Device-measured physical activity and its association with physical function in adults with type 2 diabetes mellitus.

AIM: To quantify how differences in metrics characterizing physical activity and sedentary behaviour in type 2 diabetes are associated with physical function. METHODS: This analysis included participants' data from the Chronotype of Patients with Type 2 Diabetes and Effect on Glycaemic Control (CODEC) cross-sectional study. Data were stratified into two groups according to their short physical performance battery (SPPB) score (impaired physical function = SPPB < 10 and normal physical function = SPPB ≥ 10). Hand-grip strength, sit-to-stand 60 (STS-60) and the Duke Activity Status Index (DASI) score were used to assess functional capacity, while physical activity metrics were measured with a wrist-worn accelerometer. The associations between physical activity metrics and measures of functional capacity were analysed using generalized linear modelling. RESULTS: Some 635 adults (median age 66 years, 34% female) were included in this analysis. Overall, 29% of the cohort scored < 10 in the SPPB test indicating impaired physical function. This group spent more time in prolonged sedentary behaviour (600.7 vs. 572.5 min) and undertook less-intense physical activity. Each sd increase in physical activity volume and intensity gradients for those with impaired physical function was associated with 17% more repetitions for STS-60 with similar associations seen for DASI score. Each sd in sedentary time was associated with 15% fewer repetitions in STS-60 and 16% lower DASI score in those with impaired physical function, whereas in normal physical function group it was 2% and 1%, respectively. CONCLUSIONS: The strength of the associations for physical activity measures and functional capacity were modified by physical function status, with the strongest association seen in those with impaired physical function.

Sleep duration, obesity and insulin resistance in a multi-ethnic UK population at high risk of diabetes.

AIMS: Investigating the association between sleep duration, obesity, adipokines and insulin resistance (via Leptin:Adiponectin ratio (LAR)), in those at high risk of type 2 diabetes mellitus (T2DM). METHODS: Adults with impaired glucose regulation (IGR) were included. Fasting bloods for inflammatory biomarkers and glycaemic status, 2-h glucose, anthropometrics, objective physical activity, and self-reported sleep were collected. The average number of hours slept in a 24 h period was categorised as ≤5.5, 6-6.5, 7-7.5, 8-8.5, and ≥9 h. Regression models were fitted with sleep (linear and quadratic) and logistic regression used for IGR and adjusted for age, sex, ethnicity, body mass index, waist circumference and objective physical activity. RESULTS: 2848 participants included (593 with inflammatory marker data). Short sleep and long sleep duration were significantly independently associated with higher body mass index (P < 0.001), body weight (P < 0.01), and waist circumference (P < 0.001). 6-7 h of sleep/24 h is associated with the lowest obesity measures. Fasting insulin and LAR were positively associated with sleep duration. Adiponectin levels were negatively associated with sleep duration. CONCLUSIONS: These results support the evidence of an association between short and long sleep duration and indices of obesity. We demonstrate an independent relationship between long sleep duration and insulin resistance.

Preclinical toxicity of AZD7969: Effects of GSK3ß inhibition in adult stem cells.

AZD7969 is a potent inhibitor of glycogen synthase kinase 3 (GSK3ß), which is a multifunctional serine/threonine kinase that negatively regulates the Wnt/ß-catenin signaling pathway. Treatment of rats and dogs with AZD7969 for periods of up to 4 weeks resulted in a number of changes, the most significant of which was a dose-dependent, and treatment-related, increase in proliferation in a number of tissues that was thought to arise from derepression of Wnt/ß-catenin signaling in the stem cell compartment. Phenotypically, this resulted in hyperplasia that either maintained normal tissue architecture in the gastrointestinal tract, liver, kidney, and adrenals or effaced normal tissue architecture within the bones, incisor teeth, and femorotibial joint. In addition to these changes, we noted a treatment-related increase in iron loading in the liver and proximal small intestines. This off-target effect was robust, potent, and occurred in both dogs and rats suggesting that AZD7969 might be a useful tool compound to study iron storage disorders in the laboratory.

Liver hypertrophy: a review of adaptive (adverse and non-adverse) changes--conclusions from the 3rd International ESTP Expert Workshop.

Preclinical toxicity studies have demonstrated that exposure of laboratory animals to liver enzyme inducers during preclinical safety assessment results in a signature of toxicological changes characterized by an increase in liver weight, hepatocellular hypertrophy, cell proliferation, and, frequently in long-term (life-time) studies, hepatocarcinogenesis. Recent advances over the last decade have revealed that for many xenobiotics, these changes may be induced through a common mechanism of action involving activation of the nuclear hormone receptors CAR, PXR, or PPARα. The generation of genetically engineered mice that express altered versions of these nuclear hormone receptors, together with other avenues of investigation, have now demonstrated that sensitivity to many of these effects is rodent-specific. These data are consistent with the available epidemiological and empirical human evidence and lend support to the scientific opinion that these changes have little relevance to man. The ESTP therefore convened an international panel of experts to debate the evidence in order to more clearly define for toxicologic pathologists what is considered adverse in the context of hepatocellular hypertrophy. The results of this workshop concluded that hepatomegaly as a consequence of hepatocellular hypertrophy without histologic or clinical pathology alterations indicative of liver toxicity was considered an adaptive and a non-adverse reaction. This conclusion should normally be reached by an integrative weight of evidence approach.

Life-threatening overdose with lamotrigine, citalopram, and chlorpheniramine.

Lamotrigine is a commonly used agent for seizure control in epilepsy. There are limited data on the adverse effects of lamotrigine in overdose. We report a number of serious side-effects associated with a large overdose of lamotrigine. A 23-year-old female presented to the emergency department after taking an intentional overdose of 9.2 g of lamotrigine, 56 mg of chlorpheniramine, and 220 mg of citalopram. On admission, she had a reduced level of consciousness and electrocardiographic abnormalities; a widened QRS and a prolonged corrected QT (QTc) interval. Prompt treatment with early intubation, along with the use of magnesium for cardioprotection and administration of sodium bicarbonate may have aided in a quick recovery with a short intensive care stay and good outcome.

Acute toxic effects of 'Ecstasy' (MDMA) and related compounds: overview of pathophysiology and clinical management.

Since the late 1980s 'Ecstasy' (3,4-methylenedioxymethamphetamine, MDMA) has become established as a popular recreational drug in western Europe. The UK National Criminal Intelligence Service estimates that 0.5-2 million tablets are consumed weekly in Britain. It has been reported that 4.5% of young adults (15-34 yr) in the UK have used MDMA in the previous 12 months. Clinically important toxic effects have been reported, including fatalities. While the phenomenon of hyperpyrexia and multi-organ failure is now relatively well known, other serious effects have become apparent more recently. Patients with acute MDMA toxicity may present to doctors working in Anaesthesia, Intensive Care and Emergency Medicine. A broad knowledge of these pathologies and their treatment is necessary for anyone working in an acute medical speciality. An overview of MDMA pharmacology and acute toxicity will be given followed by a plan for clinical management.

Toxic epidermal necrolysis: current evidence, practical management and future directions.

Toxic epidermal necrolysis (TEN) is a rare disorder characterized by extensive epidermal death. Almost all cases appear to be caused by an idiosyncratic drug reaction. Proposed pathogenic mechanisms are conflicting, and the evidence for the benefits of individual treatments is inadequate, and in some cases contradictory. The mortality rate remains high. We review the literature pertaining to the pathogenesis of TEN and drug reactions in general. The rationale for therapeutic interventions, together with reported evidence of efficacy, are considered. We present a composite model of TEN, based on previous work and suggested pathogeneses of TEN, mechanisms of drug reactions and reported cytotoxic lymphocyte (CTL) cytolytic pathways. In this system, TEN, like some other cutaneous drug eruptions, is an HLA class I-restricted, specific drug sensitivity, resulting in clonal expansion of CD8+ CTLs. Cytotoxicity is mediated by CTL granzyme and possibly death receptor (DR) ligand (DR-L), probably Fas ligand (FasL). Particular to TEN, there is then an amplification sequence involving further DR-L expression. FasL is likely to be particularly important but tumour necrosis factor (TNF) may well contribute, via the TNF receptor 1 (TNF-R1) death pathway. Alternatively, we suggest the possibility of upregulation of an antiapoptotic TNF-R1-nuclear factor kappaB pathway, which would proscribe treatments which downregulate this pathway. None of the published data on individual treatment efficacies is sufficiently strong to suggest a definitive single treatment. Currently a multifaceted regimen appears indicated, targeting various likely intermediary mechanisms, including elimination of residual drug, immunosuppression, inhibition of DR pathways, general antiapoptotic strategies, and aggressive supportive care. Particular attention has been directed at avoiding potential conflicts between different treatments and avoiding agents that theoretically might have a net proapoptotic rather than antiapoptotic effect. Nursing on a specialized unit is of paramount importance.

A new approach to the solution of the linear mixing model for a single isotope: application to the case of an opportunistic predator.

Mixing models are used to determine diets where the number of prey items are greater than one, however, the limitation of the linear mixing method is the lack of a unique solution when the number of potential sources is greater than the number (n) of isotopic signatures +1. Using the IsoSource program all possible combinations of each source contribution (0-100%) in preselected small increments can be examined and a range of values produced for each sample analysed. We propose the use of a Moore Penrose (M-P) pseudoinverse, which involves the inverse of a 2x2 matrix. This is easily generalized to the case of a single isotope with (p) prey sources and produces a specific solution. The Antarctic leopard seal (Hydrurga leptonyx) was used as a model species to test this method. This seal is an opportunistic predator, which preys on a wide range of species including seals, penguins, fish and krill. The M-P method was used to determine the contribution to diet from each of the four prey types based on blood and fur samples collected over three consecutive austral summers. The advantage of the M-P method was the production of a vector of fractions f for each predator isotopic value, allowing us to identify the relative variation in dietary proportions. Comparison of the calculated fractions from this method with 'means' from IsoSource allowed confidence in the new approach for the case of a single isotope, N.

Comparison of different doses of remifentanil on the cardiovascular response to laryngoscopy and tracheal intubation.

We have compared three bolus and infusion regimens of remifentanil on the cardiovascular response to laryngoscopy and orotracheal intubation in three groups of 20 ASA I-II female patients, in a randomized, double-blind study. Patients in group 1 received glycopyrolate 200 micrograms i.v. followed by a bolus dose of remifentanil 1 microgram kg-1 over 30 s and an infusion of remifentanil at a rate of 0.5 microgram kg-1 min-1. The other patients received remifentanil 0.5 microgram kg-1 over 30 s and an infusion of 0.25 microgram kg-1 min-1 with (group 2) or without (group 3) pretreatment with glycopyrrolate 200 micrograms. All patients then received a sleep dose of propofol, rocuronium 0.6 mg kg-1 and 1% isoflurane with 67% nitrous oxide in oxygen. Laryngoscopy and tracheal intubation were performed 3 min later. Heart rate and arterial pressure were recorded at 1-min intervals from before induction of anaesthesia until 5 min after intubation. Baseline heart rate was similar in all groups, but decreased in group 3 (no glycopyrrolate) after induction and remained significantly lower after intubation compared with the other groups (P < 0.05). Heart rate and arterial pressure increased slightly after intubation in each group but there were no significant differences in mean arterial pressure between groups at any time. The incidence of bradycardia (one patient in group 2) and hypotension (two patients in groups 1 and 2 and three patients in group 3) was low.

Acute generalized exanthematous pustulosis associated with oral terbinafine.

A case history of acute generalized exanthematous pustulosis (AGEP) following oral terbinafine is reported. A 64-year-old woman presented with a rapidly spreading micropustular eruption 3 days after completing a 28-day course of oral terbinafine. There was a positive family history of psoriasis but no personal history. The clinical presentation and histopathology were consistent with AGEP. There was nearly complete resolution of the pustular eruption within 3.5 weeks following cessation of oral terbinafine and treatment with topical and systemic corticosteroids. The patient has remained free of any recurrence 18 months later. A summary of drugs known to be associated with AGEP is presented. Prompt recognition of AGEP is stressed in order to avoid confusion with acute generalized pustular psoriasis or a systemic infection. The most important aspect of management is the immediate withdrawal of the suspect drug.

Common red scaly rashes. Traps for the unwary--Part 2.

BACKGROUND: Red scaly rashes often provide difficulties for GPs leading to a 'try and see' approach which, although successful on many occasions, may delay adequate treatment when there is lack of a correct diagnosis. OBJECTIVE: A study of 61 GPs' knowledge of the diagnosis and treatment of a number of red scaly rashes, was undertaken with the use of photographs and clinical history. The study highlighted areas of uncertainty particularly in diagnosis, but also in treatment of common red scaly rashes. On the basis of their responses, practical tips have been suggested to overcome them. DISCUSSION: Simple diagnostic procedures that can be done within the general practice setting include biopsy, skin scrapings and fungal microscopy. They have been highlighted as an important component of the approach to diagnosis of common red scaly rashes. While the study showed a substantial proportion of correct treatment being recommended, there was still an area of need, particularly in diagnosis, which could be enhanced by learning these simple techniques.

Pustular vasculitis of the hands.

A case of pustular vasculitis of the hands with evidence of systemic involvement is described. A 64-year-old woman presented with a 2-day history of large, tense bullae arranged symmetrically over the dorsum of the three radial digits and extending on to the radial aspect of the dorsum of each hand. The bullae caused some discomfort and prevented normal use of her hands. There was no response to antibiotic therapy initiated prior to referral to hospital. Initial investigations revealed a raised white cell count with a neutrophilia, a raised erythrocyte sedimentation rate and a raised C-reactive protein. Abnormalities of liver function were detected. Aspirates from the bullae and blood cultures were sterile. The histology of debrided tissue demonstrated a florid neutrophilic dermal infiltrate with many blood vessels associated with prominent fibrin. A diagnosis of pustular vasculitis of the hands was made. The bullae were surgically debrided and treatment with oral corticosteroids was started. Two days after commencement of oral prednisolone, a crusted pustule appeared on her upper cutaneous lip. There was rapid resolution of both the vasculitis of the hands and the pustule on her upper lip following an increase in the dose of oral prednisolone. The patient was discharged on the seventeenth day following admission.

Upper airway reactivity and upper respiratory tract infection: effect of nebulized lidocaine.

Patients presenting for elective anaesthesia and surgery may be suffering with, or recovering from, a recent upper respiratory tract infection. Airway reflexes are heightened and these individuals may be more likely to suffer airway complications on administration of general anaesthesia. We have examined the effect of nebulized lidocaine on upper airway reflexes in such subjects. Using dilute ammonia as a chemical stimulus to the upper airway, we measured upper airway reactivity in 15 volunteers (aged 22-43 yr) with symptoms of an upper respiratory tract infection for 4 days or less. The threshold concentration of ammonia producing a brief reduction in inspiratory flow was determined. Measurements were made before and after administration of a nebulized solution of 4% lidocaine 4 ml or saline. After a 2-h interval the procedure was repeated with the alternative solution. The order of administration was randomized. The observer was blind to the solution given. Ammonia threshold was found to increase in subjects after nebulized lidocaine, from a median value of 327 (range 76-878) ppm to 878 (251-1620) ppm (P = 0.0007, Wilcoxon); there was no significant change after nebulized saline. After a convalescence period of at least 4 weeks, with no return of symptoms in the preceding 2 weeks, ammonia threshold was reassessed. It was found to be increased in all 15 subjects. Comparison of the five different times of measurement showed a highly significant difference (P < 0.001, Friedman). Subsequent analysis showed significant differences (P < 0.05, Wilcoxon) between convalescent ammonia threshold and both baseline and post-saline nebulizer values. There was no significant difference between convalescent and post-lidocaine ammonia threshold. We conclude that in adult subjects, nebulized lidocaine attenuated the heightened airway reflex sensitivity associated with symptoms and signs of upper respiratory tract infection.

Common red scaly rashes. Traps for the unwary--Part 1.

BACKGROUND: Red scaly rashes often provide difficulties for general practitioners leading to a 'try and see' approach which, although successful on many occasions, may delay adequate treatment when there is lack of a correct diagnosis. OBJECTIVE: A study of 61 general practitioners, providing them with photographs and clinical history, highlighted areas of uncertainty particularly in diagnosis, but also in treatment of common red scaly rashes including seborrhoeic dermatitis, pityriasis versicolor, psoriasis, superficial basal cell carcinoma, eczema, and tinea. On the basis of their responses, practical tips have been suggested to overcome them. DISCUSSION: Simple diagnostic procedures that can be done within the general practice setting include biopsy, skin scrapings and fungal microscopy. They have been highlighted as an important component of the approach to diagnosis of common red scaly rashes. While the study showed a substantial proportion of correct treatment being recommended, there was still an area of need, particularly in diagnosis, which could be enhanced by learning these simple techniques.