Pathology review of proliferative lesions of the exocrine pancreas in two chronic feeding studies in rats with ammonium perfluorooctanoate.
Two chronic dietary studies, conducted years apart, with ammonium perfluorooctanoate (APFO) in Sprague Dawley rats have been previously reported. Although both included male 300 ppm dietary dose groups, only the later study, conducted in 1990-1992 by Biegel et al., reported an increase in proliferative lesions (hyperplasia and adenoma) of the acinar pancreas. An assessment of the significance of the differences between both studies requires careful consideration of: the diagnostic criteria for proliferative acinar cell lesions of the rat pancreas (for example, the diagnosis of pancreatic acinar cell hyperplasia versus adenoma is based on the two-dimensional size of the lesion rather than distinct morphological differences); the basis for those criteria in light of their relevance to biological behavior; and the potential diagnostic variability between individual pathologists for difficult-to-classify lesions. A pathology peer review of male exocrine pancreatic tissues from the earlier study, conducted in 1981-1983 by Butenhoff et al., was undertaken. This review identified an increase in acinar cell hyperplasia but not adenoma or carcinoma in the earlier study. Both studies observed a proliferative response in the acinar pancreas which was more pronounced in the study by Biegel et al. Definitive reasons for the greater incidence of proliferative lesions in the later study were not identified, but some possible explanations are presented herein. The relevance of this finding to human risk assessment, in the face of differences in the biological behavior of human and rat pancreatic proliferative lesions and the proposed mechanism of formation of these lesions, are questionable.


Cys-regulation: oxidized CHK1 controls cross-compartment circuit of chemoresistance.
In a recent study published in Cell, Zhang et al. integrate genome-wide CRISPRi screening with cysteine chemoproteomics to identify functionally relevant oxidation events associated with the cellular response to chemotherapy. This work uncovered checkpoint kinase 1 (CHK1) as a nuclear reactive oxygen species (ROS) sensor that mediates chemoresistance through the suppression of mitochondrial protein synthesis.


The impact of an easy access drug supply management policy law on the consumption and abuse of opioids in Catalonia: A population-based study.
Over the last two decades, the rise in opioid prescription has worsened health outcomes worldwide, increasing both levels of abuse and mortality rates. In order to reduce the scale of this public health problem, new policies have been implemented in many countries. In 2012, Spain adopted new legislation on opioid prescription (the ROE law), which meant that practitioners no longer needed to obtain extra authorisation in order to prescribe strong opioids. The objective of the paper is to assess the impact of this law on opioid use and abuse in Catalonia, Spain. We established two measures of the use of strong and weak opioids: DDDs, and abuse. We used benzodiazepines and antidepressants as controls, and adjusted for age, sex, drug co-payment level, death or near death, cancer diagnosis, morbidity group, and type of prescription. The data were obtained from administrative and dispensing drug databases in a population of 7.5 million inhabitants. We estimated two-way fixed effects using difference in difference models. The ROE law impacted reducing the monthly use of strong opioids by 0.903 DDDs, representing a 3.15% decrease in the mean monthly use of strong opioids. However, abuse rose 1.86 times compared with the average pre-ROE value, which represents an increase of 11,190 months of opioid abuse (i.e., an 11.33% of all monthly opioids use). The abolition of the duplicate prescription programme for strong opioids led to a reduction in the average monthly use of strong opioids, but an increase in abuse.


Heterogeneity of Outcome Measures Used in Randomized Controlled Trials for the Treatment of Oral Lichen Planus: A Methodological Study.
Oral lichen planus (OLP) is a chronic inflammatory immune disease, recognized as an oral potentially malignant disorder by the World Health Organization. There is considerable controversy over the standardized treatment of OLP, with great diversities in the outcome measures in clinical trials. This methodological study aimed to estimate the degree of consensus on outcome measures in randomized controlled trials (RCTs) for OLP treatment. PubMed, Embase, and Cochrane databases were searched to identify RCTs published from 2004 to 2018 about OLP treatment. All the outcome measures and measurement methods mentioned in the trials were extracted and analyzed. After identification of 1087 articles, 88 RCTs were included. A total of 193 single-outcome measures and 119 composite outcome measures were classified into 11 different domains, the chief of which consisted of clinical symptom (78 trials; 88.6%) and clinical score (58 trials; 65.9%). Visual analog scale (65 trials; 73.9%) and Thongprasom scoring system (38 trials; 43.2%) were the predominant measurement methods. Oral health-related quality of life (except for clinical symptoms) accounted for 4.8% of all the outcome measures. There was high heterogeneity in outcome measures of RCTs for OLP treatment, making it difficult to make valid comparisons between different clinical trials. A core outcome set should be developed and adopted in future trials for OLP treatment.


IBM-type inclusions in a patient with slow-channel syndrome caused by a mutation in the AChR epsilon subunit.
We report a patient with a slow-channel congenital myasthenic syndrome who carries a novel slow-channel mutation in the epsilon subunit of the acetylcholine receptor and has tubulofilamentous inclusion bodies, in skeletal muscle of the type observed in hereditary and sporadic inclusion body myositis. Ultrastructural analysis of a muscle specimen obtained at the age of 9 years showed an endplate myopathy typical of the slow-channel syndrome. Twenty years later, a second muscle specimen again showed the endplate myopathy as well numerous nuclear and cytoplasmic tubulofilamentous inclusion bodies. Molecular genetic studies revealed a novel valine to phenylalanine mutation (epsilonV259F) in the M2 domain of the acetylcholine receptor. Coexistence of the slow-channel syndrome with a feature of IBM has not been observed before.


Microfluidic Systems for Assisted Reproductive Technologies: Advantages and Potential Applications.
Microfluidic technologies have emerged as a powerful tool that can closely replicate the in-vivo physiological conditions of organ systems. Assisted reproductive technology (ART), while being able to achieve successful outcomes, still faces challenges related to technical error, efficiency, cost, and monitoring/assessment. In this review, we provide a brief overview of the uses of microfluidic devices in the culture, maintenance and study of ovarian follicle development for experimental and therapeutic applications. We discuss existing microfluidic platforms for oocyte and sperm selection and maintenance, facilitation of fertilization by in-vitro fertilization/intracytoplastimc sperm injection, and monitoring, selection and maintenance of resulting embryos. Furthermore, we discuss the possibility of future integration of these technologies onto a single platform and the limitations facing the development of these systems. In spite of these challenges, we envision that microfluidic systems will likely evolve and inevitably revolutionize both fundamental, reproductive physiology/toxicology research as well as clinically applicable ART.


Full-length RecE enhances linear-linear homologous recombination and facilitates direct cloning for bioprospecting.
Functional analysis of genome sequences requires methods for cloning DNA of interest. However, existing methods, such as library cloning and screening, are too demanding or inefficient for high-throughput application to the wealth of genomic data being delivered by massively parallel sequencing. Here we describe direct DNA cloning based on the discovery that the full-length Rac prophage protein RecE and its partner RecT mediate highly efficient linear-linear homologous recombination mechanistically distinct from conventional recombineering mediated by Redαβ from lambda phage or truncated versions of RecET. We directly cloned all ten megasynthetase gene clusters (each 10–52 kb in length) from Photorhabdus luminescens into expression vectors and expressed two of them in a heterologous host to identify the metabolites luminmycin A and luminmide A/B. We also directly cloned cDNAs and exactly defined segments from bacterial artificial chromosomes. Direct cloning with full-length RecE expands the DNA engineering toolbox and will facilitate bioprospecting for natural products.


An effective stochastic excitation strategy for finding elusive NMR signals from solids.
The versatility of using a stochastic pulse sequence to elucidate peaks with a wide range of shifts, peak widths, and T(1) relaxation times is demonstrated. A stochastic sequence is combined with high speed magic angle spinning (MAS) to obtain the broad and largely shifted peak associated with (31)P in LiNiPO(4). A stochastic sequence is also used to obtain a spectrum of 85% H(3)PO(4), which has a much longer T(1) value. The signal-to-noise was comparable for spectra of 85% H(3)PO(4) obtained with either a stochastic sequence or an optimized Ernst angle experiment. Experimental parameters for the stochastic experiment are set depending only on the ringdown of the probe and not on any inherent qualities of the sample. A stochastic sequence, therefore, combined with MAS provides a useful strategy for finding peaks with unknown T(1) relaxation constants, peak widths, and shifts.


Spatial distribution and fruiting phenology of Protium heptaphyllum (Burseraceae) determine the design of the underground foraging system of Atta sexdens L. (Hymenoptera: Formicidae).
Leaf-cutting ants have long been recognized to forage via complex trail systems but the nature and the ecological drivers of the different foraging strategies adopted remain a key topic. Here, we described the spatiotemporal use of belowground foraging galleries by Atta sexdens L. in the Brazilian Atlantic forest, and examined the adaptive advantages of this foraging strategy. Protium heptaphyllum adult trees (DBH > 10 cm), seed/seedling clumps and ant gallery entrances were mapped across two 1-ha plots during two consecutive fruiting seasons (2002 and 2004). We recorded 75 ca. 40 cm deep gallery entrances beneath 26 P. heptaphyllum trees at nest distances ranging from 14 to 57 m. Furthermore, gallery abundance and galleries associated with seed/seedling clumps correlated positively with P. heptaphyllum density. Our results indicate that A. sexdens was able to set a permanent system of underground galleries targeting P. heptaphyllum trees and their seeds on the ground. Such network of galleries was spatially arranged according to both the spatial distribution and abundance of P. heptaphyllum trees in a way that most gallery entrances were disposed beneath or in close periphery of P. heptaphyllum crowns. Our findings suggest that underground trail systems shaped by fruit resources represent a foraging strategy clearly more common than existing literature on the subject would suggest. In addition, it reinforces the notion that the spatiotemporal availability of resources combined with predation risk largely influence trail configurations as well as overall foraging strategies adopted by leaf-cutting ants.


Periocular methotrexate versus periocular triamcinolone injections for active thyroid-associated orbitopathy: a randomized clinical trial.
To assess the efficacy and safety of periocular injections of methotrexate versus triamcinolone in the management of active thyroid-associated orbitopathy. Prospective, double-masked, randomized clinical trial. Participants with bilateral active, moderate-to-severe thyroid-associated orbitopathy were randomly assigned to receive three periocular injections of 7.5 mg methotrexate in one orbit and three periocular injections of 20 mg triamcinolone in the contralateral orbit. Among the enrolled 25 patients, 18 patients completed the study. A statistically significant reduction of the mean clinical activity score was detected in both arms (from 5.2 ± 0.89 at baseline to 0.9 ± 1.7 at study endpoint, p-value < 0.001 in the methotrexate arm, and from 5.1 ± 0.9 at baseline to 1 ± 1.7 at study endpoint, p-value < 0.001 in the triamcinolone arm), mean proptosis also decreased in both arms (from 25.2 ± 3.4 mm at baseline to 23.8 ± 3.7 mm at study endpoint, p-value = 0.01 in the methotrexate arm, and from 24.2 ± 3.06 mm at baseline to 23.2 ± 3.3 mm at study endpoint, p-value = 0.049 in the triamcinolone arm). Lid aperture and soft tissue signs improved significantly in both arms in comparison to baseline. A statistically significant reduction in the intraocular pressure was observed in the methotrexate arm but not in the triamcinolone arm. 88.9% of patients in both arms were overall responders at 6 months. There was no significant difference in mean CAS, proptosis, lid aperture or rate of responders between the two arms at any visit. Both drugs were found to be safe with minimal local and systemic complications. Periocular injections of methotrexate represent an effective and safe alternative option for the management of active, moderate-to-severe thyroid-associated orbitopathy. Although no serious complications occurred during the 6-month follow-up, the possibility of late complications such as orbital fat atrophy cannot be ruled out.


Impulse conduction regulates myelin basic protein phosphorylation in rat optic nerve.
The influence of action potential conduction in myelinated axons on the state of phosphorylation of myelin basic protein was studied in rat optic nerve incubated in vitro. For this purpose we used a technique that permits continuous recording of the responses of nerves to electrical stimulation together with the "back-phosphorylation" assay. Our results indicate that action potential conduction, but not electrical stimulation, increased the state of phosphorylation of myelin basic protein. The increment in basic protein phosphorylation was related to the number of impulses conducted, up to a maximal change which occurred after 12 X 10(3) impulses. Also, the effect of action potential conduction was reversible, since the state of myelin basic protein phosphorylation returned to control levels within 5 min of stopping stimulation. These findings raise the interesting possibility that myelin basic protein phosphorylation plays a role in some dynamic function of myelin, perhaps related to ion transport or to the process of recovery of ionic gradients.


Rosai-Dorfman Disease of Rare Isolated Spinal Involvement: Report of 4 Cases and Literature Review.
Rosai-Dorfman disease (RDD) is a rare histioproliferative disorder that only occasionally involves the central nervous system (CNS). The diagnosis and treatment of 4 patients with isolated spinal RDD are discussed. All 4 patients were treated by total or subtotal surgical resection and none of them experienced recurrence. Histopathologic examination showed a characteristic emperipolesis, and the lymphocytes were engulfed in the S-100-protein-positive histiocytes with no expression of CD1a. Preoperative diagnosis of spinal RDD is still challenging because the lesion is usually a dura-based lesion that mimics a meningioma. Surgical resection is an effective treatment, and radiotherapy, steroid therapy, and chemotherapy have not shown reliable therapeutic efficiency.


Suppression of locomotor activity produced by acute injections of kainic acid into the median raphe nucleus.
Several lines of evidence suggest that cells within the immediate vicinity of the median raphe nucleus may exert an inhibitory influence on locomotor activity. If this theory were correct, one would expect that excitation of neurons within the median raphe would have a suppressive effect on behavior. This possibility was examined in the present study where low doses of the glutamate analogue kainic acid were injected into the median raphe nucleus of methylphenidate-pretreated rats. Our results indicate that these injections were able to antagonize, in a dose-dependent manner, both the horizontal locomotor activity and the nose poking induced by methylphenidate. These results provide further support for the existence of inhibitory median raphe influences on locomotion and suggest the possibility that endogenous excitatory amino acids may play a role in raphe functioning.


Effects of antireflux therapies on salivary function in normal humans.
Saliva has received recent attention because of its potential role in esophageal clearance and neutralization of refluxed gastric contents. Gastric antisecretory drugs or promotility drugs used to treat reflux have not been studied for their ability to affect salivary function. We conducted a double-blind randomized study of four antisecretory drugs, two promotility drugs, and placebo (PL) on 12 healthy volunteers on seven different days. Following a 6-hr fast, accumulated saliva was expectorated at least once per minute. The initial 10-min sample was discarded and a baseline 20-min sample collected. One of the following was given per os: PL, pirenzepine (PIR), 50 mg; propantheline (PRO), 30 mg; cimetidine (CIM), 300 mg; ranitidine (RAN), 150 mg; bethanechol (BET), 25 mg; or metoclopramide (MET), 10 mg. Saliva was collected for 60 min. Saliva was then stimulated (STIM) by sucking a peppermint lozenge for 30 min. Specimens were collected under oil, kept on ice, and analyzed within 30 min. Saliva flow in milliliters per minute and capacity for acid neutralization (CAN) in microequivalents acid per milliliter saliva were analyzed on all samples. The known effect of PRO to inhibit both basal saliva flow and STIM flow and CAN was seen. In contrast, the selective antimuscarinic PIR did not significantly decrease saliva flow or CAN. CIM, RAN, and MET did not significantly effect salivary function, but both CIM and RAN showed a tendency to increase CAN. Oral BET had no detectable effect on salivary function.


Unmet needs for treatment in 102 individuals with brief and limited intermittent psychotic symptoms (BLIPS): implications for current clinical recommendations.
To investigate clinical outcomes and unmet needs in individuals at Clinical High Risk for Psychosis presenting with Brief and Limited Intermittent Psychotic Symptoms (BLIPS). Prospective naturalistic long-term (up to 9 years) cohort study in individuals meeting BLIPS criteria at the Outreach And Support In South-London (OASIS) up to April 2016. Baseline sociodemographic and clinical characteristics, specific BLIPS features, preventive treatments received and clinical outcomes (psychotic and non-psychotic) were measured. Analyses included Kaplan Meier survival estimates and Cox regression methods. One hundred and two BLIPS individuals were followed up to 9 years. Across BLIPS cases, 35% had an abrupt onset; 32% were associated with acute stress, 45% with lifetime trauma and 20% with concurrent illicit substance use. The vast majority (80%) of BLIPS individuals, despite being systematically offered cognitive behavioural therapy for psychosis, did not fully engage with it and did not receive the minimum effective dose. Only 3% of BLIPS individuals received the appropriate dose of cognitive behavioural therapy. At 4-year follow-up, 52% of the BLIPS individuals developed a psychotic disorder, 34% were admitted to hospital and 16% received a compulsory admission. At 3-year follow-up, 52% of them received an antipsychotic treatment; at 4-year follow-up, 26% of them received an antidepressant treatment. The presence of seriously disorganising and dangerous features was a strong poor prognostic factor. BLIPS individuals display severe clinical outcomes beyond their very high risk of developing psychosis and show poor compliance with preventive cognitive behavioural therapy. BLIPS individuals have severe needs for treatment that are not met by current preventive strategies.


Dissociation of vicarious and experienced rewards by coupling frequency within the same neural pathway.
Vicarious reward, essential to social learning and decision making, is theorized to engage select brain regions similarly to experienced reward to generate a shared experience. However, it is just as important for neural systems to also differentiate vicarious from experienced rewards for social interaction. Here, we investigated the neuronal interaction between the primate anterior cingulate cortex gyrus (ACCg) and the basolateral amygdala (BLA) when social choices made by monkeys led to either vicarious or experienced reward. Coherence between ACCg spikes and BLA local field potential (LFP) selectively increased in gamma frequencies for vicarious reward, whereas it selectively increased in alpha/beta frequencies for experienced reward. These respectively enhanced couplings for vicarious and experienced rewards were uniquely observed following voluntary choices. Moreover, reward outcomes had consistently strong directional influences from ACCg to BLA. Our findings support a mechanism of vicarious reward where social agency is tagged by interareal coordination frequency within the same shared pathway.


Interleukin-5 levels in relation to malaria severity: a systematic review.
The role of cytokines such as interleukin-5 (IL-5) in the pathogenesis of malaria remains unclear. This systematic review sought to synthesize variations in IL-5 levels between severe and uncomplicated malaria, as well as between malaria and controls not afflicted with the disease. This systematic review was registered at the International Prospective Register of Systematic Reviews (PROSPERO; CRD42022368773). Searches for studies that reported IL-5 levels in patients with malaria (any severity) and/or uninfected individuals were performed in Web of Science, PubMed, EMBASE, Scopus, CENTRAL, and MEDLINE, between 1st and 10th October, 2022. The risk of bias among all included studies was minimized using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for reporting observational studies. The differences in IL-5 levels between malaria and uninfected controls, and between severe and uncomplicated malaria were synthesized by narrative synthesis. Among 1177 articles identified in the databases, 23 matched the eligibility criteria and were included in this systematic review. Qualitative syntheses showed the heterogeneity of IL-5 levels between different severities of clinical malaria and uninfected controls. The majority of the included studies (12/15 studies, 80%) found no change in IL-5 levels between malaria cases and uninfected controls. Similarly, most studies found no difference in IL-5 levels between severe (regardless of complications) and uncomplicated malaria (4/8 studies, 50%). The qualitative syntheses revealed that most studies found no difference in IL-5 levels between severe and non-severe malaria. The comprehensive review suggests that IL-5 levels are unchanged in patients with different levels of clinical severity of malaria and uninfected controls. Given the limited number of published studies on IL-5 levels in malaria, there is a need for additional research to determine the function of this cytokine in the pathogenesis of malaria.


3,3,6,6-Tetramethyl-1,2,4,5-tetroxane: a twinned crystal structure.
The title compound, C6H12O4, also known as dimeric acetone peroxide, Me2(C2O4)Me2, has crystallographically imposed inversion symmetry and adopts a chair conformation in the solid state. This structure contrasts with that of the sulfur homologue Me2(C2S4)Me2, which has crystallographically imposed -4 symmetry and crystallizes in a twist-boat conformation. Crystals of the title compound are twinned along the reciprocal c* axis.


Costoclavicular brachial plexus block: A review of current evidence.
The brachial plexus block can be performed through several approaches. The recently described ultrasound-guided costoclavicular block at the costoclavicular space has gained popularity, presenting promising results for upper limb anaesthesia and postoperative analgesia. This block comes as an alternative to the traditional infraclavicular approach, with results suggesting improved block quality and reduced risk of complications. This article presents a narrative review of the literature and the current evidence available. A bibliographic search was conducted in the database PubMed and relevant articles published between 2015 and December 2020 to this topic were selected.


Monoaminergic synapses, including dendro-dendritic synapses in the rat substantia nigra.
Intraventricular administration of 1 or 2 mg of the osmiophilic "false transmitter" 5-hydroxydopamine (5-OHDA) was used to label monoamine storage and release sites in the rat substantia nigra. Vesicles containing unusually dense cores indicative of the presence of the marker were seen forming from the Golgi apparatus in the cell bodies of medium-sized neurons of the substantia nigra, pars compacta, and from smooth endoplasmic reticulum in the dendrites of those neurons and in small unmyelinated axons of unknown origin. In serial sections, both axons and dendrites containing synaptic vesicles marked with 5-OHDA were seen to form synapses "en passage" in pars compacta, and some presynaptic dendrites containing vesicles filled by the marker were also observed to form contacts with dendrites in pars reticulata. The only identified postsynaptic elements engaging in monoaminergic synapses in the substantia nigra were dendrites of medium-sized pars compacta neurons.


Do underserved and socially vulnerable communities observe more crashes? A spatial examination of social vulnerability and crash risks in Texas.
Understanding the relationship between social vulnerability and traffic crashes is a cornerstone for promoting social justice in transportation planning and policymaking. However, few studies have examined the disparities in traffic crashes by systemically considering the influence of social vulnerability via spatial analysis approaches. This study puts forward a new approach to assess the inequity in transportation safety by spatially examining the relationships between crash risks and the social vulnerability index (SVI) established by the Centers for Disease Control and Prevention (CDC). We performed spatial autocorrelation analyses to identify the clusters of high-risk and high-vulnerable census tracts in Texas. Meanwhile, we innovatively applied the Multiscale Geographically Weighted Regression model (MGWR) to assess the impacts of CDC SVI on crash risks spatially and statistically. The results demonstrate that the crash rate and the social vulnerability are significantly correlated in the highly urbanized regions as well as the southern border along the Rio Grande in Texas. The MGWR results indicate the minority status of census tracts is strongly correlated with overall crashes in north-central and northeastern Texas, and the socioeconomic status is tightly correlated with fatal crashes across Texas. The outcomes from this study have significant implications for transportation planning and policymaking.


[Congenital lung malformations: natural history and pathophysiological mechanisms].
Congenital lung lesions comprise a broad spectrum of various malformations including congenital cystic adenomatoid malformation (CCAM), bronchopulmonary sequestration (BPS), congenital lobar emphysema, bronchial atresia and bronchogenic cyst. This review aims at the description of their natural history, and of the underlying pathophysiological mechanisms. Congenital lung lesions are frequently diagnosed antenatally and many remain asymptomatic after birth. In the absence of antenatal identification, they are usually revealed by the occurrence of infection. In some cases, spontaneous resolution of the malformation can occur. Different pathogenic hypotheses are discussed for the origin of these abnormalities, and common processes appear likely to all of these malformations. Factors involved in the process of branching seem to play a particularly important role. Prospective follow-up of operated and unoperated children would complete our knowledge about the natural history of these lesions. The contribution of experimental models has led to advances in the understanding of pathogenic mechanisms. Further studies are needed to identify the factors initiating the malformative process.


Computer-Aided Design of Eco-Friendly Imprinted Polymer Decorated Sensors Augmented by Self-Validated Ensemble Modeling Designs for the Quantitation of Drotaverine Hydrochloride in Dosage Form and Human Plasma.
Computationally designed molecular imprinted polymer (MIP) incorporation into electrochemical sensors has many advantages to the performance of the designed sensors. The innovative self-validated ensemble modeling (SVEM) approach is a smart machine learning-based (ML) technique that enables the design of more accurate predictive models using smaller data sets. The novel SVEM experimental design methodology is exploited here exclusively to optimize the composition of four eco-friendly PVC membranes augmented by a computationally designed magnetic molecularly imprinted polymer to quantitatively determine drotaverine hydrochloride (DVN) in its combined dosage form and human plasma. Furthermore, the application of hybrid computational simulations such as molecular dynamics and quantum mechanical calculations (MD/QM) is a time-saving and eco-friendly provider for the tailored design of the MIP particles. Here, for the first time, the predictive power of ML is assembled with computational simulations to develop four PVC-based sensors decorated by computationally designed MIP particles using four different experimental designs known as central composite, SVEM-LASSO, SVEM-FWD, and SVEM-PFWD. The pioneering AGREE approach further assessed the greenness of the analytical methods, proving their eco-friendliness. The proposed sensors showed decent Nernstian responses toward DVN in the range of 58.60-59.09 mV/decade with a linear quantitative range of 1 × 10-7 - 1 × 10-2 M and limits of detection in the range of 9.55 × 10-8 to 7.08 × 10-8 M. Moreover, the proposed sensors showed ultimate eco-friendliness and selectivity for their target in its combined dosage form and spiked human plasma. The proposed sensors were validated in accordance with International Union of Pure and Applied Chemistry (IUPAC) recommendations, proving their sensitivity and selectivity for drotaverine determination in dosage form and human plasma. This work presents the first ever application of both the innovative SVEM designs and MD/QM simulations in the optimization and fabrication of drotaverine-sensitive and selective MIP-decorated PVC sensors.


Self-assembling gold nanoparticles on thiol-functionalized poly(styrene-co-acrylic acid) nanospheres for fabrication of a mediatorless biosensor.
A novel strategy to construct a sensitive mediatorless sensor of H2O2 was described. At first, a cleaned gold electrode was immersed in thiol-functionalized poly(styrene-co-acrylic acid) (St-co-AA) nanosphere latex prepared by emulsifier-free emulsion polymerization St with AA and function with dithioglycol to assemble the nanospheres, then gold nanoparticles were chemisorbed onto the thiol groups and formed monolayers on the surface of poly(St-co-AA) nanospheres. Finally, horseradish peroxidase (HRP) was immobilized on the surface of the gold nanoparticles. The sensor displayed an excellent electrocatalytical response to reduction of H2O2 without the aid of an electron mediator. The biosensor showed a linear range of 8.0 micromol L(-1)-7.0 mmol L(-1) with a detection limit of 4.0 micromol L(-1). The biosensor retained more than 97.8% of its original activity after 60 days' storage. Moreover, the studied biosensor exhibited good current reproducibility and good fabrication reproducibility.


HBsAg-negative chronic active hepatitis related to hepatitis B virus.
Numerous cases of chronic hepatitis have been shown to be closely associated with persistent infection with hepatitis B virus (HBV). A group of 100 patients suffering from chronic active hepatitis (CAH) was investigated for HBV serologic markers. Of these, 35 patients were HbsAg-positive; in 26 HBsAg-negative subjects, anti-HBc were detected using counterimmune electrophoresis and complement-fixation tests. These data suggest that chronic liver disease in patients who were only anti-HBc-positive might be related to persistent infection with hepatitis B virus. Epidemiological clinical and histopathological data were different when we compared CAH patients who were HBsAg-negative, but anti-HBc-positive, with HBsAg-positive CAH patients. A sequence is proposed leading from HBsAg-positive to HBsAg-negative CAH, cirrhosis, and hepatoma in temperate areas, according to a model similar to the one described in intertropical Africa.


Diagnostic yield, complications, pathology and anatomical features in CT-guided percutaneous needle biopsy of mediastinal tumours.
This study presents the experiences of percutaneous CT-guided needle biopsy at a university hospital in Norway. A retrospective examination of all mediastinal biopsy procedures between April 2015 and August 2019 was performed at Akershus University Hospital in Norway. We registered patient and procedure characteristics, along with lesion pathology and characteristics including localization according to anatomical and Felson mediastinal compartments. The study included 48 procedures, conducted in 45 patients (29 men and 16 women) with a mean age of 60,5 years. Pneumothorax occurred in 12 procedures (60% of the transpulmonary procedures) and pneumomediastinum in 18 procedures (38%). Pneumothorax was only seen in procedures with transpulmonal access. Four of the pneumothorax cases required pleural drainage. Diagnostic yield was 96%. We found significant (p = 0,006), moderate to high association between anatomical compartment localization and histopathological diagnosis (Cramér's V = 0,49) for tumours selected for CT-guided percutaneous biopsy. Felson's compartment division on the other hand, did not show any significant associations. We found CT-guided percutaneous needle biopsy of mediastinal tumours to be an effective and safe procedure with a diagnostic yield of 96%. The main complications were pneumothorax and pnumomediastinum, with a relatively low chest drainage rate. Anatomical mediastinum compartment showed a significant, moderate to high association with the histopathological diagnosis for tumours selected for percutaneous CT-guided biopsies, where most malignancies were seen in the anterior compartment.


In vitro inhibition of IL-2 biosynthesis in activated human peripheral blood mononuclear cells by a trauma-induced glycopeptide.
Traumatic injury often results in profound immunopathology that can lead to immunosuppression, thereby increasing the morbidity and mortality due to sepsis. The isolation and partial characterization of an immunosuppressive glycopeptide (SAP) from serum of severely burned patients has previously been reported by our laboratory. Recently, this trauma peptide has also been identified in the serum of patients with multiple blunt trauma. This glycopeptide is capable of suppressing neutrophil chemotaxis, T-cell blastogenesis and the lysis of human erythrocytes. We demonstrate in this report that SAP inhibits interleukin 2 (IL-2) biosynthesis by mitogen-stimulated peripheral blood mononuclear cells. Peptide concentrations of 50 nmol and above significantly inhibited IL-2 production. Inhibition was not reduced by the addition of indomethacin or anti-PGE2 to cultures containing greater than 100 nmol of peptide, suggesting that inhibition is not entirely prostaglandin-mediated. Preliminary studies have shown that IL-2 suppression by SAP can be partially reversed by the addition of calcium ionophore. These results suggest a potential immunosuppressive mechanism of the trauma peptide in which T cell blastogenesis is inhibited by interference in IL-2 biosynthesis.


Highly flexible capacitive strain gauge for continuous long-term blood pressure monitoring.
An innovative procedure for measuring blood pressure, with none of the disadvantages of current procedures, is proposed. A highly-flexible capacitive strain gauge has been designed to measure changes in the diameter of a blood vessel; such changes are indicative of blood pressure. The sensor is implanted and wrapped around an arterial blood vessel during the normal course of a surgical procedure. In vivo tests, demonstrating the feasibility of this concept, are reported, along with in vitro tests and notes on sensor design and fabrication. These continuous blood pressure monitoring sensors may be used for a continuous long-term monitoring of blood pressure and pulse. They may also be combined with a real-time nerve stimulation technique or a course of medication to create a closed-loop system for blood-pressure control.


Reoperation in symptomatic patients after direct coronary artery revascularization.
Seventy-nine patients underwent 85 reoperations to revascularize the myocardium at intervals from 2 days to 5 years (mean 13 months) after primary direct revascularization procedures. A total of 122 bypass grafts including 43 individual veins, 43 double or triple sequential veins, and 17 internal mammary arteries (IMA) were utilized. Failure of previous bypass grafting was the most common reason for recurrent symptoms, partially due to the high failure rate of radial artery segments used as bypass conduits. One operative and three late deaths have occurred. Coronary arteriography, performed after reoperation (mean 14 months) in 15 patients, revealed a graft patency rate of 68 percent. Significant differences in postoperative complications between the first and subsequent operation could not be demonstrated. Combined nonfatal perioperative infarctions with the first and subsequent operations decreased ventricular function and probably contributed to the improved symptomatic state of some patients. It is concluded that good symptomatic relief and long-term survival can be achieved by reoperation in selected patients who have recurrent symptoms after primary direct myocardial revascularization.


[Obstetrical management in maternal tuberous sclerosis (Pringle-Bourneville syndrome)--a case report].
The rupture of visceral hamartomas in tuberous sclerosis (Pringle-Bourneville) is more likely in pregnancy because of the increased blood volume and can be followed by lifethreatening retroperitoneal hemorrhage. To avoid complications during delivery the vacuum extraction in epidural anesthesia is recommended. Preconceptional genetic counseling in this autosomal dominant disorder is obligatory.


Survival Prediction by Baseline Systemic Immune-inflammation Index (SII) and its Changes During First-line Platinum-based Treatment in a Caucasian Population of Patients With Metastatic Urothelial Carcinoma (MUC).
Systemic immune-inflammation index (SII) predicts survival of patients with various malignancies. This study explored the prognostic value of SII in metastatic urothelial carcinoma (MUC) subjects. We evaluated 181 consecutive MUC patients treated with first-line platinum-based therapy. Karnofsky performance status <80% and visceral metastasis were present in 18.2% and 46.4% of patients, respectively. SII was based on platelet × neutrophil/lymphocyte counts. Study population was dichotomized by median into high and low SII groups before the initiation of chemotherapy and at week 6. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method and compared with the log-rank test. At median follow-up of 9.6 months, 174 patients experienced disease progression and 173 died. Patients with low SII at baseline and at week 6 had significantly better PFS (HR=0.58; p=0.0002 and HR=0.55; p<0.0001) and OS (HR=0.54; p<0.0001 and HR=0.54; p<0.0001) compared to patients with high SII. Independent prognostic value of SII was confirmed in a multivariate analysis. High SII before chemotherapy that persists at week 6 negatively affects survival. SII at baseline can be used in the stratification of patients within clinical trials and in clinical practice.


Oral hyperpigmentation and occult malignancy--report of a case.
Melanocytes exist in the oral and laryngeal mucosa capable of responding with a hyperpigmentation response to occult malignancy. Such a case is presented and its differentiation from other disease processes is discussed.


A Small Molecule Activator of p300/CBP Histone Acetyltransferase Promotes Survival and Neurite Growth in a Cellular Model of Parkinson's Disease.
Parkinson's disease (PD) is a progressive neurodegenerative disease characterised by motor and non-motor symptoms, resulting from the degeneration of nigrostriatal dopaminergic neurons and peripheral autonomic neurons. Given the limited success of neurotrophic factors in clinical trials, there is a need to identify new small molecule drugs and drug targets to develop novel therapeutic strategies to protect all neurons that degenerate in PD. Epigenetic dysregulation has been implicated in neurodegenerative disorders, while targeting histone acetylation is a promising therapeutic avenue for PD. We and others have demonstrated that histone deacetylase inhibitors have neurotrophic effects in experimental models of PD. Activators of histone acetyltransferases (HAT) provide an alternative approach for the selective activation of gene expression, however little is known about the potential of HAT activators as drug therapies for PD. To explore this potential, the present study investigated the neurotrophic effects of CTPB (N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-6-pentadecyl-benzamide), which is a potent small molecule activator of the histone acetyltransferase p300/CBP, in the SH-SY5Y neuronal cell line. We report that CTPB promoted the survival and neurite growth of the SH-SY5Y cells, and also protected these cells from cell death induced by the neurotoxin 6-hydroxydopamine. This study is the first to investigate the phenotypic effects of the HAT activator CTPB, and to demonstrate that p300/CBP HAT activation has neurotrophic effects in a cellular model of PD.


Young children are not driven to explore imaginary worlds.
We address Dubourg and Baumard's claim that imaginary worlds are most appealing early in the lifespan when the exploratory drive is highest. Preschool-age children prefer fictions set in the real world, and fantastical information can be difficult for children to represent in real time. We speculate that a drive to explore imaginary worlds may emerge after children acquire substantial real-world skills and knowledge. An account of age effects on fictional preferences should encompass developmental change.


Electron transfer dissociation (ETD): the mass spectrometric breakthrough essential for O-GlcNAc protein site assignments-a study of the O-GlcNAcylated protein host cell factor C1.
The development of electron-based, unimolecular dissociation MS, i.e. electron capture and electron transfer dissociation (ECD and ETD, respectively), has greatly increased the speed and reliability of labile PTM site assignment. The field of intracellular O-GlcNAc (O-linked N-acetylglucosamine) signaling has especially advanced with the advent of ETD MS. Only within the last five years have proteomic-scale experiments utilizing ETD allowed the assignment of hundreds of O-GlcNAc sites within cells and subcellular structures. Our ability to identify and unambiguously assign the site of O-GlcNAc modifications using ETD is rapidly increasing our understanding of this regulatory glycosylation and its potential interaction with other PTMs. Here, we discuss the advantages of using ETD, complimented with collisional-activation MS, in a study of the extensively O-GlcNAcylated protein Host Cell Factor C1 (HCF-1). HCF-1 is a transcriptional coregulator that forms a stable complex with O-GlcNAc transferase and controls cell cycle progression. ETD, along with higher energy collisional dissociation (HCD) MS, was employed to assign the PTMs of the HCF-1 protein isolated from HEK293T cells. These include 19 sites of O-GlcNAcylation, two sites of phosphorylation, and two sites bearing dimethylarginine, and showcase the residue-specific, PTM complexity of this regulator of cell proliferation.


Recent taxonomic changes in the genus Enterococcus.
Recent taxonomic changes among the catalase-negative gram-positive cocci have led to the recognition of a separate genus for bacteria previously considered to be members of the genus Streptococcus. Presently, a total of 12 species of the genus Enterococcus have been described. The characteristics, taxonomy and nomenclature of these species, along with the possible clinical implications of revised enterococcal taxonomy, are discussed.


CROSS SECTIONAL ANALYTIC STUDY OF AWARENESS REGARDING FACTORS RELATED TO CHILD SURVIVAL AMONG MARRIED WOMEN IN A SEMI-URBAN COMMUNITY.
A cross sectional analytic study was undertaken on 480 married women living in a semi-urban locality in Pune, with the objective of assessing their awareness regarding factors related to child survival. It was observed that 62.1 per cent of the ladies had adequate knowledge about immunisation. A highly significant trend was evident as regards knowledge about immunisation and formal education and socio-economic status (p<0.01). 93 per cent ladies initiated breast feeding within 24 hours of birth of the new born. Significantly larger proportion of ladies from lower education favoured prolonged breast feeding (p<0.001) and favoured late introduction of top milk (p<0.001). In general, the awareness about growth chart was very poor with only 3.5 per cent ladies having adequate knowledge. Larger family size was significantly associated with declining probability of use of oral rehydration solution (ORS). Certain recommendations for improving the awareness regarding child survival have been submitted accordingly.


Deuterium NMR spectroscopy of biofluids for the identification of drug metabolites: application to N,N-dimethylformamide.
The metabolism of N,N-dimethylformamide in the Sprague-Dawley rat has been reinvestigated using NMR spectroscopy of urine. In particular, through the use of N,N-dimethylformamide-d7 (DMF-d7) and 2H-NMR spectroscopy, the principal metabolites of this compound have been confirmed in a direct manner. The use of inverse-detected two-dimensional 2H-13C correlation with 13C decoupling aided metabolite identification through the provision of 13C chemical shifts.


Extraction and characterization of phytochemical compounds from araçazeiro (Psidium cattleianum) leaf: Putative antioxidant and antimicrobial properties.
Underexplored species have phytochemical potential for pharmacological and nutraceutical applications. The fruits of such species, including aracá (Psidium cattleianum Sabine), are rich in specialized metabolites with putative antioxidant and antimicrobial activity; therefore, the leaves of these species are also a potential source of bioactive compounds. In this study, araçazeiro leaves were extracted using an aqueous infusion (Al) and a pressurized liquid extraction system with water (PLE-W), ethanol (PLE-E), and 1:1 water:ethanol ratio combination (PLE-W:E). PLE-W:E yielded a greater diversity of extracted compounds. Nonetheless, all extracts showed inhibitory activity against pathogenic Gram-positive and Gram-negative bacteria and antioxidant activity in the in vitro thiobarbituric acid reactive substances (TBARS) and reactive oxygen species (ROS) assays with rat brain and yeast model systems. Thus, araçazeiro leaves can be exploited as a promising source of bioactive compounds.


The relationship between vertical cup-disc ratio and body mass index in Port Harcourt, Nigeria.
Glaucoma is the leading cause of irreversible blindness in the world and risk factors to developing glaucoma must be determined early to prevent blindness from the disease. To determine the relationship between vertical cup disc ratio (VCDR) and body mass index (BMI) in a population screened for glaucoma in Port Harcourt, Nigeria. This study was part of a one-day screening exercise for glaucoma at the University of Port Harcourt. Demographic data included age, sex, race and occupation. Height was measured with a wall-mounted tape and weight with a bathroom scale. Intraocular pressure was measured with Perkins applanation tonometer and funduscopy was with direct ophthalmoscope. BMI was calculated as weight in kilograms divided by the square of height in meters (Weight/Height2). A total of 491 subjects were screened; consisting of 230 males (46.8%) and 261 females (53.2%). The mean age was 35±13.29 years. About 28%(n=141) of the participants were overweight while 17.7%(n=87) were obese. The mean BMI was 25.39 ± 4.82 kg/m 2 and the mean VCDR for both eyes was 0.38±0.13mmHgratios have no units. Most participants (n=864; 89.4%) had normal VCDR. Only 102 (10.6%) had cupped discs. There was no statistically significant relationship between BMI and VCDR (P= 0.947; R2 = 0.01). Obesity was not associated with a larger VCDR.


Development and evaluation of a droplet digital PCR assay for the detection of fowl adenovirus serotypes 4 and 10 in attenuated vaccines.
In recent years, there has been an increase in reported cases of fowl adenovirus serotype 4 (FAdV-4) in chickens in China. The use of live attenuated vaccines contaminated with FAdV-4 has been proved to be one of the important causes of massive outbreaks of hydropericardium syndrome. To detect the contamination with FAdV-4 in attenuated vaccines more promptly and accurately, a droplet digital PCR (ddPCR) assay was developed for the rapid detection of FAdV-4 and FAdV-10. The ability of this assay to detect FAdV-4 contamination in attenuated Newcastle disease virus vaccines was assessed in comparison to a quantitative real-time PCR (qPCR) and a conventional PCR assay. The findings indicated that the ddPCR assay could detect FAdV-4 contamination at 0.1 EID50/1,000 feathers, while the qPCR could detect FAdV-4 contamination at 1 EID50/1,000 feathers with identical genomic targets, which was 1,000-fold more sensitive than conventional PCR detection with a sensitivity of 102 EID50/1,000 feathers. The ddPCR assay also showed high specificity for FAdV-4/10 and no positive signals were detected for other FAdVs. Consequently, the intuitive and rapid results were especially suitable for the detection of FAdV-4 contamination in vaccines. In this study, a ddPCR assay was developed to effectively detect and quantify low-dose FAdV-4 contamination, providing a new method for rapid detection of FAdV-4 contamination in various samples, especially vaccines.


Adult diet does not compensate for impact of a poor larval diet on stress resistance in a tephritid fruit fly.
Adult holometabolous insects may derive metabolic resources from either larval or adult feeding, but little is known of whether adult diets can compensate for deficiencies in the larval diet in terms of stress resistance. We investigated how stress resistance is affected and compensated for by diet across life stages in the marula fruit fly Ceratitis cosyra (Diptera: Tephritidae). Larvae were fed diets containing either 8% torula yeast, the standard diet used to rear this species, or 1% yeast (low protein content similar to known host fruit). At emergence, adults from each larval diet were tested for initial mass, water content, body composition, and desiccation and starvation resistance or they were allocated to one of two adult diet treatments: sucrose only, or sucrose and yeast hydrolysate. The same assays were then repeated after 10 days of adult feeding. Development on a low protein larval diet led to lower body mass and improved desiccation and starvation resistance in newly emerged adults, even though adults from the high protein larval diet had the highest water content. Adult feeding decreased desiccation or starvation resistance, regardless of the diet provided. Irrespective of larval diet history, newly emerged, unfed adults had significantly higher dehydration tolerance than those that were fed. Lipid reserves played a role in starvation resistance. There was no evidence for metabolic water from stored nutrients extending desiccation resistance. Our findings show the possibility of a nutrient-poor larval environment leading to correlated improvement in adult performance, at least in the short term.


Interplay between Metabolism and Epigenetics: A Nuclear Adaptation to Environmental Changes.
The physiological identity of every cell is maintained by highly specific transcriptional networks that establish a coherent molecular program that is in tune with nutritional conditions. The regulation of cell-specific transcriptional networks is accomplished by an epigenetic program via chromatin-modifying enzymes, whose activity is directly dependent on metabolites such as acetyl-coenzyme A, S-adenosylmethionine, and NAD+, among others. Therefore, these nuclear activities are directly influenced by the nutritional status of the cell. In addition to nutritional availability, this highly collaborative program between epigenetic dynamics and metabolism is further interconnected with other environmental cues provided by the day-night cycles imposed by circadian rhythms. Herein, we review molecular pathways and their metabolites associated with epigenetic adaptations modulated by histone- and DNA-modifying enzymes and their responsiveness to the environment in the context of health and disease.


Forskolin induction of late-LTP and up-regulation of 5' TOP mRNAs translation via mTOR, ERK, and PI3K in hippocampal pyramidal cells.
The late phase of long-term potentiation (LTP) requires activation of the mammalian target of rapamycin (mTOR) pathway and synthesis of new proteins. mTOR regulates protein synthesis via phosphorylation of 4E-binding proteins (4E-BPs) and S6K, and via selective up-regulation of 5' terminal oligopyrimidine (5' TOP) mRNAs that encode components of the translational machinery. In this study, we explored the regulation of 5' TOP mRNAs during late-LTP (L-LTP). Synaptic plasticity was studied at Schaffer collateral--CA1 pyramidal cell synapses in rat organotypic hippocampal slices. Forskolin, an adenylate cyclase activator, induced L-LTP in organotypic slices that was mTOR-dependent. To determine if 5' TOP mRNAs are specifically up-regulated during L-LTP, we generated a 5' TOP-myr-dYFP reporter to selectively monitor 5' TOP translation. Confocal imaging experiments in cultured slices revealed an increase in somatic and dendritic fluorescence after forskolin treatment. This up-regulation was dependent on an intact TOP sequence and was mTOR, extracellular signal-regulated kinase (ERK), and phosphatidylinositol 3-kinase (PI3K)-dependent. Our findings indicate that forskolin induces L-LTP in hippocampal neurons and up-regulates 5' TOP mRNAs translation via mTOR, suggesting that up-regulation of the translational machinery is a candidate mechanism for the stabilization of LTP.


Immobilization of phospholipid vesicles and protein-lipid vesicles containing red cell membrane proteins on octyl derivatives of large-pore gels.
For improved immobilization of phospholipid vesicles and protein-lipid vesicles (cf. Sandberg, M., Lundahl, P., Greijer, E. and Belew, M. (1987) Biochim. Biophys. Acta 924, 185-192) and for chromatographic experiments with vesicles containing membrane protein, we have prepared octyl sulfide derivatives of the large-pore gels Sephacryl S-1000 and Sepharose 2B with ligand concentrations up to 14 and 5 mumol/ml gel, respectively. The Sephacryl derivatives allowed higher flow rates, gave higher rates of adsorption and showed equally high or higher capacities than the Sepharose adsorbents. 'Small', 'medium' and 'large' vesicles of radii approx. 20, 50 and 100 nm showed distribution coefficients on Sephacryl S-1000 of 0.7, 0.5 and 0.05, respectively and could be immobilized on octyl sulfide-Sephacryl S-1000 in amounts corresponding to 110, 40 and 20 mumol of phospholipids per ml gel, respectively. 'Small' vesicles became absorbed onto this gel at a rate of 1.5 mumol of phospholipids per min per ml gel until 60 mumol of phospholipids had become immobilized, whereas the initial adsorption rate was about 0.4 mumol.min-1.ml-1 on octyl sulfide-Sepharose 4B (see reference above) and on octyl sulfide-Sepharose 2B. Lower ligand concentrations gave lower capacities for 'small' vesicles. When vesicles entrapping calcein were immobilized on octyl sulfide-Sephacryl S-1000 some calcein was released during the adsorption process. For 'small' and 'medium' vesicles, respectively, the leakage was 75 and 25% at a ligand concentration of 14 mumol/ml but only 3 and 2% at 5 mumol/ml. The internal volumes of immobilized 'small' and 'medium' vesicles were estimated at 0.97 and 2.9 microliters per mumol of phospholipid by determination of entrapped calcein, which could indicate vesicle radii 20 and 50 nm, respectively. The total volumes of immobilized 'medium' lipid vesicles and 'medium' protein-lipid vesicles containing integral membrane proteins from human red cells, were estimated at 2.9 and 2.0 microliters/mumol, respectively, by chromatography of D- and L-[14C]glucose and calcein on the octyl sulfide-Sephacryl S-1000 column before and after immobilization. These volumes are roughly consistent with the internal volume of the vesicles. A zone of D-glucose eluted 90 microliters later than a zone of L-glucose on a 4- or 5-ml column of octyl sulfide-Sephacryl S-1000 with immobilized 'medium' protein-lipid vesicles containing the glucose transporter from human red cells, probably since part of the internal vesicle volume was accessible to the D-glucose but not to the L-glucose. This indicates that the glucose transporter was active in the immobilized vesicles.(ABSTRACT TRUNCATED AT 400 WORDS)


Determination of mesalazine, a low bioavailability olsalazine metabolite in human plasma by UHPLC-MS/MS: Application to a pharmacokinetic study.
Olsalazine sodium, salicylate derivative (prodrug) is effectively bioconverted to mesalazine (5-aminosalicylic acid; 5-ASA), which has an anti-inflammatory activity in ulcerative colitis. In this article, a novel highly sensitive and selective method was developed and validated to determine mesalazine in human plasma using a derivatization technique to enhance the signal intensity by using ultra- high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) with an electrospray ionization interface. The sample preparation consisted of a derivatization with propionyl anhydride followed by liquid liquid extraction (LLE) to remove the interference and minimize the matrix effect of human plasma. The multiple reaction monitoring (MRM) mode of the negative ion was performed and the transitions of m/z 208.1→107.0 and m/z 211.1→110.1 were used to measure the derivative of mesalazine and mesalazine-d3. The chromatographic separation was achieved using kinetex XB-C18 (100×4.6mm 2.6μ) analytical column with 0.1% formic acid in water and acetonitrile as mobile phase with a gradient elution. Nominal retention times of mesalazine and IS were 3.08 and 3.07min, respectively. Absolute recovery was found to be between 82-95% for analyte and about 78% for IS. The standard curves was linear (r(2)>0.995) in the concentration range 0.10 to 12.0ng/mL with lower limit of quantification (LLOQ) in human plasma was 0.10ng/mL. The average intra-day/inter-day precision values (%CV) were in the range from 0.6-2.9 % and 1.3-3.8 %, respectively, while the average accuracy value was 103.8-107.2%. This method has been successfully applied to the human pharmacokinetics of olsalazine sodium 250mg capsules following single oral administration.


Savings in acute care costs if all older adults treated for fall-related injuries completed matter of balance.
Falls among older adults are a common and serious public health problem. Evidence-based fall prevention programs delivered in community settings and targeting older adults living independently are increasingly deployed throughout the nation. These programs tend to be offered by public and private organizations that serve older adults, and recruitment usually occurs through direct marketing to the target population, rather than through referrals from healthcare providers. Matter of Balance, a program developed to reduce fear of falling and associated activity restriction in community-dwelling older adults, is currently being delivered in 38 of the 50 United States. In this study, we estimate the one-year medical care cost savings if older adults treated at Massachusetts hospitals for fall-related injuries were referred by healthcare providers to participate in Matter of Balance. Data from several sources were used for this study. We estimated annual cost savings in older adult falls recidivism for a hypothetical 100 patients presenting at an emergency department for a fall-related injury, assuming that all were referred to, and 50 % completed, Matter of Balance. This cost-saving estimate was subsequently expanded based on the actual number (43,931) of older adult patients presenting at, and discharged from Massachusetts emergency departments for all fall-related injuries in 2012. Cost savings were calculated for two additional participation rates: 25 % and 75 %. The return on investment (ROI), was calculated based on the percentage of return per each dollar invested. The calculated ROI for Matter of Balance was 144 %. Statewide savings ranged from $2.79 million assuming a 25 % participation rate to $8.37 million, assuming a 75 % participation rate. Referral to evidence-based falls prevention programs of older adult patients presenting at EDs with a fall-related injury could reduce subsequent falls and associated treatment costs.


Allogeneic Haploidentical Blood or Marrow Transplantation with Post-Transplantation Cyclophosphamide in Chronic Lymphocytic Leukemia.
Allogeneic blood or marrow transplantation (allo-BMT) remains the only treatment for chronic lymphocytic leukemia (CLL) with curative potential. Although post-transplantation cyclophosphamide (PTCy) reduces allo-BMT toxicity by decreasing the risk of graft-versus-host disease (GVHD), its effect on CLL allo-BMT outcomes is unknown. We studied 64 consecutive patients with CLL who underwent nonmyeloablative (NMA) haploidentical allo-BMT at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. In this cohort, the 4-year overall survival was 52% (95% confidence interval [CI], 40% to 68%), and progression-free survival was 37% (95% CI, 26% to 54%). Six patients experienced engraftment failure. PTCy prophylaxis was associated with a modest cumulative incidence of 1-year grade II-IV acute GVHD (27%; %95% CI, 15% to 38%) and %%%2-year chronic GVHD (17%; 95% CI, 7% to 26%). We demonstrate that NMA haploidentical allo-BMT with PTCy is a safe and effective treatment option.


Molecular mechanisms involved in the asymmetric interaction between cannabinoid and opioid systems.
The aim of this work was to study the mechanism of cross-modulation between cannabinoid and opioid systems for analgesia during acute and chronic exposure. Acute coadministration of ineffectual subanalgesic doses of the synthetic cannabinoid CP-55,940 (0.2 mg/kg i.p.) and morphine (2.5 mg/kg i.p.) resulted in significant antinociception. In chronic studies, a low dose of CP-55,940 (0.2 mg/kg, i.p.) that per se did not induce analgesia in naive animals produced a significant degree of antinociception in rats made tolerant to morphine, whereas in rats made tolerant to CP-55,940, morphine challenge did not produce any analgesic response. To identify the mechanism of these asymmetric interactions during chronic treatment, we investigated the functional activity of cannabinoid and mu opioid receptors and their effects on the cyclic AMP (cAMP) cascade. Autoradiographic-binding studies indicated a slight but significant reduction in cannabinoid receptor levels in the hippocampus and cerebellum of morphine-tolerant rats, whereas CP-55,940-stimulated [35S]GTPgammaS binding showed a significant decrease in receptor/G protein coupling in the limbic area. In CP-55,940 exposed rats, mu opioid receptor binding was significantly raised in the lateral thalamus and periaqueductal gray (PAG), with an increase in DAMGO-stimulated [35S]GTPgammaS binding in the nucleus accumbens. Finally, we tested the cAMP system's responsiveness to the cannabinoid and opioid in the striatum and dorsal mesencephalon. In vivo chronic morphine did not affect CP-55,940's ability to inhibit forskolin-stimulated cAMP production in vitro and actually induced sensitization in striatal membranes. In contrast, in vivo chronic CP-55,940 desensitized DAMGO's efficacy in inhibiting forskolin-stimulated cAMP production in vitro. The alterations to the cAMP system seem to mirror the behavioral responses, indicating that the two systems may interact at the postreceptor level. This might open up new therapeutic opportunities for relief of chronic pain through cannabinoid-opioid coadministration.


Ion-beam deposited platinum as electrical contacting material in operando electron microscopy experiments at elevated temperatures.
Establishing a stable and well conducting contacting material is critical for operando electron microscopy experiments of electrical and electrochemical devices at elevated temperatures. In this contribution, the nanostructure and electrical conductivity of ion beam deposited Pt are investigated both in vacuum and in oxygen as a function of temperature. Its microstructure is relatively stable up to a temperature of approx. 800°C and up to an applied current density of approx. 100 kA/cm2 . Its conductivity increases with temperature, attributed to densification, with changes in the hydrocarbon matrix being less important. Recommendations are provided with respect to the Pt deposition parameters in terms of maximizing stability and minimizing electrical resistance. RESEARCH HIGHLIGHTS: It is feasible to use ion beam deposited Pt as electrical contacting material in operando electron microscopy. The deposited Pt is relatively stable up to 800°C and approx. 100 kA/cm2 . The resistivity can be reduced by increasing the applied ion current during deposition and by thermal annealing at a temperature of 500°C in a few mbar of oxygen.


Novel Insights of Jailed Balloon and Jailed Corsair Technique for Percutaneous Coronary Intervention of Bifurcation Lesions.
The optimal technique for percutaneous coronary intervention (PCI) of a bifurcation lesion remains uncertain. JBT/JCT techniques are now emerging for protection of the side branch (SB). We aimed to compare jailed balloon (JBT) and jailed Corsair (JCT) techniques to the conventional jailed wire technique. We analyzed 850 consecutive patients (995 bifurcation lesions), who underwent PCI. The bifurcation lesions were classified as jailed wire (-), jailed wire (+), JBT, and JCT. We assessed temporary thrombolysis in myocardial infarction (TIMI) flow grade ≤2, permanent TIMI flow grade ≤2 in the SB, and SB occlusion related myocardial infarction and compared these endpoints with inverse probability treatment weighted analysis. The percentage of each group is as follows: jailed wire (-); 44.7%; jailed wire (+) 50.9%; JBT 1.7%; JCT 2.7%. The Corsair could not be delivered with a stent because of severe calcifications (3.7%) and a jailed balloon was entrapped with the stent after dilatation (5.9%). Compared to the jailed wire (+), JBT/JCT had a higher percentage of true bifurcations, arterial sheath size ≥7 Fr, and a lower proportion of wire recrossing (all, P < 0.05). After adjustment, temporary and permanent TIMI flow grade ≤2 in the SB, and SB occlusion related myocardial infarction were not significantly different (OR: 1.08, CI: 0.32-3.71, P = 0.90; OR: 0.88, CI: 0.11-6.91, P = 0.91; OR: 1.94, CI: 0.23-16.5, P = 0.55 respectively). Our data could not prove the efficacy of JBT/JCT, but revealed novel insights about these techniques. A larger study is necessary to prove the efficacy of JBT/JCT.


Torsional state of DNA in a transcriptionally hyperactive Balbiani ring of polytene chromosomes.
The torsional tension of unconstrained double-helical DNA was determined in transcriptionally hyperactive Balbiani ring 2 (BR2) and in inactive polytene chromosome bands of Chironomus tentans. The method used is based on the dual ability of small intercalating ligands to (a) sense, by differential binding, twists that deviate from that of regular B-form DNA and (b) create positive torsional tension in closed double-stranded DNA, thereby compensating for any negative torsional tension that existed before intercalation. Isolated nuclei of salivary glands were stained with the intercalating fluorescent dye ethidium bromide (EtBr) at various concentrations, and the temporal fluorescence intensity changes (deltaI/I per min) occurring in BR2 and in inactive bands were monitored under a confocal laser scanning microscope during the process of DNA nicking by laser irradiation or DNAase I. From the EtBr concentration at which deltaI/I per min was neither positive nor negative after nicking (i.e. at the equivalence point), the relative twist difference (RTD) was calculated. In bands, it was found to be very small, suggesting that their unconstrained DNA is under low torsional stress. In contrast, the RTD of DNA in highly expanded areas of BR2 was estimated to be negative and of a significant magnitude in absolute terms. This indicates that transcriptionally hyperactive DNA is under considerable negative torsional tension.


Primary care delivery in the United States and four northwest European countries: comparing the "corporatized" with the "socialized".
Primary care--often considered the weak link in the United States health care delivery system--is the focal point of several European systems. Thoughtful analysis of structural and service differences and similarities among these approaches--whether "corporatized" or "socialized"--reveals areas for helpful innovation in the United States. Matters of access to and continuity of services, preventive care for children, long-term care, and accountability are especially relevant for primary care in an American context.


Sheabutter V: effect of particle size on release of medicament from ointment.
An ointment prepared from fat (sheabutter) obtainable from an indigenous (African) fruit released medicaments faster than either of the two ointment bases recommended by the British Pharmacopoeia. Reduction in particle size of crystalline medicaments incorporated in ointments increased surface area and transfer from the ointment to the substrate, possibly due to greater dissolution in the base, and, therefore, increased the availability of medicament at the ointment-substrate interface.


Pleiotropic ameliorative effects of ellagitannin geraniin against metabolic syndrome induced by high-fat diet in rats.
Metabolic syndrome (MetS), a multiplex risk factor for cardiovascular disease and type 2 diabetes, is increasingly prevalent worldwide. Ellagitannin geraniin, a polyphenol found in the rind of rambutan (Nephelium lappaceum), has demonstrated therapeutic effects against metabolism dysfunction. The aim of this study was to characterize the metabolic effects and possible mechanism of geraniin in rats with MetS induced by a high-fat diet (HFD). MetS was induced in Sprague Dawley rats on an HFD, followed by a daily oral gavage of geraniin (25 mg/kg) for 4 wk. The outcomes of geraniin-treated rats were compared with those of untreated rats on either a control diet or an HFD and with rats with MetS treated with metformin on a daily basis (200 mg/kg). The supplementation of geraniin ameliorated multiple metabolic abnormalities caused by HFD, including hypertension, impaired glucose and lipid metabolism, ectopic fat deposition in the visceral fat and liver, and disturbed antioxidant mechanism and inflammatory response. The benefits conferred by geraniin were comparable to metformin. Transcriptomic analysis revealed a profound influence of geraniin on the hepatic expression profiles. The lipid and steroid metabolic processes that were aberrantly activated by HFD were suppressed by geraniin. Based on the differential transcriptomes, geraniin also exerted a significant modulatory effect on the expression of mitochondrial genes, potentially influencing the mitochondrial activity and leading to the observed beneficial effects. Geraniin supplementation mitigated metabolic anomalies of MetS in rats, making it an attractive drug candidate for further investigation.


Mycobacterial DNA-binding protein 1 is critical for BCG survival in stressful environments and simultaneously regulates gene expression.
Survival of the live attenuated Bacillus Calmette-Guérin (BCG) vaccine amidst harsh host environments is key for BCG effectiveness as it allows continuous immune response induction and protection against tuberculosis. Mycobacterial DNA binding protein 1 (MDP1), a nucleoid associated protein, is essential in BCG. However, there is limited knowledge on the extent of MDP1 gene regulation and how this influences BCG survival. Here, we demonstrate that MDP1 conditional knockdown (cKD) BCG grows slower than vector control in vitro, and dies faster upon exposure to antibiotics (bedaquiline) and oxidative stress (H2O2 and menadione). MDP1-cKD BCG also exhibited low infectivity and survival in THP-1 macrophages and mice indicating possible susceptibility to host mediated stress. Consequently, low in vivo survival resulted in reduced cytokine (IFN-gamma and TNF-alpha) production by splenocytes. Temporal transcriptome profiling showed more upregulated (81-240) than downregulated (5-175) genes in response to MDP1 suppression. Pathway analysis showed suppression of biosynthetic pathways that coincide with low in vitro growth. Notable was the deferential expression of genes involved in stress response (sigI), maintenance of DNA integrity (mutT1), REDOX balance (WhiB3), and host interactions (PE/PE_PGRS). Thus, this study shows MDP1's importance in BCG survival and highlights MDP1-dependent gene regulation suggesting its role in growth and stress adaptation.


Phytotoxicity of metabolites formed by Fusaria to cereal seedlings.
Phytotoxicity of 37 isolates of seven species ofFusarium has been studied. Metabolites of tested species exhibited signficantly different phototoxicity towards cereal seedlings. Germination was in greatest extent inhibited by metabolites ofF. subglutinans, in smallest extent by metabolites ofF. tricinctum /respectively 50% and 8%/. The growth rate of wheat seedlings was most strongly retarded by metabolites ofF. crookwellense, metabolites ofF. tricictum inhibited growth in the lowest percentage 57% and 29% respectively.


Antibody levels in children after 10 years of vaccination against hepatitis B: a Brazilian community-based study.
It is known that the hepatitis B (HB) vaccine is effective, but it is alarming that sudden drops of antibody levels may coincide with the onset of adolescence. Antibody levels against HB vaccine surface antigen (anti-HBs) and HB vaccine core antigen (anti-HBc) were measured on the blood samples of children with a mean age of 11.4 years. About 54.8% had protective levels of anti-HBs. Of those who were anti-HBc-positive (4.4%), an average of 218.4 anti-HBs mIU/mL was found. Immunological protection was found in the majority of children. However, more studies are needed to elucidate the heritability of nonresponders and establish strategies against such events.


Comparative pharmacokinetics and tissue distribution of polydatin, resveratrol, and emodin after oral administration of Huzhang and Huzhang-Guizhi herb-pair extracts to rats.
Huzhang-Guizhi herb pair (HGHP), composed of Polygonum cuspidatum (Huzhang [HZ] in Chinese, the root of Polygonum cuspidatum Sieb. & Zucc.) and Ramulus Cinnamomi (Guizhi [GZ] in Chinese, the dried twig of Cinnamomum cassia Presl.), is a popular herb pair commonly used to treat arthritis and involved in many Chinese prescriptions. In order to reveal the influence of GZ on HZ on bioavailability, the pharmacokinetic behaviors and tissue distribution variations of the three analytes from HZ were detected between oral administration of HZ and HGHP extracts to rats. Male Sprague-Dawley rats were randomly assigned to two groups for pharmacokinetics study and eight groups for tissues distribution research with the equivalent dose of 18 g crude HZ/kg. Assays for analytes from HZ (polydatin, resveratrol, emodin) were developed and validated using high performance liquid chromatography with ultraviolet detection (HPLC-UV). Part pharmacokinetic parameters including area under the concentration-time curve (AUC), the maximum plasma concentration (Cmax), biological half-life (t1/2), mean residence time (MRT), time to peak concentration (Tmax), clearance rate/bioavailability (CL/F) and volume of distribution/bioavailability (Vd/F) showed significant difference (P < 0.05) after oral administration of HGHP, as compared to those of HZ. The three analytes could be detected in heart, liver, spleen, lung, kidney and brain. Compared with the HZ group, AUC0-t of polydatin in heart, liver and kidney increased significantly (p < 0.05) while that in spleen decreased significantly (p < 0.05); AUC0-t of resveratrol in all detected tissues increased conspicuously (p < 0.05) in the HGHP group; AUC0-t of emodin in heart, liver, spleen, lung, and kidney increased conspicuously (p < 0.05), and decreased obviously (p < 0.05) in brain in the HGHP group. GZ could strongly influence the pharmacokinetic parameters and tissue distribution characteristics of polydatin, resveratrol and emodin in rats when administrated with HZ or HGHP extracts. It might provide a reference for further explanation of the compatibility mechanism and the clinical application of HGHP.


Vinegar residue compost as a growth substrate enhances cucumber resistance against the Fusarium wilt pathogen Fusarium oxysporum by regulating physiological and biochemical responses.
Fusarium wilt caused by the fungus Fusarium oxysporum f. sp. cucumerinum (FOC) is the most severe soil-borne disease attacking cucumber. To assess the positive effects of vinegar residue substrate (VRS) on the growth and incidence of Fusarium wilt on cucumber, we determined the cucumber growth parameters, disease severity, defense-related enzyme and pathogenesis-related (PR) protein activities, and stress-related gene expression levels. In in vitro and pot experiments, we demonstrated the following results: (i) the VRS extract exhibited a higher biocontrol activity than that of peat against FOC, and significantly improved the growth inhibition of FOC, with values of 48.3 %; (ii) in response to a FOC challenge, antioxidant enzymes and the key enzymes of phenylpropanoid metabolic activities, as well as the PR protein activities in the roots of cucumber, were significantly increased. Moreover, the activities of these proteins were higher in VRS than in peat; (iii) the expression levels of stress-related genes (including glu, pal, and ethylene receptor) elicited responses to the pathogens inoculated in cucumber leaves; and (iv) the FOC treatment significantly inhibited the growth of cucumber seedlings. Moreover, all of the growth indices of plants grown in VRS were significantly higher than those grown in peat. These results offer a new strategy to control cucumber Fusarium wilt, by upregulating the activity levels of defense-related enzymes and PR proteins and adjusting gene expression levels. They also provide a theoretical basis for VRS applications.


Evaluation of lemon fruit extract as an antioxidant agent against histopathological changes induced by cyclophosphamide in the testes of albino mice.
The aim of this study was to determine the protective effects of lemon fruit extracts (LFE) against histopathological changes induced in the testes of male mice treated with cyclophosphamide (CP). Thirty male mice were divided evenly into six groups: 1) group 1: the controls, 2) group 2: treated with LFE (10 ml/kg b wt.), 3) group 3: treated with CP (10 mg/kg b wt.), 4) group 4: treated with CP (20 mg/kg b wt.), 5) group 5: treated with LFE (10 ml/kg) + CP (10 mg/kg), 6) group 6: treated with LFE (10 ml/kg) + CP (20 mg/kg). Histological examination of the testes of mice treated with CP revealed histopathological changes, such as atrophy, degeneration, incomplete spermatogenic series in most seminiferous tubules, and spermatogenic necrosis with pyknotic nuclei. Advanced degree of improvement was seen in testes of mice treated with LFE co-administered with CP. Most of the seminiferous tubules restored their normal structure and spermatogenic layers appeared semi-normal with complete spermatogenic series. Lemon fruit extract in conjunction with drug treatment protects the testicular tissue against CP-induced testicular injury in mice.


Acute stress and the brain norepinephrine uptake mechanism in the rat.
The kinetic constants for norepinephrine uptake in cerebral cortical homogenates were determined in vitro immediately following an acute stress consisting of either forced immobilization, cold-wet exposure, combined cold-plus-restraint, swim stress, or electric footshock in the rat. The kinetic constants, apparent Km and Vmax, for uptake of 3H-l-norepinephrine were significantly increased only following 10 min swim at 22 degrees or following 5 min electric footshock. When severe hypothermia accompanied the stress, the findings suggested that a profound reduction in body temperature was associated with depressed responsiveness of brain noradrenergic mechanisms to stress including decreased uptake kinetic constants. In a series in which the duration of electric footshock was varied from 2 to 30 min, it was noted that the NE uptake kinetic constants were increased at 5 min, but were similar to paired controls at 2, 10 and 30 min following the onset of footshock. It was concluded that various acute stresses did not elicit a generalized response of the cortical NE uptake mechanism to stress in the rat. Furthermore, when uptake kinetic constants did change with stress, the values were often within the range of normal values seen in the rat.


Identification of an interferon antagonist protein encoded by segment 7 of infectious salmon anaemia virus.
Infectious salmon anaemia virus (ISAV) is an orthomyxovirus and member of the genus Isavirus, which contains eight genomic segments coding for ten viral proteins. This study focussed on identifying the function of the largest protein encoded by ISAV genomic segment 7 (7i), which like influenza A segment 7 encodes two proteins, one of which is based on removal of an intron from the primary transcript. Using two independent methods, an Mx1 promoter-driven reporter system and real-time PCR of FACS-sorted transfected cells, we demonstrate that the non-structural ISAV 7i protein is an interferon-signalling antagonist. Other transfection studies indicated a predominantly cytoplasmic localisation of the expressed protein, which is consistent with this role. The demonstration that ISAV segment 7 encodes a putative non-structural IFN system antagonist reveals a difference with influenza A virus, where segment 7, which shares a similar coding strategy, encodes the structural matrix proteins.


Low incidence of subsequent bacteraemia or fungaemia after removal of a colonized intravascular catheter tip.
We determined the frequency of subsequent bloodstream infection more than 2 days after removal of a catheter with positive tip cultures. We conducted a nationwide, observational study on intravascular catheter (IVC) tip cultures in Switzerland from 2008 to 2015 using data from the Swiss Antibiotic Resistance Surveillance System (ANRESIS). An IVC tip culture was included in the analysis if at least one microorganism could be cultivated from it. We excluded all data from patients with concurrent bacteraemia with the same microorganism identified 7 days before to 2 days after IVC removal. Subsequent bloodstream infection was defined as isolating (from blood cultures performed more than 2 days up to 7 days after catheter removal) the same microorganism as the one recovered from the IVC. Data on antibiotic therapy were not available in this surveillance study. Over the 8-year period, 15 033 positive IVC tip cultures were identified. Our study population comprised 12 513 episodes of positive IVC tip cultures without concurrent bacteraemia. The frequency of sBSI was 1.8% (n = 219). Subsequent bloodstream infections were more frequently detected after identification of C. albicans (10/113, 8.8%), S. marcescens (9/169, 5.3%), and S. aureus (30/623, 4.8%) on a catheter tip. A very low incidence of subsequent bloodstream infection was observed if a microorganism was identified on a removed IVC tip without concurrent bacteraemia. The risk of subsequent bloodstream infection increased if C. albicans, S. aureus, or S. marcescens were identified in this context.


The impact of non-surgical periodontal treatment on serum levels of long chain-polyunsaturated fatty acids: a pilot randomized clinical trial.
Our group recently found higher levels of serum long chain-polyunsaturated fatty acids (LC-PUFAs) in patients with chronic periodontitis compared to controls. However, the effect of periodontal treatment on LC-PUFA serum levels has not been investigated. The primary aim of the present study was to investigate the impact of periodontal treatment on LC-PUFA serum levels. A secondary aim was to assess the effect of dietary ω-3 supplementation on clinical outcome. The test group was composed of 10 patients with generalized chronic periodontitis (mean age 44 ± 6.4 years) treated with scaling and root planing associated with 4 mo of ω-3 supplementation eicosapetaenoic acid (EPA) plus docosahexaenoic acid (DHA), 3 g/d. The placebo group was composed of 11 patients (47.9 ± 10.5 years) that received scaling and root planing plus placebo. The periodontal examination included probing depth, clinical attachment level, bleeding on probing and visible plaque index. Docosapentaenoic acid (DPA), EPA, DHA and arachidonic acid (AA) were detected using gas chromatograph. In the placebo group, all LC-PUFAs levels reduced significantly (DHA, DPA and AA, p = 0.004; EPA, p = 0.008). In the test group, only DPA and AA showed a significant reduction (p = 0.005). Moreover, a significant decrease in the ratios AA/EPA and AA/DHA (p = 0.005) was observed in the test group. Non-surgical periodontal treatment reduced significantly the serum levels of all analyzed LC-PUFAs except those presented in the supplementation. The ω-3 dietary supplementation had no effect on clinical outcome of treatment.


Central nervous system action of calcitonin gene-related peptide to inhibit gastric emptying in the conscious rat.
The central nervous system action of rat alpha-calcitonin gene-related peptide (alpha-CGRP) on gastric emptying of a liquid, noncaloric, methylcellulose solution was assessed in 24-hr fasted, conscious rats using phenol red method as a marker. Intracisternal injection of alpha-CGRP (0.75-250 pmol) dose-dependently inhibited gastric emptying by 27-94% as measured 20 min after oral administration of the solution. The ED50 was 6.2 pmol. alpha-CGRP injected intravenously at 250 pmol delayed gastric emptying by 71% whereas a lower dose (75 pmol) was inactive. Intracisternal alpha-CGRP-induced inhibition of gastric emptying was completely abolished by bilateral adrenalectomy and partially suppressed by subdiaphragmatic vagotomy or coeliac/superior mesenteric ganglionectomy. Adrenalectomy or vagotomy in saline-treated animals did not significantly modify the rate of gastric emptying whereas coeliac/superior mesenteric ganglionectomy caused a significant 29% inhibition as compared to the nonoperated group. These results demonstrate that alpha-CGRP is a potent centrally acting inhibitor of gastric emptying of a nonnutrient liquid. The inhibitory effect of intracisternal injection of CGRP appears to be mediated by the adrenal gland and in part by the sympathetic and parasympathetic nervous system.


Sonic hedgehog-dependent recruitment of GABAergic interneurons into the developing visual thalamus.
Axons of retinal ganglion cells (RGCs) play critical roles in the development of inhibitory circuits in visual thalamus. We previously reported that RGC axons signal astrocytes to induce the expression of fibroblast growth factor 15 (FGF15), a motogen required for GABAergic interneuron migration into visual thalamus. However, how retinal axons induce thalamic astrocytes to generate Fgf15 and influence interneuron migration remains unknown. Here, we demonstrate that impairing RGC activity had little impact on interneuron recruitment into mouse visual thalamus. Instead, our data show that retinal-derived sonic hedgehog (SHH) is essential for interneuron recruitment. Specifically, we show that thalamus-projecting RGCs express SHH and thalamic astrocytes generate downstream components of SHH signaling. Deletion of RGC-derived SHH leads to a significant decrease in Fgf15 expression, as well as in the percentage of interneurons recruited into visual thalamus. Overall, our findings identify a morphogen-dependent neuron-astrocyte signaling mechanism essential for the migration of thalamic interneurons.


Electronic and EPR spectra of the species involved in [W10O32]4- photocatalysis. A relativistic DFT investigation.
The decatungstate anion [W(10)O(32)](4-) is widely used as a photocatalyst in different transformations, during which it undergoes one-electron reduction to [W(10)O(32)](5-), possibly protonated; the bi-reduced species [W(10)O(32)](6-) is obtained by ensuing disproportionation. Relativistic DFT calculations were used to predict the UV-VIS spectra and EPR parameters of all such species.


Giant MACPF/CDC pore forming toxins: A class of their own.
Pore Forming Toxins (PFTs) represent a key mechanism for permitting the passage of proteins and small molecules across the lipid membrane. These proteins are typically produced as soluble monomers that self-assemble into ring-like oligomeric structures on the membrane surface. Following such assembly PFTs undergo a remarkable conformational change to insert into the lipid membrane. While many different protein families have independently evolved such ability, members of the Membrane Attack Complex PerForin/Cholesterol Dependent Cytolysin (MACPF/CDC) superfamily form distinctive giant β-barrel pores comprised of up to 50 monomers and up to 300Å in diameter. In this review we focus on recent advances in understanding the structure of these giant MACPF/CDC pores as well as the underlying molecular mechanisms leading to their formation. Commonalities and evolved variations of the pore forming mechanism across the superfamily are discussed. This article is part of a Special Issue entitled: Pore-Forming Toxins edited by Mauro Dalla Serra and Franco Gambale.


Effectiveness of Adjuvant Chemotherapy with 5-FU/Leucovorin and Prognosis in Stage II Colon Cancer.
The aims of this study were to investigate the survival results and the prognostic factors of adjuvant chemotherapy in stage II colon cancer in the sparsity of Korean data. From 1993 to 2006, 363 curatively resected pathologic stage II colon cancer patients were enrolled. Six cycles of adjuvant chemotherapy was performed: intravenous bolus 5-fluorouracil (5-FU) 500 mg/m(2) with leucovorin 20 mg/m2 for 2 hours daily for 5 days, followed by a 3-week resting period (n = 308). Fifty-five patients received only curative surgery. A high risk of recurrence was defined as the presence of one or more of the following factors: T4 tumor, lympho-vascular invasion, perineural invasion, perforation, obstruction, retrieved lymph node < 12, and poorly differention. The median follow-up period was 68 months (1 to 205 months). The five-year overall survival (OS) rate was 90.1%, and the five-year disease-free survival (DFS) rate was 84.7%. Among high-risk patients, the OS and the DFS rates of the treatment group were significantly higher than those of the non-treatment group (OS: 90.6% vs. 69.1%, P < 0.0001; DFS: 85.9% vs. 54.1%, P < 0.0001). Among low-risk patients, the survival results of the treatment group were also significantly superior (OS: 97.7% vs. 88.2%, P < 0.0001; DFS: 93.0% vs. 80.0%, P = 0.001). In the multivariate analysis, adjuvant chemotherapy was a significantly favorable prognostic factor for overall survival (hazard ratio, 0.41; 95% confidence interval, 0.22 to 0.75; P = 0.004). In our population, adjuvant chemotherapy showed superior survival to curative surgery alone and significantly reduced the risk of death. A nationwide multicenter randomized trial is needed.


Retrieval of Retained Capsule Endoscopy at Small Bowel Stricture by Double-Balloon Endoscopy Significantly Decreases Surgical Treatment.
The aim is to elucidate the efficacy and safety of double-balloon endoscopy (DBE) for small bowel capsule endoscopy (SBCE) retrieval from small bowel stricture and to follow the outcome of the stricture where the SBCE was entrapped. The retention of SBCE is a serious adverse event and most retained capsules are retrieved by surgery. There is still no report analyzing the follow-up of patients with stricture after retrieval of entrapped SBCEs by DBE. This study was designed a retrospective cohort study. Subjects were 12 consecutive patients with small bowel stricture where retrieval of entrapped SBCE was attempted using DBE. Success rate of the SBCE retrieval by DBE, surgical rate of the small bowel stricture, adverse events of DBE, and outcomes in the follow-up period were evaluated. Diagnoses were Crohn's disease, nonsteroidal anti-inflammatory drugs-induced enteropathy, ischemic enteritis, and carcinoma in 8, 2, 1, and 1 patients, respectively. SBCE was successfully retrieved in 11 of the 12 patients (92%). No adverse events were encountered in all endoscopic procedures such as retrieval of SBCEs and dilation of the strictures. Nine of the 12 patients (75%) did not undergo surgical treatment for the stricture where SBCE was entrapped through the follow-up period (mean, 1675±847 d). Retrieval of SBCEs using DBE was safe, had a high success rate, and was useful to evaluate the need for surgery. Seventy-five percent of patients with small bowel stricture where the SBCE was entrapped did not require surgery through approximately 5 years.


Design and evaluation of an intelligent reduction robot system for the minimally invasive reduction in pelvic fractures.
Pelvic fracture is a severe high-energy injury with the highest disability and mortality of all fractures. Traditional open surgery is associated with extensive soft tissue damages and many complications. Minimally invasive surgery potentially mitigates the risks of open surgical procedures and is becoming a new standard for pelvic fracture treatment. The accurate reduction has been recognized as the cornerstone of minimally invasive surgery for pelvic fracture. At present, the closed reduction in pelvic fractures is limited by the current sub-optimal 2D intra-operative imaging (fluoroscopy) and by the high forces of soft tissue involved in the fragment manipulation, which might result in fracture malreduction. To overcome these shortcomings and facilitate pelvic fracture reduction, we developed an intelligent robot-assisted fracture reduction (RAFR) system for pelvic fracture. The presented method is divided into three parts. The first part is the preparation of 20 pelvic fracture models. In the second part, we offer an automatic reduction algorithm of our robotic reduction system, including Intraoperative real-time 3D navigation, reduction path planning, control and fixation, and robotic-assisted fracture reduction. In the third part, image registration accuracy and fracture reduction accuracy were calculated and analyzed. All 20 pelvic fracture bone models were reduced by the RAFR system; the mean registration error E1 of the 20 models was 1.29 ± 0.57 mm. The mean reduction error E2 of the 20 models was 2.72 ± 0.82 mm. The global error analysis of registration and reduction results showed that higher errors are mainly located at the edge of the pelvis, such as the iliac wing. The accuracy of image registration error and fracture reduction error in our study was excellent, which could reach the requirements of the clinical environment. Our study demonstrated the precision and effectiveness of our RAFR system and its applicability and usability in clinical practice, thus paving the way toward robot minimally invasive pelvic fracture surgeries.


Comparing drug effectiveness at health plans: the ethics of cluster randomized trials.
"Cluster randomized trials," in which groups of patients are randomly assigned to different therapeutic interventions, provide a powerful way of evaluating drugs. CRTs have not been widely used, in good part because of concerns about whether patients must give informed consent to participate in them. A better understanding of how CRTs fit into clinical practice resolves the concerns.