Dunedin Public Hospital

BACKGROUND: Approximately 30 per cent of people over 65 years of age and living in the community fall each year; the number is higher in institutions. Although less than one fall in 10 results in a fracture, a fifth of fall incidents require medical attention. OBJECTIVES: To assess the effects of interventions designed to reduce the incidence of falls in elderly people (living in the community, or in institutional or hospital care). SEARCH STRATEGY: We searched the Cochrane Musculoskeletal Group specialised register (January 2001), Cochrane Controlled Trials Register (The Cochrane Library, Issue 1, 2001), MEDLINE (1966 to February 2001), EMBASE (1988 to 2001 Week 14), CINAHL (1982 to March 2001), The National Research Register, Issue 1, 2001, Current Controlled Trials (www.controlled-trials.com accessed 25 May 2001), and reference lists of articles. We also contacted researchers in the field. SELECTION CRITERIA: Randomised trials of interventions designed to minimise the effect of, or exposure to, risk factors for falling in elderly people. Main outcomes of interest were the number of fallers, or falls. Trials reporting only intermediate outcomes were excluded. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. Data were pooled using the fixed effect model where appropriate. MAIN RESULTS: Interventions likely to be beneficial: ~bullet~A programme of muscle strengthening and balance retraining, individually prescribed at home by a trained health professional (3 trials, 566 participants, pooled relative risk (RR) 0.80, 95% confidence interval (95%CI) 0.66 to 0.98). ~bullet~A 15 week Tai Chi group exercise intervention (1 trial, 200 participants, risk ratio 0.51, 95%CI 0.36 to 0.73). ~bullet~Home hazard assessment and modification that is professionally prescribed for older people with a history of falling (1 trial, 530 participants, RR 0.64, 95% CI 0.49 to 0.84). A reduction in falls was seen both inside and outside the home. ~bullet~Withdrawal of psychotropic medication (1 trial, 93 participants, relative hazard 0.34, 95%CI 0.16 to 0.74). ~bullet~Multidisciplinary, multifactorial, health/environmental risk factor screening/intervention programmes, both for unselected community dwelling older people (data pooled from 3 trials, 1973 participants, pooled RR 0.73, 95%CI 0.63 to 0.86), and for older people with a history of falling, or selected because of known risk factors (data pooled from 2 trials, 713 participants, pooled RR 0.79, 95%CI 0.67 to 0.94). Interventions of unknown effectiveness: ~bullet~Group-delivered exercise interventions (9 trials, 2177 participants). ~bullet~Nutritional supplementation (1 trial, 50 participants). ~bullet~Vitamin D supplementation, with or without calcium (3 trials, 679 participants). ~bullet~Home hazard modification in association with advice on optimising medication (1 trial, 658 participants), or in association with an education package on exercise and reducing fall risk (1 trial, 3182 participants). ~bullet~Pharmacological therapy (raubasine-dihydroergocristine, 1 trial, 95 participants). ~bullet~Fall prevention programmes in institutional settings. ~bullet~Interventions using a cognitive/behavioural approach alone (2 trials, 145 participants). ~bullet~Home hazard modification for older people without a history of falling (1 trial, 530 participants). ~bullet~ Hormone replacement therapy (1 trial, 116 participants). Interventions unlikely to be beneficial: ~bullet~Brisk walking in women with an upper limb fracture in the previous two years (1 trial, 165 participants). REVIEWER'S CONCLUSIONS: Interventions to prevent falls that are likely to be effective are now available; less is known about their effectiveness in preventing fall-related injuries. Costs per fall prevented have been established for four of the interventions and careful economic modelling in the context of the local healthcare system is important. Some potential interventions are of unknown effectiveness and further research is indicated.

Abstract Objective: To assess the effectiveness of a home exercise programme of strength and balance retraining exercises in reducing falls and injuries in elderly women. Design: Randomised controlled trial of an individually tailored programme of physical therapy in the home (exercise group, n=116) compared with the usual care and an equal number of social visits (control group, n=117). Setting: 17 general practices in Dunedin, New Zealand. Subjects: Women aged 80 years and older living in the community and registered with a general practice in Dunedin. Main outcome measures: Number of falls and injuries related to falls and time between falls during one year of follow up; changes in muscle strength and balance measures after six months. Results: After one year there were 152 falls in the control group and 88 falls in the exercise group. The mean (SD) rate of falls was lower in the exercise than the control group (0.87 (1.29) v 1.34 (1.93) falls per year respectively; difference 0.47; 95% confidence interval 0.04 to 0.90). The relative hazard for the first four falls in the exercise group compared with the control group was 0.68 (0.52 to 0.90). The relative hazard for a first fall with injury in the exercise group compared with the control group was 0.61 (0.39 to 0.97). After six months, balance had improved in the exercise group (difference between groups in change in balance score 0.43 (0.21 to 0.65). Conclusions: An individual programme of strength and balance retraining exercises improved physical function and was effective in reducing falls and injuries in women 80 years and older. Key messages Modifiable risk factors for falls in elderly people have been well defined; they include loss of muscle strength and impaired balance A programme to improve strength and balance in women aged 80 years and older can be set up safely with four home visits from a physiotherapist This programme reduced falls and moderate injuries appreciably over the subsequent year in Dunedin, New Zealand The benefit was most noticeable in elderly people who fell often

This special issue of Dalton Transactions is to mark the 60th birthday of Professor Dr. Annie K. Powell. The issue highlights advances in Modern Coordination Chemistry.

The observation of spin crossover with thermal hysteresis loops of more than a few Kelvin remains relatively uncommon and unpredictable, so is a relatively underdeveloped, but important, area of spin crossover, particularly for memory applications. Lessons learnt regarding the origins, and the practicalities of the proper study and reporting, of thermal hysteresis loops are considered and explained, from a synthetic chemists perspective, after a general introduction to the field of spin crossover.

OBJECTIVE: To assess the effectiveness of psychotropic medication withdrawal and a home-based exercise program in reducing falls in older people. DESIGN: A randomized controlled trial with a two by two factorial design. SETTING: Seventeen general practices in Dunedin, New Zealand. PARTICIPANTS: Women and men aged 65 years registered with a general practitioner and currently taking psychotropic medication (n = 93). INTERVENTIONS: Two interventions: (1) gradual withdrawal of psychotropic medication versus continuing to take psychotropic medication (double blind) and (2) a home-based exercise program versus no exercise program (single blind). MEASUREMENTS: Number of falls and falls risk during 44 weeks of follow-up. Analysis was on an intent to treat basis. RESULTS: After 44 weeks, the relative hazard for falls in the medication withdrawal group compared with the group taking their original medication was .34 (95% CI, .16-.74). The risk of falling for the exercise program group compared with those not receiving the exercise program was not significantly reduced. CONCLUSIONS: Withdrawal of psychotropic medication significantly reduced the risk of falling, but permanent withdrawal is very difficult to achieve.

Keratinous materials such as wool, feathers and hooves are tough unique biological co-products that usually have high sulfur and protein contents. A high cystine content (7-13%) differentiates keratins from other structural proteins, such as collagen and elastin. Dissolution and extraction of keratin is a difficult process compared to other natural polymers, such as chitosan, starch, collagen, and a large-scale use of keratin depends on employing a relatively fast, cost-effective and time efficient extraction method. Keratin has some inherent ability to facilitate cell adhesion, proliferation, and regeneration of the tissue, therefore keratin biomaterials can provide a biocompatible matrix for regrowth and regeneration of the defective tissue. Additionally, due to its amino acid constituents, keratin can be tailored and finely tuned to meet the exact requirement of degradation, drug release or incorporation of different hydrophobic or hydrophilic tails. This review discusses the various methods available for the dissolution and extraction of keratin with emphasis on their advantages and limitations. The impacts of various methods and chemicals used on the structure and the properties of keratin are discussed with the aim of highlighting options available toward commercial keratin production. This review also reports the properties of various keratin-based biomaterials and critically examines how these materials are influenced by the keratin extraction procedure, discussing the features that make them effective as biomedical applications, as well as some of the mechanisms of action and physiological roles of keratin. Particular attention is given to the practical application of keratin biomaterials, namely addressing the advantages and limitations on the use of keratin films, 3D composite scaffolds and keratin hydrogels for tissue engineering, wound healing, hemostatic and controlled drug release.

Dissections or ruptures of aortic aneurysms remain a leading cause of death in the developed world, with the majority of deaths being preventable if individuals at risk are identified and properly managed. Genetic variants predispose individuals to these aortic diseases. In the case of thoracic aortic aneurysm and dissections (thoracic aortic disease), genetic data can be used to identify some at-risk individuals and dictate management of the associated vascular disease. For abdominal aortic aneurysms, genetic associations have been identified, which provide insight on the molecular pathogenesis but cannot be used clinically yet to identify individuals at risk for abdominal aortic aneurysms. This compendium will discuss our current understanding of the genetic basis of thoracic aortic disease and abdominal aortic aneurysm disease. Although both diseases share several pathogenic similarities, including proteolytic elastic tissue degeneration and smooth muscle dysfunction, they also have several distinct differences, including population prevalence and modes of inheritance.

OBJECTIVE: To compare the predictive accuracy and clinical utility of five risk scoring systems in the assessment of patients with upper gastrointestinal bleeding. DESIGN: International multicentre prospective study. SETTING: Six large hospitals in Europe, North America, Asia, and Oceania. PARTICIPANTS: 3012 consecutive patients presenting over 12 months with upper gastrointestinal bleeding. MAIN OUTCOME MEASURES: Comparison of pre-endoscopy scores (admission Rockall, AIMS65, and Glasgow Blatchford) and post-endoscopy scores (full Rockall and PNED) for their ability to predict predefined clinical endpoints: a composite endpoint (transfusion, endoscopic treatment, interventional radiology, surgery, or 30 day mortality), endoscopic treatment, 30 day mortality, rebleeding, and length of hospital stay. Optimum score thresholds to identify low risk and high risk patients were determined. RESULTS: The Glasgow Blatchford score was best (area under the receiver operating characteristic curve (AUROC) 0.86) at predicting intervention or death compared with the full Rockall score (0.70), PNED score (0.69), admission Rockall score (0.66, and AIMS65 score (0.68) (all P<0.001). A Glasgow Blatchford score of ≤1 was the optimum threshold to predict survival without intervention (sensitivity 98.6%, specificity 34.6%). The Glasgow Blatchford score was better at predicting endoscopic treatment (AUROC 0.75) than the AIMS65 (0.62) and admission Rockall scores (0.61) (both P<0.001). A Glasgow Blatchford score of ≥7 was the optimum threshold to predict endoscopic treatment (sensitivity 80%, specificity 57%). The PNED (AUROC 0.77) and AIMS65 scores (0.77) were best at predicting mortality, with both superior to admission Rockall score (0.72) and Glasgow Blatchford score (0.64; P<0.001). Score thresholds of ≥4 for PNED, ≥2 for AIMS65, ≥4 for admission Rockall, and ≥5 for full Rockall were optimal at predicting death, with sensitivities of 65.8-78.6% and specificities of 65.0-65.3%. No score was helpful at predicting rebleeding or length of stay. CONCLUSIONS: The Glasgow Blatchford score has high accuracy at predicting need for hospital based intervention or death. Scores of ≤1 appear the optimum threshold for directing patients to outpatient management. AUROCs of scores for the other endpoints are less than 0.80, therefore their clinical utility for these outcomes seems to be limited.Trial registration Current Controlled Trials ISRCTN16235737.

BACKGROUND: Previous research has found that mental health is strongly associated with life satisfaction. In this study we examine associations between mental health problems and life satisfaction in a birth cohort studied from 18 to 35 years. METHOD: Data were gathered during the Christchurch Health and Development Study, which is a longitudinal study of a birth cohort of 1265 children, born in Christchurch, New Zealand, in 1977. Assessments of psychiatric disorder (major depression, anxiety disorder, suicidality, alcohol dependence and illicit substance dependence) using DSM diagnostic criteria and life satisfaction were obtained at 18, 21, 25, 30 and 35 years. RESULTS: Significant associations (p < 0.01) were found between repeated measures of life satisfaction and the psychiatric disorders major depression, anxiety disorder, suicidality, alcohol dependence and substance dependence. After adjustment for non-observed sources of confounding by fixed effects, statistically significant associations (p < 0.05) remained between life satisfaction and major depression, anxiety disorder, suicidality and substance dependence. Overall, those reporting three or more mental health disorders had mean life satisfaction scores that were nearly 0.60 standard deviations below those without mental health problems. A structural equation model examined the direction of causation between life satisfaction and mental health problems. Statistically significant (p < 0.05) reciprocal associations were found between life satisfaction and mental health problems. CONCLUSIONS: After adjustment for confounding, robust and reciprocal associations were found between mental health problems and life satisfaction. Overall, this study showed evidence that life satisfaction influences mental disorder, and that mental disorder influences life satisfaction.

BACKGROUND: Pelvic floor muscle training is the most commonly used physical therapy treatment for women with stress urinary incontinence. It is sometimes recommended for mixed and less commonly urge urinary incontinence. OBJECTIVES: To determine the effects of pelvic floor muscle training for women with urinary incontinence in comparison to no treatment, placebo or sham treatments, or other inactive control treatments. SEARCH STRATEGY: The Cochrane Incontinence Group Specialised Trials Register (searched 18 February 2009) and the reference lists of relevant articles were searched. SELECTION CRITERIA: Randomised or quasi-randomised trials in women with stress, urge or mixed urinary incontinence (based on symptoms, signs, or urodynamics). One arm of the trial included pelvic floor muscle training (PFMT). Another arm was a no treatment, placebo, sham, or other inactive control treatment arm. DATA COLLECTION AND ANALYSIS: Trials were independently assessed for eligibility and methodological quality. Data were extracted then cross-checked. Disagreements were resolved by discussion. Data were processed as described in the Cochrane Handbook (Higgins 2008). Trials were subgrouped by diagnosis. Formal meta-analysis was not undertaken because of study heterogeneity. MAIN RESULTS: Fourteen trials involving 836 women (435 PFMT, 401 controls) met the inclusion criteria; twelve trials (672) contributed data to the analysis. Many studies were at moderate to high risk of bias, based on the trial reports. There was considerable variation in interventions used, study populations, and outcome measures.Women who did PFMT were more likely to report they were cured or improved than women who did not. Women who did PFMT also reported better continence specific quality of life than women who did not. PFMT women also experienced fewer incontinence episodes per day and less leakage on short office-based pad test. Of the few adverse effects reported, none were serious. The trials in stress urinary incontinent women which suggested greater benefit recommended a longer training period than the one trial in women with detrusor overactivity (urge) incontinence. AUTHORS' CONCLUSIONS: The review provides support for the widespread recommendation that PFMT be included in first-line conservative management programmes for women with stress, urge, or mixed, urinary incontinence. Statistical heterogeneity reflecting variation in incontinence type, training, and outcome measurement made interpretation difficult. The treatment effect seems greater in women with stress urinary incontinence alone, who participate in a supervised PFMT programme for at least three months, but these and other uncertainties require testing in further trials.

RATIONALE Airway inflammation in asthma is heterogeneous with different phenotypes. The inflammatory cell phenotype is modified by corticosteroids and smoking. Steroid therapy is beneficial in eosinophilic asthma (EA), but evidence is conflicting regarding non-eosinophilic asthma (NEA). OBJECTIVES To assess the inflammatory cell phenotypes in asthma after eliminating potentially confounding effects; to compare steroid response in EA versus NEA; and to investigate changes in sputum cells with inhaled corticosteroid (ICS). METHODS Subjects undertook ICS withdrawal until loss of control or 28 days. Those with airway hyper-responsiveness (AHR) took inhaled fluticasone 1000 microg daily for 28+ days. Cut-off points were > or = or <2% for sputum eosinophils and > or = or <61% for neutrophils. RESULTS After steroid withdrawal (n=94), 67% of subjects were eosinophilic, 31% paucigranulocytic and 2% mixed; there were no neutrophilic subjects. With ICS (n=88), 39% were eosinophilic, 46% paucigranulocytic, 3% mixed and 5% neutrophilic. Sputum neutrophils increased from 19.3% to 27.7% (p=0.024). The treatment response was greater in EA for symptoms (p<0.001), quality of life (p=0.012), AHR (p=0.036) and exhaled nitric oxide (p=0.007). Lesser but significant changes occurred in NEA (ie, paucigranulocytic asthma). Exhaled nitric oxide was the best predictor of steroid response in NEA for AHR (area under the curve 0.810), with an optimum cut-off point of 33 ppb. CONCLUSIONS After eliminating the effects of ICS and smoking, a neutrophilic phenotype could be identified in patients with moderate stable asthma. ICS use led to phenotype misclassification. Steroid responsiveness was greater in EA, but the absence of eosinophilia did not indicate the absence of a steroid response. In NEA this was best predicted by baseline exhaled nitric oxide.

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OBJECTIVE: Allopurinol is the most commonly used urate-lowering therapy in gout. Allopurinol hypersensitivity syndrome (AHS) is a rare but potentially fatal adverse event. Dosing guidelines based on creatinine clearance have been proposed based on the recognition that dosages of ≥300 mg/day may be associated with AHS, particularly in patients with renal impairment. However, the relationship between the allopurinol starting dose and AHS is unknown. This study was undertaken to determine the relationship between allopurinol dosing and AHS. METHODS: A retrospective case-control study of patients with gout who developed AHS between January 1998 and September 2010 was undertaken. For each case, 3 controls with gout who were receiving allopurinol but did not develop AHS were identified. Controls were matched with cases for sex, diuretic use at the time of initiating allopurinol, age (±10 years), and estimated glomerular filtration rate (estimated GFR). Starting dose and dose at the time of the reaction in cases were compared between cases and controls. RESULTS: Fifty-four AHS cases and 157 controls were identified. There was an increase in the risk of AHS as the starting dose of allopurinol corrected for the estimated GFR increased. For the highest quintile of starting dose per estimated GFR, the odds ratio was 23.2 (P < 0.01). Receiver operating characteristic analysis indicated that 91% of AHS cases and 36% of controls received a starting dose of allopurinol of ≥1.5 mg per unit of estimated GFR (mg/ml/minute). CONCLUSION: Our findings indicate that starting allopurinol at a dose of 1.5 mg per unit of estimated GFR may be associated with a reduced risk of AHS. In patients who tolerate allopurinol, the dose can be gradually increased to achieve the target serum urate level.

Previous studies examining blood pressure change over time have modeled an average population trajectory. Recent research among older adults suggests there may be subgroups with different blood pressure trajectories. Identifying subgroups at risk of developing adult hypertension early in life can inform effective risk reduction efforts. We sought to identify different systolic blood pressure trajectories from childhood, their correlated risk factors, and early-midlife cardiovascular outcomes. Blood pressure data at ages 7, 11, 18, 26, 32, and 38 years from a longitudinal, representative birth cohort study (n=975) were used to identify 4 distinct trajectory groups via group-based trajectory modeling: normal (21.8%), high-normal (43.3%), prehypertensive (31.6%), and hypertensive (4.2%). The categories refer to blood pressure beginning at the age of 7 years and most recently measured at the age of 38 years. Family history of high blood pressure (odds ratio [OR], 43.23; 95% confidence interval [CI], 5.27-354.65), male sex (OR, 109.48; 95% CI, 26.82-446.96), being first born (OR, 2.5; 95% CI, 1.00-8.69) and low birth weight (OR, 2.79; 95% CI, 2.49-3.09) were associated with hypertensive group membership (compared with the normal group). Higher body mass index and cigarette smoking resulted in increasing blood pressure across trajectories, particularly for the higher blood pressure groups. Prehypertensive and hypertensive trajectory groups had worse cardiovascular outcomes by early midlife. Harmful blood pressure trajectories are identifiable in childhood, associated with both antecedent and modifiable risk factors over time, and predict adult cardiovascular disease risk. Early detection and subsequent targeted prevention and intervention may reduce the lifecourse burden associated with higher blood pressure.

Cerebral autoregulation (CA) is a critical process for the maintenance of cerebral blood flow and oxygenation. Assessment of CA is frequently used for experimental research and in the diagnosis, monitoring, or prognosis of cerebrovascular disease; however, despite the extensive use and reference to static CA, a valid quantification of "normal" CA has not been clearly identified. While controlling for the influence of arterial Pco(2), we provide the first clear examination of static CA in healthy humans over a wide range of blood pressure. In 11 healthy humans, beat-to-beat blood pressure (radial arterial), middle cerebral artery blood velocity (MCAv; transcranial Doppler ultrasound), end-tidal Pco(2), and cerebral oxygenation (near infrared spectroscopy) were recorded continuously during pharmacological-induced changes in mean blood pressure. In a randomized order, steady-state decreases and increases in mean blood pressure (8 to 14 levels; range: approximately 40 to approximately 125 mm Hg) were achieved using intravenous infusions of sodium nitroprusside or phenylephrine, respectively. MCAv(mean) was altered by 0.82+/-0.35% per millimeter of mercury change in mean blood pressure (R(2)=0.82). Changes in cortical oxygenation index were inversely related to changes in mean blood pressure (slope=-0.18%/mm Hg; R(2)=0.60) and MCAv(mean) (slope=-0.26%/cm . s(-1); R(2)=0.54). There was a progressive increase in MCAv pulsatility with hypotension. These findings indicate that cerebral blood flow closely follows pharmacological-induced changes in blood pressure in otherwise healthy humans. Thus, a finite slope of the plateau region does not necessarily imply a defective CA. Moreover, with progressive hypotension and hypertension there are differential changes in cerebral oxygenation and MCAv(mean).

Reasons for the gender differences in prevalence rates for asthma remain unclear. We have examined the relationships between allergen skin-test reactions and diagnoses of hay fever and asthma in New Zealand boys and girls examined at the age of 13 years. Information on current and past wheezing, diagnosed asthma, and hay fever was obtained for 662 subjects (341 boys) of a birth cohort followed longitudinally to the age of 13 years, using a physician-administered questionnaire. Atopic status was determined by skin-prick tests to 11 common allergens. The proportion of 13-year-old boys with current asthma was 1.6 times higher and of ever-diagnosed asthma 1.4 times higher than in girls, but the prevalence of recurrent wheeze (> or = three episodes per year) not diagnosed as asthma, or of hay fever, was not significantly different between the sexes. The prevalence of diagnosed asthma increased with increasing numbers of positive skin tests, but hay fever without asthma was little affected above one positive skin-test. Boys had a greater prevalence of any positive skin-test (50.1% vs 37.1%), two or more positive tests (29.3% vs 21.8%), and responses to house dust mite (34.0% vs 23.1%) and cat (14.7% vs 11.2%). Gender differences for asthma became insignificant when adjusted for skin-test responsiveness to house dust mite and/or cat. The proportion of children with diagnosed asthma increased with increasing size of weals to house dust mite and cat dander. Gender differences in allergen sensitivities partly explain the gender differences in diagnosed asthma in children. In both sexes, risk of asthma was primarily associated with sensitization to indoor allergens (house dust mite and cat), and was related to the magnitude of the skin-test response, while the risk of hay fever was primarily associated with grass pollen sensitivity.

BACKGROUND: There have been many studies documenting adverse psychiatric consequences for people who have experienced childhood and adult sexual and physical abuse. These include posttraumatic stress disorder, anxiety, depression, substance abuse, eating disorders and probably some personality disorders or trait abnormalities. Much less is known about the links between abuse and physical/psychosomatic conditions in adult life. Hints of causal links are evident in the literature discussing headache, lower back pain, pelvic pain and irritable bowel syndrome. These studies are not definitive as they use clinic-based samples. METHODS: This study used interview data with a random community sample of New Zealand women, half of whom reported childhood sexual abuse and half who did not. Details about childhood physical abuse and adult abuse were also collected in a two-phase study. RESULTS: Complex relationships were found, as abuses tended to co-occur. Seven of 18 potentially relevant medical conditions emerged as significantly increased in women with one or more types of abuse. These were chronic fatigue, bladder problems, headache including migraine, asthma, diabetes and heart problems. Several of these associations with abuse are previously unreported. CONCLUSIONS: In this random community sample, a number of chronic physical conditions were found more often in women who reported different types of sexual and physical abuse, both in childhood and in adult life. The causal relationships cannot be studied in a cross-sectional retrospective design, but immature coping strategies and increased rates of dissociation appeared important only in chronic fatigue and headache, suggesting that these are not part of the causal pathway between abuse experiences and the other later physical health problems. This finding and the low co-occurrence of the identified physical conditions suggest relative specificity rather than a general vulnerability to psychosomatic conditions in women who have suffered abuses. Each condition may require separate further study.

BACKGROUND: Overactive bladder syndrome (OAB) is a common condition with a significant negative impact on quality of life characterised by urgency with or without urge incontinence, frequency and nocturia. Intravesical botulinum toxin is being increasingly used to treat severe overactive bladder refractory to standard management. An increasing body of literature is forming that supports this technique as effective, well tolerated, and safe. This review is a substantial update of the 2007 review of the same title. OBJECTIVES: The objective was to compare intravesical botulinum toxin with other treatments for neurogenic and idiopathic overactive bladder in adults. The hypothesis to be addressed were whether intravesical injection of botulinum toxin was better than placebo or no treatment; pharmacological and other non-pharmacological interventions; whether higher doses of botulinum toxin were better than lower doses; whether botulinum toxin in combination with other treatments was better than other treatments alone; whether one formulation of botulinum toxin is better than another; and whether one injection technique was better than another. SEARCH METHODS: We searched the Cochrane Incontinence Group Specialised Trials Register (searched 23 February 2010). The Register contains trials identified from MEDLINE, CINAHL, the Cochrane Central Register of Controlled Trials (CENTRAL), and handsearching of journals and conference proceedings. Additionally, all reference lists of selected trials and relevant review papers were searched. No limitations were placed on the searches. SELECTION CRITERIA: All randomised or quasi-randomised controlled trials of treatment for OAB in adults in which at least one management arm involved intravesical injection of botulinum toxin were included. Participants had either neurogenic OAB or idiopathic OAB with or without stress incontinence. Comparison interventions could include no intervention, placebo, lifestyle modification, bladder retraining, pharmacological treatments, surgery, bladder instillation techniques, neuromodulation, and different types, doses, and injection techniques of botulinum toxin. DATA COLLECTION AND ANALYSIS: Binary outcomes were presented as relative risk and continuous outcomes by mean differences. Little data could be synthesised across studies due to differing study designs and outcome measures. Where applicable standard deviations were calculated from P values according to the formula described in section 7.7.3.3 of the Cochrane Handbook of Systematic Reviews of Interventions. Data were tabulated where possible with results taken from trial reports where this was not possible. Where multiple publications were found, the reports were treated as a single source of data. MAIN RESULTS: Nineteen studies were identified that met the inclusion criteria. Most patients in the studies had neurogenic OAB, but some included patients with idiopathic OAB. All studies demonstrated superiority of botulinum toxin to placebo. Lower doses of botulinum toxin (100 to 150 U) appeared to have beneficial effects, but larger doses (300 U) may have been more effective and longer lasting, but with more side effects. Suburothelial injection had comparable efficacy to intradetrusor injection. The effect of botulinum toxin may last for a number of months and is dependent upon dose and type of toxin used. Patients receiving repeated doses do not seem to become refractory to botulinum toxin. Botulinum toxin appeared to have beneficial effects in OAB that quantitatively exceeded the effects of intravesical resiniferatoxin. Intravesical botulinum toxin appeared to be reasonably safe; however, one study was halted due to a perceived unacceptable rate of urinary retention. AUTHORS' CONCLUSIONS: Intravesical botulinum toxin appears to be an effective therapy for refractory OAB symptoms, but as yet little controlled trial data exist on benefits and safety compared with other interventions, or with placebo. Further robust data are required on long term outcomes, safety, and optimal dose of botulinum toxin for OAB.

1,1'-Carbonyldiimidazole, a carbonylating reagent, has been shown to be suitable for the activation of cross-linked agaroses for affinity chromatography. The activated matrix (an imidazolyl carbamate) is relatively stable to hydrolysis but smoothly reacts with N-nucleophiles such as those present in either affinity chromatography ligands or leashes, e.g. ethylenediamine or 6-aminohexanoic acid. If butylamine was attached via the 1,1'-carbonyldiimidazole method, the resulting product was devoid of charged groups and thus had the same titration curve as agarose. The suitability of this new matrix for affinity chromatography was demonstrated by the successful purification of trypsin by several different systems.

Recent multi-dimensional approaches to the study of complex disease have revealed powerful insights into how genetic and epigenetic factors may underlie their aetiopathogenesis. We examined genotype-epigenotype interactions in the context of Type 2 Diabetes (T2D), focussing on known regions of genomic susceptibility. We assayed DNA methylation in 60 females, stratified according to disease susceptibility haplotype using previously identified association loci. CpG methylation was assessed using methylated DNA immunoprecipitation on a targeted array (MeDIP-chip) and absolute methylation values were estimated using a Bayesian algorithm (BATMAN). Absolute methylation levels were quantified across LD blocks, and we identified increased DNA methylation on the FTO obesity susceptibility haplotype, tagged by the rs8050136 risk allele A (p = 9.40×10(-4), permutation p = 1.0×10(-3)). Further analysis across the 46 kb LD block using sliding windows localised the most significant difference to be within a 7.7 kb region (p = 1.13×10(-7)). Sequence level analysis, followed by pyrosequencing validation, revealed that the methylation difference was driven by the co-ordinated phase of CpG-creating SNPs across the risk haplotype. This 7.7 kb region of haplotype-specific methylation (HSM), encapsulates a Highly Conserved Non-Coding Element (HCNE) that has previously been validated as a long-range enhancer, supported by the histone H3K4me1 enhancer signature. This study demonstrates that integration of Genome-Wide Association (GWA) SNP and epigenomic DNA methylation data can identify potential novel genotype-epigenotype interactions within disease-associated loci, thus providing a novel route to aid unravelling common complex diseases.