Results from the Baksan Experiment on Sterile Transitions (BEST).

The Baksan Experiment on Sterile Transitions (BEST) was designed to investigate the deficit of electron neutrinos ν_{e} observed in previous gallium-based radiochemical measurements with high-intensity neutrino sources, commonly referred to as the "gallium anomaly," which could be interpreted as evidence for oscillations between ν_{e} and sterile neutrino (ν_{s}) states. A 3.414-MCi ^{51}Cr ν_{e} source was placed at the center of two nested Ga volumes and measurements were made of the production of ^{71}Ge through the charged current reaction, ^{71}Ga(ν_{e},e^{-})^{71}Ge, at two average distances. The measured production rates for the inner and the outer targets, respectively, are [54.9_{-2.4}^{+2.5}(stat)±1.4(syst)] and [55.6_{-2.6}^{+2.7}(stat)±1.4(syst)] atoms of ^{71}Ge/d. The ratio (R) of the measured rate of ^{71}Ge production at each distance to the expected rate from the known cross section and experimental efficiencies are R_{in}=0.79±0.05 and R_{out}=0.77±0.05. The ratio of the outer to the inner result is 0.97±0.07, which is consistent with unity within uncertainty. The rates at each distance were found to be similar, but 20%-24% lower than expected, thus reaffirming the anomaly. These results are consistent with ν_{e}→ν_{s} oscillations with a relatively large Δm^{2} (>0.5 eV^{2}) and mixing sin^{2}2θ (≈0.4).

Non-ohmic conduction in sodium bismuth titanate: the influence of oxide-ion conduction.

A nominal Bi-excess starting composition of sodium bismuth titanate, Na0.5Bi0.51TiO3.015 (NB0.51T) produces dielectric ceramics that exhibit mixed n-type and oxide-ion conductivity with an ionic transport number of ∼0.1 at ≥600 °C. The bulk electrical conductivity, σb, of NB0.51T ceramics under a dc bias field of ≤100 V cm-1 has been investigated by impedance spectroscopy. Over the temperature range ∼550 to 750 °C, σb increases by up to one order of magnitude under the dc bias and returns to its initial value on removal of the bias. The enhancement of conductivity is dependent on temperature, atmosphere, dc bias field and the electrode materials. A maximum conductivity enhancement of >2000% is achieved at 600 °C in nitrogen using Pt electrodes. This is in contrast to that observed for other n-type perovskite titanates and oxygen-deficient rutile where σb is suppressed under a dc bias. This 'unusual' non-ohmic behaviour is attributed mainly to the influence of highly mobile oxygen vacancies in NB0.51T. The field-enhanced σb is best described to be a consequence of increased pumping of oxygen from the cathode to the anode, in which the electrode reactions play an important role. In addition, dissociation of defect clusters may also contribute to the enhanced σb under a dc bias. The high, fast and reversible response to the dc bias voltage may expand the potential application of NBT-based materials to memory devices.

A mutation in Tubb2b, a human polymicrogyria gene, leads to lethality and abnormal cortical development in the mouse.

Human cortical malformations, including lissencephaly, polymicrogyria and other diseases of neurodevelopment, have been associated with mutations in microtubule subunits and microtubule-associated proteins. Here we report our cloning of the brain dimple (brdp) mouse mutation, which we recovered from an ENU screen for recessive perinatal phenotypes affecting neurodevelopment. We identify the causal mutation in the tubulin, beta-2b (Tubb2b) gene as a missense mutation at a highly conserved residue (N247S). Brdp/brdp homozygous mutants have significant thinning of the cortical epithelium, which is markedly more severe in the caudo-lateral portion of the telencephalon, and do not survive past birth. The cortical defects are largely due to a major increase in apoptosis and we note abnormal proliferation of the basal progenitors. Adult brdp/+ mice are viable and fertile but exhibit behavioral phenotypes. This allele of Tubb2b represents the most severely affected mouse tubulin phenotype reported to date and this is the first report of a tubulin mutation affecting neuronal proliferation and survival.

Randomized clinical trial to evaluate mental practice in enhancing advanced laparoscopic surgical performance.

BACKGROUND: Mental practice, the cognitive rehearsal of a task without physical movement, is known to enhance performance in sports and music. Investigation of this technique in surgery has been limited to basic operations. The purpose of this study was to develop mental practice scripts, and to assess their effect on advanced laparoscopic skills and surgeon stress levels in a crisis scenario. METHODS: Twenty senior surgical trainees were randomized to either conventional training or mental practice groups, the latter being trained by an expert performance psychologist. Participants' skills were assessed while performing a porcine laparoscopic jejunojejunostomy as part of a crisis scenario in a simulated operating room, using the Objective Structured Assessment of Technical Skill (OSATS) and bariatric OSATS (BOSATS) instruments. Objective and subjective stress parameters were measured, as well as non-technical skills using the Non-Technical Skills for Surgeons rating tool. RESULTS: An improvement in OSATS (P = 0.003) and BOSATS (P = 0.003) scores was seen in the mental practice group compared with the conventional training group. Seven of ten trainees improved their technical performance during the crisis scenario, whereas four of the ten conventionally trained participants deteriorated. Mental imagery ability improved significantly following mental practice training (P = 0.011), but not in the conventional group (P = 0.083). No differences in objective or subjective stress levels or non-technical skills were evident. CONCLUSION: Mental practice improves technical performance for advanced laparoscopic tasks in the simulated operating room, and allows trainees to maintain or improve their performance despite added stress.

Inflammasome induction in Rasmussen's encephalitis: cortical and associated white matter pathogenesis.

BACKGROUND: Rasmussen's encephalitis (RE) is an inflammatory encephalopathy of unknown cause defined by seizures with progressive neurological disabilities. Herein, the pathogenesis of RE was investigated focusing on inflammasome activation in the brain. METHODS: Patients with RE at the University of Alberta, Edmonton, AB, Canada, were identified and analyzed by neuroimaging, neuropsychological, molecular, and pathological tools. Primary human microglia, astrocytes, and neurons were examined using RT-PCR, enzyme-linked immunosorbent assay (ELISA), and western blotting. RESULTS: Four patients with RE were identified at the University of Alberta. Magnetic resonance imaging (MRI) disclosed increased signal intensities in cerebral white matter adjacent to cortical lesions of RE patients, accompanied by a decline in neurocognitive processing speed (P <0.05). CD3ϵ, HLA-DRA, and TNFα together with several inflammasome-associated genes (IL-1ß, IL-18, NLRP1, NLRP3, and CASP1) showed increased transcript levels in RE brains compared to non-RE controls (n = 6; P <0.05). Cultured human microglia displayed expression of inflammasome-associated genes and responded to inflammasome activators by releasing IL-1ß, which was inhibited by the caspase inhibitor, zVAD-fmk. Major histocompatibility complex (MHC) class II, IL-1ß, caspase-1, and alanine/serine/cysteine (ASC) immunoreactivity were increased in RE brain tissues, especially in white matter myeloid cells, in conjunction with mononuclear cell infiltration and gliosis. Neuroinflammation in RE brains was present in both white matter and adjacent cortex with associated induction of inflammasome components, which was correlated with neuroimaging and neuropsychological deficits. CONCLUSION: Inflammasome activation likely contributes to the disease process underlying RE and offers a mechanistic target for future therapeutic interventions.

Depth electrodes in pediatric epilepsy surgery.

BACKGROUND: The surgical removal of the epileptogenic zone in medically intractable seizures depends on accurate localization to minimize the neurological sequelae and prevent future seizures. To date, few studies have demonstrated the use of depth electrodes in a pediatric epilepsy population. Here, we report our study of pediatric epilepsy patients at our epilepsy center who were successfully operated for medically intractable seizures following the use of intracranial depth electrodes. In addition, we detail three individuals with distinct clinical scenarios in which depth electrodes were helpful and describe our technical approach to implantation and surgery. METHODS: We retrospectively reviewed 18 pediatric epilepsy patients requiring depth electrode studies who presented at the University of Alberta Comprehensive Epilepsy Program between 1999 and 2010 with medically intractable epilepsy. Patients underwent cortical resection following depth electrode placement according to the Comprehensive Epilepsy Program surgical protocols after failure of surface electroencephalogram and magnetic resonance imaging to localize ictal onset zone. RESULT: The ictal onset zone was successfully identified in all 18 patients. Treatment of all surgical patients resulted in successful seizure freedom (Engel class I) without neurological complications. CONCLUSION: Intracranial depth electrode use is safe and able to provide sufficient information for the identification of the epileptogenic zone in pediatric epilepsy patients previously not considered for epilepsy surgery.

Dopamine modulates synaptic plasticity in dendrites of rat and human dentate granule cells.

The mechanisms underlying memory formation in the hippocampal network remain a major unanswered aspect of neuroscience. Although high-frequency activity appears essential for plasticity, salience for memory formation is also provided by activity in ventral tegmental area (VTA) dopamine projections. Here, we report that activation of dopamine D1 receptors in dentate granule cells (DGCs) can preferentially increase dendritic excitability to both high-frequency afferent activity and high-frequency trains of backpropagating action potentials. Using whole-cell patch clamp recordings, calcium imaging, and neuropeptide Y to inhibit postsynaptic calcium influx, we found that activation of dendritic voltage-dependent calcium channels (VDCCs) is essential for dopamine-induced long-term potentiation (LTP), both in rat and human dentate gyrus (DG). Moreover, we demonstrate previously unreported spike-timing-dependent plasticity in the human hippocampus. These results suggest that when dopamine is released in the dentate gyrus with concurrent high-frequency activity there is an increased probability that synapses will be strengthened and reward-associated spatial memories will be formed.

Controlled-release oxycodone and naloxone in the treatment of chronic low back pain: a placebo-controlled, randomized study.

BACKGROUND: For Canadian regulatory purposes, an analgesic study was required to complement previously completed, pivotal studies on bowel effects and analgesia associated with controlled-release (CR) oxycodone/CR naloxone. OBJECTIVES: To compare the analgesic efficacy and safety of CR oxycodone/CR naloxone versus placebo in patients with chronic low back pain. METHODS: Patients requiring opioid therapy underwent a two- to seven-day opioid washout before being randomly assigned to receive either 10 mg/5 mg CR oxycodone/CR naloxone or placebo every 12 h, titrated weekly according to efficacy and tolerability to 20 mg/10 mg, 30 mg/15 mg or 40 mg/20 mg every 12 h. After four weeks, patients crossed over to the alternative treatment for an additional four weeks. Acetaminophen/codeine (300 mg/30 mg every 4 h to 6 h as needed) was provided as rescue medication. RESULTS: Of the 83 randomized patients, 54 (65%) comprised the per-protocol population. According to per-protocol analysis, CR oxycodone/CR naloxone resulted in significantly lower mean (± SD)pain scores measured on a visual analogue scale (48.6 ± 23.1 mm versus 55.9 ± 25.4 mm; P=0.0296) and five-point ordinal pain intensity scores (2.1 ± 0.8 versus 2.4 ± 0.9; P=0.0415) compared with placebo. After the double-blinded phase, patients and investigators both preferred CR oxycodone/CR naloxone over placebo. These outcomes continued in the 79% of patients who chose to continue receiving CR oxycodone/CR naloxone in a six-month, open-label evaluation. CONCLUSIONS: In patients complying with treatment as per protocol, CR oxycodone/CR naloxone was effective for the management of chronic low back pain of moderate or severe intensity.

Dynamic molecular and anatomical changes in the glucocorticoid receptor in human cortical development.

The glucocorticoid receptor (GR) has a critical role in determining the brain's capacity to respond to stress, and has been implicated in the pathogenesis of psychiatric illness. We hypothesized that key changes in cortical GR occur during adolescence and young adulthood, at a time when individuals are at increased risk of developing schizophrenia, bipolar disorder and major depression. We investigated the mRNA and protein expression of GR in the dorsolateral prefrontal cortex across seven developmental time points from infancy to adulthood. GR mRNA expression, determined by microarray and quantitative real-time PCR, was lowest in neonates and peaked around young adulthood. Western blotting revealed two dynamic patterns of GRα protein expression across the lifespan, with N-terminal variants displaying differing unique patterns of abundance. GRα-A and a 67-kDa GRα isoform mirrored mRNA trends and peaked in toddlers and late in adolescence, whereas a 40-kDa isoform, very likely a GRα-D variant, peaked in neonates and decreased across the lifespan. GRα protein was localized to pyramidal neurons throughout life and most strikingly in young adulthood, but to white matter astrocytes only in neonates and infants (<130 days). These results suggest that the neonatal and late adolescent periods represent critical windows of stress pathway development, and highlight the importance of white matter astrocytes and pyramidal neurons, respectively, at these stages of cortical development. Evidence of dynamic patterns of GR isoform expression and cellular localization across development strengthens the hypothesis that windows of vulnerability to stress exist across human cortical development.

Effect of opioid antagonists on sex hormone secretion.

BACKGROUND: Endogenous opioids have roles in various functions in different parts of the body, including intestinal motility, suppression of pain, reinforcement of behavior, and regulation of the hypothalamic-pituitary-gonadal axis. The endogenous opioid system is also recognized to be involved in the negative-feedback regulation of the release of LH and testosterone. AIM: The reviewed articles herein show the development of the current model of this regulation, the evidence supporting it, and also the observed effects of opioid antagonist (naloxone, naltrexone, and nalmefene) on the system. MATERIALS AND METHODS: Review of the studies published during the years 1979-1996 (no significant studies made after that). Search from databases Pubmed, SciFinder, and Medline with search words opioid antagonists, hormones, LH, testosterone, and GnRH, in different combinations. RESULTS/CONCLUSIONS: Opioid antagonists seem to increase the secretion of GnRH in the hypothalamus which then causes a pulsatile release of LH in the pituitary and secretion of testosterone. According to the experiments, the frequency of pulses and concentration of LH and testosterone in plasma seem to increase. These effects are seen in both men and women (at early follicular phase). More research is needed to investigate the consequences of these effects in general.

Frailty among Older Adults and Its Distribution in England.

BACKGROUND: Information on the spatial distribution of the frail population is crucial to inform service planning in health and social care. OBJECTIVES: To estimate small-area frailty prevalence among older adults using survey data. To assess whether prevalence differs between urban, rural, coastal and inland areas of England. DESIGN: Using data from the English Longitudinal Study of Ageing (ELSA), ordinal logistic regression was used to predict the probability of frailty, according to age, sex and area deprivation. Probabilities were applied to demographic and economic information in 2020 population projections to estimate the district-level prevalence of frailty. RESULTS: The prevalence of frailty in adults aged 50+ (2020) in England was estimated to be 8.1 [95% CI 7.3-8.8]%. We found substantial geographic variation, with the prevalence of frailty varying by a factor of 4.0 [3.5-4.4] between the most and least frail areas. A higher prevalence of frailty was found for urban than rural areas, and coastal than inland areas. There are widespread geographic inequalities in healthy ageing in England, with older people in urban and coastal areas disproportionately frail relative to those in rural and inland areas. CONCLUSIONS: Interventions aimed at reducing inequalities in healthy ageing should be targeted at urban and coastal areas, where the greatest benefit may be achieved.

Bottomonium above deconfinement in lattice nonrelativistic QCD.

We study the temperature dependence of bottomonium for temperatures in the range 0.4T(c) < T < 2.1T(c), using nonrelativistic dynamics for the bottom quark and full relativistic lattice QCD simulations for Nf = 2 light flavors on a highly anisotropic lattice. We find that the Υ is insensitive to the temperature in this range, while the χb propagators show a crossover from the exponential decay characterizing the hadronic phase to a power-law behavior consistent with nearly free dynamics at T ≃ 2T(c).

Cyst formation following radiosurgery for AVMs: report of 3 cases.

BACKGROUND: Stereotactically-focused radiosurgery (SRS) for the treatment of arteriovenous malformations (AVM) has been in widespread use for over two decades. Over this timeframe the indications for treatment, standardization of radiation dosage, and the results expected from treatment have been elaborated. Less well known are the long-term complications associated with SRS. We report three patients who had SRS for the treatment of AVM who developed a cyst at the site of treatment as a late complication. METHODS: From 201 patients treated by SRS for an AVM, three developed a cyst at the treatment site. Their clinical presentation, the characteristics of the AVMs and the treatment were reviewed, as well as similar cases gleaned from the literature. RESULTS: Three women, aged 28-43 years, had an AVM treated by: craniotomy and clipping of arterial feeders followed by SRS, by craniotomy for resection followed by SRS or by endovascular embolization and SRS. The patients did well following treatment but two of them developed a symptomatic and the other an asymptomatic cyst at the treatment site 3-19 years later. The symptomatic patients underwent marsupialization of the cyst and the other is under observation. CONCLUSION: Stereotactic radiosurgery is an established and safe treatment for patients with AVMs. Delayed cyst formation can occur many years after treatment and long term follow-up is indicated in patients whose AVM has been treated with SRS.

Neuroimaging in pediatric temporal lobe epilepsy: Does neuroimaging accurately predict pathology and surgical outcome?

Temporal lobe epilepsy (TLE) in children is considered different from that in adults. As such, characterizing the structural lesions present in pediatric patients with TLE and their association with long-term seizure control is important. Here, we aimed to assess the concordance between preoperative imaging and postoperative histopathological diagnoses and their associations with seizure outcomes in pediatric patients with TLE undergoing temporal lobe surgery. We retrospectively reviewed the charts of pediatric patients with TLE who underwent surgical treatment between 1988 and 2020 as a part of the Comprehensive Epilepsy Program at the University of Alberta. Demographic, age at seizure onset, age at surgery, preoperative electroencephalography (EEG), long-term video EEG, imaging (magnetic resonance imaging [MRI] and computed tomography), neuropathology, and long-term seizure outcome data were acquired and analyzed. One hundred and seventeen patients underwent surgery for refractory TLE; the preoperative MRI diagnosis was concordant with the histopathological diagnosis in 76 % of cases. Tumors were identified with high accuracy (91 %). Mesial temporal sclerosis (MTS) was strongly associated with an excellent outcome after surgery (94 %). Patients with normal imaging results or non-specific pathologies were more likely to experience poor seizure outcomes after surgery (50 %). The radiological identification of lesions was associated with good long-term seizure outcomes, whereas normal MRI results were associated with significantly poorer long-term seizure outcomes. An accurate preoperative MRI is essential to epilepsy surgery since it impacts all stages of management; these results will thereafter help inform practitioners' efforts to predict seizure outcome.

Partnering with survivors & families to determine research priorities for adult out-of-hospital cardiac arrest: A James Lind Alliance Priority Setting Partnership.

BACKGROUND: Research priority setting in health care has historically been done by expert health care providers and researchers and has not involved patients, family or the public. Survivors & family members have been particularly absent from this process in the field of resuscitation research and specifically adult out of hospital cardiac arrest (OHCA). As such, we sought to conduct a priority setting exercise in partnership with survivors, lay responders and their families in order to ensure that their priorities were visible. We partnered with the James Lind Alliance (UK) and used their commonly used consensus methodology for Public Priority Setting Partnerships (PSPs) to identify research priorities that reflected the perspectives of all stakeholders. METHODS: We used two rounds of public and health care professional surveys to create the initial priority lists. The initial survey collected open-ended questions while the second round consolidated the list of initial questions into a refined list for prioritization. This was done by reviewing existing evidence and thematic categorization by the multi-disciplinary steering committee. An in-person consensus workshop was conducted to come to consensus on the top ten priorities from all perspectives. The McMaster PPEET tool was used to measure engagement. RESULTS: The initial survey yielded more than 425 responses and 1450 "questions" from survivors and family members (18%), lay responders, health care providers and others. The second survey asked participants to rank a short list of 125 questions. The final top 25 questions were brought to the in-person meeting, and a top ten were selected through the JLA consensus process. The final list of top ten questions included how to improve the rate of lay responder CPR, what interventions used at the scene of an arrest can improve resuscitation and survival, how survival can be improved in rural areas of Canada, what resuscitation medications are most effective, what care patient's family members need, what post-discharge support is needed for survivors, how communication should work for everyone involved with a cardiac arrest, what factors best predict neurologically intact survival, whether biomarkers/genetic tests are effective in predicting OHCA and more research on the short and long-term psycho-social impacts of OHCA on survivors. The PPEET showed overwhelmingly positive results for the patient and family engagement experience during the final workshop. CONCLUSIONS: This inclusive research priority setting provides essential information for those doing resuscitation research internationally. The results provide a guide for priority areas of research and should drive our community to focus on questions that matter to survivors and their families in our work. In particular the Canadian Resuscitation Outcomes Consortium will be incorporating the top ten list into its strategic plan for the future.

Profiling health in the UK and Ireland.

The technique of describing health using a range of measures has been termed 'health profiling'. This article discusses the emergence of health profiling in the UK and Ireland over recent years, led by the public health observatories (PHOs). The steps in developing health profiles are described, including defining the purpose, consulting users, choosing indicators, establishing the methods of presentation, disseminating and evaluating. Health profiles have developed and improved through collaboration between the PHOs in the UK and Ireland. Looking to the future, the PHOs are developing inter-related health profiles ranging from small area to European regions, enhanced and informed by the addition of themed profiles for different population groups, lifestyles and diseases.

Accelerated aging and nucleolar fragmentation in yeast sgs1 mutants.

The SGS1 gene of yeast encodes a DNA helicase with homology to the human WRN gene. Mutations in WRN result in Werner's syndrome, a disease with symptoms resembling premature aging. Mutation of SGS1 is shown to cause premature aging in yeast mother cells on the basis of a shortened life-span and the aging-induced phenotypes of sterility and redistribution of the Sir3 silencing protein from telomeres to the nucleolus. Further, in old sgs1 cells the nucleolus is enlarged and fragmented-changes that also occur in old wild-type cells. These findings suggest a conserved mechanism of cellular aging that may be related to nucleolar structure.

Epilepsy surgery in the first 3 years of life: a Canadian survey.

OBJECTIVE: To determine the clinical characteristics, surgical challenges, and outcome in children younger than 3 years of age undergoing epilepsy surgery in Canada. METHODS: Retrospective data on patients younger than age 3 years who underwent epilepsy surgery at multiple centers across Canada from January 1987 to September 2005 were collected and analyzed. RESULTS: There were 116 patients from eight centers. Seizure onset was in the first year of life in 82%, and mean age at first surgery was 15.8 months (1-35 months). Second surgeries were done in 27 patients, and a third surgery in 6. Etiologies were malformations of cortical development (57), tumor (22), Sturge-Weber syndrome (19), infarct (8), and other (10). Surgeries comprised 40 hemispheric operations, 33 cortical resections, 35 lesionectomies, 7 temporal lobectomies, and one callosotomy. There was one surgical mortality. The most common surgical complications (151 operations in 116 patients) were infection (17) and aseptic meningitis in 13. Of 107 patients with seizure outcome assessed more than one year postoperatively, 72 (67.3%) were seizure free (Engel I), 15(14%) had >90% improvement (Engel II), 12 had >50% improvement (Engel III), and 8 did not benefit from surgery (Engel IV). Development improved in 55.3% after surgery. CONCLUSION: Epilepsy surgery in children younger than 3 years of age is relatively safe and is effective in controlling seizures. Very young age is not a contraindication to surgery in children with refractory epilepsy, and early surgery may impact development positively.

Selective amygdalohippocampectomy: surgical outcome in children versus adults.

INTRODUCTION: The objective of the study was to review our experience with selective amygdalohippocampectomy (SAH) in children and adults with intractable temporal lobe epilepsy. METHODS: A retrospective case series was used in the setting of a tertiary care hospital which provides epilepsy care to both children and adults. All patients underwent a selective amygdalohippocampectomy procedure and had at least one year of follow-up. Adults and children were divided into two groups and the data was compared between children and adults. RESULTS: Twenty three patients, 9 children and 14 adults were studied. Age of surgery varied from 6 to 58 years. Surgical outcome was variable between the two groups. Amongst the children, three patients (33%) were seizure-free (Engel Class I), two patients (22%) had rare seizures (Engel Class II), one patient (11%) had a worthwhile decrease in seizures (Engel class III) and three patients (32%) had refractory seizures that required re-operation with an anterior temporal lobectomy. This differed from the adults, who all had a good outcome. Ten patients (71%) were seizure-free (Engel Class I) and the remainder (29%) had rare seizures (Engel Class II). CONCLUSION: Selective amygdalohippocampectomy can lead to excellent seizure surgical outcome in adults with refractory temporal lobe epilepsy. However, preliminary results show less favorable results in children. The difference is probably related to the different pathology between the two groups. Anterior temporal lobe resection may prove to be a more successful operation than SAH in children with intractable temporal lobe epilepsy.