Impaired cardiac anti-oxidant activity in diabetes: human and correlative experimental studies

Increased reactive oxygen species (ROS) are traditionally viewed as arising from the metabolic flux of diabetes, although reduction in the activity of anti-oxidant systems has also been implicated. Among the latter is the major thiol reducing thioredoxin system, the activity of which may be diminished by high glucose-induced expression of its endogenous inhibitor, thioredoxin interacting protein (TxnIP). We assessed TxnIP mRNA/protein expression along with thioredoxin activity in human right atrial biopsy specimens from subjects with and without diabetes undergoing coronary artery grafting. In correlative experimental studies, we examined TxnIP expression in both type 1 and type 2 rodent models of diabetic cardiomyopathy. Finally, we used in vitro gene silencing to determine the contribution of changes in TxnIP abundance to the high glucose-induced reduction in thioredoxin activity. In human right atrial biopsies, diabetes was associated with a >30-fold increase in TxnIP gene expression and a 17 % increase in TxnIP protein expression (both p < 0.05). This was associated with a 21 % reduction in thioredoxin activity when compared to human non-diabetic cardiac biopsy samples (all p < 0.05). In correlative animal studies, both type 1 and type 2 diabetic rats demonstrated a significant increase in TxnIP mRNA and reduction in thioredoxin activity when compared to non-diabetic animals (all p < 0.05). This was associated with a significant increase in ROS (p < 0.05 when compared with control). In cultured cardiac myocytes, high glucose increased ROS and TxnIP mRNA expression, in association with a reduction in thioredoxin activity (p < 0.01). These findings were abrogated by TxnIP small interfering RNA (siRNA). Scrambled siRNA had no effect upon ROS or TxnIP expression. High glucose reduces thioredoxin activity and increases ROS via TxnIP overexpression. These findings suggest that impaired thiol reductive capacity, through altered TxnIP expression, contributes to increased ROS in the diabetic heart.     

Midwives and Liability: Results from the 2009 Nationwide Survey of Certified Nurse‐Midwives and Certified Midwives in the United States

Introduction: In partnership with the American College of Nurse‐Midwives (ACNM), the authors conducted a survey of ACNM members to examine the incidence of lawsuit involvement, the outcomes of the litigation in which they were involved, and coping mechanisms among midwives who had been involved in a lawsuit. Methods: In the spring of 2009, a nationwide Web‐based survey was completed by ACNM members. In addition to using chi‐square tests and nonparametric testing in data analysis, a logistic regression model was used to evaluate predictors of lawsuit involvement. Results: Among 1340 midwives responding to the survey, 32% had been named in a lawsuit at least once. The median number of years in practice when the event leading to lawsuit occurred was 6. The majority of midwifery lawsuits involved hospital births and were settled prior to going to court. Three variables were statistically significant for involvement with litigation: the midwife's age, the number of births attended, and the ACNM region of practice in the United States. Discussion: Lawsuits among midwives were significantly related to exposure to births over time. Practice patterns and job security were not greatly affected by the experience of a lawsuit. Future cyclic surveys are needed to track the frequency of litigation and the outcomes that lead to lawsuits and to better define the relationships between midwifery practice and medical malpractice litigation.     

Exploring Disease Management Programs for Diabetes Mellitus

Diabetes mellitus is a chronic illness that affects the world on an epidemic scale. It requires complex healthcare and considerable economic resources. Diabetes disease management programs use a variety of strategies to improve clinical outcome measures and reduce costs. Studies have demonstrated the effectiveness of these programs on reducing glycosylated hemoglobin levels, improving cardiovascular risks, and reducing utilization of services. However, the most effective components of disease management strategies or combination of strategies remain unknown. This narrative review explores the components, impact, benefits, and barriers of current diabetes disease management models and also presents a novel hybrid model incorporating elements of both on-site and off-site programs.On-site disease management programs include strategies characterized by unique patient identification and evaluation, implementation of intervention methods, on-site health provider team members, and specific environmental resources. Advantages of this model include the face-to-face encounter between patients and providers, the proximity of the healthcare team members to facilitate ease of communication and build independence and trust between patients and providers, and technology resources, such as the electronic medical record. A number of clinical trials have demonstrated the effectiveness and cost effectiveness of on-site diabetes disease management programs. However, because of the methodological limitations of many studies, further studies are needed to confirm such findings. Barriers to the implementation of on-site programs may include patient population characteristics such as complexity of co-morbid illness and social Stressors, including low health literacy, that require adaptation of the disease management model. In comparison, off-site disease management programs utilize administrative resources to identify patients with chronic illnesses. Other key elements include the evaluation of clinical care practices using established guidelines with auditing and feedback to providers based on their performance, and the use of reminders for both patients and providers to influence better processes of care. This process is often independent of the traditional on-site care delivered directly by providers.A hybrid disease management model that incorporates both on-site and off-site disease management components could be the ideal model for optimizing care of patients with chronic illness. The suggested hybrid model incorporates many features of previous models of disease management but gives a new construct that can be customized to different clinic settings, provider practices, and patient populations, including patients with other complex chronic illness. This hybrid model could be applied to a variety of individual or multiple chronic illnesses. This model would engage both on-site healthcare providers and support staff along with off-site administrative staff and electronic medical data to provide patients optimal care while potentially reducing overall costs.     

Developmental changes in multifrequency tympanograms

The normal maturational course of tympanometric shape, static aural acoustic admittance and ear canal wall characteristics were investigated in healthy infants, who were followed at various time intervals in the first 4 months of life. Susceptance and conductance tympanograms were recorded from both ears of each subject at four probe frequencies or more. In addition, quantitative pneumatic otoscopy was performed utilizing air pressure changes of the same magnitude as those typically used in tympanometry. Results for the group were an increase in admittance magnitude with increasing age at frequencies above 226 Hz. Admittance phase angle increased with age at all frequencies, indicating a growing contribution of compliant elements in the first 4 months of life. The course of development of input admittance at the tympanic membrane differed among individual infants. Otoscopic findings indicated that external ear canal differences cannot completely account for tympanometric differences between young infants and adults.     

Duloxetine pharmacology: profile of a dual monoamine modulator

Dysregulation within central monoaminergic systems is believed to underlie the pathology of depression. Drugs that selectively inhibit the reuptake of central monoamines have been used clinically to alleviate symptoms of depressive illnesses. Duloxetine, a novel compound currently under investigation for the treatment of depression, binds selectively with high affinity to both norepinephrine (NE) and serotonin (5-HT) transporters and lacks affinity for monoamine receptors within the central nervous system. It has been suggested that dual inhibition of monoamine reuptake processes may offer advantages over other antidepressants currently in use. In preclinical studies, duloxetine mimics many physiologic effects of antidepressants. Consistent with other antidepressants, duloxetine, by acute administration, elevates extracellular monoamine levels, while by chronic administration it does not alter basal monoamine levels. Like the selective serotonin reuptake inhibitor, fluoxetine, by microiontophoretic application, duloxetine inhibits neuronal cell firing. However, in comparison with fluoxetine, duloxetine is a more potent serotonin reuptake inhibitor. Furthermore, in behavioral experiments, duloxetine attenuates immobility in forced swim tests in animal models of depression to a greater extent than several other commonly used antidepressants. In a six-week open label uncontrolled study, duloxetine was evaluated in patients with a history of depression. Duloxetine was effective in treating depression as determined by marked reduction in Hamilton Depression Rating scores. Adverse effects reported during duloxetine treatment were minor and similar to those of other antidepressants. In an eight-week multicenter, double-blind, placebo-controlled study in patients with a major depressive disorder, duloxetine was effective as an antidepressant, particularly in patients with greater symptom severity. Only limited data are available regarding the pharmacokinetic profile of duloxetine in humans, although a half-life of 10 to 15 h has been reported. Studies conducted in healthy human subjects confirm the preclinical profile of duloxetine as an inhibitor of 5-HT and NE reuptake. Taken together, existing data suggest that duloxetine is a novel and effective antidepressant.     

ERK5 activation of MEF2-mediated gene expression plays a critical role in BDNF-promoted survival of developing but not mature cortical neurons

Extracellular signal-regulated kinase 5 (ERK5) is a member of the mitogen-activated protein kinase family whose biological function in the CNS has not been defined. In contrast to ERK1 and ERK2, which are activated by neurotrophins (NTs), cAMP, and neuronal activity in cortical neurons, ERK5 is activated only by NTs. Here, we report that ERK5 expression is high in the brain during early embryonic development but declines as the brain matures to almost undetectable levels by postnatal day (P) 49. Interestingly, expression of a dominant-negative ERK5 blocked brain-derived neurotrophic factor protection against trophic withdrawal in primary cortical neurons cultured from embryonic day (E) 17 but not P0. Furthermore, expression of a dominant-negative ERK5 induced apoptosis in E17 but not P0 cortical neurons maintained in the presence of serum. We also present evidence that ERK5 protection of E17 cortical neurons may be mediated through myocyte enhancer factor 2-induced gene expression. These data suggest that ERK5 activation of myocyte enhancer factor 2-induced gene expression may play an important and novel role in the development of the CNS by mediating NT-promoted survival of embryonic neurons.     

Flux through the hexosamine pathway is a determinant of nuclear factor kappaB- dependent promoter activation

The hexosamine pathway may mediate some of the toxic effects of glucose. We hypothesized that flux through this pathway might regulate the activity of nuclear factor kappaB (NF-kappaB)-dependent genes in mesangial cells (MCs). In MCs, RT-PCR revealed that high glucose (30 mmol/l) and glucosamine (1 mmol/l) increased mRNA levels for vascular cell adhesion molecule 1 (VCAM-1) and increased the activity of an NF-kappaB enhancer by 1.5- and 2-fold, respectively. Overexpression of glutamine:fructose-6-phosphate amidotransferase (GFAT), the rate-limiting enzyme for flux through the hexosamine pathway, led to a 2.2-fold increase in NF-kappaB enhancer activity; the combination of GFAT overexpression and high glucose increased activity 2.8-fold, and these increases were prevented by 40 micromol/l O-diazoacetyl-L-serine (azaserine) or 6-diazo-5-oxonorleucine. High glucose, glucosamine, and GFAT overexpression increased binding of MC nuclear proteins to NF-kappaB consensus sequences. Immunoblotting revealed that the p65 subunit of NF-kappaB was O-glycosylated in MC cultured in physiologic glucose and that significant enhancement occurred with high glucose and glucosamine. Both glucose and glucosamine dose-dependently increased human VCAM-1 promoter activity. In addition, GFAT overexpression activated the VCAM-1 promoter (2.25-fold), with further augmentation by high glucose and abrogation by inhibitors of GFAT, NF-kappaB, and O-glycosylation. Inactivation of the two NF-kappaB sites in the VCAM-1 promoter abolished its response to high glucose, glucosamine, and GFAT overexpression. These results suggest that increased flux through the hexosamine pathway leads to NF-kappaB-dependent promoter activation in MCs.     

Age, sex, ethnicity, body composition, and resting energy expenditure of obese African American and white children and adolescents

BACKGROUND: African Americans may have a lower resting energy expenditure (REE) than do whites, although the data are limited for obese children and adolescents and for boys. Differences in bone density and trunk lean body mass may account for some of these measured differences in REE. OBJECTIVE: We assessed the REE and body composition of obese African American and white children and adolescents. DESIGN: Obese, 5-17-y-old children and adolescents were evaluated (n = 203). Body composition was assessed by dual-energy X-ray absorptiometry. REE was measured by open-circuit calorimetry. African American and white children were compared. The relation between REE and the independent variables (age, sex, ethnic group, fat mass, and fat-free mass or lean tissue mass) was assessed. RESULTS: Of those evaluated, 66% were girls and 34% were African American. Age, sex, pubertal status, and body composition did not differ significantly by ethnic group. All the independent variables were significantly associated with REE. Using lean tissue mass to account for differences in bone density did not significantly alter the results. REE decreased with age and was lower in the girls than in the boys and in the African Americans than in the whites. When trunk fat-free mass was included in the model in place of whole-body fat-free mass, the ethnic difference in REE decreased. CONCLUSIONS: Adjustment for trunk lean tissue mass partially explains the lower REE of obese African American children and adolescents. The lower relative REE of older obese children suggests the importance of early intervention in the prevention of childhood obesity. The lower REE of girls and of African Americans may contribute to the difficulty in weight management in these groups.