Prevalence of male DNA on female worn undergarments. How small datasets may support robust opinions in activity level evaluative reporting.

In cases of sexual assault, the interpretation of biological traces on clothing, and particularly undergarments, may be complex. This is especially so when the complainant and defendant interact socially, for instance as (ex-)partners or by co-habitation. Here we present the results from a study where latent male DNA on female worn undergarments is recovered in four groups with different levels of male-female social interaction. The results conform to prior expectation, in that less interaction tend to result in less male DNA on undergarments. We explore the use of these experimental data for evaluative reporting given activity level propositions in a mock case scenario. We show how the selection of different populations to represent the social interaction between complainant and defendant may affect the strength of the evidence. We further show how datasets of limited size can be used for robust activity level evaluative reporting.

The Ogden and the extended tube model as backbone in describing electroactive polymers: advancements in modelling nonlinear behaviour and fracture.

Hyperelastic constitutive relations form the basis of advanced models for novel materials. Such elastic deformation potentials are the backbone for complex material formulations at elastic and inelastic deformations, especially when embedded into powerful frameworks like generalized standard materials, as well as multiphysical and multiscale formulations. With the focus on electroactive polymers, the article at hand demonstrates the derivation of a variational, rate-dependent electromechanical model for quasi-incompressible polymers and the derivation of an electromechanical model for regularized fracture mechanics by means of the phase-field method. Starting at the prominent Ogden and the extended tube model, some developments from the last decades are revisited and presented via the principle of virtual power, for instance, the established mixed element formulation, nonlinear viscoelasticity and electromechanical coupling. An electromechanically fully coupled representative crack element is used to derive a novel phase-field model for fracture. A key property of the proposed model is the ability to describe the electrical free-space behaviour inside the crack gap, which is demonstrated by adopting three common crack-face conditions. This article is part of the theme issue 'The Ogden model of rubber mechanics: Fifty years of impact on nonlinear elasticity'.

Oxygenated Cyclopentenones via the Pauson-Khand Reaction of Silyl Enol Ether Substrates.

We report here the application of silyl enol ether moieties as efficient alkene coupling partners within cobalt-mediated intramolecular Pauson-Khand reactions. This cyclization strategy delivers synthetically valuable oxygenated cyclopentenone products in yields of ≤93% from both ketone- and aldehyde-derived silyl enol ethers, incorporates both terminal and internal alkyne partners, and delivers a variety of decorated systems, including more complex tricyclic structures. Facile removal of the silyl protecting group reveals oxygenated sites for potential further elaboration.

Capacity for consciousness under ketamine anaesthesia is selectively associated with activity in posteromedial cortex in rats.

It remains unclear how specific cortical regions contribute to the brain's overall capacity for consciousness. Clarifying this could help distinguish between theories of consciousness. Here, we investigate the association between markers of regionally specific (de)activation and the brain's overall capacity for consciousness. We recorded electroencephalographic responses to cortical electrical stimulation in six rats and computed Perturbational Complexity Index state-transition (PCIST), which has been extensively validated as an index of the capacity for consciousness in humans. We also estimated the balance between activation and inhibition of specific cortical areas with the ratio between high and low frequency power from spontaneous electroencephalographic activity at each electrode. We repeated these measurements during wakefulness, and during two levels of ketamine anaesthesia: with the minimal dose needed to induce behavioural unresponsiveness and twice this dose. We found that PCIST was only slightly reduced from wakefulness to light ketamine anaesthesia, but dropped significantly with deeper anaesthesia. The high-dose effect was selectively associated with reduced high frequency/low frequency ratio in the posteromedial cortex, which strongly correlated with PCIST. Conversely, behavioural unresponsiveness induced by light ketamine anaesthesia was associated with similar spectral changes in frontal, but not posterior cortical regions. Thus, activity in the posteromedial cortex correlates with the capacity for consciousness, as assessed by PCIST, during different depths of ketamine anaesthesia, in rats, independently of behaviour. These results are discussed in relation to different theories of consciousness.

General Anesthesia Disrupts Complex Cortical Dynamics in Response to Intracranial Electrical Stimulation in Rats.

The capacity of human brain to sustain complex cortical dynamics appears to be strongly associated with conscious experience and consistently drops when consciousness fades. For example, several recent studies in humans found a remarkable reduction of the spatiotemporal complexity of cortical responses to local stimulation during dreamless sleep, general anesthesia, and coma. However, this perturbational complexity has never been directly estimated in non-human animals in vivo previously, and the mechanisms that prevent neocortical neurons to engage in complex interactions are still unclear. Here, we quantify the complexity of electroencephalographic (EEG) responses to intracranial electrical stimulation in rats, comparing wakefulness to propofol, sevoflurane, and ketamine anesthesia. The evoked activity changed from highly complex in wakefulness to far simpler with propofol and sevoflurane. The reduced complexity was associated with a suppression of high frequencies that preceded a reduced phase-locking, and disruption of functional connectivity and pattern diversity. We then showed how these parameters dissociate with ketamine and depend on intensity and site of stimulation. Our results support the idea that brief periods of activity-dependent neuronal silence can interrupt complex interactions in neocortical circuits, and open the way for further mechanistic investigations of the neuronal basis for consciousness and loss of consciousness across species.

Demonstration of full tensor current density imaging using ultra-low field MRI.

Direct imaging of impressed dc currents inside the head can provide valuable conductivity information, possibly improving electro-magnetic neuroimaging. Ultra-low field magnetic resonance imaging (ULF MRI) at µT Larmor fields can be utilized for current density imaging (CDI). Here, a measurable impact of the magnetic field BJ, generated by the impressed current density J, on the MR signal is probed using specialized sequences. In contrast to high-field MRI, the full tensor of BJ can be derived without rotation of the subject in the scanner, due to a larger flexibility in the sequence design. We present an ULF MRI setup based on a superconducting quantum interference device (SQUID), which is operating at a noise level of 380 aT Hz-1/2 and capable of switching all imaging fields within a pulse sequence. Thereby, the system enables zero-field encoding, where the full tensor of BJ is probed in the absence of other magnetic fields. 3D CDI is demonstrated on phantoms with different geometries carrying currents of approximately 2 mA corresponding to current densities between 0.45 and 8 A/m2. By comparison to an in vivo acquired head image, we provide insights to necessary improvements in signal-to-noise ratio.

A distance to the Large Magellanic Cloud that is precise to one per cent.

In the era of precision cosmology, it is essential to determine the Hubble constant empirically with an accuracy of one per cent or better1. At present, the uncertainty on this constant is dominated by the uncertainty in the calibration of the Cepheid period-luminosity relationship2,3 (also known as the Leavitt law). The Large Magellanic Cloud has traditionally served as the best galaxy with which to calibrate Cepheid period-luminosity relations, and as a result has become the best anchor point for the cosmic distance scale4,5. Eclipsing binary systems composed of late-type stars offer the most precise and accurate way to measure the distance to the Large Magellanic Cloud. Currently the limit of the precision attainable with this technique is about two per cent, and is set by the precision of the existing calibrations of the surface brightness-colour relation5,6. Here we report a calibration of the surface brightness-colour relation with a precision of 0.8 per cent. We use this calibration to determine a geometrical distance to the Large Magellanic Cloud that is precise to 1 per cent based on 20 eclipsing binary systems. The final distance is 49.59 ± 0.09 (statistical) ± 0.54 (systematic) kiloparsecs.

Kidney Disease Among Registered Métis Citizens of Ontario: A Population-Based Cohort Study.

BACKGROUND: Indigenous peoples in Canada have higher rates of kidney disease than non-Indigenous Canadians. However, little is known about the risk of kidney disease specifically in the Métis population in Canada. OBJECTIVE: To compare the prevalence of chronic kidney disease and incidence of acute kidney injury and end-stage kidney disease among registered Métis citizens in Ontario and a matched sample from the general Ontario population. DESIGN: Population-based, retrospective cohort study using data from the Métis Nation of Ontario's Citizenship Registry and administrative databases. SETTING: Ontario, Canada; 2003-2013. PATIENTS: Ontario residents ≥18 years. MEASUREMENTS: Prevalence of chronic kidney disease and incidence of acute kidney injury and end-stage kidney disease. Secondary outcomes among patients hospitalized with acute kidney injury included non-recovery of kidney function and mortality within 1 year of discharge. METHODS: Database codes and laboratory values were used to determine study outcomes. Métis citizens were matched (1:4) to Ontario residents on age, sex, and area of residence. The analysis included 12 229 registered Métis citizens and 48 916 adults from the general population. RESULTS: We found the prevalence of chronic kidney disease was slightly higher among Métis citizens compared with the general population (3.1% vs 2.6%, P = 0.002). The incidence of acute kidney injury was 1.2 per 1000 person-years in both Métis citizens and the general population (P = 0.54). Of those hospitalized with acute kidney injury, outcomes were similar among Métis citizens and the general population except 1-year mortality, which was higher for Métis citizens (24.5% vs 15.3%, P = 0.03). The incidence of end-stage kidney disease did not differ between groups (<3.0 per 10 000 person-years, P = 0.73). LIMITATIONS: The Métis Nation of Ontario Citizenship Registry only captures about 20% of Métis people in Ontario. Administrative health care codes used to identify kidney disease are highly specific but have low sensitivity. CONCLUSIONS: Rates of kidney disease were similar or slightly higher for Métis citizens in Ontario compared with the matched general population.

CONTEXTE: Les autochtones du Canada présentent des taux plus élevés d'insuffisance rénale que les Canadiens non autochtones. Cependant, on en sait encore très peu au sujet des risques de maladies rénales spécifiques aux populations de Métis au Canada. OBJECTIF: L'étude visait à comparer la prévalence de l'insuffisance rénale chronique et l'incidence de l'insuffisance rénale aigüe ou terminale parmi les citoyens métis inscrits en Ontario avec un échantillon apparié de la population non autochtone de l'Ontario. MODÈLE D'ÉTUDE: Il s'agit d'une étude de cohorte rétrospective basée sur la population qui a utilisé les données du registre de citoyenneté de la nation métisse de l'Ontario et les bases de données administratives. CADRE DE L'ÉTUDE: L'étude a été menée en Ontario, au Canada, entre 2003 et 2013. PATIENTS: La cohorte était constituée d'adultes résidants de l'Ontario. MESURES: La prévalence de l'insuffisance rénale chronique et l'incidence de l'insuffisance rénale aigüe ou terminale ont été mesurées. Les critères d'évaluation secondaires observés chez les patients hospitalisés pour insuffisance rénale aigüe incluaient le non-recouvrement de la fonction rénale et la mortalité du patient dans l'année suivant la sortie de l'hôpital. MÉTHODOLOGIE: Les codes des bases de données et les valeurs de laboratoire ont été utilisés pour déterminer les résultats de l'étude. Les citoyens métis ont été appariés (1:4) à des résidents non autochtones de l'Ontario en tenant compte de l'âge, du sexe et de la région de résidence. L'analyse a porté sur un total de 12 229 citoyens métis inscrits et 48 916 adultes de la population générale. RÉSULTATS: Nous avons constaté que la prévalence de l'insuffisance rénale chronique était légèrement plus élevée chez les citoyens métis par rapport à la population générale (3.1% contre 2.6%, P = 0.002). L'incidence de l'insuffisance rénale aigüe a été de 1.2 pour 1000 années-personnes tant pour les citoyens métis que pour l'ensemble de la population (P = 0.54). Parmi les personnes hospitalisées pour insuffisance rénale aigüe, les résultats étaient similaires pour les citoyens métis et la population générale sauf en ce qui a trait à la mortalité du patient dans l'année suivant l'hospitalisation, qui s'est avérée plus élevée chez les citoyens métis (24.5% contre 15.3%, P = 0.03). Quant à l'incidence de l'insuffisance rénale terminale, aucune différence n'a été observée entre les deux groupes (<3.0 pour 10 000 années-personnes, P = 0.73). LIMITES DE L'ÉTUDE: Le registre des citoyens de la nation métisse de l'Ontario ne répertorie que 20% environ des Métis résidant en Ontario. Les codes administratifs du système de santé qui servent à repérer les cas d'insuffisance rénale sont très spécifiques, mais présentent une faible sensibilité. CONCLUSION: Les taux d'insuffisance rénale se sont avérés similaires ou légèrement plus élevés pour les citoyens métis par rapport à la population générale en Ontario.

Rare complications of a low lying median arcuate coeliac ligament.

Pancreaticoduodenal artery aneurysm is a rare complication of coeliac artery stenosis secondary to a low lying median arcuate coeliac ligament. This article reports the case of a 69-year old man who presented with left arm and leg weakness, clinically in keeping with right hemisphere stroke. Initial CT brain scan was within normal limits. The patient did not receive thrombolysis as he was outside the time window. 3 hours later the patient experienced sudden onset epigastric pain and acute shock. CT aorta abdominal was diagnostic of a ruptured inferior pancreaticoduodenal artery aneurysm. Repeat CT brain the following day showed subacute infarction within the right frontal lobe. Embolisation of the aneurysm was successfully performed. It is well documented that ischaemic stroke can cause acute hypertension. This acute hypertension probably contributed to the rupture of the pancreaticoduodenal artery aneurysm. The patient was well on discharge and remains well 2 months on.

Osteoporosis management and fractures in the Métis of Ontario, Canada.

UNLABELLED: Half of Métis citizens, compared to less than 10 % of the general population of Ontario, reside in northern regions, with little access to bone mineral density (BMD) testing. Métis citizens had lower sex-specific and age-standardized rates of BMD testing, yet similar rates of fracture (both sexes) and pharmacotherapy (women only). PURPOSE: To examine osteoporosis management and common osteoporosis-related fractures among Métis citizens compared to the general population of older adults residing in Ontario. METHODS: We linked healthcare (medical and pharmacy) utilization and administrative (demographic) databases with the Métis Nation of Ontario citizenship registry to estimate osteoporosis management (bone mineral density [BMD] testing, pharmacotherapy) and fractures (hip, humerus, radius/ulna) among adults aged ≥50 years, from April 1, 2006 to March 31, 2011. Pharmacotherapy data were limited to residents aged ≥65 years. Sex-specific and age-standardized rates were compared between the Métis and the general population. Multivariable logistic regression was used to compare rates of BMD testing after controlling for differences in age and region of residence between the Métis and the general population. RESULTS: We studied 4219 Métis citizens (55 % men), and 140 (3 %) experienced a fracture. Half of Métis citizens, compared to less than 10 % of the general population of Ontario, resided in northern regions. We identified significantly lower sex-specific and age-standardized rates of BMD testing among Métis compared to the general population, yet found little difference in fracture rates (both sexes) or pharmacotherapy (women only). Differences in BMD testing disappeared after adjusting for region of residence among women yet remained significant among men. CONCLUSIONS: Despite finding significantly lower rates of osteoporosis management among men, Métis men and women were found to have similar age-standardized fracture rates to the general population.

Cardiovascular disease rates, outcomes, and quality of care in Ontario Métis: a population-based cohort study.

BACKGROUND: The burden of cardiovascular disease in the Métis, Canada's fastest growing Aboriginal group, is not well studied. We determined rates of five cardiovascular diseases and associated outcomes in Ontario Métis, compared to the general Ontario population. METHODS: Métis persons were identified using the Métis Nation of Ontario Citizenship Registry. Métis citizens aged 20-105 were linked to Ontario health databases for the period of April 2006 to March 2011. Age- and sex-standardized prevalence and incidence of acute coronary syndromes (ACS), congestive heart failure (CHF), cerebrovascular disease (stroke), atrial fibrillation, and hypertension were compared between the Métis and the general population. Secondary outcome measures included one-year hospitalizations and mortality following the incident cardiovascular diagnosis, as well as quality-of-care measures. RESULTS: There were 12,550 eligible Métis persons and 10,144,002 in the general population. The adjusted prevalence of each disease was higher (p<0.05) among the Métis compared to the general population: ACS 5.3% vs. 3.0%; CHF 5.1% vs. 3.9%; stroke 1.4% vs. 1.1%; atrial fibrillation 2.1% vs. 1.4%; hypertension 34.9% vs. 29.8%. Incident ACS, stroke, and atrial fibrillation were also higher (p<0.05) among the Métis: ACS 2.4% vs. 1.5%; stroke 0.8% vs. 0.6%; atrial fibrillation 0.6% vs. 0.3%. One-year all-cause and cardiovascular-related mortality were not significantly different. Hospitalizations were higher for Métis persons with CHF (OR 1.93; 95% CI 1.34-2.78) and hypertension (OR 2.27; 95% CI 1.88-2.74). Métis with CHF made more emergency department (ED) visits in the year after diagnosis compared to non-Métis with CHF, while Métis aged ≥65 with ACS were more likely to be on beta-blockers following diagnosis. CONCLUSIONS: The burden of cardiovascular disease was markedly higher in the Métis compared to the general population: prevalence rates for five cardiovascular conditions were 25% to 77% higher. Métis persons with CHF had more frequent hospitalizations and ED visits following their diagnosis.

Kinetic and structural mechanisms of (5'S)-8,5'-cyclo-2'-deoxyguanosine-induced dna replication stalling.

The (5'S)-8,5'-cyclo-2'-deoxyguanosine (S-cdG) lesion is produced from reactions of DNA with hydroxyl radicals generated from ionizing radiation or endogenous oxidative metabolisms. An elevated level of S-cdG has been detected in Xeroderma pigmentosum, Cockayne syndrome, breast cancer patients, and aged mice. S-dG blocks DNA replication and transcription in vitro and in human cells and produces mutant replication and transcription products in vitro and in vivo. Major cellular protection against S-dG includes nucleotide excision repair and translesion DNA synthesis. We used kinetic and crystallographic approaches to elucidate the molecular mechanisms of S-cdG-induced DNA replication stalling using model B-family Sulfolobus solfataricus P2 DNA polymerase B1 (Dpo1) and Y-family S. solfataricus P2 DNA polymerase IV (Dpo4). Dpo1 and Dpo4 inefficiently bypassed S-cdG with dCTP preferably incorporated and dTTP (for Dpo4) or dATP (for Dpo1) misincorporated. Pre-steady-state kinetics and crystallographic data mechanistically explained the low-efficiency bypass. For Dpo1, S-cdG attenuated Kd,dNTP,app and kpol. For Dpo4, the S-cdG-adducted duplex caused a 6-fold decrease in Dpo4:DNA binding affinity and significantly reduced the concentration of the productive Dpo4:DNA:dCTP complex. Consistent with the inefficient bypass, crystal structures of Dpo4:DNA(S-cdG):dCTP (error-free) and Dpo4:DNA(S-cdG):dTTP (error-prone) complexes were catalytically incompetent. In the Dpo4:DNA(S-cdG):dTTP structure, S-cdG induced a loop structure and caused an unusual 5'-template base clustering at the active site, providing the first structural evidence of the previously suggested template loop structure that can be induced by a cyclopurine lesion. Together, our results provided mechanistic insights into S-cdG-induced DNA replication stalling.

Asthma and chronic obstructive pulmonary disease (COPD) prevalence and health services use in Ontario Métis: a population-based cohort study.

INTRODUCTION: Chronic respiratory diseases cause a significant health and economic burden around the world. In Canada, Aboriginal populations are at increased risk of asthma and chronic obstructive pulmonary disease (COPD). There is little known, however, about these diseases in the Canadian Métis population, who have mixed Aboriginal and European ancestry. A population-based study was conducted to quantify asthma and COPD prevalence and health services use in the Métis population of Ontario, Canada's largest province. METHODS: The Métis Nation of Ontario Citizenship Registry was linked to provincial health administrative databases to measure and compare burden of asthma and COPD between the Métis and non-Métis populations of Ontario between 2009 and 2012. Asthma and COPD prevalence, health services use (general physician and specialist visits, emergency department visits, hospitalizations), and mortality were measured. RESULTS: Prevalences of asthma and COPD were 30% and 70% higher, respectively, in the Métis compared to the general Ontario population (p<0.001). General physician and specialist visits were significantly lower in Métis with asthma, while general physician visits for COPD were significantly higher. Emergency department visits and hospitalizations were generally higher for Métis compared to non-Métis with either disease. All-cause mortality in Métis with COPD was 1.3 times higher compared to non-Métis with COPD (p = 0.01). CONCLUSION: There is a high burden of asthma and COPD in Ontario Métis, with significant prevalence and acute health services use related to these diseases. Lower rates of physician visits suggest barriers in access to primary care services.

An eclipsing-binary distance to the Large Magellanic Cloud accurate to two per cent.

In the era of precision cosmology, it is essential to determine the Hubble constant to an accuracy of three per cent or better. At present, its uncertainty is dominated by the uncertainty in the distance to the Large Magellanic Cloud (LMC), which, being our second-closest galaxy, serves as the best anchor point for the cosmic distance scale. Observations of eclipsing binaries offer a unique opportunity to measure stellar parameters and distances precisely and accurately. The eclipsing-binary method was previously applied to the LMC, but the accuracy of the distance results was lessened by the need to model the bright, early-type systems used in those studies. Here we report determinations of the distances to eight long-period, late-type eclipsing systems in the LMC, composed of cool, giant stars. For these systems, we can accurately measure both the linear and the angular sizes of their components and avoid the most important problems related to the hot, early-type systems. The LMC distance that we derive from these systems (49.97 ± 0.19 (statistical) ± 1.11 (systematic) kiloparsecs) is accurate to 2.2 per cent and provides a firm base for a 3-per-cent determination of the Hubble constant, with prospects for improvement to 2 per cent in the future.

RR-Lyrae-type pulsations from a 0.26-solar-mass star in a binary system.

RR Lyrae pulsating stars have been extensively used as tracers of old stellar populations for the purpose of determining the ages of galaxies, and as tools to measure distances to nearby galaxies. There was accordingly considerable interest when the RR Lyrae star OGLE-BLG-RRLYR-02792 (referred to here as RRLYR-02792) was found to be a member of an eclipsing binary system, because the mass of the pulsator (hitherto constrained only by models) could be unambiguously determined. Here we report that RRLYR-02792 has a mass of 0.26 solar masses M[symbol see text] and therefore cannot be a classical RR Lyrae star. Using models, we find that its properties are best explained by the evolution of a close binary system that started with M[symbol see text] and 0.8M[symbol see text]stars orbiting each other with an initial period of 2.9 days. Mass exchange over 5.4 billion years produced the observed system, which is now in a very short-lived phase where the physical properties of the pulsator happen to place it in the same instability strip of the Hertzsprung-Russell diagram as that occupied by RR Lyrae stars. We estimate that only 0.2 per cent of RR Lyrae stars may be contaminated by systems similar to this one, which implies that distances measured with RR Lyrae stars should not be significantly affected by these binary interlopers.

Two distinct pools of large-conductance calcium-activated potassium channels in the somatic plasma membrane of central principal neurons.

Although nerve cell membranes are often assumed to be uniform with respect to electrical properties, there is increasing evidence for compartmentalization into subdomains with heterogeneous impacts on the overall cell function. Such microdomains are characterized by specific sets of proteins determining their functional properties. Recently, clustering of large-conductance calcium-activated potassium (BK(Ca)) channels was shown at sites of subsurface membrane cisterns in cerebellar Purkinje cells (PC), where they likely participate in building a subcellular signaling unit, the 'PLasmERosome'. By applying SDS-digested freeze-fracture replica labeling (SDS-FRL) and postembedding immunogold electron microscopy, we have now studied the spatial organization of somatic BK(Ca) channels in neocortical layer 5 pyramidal neurons, principal neurons of the central and basolateral amygdaloid nuclei, hippocampal pyramidal neurons and dentate gyrus (DG) granule cells to establish whether there is a common organizational principle in the distribution of BK(Ca) channels in central principal neurons. In all cell types analyzed, somatic BK(Ca) channels were found to be non-homogenously distributed in the plasma membrane, forming two pools of channels with one pool consisting of clustered channels and the other of scattered channels in the extrasynaptic membrane. Quantitative analysis by means of SDS-FRL revealed that about two-thirds of BK(Ca) channels belong to the scattered pool and about one-third to the clustered pool in principal cell somata. Overall densities of channels in both pools differed in the different cell types analyzed, although being considerably lower compared to cerebellar PC. Postembedding immunogold labeling revealed association of clustered channels with subsurface membrane cisterns and confirmed extrasynaptic localization of scattered channels. This study indicates a common organizational principle for somatic BK(Ca) channels in central principal neurons with the formation of a clustered and a scattered pool of channels, and a cell-type specific density of this channel type.

Kv7/KCNQ/M-channels in rat glutamatergic hippocampal axons and their role in regulation of excitability and transmitter release.

M-current (I(M)) plays a key role in regulating neuronal excitability. Mutations in Kv7/KCNQ subunits, the molecular correlates of I(M), are associated with a familial human epilepsy syndrome. Kv7/KCNQ subunits are widely expressed, and I(M) has been recorded in somata of several types of neurons, but the subcellular distribution of M-channels remains elusive. By combining field-potential, whole-cell and intracellular recordings from area CA1 in rat hippocampal slices, and computational modelling, we provide evidence for functional M-channels in unmyelinated axons in the brain. Our data indicate that presynaptic M-channels can regulate axonal excitability and synaptic transmission, provided the axons are depolarized into the I(M) activation range (beyond approximately -65 mV). Here, such depolarization was achieved by increasing the extracellular K(+) concentration ([K(+)](o)). Extracellular recordings in the presence of moderately elevated [K(+)](o) (7-11 mm), showed that the specific M-channel blocker XE991 reduced the amplitude of the presynaptic fibre volley and the field EPSP in a [K(+)](o)-dependent manner, both in stratum radiatum and in stratum lacknosum moleculare. The M-channel opener, retigabine, had opposite effects. The higher the [K(+)](o), the greater the effects of XE991 and retigabine. Similar pharmacological modulation of EPSPs recorded intracellularly from CA1 pyramidal neurons, while blocking postsynaptic K(+) channels with intracellular Cs(+), confirmed that active M-channels are located presynaptically. Computational analysis with an axon model showed that presynaptic I(M) can control Na(+) channel inactivation and thereby affect the presynaptic action potential amplitude and Ca(2+) influx, provided the axonal membrane potential is sufficiently depolarized. Finally, we compared the effects of blocking I(M) on the spike after-depolarization and bursting in CA3 pyramidal neuron somata versus their axons. In standard [K(+)](o) (2.5 mm), XE991 increased the ADP and promoted burst firing at the soma, but not in the axons. However, I(M) contributed to the refractory period in the axons when spikes were broadened by a low dose 4-aminopyridine (200 microm). Our results indicate that functional Kv7/KCNQ/M-channels are present in unmyelinated axons in the brain, and that these channels may have contrasting effects on excitability depending on their subcellular localization.

Cerebellar ataxia and Purkinje cell dysfunction caused by Ca2+-activated K+ channel deficiency.

Malfunctions of potassium channels are increasingly implicated as causes of neurological disorders. However, the functional roles of the large-conductance voltage- and Ca(2+)-activated K(+) channel (BK channel), a unique calcium, and voltage-activated potassium channel type have remained elusive. Here we report that mice lacking BK channels (BK(-/-)) show cerebellar dysfunction in the form of abnormal conditioned eye-blink reflex, abnormal locomotion and pronounced deficiency in motor coordination, which are likely consequences of cerebellar learning deficiency. At the cellular level, the BK(-/-) mice showed a dramatic reduction in spontaneous activity of the BK(-/-) cerebellar Purkinje neurons, which generate the sole output of the cerebellar cortex and, in addition, enhanced short-term depression at the only output synapses of the cerebellar cortex, in the deep cerebellar nuclei. The impairing cellular effects caused by the lack of postsynaptic BK channels were found to be due to depolarization-induced inactivation of the action potential mechanism. These results identify previously unknown roles of potassium channels in mammalian cerebellar function and motor control. In addition, they provide a previously undescribed animal model of cerebellar ataxia.

Twenty-year trends in physical activity among Canadian adults.

OBJECTIVE: Physical inactivity is associated with increased risk of mortality and chronic diseases, yet trend information is lacking in most countries. This investigation examines physical activity levels of Canadian adults aged 18 years and older. METHODS: Data were collected in six national surveys between 1981 and 2000. Sample sizes ranged from 2,500 to 18,000. Prevalences were tested using Chi-square and Student's t-tests. Socio-demographic correlates were examined using odds ratios adjusted for age, sex, education and income. RESULTS: Physical activity increased in the 1980s and 1990s among men and women and for all age, education and income groups (p<0.01). Although education differentials narrowed over the period, age differentials widened and income differentials emerged. DISCUSSION: The positive trend in Canada is consistent with Finland, but contrary to recent trends for Australia, England and the United States. Despite increases, sedentary living remains a public health issue particularly among women, older adults and lower income groups.

Reliability and validity of Canada's Physical Activity Monitor for assessing trends.

PURPOSE: This investigation assessed the reliability and criterion validity of the Physical Activity Monitor, a telephone-interview adaptation of the Minnesota Leisure Time Physical Activity Questionnaire (MLTPAQ), which is currently used to assess trends in the Canadian population. METHODS: A sample of 512 people aged 18 yr and older was selected by random-digit dialing for telephone interviewing in the reliability study. The Monitor questions were administered twice, 3 wk apart. For the criterion validity study, a sample of 148 people aged 18-69 yr was selected at random from households. Participants completed the Monitor questions by telephone and an in-home step test to estimate maximum oxygen uptake. Another random sample of individuals aged 18-69 yr participated in a comparison study of the Monitor against the 1988 Campbell's Survey of Well-Being (CSWB) instrument. All studies were conducted in the vicinity of Toronto, Ontario. Spearman correlations controlling for age and sex were calculated as a measure of association for the reliability, validity, and comparison studies. Validity estimates were further adjusted for body mass index and physical activity demands of work and chores. RESULTS: The Monitor instrument produced reliable estimates of total energy expenditure (P=0.90, P<0.0001) with criterion validity of 0.36 (P<0.0001). The association between estimates of total energy expenditure derived from the Monitor and CSWB instruments was 0.77 (P<0.0001). CONCLUSION: The Physical Activity Monitor has acceptable test-retest reliability and criterion validity. The research also demonstrated that for the purpose of population monitoring a change in data collection mode-telephone interview versus self-administration in households-can yield reasonably comparable estimates from two adaptations of the MLTPAQ.