The aetiology of psychogenic non-epileptic seizures: risk factors and comorbidities.
Psychogenic non-epileptic seizures (PNES), also known as dissociative seizures, are paroxysms of altered subjective experience, involuntary movements and reduced self-control that can resemble epileptic seizures, but have distinct clinical characteristics and a complex neuropsychiatric aetiology. They are common, accounting for over 10% of seizure emergencies and around 30% of cases in tertiary epilepsy units, but the diagnosis is often missed or delayed. The recently proposed "integrative cognitive model" accommodates current research on experiential, psychological and biological risk factors for the development of PNES, but in view of the considerable heterogeneity of presentations and medical context, it is not certain that a universal model can capture the full range of PNES manifestations. This narrative review addresses key learning objectives of the ILAE curriculum by describing the demographic profile, common risk factors (such as trauma or acute stress) and comorbid disorders (such as other dissociative and functional disorders, post-traumatic stress disorder, depressive and anxiety disorders, personality disorders, comorbid epilepsy, head injury, cognitive and sleep problems, migraine, pain, and asthma). The clinical implications of demographic and aetiological factors for diagnosis and treatment planning are addressed.


Impact of the Prevalence of Concordant and Discordant Conditions on the Quality of Diabetes Care in Family Practices in England.
The purpose of this study was to examine the association between the prevalence of both diabetes-concordant and diabetes-discordant conditions and the quality of diabetes care at the family practice level in England. We hypothesized that the prevalence of concordant (or discordant) conditions would be associated with better (or worse) quality of diabetes care. We conducted a cross-sectional study using practice-level data (7,884 practices). We estimated the practice-level prevalence of diabetes and 15 other chronic conditions, which were classified as diabetes concordant (ie, with the same pathophysiologic risk profile and therefore more likely to be part of the same management plan) or diabetes discordant (ie, not directly related in either their pathogenesis or management). We measured quality of diabetes care with diabetes-specific indicators (8 processes and 3 intermediate outcomes of care). We used linear regression models to quantify the effect of the prevalence of the conditions on aggregate achievement rate for quality of diabetes care. Consistent with the proposed model, the prevalence rates of 4 of 7 concordant conditions (obesity, chronic kidney disease, atrial fibrillation, heart failure) were positively associated with quality of diabetes care. Similarly, negative associations were observed as predicted for 2 of the 8 discordant conditions (epilepsy, mental health). Observations for other concordant and discordant conditions did not match predictions in the hypothesized model. The quality of diabetes care provided in English family practices is associated with the prevalence of other major chronic conditions at the practice level. The nature and direction of the observed associations cannot be fully explained by the concordant-discordant model.


Heterogeneity and Remodeling of Ion Currents in Cultured Right Atrial Fibroblasts From Patients With Sinus Rhythm or Atrial Fibrillation.
Cardiac fibroblasts express multiple voltage-dependent ion channels. Even though fibroblasts do not generate action potentials, they may influence cardiac electrophysiology by electrical coupling via gap junctions with cardiomyocytes, and through fibrosis. Here, we investigate the electrophysiological phenotype of cultured fibroblasts from right atrial appendage tissue of patients with sinus rhythm (SR) or atrial fibrillation (AF). Using the patch-clamp technique in whole-cell mode, we observed steady-state outward currents exhibiting either no rectification or inward and/or outward rectification. The distributions of current patterns between fibroblasts from SR and AF patients were not significantly different. In response to depolarizing voltage pulses, we measured transient outward currents with fast and slow activation kinetics, an outward background current, and an inward current with a potential-dependence resembling that of L-type Ca2+ channels. In cell-attached patch-clamp mode, large amplitude, paxilline-sensitive single channel openings were found in ≈65% of SR and ∼38% of AF fibroblasts, suggesting the presence of "big conductance Ca2+-activated K+ (BK Ca )" channels. The open probability of BK Ca was significantly lower in AF than in SR fibroblasts. When cultured in the presence of paxilline, the shape of fibroblasts became wider and less spindle-like. Our data confirm previous findings on cardiac fibroblast electrophysiology and extend them by illustrating differential channel expression in human atrial fibroblasts from SR and AF tissue.


Molecular genetic methods in diagnosis and direct characterization of acute bacterial central nervous system infections.
Acute bacterial infection of the central nervous system requires rapid and adequate management. Etiological diagnosis is hence crucial. Moreover, the epidemic threat of certain bacteria necessitates a reliable characterization of the involved bacterial strains to follow the spread of epidemic strains. Conventional identification and characterization of etiological agents are basically based on culture and identification of bacterial markers most frequently by serological assays. Molecular identification and characterization of bacteria have been employed. They provide more reliable analysis of bacterial isolates. Molecular methods for non-culture diagnosis of bacterial infections have recently been developed. In many cases, the molecular assays have decreased the identification time of positive cultures and rescued detection of pathogens in culture-negative clinical samples.


Noise-free visualization of microscopic calcium signaling by pixel-wise fitting.
Our insights into physiological and pathophysiological cardiac excitation-contraction coupling has greatly benefited from significant advancement in optical technologies such as high-speed confocal microscopy. This has pushed pixel dwell times into the time domain of nanoseconds, resulting in low signal-to-noise ratios, which have limited data analysis and interpretation. Line scan imaging has been and still is dominant in high speed confocal recording. It allows analysis only of a small fraction of a cell's cross section (1.5%), but the appreciation of spatiotemporal fine details of excitation-contraction coupling is instrumental for the further understanding of pathological mechanisms. We aim to provide a novel analysis tool to extract otherwise hidden fine details in cardiac excitation-contraction coupling from high-speed 2-dimensional confocal image series. We demonstrate that high-speed 2-dimensional confocal data (150 frames/s) can be analyzed quantitatively by a pixel-wise fitting approach, using a mathematical formalism to phenomenologically describe local calcium transients. Such an approach produces virtually noise-free fluorescence data originating from minute volumes (0.025 femtoliter) and allows extraction of detailed and most importantly quantitative and mechanistically novel information on microscopic calcium signaling and excitation-contraction coupling in a robust manner. Pixel-wise fitting provides novel insights into cardiac excitation-contraction coupling. Specifically, it revealed microscopic calcium alternans on the level of individual coupling sites. Microscopic calcium alternans is an early precursor of cellular alternans and as such will shed more light onto this mechanism leading to cardiac arrhythmia.


Patient-reported outcome after total hip arthroplasty: comparison between lateral and posterior approach.
Background and purpose - Criticism of the lateral approach (LA) for hip arthroplasty is mainly based on the risk of poor patient-reported outcomes compared to the posterior approach (PA). However, there have been no controlled studies comparing patient-reported outcomes between them. In this randomized controlled trial, we tested the hypothesis that patient-reported outcomes are better in patients who have undergone total hip arthroplasty (THA) with PA than in those who have undergone THA with LA, 12 months postoperatively. Patients and methods - 80 patients with hip osteoarthritis (mean age 61 years) were randomized to THA using PA or the modified direct LA. We recorded outcome measures preoperatively and 3, 6, and 12 months postoperatively using the Hip Disability and Osteoarthritis Outcome Score-Physical Function Short Form (HOOS-PS) as the primary outcome. Secondary outcomes were HOOS-Pain, HOOS-Quality-Of-Life, EQ-5D, UCLA Activity Score, and limping. Results - We found no statistically significant difference in the improvements in HOOS-PS between the treatment groups at 12-month follow-up. All secondary outcomes showed similar results except for limping, where PA patients improved significantly more than LA patients. Interpretation - Contrary to our hypothesis, patients treated with PA did not improve more than patients treated with LA regarding physical function, pain, physical activity, and quality of life 12 months postoperatively. However, limping was more pronounced in the LA patients.


Sequential encoding with multislit spectrometers.
A new method for optically encoding the spectral output of multislit spectrometers is proposed. It is based on sequential measurements of the total intensity of light in combinations of selected spectral bands. The resulting encoded optical information is obtained as a set of simultaneous linear algebraic equations, and spectrum reconstruction is accomplished through the use of matrix inversion techniques. This encoding method avoids the problems associated with frequency transform encoding, because it is not based on the usual Fourier or Fresnel transforms. Rather, it makes use of the theory of simultaneous linear algebraic equations.


Effects of relaxation on anxiety in children: implications for coping with stress.
Although research shows that relaxation has the potential to reduce stress and anxiety in adults, there is little evidence to support this effect in children. This study examined the effects of relaxation on anxiety in 46 second-grade children in two classrooms. A nonequivalent control group design was strengthened by providing relaxation treatment to the control group after the second measure of anxiety. A third measure of anxiety was then given to both classes. The children were not significantly different with respect to sex, age, and initial anxiety. Although the main hypothesis was not supported (at p less than .05), a reduction in anxiety resulted for both classes after they completed the program. Subgroup analyses showed a significant treatment effect with the group receiving relaxation exhibiting less anxiety than the control group. This finding indicates that relaxation may be learned by children and may be beneficial in coping with stress.


Repeated magnetic resonance imaging in 154 hips with large-diameter metal-on-metal hip replacement.
The US Food and Drug Administration and the UK Medicines and Health Regulation Agency recommend using MRI in the evaluation of patients with large-diameter metal-on-metal (LD-MoM) hips. Such recommendations do not take into account the relevance of repeated cross-sectional imaging. We therefore investigated the natural course of pseudotumors in patients with LD-MoM hip replacements. Of 888 ASR patients (1,036 hips) 674 patients (798 hips) underwent 2 follow-up visits at our institution. Of these, we identified 124 patients (154 hips) who had undergone repeated clinical assessment including MRI and whole-blood metal ion assessment. A change in classification in imaging findings between the 2 MRIs was seen in 17 of the 154 hips (11%). In 13 hips (8%), a significant progression of the pseudotumor was evident, while in 4 (3 %) there was a retrogressive change. 10 of these 13 hips had had a normal first MRI. Patients with a progressive change in the scans did not differ significantly from those without a change in MRI classification regarding follow-up time, time interval between MRIs, or changes in whole-blood Cr and Co levels between assessments. A change in classification was rare, considering that all patients had a clinical indication for repeated imaging. Progression of the findings did not appear to correlate clearly with symptoms or whole-blood metal values.


The Gut Microbiota Regulates Intestinal CD4 T Cells Expressing RORγt and Controls Metabolic Disease.
A high-fat diet (HFD) induces metabolic disease and low-grade metabolic inflammation in response to changes in the intestinal microbiota through as-yet-unknown mechanisms. Here, we show that a HFD-derived ileum microbiota is responsible for a decrease in Th17 cells of the lamina propria in axenic colonized mice. The HFD also changed the expression profiles of intestinal antigen-presenting cells and their ability to generate Th17 cells in vitro. Consistent with these data, the metabolic phenotype was mimicked in RORγt-deficient mice, which lack IL17 and IL22 function, and in the adoptive transfer experiment of T cells from RORγt-deficient mice into Rag1-deficient mice. We conclude that the microbiota of the ileum regulates Th17 cell homeostasis in the small intestine and determines the outcome of metabolic disease.


Variation in breast cancer risk with mutation position, smoking, alcohol, and chest X-ray history, in the French National BRCA1/2 carrier cohort (GENEPSO).
Germline mutations in BRCA1/2 confer a high risk of breast cancer (BC), but the magnitude of this risk varies according to various factors. Although controversial, there are data to support the hypothesis of allelic-risk heterogeneity. We assessed variation in BC risk according to the location of mutations recorded in the French study GENEPSO. Since the women in this study were selected from high-risk families, oversampling of affected women was eliminated by using a weighted Cox-regression model. Women were censored at the date of diagnosis when affected by any cancer, or the date of interview when unaffected. A total of 990 women were selected for the analysis: 379 were classified as affected, 611 as unaffected. For BRCA1, there was some evidence of a central region where the risk of BC is lower (codons 374-1161) (HR = 0.59, P = 0.04). For BRCA2, there was a strong evidence for a region at decreased risk (codons 957-1827) (HR = 0.35, P = 0.005) and for one at increased risk (codons 2546-2968) (HR = 3.56, P = 0.01). Moreover, we found an important association between radiation exposure from chest X-rays and BC risk (HR = 4.29, P < 10(-3)) and a positive association between smoking more than 21 pack-years and BC risk (HR = 2.09, P = 0.04). No significant variation in BC risk associated with chest X-ray exposure, smoking, and alcohol consumption was found according to the location of the mutation in BRCA1 and BRCA2. Our findings are consistent with those suggesting that the risk of BC is lower in the central regions of BRCA1/2. A new high-risk region in BRCA2 is described. Taking into account environmental and lifestyle modifiers, the location of mutations might be important in the clinical management of BRCA mutation carriers.


Estimation of optimal PDE-based denoising in the SNR sense.
This paper is concerned with finding the best partial differential equation-based denoising process, out of a set of possible ones. We focus on either finding the proper weight of the fidelity term in the energy minimization formulation or on determining the optimal stopping time of a nonlinear diffusion process. A necessary condition for achieving maximal SNR is stated, based on the covariance of the noise and the residual part. We provide two practical alternatives for estimating this condition by observing that the filtering of the image and the noise can be approximated by a decoupling technique, with respect to the weight or time parameters. Our automatic algorithm obtains quite accurate results on a variety of synthetic and natural images, including piecewise smooth and textured ones. We assume that the statistics of the noise were previously estimated. No a priori knowledge regarding the characteristics of the clean image is required. A theoretical analysis is carried out, where several SNR performance bounds are established for the optimal strategy and for a widely used method, wherein the variance of the residual part equals the variance of the noise.


Androgens and estrogens in the etiology and prevention of breast cancer.
Breast cancer is the most common cause of cancer death in women worldwide. Rates vary about fivefold around the world, but they are increasing in regions that until recently had low rates of disease. Despite the numerous uncertainties surrounding the etiology of breast cancer, intensive epidemiological, clinical, and genetic studies have identified a number of biologic and social traits as risk factors associated with breast cancer. Principal among them are the evidence of BRCA1 and BRCA2 susceptibility genes, familial history of breast cancer, age, higher socioeconomic status, ionizing radiation, tallness in adult life, alcohol consumption, and a variety of hormone and metabolic factors. Among the hormonal influences, a relevant etiological function has been ascribed to elevated levels of estrogens, their active metabolites, and androgens. These endocrine factors may represent future targets for breast cancer prevention.


Estrogen control of central neurotransmission: effect on mood, mental state, and memory.
1. Estrogen exerts profound effects on mood, mental state and memory by acting on both "classical" monoamine and neuropeptide transmitter mechanisms in brain. Here we review an example of each type of action. 2. With respect to the effect of estrogen on central monoamine neurotransmission, low levels of estrogen in women are associated with the premenstrual syndrome, postnatal depression and post-menopausal depression. Sex differences in schizophrenia have also been attributed to estrogen. Previous studies have shown that estrogen stimulates a significant increase in dopamine2 (D2) receptors in the striatum. Here we show for the first time that estrogen also stimulates a significant increase in the density of 5-hydroxytryptamine2A (5-HT2A) binding sites in anterior frontal, cingulate and primary olfactory cortex and in the nucleus accumbens, areas of the brain concerned with the control of mood, mental state, cognition, emotion and behavior. These findings explain, for example, the efficacy of estrogen therapy or 5-HT uptake blockers such as fluoxetine in treating the depressive symptoms of the premenstrual syndrome. and suggest that the sex differences in schizophrenia may also be due to an action of estrogen mediated by way of 5-HT2A receptors. 3. With respect to the effect of estrogen on central neuropeptide transmission, estrogen stimulates the expression of the arginine vasopressin (AVP) gene in the bed nucleus of the stria terminalis (BNST) in rodents. This results in a 100-fold increase in AVP mRNA in the BNST and a massive increase in AVP peptide in the BNST and its projections to the lateral septum and lateral habenula. The BNST-AVP system enhances and/or maintains "social" or "olfactory" memory, and thus provides a powerful model for correlating transcriptional control of neuropeptide gene expression with behavior. Whether similar mechanisms operate in the human remain to be determined. 4. These two examples of the action of estrogen on central neurotransmission are discussed in terms of their immediate clinical importance for the treatment of depressive symptoms, their use as powerful models for investigations on the steroid control of central neurotransmitter mechanisms, and the role of estrogen as "Nature's" psychoprotectant.


Assessing publication bias in genetic association studies: evidence from a recent meta-analysis.
Publication bias may exist when nonsignificant findings remain unpublished, thereby artificially inflating the apparent magnitude of an effect. This concern is not new, but it is particularly current in relation to genetic association studies. Data from a recent meta-analysis of association studies of personality were used to assess the potential of different graphical and statistical methods for assessing evidence of publication bias. The results suggest that no single method is sufficient for assessing evidence of publication bias, and that such methods may also offer insight into potential sources of heterogeneity, which may in turn guide the design of future studies.


Polymer/Iron Oxide Nanoparticle Composites--A Straight Forward and Scalable Synthesis Approach.
Magnetic nanoparticle systems can be divided into single-core nanoparticles (with only one magnetic core per particle) and magnetic multi-core nanoparticles (with several magnetic cores per particle). Here, we report multi-core nanoparticle synthesis based on a controlled precipitation process within a well-defined oil in water emulsion to trap the superparamagnetic iron oxide nanoparticles (SPION) in a range of polymer matrices of choice, such as poly(styrene), poly(lactid acid), poly(methyl methacrylate), and poly(caprolactone). Multi-core particles were obtained within the Z-average size range of 130 to 340 nm. With the aim to combine the fast room temperature magnetic relaxation of small individual cores with high magnetization of the ensemble of SPIONs, we used small (<10 nm) core nanoparticles. The performed synthesis is highly flexible with respect to the choice of polymer and SPION loading and gives rise to multi-core particles with interesting magnetic properties and magnetic resonance imaging (MRI) contrast efficacy.


Effect of the menstrual cycle phase on post-operative pain perception and analgesic requirements.
Research has shown that menstrual cycle phase may affect pain sensitivity. There is a lack of studies evaluating this effect on post-operative pain and analgesic needs. In this prospective cohort study, we determined the effect of menstrual cycle phase on pain perception and analgesic requirements following total abdominal hysterectomy. Sixty women with regular menstrual cycles undergoing elective surgery were recruited and divided into 'follicular' and 'luteal' groups according to their menstrual history. Post-operative pain was managed with intravenous patient-controlled analgesia using tramadol. Intravenous morphine was used for rescue analgesia, and pain was assessed for 24 h. Pain scores in the recovery room and ward six and 24 h post-operatively were similar in the groups at rest and on coughing. Pain scores at rest 12 h post-operatively were significantly higher in the luteal group (P = 0.043), while they were similar on coughing. There was no significant difference in the total tramadol requirement. Number of patients requiring rescue analgesia and the amount of morphine used was also similar. There was no difference in pain scores or analgesic requirements between the two groups except for rest pain at 12 h, which was significantly higher in the luteal group. As pain was assessed at 13 different time points, a significant difference seen only at one point could be due to random chance. We suggest that future research should concentrate on studying this issue in patients of relatively younger age groups with more pronounced hormonal variations during the cycle.


If we build it, will they come? Results of a quasi-experimental study assessing the impact of maternity waiting homes on facility-based childbirth and maternity care in Zambia.
Maternity waiting homes (MWHs) aim to increase access to maternity and emergency obstetric care by allowing women to stay near a health centre before delivery. An improved MWH model was developed with community input and included infrastructure, policies and linkages to health centres. We hypothesised this MWH model would increase health facility delivery among remote-living women in Zambia. We conducted a quasi-experimental study at 40 rural health centres (RHC) that offer basic emergency obstetric care and had no recent stockouts of oxytocin or magnesium sulfate, located within 2 hours of a referral hospital. Intervention clusters (n=20) received an improved MWH model. Control clusters (n=20) implemented standard of care. Clusters were assigned to study arm using a matched-pair randomisation procedure (n=20) or non-randomly with matching criteria (n=20). We interviewed repeated cross-sectional random samples of women in villages 10+ kilometres from their RHC. The primary outcome was facility delivery; secondary outcomes included postnatal care utilisation, counselling, services received and expenditures. Intention-to-treat analysis was conducted. Generalised estimating equations were used to estimate ORs. We interviewed 2381 women at baseline (March 2016) and 2330 at endline (October 2018). The improved MWH model was associated with increased odds of facility delivery (OR 1.60 (95% CI: 1.13 to 2.27); p<0.001) and MWH utilisation (OR 2.44 (1.62 to 3.67); p<0.001). The intervention was also associated with increased odds of postnatal attendance (OR 1.55 (1.10 to 2.19); p<0.001); counselling for family planning (OR 1.48 (1.15 to 1.91); p=0.002), breast feeding (OR 1.51 (1.20 to 1.90); p<0.001), and kangaroo care (OR 1.44 (1.15, 1.79); p=0.001); and caesarean section (OR 1.71 (1.16 to 2.54); p=0.007). No differences were observed in household expenditures for delivery. MWHs near well-equipped RHCs increased access to facility delivery, encouraged use of facilities with emergency care capacity, and improved exposure to counselling. MWHs can be useful in the effort to increase delivery at advanced facilities in areas where substantial numbers of women live remotely. NCT02620436.


Can the optimal cervical length for placing ultrasound-indicated cerclage be identified?
To assess a continuum of cervical length (CL) cut-offs for the efficacy of ultrasound-indicated cerclage in women with previous spontaneous preterm birth (PTB). This was a planned secondary analysis of a multicenter randomized clinical trial of ultrasound-indicated cerclage for the prevention of PTB in high-risk women. The efficacy of cerclage for preventing recurrent PTB < 35, < 32 and < 24 weeks' gestation was assessed using multivariable logistic regression analysis. Odds ratios (ORs) and CIs were estimated for a range of CL cut-offs using bootstrap regression. The 2.5(th) and 97.5(th) percentiles of bootstrapped ORs determined the CIs. Results were illustrated using smoothed curves superimposed on estimated ORs by CL cut-off. Of 301 women with a CL < 25 mm, 142 underwent ultrasound-indicated cerclage and 159 did not have cerclage placement. The few cases with CL < 10 mm limited the evaluation to CL cut-offs between < 10 mm and < 25 mm. For PTB < 35 weeks, ORs in women with a cerclage and CL < 25 mm were statistically significantly lower than in those without cerclage, and efficacy was maintained at smaller CL cut-offs. Results were similar for PTB < 32 weeks. For PTB < 24 weeks, results differed, with ORs increasing toward unity (no benefit), with wide CIs, for CL cut-offs between < 10 mm and < 15 mm, attributed to the small number of births < 24 weeks. The efficacy of ultrasound-indicated cerclage in women with previous spontaneous PTB varies by action point CL cut-off and by PTB gestational age of interest. Cerclage significantly reduces the risk of PTB < 35 and < 32 weeks, at CL cut-offs between < 10 mm and < 25 mm, with the greatest reduction at shorter CL, affirming that women with prior spontaneous PTB and a short CL are appropriate candidates for ultrasound-indicated cerclage. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.


Proteomic interactions in the mouse vitreous-retina complex.
Human vitreoretinal diseases are due to presumed abnormal mechanical interactions between the vitreous and retina, and translational models are limited. This study determined whether nonstructural proteins and potential retinal biomarkers were expressed by the normal mouse vitreous and retina. Vitreous and retina samples from mice were collected by evisceration and analyzed by liquid chromatography-tandem mass spectrometry. Identified proteins were further analyzed for differential expression and functional interactions using bioinformatic software. We identified 1,680 unique proteins in the retina and 675 unique proteins in the vitreous. Unbiased clustering identified protein pathways that distinguish retina from vitreous including oxidative phosphorylation and neurofilament cytoskeletal remodeling, whereas the vitreous expressed oxidative stress and innate immunology pathways. Some intracellular protein pathways were found in both retina and vitreous, such as glycolysis and gluconeogenesis and neuronal signaling, suggesting proteins might be shuttled between the retina and vitreous. We also identified human disease biomarkers represented in the mouse vitreous and retina, including carbonic anhydrase-2 and 3, crystallins, macrophage inhibitory factor, glutathione peroxidase, peroxiredoxins, S100 precursors, and von Willebrand factor. Our analysis suggests the vitreous expresses nonstructural proteins that functionally interact with the retina to manage oxidative stress, immune reactions, and intracellular proteins may be exchanged between the retina and vitreous. This novel proteomic dataset can be used for investigating human vitreoretinopathies in mouse models. Validation of vitreoretinal biomarkers for human ocular diseases will provide a critical tool for diagnostics and an avenue for therapeutics.


Tissue Na, K, and Ca changes in regional cerebral ischemia: their measurement and interpretation.
A simple and reliable method of quantifying tissue damage is described. This method, based on atomic absorption spectroscopic determinations of Na, K, and Ca concentrations in small brain samples, was applied to the rat middle cerebral artery occlusion model (MCAo). At the infarct site by 24 hours, Na concentration more than doubled, Ca concentration increased by greater than 70%, and K concentration fell nearly 80%; these changes are consistent with a greater than 80% disruption of cells. A remarkable acceleration of ionic shifts occurred between 4 and 6 hours after MCAo. At 4 hours, only 20-30% of the ionic shifts found at 24 hours had occurred; by 6 hours, 80-100% of the ionic shifts found at 24 hours had taken place. Since the measurements reflect ionic movement into and out of the tissue, they are likely to represent irreversible tissue damage. Although blood brain barrier breakdown may have contributed to an increased rate of ionic shifts, large ionic gradients must have been present between the extracellular space and the vascular compartment at 4-6 hours to drive the ionic shifts. Our results suggest an upper time limit of 4 hours for treatments of acute ischemic tissue damage in the rat MCAo model. The methods and analytical approach described may be useful for determining the time window for therapeutic intervention in acute CNS injuries, as well as for evaluating treatment effects.


Early versus late antiepileptic drug withdrawal for people with epilepsy in remission.
Epilepsy is a chronic neurological disorder which affects millions of people around the world. Antiepileptic drugs (AED) are the main interventions used to prevent seizures and control epilepsy. Although effective in most cases, AEDs are related to long-term adverse effects, such as cognitive and behavioural alterations. Thus when epilepsy is in remission, it may be in the individual's best interest to discontinue medication. However, the optimal timing of AED discontinuation is still unknown.This is an updated version of the original Cochrane review published in Issue 3, 2001. (1) To quantify and compare risk of seizure recurrence, status epilepticus and mortality after early and late AED discontinuation in adult and pediatric epilepsy patients.(2) To assess which variables modify the risk of seizure recurrence.(3) To define a subpopulation in which early AED discontinuation is safe. We searched the Cochrane Epilepsy Group Specialised Register (June 2014); CENTRAL (Issue 5, The Cochrane Library, May 2014); MEDLINE (1946 to June 2014); CINAHL (23 June 2014); Scopus (1823 to June 2014); ClinicalTrials.gov (23 June 2014); and WHO International Clinical Trials Registry Platform (23 June 2014). We also checked the reference lists of studies found through the electronic searches. Randomised controlled trials that evaluate withdrawal of AEDs after varying periods of seizure remission in adults and children with epilepsy. Included studies compared an early AED discontinuation time (defined as a period of remission of seizures of less than two years) versus a late AED discontinuation time (defined as a period of remission of seizures of more than two years). Two authors independently extracted data and assessed trial quality. Risk ratio (RR) with 95% confidence interval (CI) was calculated for each trial. Summary RRs and 95% CIs for dichotomous data were calculated using a fixed-effect model. A test of statistical heterogeneity was conducted for each pooled risk ratio calculation. Each included study underwent a 'Risk of bias' assessment, based on the Cochrane Handbook recommendations, and we examined the overall quality of information through the GRADE system, presented in two 'Summary of Findings' tables. Five trials were included in this review, representing 924 randomised children with epilepsy, all under 16 years of age at randomisation, with a median follow-up of 5.6 years. No eligible trial evaluated adults or assessed mortality or status epilepticus as outcomes. The pooled risk ratio for seizure relapse after AED withdrawal was 1.34 (95% CI 1.13 to 1.59, P = 0.0007). Conforming to this estimate, the number needed to harm, that is expose an individual to a higher risk of seizure relapse because of early withdrawal of AED, is 8 (95% CI 5 to 20). Early discontinuation was associated with greater relapse rates in people with partial seizures with a pooled risk ratio of 1.51 (95% CI 0.97 to 2.35, P = 0.07). Absence type epilepsy showed a lower risk of relapse. Variables associated with higher risk of seizure relapse were abnormal EEG findings (pooled RR 1.44, 95% CI 1.13 to 1.83, P = 0.003), especially epileptiform activity (RR 2.58, 95% CI 2.03 to 3.28, P < 0.0001); epilepsy onset before 2 years or after 10 years of age; history of status epilepticus; intellectual disability (IQ < 70); and high seizure frequency before and during treatment. Gender and family history did not show any significant influence over seizure relapse. Overall, the included trials were classified as low or unclear risk of bias where methodological information was not reported and could not be provided by original study authors. There is evidence to support waiting for at least two seizure-free years before discontinuing AEDs in children, particularly if individuals have an abnormal EEG or partial seizures, or both. There is insufficient evidence to establish when to withdraw AEDs in children with generalised seizures. There is no evidence to guide the timing of withdrawal of AEDs in seizure-free adults. Further high-quality randomised controlled trials are needed, particularly recruiting adults and recruiting those with generalised seizure types, to identify the optimal timing of AED withdrawal and risk factors predictive of relapse.


C-reactive protein and risk of lung cancer.
Chronic inflammation could play a role in lung carcinogenesis, underscoring the potential for lung cancer prevention and screening. We investigated the association of circulating high-sensitivity C-reactive protein (CRP, an inflammation biomarker) and CRP single nucleotide polymorphisms (SNPs) with prospective lung cancer risk. We conducted a nested case-control study of 592 lung cancer patients and 670 controls with available prediagnostic serum and 378 patients and 447 controls with DNA within the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (N = 77,464). Controls were matched to patients on age, sex, entry year, follow-up time, and smoking. We measured CRP levels in baseline serum samples and genotyped five common CRP SNPs. Elevated CRP levels were associated with increased lung cancer risk (odds ratio [OR], 1.98; 95% CI, 1.35 to 2.89; P-trend < .001 for fourth quartile [Q4, > or = 5.6 mg/L] v Q1 [< 1.0 mg/L]). The CRP association did not differ significantly by histology, follow-up time, or smoking status, but was most apparent for squamous cell carcinomas (OR, 2.92; 95% CI, 1.30 to 6.54), 2 to 5 years before lung cancer diagnosis (OR, 2.33; 95% CI, 1.24 to 4.39), and among former smokers (OR, 2.48; 95% CI, 1.53 to 4.03) and current smokers (OR, 1.90; 95% CI, 1.06 to 3.41). Although CRP SNPs and haplotypes were associated with CRP levels, they were not associated with lung cancer risk. Ten-year standardized absolute risks of lung cancer were higher with elevated CRP levels among former smokers (Q4: 2.55%; 95% CI, 1.98% to 3.27% v Q1: 1.39%; 95% CI, 1.07% to 1.81%) and current smokers (Q4: 7.37%; 95% CI, 5.81% to 9.33% v Q1: 4.03%; 95% CI, 3.01% to 5.40%). Elevated CRP levels are associated with subsequently increased lung cancer risk, suggesting an etiologic role for chronic pulmonary inflammation in lung carcinogenesis.


Automatic Classification of Bloodstain Patterns Caused by Gunshot and Blunt Impact at Various Distances.
The forensics discipline of bloodstain pattern analysis plays an important role in crime scene analysis and reconstruction. One reconstruction question is whether the blood has been spattered via gunshot or blunt impact such as beating or stabbing. This paper proposes an automated framework to classify bloodstain spatter patterns generated under controlled conditions into either gunshot or blunt impact classes. Classification is performed using machine learning. The study is performed with 94 blood spatter patterns which are available as public data sets, designs a set of features with possible relevance to classification, and uses the random forests method to rank the most useful features and perform classification. The study shows that classification accuracy decreases with the increasing distance between the target surface collecting the stains and the blood source. Based on the data set used in this study, the model achieves 99% accuracy in classifying spatter patterns at distances of 30 cm, 93% accuracy at distances of 60 cm, and 86% accuracy at distances of 120 cm. Results with 10 additional backspatter patterns also show that the presence of muzzle gases can reduce classification accuracy.


Joint surface defects: clinical course and cellular response in spontaneous and experimental lesions.
Joint surface defects (JSD) involving the articular cartilage and the subchondral bone are a common clinical problem in rheumatology and orthopaedics. The recent availability of accurate imaging for diagnosis and efficacious therapeutic options has stirred new interest in their natural history and biology. The evidence that some of these lesions can heal spontaneously whereas others precipitate osteoarthritis has raised important questions as to which lesions should be treated, when, and how. Evidence of repair of some of these lesions has also stimulated research into which factors contribute to successful healing and which ones determine chronic evolution and development of osteoarthritis (OA). Older anatomical observations, together with novel molecular tools and experimental models, have revealed a complex cellular and molecular response of cartilage to focal defects, which could explain differences in healing responses between individuals, and may provide clues to stimulating intrinsic tissue repair. In the first part of this review we will discuss clinical aspects of these lesions in the patient, with particular emphasis on their biology and natural history. In the second part we will summarize the data coming from in vitro and in vivo models of cartilage injury and regeneration, focussing on the molecular control of cartilage homeostasis after creation of cartilage surface defects.


High potential for using DNA from ancient herring bones to inform modern fisheries management and conservation.
Pacific herring (Clupea pallasi) are an abundant and important component of the coastal ecosystems for the west coast of North America. Current Canadian federal herring management assumes five regional herring populations in British Columbia with a high degree of exchange between units, and few distinct local populations within them. Indigenous traditional knowledge and historic sources, however, suggest that locally adapted, distinct regional herring populations may have been more prevalent in the past. Within the last century, the combined effects of commercial fishing and other anthropogenic factors have resulted in severe declines of herring populations, with contemporary populations potentially reflecting only the remnants of a previously more abundant and genetically diverse metapopulation. Through the analysis of 85 archaeological herring bones, this study attempted to reconstruct the genetic diversity and population structure of ancient herring populations using three different marker systems (mitochondrial DNA (mtDNA), microsatellites and SNPs). A high success rate (91%) of DNA recovery was obtained from the extremely small herring bone samples (often <10 mg). The ancient herring mtDNA revealed high haplotype diversity comparable to modern populations, although population discrimination was not possible due to the limited power of the mtDNA marker. Ancient microsatellite diversity was also similar to modern samples, but the data quality was compromised by large allele drop-out and stuttering. In contrast, SNPs were found to have low error rates with no evidence for deviations from Hardy-Weinberg equilibrium, and simulations indicated high power to detect genetic differentiation if loci under selection are used. This study demonstrates that SNPs may be the most effective and feasible approach to survey genetic population structure in ancient remains, and further efforts should be made to screen for high differentiation markers.This study provides the much needed foundation for wider scale studies on temporal genetic variation in herring, with important implications for herring fisheries management, Aboriginal title rights and herring conservation.


Measurement of submucosal forces transmitted to dental implants.
Early loading of dental implants after placement is believed to be a major cause for premature implant failure. If a transitional denture or partial denture is used during the healing period, occlusal forces may be transmitted to the submerged implant, leading to poorly differentiated growth of bone cells and/or potential inhibition of osseointegration at the bone-implant interface. The objective of this study was to develop an experimental model to measure the force transmission and to characterize the effect of selected loading conditions and relief methods on the forces transmitted to the implant. The loading conditions studied included unilateral and bilateral loading of the prosthesis. Forces were measured at two different relief conditions (relief with and without soft liner) and were compared against a control with no relief. The results show that fabrication of the prosthesis with a proper relief at the implant-denture junction can eliminate the submucosal force transmission to the implant on loading the denture both under unilateral and bilateral loading conditions. When a soft liner is used at the relief site, the transmitted force is small, but a finite value is reproducibly recorded. With no relief, the submucosal force transmission is high and may adversely affect the healing process or osseointegration. The experimental model is valuable in measuring and understanding the submucosal forces that are transmitted to the implant by loading the transitional prosthesis, and such measurement may assist in the proper design of the prosthesis for improved clinical durability and for other uses.


Use of aripiprazole in adolescents with a history of lupus-associated psychosis and refractory psychiatric manifestations.
Neurologic and psychiatric manifestations are prevalent in children and adults with lupus (labeled by convention neuropsychiatric systemic lupus erythematosus or NPSLE). However, there is a paucity of data on the evaluation and management of NPSLE in youth, with only a few publications describing the use of atypical antipsychotics in children and adolescents with lupus. In children, aripiprazole, a D2/5-HT1A partial agonist, appears to cause less prominent metabolic derangements than other second-generation antipsychotics. This agent may be an important tool in the treatment of pediatric patients with lupus who are at risk for weight gain and dyslipidemia due to disease and corticosteroid effects. The authors present two cases in which psychiatric symptoms associated with treatment-refractory lupus responded to aripiprazole pharmacotherapy.


Cognitive enhancement of healthy older adults using hyperbaric oxygen: a randomized controlled trial.
More than half of community-dwelling individuals sixty years and older express concern about declining cognitive abilities. The current study's aim was to evaluate hyperbaric oxygen therapy (HBOT) effect on cognitive functions in healthy aging adults.A randomized controlled clinical trial randomized 63 healthy adults (>64) either to HBOT(n=33) or control arms(n=30) for three months. Primary endpoint included the general cognitive function measured post intervention/control. Cerebral blood flow (CBF) was evaluated by perfusion magnetic resonance imaging.There was a significant group-by-time interaction in global cognitive function post-HBOT compared to control (p=0.0017). The most striking improvements were in attention (net effect size=0.745) and information processing speed (net effect size=0.788).Voxel-based analysis showed significant cerebral blood flow increases in the HBOT group compared to the control group in the right superior medial frontal gyrus (BA10), right and left supplementary motor area (BA6), right middle frontal gyrus (BA6), left middle frontal gyrus (BA9), left superior frontal gyrus (BA8) and the right superior parietal gyrus (BA7).In this study, HBOT was shown to induce cognitive enhancements in healthy aging adults via mechanisms involving regional changes in CBF. The main improvements include attention, information processing speed and executive functions, which normally decline with aging.


Structural investigation of coal humic substances by selective isotopic exchange and high-resolution mass spectrometry.
Here, we report the application of a selective liquid-phase hydrogen/deuterium exchange (HDX) coupled to ultra-high resolution FTICR MS for structural investigations of individual constituents of humic substances (HS) isolated from three coal samples of different geographical origin. Selectivity was achieved by conducting reactions in DCl or NaOD solutions for catalyzing HDX in aromatic ring and side-chain positions with enhanced C-H acidity, respectively. FTICR MS analysis showed a significant overlap of molecular compositions in the HS samples under study, with 2000 common formulae. Using HDX, we demonstrated that the determined common formulae are presented by different structural isomers. We found that aromatic compounds varied both in the substitution pattern and the number of aromatic protons. Depending on the sample, lignin components with the same molecular formulae were composed of coumaryl, coniferyl or sinapyl moieties. Enumeration of HDX series for the 800 most abundant compounds showed that the results of HDX agreed well with the model structures suggested for humic components occupying a van Krevelen plot. In addition, we explored chemical transformations, which could connect individual constituents of coal HS. These transformations included hydrolysis of a guaiacyl moiety and reduction of a catechol unit, which corresponds to the conversion of a coniferyl fragment into a coumaryl unit. The obtained results were supportive of the hypothesis of the reducing humification pathway suggested for lignin transformation in the environment. The conclusion was made that the molecular ensemble of coal HS is composed of individual constituents produced at different humification stages.


Widespread global peatland establishment and persistence over the last 130,000 y.
Glacial-interglacial variations in CO2 and methane in polar ice cores have been attributed, in part, to changes in global wetland extent, but the wetland distribution before the Last Glacial Maximum (LGM, 21 ka to 18 ka) remains virtually unknown. We present a study of global peatland extent and carbon (C) stocks through the last glacial cycle (130 ka to present) using a newly compiled database of 1,063 detailed stratigraphic records of peat deposits buried by mineral sediments, as well as a global peatland model. Quantitative agreement between modeling and observations shows extensive peat accumulation before the LGM in northern latitudes (>40°N), particularly during warmer periods including the last interglacial (130 ka to 116 ka, MIS 5e) and the interstadial (57 ka to 29 ka, MIS 3). During cooling periods of glacial advance and permafrost formation, the burial of northern peatlands by glaciers and mineral sediments decreased active peatland extent, thickness, and modeled C stocks by 70 to 90% from warmer times. Tropical peatland extent and C stocks show little temporal variation throughout the study period. While the increased burial of northern peats was correlated with cooling periods, the burial of tropical peat was predominately driven by changes in sea level and regional hydrology. Peat burial by mineral sediments represents a mechanism for long-term terrestrial C storage in the Earth system. These results show that northern peatlands accumulate significant C stocks during warmer times, indicating their potential for C sequestration during the warming Anthropocene.


Function of the intercostal muscles in trotting dogs: ventilation or locomotion?
Although the intercostal muscles play an important role in lung ventilation, observations from fishes and ectothermic tetrapods suggest that their primary function may be locomotion. To provide a broader understanding of the role these muscles play in locomotion, I measured ventilatory airflow at the mouth and activity of the fourth and ninth intercostal muscles in four dogs trotting on a treadmill. During rest and thermoregulatory panting, activity of the intercostal muscles was associated with inspiratory and expiratory airflow. However, during trotting, activity of the interosseous portions of the intercostal muscles was correlated with locomotion. When ventilation and stride cycles were not synchronized, activity of the interosseous intercostal muscles stayed locked to the locomotor events and drifted in time relative to ventilation. In contrast, activity of the parasternal portion of the internal intercostal muscles was always associated with inspiratory airflow. These observations suggest that, in dogs, locomotion is the dominant function of the interosseous portions of the intercostal muscles. However, the parasternal intercostal muscles are primarily inspiratory in function.


Novel broadband reconfigurable optical add-drop multiplexer employing custom fiber arrays and Opto-VLSI processors.
A reconfigurable optical add/drop multiplexer (ROADM) structure based on using a custom-made fiber array and an Opto-VLSI processor is proposed and demonstrated. The fiber array consists of N pairs of angled fibers corresponding to N channels, each of which can independently perform add, drop, and thru functions through a reconfigurable Opto-VLSI beam steerer. Experimental results show that the ROADM structure can attain an average add, drop/thru insertion loss of 5.5 dB and a uniformity of 0.3 dB over a wide bandwidth from 1524 nm to 1576 nm, and a drop/thru crosstalk level as small as -40 dB.


Physiological effects of Shinrin-yoku (taking in the atmosphere of the forest)--using salivary cortisol and cerebral activity as indicators.
The purpose of this study is to examine the physiological effects of Shinrin-yoku (taking in the atmosphere of the forest). The subjects were 12 male students (22.8+/-1.4 yr). On the first day of the experiments, one group of 6 subjects was sent to a forest area, and the other group of 6 subjects was sent to a city area. On the second day, each group was sent to the opposite area for a cross check. In the forenoon, the subjects were asked to walk around their given area for 20 minutes. In the afternoon, they were asked to sit on chairs and watch the landscapes of their given area for 20 minutes. Cerebral activity in the prefrontal area and salivary cortisol were measured as physiological indices in the morning at the place of accommodation, before and after walking in the forest or city areas during the forenoon, and before and after watching the landscapes in the afternoon in the forest and city areas, and in the evening at the place of accommodation. The results indicated that cerebral activity in the prefrontal area of the forest area group was significantly lower than that of the group in the city area after walking; the concentration of salivary cortisol in the forest area group was significantly lower than that of the group in the city area before and after watching each landscape. The results of the physiological measurements show that Shinrin-yoku can effectively relax both people's body and spirit.


Assessment of the bio-preparedness and of the training of the French hospital laboratories in the event of biological threat.
A national laboratory network 'Biotox-Piratox' was created in 2003 in France with the purpose of detecting, confirming and reporting potential biological and chemical threat agents. This network is divided into three levels: Level 1 is dedicated to the evaluation of risks (biological, chemical, radiological), to sampling and packing. Level 2 consists of university and military hospitals, who deal with biological specimens, and of environmental and veterinary laboratories, who deal with environmental and animal samples. Level 3 comprises national reference laboratories and the Jean Mérieux biosafety level (BSL)-4 laboratory in Lyon. This report presents the results of four bio-preparedness exercises to check critical points in the processing of samples. These exercises took place in 2007, 2009, 2010 and 2011. Each of them consisted of two parts. The first part was the identification of an unknown bacterial strain and its susceptibility to antibiotics used as a default in case of a bioterrorist event. The second part was the detection of Class III microorganisms, mainly by molecular techniques. The main lesson learnt in these exercises was that the key to successful detection of biological agents in case of a biological threat was standardisation and validation of the methods implemented by all the laboratories belonging to the network.


Complete chloroplast genome sequences of important oilseed crop Sesamum indicum L.
Sesamum indicum is an important crop plant species for yielding oil. The complete chloroplast (cp) genome of S. indicum (GenBank acc no. JN637766) is 153,324 bp in length, and has a pair of inverted repeat (IR) regions consisting of 25,141 bp each. The lengths of the large single copy (LSC) and the small single copy (SSC) regions are 85,170 bp and 17,872 bp, respectively. Comparative cp DNA sequence analyses of S. indicum with other cp genomes reveal that the genome structure, gene order, gene and intron contents, AT contents, codon usage, and transcription units are similar to the typical angiosperm cp genomes. Nucleotide diversity of the IR region between Sesamum and three other cp genomes is much lower than that of the LSC and SSC regions in both the coding region and noncoding region. As a summary, the regional constraints strongly affect the sequence evolution of the cp genomes, while the functional constraints weakly affect the sequence evolution of cp genomes. Five short inversions associated with short palindromic sequences that form step-loop structures were observed in the chloroplast genome of S. indicum. Twenty-eight different simple sequence repeat loci have been detected in the chloroplast genome of S. indicum. Almost all of the SSR loci were composed of A or T, so this may also contribute to the A-T richness of the cp genome of S. indicum. Seven large repeated loci in the chloroplast genome of S. indicum were also identified and these loci are useful to developing S. indicum-specific cp genome vectors. The complete cp DNA sequences of S. indicum reported in this paper are prerequisite to modifying this important oilseed crop by cp genetic engineering techniques.


A quantitative method for determining spatial discriminative capacity.
The traditional two-point discrimination (TPD) test, a widely used tactile spatial acuity measure, has been criticized as being imprecise because it is based on subjective criteria and involves a number of non-spatial cues. The results of a recent study showed that as two stimuli were delivered simultaneously, vibrotactile amplitude discrimination became worse when the two stimuli were positioned relatively close together and was significantly degraded when the probes were within a subject's two-point limen. The impairment of amplitude discrimination with decreasing inter-probe distance suggested that the metric of amplitude discrimination could possibly provide a means of objective and quantitative measurement of spatial discrimination capacity. A two alternative forced-choice (2AFC) tracking procedure was used to assess a subject's ability to discriminate the amplitude difference between two stimuli positioned at near-adjacent skin sites. Two 25 Hz flutter stimuli, identical except for a constant difference in amplitude, were delivered simultaneously to the hand dorsum. The stimuli were initially spaced 30 mm apart, and the inter-stimulus distance was modified on a trial-by-trial basis based on the subject's performance of discriminating the stimulus with higher intensity. The experiment was repeated via sequential, rather than simultaneous, delivery of the same vibrotactile stimuli. Results obtained from this study showed that the performance of the amplitude discrimination task was significantly degraded when the stimuli were delivered simultaneously and were near a subject's two-point limen. In contrast, subjects were able to correctly discriminate between the amplitudes of the two stimuli when they were sequentially delivered at all inter-probe distances (including those within the two-point limen), and improved when an adapting stimulus was delivered prior to simultaneously delivered stimuli. Subjects' capacity to discriminate the amplitude difference between two vibrotactile stimulations was degraded as the inter-stimulus distance approached the limit of their two-point spatial discriminative capacity. This degradation of spatial discriminative capacity lessened when an adapting stimulus was used. Performance of the task, as well as improvement on the task with adaptation, would most likely be impaired if the cortical information processing capacity of a subject or subject population were systemically altered, and thus, the methods described could be effective measures for use in clinical or clinical research applications.


Key role for gene dosage and synaptic homeostasis in autism spectrum disorders.
Autism spectrum disorders (ASD) are characterized by impairments in reciprocal social communication, and repetitive, stereotyped verbal and non-verbal behaviors. Genetic studies have provided a relatively large number of genes that constitute a comprehensive framework to better understand this complex and heterogeneous syndrome. Based on the most robust findings, three observations can be made. First, genetic contributions to ASD are highly heterogeneous and most probably involve a combination of alleles with low and high penetrance. Second, the majority of the mutations apparently affect a single allele, suggesting a key role for gene dosage in susceptibility to ASD. Finally, the broad expression and function of the causative genes suggest that alteration of synaptic homeostasis could be a common biological process associated with ASD. Understanding the mechanisms that regulate synaptic homeostasis should shed new light on the causes of ASD and could provide a means to modulate the severity of the symptoms.


Equality and difference: persisting historical themes in health and alcohol policies affecting Indigenous Australians.
Disseminating national health and alcohol policies to Aboriginal and Torres Strait Islander people in Australia has been a challenging task for governments and public servants. This has been for a number of reasons, including the enduring (negative) legacy of past "Aboriginal affairs" policies, the fact that Indigenous health programmes and alcohol programmes have been treated separately since the 1970s, and a more recent context in which the recognition of cultural difference was privileged. Confronted with the politics of difference, health departments were slow to examine avenues through which best practice advice emanating from WHO, and alcohol policies such as harm minimisation and early identification and treatment in primary health care, could be communicated in culturally recognisable ways to independent Indigenous services. In addition, there was hostility towards harm minimisation policies from Indigenous service providers, and Indigenous treatment programmes remained largely committed to abstinence-oriented modalities and the disease model of alcoholism, despite moves away from these approaches in the mainstream. However, genuinely innovative acute interventions and environmental controls over alcohol have been developed by Indigenous community-based organisations, approaches that are reinforced by international policy research evidence.


Update in diagnosis and management of interstitial lung disease.
The field of interstitial lung disease (ILD) has undergone significant evolution in recent years, with an increasing incidence and more complex, ever expanding disease classification. In their most severe forms, these diseases lead to progressive loss of lung function, respiratory failure and eventually death. Despite notable advances, progress has been challenged by a poor understanding of pathological mechanisms and patient heterogeneity, including variable progression. The diagnostic pathway is thus being continually refined, with the introduction of tools such as transbronchial cryo lung biopsy and a move towards genetically aided, precision medicine. In this review, we focus on how to approach a patient with ILD and the diagnostic process.


First-episode schizophrenia patients neuropsychologically within the normal limits: evidence of deterioration in speed of processing.
In apparent contradiction to the notion of cognitive impairment as a core feature of schizophrenia, some studies have described a subgroup of patients neuropsychologically within normal limits. It remains to be determined whether this subgroup has intact cognitive functioning or a higher premorbid functioning that attenuates the evidence of deterioration. Out of a total of 111 patients with FES or schizophreniform disorder, 25 (23%) were classified as cognitive normal (CN) according to criteria based on performance in six basic cognitive dimensions and an overall composite score, and their cognitive profile was compared with that of 28 controls. The CN subgroup had better social premorbid adjustment and had a higher premorbid IQ than the cognitive impaired subgroup. There were no differences in the other pretreatment variables examined. The CN subgroup performed similarly to controls in the cognitive dimensions, including sustained attention, verbal memory and executive functions. These profiles remained mostly unaltered after controlling for premorbid IQ. The cognitive deterioration index, calculated by ratio of performance in general knowledge and vocabulary abilities to a measure of processing speed , showed that both patient subgroups had similar levels of deterioration and that this was significantly different to that of controls. Although FES patients performed within normal limits and better than cognitive impaired patients in a processing speed task, they did nevertheless display a pattern of deterioration in processing speed (in relation to their premorbid IQ) equivalent to that of those with marked impairments.


A chromatin link to caste identity in the carpenter ant Camponotus floridanus.
In many ant species, sibling larvae follow alternative ontogenetic trajectories that generate striking variation in morphology and behavior among adults. These organism-level outcomes are often determined by environmental rather than genetic factors. Therefore, epigenetic mechanisms may mediate the expression of adult polyphenisms. We produced the first genome-wide maps of chromatin structure in a eusocial insect and found that gene-proximal changes in histone modifications, notably H3K27 acetylation, discriminate two female worker and male castes in Camponotus floridanus ants and partially explain differential gene expression between castes. Genes showing coordinated changes in H3K27ac and RNA implicate muscle development, neuronal regulation, and sensory responses in modulating caste identity. Binding sites of the acetyltransferase CBP harbor the greatest caste variation in H3K27ac, are enriched with motifs for conserved transcription factors, and show evolutionary expansion near developmental and neuronal genes. These results suggest that environmental effects on caste identity may be mediated by differential recruitment of CBP to chromatin. We propose that epigenetic mechanisms that modify chromatin structure may help orchestrate the generation and maintenance of polyphenic caste morphology and social behavior in ants.


Inhibitory effect of a growth hormone receptor antagonist (G120K-PEG) on renal enlargement, glomerular hypertrophy, and urinary albumin excretion in experimental diabetes in mice.
Growth hormone (GH) and IGFs have a long and distinguished history in diabetes, with possible participation in the development of renal complications. To investigate the effect of a newly developed GH receptor (GHR) antagonist (G120K-PEG) on renal/glomerular hypertrophy and urinary albumin excretion (UAE), streptozotocin-induced diabetic and nondiabetic mice were injected with G120K-PEG every 2nd day for 28 days. Placebo-treated diabetic and nondiabetic animals were used as reference groups. Placebo-treated diabetic animals were characterized by growth retardation, hyperphagia, hyperglycemia, increased serum GH levels, reduced serum IGF-I, IGF-binding protein (IGFBP)-3, and liver IGF-I levels, increased kidney IGF-I, renal/glomerular hypertrophy, and increased UAE when compared with nondiabetic animals. No differences were seen between the two diabetic groups with respect to body weight, food intake, blood glucose, serum GH, IGF-I, and IGFBP-3 levels or hepatic IGF-I levels. Kidney IGF-I, kidney weight, and glomerular volume were normalized, while the rise in UAE was partially attenuated in the G120K-PEG-treated diabetic animals. No effect of G120K-PEG treatment on any of the parameters mentioned above was seen in nondiabetic animals. In conclusion, administration of a GHR antagonist in diabetic mice has renal effects without affecting metabolic control and circulating levels of GH, IGF-I, or IGFBP-3, thus indicating that the effect of G120K-PEG may be mediated through a direct inhibitory effect on renal IGF-I through the renal GHR. The present study suggests that specific GHR blockade may present a new concept in the treatment of diabetic kidney disease.


Sequence quality analysis tool for HIV type 1 protease and reverse transcriptase.
Access to antiretroviral therapy is increasing globally and drug resistance evolution is anticipated. Currently, protease (PR) and reverse transcriptase (RT) sequence generation is increasing, including the use of in-house sequencing assays, and quality assessment prior to sequence analysis is essential. We created a computational HIV PR/RT Sequence Quality Analysis Tool (SQUAT) that runs in the R statistical environment. Sequence quality thresholds are calculated from a large dataset (46,802 PR and 44,432 RT sequences) from the published literature ( http://hivdb.Stanford.edu ). Nucleic acid sequences are read into SQUAT, identified, aligned, and translated. Nucleic acid sequences are flagged if with >five 1-2-base insertions; >one 3-base insertion; >one deletion; >six PR or >18 RT ambiguous bases; >three consecutive PR or >four RT nucleic acid mutations; >zero stop codons; >three PR or >six RT ambiguous amino acids; >three consecutive PR or >four RT amino acid mutations; >zero unique amino acids; or <0.5% or >15% genetic distance from another submitted sequence. Thresholds are user modifiable. SQUAT output includes a summary report with detailed comments for troubleshooting of flagged sequences, histograms of pairwise genetic distances, neighbor joining phylogenetic trees, and aligned nucleic and amino acid sequences. SQUAT is a stand-alone, free, web-independent tool to ensure use of high-quality HIV PR/RT sequences in interpretation and reporting of drug resistance, while increasing awareness and expertise and facilitating troubleshooting of potentially problematic sequences.


Physical and Psychosocial Characteristics of Current Child Dancers and Nondancers With Systemic Joint Hypermobility: A Descriptive Analysis.
Study Design Cross-sectional study. Background The effect of current participation in dance training on joint pain and instability, fatigue, and quality of life is unknown. Objectives To examine differences in joint pain, instability, gross motor skills, nonmusculoskeletal systemic manifestations, health-related quality of life (HRQoL), and fatigue between children with joint hypermobility syndrome/Ehlers-Danlos syndrome-hypermobility type (JHS/EDS-HT) who currently undertake formal dance training and those who do not. Methods Children with JHS/EDS-HT and 1 parent completed reports providing data on demographic variables, symptoms, organized activity participation, HRQoL, and fatigue. Physical and functional measures included extent of hypermobility, aerobic fitness, balance, and muscle endurance. Results Of the 102 participating children, 22 currently undertook dance classes, averaging 3.3 h/wk. While the dancers reported a number of painful joints similar to that reported by nondancers (mean ± SD, 5.5 ± 3.7 versus 6.4 ± 3.9 joints, respectively; P = .36), they reported significantly lower pain levels on a 0-to-10 scale (3.8 ± 3.3 versus 5.6 ± 3.4, P = .04) and found pain to be less problematic, affecting less of their body. They reported fewer unstable joints (1.0 ± 1.0 versus 2.0 ± 1.8 joints, P = .001), despite being more hypermobile (Beighton score, 7.3 ± 1.4 versus 6.6 ± 1.6 on a 9-point scale, P = .047; Lower Limb Assessment Score, 9.2 ± 2.0 versus 8.1 ± 1.9 on a 12-point scale, P = .02). The dancers had significantly better HRQoL in the subdomain of school functioning (P = .004) and reported less fatigue (P = .024). Conclusion Children with JHS/EDS-HT who are currently undertaking formal dance training have fewer joint pain and instability symptoms, less fatigue, and better HRQoL; however, the cross-sectional nature of the study means that causation cannot be determined. Level of Evidence Therapy, level 2b. J Orthop Sports Phys Ther 2017;47(10):782-791. Epub 4 Sep 2017. doi:10.2519/jospt.2017.7331.


Staphylococcus aureus sortase transpeptidase SrtA: insight into the kinetic mechanism and evidence for a reverse protonation catalytic mechanism.
The Staphylococcus aureus transpeptidase SrtA catalyzes the covalent attachment of LPXTG-containing virulence and colonization-associated proteins to cell-wall peptidoglycan in Gram-positive bacteria. Recent structural characterizations of staphylococcal SrtA, and related transpeptidases SrtB from S. aureus and Bacillus anthracis, provide many details regarding the active site environment, yet raise questions with regard to the nature of catalysis and active site cysteine thiol activation. Here we re-evaluate the kinetic mechanism of SrtA and shed light on aspects of its catalytic mechanism. Using steady-state, pre-steady-state, bisubstrate kinetic studies, and high-resolution electrospray mass spectrometry, revised steady-state kinetic parameters and a ping-pong hydrolytic shunt kinetic mechanism were determined for recombinant SrtA. The pH dependencies of kinetic parameters k(cat)/K(m) and k(cat) for the substrate Abz-LPETG-Dap(Dnp)-NH(2) were bell-shaped with pK(a) values of 6.3 +/- 0.2 and 9.4 +/- 0.2 for k(cat) and 6.2 +/- 0.2 and 9.4 +/- 0.2 for k(cat)/K(m). Solvent isotope effect (SIE) measurements revealed inverse behavior, with a (D)2(O)k(cat) of 0.89 +/- 0.01 and a (D)2(O)(k(cat)/K(m)) of 0.57 +/- 0.03 reflecting an equilibrium SIE. In addition, SIE measurements strongly implicated Cys184 participation in the isotope-sensitive rate-determining chemical step when considered in conjunction with an inverse linear proton inventory for k(cat). Last, the pH dependence of SrtA inactivation by iodoacetamide revealed a single ionization for inactivation. These studies collectively provide compelling evidence for a reverse protonation mechanism where a small fraction (ca. 0.06%) of SrtA is competent for catalysis at physiological pH, yet is highly active with an estimated k(cat)/K(m) of >10(5) M(-)(1) s(-)(1).


Qualitative and quantitative morphology of the vagus nerve in experimental Chagas' disease in rats: a light microscopy study.
Male Wistar rats were inoculated intraperitoneally with approximately 2 x 10(6) Trypanosoma cruzi Y strain blood forms. On days 7, 50, and 185 after inoculation, the animals were killed, and the right cervical vagus nerve was dissected, postfixed in 1% osmium tetroxide, and embedded in epoxy resin (Araldite). Semi-thin transverse sections were stained with 1% toluidine blue, examined by light microscopy, and photographed. An image analysis system was used to measure the area and diameter of each nerve and each fiber visible on the photomicrographs. Inoculated animals killed on days 7 and 185 after inoculation did not present morphologic or morphometric alterations of the vagus nerve. Inoculated animals killed on day 50 after inoculation presented several degrees of structural disorders in the myelin sheaths compared with control animals. The morphometric data demonstrated that the diameter of the myelinated fibers was generally increased in inoculated animals killed on day 50 after inoculation. These results suggest that experimental Chagas' disease in rats causes myelin damage and axonal swelling of the myelinated fibers of the vagus nerve, and that this injury to the vagus nerve may be important for a better understanding of the pathogenic mechanisms of the cardiac and digestive alterations caused by T. cruzi.


On the tip-of-the-tongue: neural correlates of increased word-finding failures in normal aging.
Tip-of-the-tongue (TOT) experiences are frustrating word-finding failures where people are temporarily unable to produce a word they are certain they know. TOT frequency increases with normal aging during adulthood, and behavioral evidence suggests that the underlying deficit is in retrieving the complete phonology of the target word during production. The present study investigated the neural correlates of this phonological retrieval deficit. We obtained 3-D T1-weighted structural magnetic resonance images (MRI) for healthy participants between 19 and 88 years old and used voxel-based morphometry to measure gray matter density throughout the brain. In a separate session, participants named celebrities cued by pictures and descriptions, indicating when they had a TOT, and also completed Raven's Progressive Matrices (RPM), a task that does not involve phonological production. The number of TOTs increased with age and also with gray matter atrophy in the left insula, an area implicated in phonological production. The relation between TOTs and left insula atrophy cannot be attributed to the correlation of each variable with age because TOTs were related to insula atrophy even with age effects removed. Moreover, errors on the RPM increased with age, but performance did not correlate with gray matter density in the insula. These results provide, for the first time, an association between a region in the neural language system and the rise in age-related word-finding failures and suggest that age-related atrophy in neural regions important for phonological production may contribute to age-related word production failures.


Brain Volumes and Longitudinal Cognitive Change: A Population-based Study.
To investigate the association of brain volumes, white matter lesion (WML) volumes, and lacunes, with cognitive decline in a population-based cohort of nondemented persons. Within the Rotterdam Study, 3624 participants underwent brain magnetic resonance imaging. Cognition was evaluated at baseline (2005 to 2009) and at the follow-up visit (2011 to 2013). We used a test battery that tapped into domains of executive function, information processing speed, motor speed, and memory. The volumetric measures assessed were total brain volume, lobar (gray matter and white matter) volumes, and hippocampal volumes. We also studied the association of WML volumes and lacunes with cognitive decline using linear regression models. Total brain volume was associated with decline in global cognition, information processing, and motor speed (P<0.001) in analyses controlled for demographic and vascular factors. Specifically, smaller frontal and parietal lobes were associated with decline in information processing and motor speed, and smaller temporal and parietal lobes were associated with decline in general cognition and motor speed (P<0.001 for all tests). Total WML volume was associated with decline in executive function. Lobar WML volume, hippocampal volume, and lacunes were not associated with cognitive decline. Lower brain volume is associated with subsequent cognitive decline. Although lower total brain volume was significantly associated with decline in global cognition, specific lobar volumes were associated with decline in certain cognitive domains.


Modeling electrical double-layer effects for microfluidic impedance spectroscopy from 100 kHz to 110 GHz.
Broadband microfluidic-based impedance spectroscopy can be used to characterize complex fluids, with applications in medical diagnostics and in chemical and pharmacological manufacturing. Many relevant fluids are ionic; during impedance measurements ions migrate to the electrodes, forming an electrical double-layer. Effects from the electrical double-layer dominate over, and reduce sensitivity to, the intrinsic impedance of the fluid below a characteristic frequency. Here we use calibrated measurements of saline solution in microfluidic coplanar waveguide devices at frequencies between 100 kHz and 110 GHz to directly measure the double-layer admittance for solutions of varying ionic conductivity. We successfully model the double-layer admittance using a combination of a Cole-Cole response with a constant phase element contribution. Our analysis yields a double-layer relaxation time that decreases linearly with solution conductivity, and allows for double-layer effects to be separated from the intrinsic fluid response and quantified for a wide range of conducting fluids.


Who Benefits From a Prostate Rectal Spacer? Secondary Analysis of a Phase III Trial.
Previously a phase III trial of a hydrogel rectal spacer during prostate radiation therapy found decreased toxicity and a clinically significant improvement in bowel quality of life (QOL) at 3 years by the Expanded Prostate Cancer Index. We performed a secondary analysis to identify men less likely to benefit. Clinical and dosimetric data for the 222 patients enrolled on the SpaceOAR phase III trial were analyzed. The volume of rectum treated to 70 Gy (V70) and the quantitative analysis of normal tissue effects in the clinic (QUANTEC) rectal dose goals were used as surrogates for clinical benefit and plan quality. Mean bowel QOL was assessed at 15 and 36 months posttreatment and the likelihood of 1× (5 points) or 2× (10 points) minimally important difference changes were assessed. Rectal V70 was correlated with physician scored toxicity (P = .033) and was used as a surrogate for plan quality. There was no correlation between prostate volume and rectal V70 (r = 0.077). Rectal V70 pre- and post-hydrogel was 13% and 3% for the smallest prostates (<40 mL) and 12% and 2% for the largest (>80 mL). The relative reduction in rectal V70 of 78% did not vary by prespacer V70, but the absolute reduction was greater for a higher V70. All spacer plans met the 5 QUANTEC rectal dose constraints, although 92% of control plans met all constraints. At 3 years, those not meeting all QUANTEC goals had a 15.0-point (standard deviation 15.1) decline, control patients meeting QUANTEC goals had a 4.0-point (9.5) decline, and spacer had >0.5 (7.6; P < .01). Previous surgery was not correlated with QOL (P = .8). Across prognostic groups, including age, body mass index, previous surgery, target volume, or quality of radiation plans, there was no statistically significant heterogeneity in the relative benefit of spacer in decreasing the risk of 1× or 2× the minimally important difference declines. There was little heterogeneity in the likelihood of spacer reducing the risk of declines in bowel QOL across clinical and dosimetric variables. Even for the >95% of plans meeting QUANTEC rectal criteria, hydrogel spacer provided potentially meaningful benefits.


Impregnation of bone chips with alendronate and cefazolin, combined with demineralized bone matrix: a bone chamber study in goats.
Bone grafts from bone banks might be mixed with bisphosphonates to inhibit the osteoclastic response. This inhibition prevents the osteoclasts to resorb the allograft bone before new bone has been formed by the osteoblasts, which might prevent instability. Since bisphosphonates may not only inhibit osteoclasts, but also osteoblasts and thus bone formation, we studied different bisphosphonate concentrations combined with allograft bone. We investigated whether locally applied alendronate has an optimum dose with respect to bone resorption and formation. Further, we questioned whether the addition of demineralized bone matrix (DBM), would stimulate bone formation. Finally, we studied the effect of high levels of antibiotics on bone allograft healing, since mixing allograft bone with antibiotics might reduce the infection risk. 25 goats received eight bone conduction chambers in the cortical bone of the proximal medial tibia. Five concentrations of alendronate (0, 0.5 mg/mL, 1 mg/mL, 2 mg/mL, and 10 mg/mL) were tested in combination with allograft bone and supplemented with cefazolin (200 μg/mL). Allograft not supplemented with alendronate and cefazolin served as control. In addition, allograft mixed with demineralized bone matrix, with and without alendronate, was tested. After 12 weeks, graft bone area and new bone area were determined with manual point counting. Graft resorption decreased significantly (p < 0.001) with increasing alendronate concentration. The area of new bone in the 1 mg/mL alendronate group was significantly (p = 0.002) higher when compared to the 10 mg/mL group. No differences could be observed between the group without alendronate, but with demineralized bone, and the control groups. A dose-response relationship for local application of alendronate has been shown in this study. Most new bone was present at 1 mg/mL alendronate. Local application of cefazolin had no effect on bone remodelling.


Electromagnetic pulses induce fluctuations in blood pressure in rats.
To investigate the effects of exposure to electromagnetic pulses (EMP) on functional indices of the cardiovascular system in male Sprague-Dawley rats. A tapered parallel plate Gigahertz Transverse Electromagnetic cell (GTEM cell) with a flared rectangular coaxial transmission line was used to expose the rats to EMP (0.5 pps, total 200 pulses and whole-body averaged specific absorption rate 50 mW/kg at 200 kV/m or 75 mW/kg at 400 kV/m). Concurrent sham-exposed animals were used as controls. Cardiovascular functions, namely, heart rate, and systolic, mean and diastolic blood pressures were measured immediately and up to 4 weeks post-exposure using a non-invasive tail-cuff photoelectric sensor sphygmomanometer. The heart rates in sham- and EMP-exposed rats were not significantly changed. In the exposed rats, increased systolic blood pressure (SBP) occurred at 0 h and decreased SBP occurred at 1 day and 3 days after exposure. Significantly higher diastolic blood pressure (DBP) was found at 0 h and significantly lower DBP was found at 12 h, 1 day, and 1 month after exposure. Significantly higher mean arterial pressure (MAP) was noted at 0 h and significantly lower MAP was noted at 1 day. Significant alterations in arterial blood pressure were observed in rats exposed to EMP exposure while heart rate was not altered.


Characteristic metabolism of free amino acids in cetacean plasma: cluster analysis and comparison with mice.
From an evolutionary perspective, the ancestors of cetaceans first lived in terrestrial environments prior to adapting to aquatic environments. Whereas anatomical and morphological adaptations to aquatic environments have been well studied, few studies have focused on physiological changes. We focused on plasma amino acid concentrations (aminograms) since they show distinct patterns under various physiological conditions. Plasma and urine aminograms were obtained from bottlenose dolphins, pacific white-sided dolphins, Risso's dolphins, false-killer whales and C57BL/6J and ICR mice. Hierarchical cluster analyses were employed to uncover a multitude of amino acid relationships among different species, which can help us understand the complex interrelations comprising metabolic adaptations. The cetacean aminograms formed a cluster that was markedly distinguishable from the mouse cluster, indicating that cetaceans and terrestrial mammals have quite different metabolic machinery for amino acids. Levels of carnosine and 3-methylhistidine, both of which are antioxidants, were substantially higher in cetaceans. Urea was markedly elevated in cetaceans, whereas the level of urea cycle-related amino acids was lower. Because diving mammals must cope with high rates of reactive oxygen species generation due to alterations in apnea/reoxygenation and ischemia-reperfusion processes, high concentrations of antioxidative amino acids are advantageous. Moreover, shifting the set point of urea cycle may be an adaptation used for body water conservation in the hyperosmotic sea water environment, because urea functions as a major blood osmolyte. Furthermore, since dolphins are kept in many aquariums for observation, the evaluation of these aminograms may provide useful diagnostic indices for the assessment of cetacean health in artificial environments in the future.


The effect of group psychosocial support on survival in metastatic breast cancer.
Supportive-expressive group therapy has been reported to prolong survival among women with metastatic breast cancer. However, in recent studies, various psychosocial interventions have not prolonged survival. In a multicenter trial, we randomly assigned 235 women with metastatic breast cancer who were expected to survive at least three months in a 2:1 ratio to an intervention group that participated in weekly supportive-expressive group therapy (158 women) or to a control group that received no such intervention (77 women). All the women received educational materials and any medical or psychosocial care that was deemed necessary. The primary outcome was survival; psychosocial function was assessed by self-reported questionnaires. Women assigned to supportive-expressive therapy had greater improvement in psychological symptoms and reported less pain (P=0.04) than women in the control group. A significant interaction of treatment-group assignment with base-line psychological score was found (P</=0.003 for the comparison of mood variables; P=0.04 for the comparison of pain); women who were more distressed benefited, whereas those who were less distressed did not. The psychological intervention did not prolong survival (median survival, 17.9 months in the intervention group and 17.6 months in the control group; hazard ratio for death according to the univariate analysis, 1.06 [95 percent confidence interval, 0.78 to 1.45]; hazard ratio according to the multivariate analysis, 1.23 [95 percent confidence interval, 0.88 to 1.72]). Supportive-expressive group therapy does not prolong survival in women with metastatic breast cancer. It improves mood and the perception of pain, particularly in women who are initially more distressed.


Telomerase activation in normal B lymphocytes and non-Hodgkin's lymphomas.
Activation of telomerase seems to be a prerequisite for immortalization and is found in permanent cell lines and most malignant tumors. Normal somatic cells are generally telomerase negative, except for bone marrow stem cells. Weak activity is also present in peripheral blood cells. In the present study strong telomerase activity was demonstrated in vivo in normal mature cells of the immune system, as well as in malignant lymphomas. Benign lymph nodes had lower telomerase activity than benign tonsils, which exhibited intermediate to high activity comparable with findings in malignant lymphomas. In benign tonsils the activity seemed to be restricted to germinal center B cells. In benign lymphoid tissues telomerase activity correlated with B-cell numbers and cell proliferation, but this was not observed in the lymphoma group. High-grade lymphomas exhibited higher levels of telomerase compared with low-grade cases. The data showed that in vivo activation of telomerase is a characteristic feature of germinal center B cells. Different signals for activation of telomerase are likely to exist, one of them being immune stimulation. The data suggest that telomerase activity in malignant lymphomas can be explained by an "induction and retention" model, ie, transformation occurs in a normal, mature B cell with reactivated telomerase, which is retained in the neoplastic clone.


Efficacy of a dopamine-somatostatin chimeric molecule, BIM-23A760, in the control of cell growth from primary cultures of human non-functioning pituitary adenomas: a multi-center study.
Dopamine D2 and somatostatin receptors (sstrs) were reported to affect non-functioning pituitary adenoma (NFPA) proliferation in vitro. However, the reported results differ according to the experimental conditions used. We established an experimental protocol allowing reproducible evaluation of NFPA cell proliferation in vitro, to test and compare the antiproliferative effects of dopamine and somatostatin analogs (alone or in combination) with the activity of the dopamine-somatostatin chimeric molecule BIM-23A760. The protocol was utilized by four independent laboratories, studying 38 fibroblast-deprived NFPA cell cultures. Cells were characterized for GH, POMC, sstr1-sstr5, total dopamine D2 receptor (D2R) (in all cases), and D2 receptor long and short isoforms (in 15 out of 38 cases) mRNA expression and for alpha-subunit, LH, and FSH release. D2R, sstr3, and sstr2 mRNAs were consistently observed, with the dominant expression of D2R (2.9+/-2.6 copy/copy beta-glucuronidase; mean+/-s.e.m.), when compared with sstr3 and sstr2 (0.6+/-1.0 and 0.3+/-0.6 respectively). BIM-23A760, a molecule with high affinity for D2R and sstr2, significantly inhibited [3H]thymidine incorporation in 23 out of 38 (60%) NFPA cultures (EC50=1.2 pM and Emax=-33.6+/-3.7%). BIM-23A760 effects were similar to those induced by the selective D2R agonist cabergoline that showed a statistically significant inhibition in 18 out of 27 tumors (compared with a significant inhibition obtained in 17 out of 27 tumors using BIM-23A760, in the same subgroup of adenomas analyzed), while octreotide was effective in 13 out of 27 cases. In conclusion, superimposable data generated in four independent laboratories using a standardized protocol demonstrate that, in vitro, chimeric dopamine/sstr agonists are effective in inhibiting cell proliferation in two-thirds of NFPAs.


Meta-analytic evidence for a superordinate cognitive control network subserving diverse executive functions.
Classic cognitive theory conceptualizes executive functions as involving multiple specific domains, including initiation, inhibition, working memory, flexibility, planning, and vigilance. Lesion and neuroimaging experiments over the past two decades have suggested that both common and unique processes contribute to executive functions during higher cognition. It has been suggested that a superordinate fronto-cingulo-parietal network supporting cognitive control may also underlie a range of distinct executive functions. To test this hypothesis in the largest sample to date, we used quantitative meta-analytic methods to analyze 193 functional neuroimaging studies of 2,832 healthy individuals, ages 18-60, in which performance on executive function measures was contrasted with an active control condition. A common pattern of activation was observed in the prefrontal, dorsal anterior cingulate, and parietal cortices across executive function domains, supporting the idea that executive functions are supported by a superordinate cognitive control network. However, domain-specific analyses showed some variation in the recruitment of anterior prefrontal cortex, anterior and midcingulate regions, and unique subcortical regions such as the basal ganglia and cerebellum. These results are consistent with the existence of a superordinate cognitive control network in the brain, involving dorsolateral prefrontal, anterior cingulate, and parietal cortices, that supports a broad range of executive functions.


Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment.
Complex interactions between the immune system and the brain might have important aetiological and therapeutic implications for neuropsychiatric brain disorders. A possible association between schizophrenia and the immune system was postulated over a century ago, and is supported by epidemiological and genetic studies pointing to links with infection and inflammation. Contrary to the traditional view that the brain is an immunologically privileged site shielded behind the blood-brain barrier, studies in the past 20 years have noted complex interactions between the immune system, systemic inflammation, and the brain, which can lead to changes in mood, cognition, and behaviour. In this Review, we describe some of the important areas of research regarding innate and adaptive immune response in schizophrenia and related psychotic disorders that, we think, will be of interest to psychiatric clinicians and researchers. We discuss potential mechanisms and therapeutic implications of these findings, including studies of anti-inflammatory drugs in schizophrenia, describe areas for development, and offer testable hypotheses for future investigations.


TREM2 protects against cerebral ischemia/reperfusion injury.
Although post-ischemic inflammation induced by the innate immune response is considered an essential step in the progression of cerebral ischemia injury, the role of triggering receptor expressed on myeloid cells 2 (TREM2) in the pathogenesis of ischemic stroke remains to be elucidated. Here, we found that the transcriptional and post-transcriptional levels of TREM2 were increased in cultured primary microglia after oxygen-glucose deprivation and reoxygenation and in the ischemic penumbra of the cerebral cortex after middle cerebral artery occlusion (MCAO) and reperfusion in mice. TREM2 was mainly expressed in microglia, but not in astrocytes, neurons, or oligodendrocytes in mice subjected to MCAO. Manipulating TREM2 expression levels in vitro and in vivo significantly regulated the production of pro- and anti-inflammatory mediators after ischemic stroke. TREM2 overexpression markedly suppressed the inflammatory response and neuronal apoptosis. By contrast, TREM2 gene silencing intensified the inflammatory response, increased neuronal apoptosis and infarct volume, and further exacerbated neurological dysfunction. Our study demonstrated that TREM2 protects against cerebral ischemia/reperfusion injury through the aspect of post-ischemic inflammatory response and neuronal apoptosis. Pharmacological targeting of TREM2 to suppress the inflammatory response may provide a new approach for developing therapeutic strategies in the treatment of ischemic stroke and other cerebrovascular diseases.


Targeted deletion of the CD59 gene causes spontaneous intravascular hemolysis and hemoglobinuria.
The glycolipid-anchored glycoprotein CD59 inhibits assembly of the lytic membrane attack complex of complement by incorporation into the forming complex. Absence of CD59 and other glycolipid-anchored molecules on circulating cells in the human hemolytic disorder paroxysmal nocturnal hemoglobinuria is associated with intravascular hemolysis and thrombosis. To examine the role of CD59 in protecting host tissues in health and disease, CD59-deficient (CD59(-/-)) mice were produced by gene targeting in embryonic stem cells. Absence of CD59 was confirmed by staining cells and tissues with specific antibody. Despite the complete absence of CD59, mice were healthy and fertile. Erythrocytes in vitro displayed increased susceptibility to complement and were positive in an acidified serum lysis test. Despite this, CD59(-/-) mice were not anemic but had elevated reticulocyte counts, indicating accelerated erythrocyte turnover. Fresh plasma and urine from CD59(-/-) mice contained increased amounts of hemoglobin when compared with littermate controls, providing further evidence for spontaneous intravascular hemolysis. Intravascular hemolysis was increased following administration of cobra venom factor to trigger complement activation. CD59(-/-) mice will provide a tool for characterizing the importance of CD59 in protection of self tissues from membrane attack complex damage in health and during diseases in which complement is activated.