Prodromes in demyelinating disorders, amyotrophic lateral sclerosis, Parkinson disease, and Alzheimer's dementia.

A prodrome is an early set of symptoms, which indicates the onset of a disease; these symptoms are often non-specific. Prodromal phases are now recognized in multiple central nervous system diseases. The depth of understanding of the prodromal phase varies across diseases, being more nascent for multiple sclerosis for example, than for Parkinson disease or Alzheimer's disease. Key challenges when identifying the prodromal phase of a disease include the lack of specificity of prodromal symptoms, and consequent need for accessible and informative biomarkers. Further, heterogeneity of the prodromal phase may be influenced by age, sex, genetics and other poorly understood factors. Nonetheless, recognition that an individual is in the prodromal phase of disease offers the opportunity for earlier diagnosis and with it the opportunity for earlier intervention.

A comprehensive profile of the sociodemographic, psychosocial and health characteristics of Ontario home care clients with dementia.

INTRODUCTION: This study provides a comprehensive summary of the sociodemographic, psychosocial and health characteristics of a large population-based cohort of Ontario home care clients (aged 50 years and over) with dementia and examines the variation in these characteristics in those with co-existing neurological conditions. METHODS: Clients were assessed with the Resident Assessment Instrument-Home Care (RAI-HC) between January 2003 and December 2010. Descriptive analyses examined the distribution of these characteristics among clients with dementia relative to several comparison groups, as well as clients with other recorded neurological conditions. RESULTS: Approximately 22% of clients (n=104 802) had a diagnosis of dementia (average age 83 years, 64% female) and about one in four within this group had a co-existing neurological condition (most commonly stroke or Parkinson disease). About 43% of those with dementia did not live with their primary caregiver. Relative to several comparison groups, clients with dementia showed considerably higher levels of cognitive and functional impairment, aggression, anxiety, wandering, hallucinations/delusions, caregiver distress and a greater risk for institutionalization. Conversely, they showed a lower prevalence of several chronic conditions and lower levels of recent health service use. Depressive symptoms were relatively common in the dementia and other neurological groups. CONCLUSION: Clients with co-existing neurological conditions exhibited unique clinical profiles illustrating the need for tailored and flexible home care services and enhanced caregiver assistance programs.

TITRE: Profil complet des caractéristiques sociodémographiques, psychosociales et sanitaires des clients des soins à domicile atteints de démence en Ontario. INTRODUCTION: Cette étude fournit une synthèse des caractéristiques sociodémographiques, psychosociales et sanitaires d'une vaste cohorte représentative des clients des soins à domicile en Ontario (âgés de 50 ans ou plus) atteints de démence et elle examine les variations de ces caractéristiques chez les clients atteints de maladies neurologiques concomitantes. MÉTHODOLOGIE: Les clients ont été évalués à l'aide de l'Instrument d'évaluation des résidents ­ Soins à domicile (RAI-HC) entre janvier 2003 et décembre 2010. Les analyses descriptives fournissent la répartition de ces caractéristiques en comparant les clients atteints de démence et ceux de plusieurs autres groupes ainsi que ceux atteints d'autres maladies neurologiques documentées. RÉSULTATS: Environ 22 % des clients (n = 104 802) avaient reçu un diagnostic de démence (âge moyen de 83 ans, 64 % de femmes) et un sur quatre parmi eux était atteint d'une maladie neurologique concomitante (AVC ou maladie de Parkinson la plupart du temps). Environ 43 % des clients atteints de démence n'habitaient pas avec leur principal aidant. Par rapport aux clients des groupes de comparaison, les clients atteints de démence présentaient des taux considérablement plus élevés de déficit cognitif et fonctionnel, d'agressivité, d'anxiété, d'errance et d'hallucinations ou de délire, avaient plus souvent un aidant en détresse et couraient un plus grand risque de placement en établissement. Par contre, ils étaient moins souvent atteints de diverses maladies chroniques et étaient moins nombreux à avoir eu recours à des services de santé récemment. Les symptômes de dépression étaient relativement fréquents chez les clients atteints de démence et chez ceux atteints d'une autre maladie neurologique. CONCLUSION: Les clients atteints de maladies neurologiques concomitantes présentaient des profils cliniques bien particuliers illustrant la nécessité de personnaliser et d'assouplir les services de soins à domicile et d'améliorer les programmes de soutien pour les aidants.

Osteoporosis management among residents living in long-term care.

UNLABELLED: Fractures in long-term care (LTC) residents have substantial economic and human costs. Osteoporosis management in residents with fractures or osteoporosis is low, and certain subgroups are less likely to receive therapy, e.g., those with >5 comorbidities, dementia, and wheelchair use. Many LTC residents who are at risk of fracture are not receiving optimal osteoporosis management. INTRODUCTION: The objective of this study was to describe the prevalence and predictors of osteoporosis management among LTC residents with osteoporosis or fractures. METHODS: In a retrospective study, LTC residents of 17 facilities in Ontario and Manitoba, Canada were investigated. The participants were 65+ years old with osteoporosis, history of hip fracture, or recent fracture. Comprehensive assessments were conducted by trained nurse assessors between June 2005 and June 2006 using a standardized instrument, known as the Resident Assessment Instrument 2.0. RESULTS: Among residents (n = 525) with osteoporosis or fractures, 177 (34%) had had a recent fall. Bisphosphonate use was reported in 199 (38%) residents, calcitonin use in six (1%), and raloxifene use in six (1%). Calcium and vitamin D supplementation were reported in 140 (27%) residents. Fifty-four (10.3%) residents were on a bisphosphonate but were not taking vitamin D or multivitamin. Variables negatively associated with osteoporosis therapy [OR (95% CI)]: six or more comorbidities [0.46 (0.28-0.77), p = 0.028], wheelchair use [0.62 (0.40-0.95), p = 0.003], cognitive impairment [0.71 (0.55-0.92), p = 0.009], depression [0.54 (0.34-0.87), p = 0.01], swallowing difficulties [0.99 (0.988-0.999), p = 0.034] or Manitoba residence [0.47 (0.28-0.78), p = 0.004]. Prescription of 10+ medications was positively associated with therapy [3.34 (2.32-4.84), p < 0.001]. CONCLUSION: Osteoporosis management is not optimal among residents at risk of future fracture. Identifying at-risk subgroups of residents that are not receiving therapy may facilitate closing the osteoporosis care gap.

Regional variation in the use of medications by older Canadians--a persistent and incompletely understood phenomena.

BACKGROUND: We have previously reported on regional variability in medication consumption by older Canadians. In this study, we used longitudinal data to determine whether regional differences in commonly consumed medications persisted and to explore potential explanatory factors for observed differences. METHODS: We utilized data from the second phase of the Canadian Study of Health and Aging to assess the number, types, and variability of medications used between regions. Linear and logistic regressions (LRs) were used to predict the number of medications and the use of specific agents where significant regional variability was found to exist. RESULTS: There were significant regional differences in the number of medications consumed and in the prevalence of use of acetaminophen (p < 0.002), benzodiazepines (p < 0.020), nitrates (p = 0.040), and complementary and alternative medicines (CAMs; p < 0.020). The proportion of subjects using acetaminophen was highest in British Columbia (44.6%) and lowest in Quebec (27.3%). Benzodiazepine and nitrate consumption was highest in Quebec (35.9 and 19%, respectively) and lowest in the Praires (18.2%) and Atlantic Canada (6.6%). CAM use was highest in British Columbia (47.1%) and lowest in the Atlantic region (26.8%). Similar inter-regional differences had been found 5 years previously. There were no significant regional differences in the prevalence of hypertension, myocardial infarction, diabetes, arthritis/rheumatism, or depression. Region remained a significant explanatory variable for the number of medications and nitrate, benzodiazepine, and CAM use in our multivariate models. CONCLUSIONS: Regional differences in medication use persisted over the course of this longitudinal study. Much of the variability remains unexplained. The reasons for regional differences in consumption of drugs and their clinical significance should be addressed.

The influence of promoter and of electrode material on the cyclic voltammetry of Pisum sativum plastocyanin.

The reversible cyclic voltammetry of pea plastocyanin (Pisum sativum) was studied with a wide range of electrodes: edge-oriented pyrolytic graphite (PGE), glassy carbon (GCE), gold (Au) and platinum (Pt) electrodes. Plastocyanin was coated onto the electrode surface by exploiting the electrostatic interaction between the negatively charged protein and a wide range of positively charged promoters. The effect of the redox response with an extended range of promoters, including poly-L-lysine, polymyxin B, neomycin, tobramycin, geneticin, spermine and spermidine, were included in this study. The resulting cyclic voltammograms reveal that the observed midpoint potential for plastocyanin can be shifted significantly depending on the choice of promoter. The stability of the negatively charged plastocyanin-promoter layer on an electrode was gauged by the rate of bulk diffusion of the protein from the immobilised film into the solution. Reversible cyclic voltammograms were obtained using edge-oriented pyrolytic graphite (PGE) and glassy carbon electrodes (GCE) with all promoters; however, platinum and gold electrodes were unable to sustain a defined redox response. The combination of pyrolytic graphite electrode/poly-L-lysine/plastocyanin was found to be the most stable combination, with a redox response which remained well defined in solution for more than 1 h at pH 7.0. The midpoint potentials obtained in this manner differed between the two graphite electrodes PGE and GCE using poly-L-lysine as the promoter. This effect was in addition to the expected pH dependence of the midpoint potential for plastocyanin and the results indicated that the pK(a) for plastocyanin on PGE was 4.94 compared to that on GCE of 4.66. It is concluded that both the electrode material and the nature of the promoter can influence the position of the redox potentials for proteins measured in vitro. This study extends the range of biogenic promoters used in combination with electrode materials. Thus, we can begin to develop a more comprehensive understanding of electrode-protein interactions and draw conclusions as to metalloprotein function, in vivo. To support these studies, we have sought information as to the nature of the electrode/promoter/protein interaction using scanning tunneling microscopy (STM) to study both the promoter and the plastocyanin protein on a gold surface.

A randomized controlled trial of a community-based consultation service to prevent falls.

BACKGROUND: Multifaceted programs that combine assessment with interventions have been shown to reduce subsequent falls in some clinical trials. We tested this approach to see whether it would be effective if offered as a consultation service using existing health care resources. METHODS: The subjects of this randomized controlled trial had to be aged 65 years or more and had to have fallen within the previous 3 months. They were randomly assigned to receive either usual care or the intervention, which consisted of in-home assessment in conjunction with the development of an individualized treatment plan, including an exercise program for those deemed likely to benefit. The primary outcomes were the proportion of participants who fell and the rate of falling during the following year. Visits to the emergency department and admissions to hospital were secondary outcomes. RESULTS: One hundred and sixty-three subjects were randomly assigned to either the control or the intervention group, and 152 provided data about their falls. There were no significant differences between the control and intervention groups in the cumulative number of falls (311 v. 241, p = 0.34), having one or more falls (79.2% v. 72.0%, p = 0.30) or in the mean number of falls (4.0 v. 3.2, p = 0.43). Analysis of secondary outcomes (health care use) also showed no significant differences between the intervention group and the control group. In the Cox regression analysis, there was no significant difference between the groups in the proportion of subjects having one or more falls (p = 0.55), but there was a significantly (p < 0.001) longer time between falls in the intervention group. In a post hoc subgroup analysis, subjects with more than 2 falls in the 3 months preceding study entry who had been assigned to the intervention group were less likely to fall (p = 0.046) and had a significantly longer time between falls (p < 0.001), when compared with the group who received usual care. INTERPRETATION: The intervention did not decrease significantly the cumulative number of falls, the likelihood of participants having at least one fall over the next year or the mean number of falls. It did increase significantly the time between falls in a survival analysis when age, sex and history of falling were used as covariates.

Factors important in promoting cervical cancer screening among Canadian women: findings from the 1996-97 National Population Health Survey (NPHS).

Although routine Pap screening represents an effective tool in the early detection of cervical cancer, it remains underused by some Canadian women. This study examines selected sociodemographic, health, lifestyle, and system barriers to Pap test participation among 33,817 women aged 18+ years in the cross-sectional 1996-97 National Population Health Survey (NPHS). Among women 18 years and over, 87% reported ever having had a Pap test while 72% reported a recent (< 3 years) test. A report of ever and recent use was most common among women 25-34 (92% and 86.9%, respectively). Only 0.6% of recently screened women reported access problems. Among those without a recent test, most (53%) reported that they did not think it was necessary. Pap test use varied little across provinces and was less common among older and single women, those with lower education, a spoken language other than English, a birth place outside Canada and negative health and lifestyle characteristics.

Predictors of mammography use among Canadian women aged 50-69: findings from the 1996/97 National Population Health Survey.

BACKGROUND: Screening mammography, although recommended every 2 years for women aged 50-69, is thought to be underused among select groups of Canadian women. METHODS: We used data from the 1996/97 National Population Health Survey to describe current patterns in mammography use (including reasons for not having a mammogram within the 2 years before the survey and future screening intentions) in Canada and to determine factors associated with nonparticipation and time-inappropriate use (mammogram 2 or more years before the survey) among women aged 50-69. RESULTS: Among respondents aged 50-69, 79.1% (95% confidence interval [CI] 76.9%-81.2%) reported ever having had a mammogram, and 53.6% (95% CI 51.4%-55.9%) had had a recent (time-appropriate) mammogram (within the 2 years before the survey). Only 0.6% (95% CI 0.3%-0.9%) of recently screened women reported problems of access, and few reported personal or health system barriers as reasons for not obtaining a recent mammogram. Over 50% of the women who had not had a recent mammogram reported that they did not think it was necessary, and only 28.2% (95% CI 23.8%-32.7%) of those who had never had a mammogram planned to have one within the 2 years following the survey. The rate of time-appropriate mammography varied significantly by province, from 41.1% (95% CI 29.3%-52.9%) in Newfoundland to 69.4% (95% CI 61.3%-77.6%) in British Columbia. Significant predictors of never having had a mammogram included higher age, residence in a rural area, Asia as place of birth, no involvement in volunteer groups, no regular physician or recent medical consultations (including recent blood pressure check), current smoking, infrequent physical activity and no hormone replacement therapy. INTERPRETATION: Despite increases in mammography screening rates since the 1994/95 National Population Health Survey, current estimates indicate that almost 50% of women aged 50-69 have not had a time-appropriate mammogram. Our findings confirm continued low mammography participation rates among older women and those in rural areas, select ethnic groups and women with negative health care and lifestyle characteristics.

The prevalence and correlates of influenza vaccination among a home care population.

OBJECTIVE: To estimate the prevalence and correlates of influenza vaccination in a Home Care population. METHODS: This was a cross-sectional investigation involving linkage of three population-based databases from a rural Alberta Regional Health Authority, i.e., the Regional immunization and the Regional home oxygen information systems to the Regional home care information system. The sample comprised 649 persons who had been admitted or discharged from the Regional Home Care Program in the period Oct. 1-Dec. 31, 1998. An anonymous data file was released to the investigators. We estimated the proportion ever vaccinated against influenza, the proportion vaccinated in the period Oct. 1-Dec. 31, 1998 ("currently vaccinated"); and explored sociodemographic and program correlates of current vaccination. RESULTS: 67% had ever been vaccinated against influenza; 60.7% were currently vaccinated. Factors associated with current vaccination (multivariate analysis) include older age, being married, not receiving nursing services, district of residence and program status. CONCLUSIONS: Influenza vaccination rates were suboptimal. The correlates of vaccination suggest systems-level impediments to influenza vaccination.

Alcohol as a risk factor for HIV transmission among American Indian and Alaska Native drug users.

Quantitative alcohol interviews conducted as part of the National Institute on Drug Abuse (NIDA) Native American Supplement revealed very high rates of alcohol use among American Indian and Alaska Native active crack and injection drug users (IDUs). Of 147 respondents who completed the alcohol questionnaire, 100& percent had drunk alcohol within the past month, almost 42& percent reported that they drank every day, and 50& percent drank until they were drunk one-half of the time or more. Injection drug users (IDUs) demonstrated the highest frequency and quantity of alcohol use in the past 30 days. A significant positive association was also found between crack and alcohol use in the past 48 hours (c(2)=5.30, p<.05). Finally, those claiming more episodes of using alcohol before or during sex, reported significantly more events of unprotected sexual intercourse. Qualitative data from all four sites corroborated these quantitative findings. Many individuals also reported episodes of blacking out while drinking, and learned later that they had had unprotected sex with complete strangers or individuals they would not otherwise accept as partners. Implications of these findings for HIV/AIDS prevention efforts are addressed.

Nifedipine and mortality risk in the elderly: relevance of drug formulation, dose and duration.

PURPOSE: This study examines the risk of all-cause and cardiac-related mortality associated with calcium channel blockers (CCBs) and other antihypertensives/diuretics compared with beta-blockers among an elderly cohort. We explored variations in mortality risk according to CCB formulation, dose and duration of use. METHODS: Data are from the clinical sample of the Canadian Study of Health and Aging, a population-based prospective study of community and institutional residing persons aged 65+ years. The sample comprised 837 subjects without dementia and reporting use of 1+ antihypertensive/diuretic agents at baseline (1991) and with survival data during follow-up (1996). RESULTS: Risk of all-cause and cardiac-related mortality was significantly higher among nifedipine users (HR=1.85, 95%CI 1.12, 3.05 and HR=2.22, 95%CI 1.02, 4.84, respectively) compared with beta-blocker users. After adjusting for covariates, the hazard ratios (95% confidence interval) for selected drug classes compared with beta-blockers were: nifedipine HR=1.82 (1.09-3.04), diltiazem/verapamil HR=0.96 (0.58-1.60), loop diuretics HR=1.84 (1.21-2.82), ACE inhibitors HR=0.98 (0.54-1.78) and other diuretics/antihypertensives HR=1.10 (0.70-1.72). Among nifedipine users, mortality risk increased with average daily dose and with recent (

Calcium-channel blockers and cognitive function in elderly people: results from the Canadian Study of Health and Aging.

BACKGROUND: Concern has been raised about the potential for adverse cognitive effects associated with the use of calcium-channel blockers (CCBs) in older people. This study was undertaken to examine prospectively the association between the use of these and other antihypertensive drugs and cognitive function. METHODS: The authors examined data from the Canadian Study of Health and Aging (CSHA), a population-based, prospective 5-year investigation of the epidemiology of dementia and other health problems in Canadians 65 years of age and older. The risk of cognitive decline, as indicated by a decline in performance on the Modified Mini-Mental State (3MS) examination over the 5-year period, was assessed in relation to the use of antihypertensive and diuretic drugs by 205 subjects with a history of hypertension and no evidence of dementia at baseline. RESULTS: The proportion of subjects whose cognitive performance declined over the study period was significantly higher in the group using CCBs than in the group using other antihypertensive agents (75% v. 59%). The adjusted odds ratio (OR) for a significant decline in cognitive performance (defined as a decrease in 3MS score of 10 points or more) was 2.28 (95% confidence interval [CI] 1.12-4.66) for subjects using CCBs. The adjusted ORs (and 95% CIs) for cognitive decline in subjects using selected antihypertensive agents or diuretics relative to those exposed to beta-blockers were as follows: angiotensin-converting-enzyme inhibitor, OR 1.36 (95% CI 0.41-4.55); diuretic or other antihypertensive drug, OR 1.45 (95% CI 0.51-4.14); dihydropyridine CCB (nifedipine), OR 1.94 (95% CI 0.52-7.27) and non-dihydropyridine CCB (diltiazem or verapamil), OR 3.72 (95% CI 1.22-11.36). INTERPRETATION: Older people taking CCBs were significantly more likely than those using other agents to experience cognitive decline. These findings are consistent with the results of previous cross-sectional research and emphasize the need for further trials to examine the associations between CCB use, blood pressure and cognitive impairment in elderly patients.

Nitroaromatic munition compounds: environmental effects and screening values.

Available data on the occurrence, transport, transformation, and toxicity of eight nitroaromatic munition compounds and their degradation products, TNT, TNB, DNB, DNA, 2-ADNT, RDX, HMX, and tetryl were used to identify potential fate in the environment and to calculate screening benchmarks or safe environmental levels for aquatic and terrestrial organisms. Results of monitoring studies revealed that some of these compounds persist at sites where they were produced or processed. Most of the compounds are present in soil, sediment, and surface water or groundwater at military sites. Soil adsorption coefficients indicate that these chemicals are only moderately adsorbed to soil and may leach to groundwater. Most of these compounds are transformed by abiotic or biotic mechanisms in environmental media. Primary transformation mechanisms involve photolysis (TNT, RDX, HMX, tetryl), hydrolysis (tetryl), and microbial degradation (TNT, TNB, DNB, DNA, 2-ADNT, and HMX). Microbial degradation for both nitro and nitramine aromatic compounds involves rapid reduction of nitro groups to amino groups, but further metabolism is slow. With the exception of DNB, complete mineralization did not usually occur under the conditions of the studies. RDX was resistant to microbial degradation. Available ecotoxicological data on acute and chronic studies with freshwater fish and invertebrates were summarized, and water quality criteria or ecotoxicological screening benchmarks were developed. Depending on the available data, criteria/benchmarks were calculated according to USEPA Tier I or Tier II guidelines. The munitions chemicals are moderately to highly toxic to freshwater organisms, with chronic screening values < 1 mg/L. For some chemicals, these low values are caused by inherent toxicity; in other cases, they result from the conservative methods used in the absence of data. For nonionic organic munitions chemicals, sediment quality benchmarks were calculated (based on Kow values and the final chronic value) according to USEPA guidelines. Available data indicate that none of the compounds is expected to bioconcentrate. In the same manner in which reference doses for humans are based on studies with laboratory animals, reference doses or screening benchmarks for wildlife may also be calculated by extrapolation among mammalian species. Chronic NOAELs for the compounds of interest were determined from available laboratory studies. Endpoints selected for wildlife species were those that diminish population growth or survival. Equivalent NOAELs for wildlife were calculated by scaling the test data on the basis of differences in body weight. Data on food and water intake for seven selected wildlife species--short-tailed shrew, white-footed mouse, meadow vole, cottontail rabbit, mink, red fox, and whitetail deer--were used to calculate NOAELs for oral intake. In the case of TNB, a comparison of toxicity data from studies conducted with both the white-footed mouse and the laboratory rat indicates that the white-footed mouse may be more resistant to the toxic effects of chemicals than the laboratory rat and may further indicate the lesser sensitivity of wildlife species to chemical insult. Chronic NOAEL values for the test species based on the laboratory studies indicate that, by the oral route of exposure, TNB and RDX are not highly toxic to mammalian species. However, as seen with TNB, values are less conservative when chronic studies are available or when studies were conducted with wildlife species. Insufficient data were located to calculate NOAELs for avian species. In the absence of criteria or guidelines for terrestrial plants, invertebrates, and soil heterotrophic processes, LOECs were used as screening benchmarks for effect levels in the environment. In most cases, too few data were available to derive a screening benchmark or to have a high degree of confidence in the benchmarks that were derived. (ABSTRACT TRUNCATED)

Differences between males and females in risk of NSAID-related severe gastrointestinal events.

PURPOSE: NSAID use has long been established as a risk factor for severe gastrointestinal (GI) events. It is also known that age and gender affect the risk of such events independently of nonsteroidal antiinflammatory drug (NSAID) use. The objective of the present study is to distinguish between gender as an independent risk factor for severe GI events, and the differences between males and females in risk of NSAID-related severe GI events. METHODS: The study design was a nested case-control study. During the study period, 1029 cases were hospitalized with GI bleeds and/or perforations and 14 481 controls without such GI events were selected. Exposure consisted of the number of NSAID prescriptions dispensed by a pharmacy, prior to the data of hospitalization for cases and a corresponding date for controls. RESULTS: Males have a risk of serious GI events 1.4 times greater than females, independent of NSAID use. However, females have the greater increase in risk of NSAID-related GI events, e.g. at four prescriptions women have an odds ratio (OR) of 7.4 (p<0.05), while men have a corresponding OR of 3.2 (p<0.05). The increasing risk of severe GI events with number of NSAID prescriptions was considerably greater for females than for males, indicating effect-modification. In a stratified analysis by age and gender, it was clear that gender was the greater influence. Various metabolic and epidemiological potential explanations are discussed. CONCLUSIONS: Age and gender are separate risk factors for GI complications as related to NSAID use. Although implied in other studies, the effect of gender on the risk of NSAID-related GI events is clearly stated in this study.

Role of the S4 in cooperativity of voltage-dependent potassium channel activation.

Charged residues in the S4 transmembrane segment of voltage-gated cation channels play a key role in opening channels in response to changes in voltage across the cell membrane. However, the molecular mechanism of channel activation is not well understood. To learn more about the role of the S4 in channel gating, we constructed chimeras in which S4 segments from several divergent potassium channels, Shab, Shal, Shaw, and Kv3.2, were inserted into a Shaker potassium channel background. These S4 donor channels have distinctly different voltage-dependent gating properties and S4 amino acid sequences. None of the S4 chimeras have the gating behavior of their respective S4 donor channels. The conductance-voltage relations of all S4 chimeras are shifted to more positive voltages and the slopes are decreased. There is no consistent correlation between the nominal charge content of the S4 and the slope of the conductance-voltage relation, suggesting that the mutations introduced by the S4 chimeras may alter cooperative interactions in the gating process. We compared the gating behavior of the Shaw S4 chimera with its parent channels, Shaker and Shaw, in detail. The Shaw S4 substitution alters activation gating profoundly without introducing obvious changes in other channel functions. Analysis of the voltage-dependent gating kinetics suggests that the dominant effect of the Shaw S4 substitution is to alter a single cooperative transition late in the activation pathway, making it rate limiting. This interpretation is supported further by studies of channels assembled from tandem heterodimer constructs with both Shaker and Shaw S4 subunits. Activation gating in the heterodimer channels can be predicted from the properties of the homotetrameric channels only if it is assumed that the mutations alter a cooperative transition in the activation pathway rather than independent transitions.

Uncharged S4 residues and cooperativity in voltage-dependent potassium channel activation.

Substitution of the S4 of Shaw into Shaker alters cooperativity in channel activation by slowing a cooperative transition late in the activation pathway. To determine the amino acids responsible for the functional changes in Shaw S4, we created several mutants by substituting amino acids from Shaw S4 into Shaker. The S4 amino acid sequences of Shaker and Shaw S4 differ at 11 positions. Simultaneous substitution of just three noncharged residues from Shaw S4 into Shaker (V369I, I372L, S376T; ILT) reproduces the kinetic and voltage-dependent properties of Shaw S4 channel activation. These substitutions cause very small changes in the structural and chemical properties of the amino acid side chains. In contrast, substituting the positively charged basic residues in the S4 of Shaker with neutral or negative residues from the S4 of Shaw S4 does not reproduce the shallow voltage dependence or other properties of Shaw S4 opening. Macroscopic ionic currents for ILT could be fit by modifying a single set of transitions in a model for Shaker channel gating (Zagotta, W.N., T. Hoshi, and R.W. Aldrich. 1994. J. Gen. Physiol. 103:321-362). Changing the rate and voltage dependence of a final cooperative step in activation successfully reproduces the kinetic, steady state, and voltage-dependent properties of ILT ionic currents. Consistent with the model, ILT gating currents activate at negative voltages where the channel does not open and, at more positive voltages, they precede the ionic currents, confirming the existence of voltage-dependent transitions between closed states in the activation pathway. Of the three substitutions in ILT, the I372L substitution is primarily responsible for the changes in cooperativity and voltage dependence. These results suggest that noncharged residues in the S4 play a crucial role in Shaker potassium channel gating and that small steric changes in these residues can lead to large changes in cooperativity within the channel protein.

Factors important in promoting mammography screening among Canadian women.

Among women aged 50 to 69 years, regular screening by mammography in combination with clinical examination, can substantially decrease the morbidity and mortality associated with breast cancer by facilitating early detection. Unfortunately, many Canadian women are not screened in accordance with current guidelines. Research to date is based primarily on large surveys conducted in the United States and less is known about the relevance of specific barriers to mammography screening among Canadian women. Multivariate results from the 1994-95 National Population Health Survey (NPHS) indicate that younger (40-49) and older (70+) women, those who are socioeconomically disadvantaged, and minority women are least likely to report having had a mammogram. Conversely, women with positive health behaviours, high social support, and positive mental health attributes are more likely to participate in mammography screening. These findings are discussed in terms of the implications for developing successful intervention programs for Canadian women and for setting priorities for further research.

Calculation of soil-water and benthic sediment partition coefficients for mercury.

To accurately model mercury transport to water bodies, an assessment of this pollutant's behavior in the watershed is critical. Partition coefficients, defined as an estimate of the ratio of the pollutant concentration sorbed onto soil/sediment particles to the pollutant concentration dissolved in pore water at equilibrium, is an important term in multimedia models. In this paper, partition coefficients are calculated for two broad species of mercury: inorganic mercuric mercury (Hg-II) and methylmercury (MHg). Although there is considerable variability in the calculated values, the approximate mean values for the soil-water partition coefficients range from 3.3 x 10(3) to 6.0 x 10(4) L/kg for Hg-II and 2.0 x 10(1) to 6.7 x 10(3) L/kg for MHg. For the benthic sediment partition coefficients, the values range from 5.7 x 10(3) to 9.9 x 10(5) L/kg for Hg-II, and 6.5 x 10(2) to 1.1 x 10(5) L/kg for MHg.

A prospective study of falls after benzodiazepine use: a comparison of new and repeat use.

Although research has consistently demonstrated an increased risk for falls and fall-related fractures among persons receiving benzodiazepine (BZD) medications, the association between new as compared with chronic use and fall-related morbidity among different age groups is less clear. The objectives of this prospective cohort study were to examine the associations between BZD sedative and tranquillizer use and fall-related hospitalizations within 28 days of the fill date, and to explore variations in risks among new (after the first prescription) and chronic (after the third prescription) BZD users of different ages. Data were derived from the Saskatchewan Health linked databases for the years 1979-1986. Fall rates increased with age (especially beyond 70 years) and were highest among those receiving BZD sedatives and tranquillizers compared with controls for both new and chronic users. After adjusting for age, sex and selected health and social factors, a significantly increased risk of fall-related hospitalization was found among new BZD sedative (OR=2.8) and tranquillizer (OR=2.0) users compared with controls, and this risk was only slightly reduced among chronic BZD sedative (OR=2.4) and tranquillizer (OR=1.6) users. These risk estimates were consistent across age, with the exception that chronic BZD tranquillizer use remained significant only among those aged 70 years and older.