Health Status Among 28,000 Women Veterans

BACKGROUND: Male veterans receiving Veterans Health Administration (VA) care have worse health than men in the general population. Less is known about health status in women veteran VA patients, a rapidly growing population.
OBJECTIVE: To characterize health status of women (vs men) veteran VA patients across age cohorts, and assess gender differences in the effect of social support upon health status.
DESIGN AND PATIENTS: Data came from the national 1999 Large Health Survey of Veteran Enrollees (response rate 63%) and included 28,048 women and 651,811 men who used VA in the prior 3 years.
MEASUREMENTS: Dimensions of health status from validated Veterans Short Form-36 instrument; social support (married, living arrangement, have someone to take patient to the doctor).
RESULTS: In each age stratum (18 to 44, 45 to 64, and ≥65 years), Physical Component Summary (PCS) and Mental Component Summary (MCS) scores were clinically comparable by gender, except that for those aged ≥65, mean MCS was better for women than men (49.3 vs 45.9, P <.001). Patient gender had a clinically insignificant effect upon PCS and MCS after adjusting for age, race/ethnicity, and education. Women had lower levels of social support than men; in patients aged <65, being married or living with someone benefited MCS more in men than in women.
CONCLUSIONS: Women veteran VA patients have as heavy a burden of physical and mental illness as do men in VA, and are expected to require comparable intensity of health care services. Their ill health occurs in the context of poor social support, and varies by age.     

Electrophysiological effects of allopregnanolone in rats with a history of ethanol exposure

BACKGROUND: Sensitivity to the anticonvulsant effects of allopregnanolone (ALLO) is enhanced during the early phase of ethanol (EtOH) withdrawal. However, it is unclear whether this enhanced sensitivity generalizes to ALLO's neurobehavioral effects during protracted abstinence. The purpose of this study was to examine the neurophysiological effects of ALLO in rats with a history of chronic EtOH exposure after a protracted period of abstinence. METHODS: Male Wistar rats were exposed to EtOH vapor for 14 hr/day for 5 weeks. Blood EtOH levels were maintained between 200 and 250 mg/dl. The effects of ALLO (0.0-10 mg/kg, intraperitoneally) on motor activity, the electroencephalogram (EEG), and auditory event-related potentials then were assessed after 6 to 8 weeks of abstinence from EtOH. RESULTS: ALLO's effects on the EEG were consistent with previous studies and were unaffected by EtOH exposure. ALLO increased high-frequency EEG power and shifted peak EEG frequencies in a benzodiazepine- and barbiturate-like manner in both the cortex and the hippocampus. The effects of ALLO on event-related potentials were attenuated in rats with a history of EtOH exposure. Low doses of ALLO (1 and 5 mg/kg) reduced cortical P1 amplitude in response to the standard tone but only in the control group. ALLO also increased N1 amplitude in the hippocampus of the control group while having no significant effect in EtOH-exposed rats. Low doses of ALLO (1 and 5 mg/kg) were found to increase motor activity. CONCLUSIONS: These data indicate that a history of EtOH exposure attenuates some of the neurophysiological effects of ALLO in a manner consistent with cross-tolerance. Taken together, these data suggest that increased sensitivity to ALLO's neurobehavioral effects is limited to the early phases of EtOH withdrawal and may not extend to more protracted periods of abstinence.     

Ponce de Leon's Fountain: stem cells and the regenerating heart

Despite current pharmacologic and whole organ transplantation strategies, advanced heart failure remains a common and deadly disease. Limited availability of donor organs for use in orthotopic heart transplantation has prompted the examination of alternative therapies, including cell transfer strategies. Stem cell populations have been identified in virtually all postnatal tissues with the exception of the heart, and these stem cells function in the maintenance and regeneration of the respective tissues. Recent studies challenge preexisting notions regarding cardiac repair and suggest that the heart is capable of limited regeneration through the activation of resident cardiac stem cells or the recruitment of stem cell populations from other tissues such as the bone marrow. This review highlights animal models that have the capacity for myocardial regeneration and examines potential sources of stem cell populations that may participate in tissue regeneration. While some authors view these cell-based strategies as a Fountain of Youth for the myopathic heart, future studies will decipher the regulatory mechanisms of stem cell populations and serve as a prelude to stem cell-based strategies.     

Prediction of one-year mortality among 30-day survivors after primary percutaneous coronary interventions

Little information exists on the features that influence risk factors for death at 1 year among 30-day survivors of ST-elevation myocardial infarction (STEMI) that is treated with primary percutaneous coronary intervention (PCI). Accordingly, we examined 3,280 patients with STEMI who were enrolled in Stent-PAMI and CADILLAC trials, were treated with primary PCI, and survived >30 days after STEMI. Death at 1 year occurred in 74 patients (2.3%) who survived >30 days after their index STEMI. Patients who died at 1 year were more likely to be older and women and have lower body weight and greater prevalence of previous stroke. Similarly, the sum of ST elevations, 3-vessel or left anterior coronary disease, and final Thrombolysis In Myocardial Infarction grade <3 flow was higher, whereas left ventricular ejection fraction was lower among patients who died versus those who survived. The multivariate logistic regression model identified age >70 years (odds ratio [OR] 3.3 95% confidence interval [CI] 1.9 to 5.7), weight <80 kg (OR 1.9, 95% CI 1.1 to 3.6), any tachyarrhythmia during index hospitalization (defined as ventricular or supraventricular tachycardia that required treatment) (OR 2.4, 95% CI 1.2 to 4.8), number of diseased coronary arteries (OR 1.5, 95% CI 1.1 to 2.1), and left ventricular ejection fraction (each 10% decrease, OR 1.5, 95% CI 1.2 to 1.8) as factors independently associated with risk of death at 1 year among 30-day survivors. In conclusion, our study provides a method for clinicians to advise patients who are treated with primary PCI and survive the acute phase of STEMI with regard to patients' long-term prognosis, thus enhancing planning and setting up of realistic expectations.     

Advanced Care for Patients After Coronary Artery Bypass Graft

There was an increase in respiratory failure after coronary artery bypass graft (CABG) at Baptist Heart Institute during the first three quarters of 2000. Thirteen percent of patients required ventilation over 24 hours. The reintubation rate after initial extubation was 18.3% and the mortality rate in the group was 19.7%. After instituting an advanced care team during the first three quarters of 2002, the prolonged ventilation requirement was 7%, reintubation was 4.2%, and the mortality rate 15.4%. These results suggest that an advanced care team could improve clinical outcome and reduce health care costs.     

Pancreatic beta cell function following liraglutide-augmented weight loss in individuals with prediabetes: analysis of a randomised,placebo-controlled study

Aims/hypothesis

Liraglutide can modulate insulin secretion by directly stimulating beta cells or indirectly through weight loss and enhanced insulin sensitivity. Recently, we showed that liraglutide treatment in overweight individuals with prediabetes (impaired fasting glucose and/or impaired glucose tolerance) led to greater weight loss (?7.7% vs ?3.9%) and improvement in insulin resistance compared with placebo. The current study evaluates the effects on beta cell function of weight loss augmented by liraglutide compared with weight loss alone.

Methods

This was a parallel, randomised study conducted in a single academic centre. Both participants and study administrators were blinded to treatment assignment. Individuals who were 40–70 years old, overweight (BMI 27–40 kg/m²) and with prediabetes were randomised (via a computerised system) to receive liraglutide (n?=?35) or matching placebo (n?=?33), and 49 participants were analysed. All were instructed to follow an energy-restricted diet. Primary outcome was insulin secretory function, which was evaluated in response to graded infusions of glucose and day-long mixed meals.

Results

Liraglutide treatment (n?=?24) significantly (p?≤?0.03) increased the insulin secretion rate (% mean change [95% CI]; 21% [12, 31] vs ?4% [?11, 3]) and pancreatic beta cell sensitivity to intravenous glucose (229% [161, 276] vs ?0.5% (?15, 14]), and decreased insulin clearance rate (?3.5% [?11, 4] vs 8.2 [0.2, 16]) as compared with placebo (n?=?25). The liraglutide-treated group also had significantly (p?≤?0.03) lower day-long glucose (?8.2% [?11, ?6] vs ?0.1 [?3, 2]) and NEFA concentrations (?14 [?20, ?8] vs ?2.1 [?10, 6]) following mixed meals, whereas day-long insulin concentrations did not significantly differ as compared with placebo. In a multivariate regression analysis, weight loss was associated with a decrease in insulin secretion rate and day-long glucose and insulin concentrations in the placebo group (p?≤?0.05), but there was no association with weight loss in the liraglutide group. The most common side effect of liraglutide was nausea.

Conclusions/interpretation

A direct stimulatory effect on beta cell function was the predominant change in liraglutide-augmented weight loss. These changes appear to be independent of weight loss.

Trial registration

ClinicalTrials.gov NCT01784965

Funding

The study was funded by the ADA.     

A signaling pathway contributing to platelet storage lesion development: targeting PI3-kinase–dependent Rap1 activation slows storage-induced platelet deterioration

BACKGROUND: The term platelet storage lesion (PSL) describes the structural and biochemical changes in platelets (PLTs) during storage. These are typified by alterations of morphologic features and PLT metabolism leading to reduced functionality and hence reduced viability for transfusion. While the manifestations of the storage lesion are well characterized, the biochemical pathways involved in the initiation of this process are unknown.
STUDY DESIGN AND METHODS: A complementary proteomic approach has recently been applied to analyze changes in the PLT proteome during storage. By employing stringent proteomic criteria, 12 proteins were identified as significantly and consistently changing in relative concentration over a 7-day storage period. Microscopy, Western blot analysis, flow cytometry, and PLT functionality analyses were used to unravel the involvement of a subset of these 12 proteins, which are connected through integrin signaling in one potential signaling pathway underlying storage lesion development.
RESULTS: Microscopic analysis revealed changes in localization of glycoprotein IIIa, Rap1, and talin during storage. Rap1 activation was observed to correlate with expression of the PLT activation marker CD62P. PLTs incubated for 7 days with the PI3-kinase inhibitor LY294002 showed diminished Rap1 activation as well as a moderate reduction in integrin αIIbβ3 activation and release of α-granules. Furthermore, this inhibitor seemed to improve PLT integrity and quality during storage as several in vitro probes showed a deceleration of PLT activation.
CONCLUSION: These results provide the first evidence for a signaling pathway mediating PSL in which PI3-kinase–dependent Rap1 activation leads to integrin αIIbβ3 activation and PLT degranulation.     

Enhanced prepulse inhibition following adolescent ethanol exposure in Sprague-Dawley rats

OBJECTIVES: Recent studies have demonstrated that ethanol exposure differentially affects adolescents and adults. The current studies were designed to compare the effects of 2-week exposure to ethanol during adolescence or adulthood on the acoustic startle response (ASR) and prepulse inhibition (PPI) METHODS: Male Sprague-Dawley rats were exposed to ethanol vapor 12 hr/d (on from 6 pm to 6 am) for 14 days during adolescence or adulthood. Six days after the cessation of ethanol vapor exposure, the ASR and PPI were assessed. RESULTS: During ethanol treatment, overall blood alcohol levels averaged 230 to 250 mg/dl in the adolescent and adult treatment groups. Assessment of the ASR revealed that latency to startle was more rapid in adolescents than in adults, but ASR latency was not altered by ethanol exposure. In addition, ASR magnitude was lower in adolescents and was decreased in ethanol-exposed rats on startle trials. Ethanol exposure significantly enhanced PPI, but only after adolescent exposure CONCLUSIONS: These data further demonstrate a differential sensitivity of adolescents and adults to the effects of ethanol exposure. Specifically, a 2-week period of ethanol exposure during adolescence selectively enhanced PPI, a neurobehavioral index of sensorimotor gating. However, ASR magnitude was decreased by ethanol exposure regardless of age. On the basis of previous studies, the effects of ethanol exposure on PPI data could indicate that adolescent rats exposed to ethanol are more likely to exhibit behavioral inflexibility and that ethanol exposure acts as a more potent physical stressor in adolescent rats.     

A novel system for efficient gene transfer into primary human hepatocytes via cell-permeable hepatitis B virus-like particle

Protein transduction domains (PTDs) have been used to deliver a variety of biologically active cargo across cellular membranes. However the potential of PTDs to mediate transport of nanoparticular structures into the cytoplasm bypassing the endosomal compartment remains unclear. Cell-permeable virus-like particles (VLPs) harboring a marker gene based on hepatitis B virus nucleocaspids were established. Cell permeability was achieved by fusion with translocation motif (TLM)-PTD. Electron and confocal microscopy revealed that these VLPs translocate as complete particles across the plasma membrane and transverse the cytoplasm toward the nucleus. Inhibition of endocytosis did not affect translocation of these VLPs into the cytoplasm. Based on these particles, a gene transfer system was developed. To this end the particles were loaded with DNA-encoding small hepatitis B virus surface antigen (SHBs) or green fluorescence protein (eGFP) that served as marker genes. Although the DNA-packaging efficiency was very low, applying the appropriate number of VLPs to primary human hepatocytes a gene transfer efficiency of approximately 95% was observed. In conclusion, the TLM-PTD has the potential to mediate efficient transfer of assembled particles and its cargo, nucleic acids, into primary human hepatocytes. This provides the basis for development of novel transducible therapeutic or diagnostic particles.