Laser-controlled fluorescence in two-level systems.
The ability to modify the character of fluorescent emission by a laser-controlled, optically nonlinear process has recently been shown theoretically feasible, and several possible applications have already been identified. In operation, a pulse of off-resonant probe laser beam, of sufficient intensity, is applied to a system exhibiting fluorescence, during the interval of excited-state decay following the initial excitation. The result is a rate of decay that can be controllably modified, the associated changes in fluorescence behavior affording new, chemically specific information. In this paper, a two-level emission model is employed in the further analysis of this all-optical process; the results should prove especially relevant to the analysis and imaging of physical systems employing fluorescent markers, these ranging from quantum dots to green fluorescence protein. Expressions are presented for the laser-controlled fluorescence anisotropy exhibited by samples in which the fluorophores are randomly oriented. It is also shown that, in systems with suitably configured electronic levels and symmetry properties, fluorescence emission can be produced from energy levels that would normally decay nonradiatively.


The effects of heat stress and its effect modifiers on stroke hospitalizations in Allegheny County, Pennsylvania.
Heat has been known to increase the risk of many health endpoints. However, few studies have examined its effects on stroke. The objective of this case-crossover study is to investigate the effects of high heat and its effect modifiers on the risk of stroke hospitalization in Allegheny County, Pennsylvania. We obtained data on first stroke hospitalizations among adults ages 65 and older and daily meteorological information during warm seasons (May-September) from 1994 to 2000 in Allegheny County, Pennsylvania. Using conditional multiple logistic regressions, the effects of heat days (any day with a temperature greater than the 95th percentile) and heat wave days (at least two continuous heat days) on the risk of stroke hospitalization were investigated. The potential interactions between high heat and age, type of stroke, and gender were also examined. Heat day and heat wave at lag-2 day were significantly associated with an increased risk for stroke hospitalization (OR 1.121, 95 % CI 1.013-1.242; OR 1.173, 95 % CI 1.047-1.315, respectively) after adjusting for important covariates. In addition, having two or more heat wave days within the 4 day window prior to the event was also significantly associated with an increased risk (OR 1.119, 95 % CI 1.004, 1.246) compared to having no heat wave days during the period. The effect of high heat on stroke was more significant for ischemic stroke, men, and subjects ages 80 years or older. Our study suggests that high heat may have adverse effects on stroke and that some subgroups may be particularly susceptible to heat.


Particulate Air Pollution and Risk of Neuropsychiatric Outcomes. What We Breathe, Swallow, and Put on Our Skin Matters.
We appraise newly accumulated evidence of the impact of particle pollution on the brain, the portals of entry, the neural damage mechanisms, and ultimately the neurological and psychiatric outcomes statistically associated with exposures. PM pollution comes from natural and anthropogenic sources such as fossil fuel combustion, engineered nanoparticles (NP ≤ 100 nm), wildfires, and wood burning. We are all constantly exposed during normal daily activities to some level of particle pollution of various sizes-PM2.5 (≤2.5 µm), ultrafine PM (UFP ≤ 100 nm), or NPs. Inhalation, ingestion, and dermal absorption are key portals of entry. Selected literature provides context for the US Environmental Protection Agency (US EPA) ambient air quality standards, the conclusions of an Independent Particulate Matter Review Panel, the importance of internal combustion emissions, and evidence suggesting UFPs/NPs cross biological barriers and reach the brain. NPs produce oxidative stress and neuroinflammation, neurovascular unit, mitochondrial, endoplasmic reticulum and DNA damage, protein aggregation and misfolding, and other effects. Exposure to ambient PM2.5 concentrations at or below current US standards can increase the risk for TIAs, ischemic and hemorrhagic stroke, cognitive deficits, dementia, and Alzheimer's and Parkinson's diseases. Residing in a highly polluted megacity is associated with Alzheimer neuropathology hallmarks in 99.5% of residents between 11 months and ≤40 y. PD risk and aggravation are linked to air pollution and exposure to diesel exhaust increases ALS risk. Overall, the literature supports that particle pollution contributes to targeted neurological and psychiatric outcomes and highlights the complexity of the pathophysiologic mechanisms and the marked differences in pollution profiles inducing neural damage. Factors such as emission source intensity, genetics, nutrition, comorbidities, and others also play a role. PM2.5 is a threat for neurological and psychiatric diseases. Thus, future research should address specifically the potential role of UFPs/NPs in inducing neural damage.


Phase I study of troxacitabine administered by continuous infusion in subjects with advanced solid malignancies.
Troxacitabine is a novel L-nucleoside analogue. Preclinical studies showed improved activity with infusions of at least 3 days compared with bolus regimens, especially at concentrations >20 ng/ml. This phase I study tested the feasibility of achieving a troxacitabine steady-state concentration of 20 ng/ml for at least 72 h in patients with solid tumors. Patients with solid tumors received troxacitabine as a progressively longer infusion on days 1-4 of a 28-day cycle. The initial length of infusion and infusion rate were 48 h and 3 mg/m(2)/day. Twenty-one patients were treated at infusion lengths that increased from 48 to 72 h and then 96 h. The infusion rate was decreased from 3 to 1.88 mg/m(2)/day due to toxicity. Dose-limiting toxicities consisted of grade 4 neutropenia (three) and grade 3 constipation (one). The maximum tolerated dose of continuous infusion troxacitabine in patients with solid tumors is 7.5 mg/m(2) administered over 96 h. This dose level resulted in steady-state drug concentration of at least 20 ng/ml for 72 h. Administration of troxacitabine by continuous infusion achieved the prospectively defined target plasma concentration. Pharmacokinetics (PK) modeling coupled with real-time PK assessment was an efficient approach to conduct hypothesis-driven phase I trials.


The Effects of the Jump-In Whole-School Intervention on the Weight Development of Children in Amsterdam, the Netherlands.
This study assessed the effects of the "Jump-in" whole-school intervention in Amsterdam, the Netherlands, on children's weight development by comparing children exposed to the intervention and controls from 3 other large Dutch cities. Jump-in is a comprehensive intervention that aims to stimulate healthy nutrition and physical activity in children at primary schools in Amsterdam. In addition, the relationship between the intervention's implementation degree and its effectiveness was studied. Demographic and anthropometric data, collected by youth health care professionals via routine health checks at T0 (2014) and T1 (2019), were used to analyze possible intervention effects by comparing the weight development of children exposed to the Jump-in intervention versus unexposed controls. Implementation logs from health promotion professionals were used to determine intervention effects per implementation degree. Multilevel regression analyses were used for all analyses. In total, 4299 children were included mean age ± 5.5 years (T0), 10.6 years (T1), and ≈50% boys/girls at both times. Receiving the fully implemented intervention resulted in a decline in standardized body-mass index (zBMI) compared to the controls (-0.23, confidence interval [CI] -0.33, -0.13). It also led to higher odds to move into a healthier weight category over time (odds ratio [OR] 1.36, CI 1.06, 1.74), yet no statistically significant shift towards a healthy weight was found. Relative to the controls, children exposed to the intervention showed positive zBMI developments, with stronger effects when the implementation degree was higher. Despite positive results, creating more impact might require the further integration of school-based programs into whole-systems approaches that include other energy-balance behaviors.


Hypoxic cell radiosensitization by 8-methoxypsoralen.
8-Methoxypsoralen has been shown to act as a radiosensitizer of hypoxic bacteriophage and bacteria. Radiosensitization of bacteriophage requires irradiation in the presence of excess scavenger. Bacterial radiosensitization requires deficiencies in uvr and rec genes. For the drug to be effective it must be present during irradiation. Pulse radiolysis studies have shown that, like electron-affinic radiosensitizers, 8MOP can efficiently oxidize free radicals. Unlike oxygen and most electron-affinic radiosensitizers 8MOP does not act in a purely dose-modifying fashion, and can radiosensitize beyond the oxygen effect.


In Silico Molecular Characterization of Cysteine Protease YopT from Yersinia pestis by Homology Modeling and Binding Site Identification.
Plague is a major health concern and Yersinia pestis plays the central causal role in this disease. Yersinia pestis has developed resistance against the commonly available drugs. So, it is now a key concern to find a new drug target. Cysteine protease YopT enzyme is an important factor used by Yersinia pestis for pathogenesis in its host and it has the anti-phagocytic function of removal of C-termini lipid modification. The 3D structure of cysteine protease YopT of Yersinia pestis was determined by means of homology modeling through multiple alignments followed by intensive optimization and validation. The modeling was done by Phyre 2 and refined by ModRefiner. The obtained model was verified with structure validation programs such as PROCHECK, verify 3D and ERRAT for reliability. Interacting partners and active sites were also determined. PROCHECK analysis showed that 93% of the residues are in the most favored region, 5.9% are in the additional allowed region and 1.1% are in the generously allowed region of the Ramachandran plot. The verify 3D value of 0.78 indicates that the environmental profile of the model is good. SOPMA is employed for calculation of the secondary structural features of cysteine protease YopT. Active site determination through CASTp proposes that this protein can be utilized as a potential drug target. However, these findings should further be confirmed by wet lab studies for a targeted therapeutic agent design against Yersinia pestis.


[Animal models of drug dependence using the drug self-administration method].
This paper will review 1) experimental models of drug-seeking behavior and 2) mechanisms underlying the behavior, focusing on cocaine self-administration. After the acquisition of self-administration, vigorous lever-pressing is generally observable after the drug was replaced by saline. This lever-pressing behavior under saline infusion can be considered "drug-seeking behavior". Drug-seeking behavior is reinstated by non-contingent injection of the drug, stress exposure and presentation of drug-associated stimuli even after extinction. This is called a relapse/reinstatement model. Electrophysiological studies showed that the majority of accumbal neurons is tonically inhibited during cocaine self-administration and exhibited phasic increases in firing time-locked to cocaine self-infusion, which might represent the craving state or drive animals to drug-seeking behavior. Voltammetry and microdialysis studies indicated that the timing of drug-seeking responses can be predicted from fluctuations in accumbal extracellular dopamine concentration. Whereas dopamine D2-like agonists reinstated extinguished cocaine-seeking behavior, D1-like agonists prevented the relapse in cocaine-seeking behavior induced by cocaine itself. Given that an AMPA receptor antagonist, but not dopamine antagonist, prevented cocaine-seeking behavior induced by cocaine, glutamate transmission in the nucleus accumbens is thought to be important for expression of craving or drug-seeking behavior.


[The method for early diagnosis of the gastric cancer based metabolomics research].
This paper deals with the questions of the usage of metabolomics research results in the diagnosis of gastric cancer. The central idea metabolomics is to identify the specific biomarkers in a biological sample used in a diagnostics this disease. The volatile organic compounds--metabolites isolated from the urine samples from patients are considered as biomarkers. The paper also describes main methods of separation and identification of volatile organic compounds (gas chromatography, mass spectrometry) applied in metabolomics. The paper presents some results of laboratory research aimed at the detection of biomarkers of gastric cancer. The presented material will be of some help in solving the problems of early diagnosis of this disease.


Clinical features of patients with GJB2 (connexin 26) mutations: severity of hearing loss is correlated with genotypes and protein expression patterns.
Mutations in the GJB2 (connexin 26, Cx26) gene are the major cause of nonsyndromic hearing impairment in many populations. Genetic testing offers opportunities to determine the cause of deafness and predict the course of hearing, enabling the prognostication of language development. In the current study, we compared severity of hearing impairment in 60 patients associated with biallelic GJB2 mutations and assessed the correlation of genotypes and phenotypes. Within a spectrum of GJB2 mutations found in the Japanese population, the phenotype of the most prevalent mutation, 235delC, was found to show more severe hearing impairment than that of V37I, which is the second most frequent mutation. The results of the present study, taken together with phenotypes caused by other types of mutations, support the general rule that phenotypes caused by the truncating GJB2 mutations are more severe than those caused by missense mutations. The present in vitro study further confirmed that differences in phenotypes could be explained by the protein expression pattern.


Prostaglandins and potassium relaxation in vascular smooth muscle of the rat. The role of Na-K ATPase.
We explored the hypothesis that postaglandin-induced vasodilation is caused by activation of the electrogenic sodium-potassium pump which results in membrane hyperpolarization and relaxation of vascular smooth muscle. Helical strips of rat tail artery relax in response to potassium after norepinephrine-induced contractions in physiological salt solution containing a low-potassium concentration. The amplitude of this potassium relaxation is used as an index of sodium-potassium ATPase activity. It was observed that PGA1, PGE2, and PGF2alpha (10(-6) g/ml) significantly enhanced the magnitut. PGE2 caused relaxation of contractions induced by either 25 mM KCl or norepinephrine (10(-9) g/ml), and these relaxations were inhibited by 10(-4) M ouabain. Indomethacin (5.3 x 10(-6) g/ml) and meclofenamate (10(-6) g/ml) reduced the magnitude of potassium-induced relaxation by more than 30% of control. PGF2alpha (10(-5) g/ml) reversed the inhibition of potassium relaxation by meclofenamate. These observations suggest that prostaglandins induce vascular smooth muscle relaxation by stimulation of the sodium pump and that endogenous prostaglandins normally potassium relaxation.


A VLSI recurrent network of integrate-and-fire neurons connected by plastic synapses with long-term memory.
Electronic neuromorphic devices with on-chip, on-line learning should be able to modify quickly the synaptic couplings to acquire information about new patterns to be stored (synaptic plasticity) and, at the same time, preserve this information on very long time scales (synaptic stability). Here, we illustrate the electronic implementation of a simple solution to this stability-plasticity problem, recently proposed and studied in various contexts. It is based on the observation that reducing the analog depth of the synapses to the extreme (bistable synapses) does not necessarily disrupt the performance of the device as an associative memory, provided that 1) the number of neurons is large enough; 2) the transitions between stable synaptic states are stochastic; and 3) learning is slow. The drastic reduction of the analog depth of the synaptic variable also makes this solution appealing from the point of view of electronic implementation and offers a simple methodological alternative to the technological solution based on floating gates. We describe the full custom analog very large-scale integration (VLSI) realization of a small network of integrate-and-fire neurons connected by bistable deterministic plastic synapses which can implement the idea of stochastic learning. In the absence of stimuli, the memory is preserved indefinitely. During the stimulation the synapse undergoes quick temporary changes through the activities of the pre- and postsynaptic neurons; those changes stochastically result in a long-term modification of the synaptic efficacy. The intentionally disordered pattern of connectivity allows the system to generate a randomness suited to drive the stochastic selection mechanism. We check by a suitable stimulation protocol that the stochastic synaptic plasticity produces the expected pattern of potentiation and depression in the electronic network.


[Progression of early childhood sensorineural hearing damage].
44 patients with early childhood sensorineural hearing impairments were assessed. Hearing ability appeared definitely assessable from the fifth year onwards. The average observation time was 6 years. In one third of our 44 cases, a progressive sensorineural hearing impairment on both ears could be determined. In two thirds of the cases no sound threshold shift was found. It appears that the female sex is slightly more prone to gradual hearing impairment. Finally, differential diagnostic questions (fluctuating hearing, impediment caused by artificial hearing aids) and therapeutical possibilities (genetic advice, microcirculatory impediments, autoimmune diseases, and operative possibilities) are discussed.


Proteasome inhibitors activate autophagy involving inhibition of PI3K-Akt-mTOR pathway as an anti-oxidation defense in human RPE cells.
The two major intracellular protein degradation systems, the ubiquitin-proteasome system (UPS) and autophagy, work collaboratively in many biological processes including development, apoptosis, aging, and countering oxidative injuries. We report here that, in human retinal pigment epithelial cells (RPE), ARPE-19 cells, proteasome inhibitors, clasto-lactacystinβ-lactone (LA) or epoxomicin (Epo), at non-lethal doses, increased the protein levels of autophagy-specific genes Atg5 and Atg7 and enhanced the conversion of microtubule-associated protein light chain (LC3) from LC3-I to its lipidative form, LC3-II, which was enhanced by co-addition of the saturated concentration of Bafilomycin A1 (Baf). Detection of co-localization for LC3 staining and labeled-lysosome further confirmed autophagic flux induced by LA or Epo. LA or Epo reduced the phosphorylation of the protein kinase B (Akt), a downstream target of phosphatidylinositol-3-kinases (PI3K), and mammalian target of rapamycin (mTOR) in ARPE-19 cells; by contrast, the induced changes of autophagy substrate, p62, showed biphasic pattern. The autophagy inhibitor, Baf, attenuated the reduction in oxidative injury conferred by treatment with low doses of LA and Epo in ARPE-19 cells exposed to menadione (VK3) or 4-hydroxynonenal (4-HNE). Knockdown of Atg7 with siRNA in ARPE-19 cells reduced the protective effects of LA or Epo against VK3. Overall, our results suggest that treatment with low levels of proteasome inhibitors confers resistance to oxidative injury by a pathway involving inhibition of the PI3K-Akt-mTOR pathway and activation of autophagy.


Photo-thermal effects in gold nanoparticles dispersed in thermotropic nematic liquid crystals.
The last few years have seen a growing interest in the ability of metallic nanoparticles (MNPs) to control temperature at the nanoscale. Under a suitable optical radiation, MNPs feature an enhanced light absorption/scattering, thus turning into an ideal nano-source of heat, remotely controllable by means of light. In this framework, we report our recent efforts on modeling and characterizing the photo-thermal effects observed in gold nanoparticles (GNPs) dispersed in thermotropic Liquid Crystals (LCs). Photo-induced temperature variations in GNPs dispersed in Nematic LCs (NLCs) have been studied by implementing an ad hoc theoretical model based on the thermal heating equation applied to an anisotropic medium. Theoretical predictions have been verified by performing photo-heating experiments on a sample containing a small percentage of GNPs dispersed in NLCs. Both theory and experiments represent an important achievement in understanding the physics of heat transfer at the nanoscale, with applications ranging from photonics to nanomedicine.


A series of cases of rhabdomyolysis after ingestion of Tricholoma equestre.
Tricholoma equestre (hereinafter - T. equestre) is a common edible fungus that is considered to be toxic under certain conditions. Here, we report four cases of acute poisoning caused by T. equestre, including one lethal outcome in Lithuania between 2004 and 2013. In the severe case, fatigue, nausea without vomiting and muscle pain, profuse sweating without fever, and respiratory insufficiency occurred. Laboratory tests showed an elevation of creatine kinase (CK), aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Although clinical findings and laboratory tests support evidence of rhabdomyolysis, no renal insufficiency was observed. Significance of T. equestre in cardiac changes is feasible but remains unclear.


Neutrophil-to-lymphocyte ratio as an independent risk factor for mortality in hospitalized patients with COVID-19.
Several studies have described the clinical characteristics of patients with novel coronavirus (SARS-CoV-2) infected pneumonia (COVID-19), indicating severe patients tended to have higher neutrophil to lymphocyte ratio (NLR). Whether baseline NLR could be an independent predictor of in-hospital death in Chinese COVID-19 patients remains to be investigated. A cohort of patients with COVID-19 admitted to the Zhongnan Hospital of Wuhan University from January 1 to February 29 was retrospectively analyzed. The baseline data of laboratory examinations, including NLR, were collected. Univariate and multivariate logistic regression models were developed to assess the independent relationship between the baseline NLR and in-hospital all-cause death. A sensitivity analysis was performed by converting NLR from a continuous variable to a categorical variable according to tertile. Interaction and stratified analyses were conducted as well. 245 COVID-19 patients were included in the final analyses, and the in-hospital mortality was 13.47%. Multivariate analysis demonstrated that there was 8% higher risk of in-hospital mortality for each unit increase in NLR (Odds ratio [OR] = 1.08; 95% confidence interval [95% CI], 1.01 to 1.14; P = 0.0147). Compared with patients in the lowest tertile, the NLR of patients in the highest tertile had a 15.04-fold higher risk of death (OR = 16.04; 95% CI, 1.14 to 224.95; P = 0.0395) after adjustment for potential confounders. Notably, the fully adjusted OR for mortality was 1.10 in males for each unit increase of NLR (OR = 1.10; 95% CI, 1.02 to 1.19; P = 0.016). NLR is an independent risk factor of the in-hospital mortality for COVID-19 patients especially for male. Assessment of NLR may help identify high risk individuals with COVID-19.


The AEDUCATE Collaboration. Comprehensive antenatal education birth preparation programmes to reduce the rates of caesarean section in nulliparous women. Protocol for an individual participant data prospective meta-analysis.
Rates of medical interventions in normal labour and birth are increasing. This prospective meta-analysis (PMA) proposes to assess whether the addition of a comprehensive multicomponent birth preparation programme reduces caesarean section (CS) in nulliparous women compared with standard hospital care. Additionally, do participant characteristics, intervention components or hospital characteristics modify the effectiveness of the programme? METHODS AND ANALYSIS: Population: women with singleton vertex pregnancies, no planned caesarean section (CS) or epidural.Intervention: in addition to hospital-based standard care, a comprehensive antenatal education programme that includes multiple components for birth preparation, addressing the three objectives: preparing women and their birth partner/support person for childbirth through education on physiological/hormonal birth (knowledge and understanding); building women's confidence through psychological preparation (positive mindset) and support their ability to birth without pain relief using evidence-based tools (tools and techniques). The intervention could occur in a hospital-based or community setting.Comparator: standard care alone in hospital-based maternity units. Primary: CS.Secondary: epidural analgesia, mode of birth, perineal trauma, postpartum haemorrhage, newborn resuscitation, psychosocial well-being.Subgroup analysis: parity, model of care, maternal risk status, maternal education, maternal socio-economic status, intervention components. An individual participant data (IPD) prospective meta-analysis (PMA) of randomised controlled trials, including cluster design. Each trial is conducted independently but share core protocol elements to contribute data to the PMA. Participating trials are deemed eligible for the PMA if their results are not yet known outside their Data Monitoring Committees. Participants in the individual trials will consent to participation, with respective trials receiving ethical approval by their local Human Research Ethics Committees. Individual datasets remain the property of trialists, and can be published prior to the publication of final PMA results. The overall data for meta-analysis will be held, analysed and published by the collaborative group, led by the Cochrane PMA group. CRD42020103857.


Measuring surface charge density and particle height using surface plasmon resonance technique.
We demonstrate a method to measure surface charge density and particle height using surface plasmon resonance (SPR) detection. It is based on two facts: (1) The equilibrium height of a charged particle over a charged surface depends on the electrostatic interaction between the particle and the surface; and (2) SPR is extremely sensitive to the height of the particle. We perform numerical simulations to establish the relations between the SPR signal and the particle height, and between the particle height and the surface charge density, and carry out systematic experiments, including effects of different buffer concentrations, particle sizes, and concentrations, to examine the relations. The simulation and experimental results are in good agreement with each other. Using the method, we determine surface charge density of gold surface functionalized with different molecules. If the surface charge density is known, the method can also be used to determine the charges of the particles.


Safety and efficacy of Sorbiflore®ADVANCE (Lactobacillus rhamnosus CNCM I-3698 and Lactobacillus farciminis CNCM I-3699) as a feed additive for chickens for fattening.
Following a request from the European Commission, the EFSA Panel on Additives and products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of Sorbiflore® ADVANCE when used as a zootechnical feed additive for chickens for fattening. Sorbiflore® ADVANCE is an additive resulting from the fermentation of milk-based broth with Lactobacillus rhamnosus CNCM I-3698 and Lactobacillus farciminis CNCM I-3699. Sorbiflore® ADVANCE is intended for use in feed for chickens for fattening at the minimum concentration of 5 × 107 Viable Forming Units (VFU)/kg and the maximum concentration of 2 × 108 VFU/kg complete feed. The data submitted did not allow a full characterisation of the additive, and therefore, uncertainty remains on the nature of the product in terms of viability, on the ratio between the active agents and on the stability and homogeneity of the additive. The active agents fulfil the requirements of the Qualified Presumption of Safety (QPS) approach to the assessment of safety and no concerns are expected from other components of the additive. Consequently, Sorbiflore® ADVANCE is presumed to be safe for the target animals, consumers of products from animals receiving the additive and the environment. The additive should be considered a respiratory sensitiser. In the absence of data, no conclusions can be drawn on the irritancy of Sorbiflore® ADVANCE to skin and eyes and on its dermal sensitisation potential. Sorbiflore® ADVANCE at 2 × 108 VFU/kg feed has the potential to be efficacious in chickens for fattening.


KEX2 mutations suppress RNA polymerase II mutants and alter the temperature range of yeast cell growth.
Suppressors of a temperature-sensitive RNA polymerase II mutation were isolated to identify proteins that interact with RNA polymerase II in yeast cells. Ten independently isolated extragenic mutations that suppressed the temperature-sensitive mutation rpb1-1 and produced a cold-sensitive phenotype were all found to be alleles of a single gene, SRB1. An SRB1 partial deletion mutant was further investigated and found to exhibit several pleiotropic phenotypes. These included suppression of numerous temperature-sensitive RNA polymerase II mutations, alteration of the temperature growth range of cells containing wild-type RNA polymerase, and sterility of cells of alpha mating type. The ability of SRB1 mutations to suppress the temperature-sensitive phenotype of RNA polymerase II mutants did not extend to other temperature-sensitive mutants investigated. Isolation of the SRB1 gene revealed that SRB1 is KEX2. These results indicate that the KEX2 protease, whose only known substrates are hormone precursors, can have an important influence on RNA polymerase II and the temperature-dependent growth properties of yeast cells.


Effects of castration and weaning conducted concurrently or consecutively on behaviour, blood traits and performance in beef calves.
The objectives of this study were to evaluate the effects of Burdizzo castration and abrupt weaning on the behaviour, blood traits and performance of beef calves when weaning was conducted concurrently or consecutively to castration. In total, 64 male beef calves aged between 6 and 7 months were assigned to a 2×2 factorial design with the following treatment groups (n=16 animals per treatment): (1) castrated and concurrently weaned in week 0 (CAS-WEA); (2) castrated in week 0 and weaned in week 4 (CAS-CON); (3) bulls weaned in week 0 (BUL-WEA); and (4) bulls weaned in week 4 (BUL-CON). The behaviour of the calves was observed for 3 days following weaning. Blood was collected weekly from weeks 0 to 5 and analysed for the acute-phase protein haptoglobin, and neutrophil and lymphocyte percentages. BW was recorded weekly from weeks 0 to 7. Animals were slaughtered at 17 months and weight, dressing percentage and carcass classifications were recorded. On day 1 after weaning, the number of vocalizations (calls/10 min) was higher in BUL-WEA (7.2) and CAS-WEA (5.4) than in calves of CAS-CON (2.8) and BUL-CON (2.9) groups (P<0.05). From days 1 to 3 vocalizations decreased in all groups. CAS-CON and BUL-CON animals spent 20% lying on day 1 after weaning compared with 40% in CAS-WEA and BUL-WEA calves (P<0.05). The haptoglobin concentration decreased during the first 5 weeks after weaning in all groups independent of the castration, weaning group or its interaction (P>0.05). WEA groups showed an increased average daily gain (ADG) during weeks 0 to 3 and a reduced ADG during 4 to 7 weeks in comparison with CON animals. At slaughter, bulls were about 80 kg heavier than castrates and had a superior dressing percentage and carcass classification (P>0.05). In conclusion, weaning had a greater effect on the number of vocalizations, standing/walking and lying behaviour and ADG compared with Burdizzo castration. In comparison with undertaking the procedures separately, concurrent castration and weaning neither affected behaviour and haematological parameters nor impaired performance. There was no evidence that the concurrent application of both treatments markedly increased the stress response compared with their application at intervals of a few weeks.


H-coil repetitive transcranial magnetic stimulation for treatment of temporal lobe epilepsy: A case report.
Low frequency repetitive TMS (rTMS) of a cortical seizure focus is emerging as an antiepileptic treatment. While conventional rTMS stimulators activate only superficial cortical areas, reaching deep epileptic foci, for example in temporal lobe epilepsy (TLE), is possible using specially designed H-coils. We report the results of rTMS in a young adult with pharmacoresistant bilateral TLE who underwent three courses (of 10, 15, and 30 daily sessions) of unilateral rTMS over the hemisphere from which seizures originated most often. Seizure frequency was assessed before and after each block of rTMS sessions, as was the tolerability of the procedure. Seizure frequency declined significantly, by 50 to 70% following each rTMS course. All sessions were well-tolerated.


Generation and reception of ultrasonic guided waves in composite plates using conformable piezoelectric transmitters and optical-fiber detectors.
A condition monitoring nondestructive evaluation (NDE) system, combining the generation of ultrasonic Lamb waves in thin composite plates and their subsequent detection using an embedded optical fiber system is described. The acoustic source is of low profile with respect to the composite plate thickness, surface conformable, and able to efficiently launch a known Lamb wave mode, at operating frequencies between 100 and 500 kHz, over typical propagation distances of 100 to 500 mm. It incorporates both piezocomposite technology and interdigital design techniques to generate the fundamental symmetrical Lamb wave mode in both metallic and carbon-fiber composite plates. Linear systems and finite element modeling techniques have been used to evaluate the operation of the transducer structure, and this is supplemented by experimental verification of the simulated data. An optical fiber, either bonded to the surface or embedded across the length of the composite plate samples, is used to detect the propagating ultrasonic Lamb waves. Single mode silica fiber has been used in conjunction with a portable 633 nm Mach-Zehnder interferometer for signal demodulation and subsequent data acquisition. This hybrid system is shown to generate and detect the fundamental symmetrical Lamb wave (s(0)) in both carbon-fiber and glass-fiber reinforced composite plates. Importantly, the system signal-to-noise ratio (SNR) associated with the acoustic source compares favorably with s(0) Lamb wave generation using a conventional transducer and angled perspex wedge arrangement.


Tumor-caused changes in host protein synthesis under different dietary situations.
The effect of the AC33 tumor on protein synthesis in Lewis-Wistar rats was investigated under four different dietary regimens. The four diets used were: (a) 1.25 g amino acids plus 12.5 g glucose per day, (b) 1.25 g amino acids, (c) 1.25 g glucose per day, and (d) 12.5 g glucose per day. The rats were maintained on these four diets for 4 days. On the 5th day, 65 to 75 mg 99.2% [15N] glycine were added to the infusate and infused at a constant rate for the next 18 hr. The rats were then sacrificed and the liver, lung, heart, kidney, anterior tibialis muscle, and tumor were rapidly removed and frozen in liquid nitrogen. The rate of protein synthesis for these tissues was calculated from the ratio of 15N in the tissue protein to that in the tissue intracellular fluid. The protein synthesis rates were compared with the values found for a series of nontumor control rats fed the same diets. Relative to the control rats, muscle protein synthesis decreased on Diet 1, and liver protein synthesis increased with the three deficient diets.


Transcriptional Regulation of Drought Response in Arabidopsis and Woody Plants.
Within the context of global warming, long-living plants such as perennial woody species endure adverse conditions. Among all of the abiotic stresses, drought stress is one of the most detrimental stresses that inhibit plant growth and productivity. Plants have evolved multiple mechanisms to respond to drought stress, among which transcriptional regulation is one of the key mechanisms. In this review, we summarize recent progress on the regulation of drought response by transcription factor (TF) families, which include abscisic acid (ABA)-dependent ABA-responsive element/ABRE-binding factors (ABRE/ABF), WRKY, and Nuclear Factor Y families, as well as ABA-independent AP2/ERF and NAC families, in the model plant Arabidopsis. We also review what is known in woody species, particularly Populus, due to its importance and relevance in economic and ecological processes. We discuss opportunities for a deeper understanding of drought response in woody plants with the development of high-throughput omics analyses and advanced genome editing techniques.


The remarkable diversity of plant PEPC (phosphoenolpyruvate carboxylase): recent insights into the physiological functions and post-translational controls of non-photosynthetic PEPCs.
PEPC [PEP (phosphoenolpyruvate) carboxylase] is a tightly controlled enzyme located at the core of plant C-metabolism that catalyses the irreversible β-carboxylation of PEP to form oxaloacetate and Pi. The critical role of PEPC in assimilating atmospheric CO(2) during C(4) and Crassulacean acid metabolism photosynthesis has been studied extensively. PEPC also fulfils a broad spectrum of non-photosynthetic functions, particularly the anaplerotic replenishment of tricarboxylic acid cycle intermediates consumed during biosynthesis and nitrogen assimilation. An impressive array of strategies has evolved to co-ordinate in vivo PEPC activity with cellular demands for C(4)-C(6) carboxylic acids. To achieve its diverse roles and complex regulation, PEPC belongs to a small multigene family encoding several closely related PTPCs (plant-type PEPCs), along with a distantly related BTPC (bacterial-type PEPC). PTPC genes encode ~110-kDa polypeptides containing conserved serine-phosphorylation and lysine-mono-ubiquitination sites, and typically exist as homotetrameric Class-1 PEPCs. In contrast, BTPC genes encode larger ~117-kDa polypeptides owing to a unique intrinsically disordered domain that mediates BTPC's tight interaction with co-expressed PTPC subunits. This association results in the formation of unusual ~900-kDa Class-2 PEPC hetero-octameric complexes that are desensitized to allosteric effectors. BTPC is a catalytic and regulatory subunit of Class-2 PEPC that is subject to multi-site regulatory phosphorylation in vivo. The interaction between divergent PEPC polypeptides within Class-2 PEPCs adds another layer of complexity to the evolution, physiological functions and metabolic control of this essential CO(2)-fixing plant enzyme. The present review summarizes exciting developments concerning the functions, post-translational controls and subcellular location of plant PTPC and BTPC isoenzymes.


Breathing not properly 10 years later: what we have learned and what we still need to learn.
Since the initial studies showing the usefulness of B-type natriuretic peptide for aiding in heart failure diagnosis, a vast number of other clinical applications for this neurohormone have emerged. In addition to refining our capabilities to diagnose and prognosticate in acute heart failure, natriuretic peptides are now being used in outpatient heart failure clinics, in screening programs, and in risk prediction algorithms in various settings. In just 10 years, B-type natriuretic peptide has gone from being an unknown biomarker to being one of the most useful in cardiology and beyond. In this perspective piece, the investigators review what we have learned about using natriuretic peptides over the past 10 years and the anticipated advances in their use over the next decade.


Structural and biochemical characterization of an active arylamine N-acetyltransferase possessing a non-canonical Cys-His-Glu catalytic triad.
Arylamine N-acetyltransferases (NATs), a class of xenobiotic-metabolizing enzymes, catalyze the acetylation of aromatic amine compounds through a strictly conserved Cys-His-Asp catalytic triad. Each residue is essential for catalysis in both prokaryotic and eukaryotic NATs. Indeed, in (HUMAN)NAT2 variants, mutation of the Asp residue to Asn, Gln, or Glu dramatically impairs enzyme activity. However, a putative atypical NAT harboring a catalytic triad Glu residue was recently identified in Bacillus cereus ((BACCR)NAT3) but has not yet been characterized. We report here the crystal structure and functional characterization of this atypical NAT. The overall fold of (BACCR)NAT3 and the geometry of its Cys-His-Glu catalytic triad are similar to those present in functional NATs. Importantly, the enzyme was found to be active and to acetylate prototypic arylamine NAT substrates. In contrast to (HUMAN) NAT2, the presence of a Glu or Asp in the triad of (BACCR)NAT3 did not significantly affect enzyme structure or function. Computational analysis identified differences in residue packing and steric constraints in the active site of (BACCR)NAT3 that allow it to accommodate a Cys-His-Glu triad. These findings overturn the conventional view, demonstrating that the catalytic triad of this family of acetyltransferases is plastic. Moreover, they highlight the need for further study of the evolutionary history of NATs and the functional significance of the predominant Cys-His-Asp triad in both prokaryotic and eukaryotic forms.


Bmp7 mediates early signaling events during induction of chick epidermal organs.
The induction and specification of a large number of vertebrate organs require reciprocal signaling between an epithelium and subjacent mesenchyme. In the formation of integumentary organs, the initial inductive signaling events leading to the formation of the organ primordia stem from the mesenchyme. However, the epithelium must have the capacity to respond to these signals. We demonstrate that bone morphogenetic protein 7 (Bmp7) is an early molecular marker for epidermal organ development during development of feathers and scales of the chick. Bmp7 is expressed broadly in the preplacode epidermis and subsequently becomes localized to the forming placodes of feathers and scales. An examination of Bmp7 expression in the scaleless mutant chicken integument indicates that Bmp7 expression in the epidermis is associated with the ability to form epidermal organs. We show that BMP7 function is necessary for the formation of epidermal placodes in both feather and scale forming epidermis. In addition, precocious expression of Bmp7 in the metatarsal epidermis of the Silkie mutant or treatment of the metatarsus with ectopic BMP7 protein results in feather development from scale forming integument. From these data, we propose that Bmp7 is necessary and sufficient, in a developmental context, to mediate the competence of an epithelium to respond to inductive signals from the underlying mesenchyme to form epidermal organs in the chick. We propose that regulation of Bmp7 in localized areas of the embryonic epidermis facilitates the development of regional formation of integumentary organs.


Triangular lipodermal flaps in Wise pattern reduction mammoplasty (superomedial pedicle): A novel technique to reduce T-junction necrosis.
Although Wise pattern reduction mammoplasty is one of the most prevalent procedures providing satisfactory cutaneous reduction, it is at the expense of inevitable lengthier scars and wound complications, especially at the inverted T junction. To describe a novel technique providing tension-free closure at the T junction through performing triangular lipodermal flaps. The aim is to alleviate skin tension, thus reducing skin necrosis, dehiscence and excessive scarring at the T junction. One hundred seventy-three consecutive procedures were performed on 137 patients between 2009 and 2013. Data collected included demographics, perioperative morbidity and resected breast tissue weight. The follow-up period ranged from three to 30 months; early and late postoperative complications and patient satisfaction were recorded. Superficial epidermolysis without T-junction dehiscence was experienced in eight (4.6%) procedures while five (2.9%) procedures developed full-thickness wound dehiscence. Ninety-four percent of patients were highly satisfied with the outcome. The technique is safe, versatile and easy to execute, providing a tension-free zone and acting as internal dermal sling, thus providing better wound healing with more favourable aesthetic outcome and maintaining breast projection.


[Feline hemoplasmas in Switzerland: identification of a novel species, diagnosis, prevalence, and clinical importance].
Two feline hemotropic mycoplasma spp. (aka hemoplasma) have previously been recognized. We recently discovered a third novel species in a cat with hemolytic anemia, designated 'Candidatus Mycoplasma turicensis', which is closely related to rodent haemoplasmas. This novel species induced anemia after experimental transmission to two SPF cats. Three quantitative real-time PCR assays were newly designed and applied to an epidemiological study surveying the Swiss pet cat population. Blood samples from 713 healthy and ill cats were analyzed. Up to 104 parameters per cat (detailed questionnaire, case history, laboratory parameters and retroviral infections) were evaluated. 'Candidatus Mycoplasma haemominutum' infection was more prevalent (8.5%) than Mycoplasma haemofelis (0.5%) and 'Candidatus Mycoplasma turicensis' (1%). Hemoplasma infections were associated with male gender, outdoor access, and old age, but not with disease or anemia. Infections were more frequently found in the South and West of Switzerland. Several hemoplasma infected cats, some acutely infected, others co-infected with FIV or FeLV, showed hemolytic anemia indicating that additional factors might play a role in the pathogenesis of the disease.


[Role of economic studies in animal health decisions: Example of the cost-benefit ratio of eradication of bovine viral diarrhea in France].
To help livestock production groups to rationalise health decisions, and at the request of the Association for the certification of livestock health (Association pour la certification de la santé animale en élevage: ACERSA), an economic study was conducted to assess the possible cost-effectiveness of the eradication of bovine virus diarrhoea in France. The study was performed using a fictitious average region comprising 235,000 cattle belonging to 3,300 farms, which corresponds to one-eighty-fifth of the total cattle population of France. In the first phase of the study, the cost of the disease in this region was estimated to be approximately six million French francs (US$989,937) per year. Subsequently, the cost of an eradication strategy based on the inspection of all animals when introduced into a herd, the screening of permanently-infected immunotolerant animals (IPI) and the elimination of these animals, was evaluated at nearly eleven million francs (US$1,814,884) during the first year. Theories were then formulated regarding the time required to achieve eradication (twenty years) and to reduce the epidemiological parameters (development curve of the eradication of IPI animals and of animals which had given positive results to serological tests). The reduction in the cost of the disease as a result of the eradication policy was then simulated in accordance with the evolution of the epidemiological parameters. Finally, the cost of controlling the disease, together with the residual cost of the disease, were compared with the cost of the disease without control measures. This demonstrated that such an eradication policy would, in theory, only begin to become cost-effective after approximately fifteen years. In view of the long period required to achieve cost-effectiveness, the considerable complexity of implementing an eradication programme and imponderables (particularly concerning virus spread), the recommendation of such a course of action to cattle-breeder groups is questionable. This research demonstrates that a relatively simple economic approach can serve as a useful decision-making aid.


Getting to the bottom of research funding: Acknowledging the complexity of funding dynamics.
Research funding is an important factor for public science. Funding may affect which research topics get addressed, and what research outputs are produced. However, funding has often been studied simplistically, using top-down or system-led perspectives. Such approaches often restrict analysis to confined national funding landscapes or single funding organizations and instruments in isolation. This overlooks interlinkages, broader funding researchers might access, and trends of growing funding complexity. This paper instead frames a 'bottom-up' approach that analytically distinguishes between increasing levels of aggregation of funding instrument co-use. Funding of research outputs is selected as one way to test this approach, with levels traced via funding acknowledgements (FAs) in papers published 2009-18 by researchers affiliated to Denmark, the Netherlands or Norway, in two test research fields (Food Science, Renewable Energy Research). Three funding aggregation levels are delineated: at the bottom, 'funding configurations' of funding instruments co-used by individual researchers (from single-authored papers with two or more FAs); a middle, 'funding amalgamations' level, of instruments co-used by collaborating researchers (from multi-authored papers with two or more FAs); and a 'co-funding network' of instruments co-used across all researchers active in a research field (all papers with two or more FAs). All three levels are found to include heterogenous funding co-use from inside and outside the test countries. There is also co-funding variety in terms of instrument 'type' (public, private, university or non-profit) and 'origin' (domestic, foreign or supranational). Limitations of the approach are noted, as well as its applicability for future analyses not using paper FAs to address finer details of research funding dynamics.


Metformin is Protective Against the Development of Mood Disorders.
Mood disorders are a major cause of disability, and current treatment options are inadequate for reducing the burden on a global scale. The aim of this project was to identify drugs suitable for repurposing to treat mood disorders. This mixed-method study utilized gene expression signature technology and pharmacoepidemiology to investigate drugs that may be suitable for repurposing to treat mood disorders. The transcriptional effects of a combination of drugs commonly used to treat mood disorders included regulation of the steroid and terpenoid backbone biosynthesis pathways, suggesting a mechanism involving cholesterol biosynthesis, and effects on the thyroid hormone signaling pathway. Connectivity Map analysis highlighted metformin, an FDA-approved treatment for type 2 diabetes, as a drug having global transcriptional effects similar to the mood disorder drug combination investigated. In a retrospective cohort study, we found evidence that metformin is protective against the onset of mood disorders. These results provide proof-of-principle of combining gene expression signature technology with pharmacoepidemiology to identify potential novel drugs for treating mood disorders. Importantly, metformin may have utility in the treatment of mood disorders, warranting future randomized controlled trials to test its efficacy.


Competing pathways in the near-UV photochemistry of acetaldehyde.
Time-resolved ion imaging measurements have been performed to explore the photochemistry of acetaldehyde at photolysis wavelengths spanning the range 265-328 nm. Ion images recorded probing CH3 radicals with single-photon VUV ionization show different dissociation dynamics in three distinct wavelength regions. At the longest photolysis wavelengths, λ > 318 nm, CH3 radicals are formed over tens of nanoseconds with a speed distribution that is consistent with statistical unimolecular dissociation on the S0 surface following internal conversion. In the range 292 nm ≤ λ ≤ 318 nm, dissociation occurs almost exclusively on the T1 surface following intersystem crossing and passage over a barrier, leading to the available energy being partitioned primarily into photofragment recoil. The CH3 speed distributions become bimodal at λ < 292 nm. In addition to the translationally fast T1 products, a new translationally slow, but non-statistical, component appears and grows in importance as the photolysis wavelength is decreased. Photofragment excitation (PHOFEX) spectra of CH3CHO obtained probing CH3 and HCO products are identical across the absorption band, indicating that three-body fragmentation is not responsible for the non-statistical slow component. Rather, translationally slow products are attributed to dissociation on S0, accessed via a conical intersection between the S1 and S0 surfaces at extended C-C distances. Time-resolved ion images of CH3 radicals measured using a picosecond laser operating at a photolysis wavelength of 266 nm show that product formation on T1 and S0via the conical intersection occurs with time constants of 240 ps and 560 ps, respectively.


Intramolecular electron transfer in bipyridinium disulfides.
Reductive cleavage of disulfide bonds is an important step in many biological and chemical processes. Whether cleavage occurs stepwise or concertedly with electron transfer is of interest. Also of interest is whether the disulfide bond is reduced directly by intermolecular electron transfer from an external reducing agent or mediated intramolecularly by internal electron transfer from another redox-active moiety elsewhere within the molecule. The electrochemical reductions of 4,4'-bipyridyl-3,3'-disulfide (1) and the di-N-methylated derivative (2(2+)) have been studied in acetonitrile. Simulations of the cyclic voltammograms in combination with DFT (density functional theory) computations provide a consistent model of the reductive processes. Compound 1 undergoes reduction directly at the disulfide moiety with a substantially more negative potential for the first electron than for the second electron, resulting in an overall two-electron reduction and rapid cleavage of the S-S bond to form the dithiolate. In contrast, compound 2(2+) is reduced at less negative potential than 1 and at the dimethyl bipyridinium moiety rather than at the disulfide moiety. Most interesting, the second reduction of the bipyridinium moiety results in a fast and reversible intramolecular two-electron transfer to reduce the disulfide moiety and form the dithiolate. Thus, the redox-active bipyridinium moiety provides a low energy pathway for reductive cleavage of the S-S bond that avoids the highly negative potential for the first direct electron reduction. Following the intramolecular two-electron transfer and cleavage of the S-S bond the bipyridinium undergoes two additional reversible reductions at more negative potentials.


Coccidioidomycosis in the llama: case report and epidemiologic survey.
An 8-year-old nongravid female llama with a 1-month history of progressive posterior paresis was referred because of suspected degenerative myelopathy secondary to copper deficiency or plant poisoning. Neurologic examination revealed loss of conscious proprioception and slightly depressed bilateral patellar reflexes. Electromyographic examination of hindlimb flexors and extensors did not elicit evidence of lower motor neuron disease. Possible fragmentation and mottling of the 10th thoracic vertebral body were noted radiographically. Results of a lumbar CSF tap, complete blood count, and fecal flotation were not diagnostic. In the face of poor prognosis, the llama was euthanatized. Postmortem and histologic evaluation revealed, in addition to disseminated visceral granulomas, an extradural pyogranulomatous mass compressing the cord laterally at the level of T-10. Large numbers of Coccidioides immitis were dispersed throughout the granulomas. Complement fixing antibody tests in 11 other herd members showed evidence of C immitis infection in three.


The prevalence and determinants of helmet use amongst commercial motorcyclists in Ido-Osi local government area.
Commercial motorcycle (CM) accidents constitute a major public concern in Nigeria. There is 8:10 chance that injuries resulting from these accidents are severe and debilitating including head and spinal injuries. This study is aimed at producing useful data on the prevalence, frequency, and determinants of helmet use among commercial motorcyclist in Ido-Osi Local Government Area, Ekiti State, Nigeria. The study was a descriptive/cross-sectional study. A total of 360 respondents were selected by multi-stage sampling technique and interviewed using assisted self-administered, semi-structured questionnaire. Data were analyzed using SPSS version 21. Determinants of helmet use examined included age, educational level, marital status and religion. There was a 100% response rate. More than half of the respondents were within the age range of 20-29 years 164(53.6%) with the mean age of the study participants 29.9. The prevalence of helmet usage among commercial motorcyclist was 23.5%. The commonest reason for not using a crash helmet in this study was non-availability. The commonest reason for the non-availability of the welding helmet was the cost of the helmet. Less than half of the respondents were able to show or present helmet although some of the helmet presented were sub-standard (39.7%). The study also revealed irregular use of helmets among the respondents that used a helmet while riding a motorcycle as only 2.7% of them used it for all the five riding sessions assessed in this study. There was a statistically significant relationship between age, educational level, marital status and the use of helmets among respondents with p values of 0.005, 0.027, and 0.009, respectively. The prevalence of the use of helmets among the motorcyclist in this study is low despite the high level of awareness of legislation among the respondents on the use of helmets during riding. There is a need for the government to make provision for a safety helmet for this group of people at a subsidized rate if it cannot be given free of charge because of the economic situation of the country. There is a need to carry out behavioral change communication for this group of people.


Anti-platelet aggregation and vasorelaxing effects of the constituents of the rhizomes of Zingiber officinale.
In the present study, the chemical investigation of the bioactive fractions of the rhizomes of Zingiber officinale has resulted in the identification of twenty-nine compounds including one new compound, O-methyldehydrogingerol. Some of the isolates were subjected into the evaluation of their antiplatelet aggregation and vasorelaxing bioactivities. Among the tested compounds, [6]-gingerol and [6]-shogaol exhibited potent anti-platelet aggregation bioactivity. In addition, [10]-gingerol inhibited the Ca²⁺-dependent contractions in high K⁺ medium. According to the results in the present research, the bioactivity of ginger could be related to the anti-platelet aggregation and vasorelaxing mechanism.


Perfluorooctane sulfonate (PFOS) induces several behavioural defects in Caenorhabditis elegans that can also be transferred to the next generations.
Perfluorooctane sulfonate (PFOS) is a well-known global persistent organic pollutant of grave concern to ecological and human health. Toxicity of PFOS to animals and humans are well studied. Although few studies have reported the behavioral effect of PFOS on nematode Caenorhabditis elegans, it's transgenerational effects were seldom studied. Therefore, we investigated the toxicity of PFOS on several behavioral responses besides bioaccumulation and transgenerational effects in C. elegans. In contrast to the several published studies, we used lower concentrations (0.5-1000 μg/L or 0.001-2.0 μM) that are environmentally relevant and reported to occur close to the contaminated areas. The 48 h median lethal concentration of PFOS was found to be 3.15 μM (1575 μg/L). PFOS (≥0.01 μM) caused severe toxicity to locomotion, and this effect was even transferred to progeny. However, after a few generations, the defect was rectified in the progeny of single-time exposed parent nematodes. Whereas, continuous exposure at 0.001 μM PFOS, no visible defects were observed in the progeny. PFOS (≥0.01 μM) also significantly decreased the brood size in a concentration-dependent manner. Besides, lifespan was affected by the higher concentration of PFOS (≥1.0 μM). These two behavioral endpoints, lifespan and reproduction defects, became less severe in the progeny. Chemotaxis plasticity was also significantly retarded by ≥ 1.0 μM PFOS compared to the control group. Results indicate that PFOS can exert severe neurobehavioral defects that can be transferred from parents to their offspring. The findings of this study have significant implications for the risk assessment of perfluorinated substances in the environment.


Ultrasonographic quantification of spinal cord and dural pulsations during cervical laminoplasty in patients with compressive myelopathy.
Pulsatile movements of the dura mater have been interpreted as a sign that the cord is free within the subarachnoid space, with no extrinsic compression. However, the association between restoration of pulsation and adequate decompression of the spinal cord has not been established. The present study investigated the relationship between the extent of spinal cord decompression and spinal cord and dural pulsations based on quantitative analysis of intraoperative ultrasonography (US). Eighty-five consecutive patients (55 males, 30 females; mean age, 64 ± 13 years) who underwent cervical double-door laminoplasty to relieve compressive myelopathy were enrolled. Spinal cord decompression status was classified as: Type 1 (non-contact), the subarachnoid space was retained on the ventral side of the cord, Type 2 (contact and apart), the cord showed both contact with and separation from the anterior element of the cervical spine, or Type 3 (contact), the cord showed continuous contact with the anterior element of the cervical spine. Spinal cord and dura mater dynamics were quantitatively analyzed using automatic video-tracking software. Furthermore, the intensity of spinal and dural pulsation was compared with the recovery of motor function at 1 year after surgery as measured by increase in the Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ). Spinal cord pulsation amplitude ranged from 0.01 to 0.84 mm (mean 0.30 ± 0.16 mm) and dural pulsation amplitude ranged from 0.01 to 0.38 mm (mean 0.14 ± 0.08 mm). Average spinal cord pulsation amplitude in Type 2 patients was significantly larger than that in the other groups, whereas, average dural pulsation amplitudes were similar for all three groups. There was a significant correlation between spinal cord and dural pulsation amplitudes in Type 1 patients, but not in Type 2 or Type 3 patients. Type 3 patients showed a particularly poor correlation between spinal cord and dural pulsations. Spinal cord pulsation amplitude was moderately correlated with the recovery of motor function evaluated by JOACMEQ. The present results suggest that restoration of dural pulsation is not an adequate indicator of sufficient decompression of the spinal cord following a surgical procedure.


Early onset oral tongue squamous cell carcinoma: Associated factors and patient outcomes.
Incidence of oral tongue squamous cell carcinoma (OTC) is rising among those under age 50 years. The etiology is unknown. A total of 395 cases of OTC diagnosed and/or treated at Vanderbilt University Medical Center between 2000 and 2017 were identified. Of those, 113 (28.6%) were early onset (age < 50 years). Logistic regression was used to identify factors associated with early onset OTC. Cox proportional hazards models evaluated survival and recurrence. Compared to typical onset patients, patients with early onset OTC were more likely to receive multimodality treatment (surgery and radiation; adjusted odds ratio [aOR], 2.7; 95% confidence interval [CI], 1.2-6.3) and report a history of snuff use (aOR, 5.4; 95% CI, 1.8-15.8) and were less likely to report a history of cigarette use (aOR, 0.5; 95% CI, 0.2-0.9). Early onset patients had better overall survival (adjusted hazard ratio, 0.6). This is the largest study to evaluate factors associated with early onset OTC and the first to report an association with snuff.


Nanoscale Characteristics of Ocular Lipid Thin Films Using Kelvin Probe Force Microscopy.
To describe the use of Kelvin probe force microscopy (KPFM) to investigate the electrical surface potential of human meibum and to demonstrate successful use of this instrument on both human meibum and a meibum model system (six-lipid stock [6LS]) to elucidate nanoscale surface chemistry and self-assembly characteristics. 6LS and meibum were analyzed in this study. Mica-supported thin films were created using the Langmuir-Blodgett trough. Topography and electrical surface potential were quantified using simultaneous atomic force microscopy/KPFM imaging. Both lipid mixtures formed thin film patches on the surface of the mica substrate, with large aggregates resting atop. The 6LS had aggregate heights ranging from 41 to 153 nm. The range in surface potential was 33.0 to 125.9 mV. The meibum thin films at P = 5 mN/m had aggregates of 170 to 459 nm in height and surface potential ranging from 15.9 to 76.1 mV, while thin films at P = 10 mN/m showed an aggregate size range of 147 to 407 nm and a surface potential range of 11.5 to 255.1 mV. This study showed imaging of the differences in electrical surface potential of meibum via KPFM and showed similarities in nanoscale topography. 6LS was also successfully analyzed, showing the capabilities of this method for use in both in vitro and ex vivo ocular research. This study describes the use of KPFM for the study of ocular surface lipids for the first time and outlines possibilities for future studies to be carried out using this concept.


Specifying type and location of peer victimization in a national sample of children and youth.
Much of the existing research on the prevalence and consequences of peer victimization focuses on "bullying" at school, often omitting from consideration non-bullying types of peer victimization as well as events that occur outside of school. The purpose of this study was to examine past-year exposure to peer-perpetrated victimization, occurring both within and outside of school contexts, among school-aged children in the United States. The study is based on a representative sample of 2,999 youth ages 6-17 (50% female; 45% non-white) from the 2008 National Survey of Children's Exposure to Violence (NatSCEV). Findings revealed age, gender, race, and family structure variations in many forms of peer victimization and demonstrated significant independent and cumulative effects of six different types of peer victimization (physical assault, physical intimidation, emotional victimization, sexual victimization, property crime, and internet harassment) on trauma symptoms. Findings also showed that, although victimization at school is substantial, a considerable proportion of peer victimizations occur away from school contexts. The findings highlight the importance of comprehensive measurement of multiple forms of peer victimization that occur both at school and elsewhere, rather than focusing exclusively on traditional measures of school-focused bullying.


Recording of incoherent-object hologram as complex spatial coherence function using Sagnac radial shearing interferometer and a Pockels cell.
The ideas of incoherent holography were conceived after the invention of coherent-light holography and their concepts seems indirectly related to it. In this work, we adopt an approach based on statistical optics to describe the process of recording of an incoherent-object hologram as a complex spatial coherence function. A Sagnac radial shearing interferometer is used for the correlation of optical fields and a Pockels cell is used to phase shift the interfering fields with the objective to quantify and to retrieve the spatial coherence function.


Evaluation of a canine rabies vaccination campaign and characterization of owned-dog populations in the Philippines.
A mass canine rabies vaccination campaign in Sorsogon Province, the Republic of the Philippines, was conducted in April and May 1993. From 1 to 14 days following visits by vaccination teams to 30 selected villages (barangays), survey teams revisited the barangays to assess vaccine coverage. Modified cluster survey methods were used to gather information about vaccine coverage in the owned-dog population (210 households) and about characteristics of owned-dogs and factors influencing owner willingness to participate in the campaign. Vaccinated dogs were identified by asking owners about receipt of certificates given by the vaccinating teams and examining each animal for a special collar or paint mark placed on the animal at the time of vaccination. Survey results indicated that 73% (178/243) of eligible dogs were vaccinated and 82% of vaccinated dogs were marked with a collar or paint. Dogs were owned by 69% of households and ranged in age from 3 days to 13 years (median = 1 year), and the ratio of male to females dogs was 1:1. The dog-to-human ratio was 1:3.8, with an average of 1.4 dogs per household or 2.1 dogs per dog-owning household. Most dogs were kept as guards (83%) and most were free-ranging (85%). The most common reasons dogs were not vaccinated included they could not be restrained (11/64), the owner was not home (10/64), and fear of injury resulting from vaccination (10/64). The owners of 20% of vaccinated dogs reported some adverse reaction in their pet. Improved vaccine coverage was significantly associated with restrained dogs kept primarily for guard functions by owners who received information about the vaccination campaign from multiple sources. Vaccine coverage was sufficiently high to potentially control rabies transmission among dogs through herd immunity and indicated a successful vaccine campaign.


Dietary patterns and prostate cancer risk: report from the population based ULSAM cohort study of Swedish men.
Dietary pattern analyses have increased the possibilities to detect associations between diet and disease. However, studies on dietary pattern and prostate cancer are scarce. Food intake data in the Uppsala Longitudinal Study of Adult Men cohort was determined by 7-day food records. Adherence to a modified Mediterranean Diet Score (mMDS) and a low carbohydrate-high protein (LCHP) score were grouped as low, medium, or high in the whole study population (n = 1,044) and in those identified as adequate reporters of energy intake (n = 566), respectively. Prostate cancer risk was analyzed with Cox proportional hazard regression (median follow-up 13 years) and competing risk of death was considered. There were no associations between dietary patterns and prostate cancer (n = 133) in the whole study population. Among adequate reporters the mMDS was not associated with prostate cancer (n = 72). The LCHP score was inversely related to prostate cancer in adequate reporters, adjusted hazard ratios; 0.55 (0.32-0.96) for medium and 0.47 (0.21-1.04) for high compared to low adherent participants (P-for-trend 0.04). Risk relations were not attributable to competing risk of death. In this study, a LCHP diet was associated with lower prostate cancer incidence. Relations emerged in adequate reporters, underscoring the importance of high-quality dietary data.


The ortho backbone amide linker (o-BAL) is an easily prepared and highly acid-labile handle for solid-phase synthesis.
The tris(alkoxy)benzyl backbone amide linker (BAL) has found widespread application in solid-phase synthesis. The key intermediate for preparation of para BAL (p-BAL) is 2,6-dimethoxy-4-hydroxybenzaldehyde; several reports on its synthesis have appeared. However, the ortho analogue of the handle (o-BAL) has successfully been used by us for the synthesis of C-terminal-modified peptides, oligosaccharides, and substituted anilines. Here, we present a new and convenient synthesis of the key intermediate for o-BAL, 4,6-dimethoxy-2-hydroxybenzaldehyde, by a highly regioselective demethylation with BBr3, followed by purification through steam distillation. Cleavage studies of Leu-enkephalin anchored to either o-BAL or p-BAL handles revealed that both handles were surprisingly acid-labile and released the peptide with dilute TFA (5% and even 1% TFA in CH2Cl2). This useful property allowed the synthesis of fully protected Leu-enkephalin. The very convenient synthesis of 4,6-dimethoxy-2-hydroxybenzaldehyde combined with the benign properties of the o-BAL handle may make it the preferred regioisomer.


On the unique binding and activating properties of xanomeline at the M1 muscarinic acetylcholine receptor.
We investigated the molecular nature of the interaction between the functionally selective M1 muscarinic acetylcholine receptor (mAChR) agonist xanomeline and the human M1 mAChR expressed in Chinese hamster ovary (CHO) cells. In contrast to the non-subtype-selective agonist carbachol, xanomeline demonstrated M1 mAChR binding that was resistant to extensive washout, resulting in a significant reduction in apparent N-[3H]methylscopolamine saturation binding affinity in intact cells. Functional assays, using both M1 mAChR-mediated phosphoinositide hydrolysis and activation of neuronal nitric oxide synthase, confirmed that this persistent binding resulted in elevated basal levels of system activity. Furthermore, this phenomenon could be reversed by the addition of the antagonist atropine. However, pharmacological analysis of the inhibition by atropine of xanomeline-mediated functional responses indicated a possible element of noncompetitive behavior that was not evident in several kinetic and equilibrium binding experimental paradigms. Taken together, our findings indicate for the first time a novel mode of interaction between an mAChR agonist and the M1 mAChR, which may involve unusually avid binding of xanomeline to the receptor. This yields a fraction of added agonist that is retained at the level of the receptor compartment to persistently bind to and activate the receptor subsequent to washout. The results of the current study suggest that elucidation of the mechanism or mechanisms of interaction of xanomeline with the M1 mAChR is particularly important in relation to the potential therapeutic use of this agent in the treatment of Alzheimer's disease.


A cluster of genes that affects nucleoid segregation in Salmonella typhimurium.
Thirteen conditional lethal mutations in genes of Salmonella typhimurium map at the clmF locus and affect both viability and the faithful partitioning of daughter nucleoids. These mutations have now been divided into three complementation groups by using cloned fragments of S. typhimurium DNA and renamed parC, parE, and parF. The proteins produced from the cloned fragments predict that ParC is an 85-kD protein, ParE is 75 kD in size, and ParF, 27 kD. The parE gene is about 5 kb upstream of the parC gene, and parC is just upstream of parF. Genes situated between parC and parE produce at least two proteins of unknown function. The DNA sequence of the S. typhimurium parC gene was determined and has 56% homology with the first 1400 base pairs of the Escherichia coli gryA gene, which encodes the A subunit of DNA gyrase, and 85% homology with the E. coli parC gene. Despite the strong homology between gryA and parC, these two genes cannot substitute for one another. The DNA sequence of the S. typhimurium parF gene was determined and predicts a protein with a hydrophobic N terminus. The ParF protein may interact with ParC and ParE to anchor these proteins to the membrane. These results raise questions about the relative roles of gyrase and ParCEF in nucleoid decatenation. In addition, the parC and gyrA genes provide an example of the evolution of essential functions by gene duplication.


Necrotizing arteritis associated with blastomycosis.
We have described a patient with cavitary pulmonary fungal infection, probably blastomycosis, with necrotizing arteritis of the skin. The pulmonary and skin lesions resolved with amphotericin B therapy.


Cancer and the healthy immigrant effect: a statistical analysis of cancer diagnosis using a linked Census-cancer registry administrative database.
A large volume of research has been published on both the socio economic and demographic determinants of cancer and on the health of immigrants and minority groups. Yet because of data limitations, little research examines differences in the occurrence of cancer incidence between immigrants and non-immigrants and among immigrants defined by region of birth and time in the host country. In particular it is not known whether a healthy immigrant effect is present for cancer and if so, whether this advantage is lost with additional years of residence in the host country. This paper uses a large data file from Statistics Canada that links Census information on immigrant status, socioeconomic status including educational attainment, and other person-level information with administrative data on cancer and mortality over a continuous 13 year period of observation. It estimates discrete and continuous time duration models to identify differences in cancer diagnosis by immigrant subgroup after controlling for a variety of potential confounders. Differences in historical smoking behavior are not observable at the individual level in the dataset but are accounted for indirectly using various methods. Results in general confirm the existence of a healthy immigrant effect for cancer in that, overall, recent immigrants to Canada are significantly less likely than otherwise comparable non-immigrant Canadians to be diagnosed with any cancer and the most common forms of cancer by site. As well, this gap appears to decline with additional years in Canada for immigrant men and women, eventually converging to Canadian-born levels. Differentiating among immigrant subgroups by period of arrival and country of birth reveals significant variation across immigrant subgroups, with immigrant men and women from developing countries typically having a lower likelihood of being diagnosed with cancer than immigrants from the US, UK and continental Europe. As well, controlling for immigrant heterogeneity this way weakens the conclusion that the gap narrows with years in Canada. Immigrant men overall continue to exhibit convergence to Canadian-born levels for diagnosis of any cancer and for prostate cancer, while immigrant women exhibit narrowing over time only for breast cancer. Although smoking behavior is not directly observed, controlling for subgroup-specific lifetime smoking behavior using survey data has only a relatively minor effect on the estimated differences. The specificity of the results by cancer type, gender, immigrant status and ethnicity provides useful guidance for future research by helping to narrow the possible channels through which social and economic characteristics may be affecting cancer incidence.


Reduction and precipitation of chromium(VI) using a palladized membrane biofilm reactor.
H2-driven reduction of hexavalent chromium (Cr(VI)) using precious-metal catalysts is promising, but its implementation in water treatment has been restricted by poor H2-transfer efficiency and high catalyst loss. We investigated the reduction of Cr(VI) through hydrogenation catalyzed by elemental-palladium nanoparticles (PdNPs) generated in-situ within biofilm of a membrane biofilm reactor (MBfR), creating a Pd-MBfR. Experiments were conducted using a Pd-MBfR and a non-Pd MBfR. The Pd-MBfR achieved Cr(VI) (1000 μg L-1) reduction of >99 % and reduced the concentration of total Cr to below 50 μg L-1, much lower than the total Cr concentration in the non-Pd MBfR effluent (290 μg L-1). The Pd-MBfR also had a lower concentration of dissolved organic compounds compared to the non-Pd MBfR, which minimized the formation of soluble organo-Cr(III) complexes and promoted precipitation of Cr(OH)3. Solid-state characterizations documented deposition of Cr(OH)3 as the product of Cr(VI) reduction in the Pd-MBfR. Metagenomic analyses revealed that the addition and reduction of Cr(VI) had minimal impact on the microbial community (dominated by Dechloromonas) and functional genes in the biofilm of the Pd-MBfR, since the PdNP-catalyzed reduction process was rapid. This study documented efficient Cr(VI) reduction and precipitation of Cr(OH)3 by the Pd-MBfR technology.


Brain Abscess as a Rare Complication of Primary Extranodal Nasal-type Natural Killer/T-cell Lymphoma.
We present the case of a 58-year-old Japanese woman with a natural killer T (NK/T)-cell lymphoma complicated by brain abscess. NK/T-cell lymphomas represent a rare type of lymphoma derived from either activated NK cells or, rarely, cytotoxic T cells. They are aggressive Epstein-Barr virus (EBV)-associated lymphomas that involve mainly the nasal cavity. Brain abscess associated with primary extranodal nasal-type NK/T-cell lymphoma is extremely uncommon: to our knowledge, this is the first reported case of this lymphoma with brain abscess as the initial clinical manifestation. Endoscopic surgery was performed for definitive diagnosis under intraoperative navigation system. Chemotherapy followed by radiotherapy was performed and was effective: 72 months later the tumor has not recurred. Recommendations of endoscopic management for diagnosis and treatment of this rare neoplasm are discussed.


Six years of fruit fly surveys in Bangladesh: a new species, 33 new country records and discovery of the highly invasive Bactrocera carambolae (Diptera, Tephritidae).
We engaged in six years of snap-shot surveys for fruit flies in rural environments and ten protected forest areas of Bangladesh, using traps baited with male lures (cue-lure, methyl eugenol, zingerone). Our work has increased the recorded number of species of Tephritidae in the country from seven to 37. We summarize these surveys and report eight new country occurrence records, and a new species (Zeugodacus madhupuri Leblanc & Doorenweerd, sp. nov.) is described. The highlight among the new records is the discovery, and significant westward range extension, of Bactrocera carambolae Drew & Hancock, a major fruit pest detected in the Chattogram and Sylhet Divisions. We rectify the previously published erroneous record of Bactrocera bogorensis (Hardy), which was based on a misidentification of Zeugodacus diaphorus (Hendel). We also report the occurrence in Bangladesh of nine other Tephritidae, the rearing of three primary fruit fly parasitoids from Zeugodacus, and records of non-target attraction to fruit fly lures.


Aberrant promoter methylation of p16 in colorectal adenocarcinoma in North Indian patients.
To investigate p16 gene methylation and its expression in 30 patients with sporadic colorectal adenocarcinoma in a North Indian population. Methylation specific polymerase chain reaction was used to detect p16 gene methylation and immunohistochemistry was used to study the p16 expression in 30 sporadic colorectal tumors as well as adjoining and normal tissue specimens. Aberrant promoter methylation of p16 gene was detected in 12 (40%) tumor specimens, whereas no promoter methylation was observed in adjoining and normal tissue. Immunohistochemistry showed expression of p16 protein in 26 (86.6%) colorectal tumors whereas complete loss of expression was seen in 4 (13.3%) and reduced expression was observed in 12 (40%) tumors. In the adjoining mucosa, expression of p16 was in 11 (36.6%) whereas no clear positivity for p16 protein was seen in normal tissue. There was a significant difference in the expression of p16 protein in tumor tissue and adjoining mucosa (P < 0.001). The methylation of the p16 gene had a significant effect on the expression of p16 protein (P = 0.021). There was a significant association of methylation of p16 gene with the tumor size (P = 0.015) and of the loss/reduced expression of p16 protein with the proximal site of the tumor (P = 0.047). Promoter methylation and expression of p16 had no relation with the survival of the patients (P > 0.05). Our study demonstrated that promoter hypermethylation of the p16 gene results in loss/reduced expression of p16 protein and this loss/reduced expression may contribute to tumor enlargement.


Development and Validation of a LC-MS/MS Method for the Simultaneous Estimation of Amlodipine and Valsartan in Human Plasma: Application to a Bioequivalence Study.
A reliable, simple, and robust liquid chromatography-tandem mass spectro-metric (LC-MS/MS) method has been developed and validated that employs solid-phase extraction for the simultaneous estimation of amlodipine and valsartan in human K3EDTA plasma using amlodipine-d4 and valsartan-d9 as internal standards. Chromatographic separation of amlodipine and valsartan was achieved on the Luna C18 (2)100A (150 × 4.6 mm, 5 μm) column using acetonitrile: 5 mM ammonium formate solution (80:20, v/v) as the mobile phase at a flow rate of 0.8 mL/min in isocratic mode. Quantification was achieved using an electrospray ion interface operating in positive mode, under multiple reaction monitoring (MRM) conditions. The assay was found to be linear over the range of 0.302-20.725 ng/mL for amlodipine and 6.062-18060.792 ng/mL for valsartan. The method has shown good reproducibility, as intra- and interday precisions were within 10% and accuracies were within 8% of nominal values for both analytes. The method was successfully applied for the bioequivalence study of amlodipine and valsartan after oral administration of a fixed dose of the combination. Additionally, as required by the current regulatory bodies, incurred sample reanalysis was performed and found to be acceptable.


Factors associated with pregnancy-related knowledge in women of reproductive age with inflammatory bowel disease.
Inflammatory bowel disease (IBD) usually develops at a young age, and many women experience marriage, pregnancy, and delivery during the disease course. We aimed to evaluate the pregnancy-related knowledge of women with IBD in Korea and investigate the associated factors. A total of 270 women with IBD, aged 19-45 years, from four tertiary hospitals in Korea were administered a questionnaire comprising 17 questions from the validated Crohn's and Colitis Pregnancy Knowledge Score (CCPKnow) that were translated into Korean. The average CCPKnow score of the 270 patients was 7.47 ± 3.07; and most of the patients (51.5%) exhibited a poor knowledge level. Younger age at diagnosis, Crohn's disease rather than ulcerative colitis, longer disease duration, anti-TNF-α medication history, higher household income, and delivery after diagnosis were associated with an appropriate level of pregnancy-related knowledge. Younger age at diagnosis (odds ratio [OR], 1.87; p = .036), anti-TNF-α therapy (OR, 1.87; p = .047), and delivery while suffering from IBD (OR, 3.07; p = .002) were independent factors affecting the pregnancy-related knowledge level. Approximately 69.6% of patients acquired related knowledge from their gastroenterology doctor, whereas 19.4% of patients intended to remain childless. To our knowledge, this is the first study to assess the pregnancy-related knowledge of women of reproductive-age with IBD and their perceptions by using a questionnaire in Asia. As more than half of the patients showed a poor knowledge level of IBD, a general education program should be conducted by gastroenterology doctors.


Prognostic factors and therapeutic outcomes in 22 patients with pleomorphic xanthoastrocytoma.
Pleomorphic xanthoastrocytoma (PXA) is a rare primary low-grade astrocytic tumor classified as WHO II. It is generally benign, but disease progression and malignant transformation have been reported. Prognostic factors for PXA and optimal therapies are not well known. The study period was January 2000 to March 2012. Data on MR findings, histology, surgical extents and adjuvant therapies were reviewed in twenty-two patients diagnosed with PXA. The frequent symptoms of PXA included seizures, headaches and neurologic deficits. Tumors were most common in the temporal lobe followed by frontal, parietal and occipital lobes. One patient who died from immediate post-operative complications was excluded from the statistical analysis. Of the remaining 21 patients, 3 (14%) died and 7 (33%) showed disease progression. Atypical tumor location (p<0.001), peritumoral edema (p=0.022) and large tumor size (p=0.048) were correlated with disease progression, however, Ki-67 index and necrosis were not statistically significant. Disease progression occurred in three (21%) of 14 patients who underwent GTR, compared with 4 (57%) of 7 patients who did not undergo GTR, however, it was not statistically significant. Ten patients received adjuvant radiotherapy and the tumors were controlled in 5 of these patients. The prognosis for PXA is good; in our patients overall survival was 84%, and event-free survival was 59% at 3 years. Atypical tumor location, peritumoral edema and large tumor size are significantly correlated with disease progression. GTR may provide prolonged disease control, and adjuvant radiotherapy may be beneficial, but further study is needed.


Reciprocal regulation of AMP-activated protein kinase and phospholipase D.
AMP-activated protein kinase (AMPK), a critical sensor of energy sufficiency, acts as central metabolic switch in cell metabolism. Once activated by low energy status, AMPK phosphorylates key regulatory substrates and turns off anabolic biosynthetic pathways. In contrast, the mammalian/mechanistic target of rapamycin (mTOR) is active when there are sufficient nutrients for anabolic reactions. A critical factor regulating mTOR is phosphatidic acid (PA), a central metabolite of membrane lipid biosynthesis and the product of the phospholipase D (PLD)-catalyzed hydrolysis of phosphatidylcholine. PLD is a downstream target of the GTPase Rheb, which is turned off in response to AMPK via the tuberous sclerosis complex. Although many studies have linked AMPK with mTOR, very little is known about the connection between AMPK and PLD. In this report, we provide evidence for reciprocal regulation of PLD by AMPK and regulation of AMPK by PLD and PA. Suppression of AMPK activity led to an increase in PLD activity, and conversely, activation of AMPK suppressed PLD activity. Suppression of PLD activity resulted in elevated AMPK activity. Exogenously supplied PA abolished the inhibitory effects of elevated AMPK activity on mTOR signaling. In contrast, exogenously supplied PA could not overcome the effect AMPK activation if either mTOR or Raptor was suppressed, indicating that the inhibitory effects of PLD and PA on AMPK activity are mediated by mTOR. These data suggest a reciprocal feedback mechanism involving AMPK and the PLD/mTOR signaling node in cancer cells with therapeutic implications.


Listening to those on the frontline: lessons for community-based tuberculosis programmes from a qualitative study in Swaziland.
This study explored the experience of people involved in a new community-based tuberculosis (TB) programme in rural Swaziland. Patients have their treatment observed in the community after choosing a treatment supporter (either community health worker or family member) in dialogue with the TB nurse. Interviews were conducted with TB patients, treatment supporters, clinic nurses, nurses working in the hospital-based TB team and medical staff. The study generated two main themes: (1) issues relating to the TB programme and (2) wider societal issues. Both are important, however this paper reports only the issues directly related to the TB programme. The study found that community-based care is preferred to hospital care, which should be retained only for the very ill patients. The importance of selecting suitable patients and ensuring individualised and flexible arrangements was highlighted. Although treatment outcomes are known to have improved since introducing the new TB programme a number of issues require further attention. Communication between different levels of the health service needs to be improved and consultation communication skills, taught prior to introducing the programme, need to be refreshed. All relevant staff must be trained on the TB programme and patient education (on TB, HIV and treatment adherence) needs to be reinforced throughout TB treatment. Health education of the wider community is also needed. Ongoing support of treatment supporters must recognise that their role is not simply treatment observation. In this context, where the large majority of TB patients are HIV positive, better co-ordination with the HIV/AIDS services is required, including treatment of other HIV-related infections and home-based care for TB patients who deteriorate. Although the findings and recommendations of this study are context specific they are likely to be of relevance to other programmes.


Standardization of physical measurements in European health examination surveys-experiences from the site visits.
Health examination surveys (HESs) provide valuable data on health and its determinants at the population level. Comparison of HES results within and between countries and over time requires measurements which are free of bias due to differences in or adherence to measurement procedures and/or measurement devices. In the European HES (EHES) Pilot Project, 12 countries conducted a pilot HES in 2010-11 using standardized measurement protocols and centralized training. External evaluation visits (site visits) were performed by the EHES Reference Centre staff to evaluate the success of standardization and quality of data collection. In general, standardized EHES protocols were followed adequately in all the pilot surveys. Small deviations were observed in the posture of participants during the blood pressure and height measurement; in the use of a tourniquet when drawing blood samples; and in the calibration of measurement devices. Occasionally, problems with disturbing noise from outside or people coming into the room during the measurements were observed. In countries with an ongoing national HES or a long tradition of conducting national HESs at regular intervals, it was more difficult to modify national protocols to fulfil EHES requirements. The EHES protocols to standardize HES measurements and procedures for collection of blood samples are feasible in cross-country settings. The prerequisite for successful standardization is adequate training. External and internal evaluation activities during the survey fieldwork are also needed to monitor compliance to standards.


Lack of Awareness of Human Immunodeficiency Virus (HIV) Infection: Problems and Solutions With Self-reported HIV Serostatus of Men Who Have Sex With Men.
Lack of human immunodeficiency virus (HIV) infection awareness may be a driver of racial disparities in HIV infection among men who have sex with men (MSM). Lack of awareness is typically measured by comparing HIV test result to self-reported HIV status. This measure may be subject to reporting bias and alternatives are needed. The InvolveMENt study examined HIV disparities between black and white MSM from Atlanta. Among HIV-positive participants who did not report knowing they were positive, we examined other measures of awareness: HIV viral load (VL) <1000 copies/mL (low VL), antiretroviral (ARV) drugs in blood, and previous HIV case surveillance report. Using self-report only, 32% (62 of 192) of black and 16% (7 of 45) of white MSM were not aware of their HIV infection (P = .03). Using self-report and low VL, 25% (48 of 192) black and 16% (7 of 45) white MSM lacked awareness (P = .18). Using self-report and ARVs, 26% (50 of 192) black and 16% (7 of 45) white MSM lacked awareness (P = .14). Using self-report and surveillance report, 15% (28 of 192) black and 13% (6 of 45) white MSM lacked awareness (P = .83). Self-report only may overestimate true lack of awareness of HIV status for black MSM. If, as our data suggest, black MSM are not less likely to be aware of their HIV infection than are white MSM, then this factor is not a substantial driver of HIV disparity. Future HIV research that depends on accurate measurement of HIV status awareness should consider including additional laboratory and case surveillance data.