The global landscape of availability, accessibility and affordability of essential diagnostics and therapeutics for the management of HER2-positive breast cancer: The ONCOLLEGE-001 survey.

AIM OF THE STUDY: Barriers in access to essential care are key determinants of disparities in cancer survival. Breast cancer (BC) is the most common cancer and lead cause of mortality among women, 60 % occurring in low- and middle-income countries (LMs). A quarter of BC are characterized by an over-expression of the epidermal growth factor receptor 2 (HER2). Valuable strategies to diagnose and manage patients with HER2-positive BC have been determined and some considered essential health interventions. ONCOLLEGE-001 is a global survey of availability, accessibility, and affordability of essential HER2 diagnostics and therapeutics. METHOD: A self-administered questionnaire was shared electronically to oncologists, identified from oncology networks. Data were analyzed using descriptive statistics, per income areas and geographic regions. RESULTS: We received 191 responses (84 % response rate). The majority of the responders were from LMs (n = 153) and were physician providers. Immunohistochemistry was the most common HER2 diagnostics available (n = 185). A third of the responders from low/lower-middle and a half of upper-middle income countries had HER2 testing only in the private sector. Trastuzumab was not available for 8 %: when available, 15%-21% reported accessibility only as out-of-pocket expenditure; when not reimbursed, only 10 % of the providers could significantly offer this intervention. Availability of trastuzumab biosimilars was reported in more than a half of the responders (n = 107). CONCLUSION: Stark disparities are reported, with high out-of-pocket expenses for HER2 testing and significant financial barriers to access trastuzumab treatments. Policy solutions are urgently warranted for the selection, prioritization, and reimbursement of essential health interventions, to result in improved population health. POLICY SUMMARY STATEMENT: the inclusion of essential services for cancer management should be assured and financed in the benefit packages of healthcare to all. Prioritizing high-value health interventions, including medicines and medical devices, is critical to deliver impactful programs on population health.

Left ventricular apical rotation is associated with mitral annular function in healthy subjects. Results from the three-dimensional speckle-tracking echocardiographic MAGYAR-Healthy Study.

INTRODUCTION: Left ventricular (LV) twist is considered an essential part of LV function due to oppositely directed LV basal and apical rotations. Several factors could play a role in determining LV rotational mechanics in normal circumstances. This study aimed to investigate the relationship between LV rotational mechanics and mitral annular (MA) size and function in healthy subjects. METHODS: The study comprised 118 healthy adult volunteers (mean age: 31.5 ± 11.8 years, 50 males). All subjects had undergone complete two-dimensional (2D) Doppler echocardiography and three-dimensional speckle-tracking echocardiography (3DSTE) at the same time by the same echocardiography equipment. RESULTS: The normal mean LV apical and basal rotations proved to be 9.57 ± 3.33 and -3.75 ± 1.98°, respectively. LV apical rotation correlated with end-systolic MA diameter, area, perimeter, fractional area change, and fractional shortening, but did not correlate with any end-diastolic mitral annular morphologic parameters. The logistic regression model identified MA fractional area change as an independent predictor of ≤6° left ventricular apical rotation (P < 0.003). CONCLUSIONS: Correlations could be detected between apical LV rotation and end-systolic MA size and function, suggesting relationships between MA dimensions and function and LV rotational mechanics.

Use of glucose-lowering drugs in Hungary between 2008 and 2017: the increasing use of novel glucose-lowering drug groups.

AIMS: To analyse glucose-lowering drug utilization, focusing on the novel glucose-lowering drug groups dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors, and the financial burden they entail. METHODS: Crude reimbursed national drug utilization and expenditure data for the entire population of Hungary were obtained from the National Health Insurance Fund for the study period: 2008 to 2017. Data were analysed using the WHO's Anatomical Therapeutic Chemical Classification/defined daily dose system and were expressed in defined daily dose per 1000 inhabitants per day. RESULTS: Total glucose-lowering drug consumption in Hungary showed an 18% increase over the study period, reaching 74.7 defined daily doses per 1000 inhabitants per day, while novel glucose-lowering drug use increased to 11.7 defined daily doses per 1000 inhabitants per day (16% of total glucose-lowering drug use) by 2017. Dipeptidyl-peptidase 4 inhibitor consumption grew to 7.4 defined daily doses per 1000 inhabitants per day by 2017. The most widely used dipeptidyl-peptidase 4 inhibitor was sitagliptin. Glucagon-like peptide-1 receptor agonists were used the least, but by 2017 rose to 1.5 defined daily doses per 1000 inhabitants per day, led by liraglutide. Sodium-glucose co-transporter-2 inhibitors appeared in the utilization data in 2014 and their consumption, mainly empagliflozin, reached 2.8 defined daily doses per 1000 inhabitants per day by 2017. The total expenditure on glucose-lowering drugs increased 94% between 2008 and 2017, and the total cost of novel glucose-lowering drug utilization comprised 44% of the total glucose-lowering drug expenditure in 2017. CONCLUSIONS: Both the use of and the financial burden posed by novel glucose-lowering drugs in Hungary increased steadily between 2008 and 2017. This increase is expected to continue.

Modified Texture Food Use is Associated with Malnutrition in Long Term Care: An Analysis of Making the Most of Mealtimes (M3) Project.

OBJECTIVE: Modified texture food (MTF), especially pureed is associated with a high prevalence of under-nutrition and weight loss among older adults in long term care (LTC); however, this may be confounded by other factors such as dependence in eating. This study examined if the prescription of MTF as compared to regular texture food is associated with malnutrition risk in residents of LTC homes when diverse relevant resident and home-level covariates are considered. DESIGN: Making the Most of Mealtimes (M3) is a cross-sectional multi-site study. SETTING: 32 LTC homes in four Canadian provinces. PARTICIPANTS: Regular (n= 337) and modified texture food consumers (minced n= 139; pureed n= 68). MEASUREMENTS: Malnutrition risk was determined using the Mini Nutritional Assessment short-form (MNA-SF) score. The use of MTFs, and resident and site characteristics were identified from health records, observations, and standardized assessments. Hierarchical linear regression analyses, accounting for clustering, were performed to determine if the prescription of MTFs is associated with malnutrition risk while controlling for important covariates, such as eating assistance. RESULTS: Prescription of minced food [F(1, 382)=5.01, p=0.03], as well as pureed food [F(1, 279)=4.95, p=0.03], were both significantly associated with malnutrition risk among residents. After adjusting for age and sex, other significant covariates were: use of oral nutritional supplements, eating challenges (e.g., spitting food out of mouth), poor oral health, and cognitive impairment. CONCLUSIONS: Prescription of minced or pureed foods was significantly associated with the risk of malnutrition among residents living in LTC facilities while adjusting for other covariates. Further work needs to consider improving the nutrient density and sensory appeal of MTFs and target modifiable covariates.

Is there a relationship between increased aortic stiffness and segmental left ventricular deformation in elite athletes? (Insights from the MAGYAR-Sport Study).

Introduction Myocardial contractility of the left ventricle (LV) is related to arterial distensibility. Sport activity is frequently associated with changes in both LV and arterial functions. This study aimed to find correlations between three-dimensional speckle-tracking echocardiography-derived segmental LV deformation parameters and echocardiographically assessed aortic stiffness index (ASI) in athletes. This study comprised 26 young elite athletes (mean age: 26.7 ± 8.4 years, nine men). Results Among segmental circumferential strains (CSs), only that of apical anterior (r = 0.40, p = 0.05), septal (r = 0.47, p = 0.01), inferior (r = 0.59, p = 0.001), lateral (r = 0.44, p < 0.05), and midventricular anteroseptal (r = 0.44, p < 0.05) segments correlated with ASI, whereas LV-CS of the midventricular anterior segment showed a correlation tendency. Only longitudinal strain of basal anteroseptal (r = -0.46, p < 0.05) and inferoseptal (r = -0.57, p < 0.01) segments showed correlations with ASI, whereas that of the basal anterior segment had only a tendency to correlate. Some segmental multidirectional strains also correlated with ASI. Conclusions Correlations could be demonstrated between increased aortic stiffness and circular function of the apical and midventricular LV fibers and longitudinal motion of the basal septum and LV anterior wall (part of LV outflow tract) in maintaining circulation in the elite athletes.

Trajectories of Nutritional Risk: The Manitoba Follow-Up Study.

OBJECTIVES: To identify patterns of nutritional risk among older men over a four-year period and to project their survival rates over the next two and a half years. DESIGN: A prospective longitudinal study. SETTING: Canada. PARTICIPANTS: Three hundred and thirty-six male survivors of the Manitoba Follow-up Study (MFUS) cohort with an average age of 90 years in 2011. MEASUREMENTS: Four years of nutritional risk SCREEN II scores (five waves) from the male survivors of the MFUS cohort. The semi-parametric group-based trajectory approach and survival analysis were used to investigate the trajectories of nutritional risk. RESULTS: Of the participants, 30% lived alone. Five distinct developmental trajectory groups for nutritional risk score were identified. Significant statistical differences were found among the five trajectory groups for SF-36 mental health (p=.02), SF-36 physical health (p=<.001), perception of aging successfully (p=.04) and living alone (p=<.001). Among the five groups, the most pairwise differences were found in appetite, intake of meat and alternatives, and vegetables and fruit, weight change, skipping meals and eating with others. Men in the poorest nutritional risk trajectory group were two times more likely to die within a 2 1/2 year period compared to men in the best nutritional risk trajectory group (hazard rate = 2.33, p=.07). CONCLUSION: Distinct nutritional risk trajectories were found for older men over a four year period. Poor nutritional risk trajectories are associated with higher risk of mortality for very old men over a short period of time. Timely nutritional assessments by health professionals are needed to identify older men at nutritional risk. Subsequent nutrition education and follow-up may be important in preventing further decline.

Early histopathological changes in new-onset diabetes after kidney transplantation.

BACKGROUND: New-onset diabetes after transplantation (NODAT) is one of the most common complications after kidney transplantation. METHODS: Patients were randomly assigned to receive cyclosporine A-based or tacrolimus-based immunosuppression. Fasting and oral glucose tolerance tests were performed, and the patients were assigned to one of the following 3 groups, on the basis of the results: normal, impaired fasting glucose/impaired glucose tolerance, or NODAT. NODAT developed in 14% of patients receiving cyclosporine A-based immunosuppression and in 26% of patients taking tacrolimus (P = .0002). RESULTS: Albumin levels were similar, but uric acid level (P = .002) and the age of the recipient (P = .003) were significantly different between the diabetic and the normal groups. Evaluation of tissue samples revealed that acute cellular rejection and interstitial fibrosis/tubular atrophy were significantly different in the NODAT group. Changes in the Banff score provided significant difference regarding tubulitis and interstitial inflammation (P = .05). CONCLUSIONS: The pathological effect of new-onset diabetes after kidney transplantation can be detected in the morphology of the renal allograft earlier, before the development of any sign of functional impairment.

Changes in food group consumption and associations with self-rated diet, health, life satisfaction, and mental and physical functioning over 5 years in very old Canadian men: the Manitoba Follow-Up Study.

OBJECTIVE: To identify longitudinal food group consumption trends and the relationship to perceived changes in diet, health, and functioning. DESIGN: A prospective longitudinal study. SETTING: Canada. PARTICIPANTS: Seven hundred and thirty-six community-dwelling Canadian men (mean age: 2000=79.4 yrs; 2005=84.5 yrs) participating in the Manitoba Follow-up Study. MEASUREMENTS: Self-reported food consumption, self-rated diet and health, life satisfaction, physical and mental functioning from questionnaires completed in 2000 and 2005. RESULTS: The majority of participants did not consume from all four food groups daily, based on Canada's Food Guide recommendations, with only 8% in 2000 and up to 15% in 2005. However, over a five year period, more men improved their consumption in each food group than declined. An association was found between change in the self-rating of the healthiness of their diet and change in consumption of vegetables and fruit, or grain products. Men whose self-rating of the healthiness of their diet remained high or improved between 2000 and 2005, were 2.15 times more likely (95% CI=1.45, 3.17) to also have increased consumption of vegetables and fruit, and 1.71 times more likely (95% CI=1.51, 2.54) to have increased consumption of grain products, relative to men whose self-rating of the healthiness of their diet declined between 2000 and 2005. Men who consumed more food groups daily had better mental and physical component scores. CONCLUSION: Dietary improvements are possible in very old men. Greater daily food group consumption is associated with better mental and physical functioning. Given these positive findings, there is still a need to identify older men who require support to improve their dietary habits as nearly half of the participants consumed two or fewer groups daily.

Functional and histopathologic changes in renal transplant patients with new-onset diabetes and dyslipidemia.

BACKGROUND: The principal risk factors for cardiovascular mortality posttransplantation are hyperglycemia, hypertriglyceridemia, obesity, and smoking. METHODS: Among 115 patients, we assessed the risk factors for new-onset diabetes (NODM) and dyslipidemia (NODL), and their effects on the function and histopathologic changes in the allografts at 1 year posttransplantation. RESULTS: When evaluating the risk factors and the initial recipient data, we observed a significant difference in age when comparing normal vs NODM patients (P=.004), normal versus NODL patients (P=.002), and normal versus NODL + NODM patients (P=.0001). The difference in body mass index (BMI) was significant when comparing normal with NODM + NODL patients (P=.003). In regard to immunosuppressive therapy, NODM was significantly more frequent among/prescribed tacrolimus (tac; P=.005), whereas subjects who received cyclosporine (CsA) showed a significantly higher incidence of NODL (P=.001). The triglyceride levels were 3.02 ± 1.51 mmol/L among those on CsA versus 2.15 ± 1.57 mmol/L for (P=.004). The difference also proved to be significant for total cholesterol level: 5.43 ± 1.23 mmol/L versus 4.42 ± 1.31 mmol/L respectively (P=.001). In regard to allograft function a significant difference was noted at 1 year after transplantation between the NODM + NODL and the normal group in serum creatinine level (P=.02) as well as the estimated glomerular filtration rate (P=.004). Among diabetic patients, the serum creatinine level measured at posttransplant year 5 was significantly higher than that in 1 year (212.43 vs 147.00 µmol/L; P=.0003). When assessing morphologic changes in the kidney, we observed significantly more frequent interstitial fibrosis/tubular atrophy in all 3 groups compared with normal function patients. CONCLUSION: Our clinical study suggested that at 1 year after transplantation allograft function is already impaired in the presence of both medical conditions (NODM and NODL). However, in regard to morphology, a single condition (NODM or NODL) was sufficient to produce histologic changes in the kidney.

Combined pharmacological block of I(Kr) and I(Ks) increases short-term QT interval variability and provokes torsades de pointes.

BACKGROUND AND PURPOSE: Assessing the proarrhythmic potential of compounds during drug development is essential. However, reliable prediction of drug-induced torsades de pointes arrhythmia (TdP) remains elusive. Along with QT interval prolongation, assessment of the short-term variability of the QT interval (STV(QT)) may be a good predictor of TdP. We investigated the relative importance of I(Ks) and I(Kr) block in development of TdP together with correlations between QTc interval, QT interval variability and incidence of TdP. EXPERIMENTAL APPROACH: ECGs were recorded from conscious dogs and from anaesthetized rabbits given the I(Kr) blocker dofetilide (DOF), the I(Ks) blocker HMR-1556 (HMR) and their combination, intravenously. PQ, RR and QT intervals were measured and QTc and short-term variability of RR and QT intervals calculated. KEY RESULTS: DOF increased QTc interval by 20% in dogs and 8% in rabbits. HMR increased QTc in dogs by 12 and 1.9% in rabbits. Combination of DOF+HMR prolonged QTc by 33% in dogs, by 16% in rabbits. DOF or HMR given alone in dogs or HMR given alone in rabbits induced no TdP. Incidence of TdP increased after DOF+HMR combinations in dogs (63%) and following HMR+DOF (82%) and DOF+HMR combinations (71%) in rabbits. STV(QT) markedly increased only after administration of DOF+HMR combinations in both dogs and rabbits. CONCLUSION AND IMPLICATIONS: STV(QT) was markedly increased by combined pharmacological block of I(Kr) and I(Ks) and may be a better predictor of subsequent TdP development than the measurement of QTc interval prolongation.

Food group consumption and self-rated diets of elderly community-dwelling canadian men. The manitoba followup study.

BACKGROUND: Healthy eating perceptions and food group consumption practices of elderly men are largely unexplored. Understanding eating practices of elderly men and how this relates to their quality of life is important for the implementation of practical health promotion strategies. OBJECTIVE: Examine the frequency of food items consumed (daily, most days, or rarely), and the association of self-rated diet and food group consumption of elderly community-dwelling Canadian men. DESIGN: Self-reported nutrition data, obtained via mailed questionnaires in spring 2000, from 1,211 Canadian male respondents (mean age 82 years) participating in the Manitoba Follow-up Study were analyzed. RESULTS: Respondents consumed vegetables/fruit (64%) and grain products (58%) daily, and meat/alternatives (81%) most days. Milk products were equally consumed daily (47%) or most days (47%). Using multiple logistic regression models, controlling for demographic variables, a positive relationship was found between the increasing consumption of vegetables/fruit and grain products and healthier self-rated diets. Daily consumption of vegetables/fruit or grain products significantly predicted healthier self-rated diets compared to men consuming those food categories most days, OR=2.42 (95%CI=1.88, 3.11) and OR=2.18 (95%CI=1.70, 2.79), respectively. Those consuming meat/alternatives or milk products "daily" or "rarely" rated their diets as healthier than those consuming these items "most days". CONCLUSION: Daily consumption of fruits, vegetables, and grain products is viewed as important for overall health and is positively associated with healthier self-rated diets among elderly Canadian men.

Coronary flow reserve, insulin resistance and blood pressure response to standing in patients with normoglycaemia: is there a relationship?

AIMS: To establish the relationships between coronary flow reserve, cardiovascular autonomic function, and insulin resistance characterized by the homeostasis model assessment insulin resistance score in patients with normal carbohydrate metabolism according to the World Health Organization (WHO) and American Diabetes Association (ADA) criteria, and with morphologically normal epicardial coronary arteries. METHODS: Twenty-five patients [12 women and 13 men, mean (sd) age: 53 +/- 11 years] with normal coronary angiography were enrolled into the study. Coronary flow reserve was measured during stress transoesophageal echocardiography. Autonomic dysfunction was assessed by means of five standard cardiovascular reflex tests. The fasting serum glucose and insulin levels were determined and the homeostasis assessment model insulin resistance score was calculated. RESULTS: In patients with normal carbohydrate metabolism, negative correlations were observed between the coronary flow reserve and both the serum insulin level (r = -0.445, P = 0.026) and the homeostasis assessment model insulin resistance score (r = -0.449, P = 0.024). The systolic blood pressure response to standing also correlated with the coronary flow reserve (r = -0.519, P = 0.011). The heart rate response to deep breathing, the Valsalva ratio, the 30/15 ratio and the sustained handgrip test results were not correlated with the coronary flow reserve. CONCLUSIONS: Our data suggest the possible role of insulin resistance and early sympathetic nerve dysfunction in the development of decreased coronary flow reserve in patients without diabetes mellitus or impaired glucose tolerance.

Regional differences in the manifestation of gastrointestinal motor disorders in type 1 diabetic patients with autonomic neuropathy.

OBJECTIVE: The aim of this work was to establish the prevalence and severity of different gastrointestinal symptoms and their relationships to esophageal, gastric and recto-anal motor disturbances by manometry in patients with Type 1 diabetes mellitus and autonomic neuropathy. PATIENTS AND METHODS: Sixteen patients (mean age: 53.4 +/- 14.9 years) with long standing type 1 diabetes mellitus (mean diabetes duration: 22.1 +/- 14.7 years) and autonomic neuropathy (mean Ewing score: 5.73 +/- 2.34) were investigated. The gastrointestinal symptom scores were established by using the Talley dyspepsia questionnaire. The motor function of the digestive tract was tested in the esophagus, in the stomach, and in the ano-rectum by perfusion manometry. RESULTS: Manometric evaluation of the esophagus did not reveal significant abnormalities in the region of the upper sphincter in patients with diabetes mellitus. In contrast, diabetic patients had decreased peristaltic wave amplitude, prolonged duration, decreased wave propagation velocity, and increased number of simultaneous contractions in the esophageal body, and decreased lower esophageal sphincter pressures with prolonged relaxation compared to the age- and sex-matched controls. Symptom analysis showed correlations between reflux symptoms and LES relaxation times, and between dysphagia scores and esophageal body peristaltic wave duration, propagation velocity and the rate of simultaneous contractions. In the gastric antrum, frequent, and often severe, fasting motility disorders were observed, which had no correlation with dyspeptic symptoms. In the ano-rectal region the diabetic patients had a lower squeezing-resting pressure difference, and impaired fecal expulsive function. Motility disorders were simultaneously present at multiple parts of the gastrointestinal tract in 13/16 cases. CONCLUSIONS: In patients with type 1 diabetes mellitus and autonomic neuropathy gastrointestinal motility disorders were observed frequently, and in most of the cases simultaneously. While esophageal and ano-rectal symptoms correlated better with the manometric abnormalities, the lack of correlation between the impaired fasting gastric motility and dyspeptic symptoms shows that, on the basis of the clinical symptom analysis, the prevalence of such motor disorders could be underestimated. The early recognition of gastrointestinal motility disorders may be important for the better long-term management of patients with type 1 diabetes mellitus.

Brainstem auditory-evoked potential examinations in diabetic patients.

Brainstem auditory-evoked potential (BAEP) examinations were performed in 15 patients with long-standing type-1 diabetes mellitus (DM). Cardiovascular reflex tests were applied for assessment of autonomic neuropathy. The aim of our investigation was to compare the BAEP results of this patient group with controls and to look for a possible correlation between the alteration of the auditory brainstem function and the cardiovascular autonomic neuropathy. Analysis of the latencies (waves I, II, III and V) and the inter-peak latencies (waves I-III and I-V) of BAEPs revealed a significant difference between diabetics and healthy controls. The amplitudes of waves I, III and V were definitely lower in comparison with those of healthy controls. A positive correlation was observed between the overall autonomic score and the latencies (waves III and V) and inter-peak latencies (waves I-III and I-V). These data support the hypothesis that long-standing DM and diabetic neuropathy might be related as a cause of certain dysfunctions of the central auditory pathways.

Pharmacological block of the slow component of the outward delayed rectifier current (I(Ks)) fails to lengthen rabbit ventricular muscle QT(c) and action potential duration.

1. The effects of I(Ks) block by chromanol 293B and L-735,821 on rabbit QT-interval, action potential duration (APD), and membrane current were compared to those of E-4031, a recognized I(Kr) blocker. Measurements were made in rabbit Langendorff-perfused whole hearts, isolated papillary muscle, and single isolated ventricular myocytes. 2. Neither chromanol 293B (10 microM) nor L-735,821 (100 nM) had a significant effect on QTc interval in Langendorff-perfused hearts. E-4031 (100 nM), on the other hand, significantly increased QTc interval (35.6+/-3.9%, n=8, P<0.05). 3. Similarly both chromanol 293B (10 microM) and L-735,821 (100 nM) produced little increase in papillary muscle APD (less than 7%) while pacing at cycle lengths between 300 and 5000 ms. In contrast, E-4031 (100 nM) markedly increased (30 - 60%) APD in a reverse frequency-dependent manner. 4. In ventricular myocytes, the same concentrations of chromanol 293B (10 microM), L-735,821 (100 nM) and E-4031 (1 microM) markedly or totally blocked I(Ks) and I(Kr), respectively. 5. I(Ks) tail currents activated slowly (at +30 mV, tau=888.1+/-48.2 ms, n=21) and deactivated rapidly (at -40 mV, tau=157.1+/-4.7 ms, n=22), while I(Kr) tail currents activated rapidly (at +30 mV, tau=35.5+/-3.1 ms, n=26) and deactivated slowly (at -40 mV, tau(1)=641.5+/-29.0 ms, tau(2)=6531+/-343, n=35). I(Kr) was estimated to contribute substantially more to total current density during normal ventricular muscle action potentials (i.e., after a 150 ms square pulse to +30 mV) than does I(Ks). 6. These findings indicate that block of I(Ks) is not likely to provide antiarrhythmic benefit by lengthening normal ventricular muscle QTc, APD, and refractoriness over a wide range of frequencies.

Gallbladder hypomotility in diabetic polyneuropathy.

This study was performed to evaluate the gallbladder motility in long-standing diabetes mellitus. The gallbladder function of diabetic patients was measured by means of quantitative hepatobiliary scintigraphy, and the severity of the associated autonomic and sensory polyneuropathy was determined. The presence of a marked gallbladder hypomotility was established, and a positive correlation was observed between the severity of the autonomic disturbance and the contractile disorder. This study underlines the important role of the neuropathy in the development of gallbladder hypomotility accompanying long-term diabetes mellitus.

Suppression of erythromycin-induced early afterdepolarizations and torsade de pointes ventricular tachycardia by mexiletine.

Erythromycin is a selective IKr-blocking, action potential duration (APD)-prolonging drug, which may induce early afterdepolarizations (EADs) and torsade de pointes ventricular tachycardia. The successful termination of an erythromycin-induced clinical torsades de pointes by the authors with mexiletine prompted them to investigate in vitro whether erythromycin is able to induce EADs in Purkinje fibers and, if so, whether EADs are suppressible or not by mexiletine. Electrically stimulated canine Purkinje fibers (n = 9) were superfused with erythromycin (200 mg/l) and action potentials were recorded by an intracellular microelectrode technique. Erythromycin induced a pronounced prolongation of APD and the appearance of EADs in all Purkinje preparations (9/9). After the addition of mexiletine (10 mM), a marked shortening of APD and the disappearance of EADs (7/9) were observed. Mexiletine, an inhibitor of the tetrodotoxin-sensitive window Na(+)-current, may prevent IKr-blocking drug-induced torsade de pointes ventricular tachycardia by abolishing APD prolongation and EADs.

[Gallbladder hypomotility in diabetic polyneuropathy]. / Epehólyag-hypomotilitas diabeteses polyneuropathiában.

A study was made of the pathogenic role of gallbladder hypomotility, which is presumably responsible for the high incidence of gallstone disease in long-standing diabetes mellitus. The gallbladder motility of diabetic patients (n = 10) was measured by means of quantitative hepatobiliary scintigraphy, and the severity of concomitant autonomic and sensory polyneuropathy was determined. The presence of marked gallbladder hypomotility was proven, and a positive correlation was observed between the severity of autonomic neuropathy and the contractile disorder. In this group of diabetic patients, a hypaesthetic sensory polyneuropathy too was recognized, the degree of which exhibited a positive correlation with the autonomic neuropathy score. This study underlines the important role of the autonomic neural dysfunction in the development of gallbladder hypomotility accompanying long-term diabetes mellitus.