Comparative vascular effects of histamine, prostaglandin (PG) D2 and its metabolite 9 alpha,11 beta-PGF2 in human skin

In this double-blind study we have investigated the vascular effects of prostaglandin, (PG) D2, in normal skin and compared these effects with histamine and the initial PGD2 metabolite 9 alpha, 11 beta-PGF2. In eight healthy subjects the vascular response to intradermal injections of histamine, PGD2, a combination of histamine and PGD2, and 9 alpha,11 beta-PGF2, was assessed by measurement of the weal and flare area. Histamine caused dose-related increases in weal area (P less than 0.01). The weal response due to PGD2 was greater than saline control only at a dose of 71.0 and 710 nmol (P less than 0.05). Because of the small size of the weal produced by PGD2 when compared with histamine, it was not possible to determine their relative potencies. Histamine and PGD2 caused dose-related increases in flare area (P less than 0.05), and when compared at a response level of 10 cm2 and 15 cm2, histamine was 45 and 251 (P less than 0.01) times more potent than PGD2 in molar terms. Weal and flare responses due to 9 alpha,11 beta-PGF2 were similar to those observed with the equimolar concentration of PGD2. The weal and flare responses when PGD2 and histamine when combined were not significantly different from that predicted by a purely additive effect. We conclude that histamine is likely to be an important mediator contributing towards increased vascular permeability and vasodilatation following immunological activation of skin mast cells in vivo, while PGD2 and its metabolite 9 alpha, 11 beta-PGF2 play only a minor role.     

Peroxynitrite-induced mitochondrial and endonuclease-mediated nuclear DNA damage in acetaminophen hepatotoxicity

Intracellular sources of peroxynitrite formation and potential targets for this powerful oxidant and nitrating agent have not been identified after acetaminophen (AAP) overdose. Therefore, we tested the hypothesis that peroxynitrite generated in mitochondria may be responsible for mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) damage. C3Heb/FeJ mice were treated with 300 mg/kg AAP and monitored for up to 12 h. Loss of mtDNA (assayed by slot blot hybridization) and substantial nDNA fragmentation (evaluated by anti-histone enzyme-linked immunosorbent assay, terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, and agarose gel electrophoresis) were observed as early as 3 h after AAP overdose. Analysis of nitrotyrosine protein adducts in subcellular fractions established that peroxynitrite was generated predominantly in mitochondria beginning at 1 h after AAP injection. Delayed treatment with a bolus dose of glutathione (GSH) accelerated the recovery of mitochondrial glutathione, which then effectively scavenged peroxynitrite. However, mtDNA loss was only partially prevented. Despite the absence of nitrotyrosine adducts in the nucleus after AAP overdose, nDNA damage was almost completely eliminated with GSH administration. A direct comparison of nDNA damage after AAP overdose with nDNA fragmentation during tumor necrosis factor receptor-mediated apoptosis showed similar DNA ladders on agarose gels but quantitatively different results in three other assays. We conclude that peroxynitrite may be partially responsible for mtDNA loss but is not directly involved in nDNA damage. In contrast, nDNA fragmentation after AAP overdose is not caused by caspase-activated DNase but most likely by other intracellular DNase(s), whose activation is dependent on the mitochondrial oxidant stress and peroxynitrite formation.     

Race and Health Disparities in Patient Refusal of Surgery for Early-Stage Pancreatic Cancer: An NCDB Cohort Study

Aim

To identify factors associated with refusal of surgery in patients with early-stage pancreatic cancer and estimate the impact of this decision on survival.

Methods

Using the National Cancer Data Base, 26,358 patients were identified with potentially resectable tumors (pretreatment clinical stage I: T1 or T2 N0M0). Multivariate models were employed to identify factors predicting failure to undergo surgery and assess the impact on survival.

Results

Of early-stage patients who were recommended surgery, 7.8% (N?=?992) refused surgery for resectable early-stage pancreatic cancer. On multivariable analysis, patients were more likely to refuse surgery if they were older [odds ratio (OR)?=?1.18; 95% confidence interval (CI) 1.16–1.19], female (OR?=?1.52; 95% CI 1.33–1.73), African American (vs White, OR?=?1.79; 95% CI 1.37–2.34), on Medicare/Medicaid (vs private, OR?=?2.75; 95% CI 1.54–4.92) or had higher Charlson–Deyo score (2 vs 0, OR?=?1.33; 95% CI 1.03–1.72). Patients were also significantly more likely to refuse surgery if they were seen at a center that is not an academic/research program (OR 1.9; 95% CI 1.6–2.27). Patients who were recommended surgery but refused had significantly worse survival than those with stage I who received surgery [median survival 6.8 vs 24 months, Cox hazard ratio (HR) 3.41; 95% CI 3.12–3.60].

Conclusions

The percentage of patients refusing surgery for operable early-stage pancreatic cancer has been decreasing in the last decade but remains a significant issue that affects survival. Disparities in refusal of surgery are independently associated with several variables including gender, race, and insurance. To mitigate national disparities in surgical care, future studies should focus on exploring potential reasons for refusal and developing communication interventions.

     

Dementia Care Across a Tertiary Care Health System: What Exists Now and What Needs to Change

ObjectivesThis study explored the process of care for persons living with dementia (PLWDs) in various care settings across a tertiary care system and considers challenges and opportunities for change.DesignAimed at quality improvement, qualitative interviews were conducted with key stakeholders in dementia care across geriatric outpatient clinics, medical and psychiatric emergency departments, and the main hospital in 2016.Setting and participantsForty-nine interactive interviews were conducted with a purposive and snowball sampling of health care professionals (physicians, nurses, social workers, administrators) and families in a large, academic health care system.MeasuresQualitative interview guides were developed by the study team to assess the process of care for PLWDs and strengths and challenges to delivering that care.ResultsKey themes emerging from the interviews in each care setting are presented. The outpatient setting offers expertise, a multidisciplinary clinic, and research opportunities, but needs to respond to long waitlists, space limitations, and lack of consensus about who owns dementia care. The emergency department offers a low nurse/patient ratio and expertise in acute medical problems, but experiences competing demands and staff turnover; additionally, dementia does not appear on medical records, which can impede care. The hospital offers consultative services and resources, yet the physical space is confined and chaotic; sitters and antipsychotics can be overused, and placement outside of the hospital for PLWDs can be a challenge.Conclusions and implicationsFive key recommendations are provided to help health systems proactively prepare for the coming boom of PLWD and their caregivers, including outpatient education, a dementia care management program to link services, Internet-based training for providers, and repurposing sitters as Elder Life specialists.     

Potential mediators of the mortality reduction with zoledronic acid after hip fracture

Zoledronic acid reduces the risk of death by 28% after hip fracture, but the mechanisms are not known. This exploratory analysis sought to identify potential pathways for the reduction in mortality with zoledronic acid after hip fracture. This was a retrospective analysis of a randomized, controlled trial. Patients with recent hip fracture (n = 2111) were treated with zoledronic acid or placebo infusion yearly, as well as calcium and vitamin D supplementation. Causes of death were adjudicated by a blinded central review committee. Baseline comorbidities, events occurring during the study period, including subsequent fracture, change in bone density, infections, cardiovascular events, arrhythmias, and falls, were included in multivariable analyses. In a model adjusted for baseline risk factors, zoledronic acid reduced the risk of death by 25% [95% confidence interval (CI) 0.58–0.97). The effect was consistent across most subgroups. Subsequent fractures were significantly associated with death (hazard ratio 1.72, 95% CI 1.17–2.51) but explained only 8% of the zoledronic acid effect. Adjusting for acute events occurring during follow‐up eliminated the death benefit, and zoledronic acid–treated subjects were less likely to die from pneumonia (interaction p = .04) and arrhythmias (interaction p = .02) than placebo‐treated subjects. Only 8% of zoledronic acid's death benefit is due to a reduction in secondary fractures. Zoledronic acid may have an effect on cardiovascular events and pneumonia. Further studies of zoledronic acid in other acute illnesses may be warranted. Copyright © 2010 American Society for Bone and Mineral Research     

Towards the development of integrated epilepsy services: an audit of documented epilepsy care

Effective chronic disease management (CDM) requires the ready availability and communication of accurate, clinical disease specific information. Using epilepsy as a probe into CDM, we report on the availability and reliability of clinical information in the primary care records of people with epilepsy (PWE). The medical records of 374 PWE from 53 general practices in the Mid-West region of Ireland were examined. Confirmation of an epilepsy diagnosis by a neurologist was documented for 132 (35%) patients. 282 (75%) patients had no documented evidence of receiving specialist neurology review while 149 (40%) had not been reviewed by their GP in the previous two years for their epilepsy. Significant variation in documentation of epilepsy specific information together with an inadequacy and inconsistency of existing epilepsy services was highlighted.     

Antifracture Efficacy and Reduction of Mortality in Relation to Timing of the First Dose of Zoledronic Acid After Hip Fracture

Annual infusions of zoledronic acid (5 mg) significantly reduced the risk of vertebral, hip, and nonvertebral fractures in a study of postmenopausal women with osteoporosis and significantly reduced clinical fractures and all‐cause mortality in another study of women and men who had recently undergone surgical repair of hip fracture. In this analysis, we examined whether timing of the first infusion of zoledronic acid study drug after hip fracture repair influenced the antifracture efficacy and mortality benefit observed in the study. A total of 2127 patients (1065 on active treatment and 1062 on placebo; mean age, 75 yr; 76% women and 24% men) were administered zoledronic acid or placebo within 90 days after surgical repair of an osteoporotic hip fracture and annually thereafter, with a median follow‐up time of 1.9 yr. Median time to first dose after the incident hip fracture surgery was ～6 wk. Posthoc analyses were performed by dividing the study population into 2‐wk intervals (calculated from time of first infusion in relation to surgical repair) to examine effects on BMD, fracture, and mortality. Analysis by 2‐wk intervals showed a significant total hip BMD response and a consistent reduction of overall clinical fractures and mortality in patients receiving the first dose 2‐wk or later after surgical repair. Clinical fracture subgroups (vertebral, nonvertebral, and hip) were also reduced, albeit with more variation and 95% CIs crossing 1 at most time points. We concluded that administration of zoledronic acid to patients suffering a low‐trauma hip fracture 2 wk or later after surgical repair increases hip BMD, induces significant reductions in the risk of subsequent clinical vertebral, nonvertebral, and hip fractures, and reduces mortality.