Exploring residual risk for diabetes and microvascular disease in the Diabetes Prevention Program Outcomes Study (DPPOS).

AIM: Approximately half of the participants in the Diabetes Prevention Outcomes Study (DPPOS) had diabetes after 15 years of follow-up, whereas nearly all the others remained with pre-diabetes. We examined whether formerly unexplored factors in the DPPOS coexisted with known risk factors that posed additional risk for, or protection from, diabetes as well as microvascular disease. METHODS: Cox proportional hazard models were used to examine predictors of diabetes. Sequential modelling procedures considered known and formerly unexplored factors. We also constructed models to determine whether the same unexplored factors that associated with progression to diabetes also predicted the prevalence of microvascular disease. Hazard ratios (HR) are per standard deviation change in the variable. RESULTS: In models adjusted for demographics and known diabetes risk factors, two formerly unknown factors were associated with risk for both diabetes and microvascular disease: number of medications taken (HR = 1.07, 95% confidence intervals (95% CI) 1.03 to 1.12 for diabetes; odds ratio (OR) = 1.10, 95% CI 1.04 to 1.16 for microvascular disease) and variability in HbA1c (HR = 1.02, 95% CI 1.01 to 1.03 for diabetes; OR = 1.06, 95% CI 1.04 to 1.09 for microvascular disease per sd). Total comorbidities increased risk for diabetes (HR = 1.10, 95% CI 1.04 to 1.16), whereas higher systolic (OR = 1.22, 95% CI 1.13 to 1.31) and diastolic (OR = 1.14, 95% CI 1.05 to 1.22) blood pressure, as well as the use of anti-hypertensives (OR = 1.41, 95% CI 1.23 to 1.62), increased risk of microvascular disease. CONCLUSIONS: Several formerly unexplored factors in the DPPOS predicted additional risk for diabetes and/or microvascular disease - particularly hypertension and the use of anti-hypertensive medications - helping to explain some of the residual disease risk in participants of the DPPOS.

Methylomic changes during conversion to psychosis.

The onset of psychosis is the consequence of complex interactions between genetic vulnerability to psychosis and response to environmental and/or maturational changes. Epigenetics is hypothesized to mediate the interplay between genes and environment leading to the onset of psychosis. We believe we performed the first longitudinal prospective study of genomic DNA methylation during psychotic transition in help-seeking young individuals referred to a specialized outpatient unit for early detection of psychosis and enrolled in a 1-year follow-up. We used Infinium HumanMethylation450 BeadChip array after bisulfite conversion and analyzed longitudinal variations in methylation at 411 947 cytosine-phosphate-guanine (CpG) sites. Conversion to psychosis was associated with specific methylation changes. Changes in DNA methylation were significantly different between converters and non-converters in two regions: one located in 1q21.1 and a cluster of six CpG located in GSTM5 gene promoter. Methylation data were confirmed by pyrosequencing in the same population. The 100 top CpGs associated with conversion to psychosis were subjected to exploratory analyses regarding the related gene networks and their capacity to distinguish between converters and non-converters. Cluster analysis showed that the top CpG sites correctly distinguished between converters and non-converters. In this first study of methylation during conversion to psychosis, we found that alterations preferentially occurred in gene promoters and pathways relevant for psychosis, including oxidative stress regulation, axon guidance and inflammatory pathways. Although independent replications are warranted to reach definitive conclusions, these results already support that longitudinal variations in DNA methylation may reflect the biological mechanisms that precipitate some prodromal individuals into full-blown psychosis, under the influence of environmental factors and maturational processes at adolescence.

Adiponectin, C-reactive protein, fibrinogen and tissue plasminogen activator antigen levels among glucose-intolerant women with and without histories of gestational diabetes.

AIM: To examine concentrations of biomarkers (adiponectin, C-reactive protein, fibrinogen and tissue plasminogen-activator antigen) associated with glucose homeostasis and diabetes risk by history of gestational diabetes (GDM). METHODS: We conducted a secondary analysis of the Diabetes Prevention Program, a randomized trial of lifestyle intervention or metformin for diabetes prevention. At baseline, participants were overweight and had impaired glucose tolerance. Biomarkers at baseline and 1 year after enrolment were compared between parous women with (n = 350) and without histories of GDM (n = 1466). Cox proportional hazard models evaluated whether history of GDM was associated with diabetes risk, after adjustment for baseline biomarker levels as well as for change in biomarker levels, demographic factors and anthropometrics. RESULTS: At baseline, women with histories of GDM had lower adiponectin (7.5 µg/ml vs. 8.7 µg/ml; p < 0.0001) and greater log C-reactive protein (-0.90 mg/l vs. -0.78 mg/l, p = 0.04) levels than women without histories of GDM, but these associations did not persist after adjustment for demographic factors. Fibrinogen and tissue plasminogen-activator antigen were similar between women with and without histories of GDM. Women with and without histories of GDM had a similar pattern of changes in biomarkers within randomization arm. Adjustment for age, race/ethnicity, baseline weight, change in weight, baseline biomarker level and change in biomarker level did not significantly alter the association between history of GDM, and diabetes risk. CONCLUSIONS: Among women with impaired glucose tolerance, biomarkers in women with and without histories of GDM are similar and respond similarly to lifestyle changes and metformin. Adjustment for biomarker levels did not explain the higher risk of diabetes observed in women with histories of GDM.

Modeling the clinical and economic implications of obesity using microsimulation.

OBJECTIVES: The obesity epidemic has raised considerable public health concerns, but there are few validated longitudinal simulation models examining the human and economic cost of obesity. This paper describes a microsimulation model as a comprehensive tool to understand the relationship between body weight, health, and economic outcomes. METHODS: Patient health and economic outcomes were simulated annually over 10 years using a Markov-based microsimulation model. The obese population examined is nationally representative of obese adults in the US from the 2005-2012 National Health and Nutrition Examination Surveys, while a matched normal weight population was constructed to have similar demographics as the obese population during the same period. Prediction equations for onset of obesity-related comorbidities, medical expenditures, economic outcomes, mortality, and quality-of-life came from published trials and studies supplemented with original research. Model validation followed International Society for Pharmacoeconomics and Outcomes Research practice guidelines. RESULTS: Among surviving adults, relative to a matched normal weight population, obese adults averaged $3900 higher medical expenditures in the initial year, growing to $4600 higher expenditures in year 10. Obese adults had higher initial prevalence and higher simulated onset of comorbidities as they aged. Over 10 years, excess medical expenditures attributed to obesity averaged $4280 annually-ranging from $2820 for obese category I to $5100 for obese category II, and $8710 for obese category III. Each excess kilogram of weight contributed to $140 higher annual costs, on average, ranging from $136 (obese I) to $152 (obese III). Poor health associated with obesity increased work absenteeism and mortality, and lowered employment probability, personal income, and quality-of-life. CONCLUSIONS: This validated model helps illustrate why obese adults have higher medical and indirect costs relative to normal weight adults, and shows that medical costs for obese adults rise more rapidly with aging relative to normal weight adults.

Localisation and composition of skeletal muscle diacylglycerol predicts insulin resistance in humans.

AIMS/HYPOTHESIS: We sought to evaluate if the cellular localisation and molecular species of diacylglycerol (DAG) were related to insulin sensitivity in human skeletal muscle. METHODS: Healthy sedentary obese controls (Ob; n = 6; mean±SEM age 39.5 ± 2.3 years; mean ± SEM BMI 33.3 ± 1.4 kg/m(2)), individuals with type 2 diabetes (T2D; n = 6; age 44 ± 1.8 years; BMI 30.1 ± 2.3 kg/m(2)), and lean endurance-trained athletes (Ath; n = 10; age 35.4 ± 3.1 years; BMI 23.3 ± 0.8 kg/m(2)) were studied. Insulin sensitivity was determined using an IVGTT. Muscle biopsy specimens were taken after an overnight fast, fractionated using ultracentrifugation, and DAG species measured using liquid chromatography/MS/MS. RESULTS: Total muscle DAG concentration was higher in the Ob (mean ± SEM 13.3 ± 1.0 pmol/µg protein) and T2D (15.2 ± 1.0 pmol/µg protein) groups than the Ath group (10.0 ± 0.78 pmol/µg protein, p = 0.002). The majority (76-86%) DAG was localised in the membrane fraction for all groups, but was lowest in the Ath group (Ob, 86.2 ± 0.98%; T2D, 84.2 ± 1.2%; Ath, 75.9 ± 2.7%; p = 0.008). There were no differences in cytoplasmic DAG species (p > 0.12). Membrane DAG species C18:0/C20:4, Di-C16:0 and Di-C18:0 were significantly more abundant in the T2D group. Cytosolic DAG species were negatively related to activation of protein kinase C (PKC)ε but not PKCθ, whereas membrane DAG species were positively related to activation of PKCε, but not PKCθ. Only total membrane DAG (r = -0.624, p = 0.003) and Di-C18:0 (r = -0.595, p = 0.004) correlated with insulin sensitivity. Disaturated DAG species were significantly lower in the Ath group (p = 0.001), and significantly related to insulin sensitivity (r = -0.642, p = 0.002). CONCLUSIONS/INTERPRETATION: These data indicate that both cellular localisation and composition of DAG influence the relationship to insulin sensitivity. Our results suggest that only saturated DAG in skeletal muscle membranes are related to insulin resistance in humans.

Prophylactic oral dolasetron mesylate reduces nausea and vomiting after abdominal hysterectomy. The Canadian Dolasetron Study Group.

PURPOSE: The incidence of postoperative nausea and vomiting (PONV) varies from 50% to 75% after gynaecological surgery under general anaesthesia. This study evaluates the dose-response relationships, safety, and efficacy of the new 5-HT3 antagonist, dolasetron mesylate, in the prevention of PONV in women undergoing total abdominal hysterectomy (TAH). METHODS: Three hundred and seventy four women scheduled for TAH under general anaesthesia were studied at 13 Canadian centres. Patients received in a randomized, double-blind manner 25, 50, 100, or 200 mg dolasetron or placebo po one to two hours before induction of anaesthesia. The anesthetic protocol was standardized. Efficacy was evaluated for 24 hr after surgery by comparing the number of emetic episodes, administration of rescue medication, severity of nausea, and patient satisfaction. RESULTS: Analysis of complete response (no emetic episodes and no rescue for 24 hr) revealed a linear dose-response relationship across dolasetron groups (P < 0.002). Dolasetron 100 mg (P < 0.003) and 200 mg (P < 0.01) were superior to placebo. The percentage of patients with no emetic episodes increased from 29.3% (placebo) to 54.1 % (100 mg). Subgroup analysis revealed ASA status (I > II), previous history of PONV, previous history of motion sickness, and total morphine dose (> 55 mg associated with less PONV than < 55 mg) influenced the incidence of emetic symptoms, but did not alter the results of the primary analysis. CONCLUSION: Prophylactic dolasetron (100 mg and 200 mg) reduces the incidence of PONV in patients having total abdominal hysterectomy.

[Effects of different doses of edrophonium antagonism of mivacurium-induced neuromuscular block in the presence of nitrous oxide, propofol, and alfentanil anesthesia]. / Effets de différentes doses d'édrophonium sur la neutralisation du bloc neuromusculaire induit par le mivacurium en présence de N2O, de propofol et d'alfentanil.

PURPOSE: The purpose of this study was to determine the dose-response relationships for edrophonium antagonism of mivacurium-induced neuromuscular block. METHOD: Seventy-five ASA physical status I or II adults were given mivacurium 0.15 mg.kg-1 followed by an infusion (7 micrograms.kg-1.min-1) during alfentanil-propofol-N2O anaesthesia. Train-of-four stimulation (TOF) was applied to the ulnar nerve every 20 sec and the response of the adductor digiti minimi was recorded (Relaxograph NMT-100, DATEX, Helsinki, Finland). Mivacurium infusion was adjusted at five minutes intervals in order to keep the height of the first twitch in TOF (T1) at 5% of its control value. At the end of surgery, the mivacurium infusion was stopped and edrophonium 0.0, 0.05, 0.1, 0.5 or 1.0 mg.kg-1 combined respectively with glycopyrrolate 0.0, 0.0005, 0.001, 0.005 or 0.01 mg.kg-1 were administered by random allocation. RESULTS: All four edrophonium doses tested were statistically different from placebo with regard to time to attain a TOF ratio (fourth twitch in TOF/T1) = 0.7 (0.05:780 +/- 179, 0.1:727 +/- 216, 0.5:547 +/- 287 and 1.0:640 +/- 236 vs 0.0 mg.kg-1:1089 +/- 323 sec P < 0.05). Does of 0.1, 0.5 and 1.0 mg.kg-1 permitted faster recovery time of T1 from 10 to 95% (T10-95) (567 +/- 236, 419 +/- 166, 555 +/- 288 vs 861 +/- 224 sec P < 0.05) and from 25 to 75% (T25-75) (253 +/- 121, 147 +/- 92, 217 +/- 175 vs 429 +/- 154 sec P < 0.05) than did placebo. However, data showed considerable variability for all neuromuscular indices, no matter the dose of edrophonium used. CONCLUSION: Edrophonium in doses of 0.1 mg.kg-1 and higher permitted faster recovery of all indices from a mivacurium-induced block during alfentanil-propofol-N2O anaesthesia than did placebo.

Markers' influence on the duration discrimination of intermodal intervals.

The effects of sensory signal characteristics on the duration discrimination of intermodal intervals was investigated in three experiments. Temporal intervals were marked by either the successive presentation of a visual then auditory signal (VA), or by the successive presentation of an auditory then visual signal (AV). The results indicated that (1) VA intervals are generally easier to discriminate than are AV intervals, but this effect depends on the range of duration studied; (2) AV intervals are perceived as longer than VA intervals for durations ranging from 250 to 750 msec; (3) the intensity of the visual markers for both AV and VA intervals does not affect the discrimination; and (4) the perceived duration of an intermodal interval is influenced by the length of the first and second markers. The results are mainly interpreted in terms of (1) a sensory trace left by visual and auditory signals and (2) the detection of these signals.

Dose-response relationships for edrophonium antagonism of mivacurium-induced neuromuscular block during N2O-enflurane-alfentanil anaesthesia.

The purpose of this study was to determine the dose-response relationships for edrophonium antagonism of mivacurium-induced neuromuscular block. Seventy-five ASA I or II adults were given mivarcurium 0.15 mg x kg(-1) followed by an infusion (7 micrograms x kg(-1) x min(-1) during alfentanil-propofol-N2O-enflurane anaesthesia. Train-of-four stimulation (TOF) was applied to the ulnar nerve every 20 sec and the response of the adductor policis was recorded (Relaxograph NMT-100, Datex, Helsinki, Finland). Mivacurium infusion was modified at five-minute intervals in order to keep the height of the first twitch in TOF(T1) at 5% of its control value. At the end of surgery, edrophonium (0.0, 0.125, 0.25, 0.5, or 1.0 mg x kg(-1) combined glycopyrrolate (0.0, 0.0012, 0.0025, 0.005, or 0.01 mg x kg(-1) were administered by random allocation. Edrophonium doses of 0.25, 0.5 and 1.0 mg x kg(-1) were different from placebo with regard to time to attain a TOF ratio (fourth twitch in TOF/T1) = 0.7 (13.8 +/- 4.5, 11.1 +/- 3.5, 11.4 +/- 3.0 vs 19.7 +/- 4.7 min P< 0.05). Doses of 0.5 and 1.0 mg x kg(-1) permitted faster recovery time of T1 from 10 to 95% (T10-95) than did placebo (7.5 +/- 3.8, 8.9 +/- 3.5 vs 14.5 +/- 5.0 min P<0.05). Edrophonium 0.5 mg x kg(-1) was different from placebo with regard to recovery time of T1 from 25 to 75% (T25-75) (3.3 +/- 2.0 vs 6.7 +/- 2.0 min P<0.05). Only edrophonium 0.5 mg x kg(-1) provided faster recovery than placebo with regard to all three indices. It is concluded that edrophonium 0.5 + glycopyrrolate 0.005 mg x kg(-1) allow the fastest recovery from a mivacurium-induced block during enflurane-N2O anaesthesia.

Ulnar nerve palsy at the elbow after general anaesthesia.

Ulnar nerve palsy is a recognized complication of general anaesthesia. Many authors have reported several series of patients and found different incidences. In this literature review, the patho-physiology of the lesion and the anatomical characteristics of the cubital tunnel at the elbow are described together with its related conditions "cubital tunnel compression syndrome" and "recurrent ulnar nerve dislocation at the elbow." A precise and early diagnosis should be made using electromyography to determine the exact location of the lesion and the precise time-relationship of the pathology. The importance of careful positioning of the patient under anaesthesia in the prevention of ulnar nerve palsy is stressed. Unfortunately, treatment of the established lesion gives, at best, mixed results.

Low-dose sufentanil in major surgery.

The purpose of this study was to assess the efficacy of sufentanil 1 micrograms.kg-1 during N2O-O2 and intermittent isoflurane anaesthesia in major non-cardiac surgery. Thirty-one patients (18 females, 13 males; mean age 47 yr), undergoing cholecystectomy received a 1 microgram.kg-1 bolus of sufentanil before the induction of anaesthesia with thiopentone. On average, three sufentanil increments were administered, to a total (bolus + maintenance) dose of 1.5 micrograms.kg-1. Cardiovascular stability was not achieved in eleven patients who then were given isoflurane. The arterial pressure decreased after sufentanil (P less than 0.05), reaching a nadir (mean 108/65 mmHg, heart rate 63 bpm) at one minute post-incision. Clinically important hypertension or hypotension did not occur in any patient. One patient, receiving beta-blocker therapy, required atropine to control bradycardia. Postoperative respiratory depression did not occur in patients who received less than one micrograms.kg-1.hr-1 with the last increment being given more than 20 minutes before the end of anaesthesia. Slight respiratory depression in the recovery room was reported in one patient, who had received a total of 1.3 micrograms.kg-1.hr-1 of sufentanil, and the last sufentanil increment 24 min before the end of surgery. The most frequently reported side-effects were nausea (35 per cent) and vomiting (23 per cent). Induction, maintenance and recovery from anaesthesia were rated as "good" in 87, 87, and 74 per cent of the cases, respectively, and "satisfactory" in the remainder. We conclude that this technique is valuable to assure good protection of the cardiovascular system without undue respiratory depression during recovery.

Middle ear pressure variations during nitrous oxide and oxygen anaesthesia.

Many authors have reported middle ear pressure variations during inhalation of high concentrations of nitrous oxide. An on-going study on subjects anaesthetized with nitrous oxide and oxygen supplemented with halogens or narcotics and excluding operations on the ear enables us to register three typical curves of middle ear pressure according to the patency of the Eustachian tube. We recorded significant negative middle ear pressures during the recovery period when there was important obstruction of the Eustachian tube. The presence of a tympanic "neomembrane" due to an old perforation associated with important obstruction of the Eustachian tube could lead to a tympanic perforation that may be unnoticed by the anaesthetist if it is not specifically investigated. In our series, we report one case of tympanic perforation and one case of haemotympanum as examples of such consequences.

[Gas diffusion in the middle ear during anesthesia for tympanoplasty]. / Problème de la diffusion Gazeuse dans l'oreille moyenne au cours de l'anesthesie pour tympanoplastie.

The problems of diffusion of gas into the middle ear during anaesthesia have been described by several authors since 1965. The administration of anaesthetic concentrations of nitrous oxide raises middle ear pressure in the order of 3.43 to 3.92 kPa (350 to 400 mm H2O). This phenomenon disappears spontaneously after cessation of nitrous oxide anaesthesia and causes no trouble except a few cases of deafness and some rare tympanic ruptures. We have tried to solve this problem during anaesthesia for tympanoplasty by substituting air for nitrous oxide and by the use of ethrane as basic anaesthetic agent. Anaesthesia was potentiated by narcotics and the patients were adequately curarized. The results showed that this technique greatly reduced diffusion of gases if we kept the PaO2 under 17.9 kPa (135 mm Hg) and the PaCO2 at 3.9 kPa (30 mm Hg). Controls have shown that diffusion is greater with higher PaCO2. Middle ear pressure, measured with Madsen impedence-meter, was not higher than 0.68 kPa (70 mmn H2O).

Anaesthesia technicians in Quebec: the background and the role.

Anaesthesia technicians are respiratory technologists who received their education in CEGEPs. Every respiratory technologist, when he finishes his course, is specially trained to become an anaesthesia technician. The tasks are delegated to anaesthesia technicians according to the task description of the anaesthetist. This specialist in the current practice must comply with the principles of the art of medicine: he makes a diagnosis by evaluating the risk of each patient who will be anaesthetised and by evaluating the patient's state along the course of anaesthesia and operation; then he decides on the treatment, i.e. he chooses the anaesthetic technique that is suitable for him and he modifies it during the operation according to the needs of the patient. In the diagnosis-treatment procedure, we find a part of decision and a part of execution. It is clear that the decision is reserved exclusively to the anaesthetist but the execution of certain tasks may be delegated to technicians. The task description for the anaesthesia technician has been developed in accordance with these principles and in accord with the new "Guide to Anaesthesia Practice" of the Corporation of Physicians of the Province of Quebec that does not agree with double booking of anaesthetists. Finally, we discuss employment of the technicians in the various operating rooms according to the variety of surgery that is done in each room and the work load that is generated. Experience with this organization has convinced us that the anaesthesia technicians, through their clinical and technical contribution, provide an infrastructure in a department of anaesthesia which permits smooth and efficient functioning of the department. It also relieves the anaesthetist of certain energy-consuming and time-consuming tasks.