incorporating genomic data in risk assessment. The DBP toxicogenomic data set is composed of nine in vivo studies from the published literature that exposed rats to DBP during gestation and evaluated gene expression changes in testes or Wolffian ducts of male fetuses. The exercise focused on qualitative evaluation, based on a lack of available dose-response data, of the DBP toxicogenomic data set to postulate modes and mechanisms of action for the male reproductive developmental outcomes, which occur in the lower dose range. A weight-of-evidence evaluation was performed on the eight DBP toxicogenomic studies of the rat testis at the gene and pathway levels. The results showed relatively strong evidence of DBP-induced downregulation of genes in the steroidogenesis pathway and lipid/sterol/cholesterol transport pathway as well as effects on immediate early gene/growth/differentiation, transcription, peroxisome proliferator-activated receptor signaling and apoptosis pathways in the testis. Since two established modes of action (MOAs), reduced fetal testicular testosterone production and Insl3 gene expression, explain some but not all of the testis effects observed in rats after in utero DBP exposure, other MOAs are likely to be operative. A reanalysis of one DBP microarray study identified additional pathways within cell signaling, metabolism, hormone, disease, and cell adhesion biological processes. These putative new pathways may be associated with DBP effects on the testes that are currently unexplained. This case study on DBP identified data gaps and research needs for the use of toxicogenomic data in risk assessment. Furthermore, this study demonstrated an approach for evaluating toxicogenomic data in human health risk assessment that could be applied to future chemicals.


Effect of change saliency and neural entrainment on flicker-induced time dilation.
When a visual stimulus flickers periodically and rhythmically, the perceived duration tends to exceed its physical duration in the peri-second range. Although flicker-induced time dilation is a robust time illusion, its underlying neural mechanisms remain inconclusive. The neural entrainment account proposes that neural entrainment of the exogenous visual stimulus, marked by steady-state visual evoked potentials (SSVEPs) over the visual cortex, is the cause of time dilation. By contrast, the saliency account argues that the conscious perception of flicker changes is indispensable. In the current study, we examined these two accounts separately. The first two experiments manipulated the level of saliency around the critical fusion threshold (CFF) in a duration discrimination task to probe the effect of change saliency. The amount of dilation correlated with the level of change saliency. The next two experiments investigated whether neural entrainment alone could also induce perceived dilation. To preclude change saliency, we utilized a combination of two high-frequency flickers above the CFF, whereas their beat frequency still theoretically aroused neural entrainment at a low frequency. Results revealed a moderate time dilation induced by combinative high-frequency flickers. Although behavioral results suggested neural entrainment engagement, electroencephalography showed neither larger power nor inter-trial coherence (ITC) at the beat. In summary, change saliency was the most critical factor determining the perception and strength of time dilation, whereas neural entrainment had a moderate influence. These results highlight the influence of higher-level visual processing on time perception.


In vivo positron emission tomographic imaging of glial responses to amyloid-beta and tau pathologies in mouse models of Alzheimer's disease and related disorders.
Core pathologies of Alzheimer's disease (AD) are aggregated amyloid-β peptides (Aβ) and tau, and the latter is also characteristic of diverse neurodegenerative tauopathies. These amyloid lesions provoke microglial activation, and recent neuroimaging technologies have enabled visualization of this response in living brains using radioligands for the peripheral benzodiazepine receptor also known as the 18 kDa translocator protein (TSPO). Here, we elucidated contributions of Aβ and tau deposits to in vivo TSPO signals in pursuit of mechanistic and diagnostic significance of TSPO imaging in AD and other tauopathies. A new antibody to human TSPO revealed induction of TSPO-positive microgliosis by tau fibrils in tauopathy brains. Emergence of TSPO signals before occurrence of brain atrophy and thioflavin-S-positive tau amyloidosis was also demonstrated in living mice transgenic for mutant tau by positron emission tomography (PET) with two classes of TSPO radioligands, [(11)C]AC-5216 and [(18)F]fluoroethoxy-DAA1106. Meanwhile, only modest TSPO elevation was observed in aged mice modeling Aβ plaque deposition, despite the notably enhanced in vivo binding of amyloid radiotracer, [(11)C]Pittsburgh Compound-B, to plaques. In these animals, [(11)C]AC-5216 yielded better TSPO contrasts than [(18)F]fluoroethoxy-DAA1106, supporting the possibility of capturing early neurotoxicity with high-performance TSPO probes. Furthermore, an additional line of mice modeling intraneuronal Aβ accumulation displayed elevated TSPO signals following noticeable neuronal loss, unlike TSPO upregulation heralding massive neuronal death in tauopathy model mice. Our data corroborate the utility of TSPO-PET imaging as a biomarker for tau-triggered toxicity, and as a complement to amyloid scans for diagnostic assessment of tauopathies with and without Aβ pathologies.


STUDIES ON EXPERIMENTAL HYPERTENSION : XIX. THE PRODUCTION OF PERSISTENT HYPERTENSION IN SHEEP AND GOATS.
Persistent hypertension has been produced in the goat and sheep by constriction of the main renal arteries. The presence or absence of accompanying uremia depends upon the degree of constriction of the renal arteries. In both sheep and goat, constriction of one main renal artery also caused elevation of the blood pressure which tended to persist longer than in the dog. Excision of the one kidney with main renal artery constricted resulted in a prompt (24 hours) return of the blood pressure to normal. In the animals with hypertension of long duration but without renal excretory insufficiency, (the "benign" phase) no significant arterio- or arteriolosclerosis developed as a result of the hypertension alone. In the animals that had both hypertension and renal excretory insufficiency, (the "malignant" phase) the typical terminal arteriolar lesions developed in many organs. These lesions consisted of necrosis and fibrinoid degeneration of arterioles and necrotizing arteriolitis which should not be confused with arteriolosclerosis. The same humoral mechanism which is responsible for experimental renal hypertension in the dog and other animals also obtains in the pathogenesis of experimental renal hypertension in the sheep and goat.


Cytotoxicity of Peruvian propolis and Psidium guajava on human gingival fibroblasts, PBMCs and HeLa cells.
It is indisputable that every day it is demonstrated that natural products present diverse therapeutic benefits, which has boosted their incorporation within various products for clinical use. However, this must be accompanied by knowledge of their effect on cell lines to ensure their use is safe. The objective of this study was to evaluate the cytotoxic effect of two ethanolic extracts based on Peruvian natural products, on three human cell lines. Cervical cancer cell lines (HeLa), human gingival fibroblasts (HGF-1 - ATCC CRL-2014) (HGF-1) and peripheral blood mononuclear cells (PBMCs) were cultured and subsequently treated with preparations of ethanolic extracts of propolis (EEP) and Psidium guajava (EEG) from a concentration of 50 mg/mL to 0.024 mg/mL, by the 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazole bromide reduction assay. At a concentration of 0.24 mg/mL EEG, viability of 99.7±1.24%, 99.8±2.2% and 99.7±2.7% was observed in HeLa, HGF-1 and PBMCs, respectively; >90% cell viability values were observed with EPP at 0.024 mg/mL, with HGF-1 showing the highest viability (96.9±1.15%). A dose-dependent effect was observed for both extracts with a decrease in cell viability as concentrations increased (up to 50 mg/mL). EEP and EEG extracts at low concentrations do not show cytotoxicity in human cell lines, these findings are an advance in the preclinical evaluation on their safety and open a continuity to further studies for their potential applications in dentistry and medicine.


Polyaromatic hydrocarbons (PAHs) sorption behavior unaffected by the presence of multi-walled carbon nanotubes (MWNTs) in a natural soil system.
The batch equilibrium approach was used to examine the influence of multi-walled carbon nanotubes (MWNTs) on the sorption behaviors of polyaromatic hydrocarbons (PAHs) in soil. To the knowledge of the authors, this is the first study of PAH sorption to MWNTs in real natural soil systems. The sorption behavior of three PAHs (naphthalene, fluorene, and phenanthrene) in the presence of commercially available MWNTs in two natural soils (a sandy loam and a silt loam) and Ottawa sand was evaluated. Adsorption of PAHs by MWNTs in this study was three orders of magnitude higher than that of natural soils. Sorption coefficients of PAHs (Kd and Koc) were unchanged in the presence of 2 mg g(-1) MWNTs in soil (p > 0.05). A micro-mechanics approach, termed 'the rule of mixtures' was used for predicting PAH sorption behaviors in mixtures based on sorption coefficients derived from single sorbents. The equation, KT = KMα + KN(1 - α) (K, sorption coefficients, Kd or Koc), predicted sorption coefficients in a mixture based on mixture component sorption coefficients and mass fractions. Data presented in this study could be used to fill data gaps related to the environmental fate of carbon nanotubes in soil.


Influence of Light and Temperature on Gene Expression Leading to Accumulation of Specific Flavonol Glycosides and Hydroxycinnamic Acid Derivatives in Kale (Brassica oleracea var. sabellica).
Light intensity and temperature are very important signals for the regulation of plant growth and development. Plants subjected to less favorable light or temperature conditions often respond with accumulation of secondary metabolites. Some of these metabolites have been identified as bioactive compounds, considered to exert positive effects on human health when consumed regularly. In order to test a typical range of growth parameters for the winter crop Brassica oleracea var. sabellica, plants were grown either at 400 μmol m(-2) s(-1) or 100 μmol m(-2) s(-1) at 10°C, or at 400 μmol m(-2) s(-1) with 5 or 15°C. The higher light intensity overall increased flavonol content of leaves, favoring the main quercetin glycosides, a caffeic acid monoacylated kaempferol triglycoside, and disinapoyl-gentiobiose. The higher temperature mainly increased the hydroxycinnamic acid derivative disinapoyl-gentiobiose, while at lower temperature synthesis is in favor of very complex sinapic acid acylated flavonol tetraglycosides such as kaempferol-3-O-sinapoyl-sophoroside-7-O-diglucoside. A global analysis of light and temperature dependent alterations of gene expression in B. oleracea var. sabellica leaves was performed with the most comprehensive Brassica microarray. When compared to the light experiment much less genes were differentially expressed in kale leaves grown at 5 or 15°C. A structured evaluation of differentially expressed genes revealed the expected enrichment in the functional categories of e.g. protein degradation at different light intensities or phytohormone metabolism at different temperature. Genes of the secondary metabolism namely phenylpropanoids are significantly enriched with both treatments. Thus, the genome of B. oleracea was screened for predicted genes putatively involved in the biosynthesis of flavonoids and hydroxycinnamic acid derivatives. All identified B. oleracea genes were analyzed for their most specific 60-mer oligonucleotides present on the 2 × 105 K format Brassica microarray. Expression differences were correlated to the structure-dependent response of flavonoid glycosides and hydroxycinnamic acid derivatives to alterations in either light or temperature. The altered metabolite accumulation was mainly reflected on gene expression level of core biosynthetic pathway genes and gave further hints to an isoform specific functional specialization.


Treatment of rat congenital diaphragmatic hernia with sildenafil and NS-304, selexipag's active compound, at the pseudoglandular stage improves lung vasculature.
Patients with congenital diaphragmatic hernia (CDH) often suffer from severe pulmonary hypertension, and the choice of current vasodilator therapy is mostly based on trial and error. Because pulmonary vascular abnormalities are already present early during development, we performed a study to modulate these pulmonary vascular changes at an early stage during gestation. Pregnant Sprague-Dawley rats were treated with nitrofen at day 9.5 of gestation (E9.5) to induce CDH in the offspring, and subsequently, the phosphodiesterase-5 inhibitor sildenafil and/or the novel prostaglandin-I receptor agonist selexipag (active compound NS-304) were administered from E17.5 until E20.5. The clinical relevant start of the treatment corresponds to week 20 of gestation in humans, when CDH is usually detected by ultrasound. CDH pups showed increased density of air saccules that was reverted after the use of only sildenafil. The pulmonary vascular wall was thickened, and right ventricular hypertrophy was present in the CDH group and improved both after single treatment with sildenafil or selexipag, whereas the combination therapy with both compounds did not have additive value. In conclusion, antenatal treatment with sildenafil improved airway morphogenesis and pulmonary vascular development, whereas selexipag only acted positively on pulmonary vascular development. The combination of both compounds did not act synergistically, probably because of a decreased efficiency of both compounds caused by cytochrome- P450 3A4 interaction and induction. These new insights create important possibilities for future treatment of pulmonary vascular abnormalities in CDH patients already in the antenatal period of life.


Comparison of the effects of enucleation and orbital reconstruction using free-fat grafts, dermis grafts, and porous polyethylene implants in infant rabbits.
Twenty-nine infant rabbits from four litters were randomly assigned to three groups. No surgery was performed on left eyes. All right eyes were enucleated. Group 1, the control group, had no right-socket reconstruction. Group 2 had reconstruction using free-fat and dermis grafts. Group 3 had reconstruction using porous polyethylene implants. On attaining adult size, rabbits were killed, decapitated, and prepared for measurements. Orbital volume measurements were performed twice and orbital entrance areas were determined once. No significant differences were noted between first and second measurements of orbital volumes. Right orbital volumes were significantly smaller than left orbits in all groups except for the second measurement of the polyethylene implant group. Right orbital entrance areas were significantly smaller than left areas in the control and the free-fat and dermis graft groups. Right orbital entrance areas of the polyethylene group were not significantly smaller than the corresponding left orbital entrance areas. The use of free-fat and dermis grafts for orbital reconstruction in anophthalmic infant rabbits did not significantly stimulate orbital bone growth. In one trial, the polyethylene implant group displayed right orbital volumes and orbital entrance areas that were not significantly smaller than controls.


Efficacy of nivolumab and ipilimumab in patients with malignant pleural mesothelioma is related to a subtype of effector memory cytotoxic T cells: Translational evidence from two clinical trials.
Combined immune checkpoint inhibitor (ICI) treatment targeting PD-1 and CTLA-4 was suggested to yield clinical benefit over chemotherapy in malignant pleural mesothelioma (MPM), whereas aPD-1 monotherapy failed to provide benefit in phase-III trials. Success of ICI depends on the presence and activation of tumor-specific T cells. Therefore, we investigated whether T-cell characteristics are underlying clinical efficacy of ICI treatment in MPM. Comprehensive immune cell profiling was performed on screening and on treatment peripheral blood samples of mesothelioma patients treated with nivolumab (aPD-1) monotherapy (NCT02497508), or a combination of nivolumab and ipilimumab (aCTLA-4) (NCT03048474). aPD-1/aCTLA-4 combination treatment induced a profound increase in proliferation and activation of T cells, which was not observed upon aPD-1 monotherapy. Moreover, patients that responded to combination treatment had low frequencies of naive CD8 T cells and high frequencies of effector memory CD8 T cells that re-expressed RA (TEMRA) at screening. The frequency of Granzyme-B and Interferon-γ producing TEMRAs was also higher in responding patients. High proportions of TEMRAs and cytokine production by TEMRAs before treatment, was associated with a better clinical outcome. TEMRAs, which likely comprise tumor-specific T cells, tend to require blockage of both aPD-1 and aCTLA-4 to be reactivated. In conclusion, peripheral blood TEMRAs can play a key role in explaining and predicting clinical benefit upon aPD-1/aCTLA-4 combination treatment. Bristol-Myers Squibb sponsored NivoMes and INITIATE clinical trials and provided study drugs. No external funding was applicable for the flow cytometric analyses of peripheral blood samples described in this manuscript.


Type-specific cell line models for type-specific ovarian cancer research.
OVARIAN CARCINOMAS CONSIST OF AT LEAST FIVE DISTINCT DISEASES: high-grade serous, low-grade serous, clear cell, endometrioid, and mucinous. Biomarker and molecular characterization may represent a more biologically relevant basis for grouping and treating this family of tumors, rather than site of origin. Molecular characteristics have become the new standard for clinical pathology, however development of tailored type-specific therapies is hampered by a failure of basic research to recognize that model systems used to study these diseases must also be stratified. Unrelated model systems do offer value for study of biochemical processes but specific cellular context needs to be applied to assess relevant therapeutic strategies. We have focused on the identification of clear cell carcinoma cell line models. A panel of 32 "ovarian cancer" cell lines has been classified into histotypes using a combination of mutation profiles, IHC mutation-surrogates, and a validated immunohistochemical model. All cell lines were identity verified using STR analysis. Many described ovarian clear cell lines have characteristic mutations (including ARID1A and PIK3CA) and an overall molecular/immuno-profile typical of primary tumors. Mutations in TP53 were present in the majority of high-grade serous cell lines. Advanced genomic analysis of bona-fide clear cell carcinoma cell lines also support copy number changes in typical biomarkers such at MET and HNF1B and a lack of any recurrent expressed re-arrangements. As with primary ovarian tumors, mutation status of cancer genes like ARID1A and TP53 and a general immuno-profile serve well for establishing histotype of ovarian cancer cell We describe specific biomarkers and molecular features to re-classify generic "ovarian carcinoma" cell lines into type specific categories. Our data supports the use of prototype clear cell lines, such as TOV21G and JHOC-5, and questions the use of SKOV3 and A2780 as models of high-grade serous carcinoma.


Opportunities, barriers, and recommendations in down syndrome research.
Recent advances in medical care have increased life expectancy and improved the quality of life for people with Down syndrome (DS). These advances are the result of both pre-clinical and clinical research but much about DS is still poorly understood. In 2020, the NIH announced their plan to update their DS research plan and requested input from the scientific and advocacy community. The National Down Syndrome Society (NDSS) and the LuMind IDSC Foundation worked together with scientific and medical experts to develop recommendations for the NIH research plan. NDSS and LuMind IDSC assembled over 50 experts across multiple disciplines and organized them in eleven working groups focused on specific issues for people with DS. This review article summarizes the research gaps and recommendations that have the potential to improve the health and quality of life for people with DS within the next decade. This review highlights many of the scientific gaps that exist in DS research. Based on these gaps, a multidisciplinary group of DS experts has made recommendations to advance DS research. This paper may also aid policymakers and the DS community to build a comprehensive national DS research strategy.


Functional heterogeneity of nicotinic receptors in the avian lateral spiriform nucleus detected with trimethaphan.
We have examined an excitatory response mediated by nicotinic acetylcholine receptors located on the somata and/or dendrites of chick lateral spiriform neurons. On the basis of pharmacological and anatomical studies, these receptors belong to a subgroup of nicotinic receptors termed high affinity nicotine receptors, because they exhibit a high affinity for nicotinic agonists but little or no sensitivity to alpha- or kappa-bungarotoxin. We now report physiological evidence that high affinity nicotine receptors in the lateral spiriform nucleus are heterogeneous. Intracellular recording in brain slices was used to examine the pharmacological characteristics of nicotinic responses in individual lateral spiriform neurons. Nicotinic responses to brief applications of carbachol were inhibited by trimethaphan, dihydro-beta-erythroidine, or d-tubocurarine. Trimethaphan was unusual, in that a wide range of concentrations (< or = 50 microM to > 500 microM) were required to block this nicotinic response in different neurons. To quantitate the inhibition observed with trimethaphan and dihydro-beta-erythroidine, dose-response curves were generated in superfusion studies using a wide range of concentrations of both agonist (3-3000 microM carbachol in the presence of 1 microM atropine and 0.25 microM tetrodotoxin) and antagonists (10-500 microM trimethaphan or 0.1-3 microM dihydro-beta-erythroidine). The data yielded an EC50 of 25 +/- 5 microM for carbachol, with a Hill coefficient of 1.4 +/- 0.1 (mean +/- standard error; n = 8). In the case of dihydro-beta-erythroidine, a narrow range of Ki values was obtained (0.09-0.16 microM; n = 5). In contrast, Ki values for trimethaphan varied over a 15-fold concentration range (4-66 microM; n = 17), demonstrating that trimethaphan showed selectivity for different receptor subtypes found in the lateral spiriform nucleus. For both antagonists, the data indicate a competitive mode of inhibition.


Small bowel motility and transit after aortic surgery.
The inability to tolerate feedings after aortic surgery prolongs hospitalization. The aim of this study was to define jejunal manometric and small bowel transit characteristics associated with the ileus that follows transperitoneal aortic surgery. Five male patients who underwent transperitoneal infrarenal aortobifemoral bypass had intraoperative placement of a jejunal multilumen catheter. The open abdomen allowed precise placement of pressure recording ports at 20, 22, 24, 26, 28, and 38 cm past the ligament of Treitz. Three-hour manometric studies were done after surgery and for 3 postoperative days. The migrating motor complex was identified visually on the manometric tracings, and pressure waves were identified with computer and a motility index calculated. Motility data were compared with healthy control data previously reported in the literature. Small bowel transit was determined with barium and serial abdominal radiographs. All patients had ileus develop with return of bowel sounds at 2 to 7 days (median, 6 days) and flatus at 3 to 9 days (median, 7 days) after surgery. Jejunal motor activity was present within 6 hours of surgery, but the motility index was less in patients then in control subjects. The postoperative migrating motor complexes differed from control subjects in having more phase I, less phase II, and more frequent phase IIIs. Phase III retrograde migration was common in the patients but not in the control subjects. Small bowel transit was 2 days or greater in all patients. Motor activity is present in the jejunum shortly after aortic surgery. However, the activity is decreased in intensity and the fasting cycle differs from control subjects. Retrograde migration of phase III is the most likely abnormality, resulting in delayed small bowel transit. The data would predict a high rate of enteral feeding intolerance early after surgery. Future studies should focus on pharmacologic manipulation to rapidly return small bowel motility to a more normal state after aortic surgery.


Levers for addressing medical underuse and overuse: achieving high-value health care.
The preceding papers in this Series have outlined how underuse and overuse of health-care services occur within a complex system of health-care production, with a multiplicity of causes. Because poor care is ubiquitous and has considerable consequences for the health and wellbeing of billions of people around the world, remedying this problem is a morally and politically urgent task. Universal health coverage is a key step towards achieving the right care. Therefore, full consideration of potential levers of change must include an upstream perspective-ie, an understanding of the system-level factors that drive overuse and underuse, as well as the various incentives at work during a clinical encounter. One example of a system-level factor is the allocation of resources (eg, hospital beds and clinicians) to meet the needs of a local population to minimise underuse or overuse. Another example is priority setting using tools such as health technology assessment to guide the optimum diffusion of safe, effective, and cost-effective health-care services. In this Series paper we investigate a range of levers for eliminating medical underuse and overuse. Some levers could operate effectively (and be politically viable) across many different health and political systems (eg, increase patient activation with decision support) whereas other levers must be tailored to local contexts (eg, basing coverage decisions on a particular cost-effectiveness ratio). Ideally, policies must move beyond the purely incremental; that is, policies that merely tinker at the policy edges after underuse or overuse arises. In this regard, efforts to increase public awareness, mobilisation, and empowerment hold promise as universal methods to reset all other contexts and thereby enhance all other efforts to promote the right care.


Tobacco Use Worldwide: Legislative Efforts to Curb Consumption.
Tobacco smoking is recognized as a major preventable cause of disease worldwide and is linked to 6 million deaths annually, 30% of which are due to cancer. The negative health consequences of smoking currently represent one of the greatest global public health challenges. Additionally, secondhand smoke, which was declared carcinogenic by the International Agency for Research on Cancer in 2004, is a major source of morbidity and premature death in nonsmokers, particularly children. Negative health effects associated with exposure to secondhand smoke have been well documented and include lung cancer, cardiovascular disease, asthma, and other respiratory diseases. International and national policies to implement cost-effective strategies to curtail smoking will have a significant impact on population health and will protect nonsmokers. Effective interventions, such as smoking bans, tobacco price increases, easy access to tobacco cessation treatments, and anti-tobacco media campaigns, should continue. Reducing tobacco use would be a major step towards the goal of decreasing health disparities by 2030, as 80% of the projected tobacco-related deaths will occur in low and middle-income countries.


Head circumference at birth and exposure to tobacco, alcohol and illegal drugs during early pregnancy.
We aimed to assess the effects of exposure to tobacco smoke, alcohol and illegal drugs during early pregnancy on the head circumference (HC) at birth of otherwise healthy neonates. A follow-up study from the first trimester of pregnancy to birth was carried out in 419 neonates. An environmental reproductive health form was used to record data of substance exposure obtained during the first obstetric visit at the end of the first trimester. A multiple linear regression model was created for this purpose. Alcohol intake during pregnancy and medical ionizing radiation exposure were the most significant predictors of HC. The mothers' alcohol consumption increased with the mothers' and fathers' education level, net family income and fathers' alcohol consumption. In contrast, maternal smoking decreased with increasing mothers' and fathers' education level and net family income. About 13% of the surveyed embryos were exposed to illegal drugs. Mild to moderate alcohol consumption diminishes the at-birth HC of theoretically healthy newborns in a linear form. There was no threshold dose. We perceived a need for increasing the awareness, and for training, of health care professionals and parents, in regard to risks of alcohol consumption and for recommending abstinence of these substances in both parents during pregnancy. It should also be remembered that medical ionizing radiation should be performed only during the first half of the cycle in fertile women. We think that our study has an important social impact as it affords data for implementing policies for promoting "healthy pregnancies".


Cross-sectional survey of Parkinson's disease and parkinsonism in a rural area of the United Kingdom.
The objective of this study was to estimate the crude and standardized age/sex-adjusted prevalence rates of parkinsonism and Parkinson's disease (PD) in a rural area of North Wales. Cases of PD and parkinsonism in a geographically defined rural area of North Wales were ascertained from the prescription of antiparkinsonian medication in primary care, hospital records, attendance at general medical outpatient clinics and at a specialist movement disorder clinic. In this population, the crude prevalence of clinically probable/possible PD was 144 per 1000,000 (95% confidence interval [CI], 120-173) and for parkinsonism 169 per 100,000 (95% CI, 143-201). When adjusted to the UK population, the prevalence for clinically probable PD was 105 per 100,000 (95% CI, 85-124) and for parkinsonism 122 per 100,000 (95% CI, 102-143). Age- and sex-adjusted standardized rates indicate that regional variations in PD and parkinsonism may exist in the United Kingdom. There are several possible reasons for this, although methodological differences between studies may be the most likely explanations for the present findings.


Relationship between neural response and adaptation selectivity to form and color: an ERP study.
Adaptation is widely used as a tool for studying selectivity to visual features. In these studies it is usually assumed that the loci of feature selective neural responses and adaptation coincide. We used an adaptation paradigm to investigate the relationship between response and adaptation selectivity in event-related potentials (ERPs). ERPs were evoked by the presentation of colored Glass patterns in a form discrimination task. Response selectivities to form and, to some extent, color of the patterns were reflected in the C1 and N1 ERP components. Adaptation selectivity to color was reflected in N1 and was followed by a late (300-500 ms after stimulus onset) effect of form adaptation. Thus for form, response and adaptation selectivity were manifested in non-overlapping intervals. These results indicate that adaptation and response selectivity can be associated with different processes. Therefore, inferring selectivity from an adaptation paradigm requires analysis of both adaptation and neural response data.


Thymus-Derived Regulatory T Cells Infiltrate the Cardiac Allograft Before Rejection.
FOXP3+ regulatory T cells (Treg) either originate in the thymus (natural [n]Treg) or are induced in the periphery by antigen exposure and cytokines (induced [i]Treg). It is currently not elucidated which and to what extent these Treg subsets regulate intracardiac allogeneic responses in transplant patients. By using demethylation of the Treg-specific demethylated region in the FOXP3 gene as a marker for nTreg and FOXP3 messenger RNA expression as a marker for the total Treg population, we examined Treg in endomyocardial biopsies (EMBs) of both patients who developed an acute rejection necessitating therapy (rejectors; International Society for Heart and Lung Transplantation rejection grade ≥ 2R) and patients who remained free from rejection (nonrejectors). In the presence of comparable messenger RNA levels of CD3, IL-10, TGFβ, IL2, IFNγ, and IL17A, the percentage of nTreg was significantly higher in EMB with histological signs of mild rejection (rejection grade 1R) collected before rejection than in 1R EMB of nonrejectors. The total Treg population was comparable in 1R EMB of nonrejectors and 1R EMB collected before rejection, which suggests the presence of iTreg in the EMB of nonrejectors. The relative high percentage of nTreg after rejection was not related to the number of rejections, whereas the total Treg population was inversely related to the number of rejections the first year after transplantation. Our data indicate that intragraft nTreg are unable to restrain alloreactivity leading to rejection. Moreover, the indirect evidence of the presence of intragraft iTreg suggests a possible role of iTreg in the regulation of alloreactivity.


Social marketing campaigns and children's media use.
Media-related commercial marketing aimed at promoting the purchase of products and services by children, and by adults for children, is ubiquitous and has been associated with negative health consequences such as poor nutrition and physical inactivity. But, as Douglas Evans points out, not all marketing in the electronic media is confined to the sale of products. Increasingly savvy social marketers have begun to make extensive use of the same techniques and strategies used by commercial marketers to promote healthful behaviors and to counter some of the negative effects of conventional media marketing to children and adolescents. Evans points out that social marketing campaigns have been effective in helping to prevent and control tobacco use, increase physical activity, improve nutrition, and promote condom use, as well as other positive health behaviors. He reviews the evidence from a number of major recent campaigns and programming in the United States and overseas and describes the evaluation and research methods used to determine their effectiveness. He begins his review of the field of social marketing by describing how it uses many of the strategies practiced so successfully in commercial marketing. He notes the recent development of public health brands and the use of branding as a health promotion strategy. He then goes on to show how social marketing can promote healthful behavior, how it can counter media messages about unhealthful behavior, and how it can encourage discussions between parents and children. Evans concludes by noting some potential future applications to promote healthful media use by children and adolescents and to mitigate the effects of exposure to commercial marketing. These include adapting lessons learned from previous successful campaigns, such as delivering branded messages that promote healthful alternative behaviors. Evans also outlines a message strategy to promote "smart media use" to parents, children, and adolescents and suggests a brand based on personal interaction as a desirable alternative to "virtual interaction".


Overexpression of TFAP2C in invasive breast cancer correlates with a poorer response to anti-hormone therapy and reduced patient survival.
The AP-2gamma transcription factor encoded by the TFAP2C gene is a member of a family of homologous DNA binding proteins that play essential roles during vertebrate embryogenesis but show a restricted pattern of expression in the adult. Elevated expression of the AP-2alpha and AP-2gamma family members has been associated with a number of neoplasms, particularly breast cancer. Here we present an exploratory immunohistochemical study of an archival primary breast tumour series (n = 75) with parallel clinicopathological data using a new, well-characterized antibody to AP-2gamma. Heterogeneous, exclusively nuclear expression of AP-2gamma was found in the epithelial and myoepithelial compartments of normal breast and within tumour epithelial cells. In the breast cancer series, the most notable association was a correlation between elevated levels of AP-2gamma and shortened patient survival (p = 0.0009*). This relationship was also conserved in ER-positive and ErbB2-negative patients; sub-groups generally considered to have a relatively good prognosis. When patient data for survival and duration of treatment response on anti-hormone therapy were examined by multivariate analysis, AP-2gamma was revealed in this study to be an independent predictor of outcome for both survival (p = 0.005) and response to anti-hormone therapy (p = 0.046). Studies using in vitro models confirmed that while tamoxifen response is associated with lower levels of AP-2gamma, acquisition of resistance to this and other anti-hormone measures (eg faslodex or oestrogen deprivation) is associated with high levels of nuclear AP-2gamma. Together these data suggest that elevated tumour AP-2gamma expression can contribute to the failure of cells to growth arrest following anti-hormone treatment and lead to sustained growth and poorer patient outcome.


Helicase-like transcription factor exhibits increased expression and altered intracellular distribution during tumor progression in hypopharyngeal and laryngeal squamous cell carcinomas.
The helicase-like transcription factor (HLTF) belongs to the SWI/SNF family of proteins that use the energy from adenosine triphosphate hydrolysis to remodel chromatin during a variety of cellular processes. HLTF is also involved in DNA repair. Using computer-assisted microscopy, the immunohistochemical expression of HLTF was determined using a series of 100 hypopharyngeal and 56 laryngeal squamous cell carcinomas (SCCs) compared to tumor-free epithelia (60 cases) and dysplasias (92 cases). In hypopharyngeal SCC tumor progression, increased HLTF expression was associated with the percentage of immunopositive epithelial tissue areas (p = 0.02) and the staining intensity of the positive area (p = 0.0005). In the cases of laryngeal lesions, the immunolabeling intensity of HLTF significantly decreased with malignancy (p = 0.01). We also observed a significant shift of HLTF expression from the cytoplasm toward the nuclear compartment (p = 0.0007). Our data reveal an association between the presence of HLTF and neoplastic progression of hypopharyngeal and laryngeal SCCs.


T lymphocyte recruitment by interleukin-8 (IL-8). IL-8-induced degranulation of neutrophils releases potent chemoattractants for human T lymphocytes both in vitro and in vivo.
IL-8 has been shown to be a human neutrophil and T cell chemoattractant in vitro. In an effort to assess the in vivo effects of IL-8 on human leukocyte migration, we examined the ability of rhIL-8 to induce human T cell infiltration using a human/mouse model in which SCID mice were administered human peripheral blood lymphocytes intraperitoneally, followed by subcutaneous injections of rhIL-8. rhIL-8 induced predominantly murine neutrophil accumulation by 4 h after administration while recombinant human macrophage inflammatory protein-1beta (rhMIP-1beta) induced both murine monocytes and human T cell infiltration during the same time period as determined by immunohistology. Interestingly, 72 h after chemokine administration, a marked human T cell infiltrate was observed in the IL-8 injection site suggesting that rhIL-8 may be acting indirectly possibly through a murine neutrophil-derived T cell chemoattractant. This hypothesis was confirmed using granulocyte-depleted SCID mice. Moreover, human neutrophils stimulated in vitro with IL-8 were found to release granule-derived factor(s) that induce in vitro T cell and monocyte chemotaxis and chemokinesis. This T cell and monocyte chemotactic activity was detected in extracts of both azurophilic and specific granules. Together, these results demonstrate that neutrophils store and release, upon stimulation with IL-8 or other neutrophil activators, chemoattractants that mediate T cell and monocyte accumulation at sites of inflammation.


[The debate on lower back pain and its relationship to work: a retrospective study of workers on sick leave].
Lower back pain has a high prevalence among the Mexican working population, with extensive social and economic repercussions. Official figures show that lower back pain accounts for 10.0 to 15.0% of sick leave excuses. However, this fails to identify any relationship between lower back pain and job conditions, since such leave is only granted if it can be shown that the condition was not work-related. The present study shows that such a relationship does in fact exist. A retrospective study examined all cases (n = 210) in which workers were granted sick leave for lower back pain in an IMSS (Mexican Government Health Insurance) hospital in Mexico City during a seven-year period. The results show the association and interactions between debilitating lower back pain and several work-related variables: job position, time-on-the-job, and physical effort and weight-carrying associated with the position. Causes of lower back pain and the difficulty in obtaining accurate, precise back pain diagnosis are discussed. A number of clinical, epidemiological, and legal strategies for the study and prevention of back pain are suggested.


[Descriptive epidemiological study of acne on scholar pupils in France during autumn 1996].
Acne is the most common symptom prompting patients to consult a dermatologist. No previous study has been conducted in France to determine the prevalence of acne and describe the main epidemiological features. A cross sectional study was conducted in November 1996 and included 913 school children aged 11 to 18 years. This sample was statistically representative of the entire secondary school population in France during the 1996-1997 school year. The subjects were stratified by 5 criteria: age, sex, rural or urban residence, sun exposure, type of school. Taking the clinical diagnosis made by the dermatologist investigator as the main criteria, the overall prevalence of acne was 72 p. 100. It was 76.1 p. 100 using the new ECLA grading system previously described. The prevalence of acne was sex and age dependent: highest scores were found for girls aged 14-16 years and for boys aged 16-17 years. Genetic factors were very important for the outcome of acne. Finally, 41 p. 100 of the acneic subjects were following a treatment, prescribed by a dermatologist in two-third of the cases. These results are in agreement with those previously published in the literature although some differences were disclosed. It would appear important to distinguish between minimal acne with a few retentional pimples occuring during adolescence and severe acne (more than 20 pimples on the face) requiring early medical care to avoid scarring.


Regulation of insulin-like growth factor-binding protein expression by thyroid hormone in rat GH3 pituitary tumor cells.
Rat pituitary GH3 tumor cells express GH and insulin-like growth factor-I (IGF-I) mRNAs and possess specific IGF-I and IGF-II receptors which mediate the inhibitory effect of IGF on GH secretion. T3 increases the rate of cell replication and GH gene transcription, and causes an increase in IGF-I binding to cell membranes. Since the IGFs circulate in association with specific binding proteins (IGFBPs) that appear to modulate the access of IGFs to their receptors, we have investigated the effect of T3 treatment on the expression of IGFBPs in GH3 cells. Cells were grown in serum-free defined medium, and IGFBP secretion was determined by Western ligand blotting of conditioned medium after the addition of T3 and/or various peptides for 48-72 h. The conditioned medium of GH3 cells revealed a complex of bands migrating at 40-45 Mr, a pattern typical of rat (r) IGFBP-3. T3 treatment resulted in an increase in rIGFBP-3. IGF-I, IGF-II, and insulin did not alter rIGFBP-3 levels. After concentrating (10-fold) conditioned medium samples, two additional bands at 24K and 28K mol wt were also seen. These bands corresponded in size to rIGFBP-4 (24K) and its glycosylated form (28K). The mRNAs for both rIGFBP-3 and rIGFBP-4 were present in GH3 cells; T3 treatment increased steady state levels of rIGFBP-3 mRNA, but did not affect BP-4 mRNA levels. To learn whether the increased expression of IGFBPs could be responsible for the increased IGF-I binding seen after T3 treatment, [125I]IGF-I was cross-linked to GH3 membranes, and the proteins were separated on a 5-15% gradient sodium dodecyl sulfate-polyacrylamide gel under reducing conditions. T3 treatment induced a large increase in the intensity of bands migrating at 135K and 280K, representing the alpha-subunit of the IGF-I receptor and an incompletely reduced alpha-alpha-dimer, respectively. No membrane-associated IGFBPs were detected. In conclusion, GH3 cells express two IGFBPs, rIGFBP-3 and rIGFBP-4, which are differentially regulated by T3. The increased binding of IGF-I to GH3 cell membranes after T3 treatment indicates that thyroid hormone induces an up-regulation of IGF-I receptors and that the increased IGF-I binding to GH3 membranes is not due to increased expression of membrane-associated IGFBPs.


Fabrication of Defect-Free Cellulose Acetate Hollow Fibers by Optimization of Spinning Parameters.
Spinning of cellulose acetate (CA) with the additive polyvinylpyrrolidone (PVP) in N-methyl-2-pyrrolidone (NMP) solvent under different conditions was investigated. The spinning parameters of air gap, bore fluid composition, flow rate of bore fluid, and quench bath temperature were optimized based on the orthogonal experiment design (OED) method and multivariate analysis. FTIR and scanning electron microscopy were used to characterize the membrane structure and morphology. Based on the conjoint analysis in Statistical Product and Service Solutions (SPSS) software, the importance of these parameters was identified as: air gap > bore fluid composition > flow rate of bore fluid > quench bath temperature. The optimal spinning condition with the bore fluid (water + NMP (85%)), air gap (25 mm), flow rate of bore fluid (40% of dope rate), and temperature of quench bath (50 °C) was identified to make high PVP content, symmetric cross-section and highly cross-linked CA hollow fibers. The results can be used to guide the spinning of defect-free CA hollow fiber membranes with desired structures and properties as carbon membrane precursors.


Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1.
Hypoxia-inducible factor 1 (HIF-1) is a basic helix-loop-helix transcription factor which is expressed when mammalian cells are subjected to hypoxia and which activates transcription of genes encoding erythropoietin, vascular endothelial growth factor, and other proteins that are important for maintaining oxygen homeostasis. Previous studies have provided indirect evidence that HIF-1 also regulates transcription of genes encoding glycolytic enzymes. In this paper we characterize hypoxia response elements in the promoters of the ALDA, ENO1, and Ldha genes. We demonstrate that HIF-1 plays an essential role in activating transcription via these elements and show that although absolutely necessary, the presence of a HIF-1 binding site alone is not sufficient to mediate transcriptional responses to hypoxia. Analysis of hypoxia response elements in the ENO1 and Ldha gene promoters revealed that each contains two functionally-essential HIF-1 sites arranged as direct and inverted repeats, respectively. Our data establish that functional hypoxia-response elements consist of a pair of contiguous transcription factor binding sites at least one of which contains the core sequence 5'-RCGTG-3' and is recognized by HIF-1. These results provide further evidence that the coordinate transcriptional activation of genes encoding glycolytic enzymes which occurs in hypoxic cells is mediated by HIF-1.


P58-A and P58-B: novel proteins that mediate skeletogenesis in the sea urchin embryo.
During sea urchin embryogenesis, the skeleton is produced by primary mesenchyme cells (PMCs). PMCs undergo a sequence of morphogenetic behaviors that includes ingression, directed migration, and cell-cell fusion. Ultimately, PMCs deposit the calcite-containing biomineral that forms the endoskeleton of the late embryo and early larva. The endoskeleton has a stereotypical structure and is the major determinant of the distinctive, angular shape of the larva. Although many candidate biomineralization proteins have been identified, functional data concerning these proteins are scant. Here, we identify and characterize two new biomineralization genes, p58-a and p58-b. We show that these two genes are highly conserved in Strongylocentrotus purpuratus and Lytechinus variegatus, two sea urchin species whose ancestors diverged approximately 100 mya. The p58-a and p58-b genes lie in tandem on the chromosome, suggesting that one of the two genes arose via a gene duplication event. The two genes encode closely related, type I transmembrane proteins. We have established by whole mount in situ hybridization that p58-a and p58-b are expressed specifically in the PMCs in both species. Knockdown of either gene by morpholino antisense oligonucleotides leads to profound defects in skeletogenesis, although skeletal elements are not completely eliminated. The P58-A and P58-B proteins do not appear to play a role in the specification, directed migration or differentiation of the PMCs, but most likely are directly involved in biomineralization during sea urchin embryonic development.


Distinct shifts in site-specific glycosylation pattern of SARS-CoV-2 spike proteins associated with arising mutations in the D614G and Alpha variants.
Extensive glycosylation of the spike protein of severe acute respiratory syndrome coronavirus 2 virus not only shields the major part of it from host immune responses, but glycans at specific sites also act on its conformation dynamics and contribute to efficient host receptor binding, and hence infectivity. As variants of concern arise during the course of the coronavirus disease of 2019 pandemic, it is unclear if mutations accumulated within the spike protein would affect its site-specific glycosylation pattern. The Alpha variant derived from the D614G lineage is distinguished from others by having deletion mutations located right within an immunogenic supersite of the spike N-terminal domain (NTD) that make it refractory to most neutralizing antibodies directed against this domain. Despite maintaining an overall similar structural conformation, our mass spectrometry-based site-specific glycosylation analyses of similarly produced spike proteins with and without the D614G and Alpha variant mutations reveal a significant shift in the processing state of N-glycans on one specific NTD site. Its conversion to a higher proportion of complex type structures is indicative of altered spatial accessibility attributable to mutations specific to the Alpha variant that may impact its transmissibility. This and other more subtle changes in glycosylation features detected at other sites provide crucial missing information otherwise not apparent in the available cryogenic electron microscopy-derived structures of the spike protein variants.


The ontogenetic changes in the thermal properties of blubber from Atlantic bottlenose dolphin Tursiops truncatus.
In Atlantic bottlenose dolphins Tursiops truncatus, both the thickness and lipid content of blubber vary across ontogeny and across individuals of differing reproductive and nutritional status. This study investigates how these changes in blubber morphology and composition influence its thermal properties. Thermal conductivity (W m(-1) deg.(-1), where deg. is degrees C) and thermal insulation (m(2) deg. W(-1)) of dolphin blubber were measured in individuals across an ontogenetic series (fetus through adult, N=36), pregnant females (N=4) and emaciated animals (N=5). These thermal properties were determined by the simultaneous use of two common experimental approaches, the heat flux disc method and the standard material method. Thickness, lipid and water content were measured for each blubber sample. Thermal conductivity and insulation varied significantly across ontogeny. Blubber from fetuses through sub-adults was less conductive (range=0.11-0.13+/-0.02 W m(-1) deg.(-1)) than that of adults (mean=0.18 W m(-1) deg.(-1)). The conductivity of blubber from pregnant females was similar to non-adult categories, while that of emaciated animals was significantly higher (0.24 +/- 0.04 W m deg.(-1)) than all other categories. Blubber from sub-adults and pregnant females had the highest insulation values while fetuses and emaciated animals had the lowest. In nutritionally dependent life history categories, changes in blubber's thermal insulation were characterized by stable blubber quality (i.e. conductivity) and increased blubber quantity (i.e. thickness). In nutritionally independent animals, blubber quantity remained stable while blubber quality varied. A final, unexpected observation was that heat flux measurements at the deep blubber surface were significantly higher than that at the superficial surface, a pattern not observed in control materials. This apparent ability to absorb heat, coupled with blubber's fatty acid composition, suggest that dolphin integument may function as a phase change material.


Depicting surgical anatomy of the porta hepatis in living donor liver transplantation.
Visualizing the complex anatomy of vascular and biliary structures of the liver on a case-by-case basis has been challenging. A living donor liver transplant (LDLT) right hepatectomy case, with focus on the porta hepatis, was used to demonstrate an innovative method to visualize anatomy with the purpose of refining preoperative planning and teaching of complex surgical procedures. The production of an animation-enhanced video consisted of many stages including the integration of pre-surgical planning; case-specific footage and 3D models of the liver and associated vasculature, reconstructed from contrast-enhanced CTs. Reconstructions of the biliary system were modeled from intraoperative cholangiograms. The distribution of the donor portal veins, hepatic arteries and bile ducts was defined from the porta hepatis intrahepatically to the point of surgical division. Each step of the surgery was enhanced with 3D animation to provide sequential and seamless visualization from pre-surgical planning to outcome. Use of visualization techniques such as transparency and overlays allows viewers not only to see the operative field, but also the origin and course of segmental branches and their spatial relationships. This novel educational approach enables integrating case-based operative footage with advanced editing techniques for visualizing not only the surgical procedure, but also complex anatomy such as vascular and biliary structures. The surgical team has found this approach to be beneficial for preoperative planning and clinical teaching, especially for complex cases. Each animation-enhanced video case is posted to the open-access Toronto Video Atlas of Surgery (TVASurg), an education resource with a global clinical and patient user base. The novel educational system described in this paper enables integrating operative footage with 3D animation and cinematic editing techniques for seamless sequential organization from pre-surgical planning to outcome.


Post-transplantation cyclophosphamide reduces the incidence of acute graft-versus-host disease in patients with acute myeloid leukemia/myelodysplastic syndromes who receive immune checkpoint inhibitors after allogeneic hematopoietic stem cell transplantation.
Immune checkpoint inhibitors (ICIs) are being used after allogeneic hematopoietic stem cell transplantation (alloHCT) to reverse immune dysfunction. However, a major concern for the use of ICIs after alloHCT is the increased risk of graft-versus-host disease (GVHD). We analyzed the association between GVHD prophylaxis and frequency of GVHD in patients who had received ICI therapy after alloHCT. A retrospective study was performed in 21 patients with acute myeloid leukemia (n=16) or myelodysplastic syndromes (n=5) who were treated with antiprogrammed cell death protein 1 (16 patients) or anticytotoxic T lymphocyte-associated antigen 4 (5 patients) therapy for disease relapse after alloHCT. Associations between the type of GVHD prophylaxis and incidence of GVHD were analyzed. Four patients (19%) developed acute GVHD. The incidence of acute GVHD was associated only with the type of post-transplantation GVHD prophylaxis; none of the other variables included (stem cell source, donor type, age at alloHCT, conditioning regimen and prior history of GVHD) were associated with the frequency of acute GVHD. Twelve patients received post-transplantation cyclophosphamide (PTCy) for GVHD prophylaxis. Patients who received PTCy had a significantly shorter median time to initiation of ICI therapy after alloHCT compared with patients who did not receive PTCy (median 5.1 months compared with 26.6 months). Despite early ICI therapy initiation, patients who received PTCy had a lower observed cumulative incidence of grades 2-4 acute GVHD compared with patients who did not receive PTCy (16% compared with 22%; p=0.7). After controlling for comorbidities and time from alloHCT to ICI therapy initiation, the analysis showed that PTCy was associated with a 90% reduced risk of acute GVHD (HR 0.1, 95% CI 0.02 to 0.6, p=0.01). ICI therapy for relapsed acute myeloid leukemia/myelodysplastic syndromes after alloHCT may be a safe and feasible option. PTCy appears to decrease the incidence of acute GVHD in this cohort of patients.


Inhibition of potentially anti-apoptotic proteins by antisense protein kinase C-alpha (Isis 3521) and antisense bcl-2 (G3139) phosphorothioate oligodeoxynucleotides: relationship to the decreased viability of T24 bladder and PC3 prostate cancer cells.
Isis 3521 and G3139 are 20- and 18-mer phosphorothioate oligonucleotides, respectively, targeted to the protein kinase C (PKC)-alpha and bcl-2 mRNAs. Treatment of T24 bladder and PC3 prostate carcinoma cells with full-length and 3'-truncation mutants of Isis 3521 causes down-regulation of PKC-alpha protein and mRNA. However, at the level of a 15-mer and shorter, down-regulation of mRNA expression is no longer observed. Further, no diminution in cellular viability, as measured by 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide assay, in response to increasing concentrations of paclitaxel, can be observed for these shorter oligomers. These observations not only indicate that PKC-alpha protein expression can be down-regulated by both RNase H-dependent and -independent mechanisms but also that down-regulation of PKC-alpha is insufficient by itself to "chemosensitize" cells. G3139, which down-regulates bcl-2 protein and mRNA expression, also down-regulates PKC-alpha protein and mRNA expression but not that of PKC-betaI, -epsilon, or -zeta. However, the down-regulation of PKC-alpha and bcl-2 are not linked. When the carrier Eufectin 5 is employed, only bcl-2 is down-regulated in both T24 and PC3 cells at 50 nM oligonucleotide concentration. At 100 nM, both bcl-2 and PKC-alpha expression are down-regulated, and only at this concentration can "chemosensitization" to paclitaxel and carboplatin be observed. In contrast, the down-regulation of bcl-2 seems to be linked with that of RelA (p65). However, this too is also not sufficient for chemosensitization, even though it leads to the loss of expression of genes under the putative control of nuclear factor-kappaB and to detachment of the cells from plastic surfaces. These results underscore the complexity of the intracellular requirements for the initiation of chemosensitization to anti-neoplastic agents.


Glycoxidation, and protein and DNA oxidation in patients with diabetes mellitus.
1. The role of oxidative stress in the pathogenesis of the diabetic state is being investigated extensively. Although oxidative stress has been reported in terms of glycoxidation, protein oxidation and DNA oxidation in diabetes mellitus, oxidation parameters have not been determined in parallel on the same study population.2. We studied 24 patients with diabetes mellitus (14 patients with Type I diabetes with a mean age of 62.3+/-6.3 years and 10 patients with Type II diabetes aged 67.3+/-5.9 years) and compared them with age-matched non-diabetic controls. Urinary o-tyrosine, 8-hydroxy-2'-deoxyguanosine and pentosidine measurements by HPLC were made on two occasions (t1 and t2).3.A clear statistical difference was found between diabetic patients and controls at t1 or t2 for 8-hydroxy-2'-deoxyguanosine and pentosidine, but not for o-tyrosine. No significant correlations were found between clinical and other laboratory parameters except high-density lipoprotein and uric acid. We revealed significantly increased glycoxidation and DNA oxidation in patients with Type I and Type II diabetes, but protein oxidation was not different from controls.4. The finding of increased glycoxidation reflects increased oxidation of the carbohydrate moiety, whereas the increased levels of oxidized DNA may also be interpreted as due to increased DNA repair. The increased 8-hydroxy-2'-deoxyguanosine does not indicate the generation of an individual active oxygen species, but DNA could have been oxidized simply by alkenals from lipid peroxidation, as e.g. malondialdehyde. As no difference in protein oxidation (i.e. o-tyrosine) between diabetics and controls could be revealed, the oxidation of DNA by hydroxyl radical attack is unlikely, as o-tyrosine was proposed as a marker for hydroxyl radical attack. Therefore, the message is that increased glycoxidation can be confirmed, protein oxidation does not appear to take place and increased DNA oxidation is still not proven, as increased 8-hydroxy-2'-deoxyguanosine may simply reflect repair.


Genome-wide identification of the Fermentome; genes required for successful and timely completion of wine-like fermentation by Saccharomyces cerevisiae.
Wine fermentation is a harsh ecological niche to which wine yeast are well adapted. The initial high osmotic pressure and acidity of grape juice is followed by nutrient depletion and increasing concentrations of ethanol as the fermentation progresses. Yeast's adaptation to these and many other environmental stresses, enables successful completion of high-sugar fermentations. Earlier transcriptomic and growth studies have tentatively identified genes important for high-sugar fermentation. Whilst useful, such studies did not consider extended growth (>5 days) in a temporally dynamic multi-stressor environment such as that found in many industrial fermentation processes. Here, we identify genes whose deletion has minimal or no effect on growth, but results in failure to achieve timely completion of the fermentation of a chemically defined grape juice with 200 g L-1 total sugar. Micro- and laboratory-scale experimental fermentations were conducted to identify 72 clones from ~5,100 homozygous diploid single-gene yeast deletants, which exhibited protracted fermentation in a high-sugar medium. Another 21 clones (related by gene function, but initially eliminated from the screen because of possible growth defects) were also included. Clustering and numerical enrichment of genes annotated to specific Gene Ontology (GO) terms highlighted the vacuole's role in ion homeostasis and pH regulation, through vacuole acidification. We have identified 93 genes whose deletion resulted in the duration of fermentation being at least 20% longer than the wild type. An extreme phenotype, 'stuck' fermentation, was also observed when DOA4, NPT1, PLC1, PTK2, SIN3, SSQ1, TPS1, TPS2 or ZAP1 were deleted. These 93 Fermentation Essential Genes (FEG) are required to complete an extended high-sugar (wine-like) fermentation. Their importance is highlighted in our Fermentation Relevant Yeast Genes (FRYG) database, generated from literature and the fermentation-relevant phenotypic characteristics of null mutants described in the Saccharomyces Genome Database. The 93-gene set is collectively referred to as the 'Fermentome'. The fact that 10 genes highlighted in this study have not previously been linked to fermentation-related stresses, supports our experimental rationale. These findings, together with investigations of the genetic diversity of industrial strains, are crucial for understanding the mechanisms behind yeast's response and adaptation to stresses imposed during high-sugar fermentations.


Do threatened hosts have fewer parasites? A comparative study in primates.
1. Parasites and infectious diseases have become a major concern in conservation biology, in part because they can trigger or accelerate species or population declines. Focusing on primates as a well-studied host clade, we tested whether the species richness and prevalence of parasites differed between threatened and non-threatened host species. 2. We collated data on 386 species of parasites (including viruses, bacteria, protozoa, helminths and arthropods) reported to infect wild populations of 36 threatened and 81 non-threatened primate species. Analyses controlled for uneven sampling effort and host phylogeny. 3. Results showed that total parasite species richness was lower among threatened primates, supporting the prediction that small, isolated host populations harbour fewer parasite species. This trend was consistent across three major parasite groups found in primates (helminths, protozoa and viruses). Counter to our predictions, patterns of parasite species richness were independent of parasite transmission mode and the degree of host specificity. 4. We also examined the prevalence of selected parasite genera among primate sister-taxa that differed in their ranked threat categories, but found no significant differences in prevalence between threatened and non-threatened hosts. 5. This study is the first to demonstrate differences in parasite richness relative to host threat status. Results indicate that human activities and host characteristics that increase the extinction risk of wild animal species may lead simultaneously to the loss of parasites. Lower average parasite richness in threatened host taxa also points to the need for a better understanding of the cascading effects of host biodiversity loss for affiliated parasite species.


Combination therapy for KIT-mutant mast cells: targeting constitutive NFAT and KIT activity.
Resistant KIT mutations have hindered the development of KIT kinase inhibitors for treatment of patients with systemic mastocytosis. The goal of this research was to characterize the synergistic effects of a novel combination therapy involving inhibition of KIT and calcineurin phosphatase, a nuclear factor of activated T cells (NFAT) regulator, using a panel of KIT-mutant mast cell lines. The effects of monotherapy or combination therapy on the cellular viability/survival of KIT-mutant mast cells were evaluated. In addition, NFAT-dependent transcriptional activity was monitored in a representative cell line to evaluate the mechanisms responsible for the efficacy of combination therapy. Finally, shRNA was used to stably knockdown calcineurin expression to confirm the role of calcineurin in the observed synergy. The combination of a KIT inhibitor and a calcineurin phosphatase inhibitor (CNPI) synergized to reduce cell viability and induce apoptosis in six distinct KIT-mutant mast cell lines. Both KIT inhibitors and CNPIs were found to decrease NFAT-dependent transcriptional activity. NFAT-specific inhibitors induced similar synergistic apoptosis induction as CNPIs when combined with a KIT inhibitor. Notably, NFAT was constitutively active in each KIT-mutant cell line tested. Knockdown of calcineurin subunit PPP3R1 sensitized cells to KIT inhibition and increased NFAT phosphorylation and cytoplasmic localization. Constitutive activation of NFAT appears to represent a novel and targetable characteristic of KIT-mutant mast cell disease. Our studies suggest that combining KIT inhibition with NFAT inhibition might represent a new treatment strategy for mast cell disease.


Assessment of multi-directional MTF for breast tomosynthesis.
A method was developed to assess the multi-directional modulation transfer function (MTF) of breast tomosynthesis imaging systems using a sphere phantom. The method was initially developed based on a simulation dataset. Projections were simulated for a uniform voxelized breast phantom with sphere inserts using a fluence modeled from a 28 kVp beam incident upon an indirect flat-panel detector. Based on cascaded systems modeling, characteristic noise and blurring were added to each projection. The projections were reconstructed using a standard filtered backprojection technique, producing a 3D volume with an isotropic voxel size of 200 µm. ROIs that completely encompassed single spheres were extracted and conical regions were prescribed along the three major axes extending from the centroids. Pixels within the cones were used to form edge spread functions (ESFs), from which the directional MTFs were calculated. Binning size and conical range were adjusted to maximize the accuracy and to minimize the noise of the MTF. A method was further devised to remove out-of-plane artifacts from the ESF in the x-y plane. Finally, the method was applied to experimentally assess the directional MTF of a prototype tomosynthesis system. Comparisons of the sphere-based MTF along the different axes and the theoretical MTF yielded good agreement. A 30° angular cone and a 20 µm sampling were found to provide an ideal trade-off between the noise and accuracy of the measurement. The removal of artifacts in ESF yielded 'modified' MTFs that enabled a resolution-only characterization of the in-slice resolution of tomosynthesis. Drop-off frequencies in the x- and y-directional MTFs were 1.6 cycles mm(-1) and 1.5 cycles mm(-1), respectively. The presented method of separating the effective resolution and artifacts from the measured ESF was found experimentally implementable and is expected to facilitate the interpretation of MTF measurements in tomosynthesis.


Recent developments and ongoing trials in transplant oncology.
Over the past two decades since the introduction of the Milan criteria, the field of transplant oncology has undergone a rapid development with a rising proportion of liver transplantations being performed for oncological indications. For many patients with liver tumours, transplantation represents the only chance for cure. However, many challenges remain, such as the adequate patient selection, management of post-transplant recurrence and refinement of neoadjuvant treatment protocols. This review provides an overview of the current state of the art of liver transplantation for oncological indications such as hepatocellular carcinoma, cholangiocarcinoma, colorectal liver metastasis and metastatic neuroendocrine tumours. We also summarize the ongoing research and explore future trends. Clinical trials are currently studying new diagnostic modalities, innovative pharmacological treatments, novel surgical techniques, downstaging regimens and new indications for liver transplantation. These emerging results will continue to shape the field of transplant oncology and provide us with the necessary tools to better select, treat and follow patients with liver tumours qualifying for liver transplantation.


Coexisting generalist herbivores occupy unique nutritional feeding niches.
A mainstay of ecological theory and practice is that coexisting species use different resources, leading to the local development of biodiversity. However, a problem arises for understanding coexistence of multiple species if they share critical resources too generally. Here, we employ an experimental framework grounded in nutritional physiology to show that closely related, cooccurring and generalist-feeding herbivores (seven grasshopper species in the genus Melanoplus; Orthoptera: Acrididae) eat protein and carbohydrate in different absolute amounts and ratios even if they eat the same plant taxa. The existence of species-specific nutritional niches provides a cryptic mechanism that helps explain how generalist herbivores with broadly overlapping diets might coexist. We also show that performance by grasshoppers allowed to mix their diets and thus regulate their protein-carbohydrate intake matched optimal performance peaks generated from no-choice treatments. These results indicate the active nature of diet selection to achieve balanced diets and provide buffering capacity in the face of variable food quality. Our empirical findings and experimental approach can be extended to generate and test predictions concerning the intensity of biotic interactions between species, the relative abundance of species, yearly fluctuations in population size, and the nature of interactions with natural enemies in tritrophic niche space.


The effects of growth hormone-releasing peptide-2 (GHRP-2) on the release of growth hormone and growth performance in swine.
The effects of GHRP-2 (also named KP102), a new growth hormone-releasing peptide, on the release of growth hormone (GH) and growth performance were examined in swine. The single intravenous (i. v.) injection of GHRP-2 at doses of 2, 10, 30 and 100 microg/kg body weight (BW) to cross-bred castrated male swine stimulated GH release in a dose-dependent manner, with a return to the baseline by 120 min. The peak GH concentrations and GH areas under the response curves (GH AUCs) for 180 min after the injections of GHRP-2 were higher (P < 0.05) than those after the injection of saline. The GH responses to repeated i.v. injections of GHRP-2 (30 microg/kg BW) at 2-h intervals for 6 h were decreased after each injection. The chronic subcutaneous (s.c.) administration of GHRP-2 (30 microg/kg BW) once daily for 30 days consistently stimulated GH release. The GH AUCs for 300 min after the injections on d 1, 10 and 30 of treatment in GHRP-2-treated swine were higher than those in saline-treated swine. However, chronic administration of GHRP-2 caused a partial attenuation of GH response between d 1 and 10 of treatment. The chronic s.c. administration of GHRP-2 also increased average daily gain for the entire treatment period by 22.35% (P < 0.05) and feed efficiency (feed/gain) by 20.64% (P < 0.01) over the saline control values, but did not significantly affect daily feed intake. These results indicate that GHRP-2 stimulates GH release and enhancing growth performance in swine.


Scanning electrochemical microscopy at the nanometer level.
This review describes how one can perform nanometer (nm)-scale SECM experiments through advances in tip fabrication and positioning and instrumentation design. Basic SECM methodology including instrumentation and feedback and generation/collection modes are discussed. Aspects of nanoscale SECM including fabrication of nm-sized electrodes and nano SECM instrumentation are also described. State of the art applications related to nanogaps (i.e., rapid homogeneous reactions and short-lived intermediates; heterogeneous electron transfer kinetics; nanoparticles (NPs) and clusters) and nanoscale imaging (e.g., single NPs, single biological samples, combined methods) are described. Future possibilities and prospects are suggested that might lead to even better resolution, thus introducing SECM electrochemical imaging to the single atom level.


Partisan Responses to Public Health Messages: Motivated Reasoning and Sugary Drink Taxes.
This study examines the public's motivated reasoning of competitive messages about sugary drink taxes, a public health policy approach attempted with some recent success in the United States. In an experiment embedded in a nationally representative survey fielded in the fall of 2012, we randomized participants (N = 5,147) to receive one of four messages: control, a strong protax message, a two-sided message, or a message refuting arguments made in soda company antitax messages. The protax message showed no effects on tax support, while the two-sided message depressed Republicans' support. The refutation message boosted independents' support but produced backlash among Republicans. This motivated response was pronounced among Republicans who were plausibly previously exposed to the sugary drink tax debate. These findings reinforce the communication challenges in an increasingly politicized US health policy discourse.


American acupuncture and efficacy: meanings and their points of insertion.
By its very definition, efficacy's meanings remain fluid, their particularities contingent on context. The change seen as significant may occur on a symbolic level or through the removal of physical symptoms. It may address conditions of a social body. Some discussions differentiate between "healing" and "curing." Many of these meanings surface when examining what efficacy means in the practice of acupuncture in the United States. This complex phenomenon is possible largely because acupuncture draws on the qi paradigm on the one hand, allowing for the most ephemeral dimensions of experience to be included in considerations of efficacy. On the other hand, in the most material sense, acupuncture is also susceptible to being conceptualized as a device, independent of that same paradigm, allowing for the insertion of biomedical models and criteria. Pluralism within acupuncture itself intersects with, and even embodies, the medical pluralism of U.S. culture.


Delayed release pancrelipase for treatment of pancreatic exocrine insufficiency associated with chronic pancreatitis.
Pancreatic enzyme supplements (PES) are used in chronic pancreatitis (CP) for correction of pancreatic exocrine insufficiency (PEI) as well as pain and malnutrition. The use of porcine pancreatic enzymes for the correction of exocrine insufficiency is governed by the pathophysiology of the disease as well as pharmacologic properties of PES. Variability in bioequivalence of PES has been noted on in vitro and in vivo testing and has been attributed to the differences in enteric coating and the degree of micro-encapsulation. As a step towards standardizing pancreatic enzyme preparations, the Food and Drug Administration now requires the manufacturers of PES to obtain approval of marketed formulations by April 2010. In patients with treatment failure, apart from evaluating drug and dietary interactions and compliance, physicians should keep in mind that patients may benefit from switching to a different formulation. The choice of PES (enteric coated versus non-enteric coated) and the need for acid suppression should be individualized. There is no current standard test for evaluating adequacy of therapy in CP patients and studies have shown that optimization of therapy based on symptoms may be inadequate. Goals of therapy based on overall patient presentation and specific laboratory tests rather than mere correction of steatorrhea are needed.


Maternal chest radiography as supporting evidence for the diagnosis of tuberculosis in childhood.
Routine chest radiography of the mothers of 163 children investigated for possible tuberculosis accompanied by sputum culture from those mothers with suspicious chest radiographs identified active pulmonary tuberculosis in 12 (10 per cent) of the mothers of the 117 children with probable (49 cases) and confirmed (68 cases) tuberculosis. All but one of the cases of active maternal tuberculosis were identified in the mothers of children less than 1 1/2 years of age. Chest radiography of the mothers of children less than 1 1/2 years of age will aid the diagnosis of tuberculosis in the child and expedite the reduction of the infectious pool of active pulmonary tuberculosis cases in adults in the community.


Association of time-serial changes in ambient particulate matters (PMs) with respiratory emergency cases in Taipei's Wenshan District.
Ambient air pollution poses a significant risk for a group of common and often debilitating respiratory diseases, but its direct impact on cause-specific respiratory diseases using emergency room visit (ERV) as an indicator remains to be fully explored. In this study, we conducted a time-series study of ambient PM2.5, NO2, SO2 and their association with ERV for asthma, COPD and pneumonia in a four-year time span. Relative risks for ERV as per log increase in the level of ambient pollutants with time lags of up to 10 days were calculated, using a generalized additive model of Poisson regression. Daily 24-h average concentrations of PM2.5 and pollutant gases were obtained from a local Gutting air quality monitoring station. Results showed that the ERVs for pneumonia and asthma were associated with the level of PM2.5. The effects of PM2.5 on the risk of ERV for asthma were found to be significant at lag days 1 and 2 with increasing risk of 4.34% [RR: 1.091; CI: 1.020-1.166 (95%)] and 3.58% [RR: 1.074; CI: 1.007-1.146 (95%)], respectively. The ERV for pneumonia was associated with the level of PM2.5 at lag days 5, 6 and 7, with increasing risk of 1.92% [RR: 1.039; CI: 1.009-1.070 (95%)], 2.03% [RR: 1.041; CI: 1.009-1.075 (95%)], and 1.82% [RR: 1.037; CI: 1.001-1.075 (95%)], respectively. Further, PM2.5, but not NO2 and SO2, posed a significant risk of ERV for asthma during spring at lag days 0, 1 and 2 (17.12%, RR: 1.408, CI: 1.075-1.238; 15.30%, RR: 1.358 CI: 1.158-1.166; 11.94%, RR: 1.165, CI: 1.004-1.121), which was particularly evident for those who were younger than 75 years of age. In contrast, only PM2.5 was a significant risk of ERV for COPD, which was primarily for those who were younger than 75 years of age during summer season at lag days 3, 4 and 5. (26.66%, RR: 1.704, CI: 1.104-2.632; 26.99%; RR: 1.716, CI: 1.151-2.557; 24.09%; RR: 1.619, CI: 1.111-2.360). Collectively, these results suggested significant seasonal variation and differential time lag effects of PM2.5 on ERV for asthma, COPD and pneumonia.


Identification of novel mitosis regulators through data mining with human centromere/kinetochore proteins as group queries.
Proteins functioning in the same biological pathway tend to be transcriptionally co-regulated or form protein-protein interactions (PPI). Multiple spatially and temporally regulated events are coordinated during mitosis to achieve faithful chromosome segregation. The molecular players participating in mitosis regulation are still being unravelled experimentally or using in silico methods. An extensive literature review has led to a compilation of 196 human centromere/kinetochore proteins, all with experimental evidence supporting the subcellular localization. Sixty-four were designated as "core" centromere/kinetochore components based on peak expression and/or well-characterized functions during mitosis. By interrogating and integrating online resources, we have mined for genes/proteins that display transcriptional co-expression or PPI with the core centromere/kinetochore components. Top-ranked hubs in either co-expression or PPI network are not only enriched with known mitosis regulators, but also contain candidates whose mitotic functions are not yet established. Experimental validation found that KIAA1377 is a novel centrosomal protein that also associates with microtubules and midbody; while TRIP13 is a novel kinetochore protein and directly interacts with mitotic checkpoint silencing protein p31(comet). Transcriptional co-expression and PPI network analyses with known human centromere/kinetochore proteins as a query group help identify novel potential mitosis regulators.


Partly dominant transmission of schizophrenia in Iceland.
Voluminous data on the familial distribution of schizophrenia in Iceland were evaluated in terms of a partly dominant genetic mechanism. The risks were found in most instances to be proportional to the probability of harbouring the proposed gene, but penetrance rates, which generally are around 25%, appear to be elevated when additional risk factors are present. This occurs in individuals with multiple ill relatives, in offspring of two schizophrenic people, or in monozygotic co-twins. Excessive risks also occur in families with unusually severe disease.