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.

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.

Studies on antigen-antibody complexes. I. Elimination of soluble complexes from rabbit circulation.

Solid phase immunoadsorbents were prepared by coupling antigens to agarose. With this technique specific antibodies were easily isolated in large amounts. The gammaG-globulin class of antibodies isolated in this manner were not denatured as judged by their normal biological half-life in rabbits. Soluble immune complexes at fivefold antigen excess were prepared from isolated specific antibodies and HSA, human lambda-chains, human lambdaG-globulins, and a Waldenström's macroglobulin as antigens. In all these preparations a characteristic immune complex was encountered that represented the smallest stable antigen-antibody union. In the HSA-anti-HSA system they were found to be AgAb(2) complexes, and Ag(2)Ab complexes in the gammaG-anti-gammaG system. These stable complexes fixed complement ineffectively. Also, a spectrum of larger complexes was present in each system, and these complexes fixed complement effectively. With intact antibodies the disappearance curves of immune complexes from the circulation were composed of three exponential components. The immune complexes larger than AgAb(2) were quickly removed from the circulation with half-lives of 0.09-0.37 hr. Their clearance was not dependent on complement components, in that depletion of complement by cobra venom factor and aggregated gammaG-globulin did not alter the pattern of their removal from the circulation. However, when the interchain disulfide bonds of antibodies were reduced and alkylated, the removal of the lambda-anti-lambda, HSA-anti-HSA, and gammaG-anti-gammaG complexes was altered. In these experiments the disappearance curves were composed of two exponential components and the rapid removal of the greater than AgAb(2) complexes did not occur. The immune complexes prepared from reduced and alkylated antibodies fixed complement ineffectively. The presented data indicate that the rapid removal of circulating immune complexes, containing gammaG-globulin molecules as antibodies, depends primarily on the number of antibodies involved. Furthermore, complement fixation is not involved in the rapid removal of such complexes. Nevertheless, the rapid removal of immune complexes and their ability to fix complement have similarities for optimal function in that both processes require intact interchain disulfide bonds of antibodies and complexes that exceed the AgAb(2) combination.

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.

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.

An unusual case of Ecstasy poisoning.

We describe a case of poisoning with 3,4-methylenedioxymet-amphetamine Ecstasy that presented with all the features suggestive of a fatal outcome, including a creatinine phosphokinase level markedly higher than any previously reported. The patient, a paraplegic, was treated with dantrolene and made a full recovery.

An investigation into the effects of midazolam and propofol on human respiratory cilia beat frequency in vitro.

OBJECTIVE: Patients in intensive care are known to be prone to both upper and lower respiratory tract infection. Respiratory mucus forms a barrier to infection. Mucus transport rate (MTR) depends upon both the physical properties of mucus and the action of respiratory cilia. Patients undergoing anaesthesia are known to have a reduced MTR that may be related to a depressant effect on cilia beat frequency (CBF) by anaesthetic drugs. The aim of this study was to investigate the effects of two commonly used intensive care sedative agents, midazolam and propofol, on CBF using human nasal turbinate explants in vitro. DESIGN: We exposed ciliated tissue from human nasal turbinate explants to midazolam and propofol in supraclinical concentrations (20 microM midazolam and 70 microM propofol) in a controlled and blinded manner for 90 min and measured CBF by the transmitted light technique. RESULTS: After 90 min, mean (SEM) CBF in the group exposed to midazolam and its control group were 13.0 (0.2) Hz and 12.9 (0.3) Hz, respectively. Mean (SEM) CBF in the group exposed to propofol was 13.6 (0.4) Hz and in the control group the value was 12.0 (0.6) Hz. There was no significant change in CBF (midazolam: p = 0.21, propofol: p = 0.31, MANOVA for repeated measures). CONCLUSIONS: We have found no effect of midazolam or propofol in supra-clinical concentrations upon CBF in human turbinate explants after a 90-min exposure. This contrasts with previous work that has shown a depressant effect of inhalational anaesthetic agents on CBF.

Single-dose therapy of Falciparum malaria using pyrimethamine in combination with diformyldapsone or sulfadoxine.

Patients with naturally acquired chloroquine-resistant falciparum malaria were studied in Thailand. The fixed combination of pyrimethamine 75 mg and sulfadoxine 1,500 mg (adult dose) cured 85% of patients with an average pretreatment parasite count of 60,000 per mm(3). The fixed combination of pyrimethamine 50 mg and 800 mg diformyldapsone (DFD) cured 43% of patients with an average pretreatment parasite count of only 17,000 per mm(3). The difference in cure rates was statistically significant (p less than 0.01). Pyrimethamine alone was ineffective. Pyrimethamine-DFD, in the dose tested, was not sufficiently active for the treatment of established infections. Pyrimethamine-sulfadoxine did produce an acceptable cure rate but clinical improvement was often slow. We do not recommend that pyrimethamine-sulfadoxine be administered alone. Optimal results are obtained when a short course of quinine (2 to 6 days) is given until parasitemia has been eliminated, then a dose of pyrimethamine-sulfadoxine to assist in the radical cure of the falciparum infection. A modification to the W.H.O. classification is suggested. An RIII response (early treatment failure) is diagnosed if the patient's clinical condition and/or parsite density worsens within a few hours after administration of the test regimen; distinct improvement occurring within a few hours of the subsequent initiation of an intravenous infusion of quinine confirms the diagnosis of an RIII response. The RII response has been defined as marked reduction, but not clearance of asexual parasitemia. It is suggested that an RII response may be diagnosed before 7 days have elapsed.

Amodiaquine resistant falciparum malaria in Thailand.

Amodiaquine cured 38% (13/34) of patients with falciparum malaria in Southeast Thailand. Chloroquine cured 0% (0/13). The cure rates with amodiaquine were the same whether a 1.5 g or 2.0 g course was used. Most patients were resistant to amodiaquine at the RI level and to chloroquine at the RII level. In hospital, amodiaquine cleared parasitemia more frequently than did chloroquine. With the 2.0 g course of amodiaquine, the parasite clearance time was 77 hours; the fever clearance time of 36 hours was low and suggests that amodiaquine does not cause a drug fever. Because of resistance, chloroquine should not be used for falciparum malaria in Thailand. Routine use of amodiaquine is not indicated because more effective drugs are available.

Cytogenetic study of a sclerosing stromal tumor of the ovary.

We describe a sclerosing stromal tumor (SST) of the ovary with monosomy of chromosome 16 and pathologic features consistent with a low-grade malignancy. So far, all described cases of SST were considered benign.

The treatment of severe falciparum malaria.

In severe falciparum malaria there is a pathophysiological cascade beginning with changes in the parasitized red blood cells which induce intermediate effects, in turn contributing to dysfunction of several organs. A low serum albumin is a common but often unrecognized finding which may contribute to oedema especially in the lung and brain. The only irreversible complication in falciparum malaria is the acute respiratory distress syndrome, manifested by cyanosis and rapid breathing, basically distinct from acute pulmonary oedema caused by therapeutic overhydration. The pathophysiology of falciparum malaria may be complex but the treatment is simple. Drugs, other than antimalarials, are rarely needed. Guidelines for cholorquine or quinine dosage in severe disease are proposed; each drug is given at a dose of 5 to 10 mg/kg in 10 ml/kg of fluid as an intravenous infusion in four hours at a frequency of dosing every 12 to 24 hours. When the disease has been brought under control the treatment should be changed from the intravenous to the oral route.

Comparison of a 9-phenanthrene methanol (WR33063), a 4-quinoline methanol (WR30090), and quinine for falciparum malaria in Thailand.

Quinine was compared with a 9-phenanthrene methanol (WR33063) and a 4-quinoline methanol (WR30090) for the treatment of 207 patients with falciparum malaria in Southeast Thailand. Quinine eradicated parasitaemia (average 70 hours) more rapidly than either WR30090 (72 hours) or WR33063 (77 hours). But WR33063 had a higher cure rate (92%) than WR30090 (86%) or quinine (85%). The mean duration of fever and of parasitaemia were combined with the failure rate to form an arbitrary efficacy index. Using this concept WR33063 was the most effective drug. The recrudescence rate correlated with the degree and duration of parasitaemia and with the duration of fever. WR33063 was the least toxic drug. Side effects associated with WR30090 appeared to be headache, backache and urticaria. Quinine was the most toxic drug. All 3 drugs were inconvenient in having to be administered every 8 hours for 6 days. One patient did not respond to oral quinine but did respond to an intravenous quinine infusion (IVQ). A "Medication Ward Round" was perfected during the study and comprised sequential history, drug administration, physical examination, dose notation and patient observation. Falciparum nephrosis was diagnosed in one patient.

The decision to operate in rheumatoid arthritis.

The physician caring for the patient with rheumatoid arthritis should not look upon surgery as a last resort to be turned to when all else has failed and the situation is desperate. Surgical intervention may be important at any stage in the disease. Wrist fusion to obliterate pain and to restore a strong grip is advantageous whenever pain and instability compromise the function of that extremity. The knee with good painless flexion and extension cannot help but insure the patient's ability to get up and down from a chair. There are many goals that may be achieved through surgical intervention, and each of these should be considered and reviewed every time the physician sees the patient. Consider the benefits of prevention of disease progression, the stopping of bone resorption, the relief of pain, the restoration of motion, strength, and stability, and the preservation or restoration of the patient's confidence and determination to remain an independent member of society.

A questionnaire survey of the prevalence of scrapie in sheep in Britain.

An anonymous, self-administered questionnaire has been used in two independent surveys to try to determine the prevalence of scrapie in the national sheep flock. The disease was recorded in 35 counties in England and Wales. About a third (26.5 and 37.3 percent) of respondents owning 100 or more sheep indicated that they had seen sheep with scrapie in their flocks. The incidences of clinical cases recorded in affected flocks in the two surveys were 0.5 and 1.1 cases/100 ewes/year. At present there is no control over the disposal of these animals. If as has been suggested, an increase in the prevalence of scrapie was a contributory factor in the emergence of bovine spongiform encephalopathy, it would seem logical that measures should be introduced to monitor the prevalence and incidence of scrapie and to control the disposal of clinical cases.

Severity of imported falciparum malaria: effect of taking antimalarial prophylaxis.

OBJECTIVE: To investigate the effects of antimalarial chemoprophylaxis and other variables on the severity of falciparum malaria. DESIGN: Review of consecutive malaria cases between 1987 and 1991. SETTING: The Hospital for Tropical Diseases, London. SUBJECTS: 250 consecutive cases of mild and 51 consecutive cases of severe falciparum malaria. RESULTS: Prophylaxis was taken in 52.4% (131/250) of the cases of mild malaria and 21.6% (11/51) of cases of severe malaria. Severe malaria was more common in white patients than in those of African origin and was also seen more commonly in people returning from central, southern, and east Africa than in those returning from west Africa. Patients with severe malaria presented sooner than patients with mild malaria. CONCLUSIONS: Prior chemoprophylaxis led to a reduction in the severity of falciparum malaria. Ethnic origin, time to presentation, and sex were also associated with the severity of malaria.

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.

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.