Extracorporeal application of a gel-entrapment, bioartificial liver: demonstration of drug metabolism and other biochemical functions.
Metabolic activity of a gel-entrapment, hollow fiber, bioartificial liver was evaluated in vitro and during extracorporeal hemoperfusion in an anhepatic rabbit model. The bioartificial liver contained either 100 million rat hepatocytes (n = 12), fibroblasts (n = 3), or no cells (n = 7) during hemoperfusion of anhepatic rabbits. Eight other anhepatic rabbits were studied without hemoperfusion as anhepatic controls, and three sham rabbits served as normal controls. Albumin production rates (mean +/- SEM) were similar during in vitro (17.0 +/- 2.8 micrograms/h) and extracorporeal (18.0 +/- 4.0 micrograms/h) application of the hepatocyte bioartificial liver. Exogenous glucose requirements were reduced (p < 0.01) and euglycemia was prolonged (p < 0.001) in anhepatic rabbits treated with the hepatocyte bioartificial liver. The maximum rate of glucose production by the hepatocyte bioartificial liver ranged from 50-80 micrograms/h. Plasma concentrations of aromatic amino acids, proline, alanine, and ammonia were normalized in anhepatic rabbits during hepatocyte hemoperfusion. Gel-entrapped hepatocytes in the bioartifical liver performed sulfation and glucuronidation of 4-methylumbelliferone. P450 activity was demonstrated during both in vitro and extracorporeal application of the BAL device by the formation of 3-hydroxy-lidocaine, the major metabolite of lidocaine biotransformation by gel-entrapped rat hepatocytes. In summary, a gel-entrapment, bioartificial liver performed multiple hepatocyte-specific functions without adverse side effects during extracorporeal application in an anhepatic, small animal model. With its potential for short term support of acute liver failure, scale-up of the current bioartificial liver device is indicated for further investigations in large animal, preclinical trials.


Immigration to the USA and risk for mood and anxiety disorders: variation by origin and age at immigration.
Risk for mood and anxiety disorders associated with US-nativity may vary across immigrant groups. Using data from the National Epidemiological Study of Alcohol and Related Conditions (NESARC), we examined the association of lifetime risk for mood and anxiety disorders with US-nativity and age at immigration across seven subgroups of the US population defined by country or region of ancestral origin: Mexico, Puerto-Rico, Cuba, Central and South America, Western Europe, Eastern Europe, and Africa and the Caribbean. Discrete time survival models were used to compare lifetime risk between the US-born, immigrants who arrived in the USA prior to the age of 13 years and immigrants who arrived in the USA at the age of 13 years or older. The association of risk for mood and anxiety disorders with US-nativity varies significantly across ancestral origin groups (p<0.001). Among people from Mexico, Eastern Europe, and Africa or the Caribbean, risk for disorders is lower relative to the US-born among immigrants who arrived at the age of 13 years or higher (odds ratios in the range 0.34-0.49) but not among immigrants who arrived prior to the age of 13 years. There is no association between US-nativity and risk for disorder among people from Western Europe and Puerto Rico. Low risk among immigrants relative to the US-born is limited to groups among whom risk for mood and anxiety disorder is low in immigrants who spent their pre-adolescent years outside of the USA.


Epigenetic regulation in human brain-focus on histone lysine methylation.
Alterations in RNA levels are frequently reported in brain of subjects diagnosed with autism, schizophrenia, depression, and other psychiatric diseases, but it remains unclear whether the underlying molecular pathology involves changes in gene expression, as opposed to alterations in messenger RNA processing. Pre-clinical studies have revealed that stress, drugs, and a variety of other environmental factors lead to changes in RNA levels in brain via epigenetic mechanisms, including modification of histone proteins. A number of site-specific modifications of the nucleosome core histones-including the trimethylated forms of histone H3 lysines K4, K9, and K27-are of particular interest for postmortem research, because these marks differentiate between active and inactive chromatin and seem to remain relatively stable during tissue autolysis. Therefore, histone methylation profiling at promoter regions could provide important clues about mechanisms of gene expression in human brain during development and in disease. Intriguingly, mutations within the genes encoding the H3K9-specific methyltransferase, EHMT1, and the H3K4-specific histone demethylase, JARID1C/SMCX, have been linked to mental retardation and autism, respectively. In addition, the H3K4-specific methyltransferase, MLL1, is essential for hippocampal synaptic plasticity and might be involved in cortical dysfunction of some cases of schizophrenia. Together, these findings emphasize the potential significance of histone lysine methylation for orderly brain development and also as a molecular toolbox to study chromatin function in postmortem tissue.


Quantitative synteny scoring improves homology inference and partitioning of gene families.
Clustering sequences into families has long been an important step in characterization of genes and proteins. There are many algorithms developed for this purpose, most of which are based on either direct similarity between gene pairs or some sort of network structure, where weights on edges of constructed graphs are based on similarity. However, conserved synteny is an important signal that can help distinguish homology and it has not been utilized to its fullest potential. Here, we present GenFamClust, a pipeline that combines the network properties of sequence similarity and synteny to assess homology relationship and merge known homologs into groups of gene families. GenFamClust identifies homologs in a more informed and accurate manner as compared to similarity based approaches. We tested our method against the Neighborhood Correlation method on two diverse datasets consisting of fully sequenced genomes of eukaryotes and synthetic data. The results obtained from both datasets confirm that synteny helps determine homology and GenFamClust improves on Neighborhood Correlation method. The accuracy as well as the definition of synteny scores is the most valuable contribution of GenFamClust.


Patient Counseling Guidelines for the Use of Cannabis for the Treatment of Chemotherapy-Induced Nausea/Vomiting and Chronic Pain.
The use of cannabis medications has grown in recent years for the symptomatic relief of chemotherapy-induced nausea/vomiting (CINV) and chronic pain (cancer-related and non-cancer-related). As states legalize the use of cannabis, it is important for pharmacists and other health care professionals to be aware of how to counsel patients receiving prescriptions for cannabis medications. The aim of this study was to develop patient counseling guidelines for the use of cannabis products in treatment of CINV and chronic pain. A literature search was performed using Medline/PubMed resources and Google Scholar between July 2015 and August 2018 using broad search terms, e.g., cannabinoids adverse effects, cannabis, natural cannabinoids, and tetrahydrocannabinol. Using the American Society of Health-System Pharmacists patient counseling guidelines and medical information on cannabis medications gathered from drug databases, a comprehensive counseling guideline was developed. Medical evidence of the use of natural cannabis medications that are smoked or orally ingested have not been studied as extensively as oral therapeutic agents currently available. Cannabis medications have become more prevalent by approval of legislators in several states. Hence, pharmacists and health care professionals should counsel patients effectively on its use. This guideline needs to be tested to assess its utility in patients.


Chromophore binding to two cysteines increases quantum yield of near-infrared fluorescent proteins.
Phytochromes are red/far-red light sensing photoreceptors employing linear tetrapyrroles as chromophores, which are covalently bound to a cysteine (Cys) residue in the chromophore-binding domain (CBD, composed of a PAS and a GAF domain). Recently, near-infrared (NIR) fluorescent proteins (FPs) engineered from bacterial phytochromes binding biliverdin IXα (BV), such as the iRFP series, have become invaluable probes for multicolor fluorescence microscopy and in vivo imaging. However, all current NIR FPs suffer from relatively low brightness. Here, by combining biochemical, spectroscopic and resonance Raman (RR) assays, we purified and characterized an iRFP variant that contains a BV chromophore simultaneously bound to two cysteines. This protein with the unusual double-Cys attached BV showed the highest fluorescence quantum yield (FQY) of 16.6% reported for NIR FPs, whereas the initial iRFP appeared to be a mixture of species with a mean FQY of 11.1%. The purified protein was also characterized with 1.3-fold higher extinction coefficient that together with FQY resulted in almost two-fold brighter fluorescence than the original iRFP as isolated. This work shows that the high FQY of iRFPs with two cysteines is a direct consequence of the double attachment. The PAS-Cys, GAF-Cys and double-Cys attachment each entails distinct configurational constraints of the BV adduct, which can be identified by distinct RR spectroscopic features, i.e. the marker band including the C=C stretching coordinate of the ring A-B methine bridge, which was previously identified as being characteristic for rigid chromophore embedment and high FQY. Our findings can be used to rationally engineer iRFP variants with enhanced FQYs.


Chemoimmunotherapy: reengineering tumor immunity.
Cancer chemotherapy drugs have long been considered immune suppressive. However, more recent data indicate that some cytotoxic drugs effectively treat cancer in part by facilitating an immune response to the tumor when given at the standard dose and schedule. These drugs induce a form of tumor cell death that is immunologically active, thereby inducing an adaptive immune response specific for the tumor. In addition, cancer chemotherapy drugs can promote tumor immunity through ancillary and largely unappreciated immunologic effects on both the malignant and normal host cells present within the tumor microenvironment. These more subtle immunomodulatory effects are dependent on the drug itself, its dose, and its schedule in relation to an immune-based intervention. The recent approvals of two new immune-based therapies for prostate cancer and melanoma herald a new era in cancer treatment and have led to heightened interest in immunotherapy as a valid approach to cancer treatment. A detailed understanding of the cellular and molecular basis of interactions between chemotherapy drugs and the immune system is essential for devising the optimal strategy for integrating new immune-based therapies into the standard of care for various cancers, resulting in the greatest long-term clinical benefit for cancer patients.


Single-nucleotide polymorphism rs7251246 in ITPKC is associated with susceptibility and coronary artery lesions in Kawasaki disease.
Kawasaki disease (KD) is a multi-systemic vasculitis that preferentially affects children. A single nucleotide polymorphism (SNP) in inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) has been identified to be an important polymorphism in the risk of KD. This study was conducted to comprehensively investigate the associations between all tagging SNPs of ITPKC in the risk of KD in a Taiwanese population. A total of 950 subjects (381 KD patients and 569 controls) were recruited. Seven tagging SNPs (rs11673492, rs7257602, rs7251246, rs890934, rs10420685, rs2607420, rs2290692) were selected for TaqMan allelic discrimination assay. Clinical data of coronary artery lesions (CAL) and aneurysms were collected for analysis. A significant association was found between rs7251246 in ITPKC and CAL formation. Haplotype analysis for ITPKC polymorphisms also confirmed this association in the patients with CAL and aneurysm formation. This is the first study to identify that SNP rs7251246 in ITPKC is associated with the severity of KD.


Effect of depth and tubule direction on ultimate tensile strength of human coronal dentin.
The purpose of this study was to evaluate the effect of dentin depth and tubule direction on the ultimate tensile strength (UTS) of human dentin. Dentin slabs of 0.5-mm thickness were trimmed either from the mesial and distal (for specimens with the tubules parallel to the tensile force; parallel group) or from the occlusal and pulpal surfaces (perpendicular group) to reduce the cross-sectional area of the superficial, middle, and deep regions to 0.25 mm2, and subjected to microtensile testing. From SEM photomicrographs of the fractured specimens of the parallel group, the tubule density was investigated. For both parallel and perpendicular groups, superficial dentin showed a significantly higher UTS than deep dentin. The tubule density of superficial dentin was significantly lower than that of middle and deep dentin. When performing the microtensile bond test to deep dentin, it is possible that cohesive failure of dentin can occur at relatively low tensile stresses.


Development of a size-dependent aerosol deposition model utilising human airway epithelial cells for evaluating aerosol drug delivery.
Aerosol delivery to the airways of the human respiratory tract, followed by absorption, constitutes an alternative route of administration for compounds unsuitable for delivery by conventional oral and parenteral routes. The target for aerosol drug delivery is the airways epithelium, i.e. tracheal, bronchial, bronchiolar and alveolar cells, which become the site of drug deposition. These epithelial layers also serve as a barrier to the penetration of inhaled material. An in vitro model for aerosol deposition and transport across epithelia in the human airways may be a good predictor of in vivo disposition. The present preliminary studies begin an investigation that blends the dynamics of aerosol delivery and the basis of an in vitro simulated lung model to evaluate the transport properties of a series of molecular weight marker compounds across human-derived bronchiolar epithelial cell monolayers. An Andersen viable cascade impactor was used as a delivery apparatus for the deposition of size-segregated particles onto monolayers of small airway epithelial cells and Calu-3 cells. It was shown that these cell layers can withstand placement in the impactor, and that permeability can be tested subsequent to removal from the impactor.


Comparison of medetomidine, thiopental and ketamine/midazolam anesthesia in chick embryos for in ovo Magnetic Resonance Imaging free of motion artifacts.
Non-invasive assessment of the perfusion capacity of tissue engineered constructs grown on the chorioallantoic membrane by MRI is often hampered by motion artifacts. Therefore, we examined the suitability of three anesthetic regimes for sufficient sedation of the chick embryo. Medetomidine at a dosage of 0.3 mg/kg, was compared to thiopental at 100 mg/kg and ketamine/midazolam at 50 mg/kg and 1 mg/kg, respectively. These soluble anesthetics were applied by dropping a total volume of 0.3 mL onto the surface of the CAM. Motion was videotaped through the window of the eggshell and scored semi-quantitatively. Medetomidine performed best in terms of reduced motion; onset of anesthesia occurred within 10 minutes and for the following 30 minutes, allowing proper in vivo MRI measurements. The other regimen were not sedating deep enough (ketamine/midazolam) and not long enough (thiopental). In sum, medetomidine allows proper sedation for MRI assessment of the perfusion capacity in a tissue engineered construct placed on the CAM.


Potential of the predatory mite, Amblyseius swirskii to suppress the broad mite, Polyphagotarsonemus latus on the gboma eggplant, Solanum macrocarpon.
In Benin, the tarsonemid mite Polyphagotarsonemus latus (Banks) (Prostigmata: Tarsonemidae) is a key pest of gboma eggplant Solanum macrocarpon (L.) (Solanales: Solanaceae), a leafy vegetable on which it causes considerable damage to the plants and substantial reduction in yield. Predatory mites in the family Phytoseiidae have been successfully used in the biological control of numerous agricultural pests worldwide. In that respect, a population of the phytoseiid mite Amblyseius swirskii (Athias-Henriot) (Mesostigmata: Phytoseiidae) has been identified as a potential predator of P. latus, and is now a candidate for release against this pest in Benin. The objective of the present study is to determine, through laboratory experiments, the predation rate and life table parameters of A. swirskii when feeding on P. latus or alternative food such as maize pollen. Under laboratory conditions the mean number of P. latus consumed by A. swirskii, and daily oviposition, significantly increased as the number of prey increased. Total development time of A. swirskii was significantly shorter when it fed on P. latus than on maize pollen. Net reproduction rate, intrinsic rate of increase, mean generation time and the finite rate of increase of A. swirskii were were all significantly lower on P. latus than on maize pollen. However, doubling time was significantly higher on maize pollen. This study shows that A. swirskii is a good predator of P. latus, and that maize pollen can efficiently sustain A. swirskii populations when P. latus densities on plants become low. Consequently, A. swirskii can be used for the biological control of the broad mite P. latus on gboma eggplant, and on other solanaceous crops in Benin and elsewhere.


Microalbuminuria and coronary heart disease in NIDDM: an incidence study.
In most survival studies in NIDDM, microalbuminuria (urinary albumin excretion rate 20-200 microg/min) predicts early mortality; in cross-sectional studies, it is associated with coronary heart disease (CHD) morbidity. It is unclear, however, whether microalbuminuria is a risk factor for the development of CHD or the result of it, and little is known of the factors that predispose to the development of microalbuminuria in NIDDM. We examined these issues in a 7-year prospective study of a hospital-based cohort comprising 146 white NIDDM patients without clinical albuminuria. Microalbuminuria was a significant risk factor for both all-cause mortality (relative risk 3.94, 95% CI 2.04-7.62) and CHD mortality (relative risk 7.40, 95% CI 2.94-18.7) when adjusted for age only. Its independent predictive power did not persist, however, in age-adjusted multivariable survival analysis that allowed for the other significant risk factors: male sex, preexisting CHD, high levels of glycated hemoglobin, and high serum cholesterol. Among men free of CHD at baseline, the independent risk factors for CHD morbidity and mortality were microalbuminuria, current smoking, high diastolic blood pressure, and high serum cholesterol (all P < 0.05). For the 100 NIDDM patients with normoalbuminuria at baseline, the incidence of microalbuminuria was 29% over the 7-year period. In that group, fasting plasma glucose, current smoking, preexisting CHD, and high initial urinary albumin excretion rate were risk factors for the development of microalbuminuria (all P < 0.05). When men and women were analyzed separately, preexisting CHD was a significant risk factor in men only. These results demonstrate that microalbuminuria predicts incident clinical CHD in men with NIDDM. Preexisting CHD is also a risk factor for incident microalbuminuria in men, however, suggesting that microalbuminuria and CHD are not causally related but rather reflect common determinants.


Distinctive serum protein profiles involving abundant proteins in lung cancer patients based upon antibody microarray analysis.
Cancer serum protein profiling by mass spectrometry has uncovered mass profiles that are potentially diagnostic for several common types of cancer. However, direct mass spectrometric profiling has a limited dynamic range and difficulties in providing the identification of the distinctive proteins. We hypothesized that distinctive profiles may result from the differential expression of relatively abundant serum proteins associated with the host response. Eighty-four antibodies, targeting a wide range of serum proteins, were spotted onto nitrocellulose-coated microscope slides. The abundances of the corresponding proteins were measured in 80 serum samples, from 24 newly diagnosed subjects with lung cancer, 24 healthy controls, and 32 subjects with chronic obstructive pulmonary disease (COPD). Two-color rolling-circle amplification was used to measure protein abundance. Seven of the 84 antibodies gave a significant difference (p < 0.01) for the lung cancer patients as compared to healthy controls, as well as compared to COPD patients. Proteins that exhibited higher abundances in the lung cancer samples relative to the control samples included C-reactive protein (CRP; a 13.3 fold increase), serum amyloid A (SAA; a 2.0 fold increase), mucin 1 and alpha-1-antitrypsin (1.4 fold increases). The increased expression levels of CRP and SAA were validated by Western blot analysis. Leave-one-out cross-validation was used to construct Diagonal Linear Discriminant Analysis (DLDA) classifiers. At a cutoff where all 56 of the non-tumor samples were correctly classified, 15/24 lung tumor patient sera were correctly classified. Our results suggest that a distinctive serum protein profile involving abundant proteins may be observed in lung cancer patients relative to healthy subjects or patients with chronic disease and may have utility as part of strategies for detecting lung cancer.


Evaluation of the DOAC-Stop® Procedure to Overcome the Effect of DOACs on Several Thrombophilia Screening Tests.
The impact of direct oral anticoagulants (DOACs) on laboratory assays used for thrombophilia testing (e.g., antithrombin, protein S, protein C, lupus anticoagulant and activated protein-C resistance) is a well-known issue and may cause false-positive and -negative results. Therefore, the correct interpretation of tests that are performed in patients taking DOACs is mandatory to prevent misclassification and the subsequent clinical consequences. We aimed at evaluating the efficiency of a new and simple procedure (DOAC-Stop®; Haematex Research, Hornsby, Australia) to overcome the effect of all DOACs in real-life settings and to assess the percentage of erroneous results due to the presence of DOACs on thrombophilia screening tests. For this purpose, 135 DOAC-treated patients (38 apixaban, 40 dabigatran, 15 edoxaban, and 42 rivaroxaban) and 20 control patients were enrolled. A significant drop in apixaban, dabigatran, edoxaban, and rivaroxaban plasma concentrations following the DOAC-Stop® treatment was observed (74.8-8.2 ng/mL [ p < 0.0001], 95.9-4.7 ng/mL [ p < 0.0001], 102.1-8.8 ng/mL [ p = 0.001], and 111.3-7.0 ng/mL [ p < 0.0001], respectively). The DOAC-Stop® treatment was mostly effective to overcome the effect of DOACs on PTT-LA, dilute Russell's viper venom time (dRVVT) screen, and dRVVT confirm tests. Using our procedures, false-positive results due to DOACs were observed only with lupus anticoagulant tests (up to 75%) and fell to zero after the DOAC-Stop® procedure, regardless of the DOAC considered. In conclusion, the DOAC-Stop® adsorbent procedure appeared to be an effective and simple way to overcome the interference of DOAC on coagulation tests and should facilitate the interpretation of thrombophilia screening tests in patients taking DOACs.


Continuous monitoring of the Monro-Kellie doctrine: is it possible?
The Monro-Kellie doctrine describes the principle of homeostatic intracerebral volume regulation, which stipulates that the total volume of the parenchyma, cerebrospinal fluid, and blood remains constant. Hypothetically, a slow shift (e.g., brain edema development) in the irregular vasomotion-driven exchanges of these compartmental volumes may lead to increased intracranial hypertension. To evaluate this paradigm in a clinical setting and measure the processes involved in the regulation of systemic intracranial volume, we quantified cerebral blood flow velocity (CBFv) in the middle cerebral artery, arterial blood pressure (ABP), and intracranial pressure (ICP), in 238 brain-injured subjects. Relative changes in compartmental compliances C(a) (arterial) and C(i) (combined venous and CSF compartments) were mathematically estimated using these raw signals through time series analysis; C(a) and C(i) were used to compute an index of cerebral compliance (ICC) as a moving correlation coefficient between C(a) and C(i). Conceptually, a negative ICC would represent a functional Monro-Kellie doctrine by illustrating volumetric compensations between C(a) and C(i). Clinical observations show that Lundberg A-waves and arterial hypertension were associated with negative ICC, whereas in refractory intracranial hypertension, a positive ICC was observed. In subjects who died, ICC was significantly greater than in survivors (0.46 ± 0.027 versus 0.22 ± 0.017; p<0.01) over the first 5 days of intensive care. The mortality rate is 5% when ICC is less than 0, and 43% when above 0.7. ICC above 0.7 was associated with terminally elevated ICP (chi-square p=0.026). We propose that the Monro-Kellie doctrine can be monitored in real time to illustrate the state of intracranial volume regulation.


A hybrid electron donor comprising cyclopentadithiophene and dithiafulvenyl for dye-sensitized solar cells.
Two new photosensitizers featured with a cyanoacrylic acid electron acceptor (A) and a hybrid electron donor (D) of cyclopentadithiophene and dithiafulvenyl, either directly linked or separated by a phenyl ring, were synthesized and characterized. Both of them undergo two reversible oxidations and strongly absorb in the visible spectral region due to a photo-induced intramolecular charge-transfer (ICT) transition. To a great extent, the electronic interaction between the D and A units is affected by the presence of a phenyl spacer. Without a phenyl ring, the D unit appears more difficult to oxidize due to a strong electron-withdrawing effect of the A moiety. In sharp contrast, the insertion of the phenyl ring between the D and A units leads to a broken π-conjugation and therefore, the oxidation potentials remain almost unchanged compared to those of an analogue without the A group, suggesting that the electronic coupling between D and A units is relatively weak. As a consequence, the lowest-energy absorption band shows a slight hypsochromic shift upon the addition of the phenyl spacer, indicative of an increased HOMO-LUMO gap. In turn, the direct linkage of D and A units leads to an effective π-conjugation, thus substantially lowering the HOMO-LUMO gap. Moreover, the application in dye-sensitized solar cells was investigated, showing that the power conversion efficiency increases by the insertion of the phenyl unit.


Degradation of crude oil in the rhizosphere of Sorghum bicolor.
Dissipation of petroleum contaminants in the rhizosphere is likely the result of enhanced microbial degradation. Plant roots may encourage rhizosphere microbial activity through exudation of nutrients and by providing channels for increased water flow and gas diffusion. Phytoremediation of crude oil in soil was examined in this study using carefully selected plant species monitored over specific plant growth stages. Four sorghum (Sorghum bicolor L.) genotypes with differing root characteristics and levels of exudation were established in a sandy loam soil contaminated with 2700 mg crude oil/kg soil. Soils were sampled at three stages of plant growth: five leaf, flowering, and maturity. All vegetated treatments were associated with higher remediation efficiency, resulting in significantly lower total petroleum hydrocarbon concentrations than unvegetated controls. A relationship between root exudation and bioremediation efficiency was not apparent for these genotypes, although the presence of all sorghum genotypes resulted in significant removal of crude oil from the impacted soil.


Constructing the Immune Signature of Schizophrenia for Clinical Use and Research; An Integrative Review Translating Descriptives Into Diagnostics.
Schizophrenia is considered a syndrome comprised by several disease phenotypes, covering a range of underlying pathologies. One of these disease mechanisms seems to involve immune dysregulation and neuroinflammation. While the current dopamine receptor-blocking antipsychotic drugs decrease psychotic symptoms and prevent relapse in the majority of patients with schizophrenia, there is a huge need to explore new treatment options that target other pathophysiological pathways. Such studies should aim at identifying robust biomarkers in order to diagnose and monitor the immune biophenotype in schizophrenia and develop better selection procedures for clinical trials with anti-inflammatory and immune-modulating drugs. In this focused review, we describe available methods to assess inflammatory status and immune disturbances in vivo. We also outline findings of immune disturbances and signs of inflammation at cellular, protein, and brain imaging levels in patients with schizophrenia. Furthermore, we summarize the results from studies with anti-inflammatory or other immune-modulating drugs, highlighting how such studies have dealt with participant selection. Finally, we propose a strategy to construct an immune signature that may be helpful in selecting and monitoring participants in studies with immune modulating drugs and also applicable in regular clinical work.


Structured Multi-Stakeholder Workshops to Advance a Global Transformative Roadmap for Pharmaceutical Workforce.
In November 2016, the International Pharmaceutical Federation (FIP) endeavored to create an environment to foster a shared vision to lead a transformative pharmaceutical workforce roadmap. Three milestone documents were developed and presented at the Global Conference on Pharmacy and Pharmaceutical Education. Workshops with the key themes and connecting Pharmaceutical Workforce Development Goals (PWDG) were conducted and analyzed. This Note serves to summarize the key aspects of these workshops, reporting on the innovative approaches used to generate guidance for stakeholders regarding implementation. Seven workshops with a uniform structure were developed. These were designed to improve communication, harmonise outcome-generation, and allow for aggregate analysis. A team of seven conducted each workshop, each team consisted of: a Chair, a facilitator, one rapporteur, and four speakers purposively selected from FIP member organisations and other key stakeholders with expertise for sharing a variety of perspectives. Guidelines and templates were developed for all roles and each team was briefed in advance. Approximately 200 personnel participated in the seven workshops, with around 20 country representatives per workshop, covering all six World Health Organisation regions. Three key aspects of workforce transformation, using the PWDGs, were explored in each workshop: drivers for implementation; challenges to implementation; and ways of encouraging implementation. Drivers for implementation mentioned were enhancing collaboration and engagement. Challenges to implementation were identified as variance in terminology. Several ways of encouraging implementation were acknowledged, such as communication strategies, advocating for workforce development and sharing best practices to foster partnerships. The unique format of the workshops, the innovative approach to include stakeholders across an array of settings and the parallel structure in all the seven workshops, aided in creating reliable findings. The achievability of the PWDGs depends on several factors. Engagement with stakeholders and engagement from and between professional associations are important factors to achieving workforce development goals.


Non-canonical inflammasome activation targets caspase-11.
Caspase-1 activation by inflammasome scaffolds comprised of intracellular nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and the adaptor ASC is believed to be essential for production of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 during the innate immune response. Here we show, with C57BL/6 Casp11 gene-targeted mice, that caspase-11 (also known as caspase-4) is critical for caspase-1 activation and IL-1β production in macrophages infected with Escherichia coli, Citrobacter rodentium or Vibrio cholerae. Strain 129 mice, like Casp11(-/-) mice, exhibited defects in IL-1β production and harboured a mutation in the Casp11 locus that attenuated caspase-11 expression. This finding is important because published targeting of the Casp1 gene was done using strain 129 embryonic stem cells. Casp1 and Casp11 are too close in the genome to be segregated by recombination; consequently, the published Casp1(-/-) mice lack both caspase-11 and caspase-1. Interestingly, Casp11(-/-) macrophages secreted IL-1β normally in response to ATP and monosodium urate, indicating that caspase-11 is engaged by a non-canonical inflammasome. Casp1(-/-)Casp11(129mt/129mt) macrophages expressing caspase-11 from a C57BL/6 bacterial artificial chromosome transgene failed to secrete IL-1β regardless of stimulus, confirming an essential role for caspase-1 in IL-1β production. Caspase-11 rather than caspase-1, however, was required for non-canonical inflammasome-triggered macrophage cell death, indicating that caspase-11 orchestrates both caspase-1-dependent and -independent outputs. Caspase-1 activation by non-canonical stimuli required NLRP3 and ASC, but caspase-11 processing and cell death did not, implying that there is a distinct activator of caspase-11. Lastly, loss of caspase-11 rather than caspase-1 protected mice from a lethal dose of lipopolysaccharide. These data highlight a unique pro-inflammatory role for caspase-11 in the innate immune response to clinically significant bacterial infections.


Evaluating the fake news problem at the scale of the information ecosystem.
"Fake news," broadly defined as false or misleading information masquerading as legitimate news, is frequently asserted to be pervasive online with serious consequences for democracy. Using a unique multimode dataset that comprises a nationally representative sample of mobile, desktop, and television consumption, we refute this conventional wisdom on three levels. First, news consumption of any sort is heavily outweighed by other forms of media consumption, comprising at most 14.2% of Americans' daily media diets. Second, to the extent that Americans do consume news, it is overwhelmingly from television, which accounts for roughly five times as much as news consumption as online. Third, fake news comprises only 0.15% of Americans' daily media diet. Our results suggest that the origins of public misinformedness and polarization are more likely to lie in the content of ordinary news or the avoidance of news altogether as they are in overt fakery.


Large-scale mitogenomics enables insights into Schizophora (Diptera) radiation and population diversity.
True flies are insects of the order Diptera and encompass one of the most diverse groups of animals on Earth. Within dipterans, Schizophora represents a recent radiation of insects that was used as a model to develop a pipeline for generating complete mitogenomes using various sequencing platforms and strategies. 91 mitogenomes from 32 different species were sequenced and assembled with high fidelity, using amplicon, whole genome shotgun or single molecule sequencing approaches. Based on the novel mitogenomes, we estimate the origin of Schizophora within the Cretaceous-Paleogene (K-Pg) boundary, about 68.3 Ma. Detailed analyses of the blowfly family (Calliphoridae) place its origin at 22 Ma, concomitant with the radiation of grazing mammals. The emergence of ectoparasitism within calliphorids was dated 6.95 Ma for the screwworm fly and 2.3 Ma for the Australian sheep blowfly. Varying population histories were observed for the blowfly Chrysomya megacephala and the housefly Musca domestica samples in our dataset. Whereas blowflies (n = 50) appear to have undergone selective sweeps and/or severe bottlenecks in the New World, houseflies (n = 14) display variation among populations from different zoogeographical zones and low levels of gene flow. The reported high-throughput mitogenomics approach for insects enables new insights into schizophoran diversity and population history of flies.


Health technology assessment in Denmark.
The Danish healthcare services are mainly provided by public sector institutions. The system is highly decentralized. The state has little direct influence on the provision of healthcare services. State influence is exercised through legislation and budget allocations. The main task of the state is to initiate, coordinate, and advise. Counties, which run the hospitals, also decide on the placement of services. The hospital sector is controlled within the framework of legislation and global budgets. General practitioners occupy a central position in the Danish healthcare sector, acting as gatekeepers to the rest of the system. The system works well, and its structure has resulted in steady costs of health care for a long period. There is no regulatory mechanism in the Danish health services requiring use of health technology assessment (HTA) as a basis for policy decisions, planning, or administrative procedures. However, since the late 1970s a number of comprehensive assessments of health technology have formed the basis for national health policy decisions. In 1997, after years of public criticism of the quality of hospital care and health technologies, and on the basis of a previously developed national HTA strategy, a national institute for HTA (DIHTA) was established. There seems to be a growing awareness of evidence-based healthcare among health professionals and a general acceptance of health economic analyses as a basis for health policy decision making. This progress is coupled with growing regional HTA activity in the health services. HTA seems to have a bright future in Denmark.


More replenishment than priming loss of soil organic carbon with additional carbon input.
Increases in carbon (C) inputs to soil can replenish soil organic C (SOC) through various mechanisms. However, recent studies have suggested that the increased C input can also stimulate the decomposition of old SOC via priming. Whether the loss of old SOC by priming can override C replenishment has not been rigorously examined. Here we show, through data-model synthesis, that the magnitude of replenishment is greater than that of priming, resulting in a net increase in SOC by a mean of 32% of the added new C. The magnitude of the net increase in SOC is positively correlated with the nitrogen-to-C ratio of the added substrates. Additionally, model evaluation indicates that a two-pool interactive model is a parsimonious model to represent the SOC decomposition with priming and replenishment. Our findings suggest that increasing C input to soils likely promote SOC accumulation despite the enhanced decomposition of old C via priming.


Cyclosporine produces endothelial dysfunction by increased production of superoxide.
Vasoconstriction and hypertension are major side effects of cyclosporine therapy. The mechanism or mechanisms responsible for the vascular effects of cyclosporine are unclear. The vascular effects of cyclosporine may arise as a consequence of endothelial dysfunction induced by the agent. To test this possibility, we compared in vessels prepared in myographs endothelium-mediated relaxations of mesenteric resistance arteries of Wistar-Kyoto rats treated for 21 to 28 days with subcutaneous injections of cyclosporine (25 mg/kg per day), or vehicle. Endothelium-dependent relaxations in response to acetylcholine were impaired in arteries from cyclosporine-treated rats; the concentrations of acetylcholine required to produce 50% relaxation of norepinephrine activation (pD2) were 31.6 +/- 0.1 versus 5 +/- 0.1 nmol/L in control arteries (P < .05). Nitro-L-arginine produced comparable 10-fold decreases in sensitivity to acetylcholine in arteries from both rat groups, indicating that the relaxations were mediated by endothelium-derived nitric oxide. Acetylcholine-induced relaxations in cyclosporine-treated arteries were normalized by pretreatment of the arteries with superoxide dismutase (150 IU/mL; pD2, 3.6 +/- 0.1; P < .05); superoxide dismutase had no effect on relaxations in control arteries. SQ 29,548, an inhibitor of prostaglandin H2/thromboxane A2 receptors; H-7, an inhibitor of protein kinase C; and indomethacin did not alter relaxations in response to acetylcholine in either group of arteries. Cyclosporine-treated arteries were more sensitive than control arteries to nitroprusside, an agent that induces relaxation via nitric oxide (pD2, 1.3 and 6.2 mumol/L, respectively; P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)


Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation.
A substantial proportion of patients receiving fibrinolytic therapy for myocardial infarction with ST-segment elevation have inadequate reperfusion or reocclusion of the infarct-related artery, leading to an increased risk of complications and death. We enrolled 3491 patients, 18 to 75 years of age, who presented within 12 hours after the onset of an ST-elevation myocardial infarction and randomly assigned them to receive clopidogrel (300-mg loading dose, followed by 75 mg once daily) or placebo. Patients received a fibrinolytic agent, aspirin, and when appropriate, heparin (dispensed according to body weight) and were scheduled to undergo angiography 48 to 192 hours after the start of study medication. The primary efficacy end point was a composite of an occluded infarct-related artery (defined by a Thrombolysis in Myocardial Infarction flow grade of 0 or 1) on angiography or death or recurrent myocardial infarction before angiography. The rates of the primary efficacy end point were 21.7 percent in the placebo group and 15.0 percent in the clopidogrel group, representing an absolute reduction of 6.7 percentage points in the rate and a 36 percent reduction in the odds of the end point with clopidogrel therapy (95 percent confidence interval, 24 to 47 percent; P<0.001). By 30 days, clopidogrel therapy reduced the odds of the composite end point of death from cardiovascular causes, recurrent myocardial infarction, or recurrent ischemia leading to the need for urgent revascularization by 20 percent (from 14.1 to 11.6 percent, P=0.03). The rates of major bleeding and intracranial hemorrhage were similar in the two groups. In patients 75 years of age or younger who have myocardial infarction with ST-segment elevation and who receive aspirin and a standard fibrinolytic regimen, the addition of clopidogrel improves the patency rate of the infarct-related artery and reduces ischemic complications.


Shocking revelations and saccharin sweetness in the study of Drosophila olfactory memory.
It is now almost forty years since the first description of learning in the fruit fly Drosophila melanogaster. Various incarnations of the classic mutagenesis approach envisaged in the early days have provided around one hundred learning defective mutant fly strains. Recent technological advances permit temporal control of neural function in the behaving fly. These approaches have radically changed experiments in the field and have provided a neural circuit perspective of memory formation, consolidation and retrieval. Combining neural perturbations with more classical mutant intervention allows investigators to interrogate the molecular and cellular processes of memory within the defined neural circuits. Here, we summarize some of the progress made in the last ten years that indicates a remarkable conservation of the neural mechanisms of memory formation between flies and mammals. We emphasize that considering an ethologically-relevant viewpoint might provide additional experimental power in studies of Drosophila memory.


Dietary and lifestyle factors and risk of non-hodgkin's lymphoma in Oman.
The incidence of various types of cancers including the non-Hodgkin's lymphoma (NHL) has increased during the recent years. Diet and lifestyle factors have been reported to play an important role in the etiology of NHL. However, no such data are available from the Middle Eastern countries, including Oman. Forty-three histologically confirmed cases of non-Hodgkin's lymphoma (NHL) diagnosed at the Sultan Qaboos University Hospital (SQUH) and the Royal Hospital (RH), Muscat, Oman and forty-three age and gender matched controls were the subjects of this study. Frequency matching was used to select the control population. Information on social and demographic data as well as the dietary intake was collected by personal interviews, using a 117-items semi-quantitative food frequency questionnaire. A non-significant increased risk of NHL was observed with higher body mass index (BMI) (OR=1.20, 95%CI: 0.45, 2.93), whereas a significantly decreased risk of NHL was associated with a higher educational level (OR=0.12, 95%CI: 0.03, 0.53). A significantly increased risk was observed for higher intake of energy (OR=2.67, 95%CI: 0.94, 7.57), protein (OR=1.49, 95%CI: 0.54, 4.10) and carbohydrates (OR=5.32, 95%CI: 1.78, 15.86). Higher consumption of daily servings from cereals (OR=3.25, 95%CI: 0.87, 12.09) and meat groups (OR=1.55, 95%CI: 0.58, 4.15) were also found to be associated with risk of NHL, whereas a significantly reduced risk was associated with higher consumption of vegetables (OR=0.24, 95%CI: 0.07, 0.82). The consumption of fruits, milk and dairy products however showed no significant association with the risk of developing NHL. The results suggest that obesity, high caloric intake, higher consumption of carbohydrate and protein are associated with increased risk of NHL, whereas a significantly reduced risk was observed with higher intake of vegetables.


Hydrodynamic investigation of USP dissolution test apparatus II.
The USP Apparatus II is the device commonly used to conduct dissolution testing in the pharmaceutical industry. Despite its widespread use, dissolution testing remains susceptible to significant error and test failures, and limited information is available on the hydrodynamics of this apparatus. In this work, laser-Doppler velocimetry (LDV) and computational fluid dynamics (CFD) were used, respectively, to experimentally map and computationally predict the velocity distribution inside a standard USP Apparatus II under the typical operating conditions mandated by the dissolution test procedure. The flow in the apparatus is strongly dominated by the tangential component of the velocity. Secondary flows consist of an upper and lower recirculation loop in the vertical plane, above and below the impeller, respectively. A low recirculation zone was observed in the lower part of the hemispherical vessel bottom where the tablet dissolution process takes place. The radial and axial velocities in the region just below the impeller were found to be very small. This is the most critical region of the apparatus since the dissolving tablet will likely be at this location during the dissolution test. The velocities in this region change significantly over short distances along the vessel bottom. This implies that small variations in the location of the tablet on the vessel bottom caused by the randomness of the tablet descent through the liquid are likely to result in significantly different velocities and velocity gradients near the tablet. This is likely to introduce variability in the test.


Women's educational attainment and intergenerational patterns of fertility behaviour in Kenya.
There is a strong theoretical and empirical relationship between educational attainment and fertility behaviour. However, a fundamental issue that has largely been neglected is the change in this relationship across cohorts resulting from differential improvement in educational opportunities for women over time and how it relates to fertility transition. Utilizing the 1998 DHS data from Kenya this study examines the differential effect of educational attainment on women's use of modern contraception and desire for cessation of childbearing across generations. The findings indicate that even after controlling for husband's education and other relevant factors, a woman's advanced education is positively associated with use of modern contraception. However, support for a similar hypothesis on a woman's desire for family limitation was only found among the youngest cohort of women. The results suggest that for Kenya's incipient fertility transition to be sustained the government needs to continue efforts to improve female education and support access to family planning among younger women.


A systematic review of prognostic factors predicting survival in patients with spinal bone metastases.
For the selection of treatment in patients with spinal bone metastases (SBM), survival estimation plays a crucial role to avoid over- and under-treatment. To aid clinicians in this difficult task, several prediction models have been developed, consisting of many different risk factors. The aim of this systematic review was to identify prognostic factors that are associated with survival in patients with SBM to support development of predictive models. A systematic review was performed with focus on prognostic factors associated with survival in patients with SBM. Two reviewers independently selected studies for inclusion and assessed the risk of bias. A level of evidence synthesis was performed for each prognostic factor. Inter-observer agreement for the risk of bias assessment was determined by the kappa-statistic. After screening, 142 full-text articles were obtained, of which 22 met the eligibility criteria. A total of 43 different prognostic factors were investigated in the included studies, of which 17 were relevant to pre-treatment survival estimation. The prognostic factors most frequently associated with survival were the primary tumor and the performance status. The prognostic factors most frequently not associated with survival were age, gender, number and location of the SBM and the presence of a pathologic fracture. Prognostication for patients with SBM should be based on an accurate primary tumor classification, combined with a performance score. The benefit of adding other prognostic factors is doubtful.


Pollination efficiency and the evolution of specialized deceptive pollination systems.
The ultimate causes of evolution of highly specialized pollination systems are little understood. We investigated the relationship between specialization and pollination efficiency, defined as the proportion of pollinated flowers relative to those that experienced pollen removal, using orchids with different pollination strategies as a model system. Rewarding orchids showed the highest pollination efficiency. Sexually deceptive orchids had comparably high pollination efficiency, but food-deceptive orchids had significantly lower efficiency. Values for pollinator sharing (a measure of the degree of generalization in pollination systems) showed the reverse pattern, in that groups with high pollination efficiency had low values of pollinator sharing. Low pollinator sharing may thus be the basis for efficient pollination. Population genetic data indicated that both food- and sexually deceptive species have higher degrees of among-population gene flow than do rewarding orchids. Thus, the shift from food to sexual deception may be driven by selection for more efficient pollination, without compromising the high levels of gene flow that are characteristic of deceptive species.


Mapping of HKT1;5 Gene in Barley Using GWAS Approach and Its Implication in Salt Tolerance Mechanism.
Sodium (Na+) accumulation in the cytosol will result in ion homeostasis imbalance and toxicity of transpiring leaves. Studies of salinity tolerance in the diploid wheat ancestor Triticum monococcum showed that HKT1;5-like gene was a major gene in the QTL for salt tolerance, named Nax2. In the present study, we were interested in investigating the molecular mechanisms underpinning the role of the HKT1;5 gene in salt tolerance in barley (Hordeum vulgare). A USDA mini-core collection of 2,671 barley lines, part of a field trial was screened for salinity tolerance, and a Genome Wide Association Study (GWAS) was performed. Our results showed important SNPs that are correlated with salt tolerance that mapped to a region where HKT1;5 ion transporter located on chromosome four. Furthermore, sodium (Na+) and potassium (K+) content analysis revealed that tolerant lines accumulate more sodium in roots and leaf sheaths, than in the sensitive ones. In contrast, sodium concentration was reduced in leaf blades of the tolerant lines under salt stress. In the absence of NaCl, the concentration of Na+ and K+ were the same in the roots, leaf sheaths and leaf blades between the tolerant and the sensitive lines. In order to study the molecular mechanism behind that, alleles of the HKT1;5 gene from five tolerant and five sensitive barley lines were cloned and sequenced. Sequence analysis did not show the presence of any polymorphism that distinguishes between the tolerant and sensitive alleles. Our real-time RT-PCR experiments, showed that the expression of HKT1;5 gene in roots of the tolerant line was significantly induced after challenging the plants with salt stress. In contrast, in leaf sheaths the expression was decreased after salt treatment. In sensitive lines, there was no difference in the expression of HKT1;5 gene in leaf sheath under control and saline conditions, while a slight increase in the expression was observed in roots after salt treatment. These results provide stronger evidence that HKT1;5 gene in barley play a key role in withdrawing Na+ from the xylem and therefore reducing its transport to leaves. Given all that, these data support the hypothesis that HKT1;5 gene is responsible for Na+ unloading to the xylem and controlling its distribution in the shoots, which provide new insight into the understanding of this QTL for salinity tolerance in barley.


Exponentially fragile PT symmetry in lattices with localized eigenmodes.
We study the effect of localized modes in lattices of size N with parity-time (PT) symmetry. Such modes are arranged in pairs of quasidegenerate levels with splitting delta approximately exp(-N/xi) where xi is their localization length. The level "evolution" with respect to the PT breaking parameter gamma shows a cascade of bifurcations during which a pair of real levels becomes complex. The spontaneous PT symmetry breaking occurs at gammaPT approximately min{delta}, thus resulting in an exponentially narrow exact PT phase. As N/xi decreases, it becomes more robust with gammaPT approximately 1/N2 and the distribution P(gammaPT) changes from log-normal to semi-Gaussian. Our theory can be tested in the frame of optical lattices.


I want to lie about not knowing you, but my precuneus refuses to cooperate.
Previously identified neural correlates of deception, such as the prefrontal, anterior cingulate, and parietal regions, have proven to be unreliable neural markers of deception, most likely because activity in these regions reflects executive processes that are not specific to deception. Herein, we report the first fMRI study that provides strong preliminary evidence that the neural activity associated with perception but not executive processes could offer a better marker of deception with regard to face familiarity. Using a face-recognition task, activity in the left precuneus during the perception of familiar faces accurately marked 11 of 13 subjects who lied about not knowing faces that were in fact familiar to them. This level of classification accuracy is much higher than the level predicted by chance and agrees with other findings by experts in lie detection.


Effect of surfactants and drug load on physico-mechanical and dissolution properties of nanocrystalline tadalafil-loaded oral films.
The aim of the present work was to prepare tadalafil (TDF) nanocrystals-loaded oral polymeric films (OFs) and investigate the effect of hydrophilic surfactants and drug loads on the physico-mechanical and dissolution properties. The nanosuspensions of TDF were prepared by high shear homogenization. HPMC based placebo casting film gel was prepared and mixed with TDF nanosuspensions. Films were casted using an automated film applicator and dried at 60°C for 45min. Particle size (PS), polydispersity index (PDI), and zeta potential (ZP) of TDF nanosuspensions were measured in a Zetasizer. The films were characterized using SEM, AFM, DSC, TGA and PXRD. The mechanical properties and in vitro drug release were determined using standard methods. TDF existed in crystalline form and the particles remained in the nano-range in redispersed films. TDF nanocrystals were embedded in the polymeric matrix and the drug loaded films were rough on the surface. Mechanical properties of the films varied with changes in drug load and surfactant. Significant changes in the disintegration times were noticed in films containing surfactants compared to surfactant-free films. About 80% of the drug release was observed between 3 and 30min. TPGS showed better TDF release from the films at different drug loads. Hydroxy propyl methyl cellulose (PubChem CID: 57503849); Glycerol (PubChem CID: 753); Pluronic F-68 (PubChem CID: 24751); Vitamin E TPGS (PubChem CID: 71406).


The Role of the Gut Microbiota in Colorectal Cancer Causation.
Here, we reviewed emerging evidence on the role of the microbial community in colorectal carcinogenesis. A healthy gut microbiota promotes intestinal homeostasis and can exert anti-cancer effects; however, this microbiota also produces a variety of metabolites that are genotoxic and which can negatively influence epithelial cell behaviour. Disturbances in the normal microbial balance, known as dysbiosis, are frequently observed in colorectal cancer (CRC) patients. Microbial species linked to CRC include certain strains of Bacteroides fragilis, Escherichia coli, Streptococcus gallolyticus, Enterococcus faecalis and Fusobacterium nucleatum, amongst others. Whether these microbes are merely passive dwellers exploiting the tumour environment, or rather, active protagonists in the carcinogenic process is the subject of much research. The incidence of chemically-induced tumours in mice models varies, depending upon the presence or absence of these microorganisms, thus strongly suggesting influences on disease causation. Putative mechanistic explanations differentially link these strains to DNA damage, inflammation, aberrant cell behaviour and immune suppression. In the future, modulating the composition and metabolic activity of this microbial community may have a role in prevention and therapy.


Birth-cohort effects in the association between personality and fertility.
The present study investigated whether associations between individuals' personality traits and whether they have children have been modified by birth-cohort effects in the 20th-century United States. Participants were from the Midlife Development in the United States study (n = 6,259) and the Wisconsin Longitudinal Study (n = 3,994) and were born between 1914 and 1974. Data on personality traits of the Five Factor model and fertility history were collected in adulthood. Higher levels of openness to experience in both sexes and higher levels of conscientiousness in women were associated with lower fertility, and these associations strengthened linearly as birth cohorts became younger. In the total sample, high extraversion, low neuroticism, and women's high agreeableness were associated with high fertility rate, but there were no systematic cohort effects. The fertility decisions of people with certain personality traits may be influenced by prevailing societal and cultural circumstances.


Factors affecting older adults' use of adaptive equipment: review of the literature.
The purpose of this review was to identify the major findings of published research on the factors influencing older adults' use of adaptive equipment. Fourteen studies involving an older adult sample were selected from major electronic bibliographic databases searched with a series of key words related to aging and equipment use. Results of these studies were compared to determine the most common factors influencing the use of adaptive equipment among older adults. Although the reviewed studies varied in their sampling strategies and designs, many results were similar. Between 47% and 82% of prescribed equipment continues to be used by older adults, with use decreasing over time. Findings from published studies show that equipment suitability, adequate training, and pre-prescription home visits contribute to these rates of use. Lack of fit among the person, his or her environment, and the equipment was the primary reason identified for nonuse. The results of the published research provide practicing occupational therapists with a range of factors to consider when prescribing adaptive equipment to older adults. Although the findings of this review demonstrate remarkable consistency across existing research findings, future research is needed to identify what constitutes optimal device use, what factors provide personal motivation for using assistive devices, and how home visits influence use.


Carbohydrates and cancer: an overview of the epidemiological evidence.
To assess the epidemiological evidence on dietary carbohydrates and the risk of developing cancer. Review of published studies, concentrating on recent systematic reviews, meta-analyses and large prospective studies. Carbohydrates have not been intensively investigated in epidemiological studies of diet and cancer. There is a moderately large amount of data on the possible association between dietary fibre and the risk for colorectal cancer; the results of studies have varied and no firm conclusion can be drawn, but the available data suggest that high intakes of dietary fibre possibly reduce the risk for colorectal cancer. There are also limited data which suggest that high intakes of sucrose might increase the risk for colorectal cancer and that high intakes of lactose might increase the risk for ovarian cancer. For other components of carbohydrates and other types of cancer, the available data are too sparse to draw even tentative conclusions. Further research is needed on the possible associations of carbohydrates with cancer risk.


Consultation and remediation in the north: meeting international commitments to safeguard health and well-being.
International commitments exist for the safeguarding of health and the prevention of ill health. One of the earliest commitments is the Declaration of Alma-Ata (1978), which provides 5 principles guiding primary health care: equity, community participation, health promotion, intersectoral collaboration and appropriate technology. These broadly applicable international commitments are premised on the World Health Organization's multifaceted definition of health. The environment is one sector in which these commitments to safeguarding health can be applied. Giant Mine, a contaminated former gold mine in the Northwest Territories, Canada, represents potential threats to all aspects of health. Strategies for managing such threats usually involve an obligation to engage the affected communities through consultation. To examine the remediation and consultation process associated with Giant Mine within the context of commitments to safeguard health and well-being through adapting and applying the principles of primary health care. Semi-structured interviews with purposively selected key informants representing government proponents and community members were conducted. in reviewing themes which emerged from a series of interviews exploring the community consultation process for the remediation of Giant Mine, the principles guiding primary health were mapped to CONSULTATION IN the North: (a) "equity" is the capacity to fairly and meaningfully participate in the consultation; (b) "community participation" is the right to engage in the process through reciprocal dialogue; (c) "health promotion" represents the need for continued information sharing towards awareness; (d) "intersectoral collaboration" signifies the importance of including all stakeholders; and (e) "appropriate technology" is the need to employ the best remediation actions relevant to the site and the community. Within the context of mining remediation, these principles form an appropriate framework for viewing consultation as a means of meeting international obligations to safeguard health.


Recent advances in sleep-wake cycle and biological rhythms in bipolar disorder.
The cyclical nature of periodic switches in energy, motor activation and sleep-wake cycles in bipolar disorder suggests a strong underlying relationship with disturbances in chronobiology. Current research is refining our understanding of the various patterns of sleep-wake and biological rhythms alterations at early and later stages of this illness, as well as across its depressive/fatigue, manic/hypomanic and euthymic phases. This research focuses on early detection and subsequent monitoring to predict and better manage recurrent episodes. Sleep-wake cycle and biological rhythms disturbances are also well known to affect other key aspects of physical health (notably metabolic functions), cognitive performance and elevated risks for suicide. Increasing evidence now supports the integration of behavioural or pharmacological therapeutic strategies that target the sleep-wake and circadian systems in the ongoing treatment of various phases of bipolar disorder.


Population pharmacokinetics of theophylline. III. Premarketing study for a once-daily administered preparation.
The population pharmacokinetic parameters for a once-daily administered preparation, Uniphyl were estimated from data collected in the premarketing clinical trial. Altogether, 2772 serum theophylline concentrations were obtained from 131 normal subjects and 306 patients suffering from chronic asthma or chronic obstructive pulmonary disease who participated in the phase I, II, and III clinical trials in Japan. The serum concentration profile was described by a linear one-compartment model with first-order absorption. The factors affecting the pharmacokinetics of this drug were examined by the likelihood ratio test using a nonlinear mixed effect model (NONMEM). The first-order absorption rate constant (Ka) for a 200-mg tablet in a fasting condition was obtained as 0.0773 (1/h), which was smaller than the elimination rate constant (0.168 1/h), indicating the flip-flop characteristic of this preparation. Food indigestion increased the Ka by 17% and the absorption lag time by 5-fold but did not affect the extent of absorption. The 400-mg tablet showed a Ka value 19%, smaller than the 200-mg tablet. Children not older than 15 years showed 58% longer absorption lag time. The inter-individual variability in Ka was 19%, suggesting small variability in the vivo release process. The total body clearance was related to hepatic function, smoking habits, and age. Furthermore, clearance decreased in association with the severity of illness. The findings obtained here are useful not only for the initial dosage adjustment for patients with a variety of backgrounds but also for doses individualization based on serum concentration monitoring with or without the Bayesian feedback method.


Diagnosis at dusk: malignant hypertension and phaeochromocytoma in a 6-year-old girl.
Phaeochromocytoma is a rare catecholamine-secreting tumour that may arise at any age, but is particularly unusual in childhood. The case of a 6-year-old girl who presented with a prolonged history of general malaise, headaches and abdominal pain is reported. On examination, she was noted to have malignant hypertension. Subsequent imaging of the abdomen demonstrated a left adrenal mass, with the diagnosis of phaeochromocytoma being confirmed by serial raised urinary metanephrines. Sympathetic blockade was established prior to definitive surgical treatment, resulting in complete resolution of the patient's symptoms and hypertension. Genetic screening of the family has since identified a previously undocumented missense mutation in the patient's VHL gene. The case raises the importance of routine measurement of blood pressure in all paediatric patients regardless of age, presentation or other factors.


Deciphering highly similar multigene family transcripts from Iso-Seq data with IsoCon.
A significant portion of genes in vertebrate genomes belongs to multigene families, with each family containing several gene copies whose presence/absence, as well as isoform structure, can be highly variable across individuals. Existing de novo techniques for assaying the sequences of such highly-similar gene families fall short of reconstructing end-to-end transcripts with nucleotide-level precision or assigning alternatively spliced transcripts to their respective gene copies. We present IsoCon, a high-precision method using long PacBio Iso-Seq reads to tackle this challenge. We apply IsoCon to nine Y chromosome ampliconic gene families and show that it outperforms existing methods on both experimental and simulated data. IsoCon has allowed us to detect an unprecedented number of novel isoforms and has opened the door for unraveling the structure of many multigene families and gaining a deeper understanding of genome evolution and human diseases.


Steroid modulation of the chloride ionophore in rat brain: structure-activity requirements, regional dependence and mechanism of action.
Further in vitro studies of steroids active at the gamma-aminobutyric acidA (GABAA) receptor regulated Cl- channel labeled by [35S]-t-butylbicyclophosphorothionate ([35S]TBPS) reveal additional structural requirements necessary for activity. Evaluation of selected steroids for activity against TBPS-induced convulsions show similar requirements for activity. Interestingly, steroids (e.g., 5 alpha-pregnan-3 alpha, 20 alpha-diol) were identified that have high potency but limited efficacy as modulators of [35S]TBPS binding. These characteristics are reminiscent of the clinically useful benzodiazepines (BZs) such as clonazepam. However, interactions between the prototypical anesthetic-barbiturate, sodium pentobarbital, and steroids active at the Cl- channel suggest that they do not share a common site of action as allosteric modulators of [35S]TBPS and BZ receptor binding. The most potent steroid evaluated, 5 alpha-pregnan-3 alpha-ol-20-one, modulates [35S]TBPS binding at low concentrations (IC50 approximately 17 nM) in a regionally dependent manner. All [35S]TBPS binding sites appear to be functionally coupled to a steroid "modulatory site." Because several of the active steroids are metabolites of progesterone, their ability to inhibit the binding of [3H]promegestrone to the cytosolic progestin receptor in rat uterus was evaluated. Those steroids showing potent activity at the GABAA receptor-Cl- ionophore were inactive at the intracellular progestin receptor. Such specificity coupled with their high potency provide additional support for the hypothesis that some of these steroids may be involved in the homeostatic regulation of brain excitability via the GABAA-BZ receptor complex.


Single-walled carbon nanotubes as optical probes for bio-sensing and imaging.
The unique physical properties of single-walled carbon nanotubes (SWCNTs) have been exploited in novel applications in various fields including electronics and life sciences. Their photoluminescence in the near-infrared (NIR) range, where optical interference from biological tissues is minimum, has rendered them particularly attractive as optical probes in biological environments. Herein we review the use of the SWCNT NIR emission in bio-sensing and imaging. To interface the insoluble carbon nanotubes with an aqueous biological environment, biomaterials and organic polymers have been widely used for non-covalently functionalizing SWCNTs. Such functionalization minimizes the toxicity of carbon nanotubes in biological and physiological environments, while maintaining their optical properties. SWCNTs have been demonstrated as both in vitro and in vivo optical sensors, targeting biologically important molecules, such as neurotransmitters and cell signaling molecules. For optical imaging, functionalized SWCNTs were used as NIR contrast agents for probing cellular processes and imaging plants and small animals. We also discuss emerging SWCNT-based super-resolution schemes. We conclude that SWCNTs are promising optical materials for basic life science research, biomedical diagnostics, and therapeutics.


Aerobic exercise training in Kartagener's syndrome: case report.
Kartagener's syndrome is a rare, autosomal recessive inherited disease, which is characterized by a triad of chronic sinusitis, bronchiectasis, and situs inversus. In this report, we aimed to represent the effect of aerobic exercise training in addition to chest physiotherapy in an outpatient with Kartagener's syndrome. An 18-year-old female diagnosed with Kartagener's syndrome applied with the complaints of productive cough and dyspnea with exertion and attended pulmonary rehabilitation program comprising exercise training in addition to standard treatment. Aerobic exercise training was performed three times weekly at 80% of the peak heart rate, for 8 weeks as supervised sessions. Respiratory physiotherapy and postural exercises were taught to the patient to be performed at home each day of the week. Before and after pulmonary rehabilitation program, incremental shuttle walk test (ISWT) was performed; dyspnea and fatigue were assessed using Borg Scale. Pulmonary function test was evaluated using spirometer. The patient wore activity monitor for 7 consecutive days before and after training. After pulmonary rehabilitation program, 90-m increase in ISWT was observed. We recommend exercise training in patients with Kartagener's syndrome to increase exercise capacity. Further randomized control trial is needed to clarify the effects.


Direct gene delivery to synovium. An evaluation of potential vectors in vitro and in vivo.
To assess the abilities of various vectors to transfer genes to the synovial lining of joints. Vectors derived from retrovirus, adenovirus, and herpes simplex virus as well as cationic liposomes and naked plasmid DNA were evaluated. Each construct contained the lac Z marker gene; and one retroviral construct, and one plasmid also contained a gene encoding human interleukin-1 receptor antagonist. Gene expression was under the control of the human cytomegalovirus promoter in all vectors except the retrovirus, where the endogenous 5' long terminal repeat was retained as the promoter. Cultures of rabbit synovial fibroblasts were exposed to these vectors and stained with X-gal to identify lac Z+ cells. Vectors were then injected directly into rabbits' knee joints, and gene transfer and expression were assessed by X-gal staining and polymerase chain reaction (PCR). Adenovirus was a highly effective vector both in vitro and in vivo, with lac Z gene expression persisting for at least 28 days. However, an inflammatory response was noted in vivo. Cells infected in vitro and in vivo with herpes simplex virus also expressed the lac Z gene at high levels, but expression was limited by cytotoxicity. Retroviruses, in contrast, were effective only under in vitro conditions, permitting cell division. Liposomes gave variable in vitro results; when injected into joints in vivo, gene expression was low and was detectable for only a few days, even though a PCR signal persisted for at least 28 days. Unexpectedly, plasmid DNA was captured by the synoviocytes and expressed transiently following intraarticular injection. None of the vectors was ideal for in vivo gene delivery to synovium, although adenovirus was clearly the most effective of those tested. Retroviruses, although poor vectors for in vivo gene delivery, are well suited for ex vivo gene transfer to the synovial lining of joints.


Rapid restructuring of bicoid-dependent hunchback promoters within and between Dipteran species: implications for molecular coevolution.
Interacting genetic elements need to coevolve if their joint function is to be maintained; for example, the correct binding of transcriptional regulators to defined binding sites in gene promoters needs to be maintained during evolution to ensure proper function. As part of a wider investigation into the molecular coevolution of the Dipteran homeodomain-bearing regulator bicoid (bcd) and Bcd-dependent promoters, we present data on the functional, structural, and sequence differences between the promoters of the segmentation gene hunchback (hb), in several species of Cyclorrhaphan (higher) Diptera. The result of phenocopying hb mutations using RNA interference (RNAi) in Musca domestica shows broadly similar functions to the hb gene in Drosophila melanogaster. However, the Bcd-binding sites in the hb promoters of Drosophila, Musca, and the two blowfly species Lucilia sericata and Calliphora vicina differ in copy number, sequence, orientation, and spacing. Furthermore, all promoters are subject to rapid turnover by slippage-like processes leading to high densities of short repetitive motifs. A study of polymorphism among six strains of M. domestica reveals that turnover by slippage also occurs in the promoter, untranslated leader, and exonic coding sequences of hb, but to different extents. We discuss these results in terms of the known interspecific differences in bcdand the potential coevolution of selected compensatory mutations in trans and cis in response to continuous promoter restructuring.


The expression and regulation of chick EphA7 suggests roles in limb patterning and innervation.
Eph receptors and their ligands, the ephrins, have been implicated in early patterning and axon guidance in vertebrate embryos. Members of these families play pivotal roles in the formation of topographic maps in the central nervous system, the formation of brain commissures, and in the guidance of neural crest cells and motor axons through the anterior half of the somites. Here, we report a highly dynamic expression pattern of the chick EphA7 gene in the developing limb. Expression is detected in discrete domains of the dorsal mesenchyme from 3 days of incubation. The expressing cells are adjacent to the routes where axons grow to innervate the limb at several key points: the region of plexus formation, the bifurcation between dorsal and ventral fascicles, and the pathway followed by axons innervating the dorsal muscle mass. These results suggested a role for EphA7 in cell-cell contact-mediated signalling in dorsal limb patterning and/or axon guidance. We carried out experimental manipulations in the chick embryo wing bud to alter the dorsoventral patterning of the limb. The analyses of EphA7 expression and innervation in the operated wings indicate that a signal emanating from the dorsal ectoderm regulates EphA7 in such a way that, in its absence, the wing bud lacks EphA7 expression and shows innervation defects at the regions where the gene was downregulated. EphA7 downregulation in the dorsal mesenchyme after dorsal ectoderm removal is more rapid than that of Lmx-1, the gene known to mediate dorsalisation in response to the ectodermal signal. These results add a new gene to the dorsalisation signalling pathway in the limb. Moreover, they implicate the Eph receptor family in the patterning and innervation of the developing limb, extending its role in axon pathfinding to the distal periphery.


The outcome of mental health care users admitted under Section 40 of the South African Mental Health Care Act (No 17 of 2002).
To determine the outcomes of mental health care users (MHCU's) admitted in terms of Section 40 of the South African Mental Health Care Act (No 17 of 2002) (MHCA) and the factors, if any, that are associated with these outcomes. The study was a retrospective record review of MHCU's, 18 years and older, referred by the South African Police Service (SAPS) to Chris Hani Baragwanath Hospital (CHBH). All mental health care users handed over to CHBH by SAPS with completed MHCA form 22's during the period July 2007 to December 2007 were included in the study. The outcomes, demographics and clinical characteristics of these referrals were obtained from hospital records. During the six-month study period, 718 MHCU's were referred by members of SAPS to the CHBH Emergency Department. Associations were found between discharged MHCU's and i) being male, ii) being less than 35 years of age, iii) being unemployed, iv) having a lower level of education, v) having a past history of substance abuse and/or vi) a past psychiatric illness. Females were twice as likely to be unemployed and admitted to hospital (either to a psychiatric or general medical ward). MHCU's diagnosed with delirium were more likely to be admitted into a medical ward as compared to a psychiatric ward. As has been the case in most countries where police services have been incorporated into mental health acts, South Africa's new Mental Health Care Act (No 17 of 2002) has resulted in a large number of referrals by the police to mental health services. However, many of these referrals may not be necessary as most MHCU's end up not being admitted. The characteristics of police referrals suggest that the receiving facility should have the capacity to identify factors that favour outpatient care (especially substance abuse problems) and divert MHCU's presenting with such factors to appropriate treatment facilities without admitting them to the hospital.


Deep brain stimulation response in obsessive-compulsive disorder is associated with preoperative nucleus accumbens volume.
Deep brain stimulation (DBS) is a new treatment option for patients with therapy-resistant obsessive-compulsive disorder (OCD). Approximately 60% of patients benefit from DBS, which might be improved if a biomarker could identify patients who are likely to respond. Therefore, we evaluated the use of preoperative structural magnetic resonance imaging (MRI) in predicting treatment outcome for OCD patients on the group- and individual-level. In this retrospective study, we analyzed preoperative MRI data of a large cohort of patients who received DBS for OCD (n = 57). We used voxel-based morphometry to investigate whether grey matter (GM) or white matter (WM) volume surrounding the DBS electrode (nucleus accumbens (NAc), anterior thalamic radiation), and whole-brain GM/WM volume were associated with OCD severity and response status at 12-month follow-up. In addition, we performed machine learning analyses to predict treatment outcome at an individual-level and evaluated its performance using cross-validation. Larger preoperative left NAc volume was associated with lower OCD severity at 12-month follow-up (pFWE < 0.05). None of the individual-level regression/classification analyses exceeded chance-level performance. These results provide evidence that patients with larger NAc volumes show a better response to DBS, indicating that DBS success is partly determined by individual differences in brain anatomy. However, the results also indicate that structural MRI data alone does not provide sufficient information to guide clinical decision making at an individual level yet.


Parenteral and enteral metabolism of anaplerotic triheptanoin in normal rats. II. Effects on lipolysis, glucose production, and liver acyl-CoA profile.
The anaplerotic odd-medium-chain triglyceride triheptanoin is used in clinical trials for the chronic dietary treatment of patients with long-chain fatty acid oxidation disorders. We previously showed (Kinman RP, Kasumov T, Jobbins KA, Thomas KR, Adams JE, Brunengraber LN, Kutz G, Brewer WU, Roe CR, Brunengraber H. Am J Physiol Endocrinol Metab 291: E860-E866, 2006) that the intravenous infusion of triheptanoin increases lipolysis traced by the turnover of glycerol. In this study, we tested whether lipolysis induced by triheptanoin infusion is accompanied by the potentially harmful release of long-chain fatty acids. Rats were infused with heptanoate +/- glycerol or triheptanoin. Intravenous infusion of triheptanoin at 40% of caloric requirement markedly increased glycerol endogenous R(a) but not oleate endogenous R(a). Thus, the activation of lipolysis was balanced by fatty acid reesterification in the same cells. The liver acyl-CoA profile showed the accumulation of intermediates of heptanoate beta-oxidation and C(5)-ketogenesis and a decrease in free CoA but no evidence of metabolic perturbation of liver metabolism such as propionyl overload. Our data suggest that triheptanoin, administered either intravenously or intraduodenally, could be used for intensive care and nutritional support of metabolically decompensated long-chain fatty acid oxidation disorders.


Linear time-to-space mapping system using double electrooptic beam deflectors.
We propose and demonstrate a linear time-to-space mapping system, which is based on two times electrooptic sinusoidal beam deflection. The direction of each deflection is set to be mutually orthogonal with the relative deflection phase of pi/2 rad so that the circular optical beam trajectory can be achieved. The beam spot at the observation plane moves with an uniform velocity and as a result linear time-to-space mapping (an uniform temporal resolution through the mapping) can be realized. The proof-of-concept experiment are carried out and the temporal resolution of 5 ps has been demonstrated using traveling-wave type quasi-velosity-matched electrooptic beam deflectors. The developed system is expected to be applied to characterization of ultrafast optical signal or optical arbitrary waveform shaping for modulated microwave/millimeter-wave generation.


Electrospun Nanofibres Containing Antimicrobial Plant Extracts.
Over the last 10 years great research interest has been directed toward nanofibrous architectures produced by electrospinning bioactive plant extracts. The resulting structures possess antimicrobial, anti-inflammatory, and anti-oxidant activity, which are attractive for biomedical applications and food industry. This review describes the diverse approaches that have been developed to produce electrospun nanofibres that are able to deliver naturally-derived chemical compounds in a controlled way and to prevent their degradation. The efficacy of those composite nanofibres as wound dressings, scaffolds for tissue engineering, and active food packaging systems will be discussed.


Rescue Treatment with L-Citrulline Inhibits Hypoxia-Induced Pulmonary Hypertension in Newborn Pigs.
Infants with cardiopulmonary disorders associated with hypoxia develop pulmonary hypertension. We previously showed that initiation of oral L-citrulline before and continued throughout hypoxic exposure improves nitric oxide (NO) production and ameliorates pulmonary hypertension in newborn piglets. Rescue treatments, initiated after the onset of pulmonary hypertension, better approximate clinical strategies. Mechanisms by which L-citrulline improves NO production merit elucidation. The objective of this study was to determine whether starting L-citrulline after the onset of pulmonary hypertension inhibits disease progression and improves NO production by recoupling endothelial NO synthase (eNOS). Hypoxic and normoxic (control) piglets were studied. Some hypoxic piglets received oral L-citrulline starting on Day 3 of hypoxia and continuing throughout the remaining 7 days of hypoxic exposure. Catheters were placed for hemodynamic measurements, and pulmonary arteries were dissected to assess NO production and eNOS dimer-to-monomer ratios (a measure of eNOS coupling). Pulmonary vascular resistance was lower in L-citrulline-treated hypoxic piglets than in untreated hypoxic piglets but was higher than in normoxic controls. NO production and eNOS dimer-to-monomer ratios were greater in pulmonary arteries from L-citrulline-treated than from untreated hypoxic animals but were lower than in normoxic controls. When started after disease onset, oral L-citrulline treatment improves NO production by recoupling eNOS and inhibits the further development of chronic hypoxia-induced pulmonary hypertension in newborn piglets. Oral L-citrulline may be a novel strategy to halt or reverse pulmonary hypertension in infants suffering from cardiopulmonary conditions associated with hypoxia.


Intercomparison of recruitment maneuver efficacy in three models of acute lung injury.
To compare the relative efficacy of three forms of recruitment maneuvers in diverse models of acute lung injury characterized by differing pathoanatomy. We compared three recruiting maneuver (RM) techniques at three levels of post-RM positive end-expiratory pressure in three distinct porcine models of acute lung injury: oleic acid injury; injury induced purely by the mechanical stress of high-tidal airway pressures; and pneumococcal pneumonia. Laboratory in a clinical research facility. Twenty-eight anesthetized mixed-breed pigs (23.8 +/- 2.6 kg). The RM techniques tested were sustained inflation, extended sigh or incremental positive end-expiratory pressure, and pressure-controlled ventilation. Oxygenation and end-expiratory lung volume. The post-RM positive end-expiratory pressure level was the major determinant of post-maneuver PaO2, independent of the RM technique. The pressure-controlled ventilation RM caused a lasting increase of PaO2 in the ventilator-induced lung injury model, but in oleic acid injury and pneumococcal pneumonia, there were no sustained oxygenation differences for any RM technique (sustained inflation, incremental positive end-expiratory pressure, or pressure-controlled ventilation) that differed from raising positive end-expiratory pressure without RM. Recruitment by pressure-controlled ventilation is equivalent or superior to sustained inflation, with the same peak pressure in all tested models of acute lung injury, despite its lower mean airway pressure and reduced risk for hemodynamic compromise. Although RM may improve PaO2 in certain injury settings when traditional tidal volumes are used, sustained improvement depends on the post-RM positive end-expiratory pressure value.


Th2 regulation of viral myocarditis in mice: different roles for TLR3 versus TRIF in progression to chronic disease.
Viral infections are able to induce autoimmune inflammation in the heart. Here, we investigated the role of virus-activated Toll-like receptor (TLR)3 and its adaptor TRIF on the development of autoimmune coxsackievirus B3 (CVB3) myocarditis in mice. Although TLR3- or TRIF-deficient mice developed similarly worse acute CVB3 myocarditis and viral replication compared to control mice, disease was significantly worse in TRIF compared to TLR3-deficient mice. Interestingly, TLR3-deficient mice developed an interleukin (IL)-4-dominant T helper (Th)2 response during acute CVB3 myocarditis with elevated markers of alternative activation, while TRIF-deficient mice elevated the Th2-associated cytokine IL-33. Treatment of TLR3-deficient mice with recombinant IL-33 improved heart function indicating that elevated IL-33 in the context of a classic Th2-driven response protects against autoimmune heart disease. We show for the first time that TLR3 versus TRIF deficiency results in different Th2 responses that uniquely influence the progression to chronic myocarditis.


Biological interactions of CYP2C19 genotypes with CYP3A4*18, CYP3A5*3, and MDR1-3435 in living donor liver transplantation recipients.
Polymorphisms in CYP2C19 are related to the metabolic oxidation of drugs to varying degrees. The CYP3A4*18, CYP3A5*3, and MDR1-3435 variant alleles are very important, particularly in tacrolimus metabolism in organ transplant rejection. The aim of this study is o explore possible interactions among different CYP2C19 genotypes, namely, between homozygous extensive metabolizers (HomEM), heterozygous extensive metabolizers (HetEM), and poor metabolizers (PM), and the CYP3A4*18, CYP3A5*3, and MDR1-3435 variants in living donors and patients who received a living donor liver transplant (LDLT). This prospective study enrolled 133 living donors and 133 corresponding recipients. On the basis of the HomEM, HetEM, and PM CYP2C19 genotypes, the distributions of CYP3A4*18 (exon 10; T878C), CYP3A5*3 (intron 3; A6986G), and MDR1-3435 (exon 26; C3435T) genotypes were analyzed for single nucleotide polymorphisms among donors and recipients. Among 102 HomEM genotypes, including 56 donors and 46 recipients, 91.2% of individuals harbored the T/T genotype of CYP3A4*18; 53.9% possessed G/G, and 34.3% had A/G genotypes of CYP3A5*3; and 38.2% had C/C and 50.0% had C/T genotypes at MDR1-3435. Among 130 HetEM genotypes, including 58 donors and 72 recipients, 97.7% of individuals possessed T/T genotype at CYP3A4*18; 50.0% harbored G/G and 41.5% had A/G genotypes at CYP3A5*3; and 40.0% had C/C and 49.2% had C/T genotypes at MDR1-3435. In 34 PMs, including 19 donors and 15 recipients, 88.2% had T/T genotypes at CYP3A4*18; 41.2% had G/G and 58.8% had A/G genotypes at CYP3A5*3; and 47.1% possessed C/C and 47.1% had C/T genotypes at MDR1-3435. On the basis of the CYP2C19 genotypes, no statistically significant distribution of genotypes were observed between donors and recipients for all genotypes of CYP3A4*18, CYP3A5*3, and MDR1-3435 (P >0.05). In conclusion, the CYP2C19 genotypes do not affect the expression of CYP3A4*18, CYP3A5*3, or MDR1-3435 variants, which are independently distributed among donors and recipients during LDLT.


Source of stress in women junior house officers.
To determine the causes of stress in women doctors and relate these to levels of depression. Questionnaire study. Of 92 women doctors who had graduated from the universities of Leeds, Manchester, and Sheffield in 1986 and had been working as junior house officers for eight months 70 (76%) returned completed questionnaires. Mean score on the general health questionnaire was 13.79 (SD 5.20) and on the symptom checklist for depression was 1.43 (0.83). The scores of 32 subjects (46%) were above the criterion for clinical depression. Overwork was perceived as creating the most strain, followed by effects on personal life, serious failures of treatment, and talking to distressed relatives. Both stress and depression were related to effects on personal life, overwork, relations with consultants, and making decisions. Sex related sources of stress were conflicts between career and personal life, sexual harassment at work, a lack of female role models, and prejudice from patients. In addition to these, discrimination by senior doctors was related to depression. Changes are needed in the career paths of women doctors, and could be implemented.


The state-of-play and future of platinum drugs.
The year 2015 marks the 50th anniversary since the discovery of the anticancer potential of cisplatin and it remains just as useful now as it did back then, especially for the treatment of some endocrine-related cancers like ovarian and testicular carcinomas. Since its discovery, five other platin drugs have received approval in various countries. While several new platin drugs are in preclinical development, in the last decade only two new platin drugs have entered clinical trials, LA-12 and dicycloplatin, reflecting a shift in research focus from new drug design to improved formulations of already approved platin drugs. These formulations include their encapsulation with macrocycles to slow and prevent their degradation by proteins and peptides; their attachment to nanoparticles to passively target solid tumours through the enhanced permeability and retention effect and their coordination to important nutrients, proteins, antibodies and aptamers for active tumour targeting. These formulation methods have all shown potential but none have yet yielded a new marketable medicine containing a platin drug. The reasons for this are problems of consistent drug loading, controlling the location and timing of drug release and the inherent toxicity of some of the drug delivery vehicles. In addition to drug delivery, functional genomics is now playing an increasing role in predicting patients' responses to platin chemotherapy and their likelihood of experiencing severe side effects.


Single-molecule photophysics, from cryogenic to ambient conditions.
We review recent progress in characterizing and understanding the photophysics of single molecules in condensed matter, mostly at cryogenic temperatures. We discuss the central role of the triplet state in limiting the number of useful host-guest systems, notably a new channel, intermolecular intersystem crossing. Another important limitation to the use of single molecules is their photo-reactivity, leading to blinking of the fluorescence signal, and eventually to its loss by photo-bleaching. These processes are at the heart of modern super-resolution schemes. We then examine some of the new host-guest systems recently discovered following these general principles, and the mechanisms of spectral diffusion and dephasing that they have revealed. When charges are injected into organic conductors, they get trapped and influence single molecules via the local fields they create in the material, and via their coupling to localized vibrations. Understanding these processes is necessary for better control of spectral diffusion and dephasing of single molecules. We finally conclude by giving some outlook on future directions of this fascinating field.