Omapatrilat enhances adrenomedullin's reduction of cardiomyocyte cell death

The objective of this study was to determine whether adrenomedullin, a vasodilator peptide, modulates the process of cell death in cardiomyocytes and whether its effect would be enhanced by the endopeptidase inhibitor omapatrilat, which reduces adrenomedullin degradation. Further, we sought to determine whether the effect of adrenomedullin involved an action to preserve mitochondrial transmembrane potential (DeltaPsi(m)). Cardiomyocytes in culture were treated with agents that interrupted the mitochondrial electron transport chain, inhibiting glycolysis and oxidative phosphorylation. Cell death was evaluated by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay and DeltaPsi(m) was assessed by fluorescent microscopy. Cytochrome c loss from mitochondria and appearance in cytosol was determined by Western blotting. Potassium cyanide (KCN) plus deoxyglucose or antimycin A, for 24 h, produced significant (p<0.01) concentration-dependent reductions in cell viability or increases in cell death. Adrenomedullin reduced cell death produced in this manner and the effect of adrenomedullin was enhanced by treatment with omapatrilat. In contrast, there was no additional reduction in cell death by lisinopril treatment. Omapatrilat plus adrenomedullin reduced the KCN plus deoxyglucose-induced increase in cytosolic cytochrome c. A likely mechanism centers on the ability of adrenomedullin plus omapatrilat to prevent the decline in mitochondrial DeltaPsi(m) produced by KCN plus deoxyglucose treatment. In summary, adrenomedullin plus omapatrilat limited the decline in mitochondrial DeltaPsi(m) that accompanies interruption of mitochondrial metabolism and limited the extent of cell death in cardiomyocytes treated with KCN plus deoxyglucose or antimycin. Adrenomedullin plus the endopeptidase inhibitor omapatrilat may be a useful strategy to protect cardiomyocytes from cell death, in conditions associated with impairment of mitochondrial function.     

Predictors of substance abuse treatment entry for crime-involved, cocaine-dependent women

A health services utilization model was used to examine predictors of treatment entry among a large sample (N=659) of crime-involved, cocaine-dependent women. Previous research in this area has focused on women already in treatment and resultantly excluded a critical population of drug-dependent women who are actively using but not in treatment. Thus, interviews were completed with women who were participating in substance abuse treatment programs and with women who were not currently in treatment to examine what factors may have inhibited or facilitated their entering treatment. The predisposing characteristics, enabling resources, and service needs of these women were assessed in relation to their treatment utilization status. Findings indicated that variables within each of the three categories of the health services model were related to treatment entry including race/ethnicity and education (predisposing characteristics), and alcohol use and having multiple chronic health problems (need). But, overall, enabling factors, such as being legally employed, having health insurance, having custody of children, and knowing where to go to get treatment, appeared to be the most influential predictors. Implications of this research include employing multiple tactics for increasing the likelihood of treatment entry such as aggressive outreach efforts focusing on at-risk women who have the fewest social ties and who are the least integrated into mainstream society.     

Implications of laparoscopy on surgery residency training

Background

With the advent of laparoscopy, many traditional junior-level cases now require advanced laparoscopic skill. We sought to ascertain the implications of laparoscopy on residency training through the use of a large national database.

Methods

American College of Surgeons National Surgical Quality Improvement Program data were gathered for patients undergoing elective open and laparoscopic inguinal herniorrhaphy, appendectomy, and partial colectomy during 2005 and 2006. Cases were stratified by resident level and compared using univariate analysis.

Results

A total of 14,729 cases were performed during the study period. For inguinal hernia repair, 72% of open repairs were performed by postgraduate year 3 residents or below versus 41% of laparoscopic repairs (P < .0001). Similarly, 61% of open appendectomies were performed by postgraduate year 3 residents or below compared with 48% of laparoscopic appendectomies (P < .0001). Forty-six percent of open colectomies were performed by postgraduate year 3 and postgraduate year 4 residents versus 33% of laparoscopic resections (P < .0001).

Conclusions

These data show an upward shift in cases traditionally performed by junior-level residents. The implications of this shift are unknown but may lead to decreased surgical experience during the early years of training.     

Riboflavin Status in Acutely Ill Patients and Response to Dietary Supplements

Background: Although a number of studies have reported riboflavin deficiency in free‐living older people, no data are available on riboflavin intake and status in older people during acute illness. Methods: To determine the riboflavin response to dietary supplements during acute illness, 297 hospitalized, acutely ill older patients are randomly assigned to receive a daily oral nutritional supplement containing 1.3 mg of riboflavin or a placebo for 6 weeks. Outcome measures are riboflavin intake and riboflavin biochemical status at baseline, 6 weeks, and 6 months using the erythrocyte glutathione reductase activation coefficient (EGRAC), a measure of riboflavin tissue saturation. EGRAC values are inversely proportional to riboflavin status. Results: Fifty‐six percent of patients (167/297) have suboptimal riboflavin status (EGRAC > 1.30). No significant correlation is found between EGRAC and either total energy or riboflavin intakes. Significant correlations are found between total energy intake and riboflavin intakes both in hospital and at home (r = 0.67, P < .0001 and r = 0.57, P < .0001, respectively). Smokers and patients with chronic obstructive pulmonary disease (COPD) have lower riboflavin status (high EGRAC values) compared with nonsmokers and those without COPD. Riboflavin status improves significantly in the supplement group at 6 weeks compared with the placebo group, but status declines between 6 weeks and 6 months, after patients stop taking the supplements. Conclusions: A high proportion of acutely ill patients have suboptimal riboflavin status. Supplementation with a physiological amount of riboflavin in a mixed‐nutrient supplement significantly improves riboflavin status, but the effect is transient and status deteriorates again after patients stop taking the supplements.     

Drugscapes and the role of place and space in injection drug use-related HIV risk environments

Although considerable research has been conducted to identify the behavioural characteristics that predispose individuals to inject drugs or become infected with HIV via injection drug use, much less research has been conducted on structural and policy determinants, cultural norms, stigma, and ecological factors which may affect drug use risk behaviour, users' networks and HIV rates associated with drug use across geographic areas. For programme planners, whether official or grassroots, an understanding of place-based characteristics can help better identify risk environments to injection drug use-related HIV, and determine how to facilitate actions regarding public policy and harm reduction to aid in the reduction of risk. As such, we consider in this commentary the importance of geographic place and the socio-spatial and political processes related to place that may help determine where IDU-related HIV risk environments occur.     

A hemizygous SCO2 mutation in an early onset rapidly progressive, fatal cardiomyopathy

Mutations in SCO2, a metallochaperone involved in mitochondrial copper delivery, are associated with early onset, fatal hypertrophic cardiomyopathy. All reported patients carry at least one copy of the common 1541G>A (E140K) mutation. Whereas patients with one copy of the E140K allele, in combination with a more deleterious mutation, follow a severe clinical course, patients homozygous for the E140K mutation have a delayed onset of disease and a more prolonged survival. Here, we have investigated a patient who appeared homozygous for the common 1541G>A mutation based on DNA sequencing and restriction enzyme analysis of a PCR product, yet presented with early onset, severe cardiomyopathy. Restriction enzyme analysis of parental DNA revealed that the mother was heterozygous for 1541G>A, while the father was homozygous wild-type. The patient showed biparental inheritance for microsatellite markers spanning the length of chromosome 22, making isodisomy unlikely. Sequencing of several single nucleotide polymorphisms within the 5'-UTR, intron and single exon of the SCO2 gene was uninformative; however, a 16 bp deletion within the intron was present in the patient and the mother, but not the father. Restriction enzyme analysis confirmed that the mother was heterozygous and that the patient was hemizygous for the deletion. Southern blot, Northern blot, and FISH analyses were consistent with the de novo deletion of one allele of SCO2 in the patient. This is the first report of hemizygosity in a SCO2 patient. The patient phenotype underscores the strikingly similar clinical course in all patients with one copy of the E140K allele. Examination of both patient and parental genotypes by thorough molecular analyses can reveal information with important implications for genetic counseling.     

Mifepristone-induced amenorrhoea is associated with an increase in microvessel density and glucocorticoid receptor and a decrease in stromal vascular endothelial growth factor

BACKGROUND: We have previously shown that the progesterone antagonist mifepristone is a contraceptive when given in a dose of 2 or 5 mg per day. The majority of women experience amenorrhoea rather than the irregular break through bleeding usually occurring with other estrogen-free contraceptive pills, such as progestogen-only pill (POP). We investigated the effects of low-dose mifepristone on endometrial parameters which may be associated with changes in endometrial function, such as microvasculature, vascular endothelial growth factor (VEGF) and glucocorticoid receptor (GR) content. METHODS AND RESULTS: Endometrial biopsies were collected from 16 women before (late proliferative phase) and 60 and 120 days after taking 2 or 5 mg mifepristone daily for 120 days. Seven of the eight women who received 2 mg mifepristone and all eight women who received 5 mg were amenorrhoeic during the study. Mean estradiol (E(2)) concentrations remained in the mid-proliferative range, and the majority (9/16) of women showed proliferative endometrial histology at 60 and 120 days following treatment. There was a significant increase in the density of the endometrial stroma (P < 0.05) and microvessels (P < 0.01) following 120 days of treatment. Immunocytochemistry showed that GR, hitherto localized specifically in endometrial stroma, was up-regulated in the nuclei of glands (P < 0.05) and surface (luminal) epithelium (P < 0.01) by 60 days and maintained at 120 days. There was a significant reduction in stromal VEGF protein expression by day 120 of treatment (P < or = 0.01). CONCLUSION: The high incidence of amenorrhoea in women taking mifepristone may be related to changes in the regulation of vascular function.     

Structural basis for a major histocompatibility complex class Ib-restricted T cell response

In contrast to antigen-specific immunity orchestrated by major histocompatibility complex (MHC) class Ia molecules, the ancestrally related nonclassical MHC class Ib molecules generally mediate innate immune responses. Here we have demonstrated the structural basis by which the MHC class Ib molecule HLA-E mediates an adaptive MHC-restricted cytotoxic T lymphocyte response to human cytomegalovirus. Highly constrained by host genetics, the response showed notable fine specificity for position 8 of the viral peptide, which is the sole discriminator of self versus nonself. Despite the evolutionary divergence of MHC class Ia and class Ib molecules, the structure of the T cell receptor-MHC class Ib complex was very similar to that of conventional T cell receptor-MHC class Ia complexes. These results emphasize the evolutionary 'ambiguity' of HLA-E, which not only interacts with innate immune receptors but also has the functional capacity to mediate virus-specific cytotoxic T lymphocyte responses during adaptive immunity.     

Social networks,social support and burden in relationships,and mortality after breast cancer diagnosis

Though larger social networks are associated with reduced breast cancer mortality, there is a need to clarify how both social support and social burden influence this association. We included 4,530 women from the Women’s Health Initiative who were diagnosed with breast cancer between 1993 and 2009, and provided data on social networks (spouse or intimate partner, religious ties, club ties, and number of first-degree relatives) before diagnosis. Of those, 354 died during follow-up, with 190 from breast cancer. We used Cox proportional hazards regression to evaluate associations of social network members with risk of post-diagnosis mortality, further evaluating associations by social support and social burden (caregiving, social strain). In multivariate-adjusted analyses, among women with high but not low social support, being married was related to lower all-cause mortality. By contrast, among women with high but not low social burden, those with a higher number of first-degree relatives, including siblings, parents, and children, had higher all-cause and breast cancer mortality (among caregivers: 0–3 relatives (ref), 4–5 relatives, HR = 1.47 (95% CI: 0.62–3.52), 6–9 relatives, HR = 2.08 (95% CI: 0.89–4.86), 10+ relatives, HR = 3.55 (95% CI: 1.35–9.33), P-continuous = 0.02, P-interaction = 0.008). The association by social strain was similar though it was not modified by level of social support. Other social network members were unrelated to mortality. Social relationships may have both adverse and beneficial influences on breast cancer survival. Clarifying these depends on understanding the context of women’s relationships.