Substance P acting via the neurokinin-1 receptor regulates adverse myocardial remodeling in a rat model of hypertension

Background

Substance P is a sensory nerve neuropeptide located near coronary vessels in the heart. Therefore, substance P may be one of the first mediators released in the heart in response to hypertension, and can contribute to adverse myocardial remodeling via interactions with the neurokinin-1 receptor. We asked: 1) whether substance P promoted cardiac hypertrophy, including the expression of fetal genes known to be re-expressed during pathological hypertrophy; and 2) the extent to which substance P regulated collagen production and fibrosis.

Methods and results

Spontaneously hypertensive rats (SHR) were treated with the neurokinin-1 receptor antagonist L732138 (5 mg/kg/d) from 8 to 24 weeks of age. Age-matched WKY served as controls. The gene encoding substance P, TAC1, was up-regulated as blood pressure increased in SHR. Fetal gene expression by cardiomyocytes was increased in SHR and was prevented by L732138. Cardiac fibrosis also occurred in the SHR and was prevented by L732138. Endothelin-1 was up-regulated in the SHR and this was prevented by L732138. In isolated cardiac fibroblasts, substance P transiently up-regulated several genes related to cell–cell adhesion, cell–matrix adhesion, and extracellular matrix regulation, however, no changes in fibroblast function were observed.

Conclusions

Substance P activation of the neurokinin-1 receptor induced expression of fetal genes related to pathological hypertrophy in the hypertensive heart. Additionally, activation of the neurokinin-1 receptor was critical to the development of cardiac fibrosis. Since no functional changes were induced in isolated cardiac fibroblasts by substance P, we conclude that substance P mediates fibrosis via up-regulation of endothelin-1.     

N-acetylcysteine and liberase improve success of hepatocyte isolation and viability of hepatocytes isolated from normal and diseased liver

BackgroundSuccessful hepatocyte isolation is crucial for development of cellular transplantation and biochemical research. Most researchers isolate hepatocytes from surplus donor tissue or normal tissue removed during resection of liver tumours. However, most tissue available for research is from explanted diseased liver and donor tissue rejected for transplant. We previously described our experience of hepatocyte isolation using liberase from such livers with a success rate of 51% and median viability of 40%. Liberase is a highly purified collagenase that has been shown to improve the viability of isolated porcine hepatocytes. N-acetylcysteine (NAC) has been shown to improve the viability of human hepatocytes isolated from steatotic donor tissue. The aim of this study was to determine the effect of both reagents in combination on the outcome of hepatocyte isolation from normal and diseased liver.MethodsHepatocytes were isolated from 30 consecutive liver specimens as previously described (old protocol). A further 30 consecutive liver specimens were perfused with buffer containing NAC and standard collagenase substituted by liberase (new protocol). Success was defined as maintenance of cell adhesion and morphology for 48 h and/or their successful use in laboratory studies. Mann-Whitney tests were used to compare results. Fisher's exact test was used for categorical data.FindingsBaseline factors were similar for both groups. The delay to tissue processing was slightly less in the new protocol group (median 2 h vs 4 h, p=0·007). The success rate improved from 40% (12/30) with the old protocol to 70% (21/30) with the new protocol (p=0·037), and the median viable cell yield increased from 7·3 × 10⁴ to 28·3 × 10⁴ cells per g tissue (p=0·003). After multivariable analysis adjusting for the difference in time delay, the success rate (p=0·014) and viable cell yield per g tissue (p=0·001) remained significantly improved.InterpretationNAC and liberase greatly improve the success of hepatocyte isolation and result in a significantly higher viable cell yield. Use of these agents may improve the availability of hepatocytes for transplantation as well as laboratory research.FundingUK Medical Research Council.     

Predictive value of sphingosine kinase 1 expression in neoadjuvant treatment of breast cancer

Purpose

Sphingolipids play important roles in apoptosis and cell proliferation. Sphingosine kinase 1 (SphK1) expression has a prognostic impact in primary breast cancer, but its predictive value is currently unknown.

Methods

A total of 112 breast cancer specimens from a prospective neoadjuvant chemotherapy trial (GeparDuo) were studied. Using tissue microarrays of pre-treatment core cut biopsies, we determined the expression of SphK1 by immunohistochemistry. The upper quartile of the cohort according to an immune reactive score of SphK1 was used as cutoff for high expression.

Results

We observed a larger number of samples with high SphK1 expression among ER-negative cancers (36.8 vs. 20.5 % among ER-positive cancers; Fisher test p = 0.073). Eighteen of the 112 patients demonstrated a pathological complete response. A significant predictive value for pathological complete response was observed for ER negativity (p = 0.003), young age (p = 0.037), and high tumor grade (p = 0.049). An increased pCR rate was observed in tumors with high SphK1 expression within the luminal subtype (26.7 vs. 5.8 %; Fisher test p = 0.040). No significant difference in survival was detected according to SphK1 expression.

Conclusions

Our results suggest that SphK1 may be a predictive factor for pCR after neoadjuvant treatment in luminal type breast cancers and warrants further investigation.     

Psychometric Properties of the Posttraumatic Diagnostic Scale (PDS) in Alcohol-Dependent Patients

ABSTRACT

Background: A high prevalence of comorbid posttraumatic stress disorder (PTSD) is found in patients with substance use disorders (SUDs). In the few existing studies, mixed results regarding the psychometric properties of common screening instruments for PTSD have been reported for patients with SUDs. No results are available for the Posttraumatic Diagnostic Scale (PDS), an established self-report measure for PTSD.Methods: The authors assessed 105 patients with alcohol dependence according to DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) (70% male) 2 weeks after their admission to an inpatient detoxification unit. Participants were administered the PDS, the PTSD module of the Structured Clinical Interview for DSM-IV (SCID), as well as measures of depression and anxiety. Patients with other substance use disorders were excluded as were patients reporting no traumatic event. Results: Internal consistencies were good to very good for the total scale (.93) and the subscales of the PDS (.82–.91). In our sample, the PDS had a high specificity (.89) but only moderate sensitivity (.57). Diagnostic agreement with the SCID was 83% (.46). The results of a receiver operating characteristic (ROC) analysis suggested that a PDS score of 8 was the optimal cutoff to screen for PTSD. The highest diagnostic agreement between PDS and SCID (89%; .60) was achieved using a cutoff score of 24. Conclusions: These findings confirm previous results suggesting that the psychometric properties of self-report measures of PTSD in patients with SUDs might differ from those in the general population. When the PDS is used in recently detoxified patients with alcohol dependence, it seems advisable to modify the cutoff score of this instrument to improve its sensitivity and diagnostic accuracy.     

Hemobahn stent-grafts for treatment of femoropopliteal arterial obstructions: midterm results of a prospective trial

PURPOSE: To report a prospective study to evaluate safety, effectiveness, and midterm patency of self-expanding stent-grafts in patients with femoropopliteal occlusive disease. MATERIALS AND METHODS: Sixty-three Hemobahn stent-grafts were used in 52 patients for treatment of medium- or long-segment (>3 cm) occlusions (82.7%) and stenoses (17.3%) of the femoropopliteal artery. The mean length of vessel segments covered was 10.9 cm +/- 5.13. Follow-up with documentation of clinical symptoms, assessment of Rutherford clinical stage of peripheral vascular disease, and color-coded duplex sonography was performed at discharge, at 1, 3, 6, 12, 18, and 24 months after implantation, and yearly thereafter. Mean follow-up duration was 23.8 months +/- 6.9 (range, 8-36 mo). Follow-up data at 12 and 24 months after treatment were available for 47 of 52 (90.4%) and 31 of 52 patients (59.6%), respectively. RESULTS: Device implantation was technically successful in all 52 patients, yielding an overall technical success rate of 100%. Procedure-related complications were observed in 12 of 52 patients (23.1%) and consisted of distal embolization (n = 4, 7.7%), minor groin hematoma (n = 7, 13.5%), and arteriovenous fistula (n = 1, 1.9%), but prolonged hospitalization and further medical, interventional, or surgical measures were not required. Stent-graft placement induced an initial improvement of the mean resting ankle-brachial index from 0.54 +/- 0.12 to 0.89 +/- 0.14 (P <.01). Primary patency rates at 12 and 24 months were 78.4% +/- 5.8 and 74.1% +/- 6.2, respectively. Primary assisted patency rates were 82.4% +/- 5.3 at 12 months and 80.3% +/- 5.6 at 24 months. Secondary patency rates at 12 and 24 months were 88.3% +/- 4.5 and 83.2% +/- 5.5, respectively. There was no significant difference (log-rank test, P >.3) between primary patency rates in patients grouped according to lengths of implanted grafts (ie, length of the treated lesions). CONCLUSION: Endovascular placement of Hemobahn stent-grafts for percutaneous treatment of medium- to long-segment high-grade stenoses and occlusions of the femoropopliteal artery is a safe procedure with excellent initial success rates and promising midterm results.     

Stent graft of abdominal aortic aneurysm after renal transplantation

The necessity of operative treatment of abdominal aortic aneurysm (AAA) is reported in an increasing number of patients after renal transplantation as a result of improved renal graft long-term survival. In these patients, aortic surgery however, places the allograft at risk for ischemic damage. We present a first case of AAA stenting in a kidney-grafted patient. This procedure helped us avoid ischemia of the graft, which showed excellent function pre- and postoperatively. The patient had an uneventful recovery with no evidence of renal dysfunction and was discharged in good condition 7 days after stenting. This case demonstrates a useful alternative for the repair of AAA in kidney-grafted patients.     

CT-Assisted Sympathicolysis as an Additional Minimally Invasive Therapeutic Option in Primary Focal Plantar Hyperhidrosis

Purpose

The purpose of this retrospective study was to evaluate the benefit of lumbar computed tomography-assisted sympathicolysis (CTSy) in patients with primary focal hyperhidrosis of the feet.

Methods

A lumbar CTSy was conducted on 35 patients (mean age 36.6 ± 11.9 years) with primary focal hyperhidrosis of the feet, who experienced persistent symptoms after all conservative treatment options had been exhausted. The patients evaluated the severity of their symptoms before the intervention, 2 days after the intervention, and 6 and 12 months after the intervention on the basis of a Dermatology Quality of Life Index^© (DLQI) and side effects experienced.

Results

The interventions performed led to a statistically significant decrease in the preinterventional severity of symptoms 2 days after the intervention, and 6 and 12 months after CTSy (p < 0.05). No major complications occurred. As the most common side effect, 12 of the patients reported compensatory sweating.

Conclusions

After conservative measures have been exhausted or as a complement to the existing therapy regimen, CT-assisted sympathicolysis represents a therapeutic option low in side effects that provides a marked benefit to patients with primary, focal hyperhidrosis.