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Background: Polypharmacy, the use of multiple medications, has become increasingly widespread. Information on time trends in polypharmacy in people with dementia is limited, although they may be more susceptible to risks associated with polypharmacy., Objective: To examine changes in the prevalence of polypharmacy and excessive polypharmacy in people with dementia compared to changes in people without dementia., Methods: Repeated cross-sectional study of the entire Danish population aged≥65 from 2000 (n = 790,717) to 2014 (n = 1,028,377) using linked register data on diagnoses, filled prescriptions, and demographic data. Multivariate analyses were performed to explore changes in the prevalence of polypharmacy and excessive polypharmacy (≥5 and≥10 different prescription drugs). This was done before and after 2011 to examine whether increasing awareness of potential problems associated with polypharmacy has altered the trend. Estimates for people with and without dementia were compared., Results: In people with dementia, the prevalence of polypharmacy increased from 47.3% to 69.4% from 2000 to 2011 and excessive polypharmacy from 7.4% to 20.9%. In people without dementia, polypharmacy increased from 22.7% to 36.1% and excessive polypharmacy from 3.5% to 7.7%. The increase was significantly more marked in people with dementia across all age groups. From 2011 to 2014, the prevalence of polypharmacy and excessive polypharmacy remained relatively stable: Polypharmacy decreased negligibly from 69.4% to 68.1% in people with dementia and from 36.1% to 35.2% in people without dementia., Conclusion: Although the increasing trend has halted, polypharmacy remains widespread in people with dementia. Further research is needed to explore possible implications.

Background: We recently reported frequent use of opioids among elderly with dementia. Discrepancies in clinical practice may in part explain the higher use of opioids in elderly with dementia, which geographical variation may be able to clarify., Objective: To investigate geographical variation in opioid use in elderly with dementia compared to elderly without dementia., Methods: Register-based cross-sectional study in the entire elderly (≥65 years) population of Denmark in 2015. Data included place of residence, prescriptions, and discharge diagnoses from hospital contacts. Prevalence of opioid use among elderly with (n = 36,014) and without dementia (n = 1,011,787) was compared nationwide across the five Danish regions using logistic regression analysis and for the 98 municipalities using age and sex standardization., Results: 32.5% of elderly with dementia and 16.9% without were treated with an opioid in 2015. For home-living elderly with dementia, there was a 4-fold difference in opioid use (9.4 to 36.8%) between municipalities compared to a 1.6-fold (12.7 to 20.2%) difference for elderly without. In nursing home residents there was a 2-fold difference (dementia: 26.5 to 55.2%; no dementia: 31.8 to 60.4%). Differences between the five regions were minor., Conclusion: Opioid use in elderly with dementia was frequent and almost twice as high compared to elderly without dementia, which may challenge patient safety. The pronounced geographical variations at municipality level, particularly among elderly with dementia, indicate differences in the approach to treatment of chronic pain in primary care. Our study suggests that more guidance on treatment of pain in elderly with dementia is needed.

Background: Early and accurate diagnosis of dementia opens the door to appropriate treatment, support, and counseling. Despite availability of evidence-based guidelines for diagnostic evaluation of dementia, the diagnostic rate in people with dementia is low and the quality of dementia diagnoses is unknown., Objective: The overall aim of this register-based study was to analyze the quality of diagnostic evaluation of dementia by assessing nationwide geographical variations in a range of indicators., Methods: A register-based cross-sectional study of the entire Danish population aged 65 years or older in 2015 was conducted. The surrogate indicators for diagnostic quality included 1) prevalence rates of dementia diagnoses, 2) incidence rates of dementia diagnoses, 3) age at first diagnosis of dementia, 4) medical specialty responsible for diagnosis, 5) diagnostic rate of dementia subtypes, and 6) use of anti-dementia medication. The indicators were compared across the five Danish regions., Results: The national prevalence and incidence of registered dementia diagnoses was 3.0% and 0.5%, respectively. The proportion of patients diagnosed at a dementia specialist department ranged from 60.9% to 90.5% across the five regions, subtype specific diagnosis ranged from 45.3% to 75.5%, and use of anti-dementia medication ranged from 29.2% to 58.3%., Conclusion: The observed geographical variations in dementia diagnoses and treatment indicate inequality in the access to appropriate diagnostic evaluation and care for patients with dementia. Our findings call for more awareness of the benefits of timely diagnosis and for improvement in the quality of diagnostic evaluation of dementia.

Background: Polypharmacy (use of ≥5 different medications) and potentially inappropriate medication (PIM) are well-known risk factors for numerous negative health outcomes. However, the use of polypharmacy and PIM in people with dementia is not well-described., Objective: To examine the prevalence of polypharmacy and PIM in older people with and without dementia in a nationwide population., Methods: Cross-sectional study of the Danish population aged ≥65 in 2014 (n = 1,032,120) based on register data, including information on diagnoses and dispensed prescriptions. Polypharmacy and PIM use among people with (n = 35,476) and without dementia (n = 994,231) were compared, stratified by living situation and adjusted for age, sex, and comorbidity. The red-yellow-green list from the Danish Institute for Rational Pharmacotherapy and the German PRISCUS list were used to define PIM., Results: People with dementia were more frequently exposed to polypharmacy (dementia: 62.6% versus no-dementia: 35.1%, p < 0.001) and likewise PIM (red-yellow-green: 45.0% versus 29.7%, p < 0.001; PRISCUS: 24.4% versus 13.2%, p < 0.001). After adjustments for age, sex, and comorbidity, the likelihood of polypharmacy and PIM was higher for community-dwelling people with dementia than without dementia (odds ratio (OR); [95% confidence interval (CI)] polypharmacy: 1.50 [1.45-1.55]; red-yellow-green: 1.27 [1.23-1.31]; PRISCUS: 1.25 [1.20-1.30]). In contrast, dementia slightly decreased the odds of polypharmacy and PIM in nursing home residents., Conclusion: Use of polypharmacy and PIM were widespread in the older population and more so in people with dementia. This could have negative implications for patient-safety and demonstrates the need for interventions to improve drug therapy in people with dementia.

Background: Antipsychotics and other psychotropics are frequently used to treat neuropsychiatric symptoms in patients with dementia, even though the evidence for effect is limited. Concerns have been raised about the safety of antipsychotics, but concomitant use of multiple psychotropic drug classes (psychotropic polypharmacy) may also pose a risk for patients., Objective: To investigate the prevalence and predictors associated with use of psychotropic polypharmacy in patients with dementia., Methods: A population-based study using nationwide registers. Patients with dementia were identified among all Danish residents ≥65 years on January 1, 2012. Data on prescriptions and comorbidity was included in the analysis. Overlapping prescriptions for different psychotropic drug classes were used to determine psychotropic polypharmacy. A multivariable logistic regression analysis was conducted to evaluate factors independently associated with the prescription of other psychotropic drug classes among patients already using antipsychotics., Results: Among all patients registered with dementia (34,553), 25.3% (8,728) used ≥2 psychotropic drugs. Among patients treated with antipsychotics 75.8% (5,403) used at least one other psychotropic drug during the antipsychotic treatment period. Nursing home residency, number of non-psychotropic medications used in 2011, and prior psychiatric diagnosis were associated with psychotropic polypharmacy among antipsychotic drug users. The most frequent combination of psychotropic drugs was antipsychotics and antidepressants., Conclusion: Concomitant use of psychotropic drugs was frequent in dementia patients. Patients living in nursing homes had the highest risk of receiving a combination of antipsychotics and other psychotropic drugs. Concomitant use of psychotropics may cause adverse events, and potential consequences for patients' safety call for further investigation.

Background: Use of antipsychotics in elderly patients with dementia has decreased in the past decade due to safety regulations; however use is still high. Geographical variation may indicate discrepancies in clinical practice and lack of adherence to evidence-based guidelines for the management of behavioral symptoms., Objective: To investigate potential geographical variances in use of antipsychotic drugs in dementia care., Methods: A registry-based cross-sectional study in the entire elderly population of Denmark (≥65 years) conducted in 2012. Data included place of residence, prescriptions filled, and hospital discharge diagnoses. Antipsychotic drug use among elderly with (n = 34,536) and without (n = 931,203) a dementia diagnosis was compared across the five regions and 98 municipalities in Denmark, adjusted for age and sex., Results: In 2012, the national prevalence of antipsychotic drug use was 20.7% for elderly patients with dementia, with a national incidence of 3.9%. The prevalence ranged from 17.0% to 23.3% in the five regions and from 7.5% to 33.1% in the 98 municipalities, demonstrating an over four-fold difference., Conclusion: The observed geographical variation was more pronounced at municipal level as compared to regional level, suggesting that the variation may be related to variances in clinical practice in primary care. This study highlights an urgent need for further educating professional carers and physicians to guide non-pharmacological as well as pharmacological management of neuropsychiatric symptoms in elderly patients with dementia.

Background: Previous studies demonstrated lower quality diagnostic assessment of dementia in immigrant populations, but knowledge about the quality of treatment and care for dementia is still lacking., Objective: To conduct a nationwide registry-based study to determine whether inequality exists regarding access to anti-dementia treatment and care between immigrant and Danish-born patients with dementia., Methods: A cross-sectional register-based study was conducted in the entire elderly (60≥years) population with dementia in Denmark in 2012 (n = 34,877). The use of anti-dementia drugs and residency in a nursing home were compared among Danish-born and Western and non-Western immigrants with dementia. Logistic regression analysis was done with adjustment for age, sex, comorbidity, marital status, basis of inclusion, and time since dementia diagnosis., Results: Immigrant background was associated with a significantly lower likelihood of receiving anti-dementia drug therapy (odds ratio (OR) [95% confidence interval (CI)]): non-Western = 0.70 [0.56-0.87]; Western = 0.74 [0.63-0.87]). No significant differences were found in type or amount of anti-dementia medication dispensed between the population groups (proxy measure for adherence). Non-Western immigrants were significantly less likely to live in a nursing home (0.52 [0.41-0.65])., Conclusion: This nationwide registry-based study indicated a worrisome difference in access to anti-dementia treatment and care for dementia patients with an immigrant background, but similar levels of adherence compared with the Danish-born population. Further research is necessary to pinpoint barriers to access to suitable healthcare among elderly immigrants with dementia but also to identify and develop culturally sensitive methods for their treatment and care.

Objective: Clinical studies have found that patients with Alzheimer's disease report pain of less intensity and with a lower affective response, which has been thought to be due to altered pain processing. The authors wished to examine the cerebral processing of non-painful and painful stimuli using somatosensory evoked potentials and contact heat evoked potentials in patients with Alzheimer's disease and in healthy elderly controls., Design: Case-control study, Setting and Subjects: Twenty outpatients with mild-moderate Alzheimer's disease and in 17 age- and gender-matched healthy controls were included, Method: Contact heat evoked potentials and somatosensory evoked potentials were recorded in all subjects. Furthermore, warmth detection threshold and heat pain threshold were assessed. Patients and controls also rated quality and intensity of the stimuli., Results: The authors found no difference on contact heat evoked potential amplitude (P = 0.59) or latency of N2 or P2 wave (P = 0.62 and P = 0.75, respectively) between patients and controls. In addition, there was no difference in regard to pain intensity scores or pain quality. The patients and controls had similar warmth detection threshold and heat pain threshold. Somatosensory evoked potentials, amplitude, and latency were within normal range and similar for the two groups., Conclusions: The findings suggest that the processing of non-painful and painful stimuli is preserved in patients with mild to moderate Alzheimer's disease., (© 2015 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Antipsychotics are often used to treat neuropsychiatric symptoms in dementia, but the evidence for effect is limited. Antipsychotics have been associated with increased risk of adverse events and mortality in patients with dementia, leading to safety regulations worldwide., Objective: To investigate time trends in use of antipsychotics and other psychotropic drugs in dementia care., Methods: The study included longitudinal data on all Danish residents ≥65 years. The study population was defined on January 1 of each year from 2000-2012. Data included prescriptions, discharge diagnoses, and somatic and psychiatric comorbidities. Multivariate time trend analyses of psychotropic drug use in patients with dementia within 4-year age bands were performed., Results: Overall, among patients with dementia the prevalence of antipsychotic drug use decreased from 31.3% in 2000 to 20.4% in 2012. The decreasing use of antipsychotics was accompanied by decreasing use of anxiolytics and hypnotics/sedatives, but an increase in the use of antidepressants from 43.3% in 2000 to 53.8% in 2012. These changes were significant across almost all age groups. Treatment intensity among patients using antipsychotics increased as the annual median number of defined daily doses (DDD) increased from 33.3 to 42.0 DDD., Conclusions: The changing patterns of psychotropic drug use may be caused by warnings against use of antipsychotics. Further research is needed to explore the implications for patient safety.

Background/aims: Prior studies have shown that patients with dementia are at risk of receiving insufficient treatment for pain after a hip fracture. We therefore hypothesized that elderly hip fracture patients with dementia received less postoperative pain treatment than those without dementia., Method: All patients (age ≥65 years) who had been operated on for a hip fracture in the Copenhagen University Hospital region in 2009 were included. Data about analgesic use for the first 72 h after surgery were acquired from the hospitals' electronic medication system and linked with information about dementia, comorbidity, and prior drug use., Results: A total of 1,507 patients were included, of which 296 (19.6%) suffered from dementia. Both groups were equally likely to receive paracetamol and opioids. Patients with dementia received lower doses of oral morphine equivalents during the first [dementia vs. no dementia: 29.0 (26.4-31.8) vs. 34.7 (33.1-36.4) mg, p = 0.001] and second [27.8 (25.4-30.5) vs. 31.2 (29.9-32.4) mg, p = 0.019] but not on the third postoperative day (p = 0.10)., Conclusion: The lower doses of opioids may reflect uncertainty about how to treat pain patients with dementia. Further guidance is needed, as inadequate treatment of pain may have adverse consequences., (© 2016 S. Karger AG, Basel.)

Background and Study Aims: Endoscopic Vacuum Therapy (EVT) has been reported as a novel treatment option for esophageal leakage. We present our results in the treatment of iatrogenic perforation with EVT in a case series of 10 patients., Patients and Methods: An open pore polyurethane drainage was placed either intracavitary through the perforation defect or intraluminal covering the defect zone. Application of vacuum suction with an electronic device (continuous negative pressure, -125 mmHg) resulted in defect closure and internal drainage., Results: Esophageal perforations were located from the cricopharyngeus (4/10) to the esophagogastric junction (2/10). EVT was feasible in all patients. Eight patients were treated with intraluminal EVT, one with intracavitary EVT, and one with both types of treatments. All perforations (100 %) were healed in within a median of (3 - 7) days. No stenosis occurred, no complications were observed, and no additional operative treatment was necessary., Conclusions: Our study suggests that intraluminal EVT will play an important role in endoscopic management of esophageal perforation.

Cognitive impairment (CI) can develop during the course of ageing and is a feature of many neurological and neurodegenerative diseases. Many individuals with CI have substantial, sustained, and complex health care needs, which frequently include pain. However, individuals with CI can have difficulty communicating the features of their pain to others, which in turn presents a significant challenge for effective diagnosis and treatment of their pain. Herein, we review the literature on responsivity of individuals with CI to experimental pain stimuli. We discuss pain responding across a large number of neurological and neurodegenerative disorders in which CI is typically present. Overall, the existing data suggest that pain processing is altered in most individuals with CI compared with cognitively intact matched controls. The precise nature of these alterations varies with the type of CI (or associated clinical condition) and may also depend on the type of pain stimulation used and the type of pain responses assessed. Nevertheless, it is clear that regardless of the etiology of CI, patients do feel noxious stimuli, with more evidence for hypersensitivity than hyposensitivity to these stimuli compared with cognitively unimpaired individuals. Our current understanding of the neurobiological mechanisms underpinning these alterations is limited but may be enhanced through the use of animal models of CI, which also exhibit alterations in nociceptive responding. Further research using additional behavioural indices of pain is warranted. Increased understanding of altered experimental pain processing in CI will facilitate the development of improved diagnostic and therapeutic approaches for pain in individuals with CI.

Background: Pain is believed to be undertreated in patients with dementia; however, no larger studies have been conducted. The aim was to investigate prevalent use of opioids in elderly with and without dementia in the entire elderly population of Denmark., Method: A register-based cross-sectional study in the entire elderly (≥65 years) population in 2010 was conducted. Opioid use among elderly with dementia (N = 35,455) was compared with elderly without (N = 870,645), taking age, sex, comorbidity, and living status into account., Results: Nursing home residents (NHRs) used opioids most frequently (41%), followed by home-living patients with dementia (27.5%) and home-living patients without dementia (16.9%). Buprenorphine and fentanyl (primarily patches) were commonly used among NHRs (18.7%) and home-living patients with dementia (10.7%) but less often by home-living patients without dementia (2.4%)., Conclusions: Opioid use in the elderly Danish population was frequent but particularly in patients with dementia and NHR, which may challenge patient safety and needs further investigation., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Autonomic function has received little attention in Alzheimer's disease (AD). AD pathology has an impact on brain regions which are important for central autonomic control, but it is unclear if AD is associated with disturbance of autonomic function., Objective: To investigate autonomic function using standardized techniques in patients with AD and healthy age-matched controls., Method: Thirty-three patients with mild to moderate AD and 30 age- and gender-matched healthy controls, without symptoms of autonomic dysfunction, underwent standardized autonomic testing with deep breathing, Valsalva maneuver, head-up tilt, and isometric handgrip test. Brachial pressure curve and electrocardiogram were recorded for off-line analysis of blood pressure and beat-to-beat heart rate (HR)., Results: AD patients had impaired blood pressure responses to Vasalva maneuver (p < 0.0001) and HR response to isometric contraction (p = 0.0001). A modified composite autonomic scoring scale showed greater degree of autonomic impairment in patients compared to controls (patient: 2.1 ± 1.6; controls: 0.9 ± 1.1, p = 0.001). HR response to deep breathing and Valsalva ratio were similar in the two groups., Conclusion: We identified autonomic impairment ranging from mild to severe in patients with mild to moderate AD, who did not report autonomic symptoms. Autonomic impairment was mainly related to impairment of sympathetic function and evident by impaired blood pressure response to the Vasalva maneuver. The clinical implications of this finding are that AD may be associated with autonomic disturbances, but patients with AD may rarely report symptoms of autonomic dysfunction. Future research should systematically evaluate symptoms of autonomic function and characterize risk factors associated with autonomic dysfunction.

Patients with Alzheimer disease (AD) report pain less frequently than their cognitively intact peers. It has been hypothesized that pain processing is altered in AD. The aim of this study was to investigate agreement and reliability of 3 pain sensitivity tests and to examine pain threshold and tolerance in patients with AD. We examined 29 patients with mild to moderate AD and 29 age- and gender-matched healthy control subjects with quantitative sensory testing, ie, assessments of detection threshold (warmth detection threshold [WDT]) and pain threshold (heat pain threshold [HPT], pressure algometry, cold pressor test), and assessments of tolerance (pressure algometry, cold pressor test). All procedures were done twice on day 1, 1 hour apart, and repeated on day 2. We found no difference between groups for WDT (patient vs control subjects: mean [95% confidence interval]: 35.5°C [33.4°C to 37.6°C] vs 35.4°C [34.3°C to 36.5°C], P=.8) or HPT (41.2°C [40.0°C to 42.4°C] vs 42.3°C [41.1°C to 43.5°C], P=.24). We observed comparable thresholds for pressure algometry (median [25% to 75% interquartile range]: 120 kPa [100 to 142 kPa] vs 131 kPa [113 to 192 kPa], P=.10), but significantly lower tolerance in AD patients (213 kPa [188 to 306 kPa] vs 289 kPa [262 to 360 kPa], P=.008). No differences were found for the cold pressor test. The study demonstrated good replicability of the sensory testing data with comparable data variability, for both groups, which supports the use of these methods in studies of patients with mild to moderate AD. Contrary to previous studies, we observed a reduced pain tolerance in patients with mild to moderate AD, which suggests that the reduced report of pain cannot be explained by reduced processing of painful stimuli., (Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Aims/hypothesis: A diet rich in meat has been reported to contribute to the risk of type 2 diabetes. The present study aims to investigate the association between meat consumption and incident type 2 diabetes in the EPIC-InterAct study, a large prospective case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study., Methods: During 11.7 years of follow-up, 12,403 incident cases of type 2 diabetes were identified among 340,234 adults from eight European countries. A centre-stratified random subsample of 16,835 individuals was selected in order to perform a case-cohort design. Prentice-weighted Cox regression analyses were used to estimate HR and 95% CI for incident diabetes according to meat consumption., Results: Overall, multivariate analyses showed significant positive associations with incident type 2 diabetes for increasing consumption of total meat (50 g increments: HR 1.08; 95% CI 1.05, 1.12), red meat (HR 1.08; 95% CI 1.03, 1.13) and processed meat (HR 1.12; 95% CI 1.05, 1.19), and a borderline positive association with meat iron intake. Effect modifications by sex and class of BMI were observed. In men, the results of the overall analyses were confirmed. In women, the association with total and red meat persisted, although attenuated, while an association with poultry consumption also emerged (HR 1.20; 95% CI 1.07, 1.34). These associations were not evident among obese participants., Conclusions/interpretation: This prospective study confirms a positive association between high consumption of total and red meat and incident type 2 diabetes in a large cohort of European adults.

Objectives: To investigate the prevalence of self- and proxy-reported pain in a cohort with Alzheimer's disease (AD) and to identify characteristics of individuals with AD reporting pain., Design: Data were collected at the baseline visit of the Danish Alzheimer Intervention Study., Setting: Community., Participants: Three hundred twenty-one community-living individuals with AD (MMSE ≥ 20) and their primary caregivers., Measurements: Pain was assessed as part of the EuroQol EQ-5D (caregiver- and self-rated). The Cornell Scale for Depression in Dementia, Quality of Life in Alzheimer's Disease Scale, EQ-5D visual analog scale, Mini-Mental State Examination, and Neuropsychiatric Inventory Questionnaire were also used., Results: Fair agreement was found between self- and proxy ratings on pain (kappa = 0.34). Thirty-three percent of individuals with AD reported pain, whereas caregivers reported that 52% had pain ( P < .001). Individuals who had self- or proxy-rated pain were significantly more likely to be female, had more depressive and other neuropsychiatric symptoms, and rated their quality of life lower., Conclusion: Self- and proxy-reported pain differ in individuals with mild AD, with proxies rating more pain than the individuals with AD. Self- and proxy-rated pain was significantly associated with more neuropsychiatric and depressive symptoms and lower quality of life. In general, this study indicates that pain occurs frequently even in individuals with mild AD and that pain assessment may require self- and proxy report to identify individuals with need for possible treatment., (© 2012, Copyright the Authors Journal compilation © 2012, The American Geriatrics Society.)

Background: The effect of pregabalin on acute herpes zoster pain has not been previously evaluated., Methods: In a randomized, double-blind, placebo-controlled, two-session crossover study the effect of a single oral dose of pregabalin (150 mg) on pain and allodynia was evaluated in 8 subjects with herpes zoster., Results: Over 6 hours of observation, pain decreased by a mean of 33% with pregabalin and 14% with placebo (p < 0.10). Effects on allodynia and SF-MPQ were not significant., Conclusions: Compared to an earlier study of gabapentin 900 mg for acute zoster pain and allodynia that followed a nearly identical protocol, pregabalin had a similar effect on pain and was well tolerated, with no difference from placebo on sleepiness. Common side effects of light-headedness, unsteady gait, and slowed thinking were almost identical to that observed in the earlier study of gabapentin. Subject recruitment proved difficult in part due to the widespread off-label use of gabapentin and pregabalin for acute zoster pain in our region of the USA., Trial Registration: ClinicalTrials.gov Identifier: NCT00352651.

Background & Aims: There has been consistent evidence for a relationship between smoking and colorectal cancer (CRC), although it is not clear whether the colon or rectum is more sensitive to the effects of smoking. We investigated the relationships between cigarette smoking and risk of CRC and tumor location., Methods: We analyzed data from 465,879 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) study; 2741 developed CRC during the follow-up period (mean, 8.7 years). Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs)., Results: The risk of colon carcinoma was increased among ever smokers (HR, 1.18; 95% CI, 1.06-1.32) and former cigarette smokers (HR, 1.21; 95% CI, 1.08-1.36), compared with never smokers; the increased risk for current smokers was of borderline significance (HR, 1.13; 95% CI, 0.98-1.31). When stratified for tumor location, the risk of proximal colon cancer was increased for former (HR, 1.25; 95% CI, 1.04-1.50) and current smokers (HR, 1.31; 95% CI, 1.06-1.64), but the risks for cancers in the distal colon or rectum were not. Subsite analyses showed a nonsignificant difference between the proximal and distal colon (P = .45) for former smokers and a significant difference for current smokers (P = .02). For smokers who had stopped smoking for at least 20 years, the risk of developing colon cancer was similar to that of never smokers., Conclusions: Ever smokers have an increased risk of colon cancer, which appeared to be more pronounced in the proximal than the distal colon location., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Flow regulation has reduced the exchange of water, energy, and materials between rivers and floodplains, caused declines in native plant populations, and advanced the spread of nonnative plants. Naturalized flow regimes are regarded as a means to restore degraded riparian areas. We examined the effects of flood regime (short [SIFI] vs. long [LIFI] inter-flood interval) on plant community and soil inorganic nitrogen (N) dynamics in riparian forests dominated by native Populus deltoides var. wislizenii Eckenwalder (Rio Grande cottonwood) and nonnative Tamarix chinensis Lour. (salt cedar) along the regulated middle Rio Grande of New Mexico. The frequency of inundation (every 2-3 years) at SIFI sites better reflected inundation patterns prior to the closure of an upstream dam relative to the frequency of inundation at LIFI sites (> or =10 years). Riparian inundation at SIFI sites varied from 7 to 45 days during the study period (April 2001-July 2004). SIFI vs. LIFI sites had higher soil moisture but greater groundwater table elevation fluctuation in response to flooding and drought. Rates of net N mineralization were consistently higher at LIFI vs. SIFI sites, and soil inorganic N concentrations were greatest at sites with elevated leaf-litter production. Sites with stable depth to ground water (approximately 1.5 m) supported the greatest leaf-litter production. Reduced leaf production at P. deltoides SIFI sites was attributed to drought-induced recession of ground water and prolonged inundation. We recommend that natural resource managers and restoration practitioners (1) utilize naturalized flows that help maintain riparian groundwater elevations between 1 and 3 m in reaches with mature P. deltoides or where P. deltoides revegetation is desired, (2) identify areas that naturally undergo long periods of inundation and consider restoring these areas to seasonal wetlands, and (3) use native xeric-adapted riparian plants to revegetate LIFI and SIFI sites where groundwater elevations commonly drop below 3 m.

A large number of proteins contain free thiols that can be modified by the formation of internal disulphides or by mixed disulphides with low-molecular-mass thiols. The majority of these latter modifications result from the interaction of protein thiols with the endogenous glutathione pool. Protein glutathionylation and disulphide formation are of significance both for defence against oxidative damage and in redox signalling. As mitochondria are central to both oxidative damage and redox signalling within the cell, these modifications of mitochondrial proteins are of particular importance. In the present study, we review the mechanisms and physiological significance of these processes.

There are two isochorismate synthase genes entC and menF in Escherichia coli. They encode enzymes (isochorismate synthase, EC 5.4.99.6) which reversibly synthesize isochorismic acid from chorismic acid. The genes share a 24.2% identity but are differently regulated. Activity of the MenF isochorismate synthase is significantly increased under anaerobic conditions whereas the activity of the EntC isochorismate synthase is greatly stimulated during growth in an iron deficient medium. Isochorismic acid synthesized by EntC is mainly channeled into enterobactin synthesis whereas isochorismic acid synthesized by MenF is mainly channeled into menaquinone synthesis. When menF or entC were separately placed onto overexpression plasmids and the plasmids introduced into a menF(-)/entC(-) double mutant in two separate experiments, the isochorismate formed was fed into both, the menaquinone and the enterobactin pathway. Moreover, in spite of a high isochorismate synthase activity menaquinone and enterobactin formation were not fully restored, indicating that isochorismate was lost by diffusion. Thus, under these conditions channeling was not observed. We conclude that in E. coli the chromosomal position of both menF and entC in their respective clusters is a prerequisite for channeling of isochorismate in both pathways.

Groundwater-surface water (GW-SW) interaction lengthens hydraulic residence times, increases contact between solutes and biologically active surfaces, and often creates a gradient of redox conditions conducive to an array of biogeochemical processes. As such, the interaction of hydraulic patterns and biogeochemical activity is suspected to be an important determinant of elemental spiraling in streams. Hydrologic interactions may be particularly important in headwater streams, where the extent of the GW-SW mixing environment (i.e., hyporheic zone) is proportionately greater than in larger streams. From our current understanding of stream ecosystem function, we discuss nitrogen (N) spiraling, present a conceptual model of N retention in streams, and use both of these issues to generate specific research questions and testable hypotheses regarding N dynamics in streams.

Earth's subsurface offers one of the best possible sites to search for microbial life and the characteristic lithologies that life leaves behind. The subterrain may be equally valuable for astrobiology. Where surface conditions are particularly hostile, like on Mars, the subsurface may offer the only habitat for extant lifeforms and access to recognizable biosignatures. We have identified numerous unequivocally biogenic macroscopic, microscopic, and chemical/geochemical cave biosignatures. However, to be especially useful for astrobiology, we are looking for suites of characteristics. Ideally, "biosignature suites" should be both macroscopically and microscopically detectable, independently verifiable by nonmorphological means, and as independent as possible of specific details of life chemistries--demanding (and sometimes conflicting) criteria. Working in fragile, legally protected environments, we developed noninvasive and minimal impact techniques for life and biosignature detection/characterization analogous to Planetary Protection Protocols. Our difficult field conditions have shared limitations common to extraterrestrial robotic and human missions. Thus, the cave/subsurface astrobiology model addresses the most important goals from both scientific and operational points of view. We present details of cave biosignature suites involving manganese and iron oxides, calcite, and sulfur minerals. Suites include morphological fossils, mineral-coated filaments, living microbial mats and preserved biofabrics, 13C and 34S values consistent with microbial metabolism, genetic data, unusual elemental abundances and ratios, and crystallographic mineral forms.

Diseases associated with pathological fibroproliferation represent a major cause of morbidity and mortality. Despite the importance of this class of disorders, current therapy is of limited value, and no therapy is available to reduce the fibroblast population size within existing fibrotic lesions. In this regard, constitutive expression of growth-promoting genes can sensitize cells to undergo apoptosis. Studies in our laboratory have demonstrated that lovastatin potently induces apoptosis in fibroblasts constitutively expressing Myc, and that lung fibroblasts isolated from fibrotic lesions constitutively express growth-promoting genes. In this study, we sought to determine if nontransformed lung fibroblasts would manifest susceptibility to lovastatin-induced apoptosis similar to that observed in fibroblasts ectopically expressing Myc. Here we show that clinically achievable concentrations of lovastatin induce apoptosis in normal and fibrotic lung fibroblasts in vitro, as evidenced by acridine orange staining, terminal transferase nick end translation (TUNEL), and DNA laddering. Apoptosis of human lung fibroblasts was dose- and time-dependent, and blocked by exogenous mevalonic acid. Furthermore, apoptosis was associated with decreased levels of mature Ras, a molecule directly implicated in fibroblast rescue from apoptosis. The ability of lovastatin to induce fibroblast apoptosis in vivo was examined using a guinea pig wound chamber model. Lovastatin (5 microM, 8 d) reduced granulation tissue formation in the wound chambers by 64.7%, with associated ultrastructural evidence of fibroblast apoptosis. These findings support further study of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors as potential therapy for patients with fibroproliferative disorders.

Klebsiella pneumoniae 62-1, a triple mutant impaired in aromatic amino acid biosynthesis (Phe-, Tyr-, Trp-), excretes chorismic acid into the culture broth. When transformed with plasmids harbouring Escherichia coli genes entC or menF the mutant excretes a mixture of both chorismic and isochorismic acid indicating that not only entC but also menF encodes an isochorismate hydroxymutase (isochorismate synthase, EC 5.4.99.6) enzyme. These enzymes catalyze the first step in enterobactin or menaquinone biosynthesis, respectively. Although both gene products (EntC and MenF) catalyze the same reaction, they play distinct roles in the biosynthesis of menaquinone (MK8) and enterobactin. An E. coli mutant (PBB7) with an intact menF but a disrupted entC produced menaquinone (MK8) but no enterobactin, whereas a mutant (PBB9) with an intact entC but a disrupted menF produced enterobactin and only a trace of menaquinone (MK8). When both menF and entC were disrupted (mutant PBB8) neither menaquinone (MK8) nor enterobactin was detectable. Our previous assumption that entC is responsible for both menaquinone and enterobactin biosynthesis is inconsistent with these mutant studies and has to be revised. The presence in the promoter region of menF of a putative cAMP receptor protein binding site indicates that menF is regulated differently from entC. The menF gene was overexpressed as a fusion gene and its product (6xHis-tagged MenF) isolated. The enzyme catalyzed the formation of isochorismic from chorismic acid and as opposed to a previous publication also the reverse reaction. The enzyme was characterized and its kinetic data determined.

Background: In contrast to their well-known and critical role in excitation-contraction coupling of vascular smooth muscle, the effects of the myosin light chains on cardiomyocyte mechanics are poorly understood. Accordingly, we designed the present experiment to define the cardiac chamber-specific functional effects of the ventricular isoform of the regulatory myosin light chain (MLC2v)., Methods and Results: Postnatal transgenic cardiac-specific overexpression of MLC2v was achieved by use of the alpha-myosin heavy chain promoter. Enzymatically disaggregated atrial and ventricular mouse myocytes were field-stimulated at multiple frequencies, and mechanical properties and calcium kinetics were studied by use of video edge detection and FURA 2-AM, respectively. MLC2v overexpression resulted in complete replacement of the atrial with the ventricular isoform of the regulatory myosin light chain at the steady-state mRNA and protein levels in the atria of transgenic mice. Mechanical properties of transgenic atrial myocytes were enhanced to the level of ventricular myocytes of control animals in association with modest decreases in the amplitude of the calcium transient., Conclusions: MLC2v modulates chamber-specific contractility by enhanced calcium sensitivity and/or improved cross-bridge cycling of the thin and thick filaments of the cardiomyocyte.

To determine the biochemical and related functional effects of the thyroid analog diiodothyroproprionic acid (DITPA) on primate myocardium, we examined, both before and after 23 days of DITPA (3.75 mg/kg): myosin heavy-chain (MHC) isoforms and sarcoplasmic reticulum (SR) calcium cycling proteins; left ventricular (LV) function; and the LV force-frequency relation in four baboons chronically instrumented with sonomicrometers and micromanometers. The force-frequency relation was measured as the response of isovolumic contraction (dP/dtmax) to incremental pacing and the critical heart rate (HRcrit) as the rate at which dP/dtmax reached its maximum. DITPA increased basal LV dPt/dtmax (3,300 +/- 378 versus 2,943 +/- 413 mm Hg/sec; p = .09), and velocity of circumferential shortening (1.13 +/- 0.30 versus 0.76 +/- 0.30 circ/sec; p < .01), decreased the basal time constant of isovolumic relaxation (24.2 +/- 1.6 versus 29.9 +/- 2.5 msec; p < .05), and increased the HRcrit (203 +/- 19 versus 168 +/- 20 bpm; p < .05), without effecting significant changes in either basal heart rate (119 +/- 14 versus 111 +/- 17 bpm) or systolic blood pressure (137 +/- 14 versus 126 +/- 8 mm Hg). Quantitative immunoblotting revealed significant decreases in both phospholamban and the ratio of phospholamban to SR Ca2+ adenosine triphosphatase in DITPA-treated animals when compared to four untreated controls. By contrast, alpha-MHC isoform was undetectable in both DITPA treated and control baboons. Thus, DITPA favorably alters the stoichiometry between the SR calcium pump and its inhibitor, phospholamban, and has positive inotropic and lusitropic effects in the normal primate left ventricle, which may be useful in the treatment of heart failure. Unlike thyroid hormone, these changes occur in the absence of detectable alpha-MHC isoform protein expression and without an increase in heart rate.

The transcriptional, posttranscriptional, and related functional effects of thyroid hormone on primate myocardium are poorly understood. Therefore, we studied the effects of thyroid hormone on sarcoplasmic reticulum (SR) Ca(2+)-cycling proteins and myosin heavy chain (MHC) composition at the steady state mRNA and protein level and associated alterations of left ventricular (LV) performance in 8 chronically instrumented baboons. The force-frequency and relaxation-frequency relations were assessed as the response of LV isovolumic contraction (dP/dtmax) and relaxation (Tau), respectively, to incremental atrial pacing. Both the heart rate at which dP/dtmax was maximal and Tau was minimal (critical heart rates) in response to pacing were increased significantly after thyroid hormone. Postmortem LV tissue from 5 thyroid-treated and 4 additional control baboons was assayed for steady state mRNA levels with cDNA probes to MHC isoforms and SR Ca(2+)-cycling proteins. Steady state SR Ca(2+)-ATPase and phospholamban mRNA increased in the hyperthyroid state, and alpha-MHC mRNA appeared de novo, whereas beta-MHC mRNA decreased. Western analysis (4 thyroid-treated and 4 control baboons) showed directionally similar changes in MHC isoforms and a slight increase in SR Ca(2+)-ATPase. In contrast, there was a statistically nonsignificant decrease in phospholamban protein, which resulted in a significant 40% decrease in the ratio of phospholamban to SR Ca(2+)-ATPase. Thus, thyroid hormone increases the transcription of Ca(2+)-cycling proteins and shifts MHC isoform expression in the primate LV. Our data suggest that both transcriptional and posttranslational mechanisms determine the levels of these proteins in the hyperthyroid primate heart and mediate, in part, the observed enhanced basal and frequency-dependent LV performance.

To characterize alterations in gene expression which may occur during the development of compensated left ventricular pressure overload hypertrophy (CH) and the transition to decompensated congestive heart failure (DH), differential RNA display was used to compare mRNA transcripts from sham operated, 4-week, and 8-week thoracic aorta banded guinea-pigs. Of several regulated transcripts chosen for analysis, one was identified by nucleotide sequence homology as titin, a sarcomeric cytoskeletal protein. By differential display and comparative PCR, titin transcripts were increased in CH and then declined in DH. Comparative PCR of desmin and tubulin demonstrated increased mRNA levels for these cytoskeletal proteins in CH and DH. Western analysis showed associated increases in titin (DH) and desmin (CH and DH) protein expression but no increase in tubulin protein. Isolated Langendorff cardiac mechanics failed to reveal functional differences in either hypertrophy phenotype when microtubules were depolymerized (colchicine 10(-6)M). In summary, the major cytoskeletal proteins are differentially regulated in LV pressure overload hypertrophy and failure. Neither the level of beta-tubulin or its polymerization state appear to affect LV function in this model of cardiac hypertrophy.

The pivotal step in enterobactin and menaquinone biosynthesis is the conversion of chorismate to isochorismate. Circumstantial evidence pointed to Escherichia coli isochorismate hydroxymutase isogenes being responsible for this conversion. While the gene involved in enterobactin synthesis (entC) was known, the corresponding gene for menaquinone biosynthesis (menF) was not but has now been identified and sequenced. The amino acid sequence of MenF is 23.5% identical and 57.8% similar to that of EntC.

Herpes simplex virus (HSV) is one of the most common causes of severe necrotizing encephalitis in men. Without adequate acyclovir treatment it has a mortality rate of 70%. An early, reliable virological diagnosis is therefore essential. In this study, two newly-introduced diagnostic methods were assessed and compared: Polymerase Chain Reaction (PCR) for detection of HSV-genome in cerebrospinal fluid and HSV-specific isoelectric focusing (IEF) for detection of intrathecal virus specific antibody synthesis in HSV encephalitis (HSVE). PCR proved more effective for the early diagnosis of HSVE and HSVE relapses, whereas HSV-specific IEF was superior for the diagnosis of HSVE in post-acute stages of the disease.

In this study, serum and CSF samples of 55 neurological patients have been examined to confirm the diagnosis of herpes simplex virus encephalitis (HSVE). Different methods were applied, including serological titer evaluations, determination of intrathecally-produced HSV-specific antibodies by isoelectric focusing with affinity immunoblotting (IEF), as well as HSV-specific ELISA and HSV-specific polymerase chain reaction (PCR). The results of IEF and PCR have been compared and contrasted to develop general directions for virological diagnosis of HSVE. Of 14 patients suffering from clinically diagnosed HSVE, HSVE was confirmed in 12 cases by the demonstration of PCR or IEF positivity. A HSV-specific CNS infection could be excluded in 2 of these 14 patients. In 17 patients suffering from non-HSVE, PCR and IEF results were negative. Twenty-four patients, suffering from other neurological diseases, serving as a control group, were PCR- and HSV-IEF-negative. The study indicated that there are two possibilities for unequivocal demonstration of HSV-specific CNS involvement: first, performance of PCR especially in the acute phase of disease and in suspicious relapses, and second, performance of HSV-specific IEF for determination of intrathecally synthesized HSV-specific antibodies. It is suggested that these two methods should be introduced in routine diagnosis of viral encephalitis.

Many techniques for quantifying microbial biodegradation of C-labeled compounds use soil-water slurries and trap mineralization-derived CO(2) in solution wells suspended within the incubation flasks. These methods are not satisfactory for studies of arid-region soils that are highly calcareous and unsaturated because (i) slurries do not simulate unsaturated conditions and (ii) the amount of CO(2) released from calcareous soils exceeds the capacity of the suspended well. This report describes simple, inexpensive methodological modifications for quantifying microbial degradation of [C]benzene and 1,2-dichloro[U-C]ethane in calcareous soils under unsaturated conditions. Soils at 50% water holding capacity were incubated with labeled contaminants for periods up to 10 weeks, followed by acidification of the soil and trapping of the evolved CO(2) in a separate container of 2 N NaOH. The CO(2) was transferred from the incubation flask to the trap solution by a gas transfer shunt containing activated charcoal to remove any volatilized labeled organics. The amount of CO(2) in the trap solution was measured by scintillation counting (disintegrations per minute). The method was tested by using two regional unamended surface soils, a sandy aridisol and a clay-rich riparian soil. The results demonstrated that both [C]benzene and 1,2-dichloro[U-C]ethane were mineralized to release substantial amounts of CO(2) within 10 weeks. Levels of mineralization varied with contaminant type, soil type, and aeration status (anaerobic vs. aerobic); no significant degradation was observed in abiotic control samples. Methodological refinements of this technique resulted in total CO(2) recovery efficiency of approximately 90%.

Ryan Lake, a 1.6-hectare basin lake near the periphery of the tree blowdown area in the blast zone 19 km north of Mount St. Helens, was studied from August to October 1980 to determine the microbial and chemical response of the lake to the eruption. Nutrient enrichment through the addition of fresh volcanic material and the organic debris from the surrounding conifer forest stimulated intense microbial activity. Concentrations of such nutrients as phosphorus, sulfur, manganese, iron, and dissolved organic carbon were markedly elevated. Nitrogen cycle activity was especially important to the lake ecosystem in regulating biogeochemical cycling owing to the limiting abundance of nitrogen compounds. Nitrogen fixation, both aerobic and anaerobic, was active from aerobic benthic and planktonic cyanobacteria with rates up to 210 nmol of N(2) cm h and 667 nmol of N(2) liter h, respectively, and from anaerobic bacteria with rates reaching 220 nmol of N(2) liter h. Nitrification was limited to the aerobic epilimnion and littoral zones where rates were 43 and 261 nmol of NO(2) liter day, respectively. Potential denitrification rates were as high as 30 mumol of N(2)O liter day in the anaerobic hypolimnion. Total bacterial numbers ranged from 1 x 10 to 3 x 10 ml with the number of viable sulfur-metal-oxidizing bacteria reaching 2 x 10 ml in the hypolimnion. A general scenario for the microbial cycling of nitrogen, carbon, sulfur, and metals is presented for volcanically impacted lakes. The important role of nitrogen as these lakes recover from the cataclysmic eruption and proceed back towards their prior status as oligotrophic alpine lakes is emphasized.

The known effect of progesterone on carbohydrate metabolism prompted a study of some of the hepatic "lipogenic" and "gluconeogenic" enzymes in rats treated with progesterone. Several enzymes providing lipid precursors (phosphofructokinase, malic enzyme, glucose-6-phosphate dehydrogenase, and citrate cleavage enzyme) showed increased specific activity. These changes may represent insulin effects. Specific activity of phosphoenolpyruvate carboxykinase, usually associated with control of gluconeogenesis, was also increased. The latter is compatible with increased capability for glycogenesis, which is recognized as a progesterone effect.

In a catamnestic study an analysis of the clinical results as well as of the spermatograms are reported on 545 andrological patients with "atrophy" (that means reduced testis volume) or absence of one testis and a contralaterally normal developed testis. It can be demonstrated that there do not exist any differences concerning the size and consistency of the present testis and with regard to absence or lost of one testis (hemicastration). In case of testicular atrophy exists a more disadvantageous reproductive function. In case of tumor as a reason for hemicastration the teratoma shows better conditions for the quality of the spermatograms and for reproduction. Accordingly the histological findings of the testis after hemicastration/absence are not so large in the present remained testis. In cases of one-sided orchitis the spermatogram quality is better than in one-sided varicocele with atrophy at the same side.

The following results proof: in the case of Candida albicans-infection sodium-hydrogen-carbonate-treatment does not work.

To evaluate which women using oral contraceptive agents might be at risk, biochemical indices known to be affected by the estrogens and progestogens were studied in women who take oral contraceptive agents, in women who do not use oral contraceptive agents, in women in third trimester of pregnancy and 6 weeks after parturition, and in men with normal and high blood lipid levels. The most consistent changes due to oral contraceptive agents were in serum levels of copper, triglycerides, and vitamin A and in the urinary excretion of xanthurenic acid and niacin derivatives before and after a tryptophan load test. There was only a slight suggestion, with no statistical significance, that serum vitamin C levels decreased when the serum levels of ceruloplasmin were high. The highest blood pressures and serum triglycerides and vitamin A levels were obtained in those women who ingested the highest level of estrogens. Pregnant women had the lowest levels of serum vitamin A. The oral contraceptive agents users had the lowest average levels of carotenoids corresponding to the highest average levels of vitamin A in the serum. Thus, estrogens not only increase the rate of change of tryptophan to niacin but may also increase the rate of conversion of carotene to vitamin A. Relative reactivity to oral contraceptive agents and possible risk to a patient might be evaluated by a profile of blood pressure and serum triglycerides, copper, and vitamin A.