Excitatory amino acid antagonists for acute stroke.
Focal cerebral ischaemia causes release of excitatory amino acid (EAA) neurotransmitters, principally glutamate, with resultant over-stimulation of EAA receptors and downstream pathways. Excess glutamate release is a pivotal event in the evolution of irreversible ischaemic damage in animal models of ischaemia, and drugs that modulate glutamate action either by inhibiting its release, or blocking post-synaptic receptors, are potent neuroprotective agents. Many clinical trials with EAA modulating drugs have been conducted, none individually demonstrating efficacy. To synthesise all the available data on all different classes of EAA modulators and to evaluate evidence of effects on outcome systematically. Relevant trials were identified in the Specialised Register of Controlled Trials (last searched May 2001). In addition, MEDLINE and EMBASE online searches for the terms "neuroprotection" (and its variants), "neuroprotective agent", for all individual drugs and drug classes included in the review, hand searches of conference proceedings from European, International, American Heart Association and Princeton conferences on Stroke, American Neurological Association and American Academy of Neurology meetings from 1992-2001, and direct contact with individual investigators and pharmaceutical companies. Trials were included if they were randomised, controlled studies giving agents with pharmacological properties that included modification of release of EAAs, or blockade of EAA receptors, in stroke within 24h of onset. Efficacy analysis was restricted to trials with a parallel group design: dose escalation studies were excluded. Intention-to-treat analyses were performed on all data. Outcome had to be reported in terms of death or dependence 1-12 months after the acute event. Data were available for 36 of 41 relevant trials identified, involving 11,209 subjects. Data were unavailable for 632 participants (517 in trials fulfilling criteria for efficacy analysis). Seven trials did not report disability data, which were available for 29 trials involving 10,802 subjects. Twenty one of these trials, involving 10,342 subjects, were parallel group studies included in the primary efficacy analysis. Efficacy analysis included data derived from 9 trials not primarily designed to assess efficacy (1022 subjects). The primary (efficacy) end-point was the proportion of patients dead or disabled at final follow-up (defined by Barthel Index<60 at 3 months by preference). Mortality was a secondary end-point. Drugs were considered as individual agents, and also grouped principally into categories of ion channel modulators (glutamate release inhibition) and NMDA antagonists. There was no significant heterogeneity of outcome amongst individual drugs, or of drug classes either for the primary efficacy analysis (death or dependence) or for mortality at final follow-up. For the primary efficacy analysis, odds of death or dependence were 1.03 [95% confidence interval 0.96-1.12], and for mortality 1.02 [0.92-1.12]. Neither ion channel modulators (death or dependence 1.02 [0.90-1.16]) nor NMDA antagonists (death or dependence 1.05 [0.95-1.16]) differed from the principal analysis including all compounds. Trends for increased mortality with three NMDA antagonists were seen - selfotel (OR 1.19 [0.81-1.74]), aptiganel (OR 1.32 [0.91-1.93]) and gavestinel (OR 1.12 [0.95-1.32]) - but this did not achieve significance for the NMDA antagonists considered as a class (1.09 [0.96-1.23]). Aptiganel was also associated with a trend towards worse functional outcome (OR 1.20 [0.88-1.65]) although this was not the case for either of the other two compounds. No statistically significant detriment of psychotomimetic NMDA antagonists was found, although a trend towards higher mortality in this sub-group was seen (OR 1.25 [0.96-1.64]). There was no evidence of significant benefit or harm from drugs modulating excitatory amino acid action. Reductio]). There was no evidence of significant benefit or harm from drugs modulating excitatory amino acid action. Reduction of death or dependence by 8% or more has been excluded for gavestinel and lubeluzole, which contribute most of the data for this review. However, mechanistic understanding of neuroprotection is too poor to extrapolate from these two failed development plans to all glutamate modulators. Further clinical trials of neuroprotective agents remain justified, since confidence limits around estimates of effect remain wide for most agents, and cannot reliably exclude benefit. Although numbers of patients are too small to confirm or refute a trend towards increased mortality with some NMDA antagonists, further commercial development of these agents is exceedingly unlikely.


The detection of surfactant proteins A, B, C and D in the human brain and their regulation in cerebral infarction, autoimmune conditions and infections of the CNS.
Surfactant proteins (SP) have been studied intensively in the respiratory system. Surfactant protein A and surfactant protein D are proteins belonging to the family of collectins each playing a major role in the innate immune system. The ability of surfactant protein A and surfactant protein D to bind various pathogens and facilitate their elimination has been described in a vast number of studies. Surfactant proteins are very important in modulating the host's inflammatory response and participate in the clearance of apoptotic cells. Surfactant protein B and surfactant protein C are proteins responsible for lowering the surface tension in the lungs. The aim of this study was an investigation of expression of surfactant proteins in the central nervous system to assess their specific distribution patterns. The second aim was to quantify surfactant proteins in cerebrospinal fluid of healthy subjects compared to patients suffering from different neuropathologies. The expression of mRNA for the surfactant proteins was analyzed with RT-PCR done with samples from different parts of the human brain. The production of the surfactant proteins in the brain was verified using immunohistochemistry and Western blot. The concentrations of the surfactant proteins in cerebrospinal fluid from healthy subjects and patients suffering from neuropathologic conditions were quantified using ELISA. Our results revealed that surfactant proteins are present in the central nervous system and that the concentrations of one or more surfactant proteins in healthy subjects differed significantly from those of patients affected by central autoimmune processes, CNS infections or cerebral infarction. Based on the localization of the surfactant proteins in the brain, their different levels in normal versus pathologic samples of cerebrospinal fluid and their well-known functions in the lungs, it appears that the surfactant proteins may play roles in host defense of the brain, facilitation of cerebrospinal fluid secretion and maintenance of the latter's rheological properties.


Pharmacokinetic-pharmacodynamic relationship.
The dose-effect relationship can be determined by linking pharmacokinetic drug behavior with information on pharmacodynamic activity. This requires that the quantifiable concentrations of drug (or metabolites) in the plasma (systemic circulation) are related to the concentration at the site of action. Using the pharmacokinetic parameters and a pharmacokinetic-pharmacodynamic model, it is possible to predict the pharmacodynamic response to certain drugs; this provides useful information for understanding drug action and to determine dosage regimen.


Does physical activity reduce the risk of developing peptic ulcers?
Although Helicobacter pylori has been identified as a major cause of chronic gastritis, not all infected patients develop ulcers, suggesting that other factors such as lifestyle may be critical to the development of ulcer disease. To investigate the role physical activity may play in the incidence of peptic ulcer disease. The subjects were men (8529) and women (2884) who attended the Cooper Clinic in Dallas between 1970 and 1990. The presence of gastric or duodenal ulcer disease diagnosed by a doctor was determined from a mail survey in 1990. Subjects were classified into three physical activity groups according to information provided at the baseline clinic visit (before 1990): active, those who walked or ran 10 miles or more a week; moderately active, those who walked or ran less than 10 miles a week or did another regular activity; the referent group consisting of those who reported no regular physical activity. With the use of gender specific proportional hazards regression models that could be adjusted for age, smoking, alcohol use, body mass index, and self reported tension, active men were found to have a significant reduction in risk for duodenal ulcers (relative hazard (95% confidence interval) for the active group was 0.38 (0.15 to 0.94) and 0.54 (0.30 to 0.96) for the moderately active group). No association was found between physical activity and gastric ulcers for men or for either type of ulcer for women. Physical activity may provide a non-pharmacological method of reducing the incidence of duodenal ulcers among men.


The use of pharmacoeconomic data in formulary selection.
Pharmacists are encouraged to improve their knowledge and use of pharmacoeconomic data in formulary selection. The formulary selection process has changed significantly in recent years. Among its most significant uses is its potential for cost containment strategies. An overview is presented of the origin as well as the potential impact of pharmacoeconomic data. The need to balance the economic benefit with the clinical advantages for any proposed new drug for formulary inclusion remains the most critical decision to be made by pharmacists.


Consciousness and attention.
This article addresses the relationship between attention and consciousness. I take consciousness to refer, at least in an approximate sense, to those thoughts, memories, sensations, and actions of which one is aware, whereas attention refers to those processes that modulate neuronal activity. This modulation may be achieved by virtue of linking or binding distinct neuronal populations or by selecting information for further processing. Thus, consciousness and attention are different but closely related in that attention provides the glue that binds processes and representations to the prevailing cognitive set, thereby rendering them conscious. In this context, then, attention may be viewed as a control process. A number of neurologic syndromes in which disorders of attention result in the fragmentation of consciousness are discussed. Finally, the anatomic bases of attention, both cortical and subcortical, are reviewed.


Biochemical and biological properties of the human N-ras p21 protein.
We characterized the normal (Gly-12) and two mutant (Asp-12 and Val-12) forms of human N-ras proteins produced by Escherichia coli. No significant differences were found between normal and mutant p21 proteins in their affinities for GTP or GDP. Examination of GTPase activities revealed significant differences between the mutant p21s: the Val-12 mutant retained 12% of wild-type GTPase activity, whereas the Asp-12 mutant retained 43%. Both mutant proteins, however, were equally potent in causing morphological transformation and increased cell motility after their microinjection into quiescent NIH 3T3 cells. This lack of correlation between transforming potency and GTPase activity or guanine nucleotide binding suggests that position 12 mutations affect other aspects of p21 function.


What is the relationship between breast cancer risk and mammography screening? A meta-analytic review.
This meta-analytic review addresses the issue of how a woman's risk of breast cancer relates to the likelihood that she will obtain mammography screenings. Studies that compared women with or without a family history of breast cancer (n = 19) showed that women with a family history were more likely to have been screened. Studies that measured perceived risk (n = 19) showed that feeling vulnerable to breast cancer was positively related to having obtained a screening. Studies that compared women who did or did not have a history of breast problems (n = 10) showed that those with a positive history were more likely to have been screened. Finally, studies that measured worry (n = 6) showed that greater worry was related to higher screening levels. Taken together, these data suggest that increasing perceptions of personal vulnerability may increase screening behavior for breast cancer.


Ruthenium sensitizers having an ortho-dicarboxyl group as an anchoring unit for dye-sensitized solar cells: synthesis, photo- and electrochemical properties, and adsorption behavior to the TiO₂ surface.
A novel ruthenium sensitizer ((TBA)[Ru(3',4'-dicarboxyterpyridine)(NCS)3], TBA = tetrabutylammonium, TUS-28) has been synthesized as an improved model sensitizer for (TBA)[Ru(4'-(3,4-dicarboxyphenyl)terpyridine)(NCS)3] (TUS-20). The molar absorptivity of TUS-28 in the whole visible region was smaller than that of TUS-20 due to the absence of the phenyl ring at the terpyridine ligand. On the other hand, the energy levels of HOMO and LUMO of TUS-28 were still suitable for effective electron transfer reactions in dye-sensitized solar cells (DSCs). TUS-28 did not show a superior adsorptivity to the TiO2 surface just like TUS-20, even though TUS-28 has an ortho-dicarboxyl group which is reported to be an efficient anchoring unit. ATR-IR measurements revealed that both carboxyl groups of TUS-28 participate in binding to the TiO2 surface just like TUS-20. Therefore, steric hindrance between the hydrogen atom at the 4-position of 3',4'-dicarboxyterpyridine and the OH group at the TiO2 surface seems to retard the rapid adsorption, and to weaken the binding strength of TUS-28. The DSC with TUS-28 showed 8.2% conversion efficiency, which is higher than that of TUS-20 (7.5%). The J(sc) value of the DSC with TUS-28 was larger than that of TUS-20 even though the amount of dye adsorption of TUS-28 was smaller than that of TUS-20. A more effective electron injection reaction is considered to contribute mainly to the efficiency improvement of TUS-28 since the path length of the electron injection from TUS-28 to the conduction band of the TiO2 is shorter than that of TUS-20 due to the absence of the phenyl ring.


Controlling the phase delay of light transmitted through double-layer metallic subwavelength slit arrays.
We demonstrate that the phase of light transmitted through double-layer subwavelength metallic slit arrays can be controlled through lateral shift of the two layers. Our samples consist of two aluminum layers, each of which contains an array of subwavelength slits. The two layers are placed in sufficient proximity to allow coupling of the evanescent fields at resonance. By changing the lateral shift between the layers from zero to half the period, the phase of the transmitted electromagnetic field is increased by pi, while the transmitted intensity remains high. Such a controllable phase delay could open new capabilities for nanophotonic devices that cannot be achieved with single-layer structures.


Molecular cloning and genetic analysis of a chloramphenicol acetyltransferase determinant from Clostridium difficile.
A gene bank from a clinical isolate of Clostridium difficile expressing high chloramphenicol acetyltransferase activity was constructed by cloning Sau3A-cleaved clostridial DNA fragments into the plasmid vector pUC13. Among 1,020 clones tested, 11 were resistant to chloramphenicol; 1 of these, with an insert size of 1.9 kilobases (pPPM9), was studied further. The clone pPPM9 was mapped using a variety of restriction enzymes, and a 0.27-kilobase EcoRV-TaqI restriction fragment was shown to be within the chloramphenicol resistance (Cmr) gene by using transposon (Tn1000) mutagenesis. The 0.27-kilobase fragment and the 1.9-kilobase insert were radiolabeled and used as DNA probes in hybridization studies. Southern blot analysis with the gene probes against chromosomal DNA from Cmr strains of C. difficile obtained from five distinct geographical locations revealed that at least two copies of the same chloramphenicol acetyltransferase gene were present for each strain. Hybridization of the gene probes against Cmr strains of Staphylococcus epidermidis, Staphylococcus aureus, Klebsiella edwardsii, Escherichia coli, and to four other clostridial species revealed no homology even under conditions of low stringency.


Derivation and validation of a clinical severity score for acutely ill adults with suspected COVID-19: The PRIEST observational cohort study.
We aimed to derive and validate a triage tool, based on clinical assessment alone, for predicting adverse outcome in acutely ill adults with suspected COVID-19 infection. We undertook a mixed prospective and retrospective observational cohort study in 70 emergency departments across the United Kingdom (UK). We collected presenting data from 22445 people attending with suspected COVID-19 between 26 March 2020 and 28 May 2020. The primary outcome was death or organ support (respiratory, cardiovascular, or renal) by record review at 30 days. We split the cohort into derivation and validation sets, developed a clinical score based on the coefficients from multivariable analysis using the derivation set, and the estimated discriminant performance using the validation set. We analysed 11773 derivation and 9118 validation cases. Multivariable analysis identified that age, sex, respiratory rate, systolic blood pressure, oxygen saturation/inspired oxygen ratio, performance status, consciousness, history of renal impairment, and respiratory distress were retained in analyses restricted to the ten or fewer predictors. We used findings from multivariable analysis and clinical judgement to develop a score based on the NEWS2 score, age, sex, and performance status. This had a c-statistic of 0.80 (95% confidence interval 0.79-0.81) in the validation cohort and predicted adverse outcome with sensitivity 0.98 (0.97-0.98) and specificity 0.34 (0.34-0.35) for scores above four points. A clinical score based on NEWS2, age, sex, and performance status predicts adverse outcome with good discrimination in adults with suspected COVID-19 and can be used to support decision-making in emergency care. ISRCTN registry, ISRCTN28342533, http://www.isrctn.com/ISRCTN28342533.


Correlated memory defects and hippocampal dendritic spine loss after acute stress involve corticotropin-releasing hormone signaling.
Stress affects the hippocampus, a brain region crucial for memory. In rodents, acute stress may reduce density of dendritic spines, the location of postsynaptic elements of excitatory synapses, and impair long-term potentiation and memory. Steroid stress hormones and neurotransmitters have been implicated in the underlying mechanisms, but the role of corticotropin-releasing hormone (CRH), a hypothalamic hormone also released during stress within hippocampus, has not been elucidated. In addition, the causal relationship of spine loss and memory defects after acute stress is unclear. We used transgenic mice that expressed YFP in hippocampal neurons and found that a 5-h stress resulted in profound loss of learning and memory. This deficit was associated with selective disruption of long-term potentiation and of dendritic spine integrity in commissural/associational pathways of hippocampal area CA3. The degree of memory deficit in individual mice correlated significantly with the reduced density of area CA3 apical dendritic spines in the same mice. Moreover, administration of the CRH receptor type 1 (CRFR(1)) blocker NBI 30775 directly into the brain prevented the stress-induced spine loss and restored the stress-impaired cognitive functions. We conclude that acute, hours-long stress impairs learning and memory via mechanisms that disrupt the integrity of hippocampal dendritic spines. In addition, establishing the contribution of hippocampal CRH-CRFR(1) signaling to these processes highlights the complexity of the orchestrated mechanisms by which stress impacts hippocampal structure and function.


E-Health Ultrasonic Diagnostic Monitoring for Analysis of Cardiac Insufficiency and Neuronal Regulation in Patients with Sepsis in Emergency Department under Image Reconstruction Algorithm.
An anisotropic diffusion filtering- (ADF-) ultrasound (ADF-U) for ultrasound reconstruction was constructed based on the ADF to explore the diagnostic application of ultrasound imaging based on electronic health (E-health) for cardiac insufficiency and neuronal regulation in patients with sepsis. The 144 patients with sepsis were divided into an experimental group (78 patients with cardiac insufficiency) and a control group (66 patients with normal cardiac function), and another 58 healthy people were included in a blank control. The ultrasound examination was performed on all patients. In addition, new ultrasound image reconstruction and diagnosis were performed based on ADF and E-health, and its reconstruction effects were compared with those of the Bilateral Filter-ultrasonic (BFU) algorithm and the Wavelet Threshold-ultrasonic (WTU) algorithm. The left and right ventricular parameters and neuropeptide levels were detected and recorded. The results show that the running time, average gradient (AG), and peak signal-to-noise ratio (SNR) (PSNR) of the ADF-U algorithm were greater than those of the Bilateral Filter-ultrasonic (BFU) and Wavelet Threshold-ultrasonic (WTU), but the mean square error (MSE) was opposite (P < 0.05); the left ventricular end-systolic volume (LVESV) and the vertical distance between the mitral valve E-point to septal separation (EPSS) in the experimental group were higher than those in the control and blank group, while the left ventricular ejection fraction (LVEF), stroke volume (SV), cardiac output (CO), and left ventricular fractional shortening (LVFS) were opposite (P < 0.05); the systolic peak velocity of right ventricular free wall tricuspid annulus (Sm) and pulmonary valve blood velocity (PVBV) in the experimental group were lower than those of the control group and blank group (P < 0.05); the messenger ribonucleic acid (mRNA) of Proopiomelanocortin (POMC) and Cocain and amphetamine-regulated transcript (CART) was higher than the mRNA IN control group and blank group (P < 0.05). In short, the ADF-U algorithm proposed in this study improved the resolution, SNR, and reconstruction efficiency of E-health ultrasound images and provided an effective reference value for the diagnosis of cardiac insufficiency and neuronal adjustment analysis in patients with sepsis in the emergency department.


Efficient post-synthesis incorporation and conjugation of reactive ketones in RNA via 2'-acylation.
Despite the broad utility of ketones in bioconjugation, few methods exist to introduce them into RNA. Here we develop highly reactive 2'-OH acylating reagents containing strained-ring ketones, and employ them as versatile labeling handles for RNA.


Serotonin Syndrome Induced by Combined Use of Sertraline and Linezolid.
Serotonin syndrome is a potentially fatal increase in serotonergic activity in both the central nervous system and peripheral nervous system. The etiology can vary from therapeutic drug use, deliberate overdose, or drug interactions that all lead to an increase in serotonin activity. There are some drugs from different classes that can cause serotonin syndrome either alone at high doses or when combined. We present here a case of an 82-year-old female who presented to the emergency room with high-grade fever, loose stools, burning micturition, and tachycardia. Her current medications included sertraline for depression. She was initially treated on the floor for urosepsis and subsequently managed with antibiotic therapy consisting of cephalosporins. She did not improve so her antibiotics were modified and she was then started on linezolid. Within the first 24 h of taking linezolid, the patient had a rapid clinical deterioration manifesting as restlessness, diaphoresis, tremor, shivering, myoclonus, and high fever (40°C). She also had an acute decompensation of her mental status with disorientation and confusion. As a result, she was transferred to intensive care unit. On clinical examination, she had rigidity and hyperreflexia all the four limbs. Babinski sign was positive. Laboratory test results were unremarkable for sepsis. Sertraline and linezolid were stopped. Within 24 h, the patient's mental status had improved. By the 2nd day on this treatment regimen, the patient's function returned to baseline, and she was discharged from the hospital. Nevertheless, in our case, the administration of sertraline did not reveal any symptomatic interaction, as the serotonin syndrome was induced only after the addition of linezolid to the treatment regimen. This patient was diagnosed with serotonin syndrome.


Ketamine modulates hippocampal neurogenesis and pro-inflammatory cytokines but not stressor induced neurochemical changes.
Considerable recent attention has focused on the rapid antidepressant effects observed in treatment resistant patients produced by the NMDA receptor antagonist, ketamine. Surprisingly, the effects of ketamine in the context of stressor exposure, as well as the consequences of its chronic use are unclear. Thus, we assessed the impact of acute and repeated ketamine treatment together with acute [restraint or lipopolysaccharide (LPS)] or chronic (unpredictable different psychogenic challenges) stressor exposure. Importantly, acute ketamine treatment did provoke an antidepressant-like effect in a forced swim test (FST) and this effect lasted for 8 days following repeated exposure to the drug. Although acute restraint and LPS individually provoked the expected elevation of plasma corticosterone and brain-region specific monoamine variations, ketamine had no influence on corticosterone and had, at best, sparse effects on the monoamine changes. Similarly, ketamine did not appreciably influence the stressor induced neurochemical and sucrose preference alterations, it did however, dose-dependently reverse the LPS induced elevation of the pro-inflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Likewise, repeated ketamine administration increased adult hippocampal neurogenesis. These data indicate that repeated ketamine administration had greater behavioral consequences than acute treatment and that the drug might be imparting antidepressant effects through its effects on neuroplasticity and inflammatory processes rather than the typical neurochemical/hormonal factors affected by stressors. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'.


Structure of nanometre-sized Xe particles embedded in Al crystals.
The structure and lattice parameters of Xe particles about 1 nm to about 6 nm in size embedded in Al were investigated with off-Bragg condition high-resolution transmission electron microscopy. An Xe particle about 1 nm in size had different structural properties from those 2-6 nm in sizes. Some 1-nm Xe particles had an face-centred cubic (f.c.c.) structure with the same orientation as the Al matrix, whereas others of the same size had a non-f.c.c. structure. The lattice parameters of a 1-nm f.c.c. Xe particle were about 20% smaller than the average value obtained from electron diffraction, i.e. the particle was compressed by about 80%. The lattice parameters of Xe crystals about 2 nm to about 6 nm in size were almost the same as those obtained from diffraction results. One of the reasons for the extra compression seen with a 1-nm Xe particle is the increase in pressure inside an Xe particle with decreasing particle size.


Physicians under Pressure: Evidence from Antibiotics Prescribing in England.
Many physicians are experiencing increasing demands from both their patients and society. Evidence is scarce on the consequences of the pressure on physicians' decision making. We present a theoretical framework and predict that increasing pressure may make physicians disregard societal welfare when treating patients. We test our prediction on general practitioners' antibiotic-prescribing choices. Because prescribing broad-spectrum antibiotics does not require microbiological testing, it can be performed more quickly than prescribing for narrow-spectrum antibiotics and is therefore often preferred by the patient. In contrast, from a societal perspective, inappropriate prescribing of broad-spectrum antibiotics should be minimized as it may contribute to antimicrobial resistance in the general population. We combine longitudinal survey data and administrative data from 2010 to 2017 to create a balanced panel of up to 1072 English general practitioners (GPs). Using a series of linear models with GP fixed effects, we estimate the importance of different sources of pressure for GPs' prescribing. We find that the percentage of broad-spectrum antibiotics prescribed increases by 6.4% as pressure increases on English GPs. The link between pressure and prescribing holds for different sources of pressure. Our findings suggest that there may be societal costs of physicians working under pressure. Policy makers need to take these costs into account when evaluating existing policies as well as when introducing new policies affecting physicians' work pressure. An important avenue for further research is also to determine the underlying mechanisms related to the different sources of pressure.JEL-code: I11, J28, J45. Many physicians are working under increasing pressure.We test the importance of pressure on physicians' prescribing of antibiotics.The prescribed rate of broad-spectrum antibiotics increases with pressure.Policy makers should be aware of the societal costs of pressured physicians.[Formula: see text].


The effects of ayahuasca ritual participation on gay and lesbian identity.
The practice of drinking ayahuasca-a psychoactive brew indigenous to the Amazon-has been investigated in several studies and shown to have positive long-term effects on mental states, and a particularly strong positive effect on perceptions of identity. This article discusses if these previous findings can be found in the experience of gay people, who are often taught by their culture and religion that their lifestyles, values, and sexual orientation are unacceptable. The qualitative study examined the interview responses of 17 self-identified gay and lesbian participants who had drunk ayahuasca in a ceremonial context within the past three years, regarding their self-perceptions and integration of group beliefs. Participants drank either in shamanic or Santo Daime ceremonies or, in the case of one participant, with an Afro-Brazilian group that used ayahuasca. Participants reported affirmation of their sexual orientation, and no participants reported negative effects on perception of identity. Additional positive effects in other areas of their lives, which they attributed to ayahuasca sessions, contributed to the overall positive outcomes that were reported by this group as a result of their ritual participation.


Cardiomyopathy. 2. Hypertrophic and restrictive/obliterative types.
The functional classification of the three types of cardiomyopathy has been helpful in organizing practitioners' thinking. The past three decades have witnessed tremendous advances in understanding of the pathophysiology, clinical and laboratory diagnosis, and treatment of these disorders. New doors of exploration are opening to answer such nagging questions as whether medical therapy alters long-term survival rates in dilated (congestive) cardiomyopathy, whether immunologic therapy will alter the course of dilated or restrictive/obliterative cardiomyopathy, and whether genetic manipulation or in utero therapy will prevent hypertrophic cardiomyopathy. The goals of effective treatment in all these disorders remain the same: amelioration of symptoms, prevention of sudden death, and constraint or resolution of the basic disease process. Achieving these goals requires a multidisciplinary approach, involving cardiologists, surgeons, immunologists, geneticists, cell biologists, virologists, and pathologists. Prospects are that one day treatment will no longer be an imprecise, palliative art but a definitive, curative science.


The role of TNF in parasitic diseases: still more questions than answers.
The inhibition of TNF with therapeutic monoclonal antibodies or antibody/receptor fusion proteins in rheumatoid arthritis still constitutes the benchmark for a successful intervention in an ongoing auto-immune-inflammatory disease and underlines the importance of this cytokine. TNF plays a central role in the defence against intracellular infections and is responsible for the promotion of different aspects of the innate immune response such as inflammatory cell recruitment and cell differentiation. While this cytokine generally displays pro-inflammatory activities supporting the early stages of the inflammatory response, it has been demonstrated to be especially important during infection with intracellular pathogens and, consequently, leishmaniasis of TNF(-/-) mice ends fatally. However, the specific activities of TNF that confer protection are not yet fully understood. This review will summarize the current understanding of TNF function and signalling, and will discuss recent work in the models of malaria, toxoplasmosis, trypanosomiasis and leishmaniasis with particular emphasis on work with gene-deficient mouse models.


Gender Differences in Oral Health Knowledge and Practices Among Adults in Jeddah, Saudi Arabia.
To determine the knowledge and practices of adults regarding oral health and to determine the associated gender differences. A cross-sectional study design was used in Jeddah, Saudi Arabia, and a total of 1330 adults participated. Data were collected using self-administered validated questionnaire to gather information about sociodemographic data, oral health knowledge and practices. The scores of the oral health knowledge were calculated. Linear and logistic regressions were used to evaluate and compare the oral health knowledge and practices between males and females. Females had a significantly higher mean oral health knowledge score (8.5 ± 1.5) than males (8.1 ± 1.7). Regarding oral health practices, female participants reported a higher frequency of tooth brushing and mouthwash use than males (p = 0.001). The percentage of females who visited the dentist for check-ups and cleaning was significantly higher compared to males (41.5% and 35.2%, respectively). Participants with a university-level education showed a significantly higher knowledge score (coefficient = 0.27; 95% CI: -0.46 to 0.46). Respondents who were less than 40 years old brushed their teeth more than twice a day compared to older individuals (OR = 1.51; 95% CI: 1.06 to 2.13). Nonsmokers had better knowledge, and brushing their teeth twice daily was more likely among them (OR = 0.76; 95% CI: 0.59 to 0.99). Among the adult population, females were more knowledgeable about their oral health and exhibited better practices than males.


Determination of in vitro human whole blood-to-plasma ratio of THJ-018 utilizing gas chromatography-Mass spectrometry.
This study was aimed to determine in vitro human whole blood-to-plasma ratio (KWB/P) of THJ-018 by gas chromatography/mass spectrometry (GC/MS). The samples (human blood) were sprayed with THJ-018 and an internal standard and extracted using solid-phase extraction. THJ-018 was determined in the final extracts by GC/MS. The value for KWB/P was 1.56 (1.38-1.81), and red blood cell partitioning was 1.01 (1.01-1.02). The distribution of THJ-018 between whole blood and plasma was observed to be affected by temperature. The data analysis supports the proposition that the ratio of the plasma to whole blood concentrations (1.56) is a suitable parameter characterizing THJ-018 distribution in whole blood. For toxicological analysis, it would be best to refrain from converting any drug concentration measured in whole blood to that anticipated in plasma or serum; however, toxic and therapeutic concentrations should be determined for the individual specimens collected.


Conversion of nerve growth factor-receptor complexes to a slowly dissociating, Triton X-100 insoluble state by anti nerve growth factor antibodies.
Two populations of nerve growth factor (NGF) receptors can be distinguished on PC12 cells and have been termed "fast" and "slow" receptors on the basis of their respective rates of dissociation. Since a slowly dissociating state of the NGF receptor could be produced by receptor clustering, we sought to examine the effects of artificially clustering NGF-receptor complexes by using anti-NGF antibodies. At an 125I-NGF concentration of 500 pM, slow receptors account for 25% of the total NGF binding. However, if 125I-NGF is first bound to the cell surface and an anti-NGF immunoglobulin G (IgG) is added subsequently, greater than 90% of the total binding becomes slowly dissociating. Anti-NGF IgG also changes the proportion of Triton X-100 insoluble NGF binding from 10% to 50%, possibly reflecting an association of the NGF receptor with the cytoskeleton. The effects on NGF binding of low concentrations of anti-NGF IgG could be enhanced by the addition of goat anti-rabbit IgG. Neither Fab fragments nor an anti-NGF monoclonal antibody affects NGF binding, indicating that the cross-linking capacity of anti-NGF IgG is required for its activity. Wheat germ agglutinin (WGA), a multivalent lectin, also converts NGF binding into a predominantly slowly dissociating, Triton X-100 insoluble state. Both WGA and anti-NGF IgG produce their effects on NGF binding at 37 and 4 degrees C and protect the 125I-NGF-receptor complex from protease digestion.(ABSTRACT TRUNCATED AT 250 WORDS)


Pathways of influence in out-of-school time: a community-university partnership to develop ethics.
If we wish to incorporate parents and community members as full partners in building character among youth, then the activities and programs in which youth participate during their out-of-school time are potentially important venues. This chapter describes how numerous agencies in a single community partnered with a university, with the help of the cooperative extension agent, to collect local data on how adolescents used out-of-school time, what they thought about right and wrong, and how well their own behavior comported with their understandings of what was right. Results indicated that surveyed youth characterized themselves as thinking more than acting in ethical ways. For instance, nearly half acknowledged having cheated on a test at least once in the past six months, although the vast majority thought that cheating was wrong. The three pathways the community identified for reaching youth were (1) extracurricular activities at school such as sports, yearbook, and pep club; (2) organized nonschool pursuits such as music, dance, hiking, and biking; and (3) religious activities. They found that nearly 90 percent of high school-aged respondents participated in one or another of these venues.


Prevalence of Rheumatoid Arthritis and Drug Dispensing Patterns Among Medicaid and Medicaid-Medicare Dually Eligible Beneficiaries in Puerto Rico.
To estimate the prevalence of rheumatoid arthritis (RA) in Puerto Rico, to describe disease-modifying antirheumatic drug (DMARD) dispensing patterns by prescriber specialty, and to illustrate the impact of RA case definition on the estimated prevalence. This study estimated the prevalence of RA in Puerto Rico during 2016 among Medicaid and Medicaid-Medicare dually eligible beneficiaries of the Mi Salud health care plan, a federally funded health insurance program. DMARD dispensing and cost patterns were described and stratified by provider specialty. A sensitivity analysis was conducted to evaluate the effect of RA case definition on estimated prevalence. The prevalence of RA in 2016 was estimated to be 2 cases per 1,000 beneficiaries, with 3 per 1,000 beneficiaries among females, 4.5 times that of males. In total, 44% of beneficiaries received conventional synthetic DMARDs (csDMARDs) only, 32% received biologic or targeted synthetic DMARDs (b/tsDMARDs) only, and 24% received a combination of csDMARDs and b/tsDMARDs. Rheumatologists and a combination of specialties accounted for the highest median number of dispensed DMARDs, with 14 each. A sensitivity analysis revealed that when RA cases with ≥3 medical claims were restricted to having ≥1 DMARD claim, the estimated prevalence changed from 6 to 3 cases per 1,000 beneficiaries. The prevalence of RA in Puerto Rico in this study is lower than reported in the mainland US, possibly due to more stringent criteria to define RA. DMARD dispensing and cost patterns are similar to those found in other studies. Claims algorithms that identify RA have higher validity when pharmacy data is included.


Pharmacologic treatment of paraphilias.
The treatment of paraphilias remains a challenge in the mental health field. Combined pharmacologic and psychotherapeutic treatment is associated with better efficacy. The gold standard treatment of severe paraphilias in adult males is antiandrogen treatment with cognitive behavioral therapy. Selective serotonin reuptake inhibitors have been used in mild types of paraphilia and in cases of sexual compulsions and juvenile paraphilias. Antiandrogen treatments seem to be effective in severe paraphilic subjects committing sexual offenses. In particular, gonadotropin-releasing hormone analogs have shown high efficacy working in a similar way to physical castration but being reversible at any time. Treatment recommendations, side effects, and contraindications are discussed.


Preventing depression in the community by voluntary sector providers (PERSUADE): intervention development and protocol for a parallel randomised controlled feasibility trial.
Depression is now the most common illness worldwide affecting more than 300 million people. Studies modelling the impact of depression interventions have shown that the burden of depression cannot be minimised by more than 35% with existing treatments. There is a need to develop better preventative interventions. The overall aim of this programme of work is to develop interventions to reduce depression symptom scores and prevent development of depression in people with subthreshold depression. The objectives are to adapt a low intensity community-based depression prevention intervention, establish the acceptability and uptake of this model and conduct a parallel randomised controlled feasibility trial to inform a full-scale trial. Focus groups will be run with members of the public, voluntary sector providers and researchers to inform the adaptation of an existing depression prevention course. Sixty-four people with subthreshold depression, as represented by a score of between 5 and 9 on the Patient Health Questionnaire-9 depression measure, will be recruited to take part in the feasibility trial. Participants will be randomised equally to the intervention or usual care control groups. Participants in the intervention group will receive the new revised manual and attend a 1-day workshop delivered by voluntary sector service providers. Outcome measures will be completed 3 months after baseline. Quantitative data on recruitment, randomisation, attendance, retention, questionnaire completion rates will be collected. Primary analyses will be descriptive and a process evaluation will be conducted to assess the processes involved in implementing the intervention. Interviews will be conducted to explore acceptability and framework analysis will be used to analyse the data. The study has been reviewed and approved by NHS Research and Ethics Committee: NW-Greater Manchester East. The results will be actively disseminated through peer-reviewed journals, conference presentations, social media, the internet and community engagement activities. ISRCTN23278208;Pre-results.


Differential polarization of immune responses by plant 2S seed albumins, Ber e 1, and SFA8.
The plant 2S seed albumins Ber e 1 and SFA8, although structurally very similar, vary with respect to their allergenic properties. Whereas the former represents a major allergen, the latter appears to promote only weak allergenic responses. The aim of this investigation was to determine whether the allergenic properties of Ber e 1 and SFA8 reflected differential polarization of dendritic cell (DC) and Th cell responses. We thus investigated the effect of recombinant forms of both allergens on DC and Th cell responses as indicated by cell surface phenotype and cytokine production. Exposure of murine DCs to SFA8, but not Ber e 1, resulted in production of the cytokines IL-12 p40 and TNF-alpha by a mechanism independent of recognition by TLRs. Furthermore, depending on the mouse strain used, increased expression of MHC class II and costimulatory molecules such as CD40, CD80, and CD86 was associated with exposure to SFA8, but not Ber e 1. In coculture experiments using the DO11.10 transgenic T cell that recognizes OVA peptide, DCs exposed to both allergens induced T cells to produce IFN-gamma, but only Ber e 1 could induce significant production of IL-4 and IL-5. Likewise, analysis of transcription factors shows increased T-bet with respect to both allergens, but also GATA-3 with respect to Ber e 1. Overall, our data are consistent with the idea that the ability of Ber e 1, but not SFA8, to act as a potent allergen may reflect differences in their ability to induce IL-12 production.


[What students and teaching doctors in Heidelberg think about early patient contact and tasks in general practice].
In Heidelberg, the clinical curriculum of medical education was fundamentally changed in 2001 due to co-operation with the Harvard Medical School. The pre-clinical curriculum has also already been undergoing reform since 1995: the benefits of two new lectures with early patient contact and special tasks in the subject of family medicine were to be assessed. In the first year, the students therefore had to assess the seminars, tutorials, and the internships in GP by means of a standardised questionnaire. In addition, reports had to be produced on teaching practice. The teachers were also questioned following agreement with and introduction of quality assurance measures. 66-89% of students assigned good marks to the internships in GP, 40-58% for the accompanying seminars, and 70% for the tutors. The results of a general external evaluation which was carried out slightly differently were not quite so good. 87-89% of teachers agreed upon the elaborated criteria for the quality of teaching practice. The results show that GP-based education is already well accepted in the first year of training, and that early patient contact in primary care is highly appreciated by the students. On their part, the teaching GPs assess the quality promotion sessions as instruments towards continuous quality support in pre-clinical training as meaningful and necessary, especially with regard to licensing for teaching in General practice.


Medicine Targeting Epithelial-Mesenchymal Transition to Treat Airway Remodeling and Pulmonary Fibrosis Progression.
Objective. Dysregulation of epithelial-mesenchymal transition (EMT) in the airway epithelium is associated with airway remodeling and the progression of pulmonary fibrosis. Many treatments have been shown to inhibit airway remodeling and pulmonary fibrosis progression in asthma and chronic obstructive pulmonary disease (COPD) by regulating EMT and have few side effects. This review aimed to describe the development of airway remodeling through the EMT pathway, as well as the potential therapeutic targets in these pathways. Furthermore, this study aimed to review the current research on drugs to treat airway remodeling and their effects on the EMT pathway. Findings. The dysregulation of EMT was associated with airway remodeling in various respiratory diseases. The cytokines released during inflammation may induce EMT and subsequent airway remodeling. Various drugs, including herbal formulations, specific herbal compounds, cytokines, amino acid or protein inhibitors, microRNAs, and vitamins, may suppress airway remodeling by inhibiting EMT-related pathways.


Can research and care be ethically integrated?
Medical ethics assumes a clear boundary between clinical research and clinical medicine: one produces knowledge for the benefit of future patients, while the other provides optimal care to individuals right now. It also assumes that the two cannot be integrated without sacrificing the needs of the current patient to those of future patients. But integration could allow us to provide better care to everyone, now and in the future.


Leaf trait coordination and variation of blue oak across topo-environmental scales.
Trees are arguably the most diverse and complex macro-organisms on Earth. The equally diverse functions of trees directly impact fluxes of carbon, water and energy from the land surface. A number of recent studies have shed light on the substantial within-species variability across plant traits, including aspects of leaf morphology and plant allocation of photosynthates to leaf biomass. Yet, within-tree variability in leaf traits due to microclimatic variations, leaf hydraulic coordination across traits at different physiological scales and variations in leaf traits over a growing season remain poorly studied. This knowledge gap is stymieing the fundamental understanding of what drives trait variation and covariation from tissues to trees to landscapes. Here, we present an extensive dataset measuring within-tree heterogeneity in leaf traits in California's blue oak (Quercus douglasii) across an edaphic gradient and over the course of a growing season at an oak-grass savanna in Southern CA, USA. We found a high level of within-tree crown leaf area:sapwood area variation that was not attributable to sample height or aspect. We also found a higher level of trait integration at the tree level, rather than branch level, suggesting that trees optimize water use at the organismal level. Despite the large variance in traits within a tree crown and across trees, we did not find strong evidence for adaptive plasticity or acclimation in leaf morphological traits (e.g., changes to phenotype which increased fitness) across temporal and spatial water availability gradients. Collectively, our results highlight strong variation in drought-related physiology, but limited evidence for adaptive trait plasticity over shorter time scales.


AI-Enabled Advanced Development for Assessing Low Circulating Blood Volume for Emergency Medical Care: Comparison of Compensatory Reserve Machine-Learning Algorithms.
The application of artificial intelligence (AI) has provided new capabilities to develop advanced medical monitoring sensors for detection of clinical conditions of low circulating blood volume such as hemorrhage. The purpose of this study was to compare for the first time the discriminative ability of two machine learning (ML) algorithms based on real-time feature analysis of arterial waveforms obtained from a non-invasive continuous blood pressure system (Finometer®) signal to predict the onset of decompensated shock: the compensatory reserve index (CRI) and the compensatory reserve metric (CRM). One hundred ninety-one healthy volunteers underwent progressive simulated hemorrhage using lower body negative pressure (LBNP). The least squares means and standard deviations for each measure were assessed by LBNP level and stratified by tolerance status (high vs. low tolerance to central hypovolemia). Generalized Linear Mixed Models were used to perform repeated measures logistic regression analysis by regressing the onset of decompensated shock on CRI and CRM. Sensitivity and specificity were assessed by calculation of receiver-operating characteristic (ROC) area under the curve (AUC) for CRI and CRM. Values for CRI and CRM were not distinguishable across levels of LBNP independent of LBNP tolerance classification, with CRM ROC AUC (0.9268) being statistically similar (p = 0.134) to CRI ROC AUC (0.9164). Both CRI and CRM ML algorithms displayed discriminative ability to predict decompensated shock to include individual subjects with varying levels of tolerance to central hypovolemia. Arterial waveform feature analysis provides a highly sensitive and specific monitoring approach for the detection of ongoing hemorrhage, particularly for those patients at greatest risk for early onset of decompensated shock and requirement for implementation of life-saving interventions.


[Sensitivity of fungi in the genus Candida to antimicrobial preparations].
Sensitivity of 50 Candida fungus strains isolated from patients with chronic intestine diseases was studied with respect to amphotericin B, levorin, enteroseptol, intestopan and decamethoxin. The rate of forming resistant variants of the strains with respect to decamethoxin and development of their cross resistance to levorin was estimated. It was shown that decamethoxin was the most active antifungal drug among the drugs tested. Estimation of sensitivity of the Candida strains to enteroseptol and intestopan revealed that the fungicidal concentration of enteroseptol for 78 per cent of the strains ranged within 3.9-7.8 micrograms/ml. It was demonstrated that development of resistance to decamethoxin in the strains of Candida albicans was slow and did not reach high levels. No cross resistance between decamethoxin and levorin was detected.


Alveolar hydatid disease in Minnesota. First human case acquired in the contiguous United States.
A 56-year-old woman from southwestern Minnesota underwent an extended left hepatic lobectomy to remove a large multinodular mass with a necrotic central cavity. The clinical, serological, and pathological findings led to the diagnosis of alveolar hydatid disease, and specific identification of Echinococcus multilocularis was achieved by growing mature larvas in voles inoculated intraperitoneally with tissue from the hepatic lesions. The patient probably acquired her infection some years previously from pet cats or dogs that had become infected by ingesting infected rodents. In North America E multilocularis is enzootic in the northern tundra zone of Alaska and Canada. Since 1964 the cestode has been recognized with increasing frequency in several north-central states, including Minnesota. The parasite may extend its range farther south, since suitable animal hosts occur throughout the United States.


Preparing for advanced practice radiation therapy in South Africa: Conceptual and curricular considerations.
The higher education landscape in South Africa has recently changed with the new National Qualifications Framework, leading to the introduction of four-year degrees in all four radiography disciplines. Additionally, there have been developments in the extension of roles in radiography, while the need for interdisciplinary practice has also been emphasised. The Professional Board for Radiography and Clinical Technology (PBRCT) of the Health Professions Council of South Africa is currently revising the scope of the profession which will now include extended roles. However, the extended role concept in radiation therapy has not received the attention similar to Diagnostic/Medical Imaging. The aim of this paper is, therefore, to provide concept clarification and key considerations for developing a postgraduate curricular framework for training radiation therapists to practise in the envisaged extended roles. For this narrative review, a Boolean search for advanced practice and role extension in radiation therapy was done on all databases (43) available on EbscoHost to source for peer-reviewed articles published between January 1950 and September 2020. A total of 17 articles met the inclusion criteria and were used to frame the discussion. Advanced practice emerged as the more suitable concept as it goes beyond an extension of tasks to include critical characteristics that are necessary to drive transformation in the local social, professional and educational arenas. It is envisaged that some of the key points discussed in this paper could assist the PBRCT in thinking about the implementation of the proposed extended roles for radiation therapists in South Africa.


Guiding medical students through the match: perspectives from recent graduates.
Little has been written about the counseling of medical students as they go through the process of selecting and ranking residency programs for the National Resident Matching Program. The Association of Pediatric Program Directors (APPD) and the Council on Medical Student Education in Pediatrics jointly sought to evaluate the current status of advice and counseling for students going through the Match, and to elicit suggestions for improvement. Surveys evaluating satisfaction with aspects of and advice received regarding the Match were sent to each of the 199 Accreditation Council for Graduate Medical Education accredited member programs of the APPD with a request that they be distributed to all first-year pediatric residents during the orientation process for the 2001-2002 academic year. Surveys were both voluntary and anonymous. Results were compiled by the administration of the APPD. We received responses from 42% of all US pediatric categorical or combined residents entering pediatric residency in July of 2001. Respondents included at least 1 representative from every US medical school. Ninety-seven percent of respondents were either very satisfied (88%) or somewhat satisfied (9%) with where they matched, whereas 82% were either very (42%) or somewhat (40%) satisfied with the advice they received regarding the match. The Fellowship and Residency Interactive Database, the faculty advisor, and resident-to-student counseling were the top 3 resources identified by the respondents. Of 12 resources listed in the survey, only the Green Book was rated as unhelpful. Four areas for improvement regarding the advising process were identified: timing, standardization, and quantity of advice and accuracy of online information resources, with specific suggestions given for each. Overall, recent medical school graduates are quite satisfied with both where they matched in pediatrics and the process that got them there. However, several areas for improvement in the advising/counseling system were identified. Potential approaches to these concerns or resources to develop approaches to them were identified.


Dementia Literacy in the Greater Bay Area, China: Identifying the At-Risk Population and the Preferred Types of Mass Media for Receiving Dementia Information.
Background: The aim of this cross-sectional study was to assess the dementia literacy of community-dwelling adults in four cities (Hong Kong, Guangzhou, Macau, and Zhuhai) of the Greater Bay Area of China, and to determine their mass media preferences for receiving dementia information. Methods: The survey was completed by 787 community-dwelling adults. Dementia literacy was indirectly measured using two validated scales-the 30-item Alzheimer's Disease Knowledge Scale and the 20-item Dementia Attitude Scale (DAS). Participants were also asked to indicate whether they wanted to receive dementia information via digital or traditional media. Chi-square tests, logistic regressions, and MANOVA analyses were conducted. Results: Unemployed or retired people had poor attitudes towards dementia and lower levels of knowledge about dementia. Single, cohabiting, or divorced people in Hong Kong and Macau had lower DAS scores than married people. Young people and those with a secondary education preferred to get their dementia information from social media. People with a tertiary education and employed people enjoyed searching government or hospital websites for information. Middle-aged, unemployed, or retired people tended to learn about dementia from television or radio. Conclusion: It is worth educating the public about dementia and developing strategies consistent with their preferences for types of mass media.


[Malaria outside the Brazilian Amazonian region: the situation in Santa Catarina State].
This study aimed to evaluate the malaria epidemiological aspects in Santa Catarina State, Brazil, by using National Health Foundation data from 1996 to 2001. From 4,707 thick smears analyzed 5.5% were positive. Plasmodium vivax was found in 69.0%; Plasmodium falciparum in 25.6%, mixed infection with both in 5%, and Plasmodium malariae in only 0.4%. It was observed that 67.4% were heterochthonous cases and 32.6% autochthonous cases. In recent years, the incidence of heterochthonous cases has increased. The majority of these cases come from the Brazilian Amazon region and the remainder from African countries. However, the municipalities of Joinville, Blumenau, São Francisco do Sul and Florianópolis registered higher rates of autochthonous cases in 1996/1997. Control and epidemiological surveillance are necessary to prevent the reintroduction of Plasmodium in this region. It would be useful to investigate each epidemiological setting in order to prevent the reappearance of the disease in areas currently considered under control.


Multimodal image analysis of clinical influences on preterm brain development.
Premature birth is associated with numerous complex abnormalities of white and gray matter and a high incidence of long-term neurocognitive impairment. An integrated understanding of these abnormalities and their association with clinical events is lacking. The aim of this study was to identify specific patterns of abnormal cerebral development and their antenatal and postnatal antecedents. In a prospective cohort of 449 infants (226 male), we performed a multivariate and data-driven analysis combining multiple imaging modalities. Using canonical correlation analysis, we sought separable multimodal imaging markers associated with specific clinical and environmental factors and correlated to neurodevelopmental outcome at 2 years. We found five independent patterns of neuroanatomical variation that related to clinical factors including age, prematurity, sex, intrauterine complications, and postnatal adversity. We also confirmed the association between imaging markers of neuroanatomical abnormality and poor cognitive and motor outcomes at 2 years. This data-driven approach defined novel and clinically relevant imaging markers of cerebral maldevelopment, which offer new insights into the nature of preterm brain injury. Ann Neurol 2017;82:233-246.


Negative regulation of transforming growth factor-beta (TGF-beta) signaling by WW domain-containing protein 1 (WWP1).
Smad7 negatively regulates transforming growth factor (TGF)-beta superfamily signaling by binding to activated type I receptors, thereby preventing the phosphorylation of receptor-regulated Smads (R-Smads), as well as by recruiting HECT-type E3 ubiquitin ligases to degrade type I receptors through a ubiquitin-dependent mechanism. To elucidate the regulatory mechanisms of TGF-beta signaling, we searched for novel members of proteins that interact with Smad7 using a yeast two-hybrid system. One of the proteins identified was the WW domain-containing protein 1 (WWP1) that is structurally related to Smad ubiquitin regulatory factors (Smurfs), E3 ubiquitin ligases for Smads and TGF-beta superfamily receptors. Using a TGF-beta-responsive reporter in mammalian cells, we found that WWP1 inhibited transcriptional activities induced by TGF-beta. Similar to Smurfs, WWP1 associated with Smad7 and induced its nuclear export, and enhanced binding of Smad7 to TGF-beta type I receptor to cause ubiquitination and degradation of the receptor. Consistent with these results, WWP1 inhibited phosphorylation of Smad2 induced by TGF-beta. WWP1 thus negatively regulates TGF-beta signaling in cooperation with Smad7. However, unlike Smurfs, WWP1 failed to ubiquitinate R-Smads and SnoN. Importantly, WWP1 and Smurfs were expressed in distinct patterns in human tissues and carcinoma cell lines, suggesting unique pathophysiological roles of WWP1 and Smurfs.


Single molecule force spectroscopy at high data acquisition: A Bayesian nonparametric analysis.
Bayesian nonparametrics (BNPs) are poised to have a deep impact in the analysis of single molecule data as they provide posterior probabilities over entire models consistent with the supplied data, not just model parameters of one preferred model. Thus they provide an elegant and rigorous solution to the difficult problem encountered when selecting an appropriate candidate model. Nevertheless, BNPs' flexibility to learn models and their associated parameters from experimental data is a double-edged sword. Most importantly, BNPs are prone to increasing the complexity of the estimated models due to artifactual features present in time traces. Thus, because of experimental challenges unique to single molecule methods, naive application of available BNP tools is not possible. Here we consider traces with time correlations and, as a specific example, we deal with force spectroscopy traces collected at high acquisition rates. While high acquisition rates are required in order to capture dwells in short-lived molecular states, in this setup, a slow response of the optical trap instrumentation (i.e., trapped beads, ambient fluid, and tethering handles) distorts the molecular signals introducing time correlations into the data that may be misinterpreted as true states by naive BNPs. Our adaptation of BNP tools explicitly takes into consideration these response dynamics, in addition to drift and noise, and makes unsupervised time series analysis of correlated single molecule force spectroscopy measurements possible, even at acquisition rates similar to or below the trap's response times.


Combination of a Knudsen effusion cell with a quartz crystal microbalance: in situ measurement of molecular evaporation rates with a fully functional deposition source.
We describe a straightforward, reliable, and inexpensive design of a Knudsen type molecular effusion cell capable of measuring molecular evaporation rates in situ. This is accomplished by means of a quartz crystal microbalance integrated into the shutter of the effusion cell. The presented layout facilitates both the measurement of effusion rates under ultrahigh vacuum conditions without the need for a separate experimental setup and the growth of surface supported molecular layers and nanostructures. As an important prerequisite for reproducible deposition of molecular films with defined coverages ranging from submonolayers up to multilayers, the Knudsen cell features a stable deposition rate for crucible temperatures between 50 and 500 degrees C. Experimental determination of deposition rates for different crucible temperatures allows to approximate sublimation enthalpies of the evaporant based on the Clausius-Clapeyron equation.


Design of a dynamic polymer interface for chiral discrimination.
Enantioselective wetting of a chiral polymer film was demonstrated. The contact angle of chiral liquids on the film was strongly dependent on their chirality although their physical properties including surface tension were identical. Such wetting behavior resulted from the enantioselective surface reorganization involving local conformational change of the polymer chains at the liquid interface. The concept of "dynamic interface for chiral discrimination" has possible potential for the development of materials capable of chiral sensing, optical resolution, and asymmetric synthesis.


Central visual, acoustic, and motor pathway involvement in a Charcot-Marie-Tooth family with an Asn205Ser mutation in the connexin 32 gene.
X linked dominant Charcot-Marie-Tooth disease (CMT1X) is an inherited motor and sensory neuropathy that mainly affects the peripheral nervous system. CMT1X is associated with mutations in the gap junction protein connexin 32 (Cx32). Cx32 is expressed in Schwann cells and oligodendrocytes in the peripheral (PNS) and in the (CNS) respectively. A CMT1X family with a Cx32 mutation was examined clinically and electrophysiologically to determine whether PNS, or CNS, or both pathways were affected. In a CMT1X family a novel mutation (Asn205Ser) was found in the fourth transmembrane domain of Cx32. The patients showed typical clinical and electrophysiological abnormalities in the PNS, but in addition visual, acoustic, and motor pathways of the CNS were affected subclinically. This was indicated by pathological changes in visually evoked potentials (VEPs), brainstem auditory evoked potentials (BAEPs), and central motor evoked potentials (CMEPs). These findings underscore the necessity of a careful analysis of CNS pathways in patients with CMT and Cx32 mutations. Abnormal electrophysiological findings in CNS pathway examinations should raise the suspicion of CMTX and a search for gene mutations towards Cx32 should be considered.


Transcutaneous Bone-anchored Hearing Aids Versus Percutaneous Ones: Multicenter Comparative Clinical Study.
The aim of this study is to compare the clinical audiological outcomes as well as patient satisfaction of bone-anchored, hearing aid surgery between the percutaneous Dermalock and the transcutaneous Attract systems. This is a multicenter, retrospective clinical study. The patients who underwent Baha Dermalock and Baha Attract surgery were analyzed for hearing results, surgical complications, and postoperative follow-up specifications for both systems. Speech reception thresholds and bone conduction thresholds with and without aided conditions were evaluated. Patient satisfactions were also determined for both groups by Glasgow Benefit Inventory questionnaire. Both of the groups had some minor complications such as skin irritations around the abutment and skin erythema over the magnet. Both of the groups benefit from the devices audiologically; however, when the groups were compared, better results were observed in the percutaneous, bone-conduction group. We can confirm that both transcutaneous and percutaneous techniques are effective in the rehabilitation of conductive hearing loss when conventional hearing aids cannot be used. However, both of the systems have some advantages and limitations in terms of audiological and surgical perspectives.


Involvement of de novo ceramide synthesis in pro-inflammatory adipokine secretion and adipocyte-macrophage interaction.
Interaction between adipocytes and macrophages has been suggested to play a central role in the pathogenesis of obesity. Ceramide, a sphingolipid de novo synthesized from palmitate, is known to stimulate pro-inflammatory cytokine secretion from multiple types of cells. To clarify whether de novo synthesized ceramide contributes to cytokine dysregulation in adipocytes and macrophages, we observed cytokine secretion in mature 3T3-L1 adipocytes (L1) and RAW264.7 macrophages (RAW) cultured alone or co-cultured under the suppression of de novo ceramide synthesis. Palmitate enhanced ceramide accumulation and stimulated the expression and secretion of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) in L1. The suppression of serine-palmitoyl transferase, a rate-limiting enzyme of de novo ceramide synthesis, by myriocin or siRNA attenuated those palmitate-induced alterations, and a ceramide synthase inhibitor fumonisin B1 showed similar results. In contrast, the inhibitor of sphingosine kinase or a membrane-permeable ceramide analogue augmented the cytokine secretion. Myriocin effects on the palmitate-induced changes were not abrogated by toll-like receptor-4 blockade. Although palmitate stimulated RAW to secrete tumor necrosis factor-α (TNF-α), it did not significantly increase ceramide content, and neither myriocin nor fumonisin B1 attenuated the TNF-α hypersecretion. The co-culture of L1 with RAW markedly augmented IL-6 and MCP-1 levels in media. Myriocin or fumonisin B1 significantly lowered these cytokine levels and suppressed the gene expression of TNF-α and MCP-1 in RAW and of IL-6 and MCP-1 in L1. In conclusion, de novo synthesized ceramide partially mediates the palmitate effects on pro-inflammatory adipokines and is possibly involved in the interaction with macrophages.


Functional donor-site morbidity during level and uphill gait after a gastrocnemius or soleus muscle-flap procedure.
There is only limited objective information about functional donor-site morbidity after harvest of one head of the triceps surae muscles to cover a severe soft-tissue defect of the leg. The purpose of the present study was to investigate whether a functional deficit is present during level and uphill walking after such a procedure. Five subjects who had completely recovered from the initial injury were studied with use of comprehensive gait analysis during free level, fast level, and uphill walking on a ramp at a 10 degrees inclination. Gait analysis revealed no relevant donor-site morbidity affecting level gait at a free walking speed (mean, 1.27 m/sec; range, 1.18 to 1.40 m/sec). When the subjects walked at a higher velocity (mean, 1.89 m/sec; range, 1.58 to 2.43 m/sec), an asymmetry of the ground-reaction forces was seen. The second vertical peak force during push-off was reduced by a mean of 7.3% (range, 0.94% to 12.24%), and the impulse in the direction of progression was reduced by a mean of 8.7% (range, 0.13% to 17.87%) on the affected side (p = 0.04). During uphill walking, a compensatory strategy to reduce the demand on the posterior calf muscles was seen in all subjects-that is, they shortened the length of the step on the contralateral side by a mean of 3.9 cm (range, 2.2 to 6.2 cm), which corresponded to a mean side-to-side difference of 5.6% (range, 2.18% to 6.18%) (p = 0.04). A calcaneal motion pattern, denoted as increased ankle dorsiflexion, was seen in three of the five subjects during uphill walking as a sign of decreased function of the posterior calf muscles. Two of them (both with a soleus flap) also had a calcaneal pattern during fast gait. We concluded from this study that the functional donor-site morbidity after harvest of one head of the triceps surae muscles is mild in subjects who have had a complete recovery from their initial injury. Normal level gait is possible. However, deficits are seen in more demanding tasks such as fast walking or uphill walking.


Clinically Indicated Corticosteroids Do Not Affect Bone Turnover During Immune Restoration of Severely Lymphopenic HIV-Infected Patients.
Lymphopenia, corticosteroids, antiretroviral therapy (ART), and inflammation negatively impact bone turnover and decrease bone mineral density, but their combined effect has not been evaluated. We examined the association between corticosteroids on bone turnover markers in severely lymphopenic HIV-infected patients initiating ART. Levels of osteocalcin (bone formation marker) and C-terminal telopeptide (CTX; bone resorption marker) were measured at baseline, weeks 4, 12, and 48 of ART in individuals with severe lymphopenia and opportunistic infection (OI) who received (n=28) or did not receive corticosteroids (n=30) during the first year of ART, and in a control group with CD4 >200 (n=15). Wilcoxon tests were used to compare median values of variables between groups. Correlations between plasma interleukin (IL)-6 and tumor necrosis factor (TNF) levels with bone turnover marker levels were performed using Spearman's coefficient. Individuals given corticosteroids received a median of 21 days at a 35 mg prednisone-equivalent daily dose. Individuals with severe lymphopenia had lower osteocalcin levels at baseline and week 4 and higher CTX levels at ART initiation vs. Bone turnover markers did not differ in severely lymphopenic persons according to corticosteroid receipt. In those with severe lymphopenia, higher IL-6 was associated with higher CTX levels at ART initiation only. HIV-infected patients with severe lymphopenia and OI had lower levels of bone formation and higher levels of bone resorption than those initiating ART at higher CD4. Corticosteroid use, as prescribed during OI, was not associated with bone turnover. In contrast, higher markers of systemic inflammation prior to ART were associated with greater bone resorption.


[Trypanosoma rangeli Tejera, 1920. VIII. Response to reinfections in 2 mammals].
Under experimental conditions, the course of the infection and the response to the reinfection by Trypanosoma rangeli in mice and Didelphis marsupialis, are studied. During the initial infection the mice show a relatively low parasitaemia and a short patent period. A scanty parasitaemia level of four days length, was observed following the first reinfection, being the mice resistant to new reinfections by T. rangeli. In opossums a lower parasitaemia and a longer patent period than that detected in mice, were observed during the initial infection. The response to reinfections in this mammal, was similar to that observed in mice. After reinfection with T. rangeli, haemagglutinant antibodies in immune-sera of both mice and opossums, were detected. The possible immune-response at the site of deposition against the metacyclic-forms of T. rangeli, and the action of circulating antibodies against the blood forms of the parasite, are speculated to explain the resistance of mice and opossums to the reinfection by T. rangeli.


Survival of Escherichia coli in Manure-Amended Soils Is Affected by Spatiotemporal, Agricultural, and Weather Factors in the Mid-Atlantic United States.
Untreated biological soil amendments of animal origin (BSAAO), such as manure, are commonly used to fertilize soils for growing fruit and vegetable crops and can contain enteric bacterial foodborne pathogens. Little is known about the comparative longitudinal survival of pathogens in agricultural fields containing different types of BSAAO, and field data may be useful to determine intervals between manure application and harvest of produce intended for human consumption to minimize foodborne illness. This study generated 324 survival profiles from 12 different field trials at three different sites (UMES, PA, and BARC) in the Mid-Atlantic United States from 2011 to 2015 of inoculated nonpathogenic Escherichia coli (gEc) and attenuated O157 E. coli (attO157) in soils which were unamended (UN) or amended with untreated poultry litter (PL), horse manure (HM), or dairy manure solids (DMS) or liquids (DML). Site, season, inoculum level (low/high), amendment type, management (organic/conventional), and depth (surface/tilled) all significantly (P < 0.0001) influenced survival duration (dpi100mort). Spatiotemporal factors (site, year, and season) in which the field trial was conducted influenced survival durations of gEc and attO157 to a greater extent than weather effects (average daily temperature and rainfall). Initial soil moisture content was the individual factor that accounted for the greatest percentage of variability in survival duration. PL supported greater survival durations of gEc and attO157, followed by HM, UN, and DMS in amended soils. The majority of survival profiles for gEc and attO157 which survived for more than 90 days came from a specific year (i.e., 2013). The effect of management and depth on dpi100mort were dependent on the amendment type evaluated.IMPORTANCE Current language in the Food Safety Modernization Act Produce Safety Rule states no objection to a 90- or 120-day interval between application of untreated BSAAO and harvest of crops to minimize transfer of pathogens to produce intended for human consumption with the intent to limit potential cases of foodborne illness. This regional multiple season, multiple location field trial determined survival durations of Escherichia coli in soils amended with manure to determine whether this interval is appropriate. Spatiotemporal factors influence survival durations of E. coli more than amendment type, total amount of E. coli present, organic or conventional soil management, and depth of manure application. Overall, these data show poultry litter may support extended survival of E. coli compared to horse manure or dairy manure, but spatiotemporal factors like site and season may have more influence than manure type in supporting survival of E. coli beyond 90 days in amended soils in the Mid-Atlantic United States.


Measuring the effect of Family Medicine Group enrolment on avoidable visits to emergency departments by patients with diabetes in Quebec, Canada.
The Family Medicine Group (FMG) model of primary care in Quebec, Canada, was driven by the voluntary implementation of family physicians. Our main objective was to measure the effect of FMG enrolment on avoidable use of the emergency department (ED) by diabetic patients. We also sought to determine if effects differed according to whether patients were infrequent or frequent users of the ED and according to high- versus low-regional levels of enrolment. We used data from provincial health administrative databases to identify the diabetic patient population over the age of 20 years for each fiscal year between 2003-2004 and 2011-2012. We used fixed effects and marginal structural models to estimate the effect of enrolment in FMGs on avoidable use of the ED. Our results indicated that for every 10-percentage point increase in the population enrolled with an FMG in the year prior to an event, there was a 3% reduction in avoidable visits to the ED made by an individual (RR = 0.97; 95% CI = 0.95, 0.99). We found a significant reduction among diabetic patients who had at most 1 visit to the ED per year (RR = 0.97; 95% CI = 0.95, 0.99) and nonsignificant effects among more frequent users. Within low-enrolment regions, a 10-percentage point increase in enrolment in FMG practices at t - 1 led to an 18% decrease in the number of avoidable ED visits (RR = 0.82; 95% CI = 0.78, 0.87). The effect disappeared when the analyses were restricted to the high-enrolment regions (RR = 1.00; 95% CI = 0.92, 1.09). The design and implementation of the incentive to promote team-based practice may not have borne much influence on early adopters who may have been overrepresented by physicians from high-performing practices before the introduction of the reform.


Identification of key pathways and genes influencing prognosis in bladder urothelial carcinoma.
Genomic profiling can be used to identify the predictive effect of genomic subsets for determining prognosis in bladder urothelial carcinoma (BUC) after radical cystectomy. This study aimed to investigate potential gene and pathway markers associated with prognosis in BUC. A microarray dataset of BUC was obtained from The Cancer Genome Atlas database. Differentially expressed genes (DEGs) were identified by DESeq of the R platform. Kaplan-Meier analysis was applied for prognostic markers. Key pathways and genes were identified using bioinformatics tools, such as gene set enrichment analysis, gene ontology, the Kyoto Encyclopedia of Genes and Genomes, gene multiple association network integration algorithm (GeneMANIA), Search Tool for the Retrieval of Interacting Genes/Proteins, and Molecular Complex Detection. A comparative gene set enrichment analysis of tumor and adjacent normal tissues suggested BUC tumorigenesis resulted mainly from enrichment of cell cycle and DNA damage and repair-related biological processes and pathways, including TP53 and mitotic recombination. Two hundred and fifty-six genes were identified as potential prognosis-related DEGs. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed that the potential prognosis-related DEGs were enriched in angiogenesis, including the cyclic adenosine monophosphate biosynthetic process, cyclic guanosine monophosphate-protein kinase G, mitogen-activated protein kinase, Rap1, and phosphoinositide-3-kinase-AKT signaling pathway. Nine hub genes, TAGLN, ACTA2, MYH11, CALD1, MYLK, GEM, PRELP, TPM2, and OGN, were identified from the intersection of protein-protein interaction and GeneMANIA networks. Module analysis of protein-protein interaction and GeneMANIA networks mainly showed enrichment of the cyclic guanosine monophosphate-protein kinase G signaling pathway, angiogenesis, cell proliferation, and differentiation, which are associated with tumor angiogenesis and cancer prognosis. Genes and pathways related to cell cycle and DNA damage and repair may play a crucial role in BUC pathogenesis, whereas those pertaining to tumor angiogenesis may be key factors in influencing BUC prognosis, especially in advanced disease stages.


Meta-analytic review of the development of face discrimination in infancy: Face race, face gender, infant age, and methodology moderate face discrimination.
Infants show facility for discriminating between individual faces within hours of birth. Over the first year of life, infants' face discrimination shows continued improvement with familiar face types, such as own-race faces, but not with unfamiliar face types, like other-race faces. The goal of this meta-analytic review is to provide an effect size for infants' face discrimination ability overall, with own-race faces, and with other-race faces within the first year of life, how this differs with age, and how it is influenced by task methodology. Inclusion criteria were (a) infant participants aged 0 to 12 months, (b) completing a human own- or other-race face discrimination task, (c) with discrimination being determined by infant looking. Our analysis included 30 works (165 samples, 1,926 participants participated in 2,623 tasks). The effect size for infants' face discrimination was small, 6.53% greater than chance (i.e., equal looking to the novel and familiar). There was a significant difference in discrimination by race, overall (own-race, 8.18%; other-race, 3.18%) and between ages (own-race: 0- to 4.5-month-olds, 7.32%; 5- to 7.5-month-olds, 9.17%; and 8- to 12-month-olds, 7.68%; other-race: 0- to 4.5-month-olds, 6.12%; 5- to 7.5-month-olds, 3.70%; and 8- to 12-month-olds, 2.79%). Multilevel linear (mixed-effects) models were used to predict face discrimination; infants' capacity to discriminate faces is sensitive to face characteristics including race, gender, and emotion as well as the methods used, including task timing, coding method, and visual angle. (PsycINFO Database Record


Real-time imputation of missing predictor values improved the application of prediction models in daily practice.
In clinical practice, many prediction models cannot be used when predictor values are missing. We, therefore, propose and evaluate methods for real-time imputation. We describe (i) mean imputation (where missing values are replaced by the sample mean), (ii) joint modeling imputation (JMI, where we use a multivariate normal approximation to generate patient-specific imputations), and (iii) conditional modeling imputation (CMI, where a multivariable imputation model is derived for each predictor from a population). We compared these methods in a case study evaluating the root mean squared error (RMSE) and coverage of the 95% confidence intervals (i.e., the proportion of confidence intervals that contain the true predictor value) of imputed predictor values. -RMSE was lowest when adopting JMI or CMI, although imputation of individual predictors did not always lead to substantial improvements as compared to mean imputation. JMI and CMI appeared particularly useful when the values of multiple predictors of the model were missing. Coverage reached the nominal level (i.e., 95%) for both CMI and JMI. Multiple imputations using either CMI or JMI is recommended when dealing with missing predictor values in real-time settings.


Development of high-resolution multiple-SNP arrays for genetic analyses and molecular breeding through genotyping by target sequencing and liquid chip.
Genotyping platforms, as critical supports for genomics, genetics, and molecular breeding, have been well implemented at national institutions/universities in developed countries and multinational seed companies that possess high-throughput, automatic, large-scale, and shared facilities. In this study, we integrated an improved genotyping by target sequencing (GBTS) system with capture-in-solution (liquid chip) technology to develop a multiple single-nucleotide polymorphism (mSNP) approach in which mSNPs can be captured from a single amplicon. From one 40K maize mSNP panel, we developed three types of markers (40K mSNPs, 251K SNPs, and 690K haplotypes), and generated multiple panels with various marker densities (1K-40K mSNPs) by sequencing at different depths. Comparative genetic diversity analysis was performed with genic versus intergenic markers and di-allelic SNPs versus non-typical SNPs. Compared with the one-amplicon-one-SNP system, mSNPs and within-mSNP haplotypes are more powerful for genetic diversity detection, linkage disequilibrium decay analysis, and genome-wide association studies. The technologies, protocols, and application scenarios developed for maize in this study will serve as a model for the development of mSNP arrays and highly efficient GBTS systems in animals, plants, and microorganisms.


The coenzyme-binding characteristics of highly purified preparations of sheep liver cytoplasmic aldehyde dehydrogenase.
The binding of NADH and NAD+ by cytoplasmic aldehyde dehydrogenase was studied by various direct and indirect methods. At pH 7.0 at 25 degrees C there appears to be approx. 1 binding site for both nucleotides per 200 000 daltons of protein, although the NAD+-binding results are rather uncertain. Estimates of the dissociation constants of the E . NADH and E . NAD+ complexes under the stated conditions are also presented. Preparations of enzyme are sometimes found to contain significant amounts of very tightly bound NAD+ and NADH. The implications of these findings are discussed.


Anti-malarial agent artesunate inhibits TNF-alpha-induced production of proinflammatory cytokines via inhibition of NF-kappaB and PI3 kinase/Akt signal pathway in human rheumatoid arthritis fibroblast-like synoviocytes.
Recent studies indicate that the anti-malarial agent artemisinin and its derivatives may exert an anti-inflammatory effect. In this study, we explored the effect of artesunate, an artemisinin derivative, on tumour necrosis factor (TNF)-alpha-induced production of interleukins, IL-1beta, IL-6 and IL-8, in human rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS), and further investigated the signal mechanism by which this compound modulates those cytokines' production. RA FLS obtained from patients with active RA were stimulated with TNF-alpha and incubated with artesunate, and IL-1beta, IL-6 and IL-8 production was measured by ELISA. DNA-binding activity and nuclear translocation of nuclear factor kappa B (NF-kappaB) were measured by a sensitive multi-well colourimetric assay and confocal fluorescence microscopy, respectively. Signal transduction proteins expression was measured by western blot. Artesunate decreased the secretion of IL-1beta, IL-6 and IL-8 from TNF-alpha-stimulated RA FLS in a dose-dependent manner. Artesunate also prevented TNF-alpha-induced nuclear NF-kappaB translocation, DNA-binding activity and gene transcriptional activity, as well as phosphorylation and degradation of IkappaBalpha, but phosphorylation of p38 mitogen-activated protein kinase, extracellular signal-regulated kinase and c-Jun N-terminal kinase were unaffected. The production of IL-1beta, IL-6 and IL-8 induced by TNF-alpha was decreased by pyrrolidine dithiocarbamate (PDTC), a chemical inhibitor of NF-kappaB. These observations suggest that artesunate inhibits production of IL-1beta, IL-6 and IL-8 through inhibition of NF-kappaB signalling pathway. We also showed that artesunate prevented Akt phosphorylation. TNF-alpha-induced production of IL-1beta, IL-6 and IL-8 was hampered by treatment with the phosphatidylinositol 3 (PI3) kinase inhibitor LY294002, suggesting that inhibition of Akt activation might inhibit IL-1beta, IL-6 and IL-8 production induced by TNF-alpha. Our results indicate that artesunate exerts an anti-inflammatory effect in RA FLS and provide the evidence that artesunate may have therapeutic potential for RA.


Development and reliability analysis of the Work Productivity Short Inventory (WPSI) instrument measuring employee health and productivity.
The Work Productivity Short Inventory (WPSI), also known as the Wellness Inventory, was developed to quickly assess the prevalence of medical problems that may influence work productivity and the financial implications of those problems. The WPSI asks respondents to note the amount of time missed from work resulting from 15 medical conditions and the amount of unproductive time spent at work when affected by the condition. Three versions of the WPSI were compared that differed according to the length of the recall period (12 months, 3 months, or 2 weeks). The reliability of the financial metrics generated from the WPSI was assessed for each version and found to be adequate, ranging from 0.66-0.74 in this application. The WPSI was found to be a highly reliable tool for estimating the prevalence of medical conditions that influence work productivity. The dollar impact of the associated productivity losses were found to be reliable enough to meet the instrument's intended purpose, which is to help employers understand relationships between disease and productivity, thereby contributing to the design of interventions to relieve these problems. The needs of the researcher should dictate which version of the WPSI to use.


[Study of methods of inactivating a concentrated, purified cultured antirabies vaccine].
Two methods of inactivation, with ultraviolet (UV) and gamma (gamma) rays, of the concentrated purified tissue culture rabies vaccine from the Vnukovo-32 strain were studied. Under the optimal conditions of treatment of 100-fold concentrated purified virus-containing suspension, a completely inactivated vaccine with high immunogenicity indices (4.1 to 78) was obtained. Both the inactivation methods were found to be of equal value.


Quantification of fetal organ volume and fat deposition following in utero exposure to maternal Western Diet using MRI.
To examine the feasibility of using MRI to identify differences in liver size and fat deposition in fetal guinea pigs exposed to an in utero environment influenced by maternal consumption of a Western diet. Female guinea pigs fed either an energy-dense Western Diet (WD), comprised of increased saturated fats and simple sugars, or a Control Diet (CD) from weaning through pregnancy, underwent MR scanning near term (~ 60 days; term ~ 69 days). Maternal weights were collected at mating and at MR scanning. T1-weighted, T2-weighted, and IDEAL water-fat images were acquired at 3 Tesla. The images were used to segment maternal adipose tissue, fetal liver, fetal brain, fetal adipose tissue, and total fetal volumes and to measure maternal and fetal hepatic fat fractions. Weights of WD sows were lower prior to pregnancy (P = .04), however their weight gain over pregnancy did not differ from the CD group (P = .98). The WD sows had less total adipose tissue (TAT) at MR scanning (P = .04), while hepatic fat content was significantly elevated (P = .04). When controlling for litter size, WD fetuses had larger livers (P = .02), smaller brains (P = .01), and increased total adipose tissue volume (P = .01) when normalized by fetal volume. The WD fetuses also had increased hepatic fat fractions compared to CD fetal livers (P < .001). Maternal Western Diet consumption prior to and during pregnancy induces differences in maternal liver fat content, fetal liver volume and liver fat storage, as well as changes in fetal adipose tissue deposition that can be measured in utero using MRI.


Benefits and risks of different hormonal replacement therapies in post-menopausal women.
A total of 113 women who presented with climacteric symptoms participated in the study. They were randomly allocated to seven groups of 10-27 subjects, who received for 6 mth the following therapies, respectively: conjugated oestrogens (CE) 0.625 mg/day for 21 days + norethisterone (NET) 5 mg/day from day 12 to day 21; CE + cyproterone acetate (CPA) 12.5 mg/day from day 1 to day 10; oestradiol valerate (EV) 2 mg/day for 21 days + NET; EV + CPA; oestriol (E3) 2-4 mg/day; tibolone (ORG OD14) 2.5 mg/day; and placebo, one tablet/day. Hot flushes decreased significantly over the treatment period in all seven groups. However, E3 was less effective at the dose used than CE, EV or ORG OD 14. At the end of the 6 month treatment period histological examination revealed no changes in endometrial morphology in any of the patients treated. Indeed, the addition of a progestogen even induced regression of endometrial hyperplasia in 8 cases. No significant variation in the plasma levels of triglycerides, total cholesterol, high-density lipoprotein (HDL) or low-density lipoprotein (LDL) was observed after the second and sixth months of treatment with E3 or ORG OD 14. After 6 months, treatment with CE/EV + CPA produced a significant increase in HDL, while treatment with CE/EV + NET brought about a reduction in total cholesterol and HDL and an increase in LDL.