Therapeutic potential of endothelial progenitor cells in cardiovascular diseases

Endothelial dysfunction and cell loss are prominent features in cardiovascular disease. Endothelial progenitor cells (EPCs) originating from the bone marrow play a significant role in neovascularization of ischemic tissues and in re-endothelialization of injured blood vessels. Several studies have shown the therapeutic potential of EPC transplantation in rescue of tissue ischemia and in repair of blood vessels and bioengineering of prosthetic grafts. Recent small-scale trials have provided preliminary evidence of feasibility, safety, and efficacy in patients with myocardial and critical limb ischemia. However, several studies have shown that age and cardiovascular disease risk factors reduce the availability of circulating EPCs (CEPCs) and impair their function to varying degrees. In addition, the relative scarcity of CEPCs limits the ability to expand these cells in sufficient numbers for some therapeutic applications. Priority must be given to the development of strategies to enhance the number and improve the function of CEPCs. Furthermore, alternative sources of EPC such as chord blood need to be explored. Strategies for improvement of cell adhesion, survival, and prevention of cell senescence are also essential to ensure therapeutic viability. Genetic engineering of EPCs may be a useful approach to developing these cells into efficient therapeutic tools. In the clinical arena there is pressing need to standardize the protocols for isolation, culture, and therapeutic application of EPC. Large-scale multi-center randomized trials are required to evaluate the long-term safety and efficacy of EPC therapy. Despite these hurdles, the outlook for EPC-based therapy for cardiovascular disease is promising.     

Endogenous and exogenous melanocortin antagonists induce anti-allodynic effects in a model of rat neuropathic pain

A number of studies suggest melanocortin (MC) system involvement in nociceptive modulation. Although the mechanism through which this occurs is still unknown, experimental evidence would suggest a primary role of MC4 receptors. To further investigate the implication of this MC receptor subtype in chronic pain, we have studied the effects of several MC antagonists on spinal nerve ligation-induced nociceptive behavior in rats. The intrathecal injection of synthetic antagonists with different selectivity to MC4 receptor and of an endogenous antagonist (Agouti related protein; AgRP) reduced mechanical allodynia in neuropathic rats, as measured by von Frey hair test. Treatments produced an anti-allodynic effect at the dose of 1.5 nmol (25-30% maximum possible effect, MPE, P<0.05). To further investigate the possible physiological role of AgRP in pain modulation we studied its expression in both sham and neuropathic rat spinal cord and dorsal root ganglia (DRG) by quantitative real time PCR and immunohistochemistry. AgRP was present in both spinal cord and DRG, and its expression, was unchanged in neuropathic animals. In conclusion MC4 receptor antagonists with different selectivity profile, induce anti-allodynic effects in one of the most relevant neuropathic pain model. In addition the expression of AgRP in spinal cord and DRG suggests an endogenous tonic inhibitory control on MC system activity. In pathological conditions this steady control could be insufficient to cope with an over activated MC system leading to increase in nociception. These data suggest that targeting MC4 with synthetic antagonists could restore the balance and hence reduce nociception.     

Memory for time intervals is impaired in left hemi-Parkinson patients

The basal ganglia have been proposed as one of the neural correlates of timekeeping functions. Both encoding and memory retrieval components for time perception are impaired in Parkinson's disease (PD). The aim of our study was to investigate in hemi-Parkinsonian patients the existence of a specific alteration in memory for time depending on the affected side, to better understand the contribution of the left or right basal ganglia circuits in different components of time perception. Right and left hemi-PD patients performed a time reproduction task in which they were required to reproduce in the same session short (5 s) and long (15 s) time intervals, in off- and on-therapy condition. While the right hemi-PD patients overestimated the shorter interval, only the left hemi-PD group showed the memory migration effect, overestimating the shorter and underestimating the longer time intervals. These results argue for a critical involvement of the right basal ganglia in memory retrieval for time intervals, in the range of seconds.     

The role of multidetector CT in the evaluation of the left atrium and pulmonary veins anatomy before and after radio-frequency catheter ablation for atrial fibrillation. Preliminary results and work in progress. Technical note

Radio-frequency catheter ablation (RFCA) of the distal pulmonary veins is increasingly being used to treat recurrent or refractory atrial fibrillation that doesn't respond to pharmacologic therapy or cardioversion. Successful RFCA of atrial fibrillation depends on the pre-procedural understanding of the complex anatomy of the distal pulmonary veins and the left atrium. Aim of this paper is to describe the technical main features that characterise the multidetector helical computed tomography in the evaluation of this anatomic region before and after RFCA procedure. The 3D post-processing techniques useful for pre-RFCA planning are straightforward.     

Renal safety and efficacy of i.v. bisphosphonates in patients with skeletal metastases treated for up to 10 Years

INTRODUCTION: Bisphosphonates (BPs) delay the onset or reduce the incidence of skeletal complications in patients with bone metastases. However, there are few data on the renal safety and activity of i.v. BPs beyond 2 years of administration. MATERIALS AND METHODS: We retrospectively analyzed serum creatinine (SCr) levels and skeletal-related events (SREs) in cancer patients receiving i.v. BPs for >or= 24 months. All patients received 90 mg pamidronate every 3-4 weeks. Pre- and post-treatment SCr levels and the peak levels attained were recorded. A notable SCr increase was defined as: an increase >0.5 mg/dl for patients with baseline SCr <1.4 mg/dl; an increase >1 mg/dl for patients with baseline SCr >1.4 mg/dl; or doubling over baseline. The following parameters were also analyzed: the proportion of patients with at least one SRE, the distribution of each type of SRE, the time to first SRE, and the skeletal morbidity rate (SMR). RESULTS: Fifty-seven patients with bone metastases resulting from breast cancer (BC) (n = 48), multiple myeloma (n = 7), renal cell carcinoma (n = 1), and prostate cancer (n = 1) were evaluated. The median age at the start of treatment was 57 years (range, 27-81); 25% of the patients were >70 years old. Forty-three patients received pamidronate then switched to zoledronic acid. The median overall duration of BP administration was 34 months (range, 24+ to 131+), with a median duration of zoledronic acid therapy of 25 months (range, 2-40). Twenty-seven of 48 BC patients received different chemotherapy regimens (median number of lines, 2; range, 1-6). The median SCr levels were: baseline, 0.82 mg/dl (range, 0.4-1.4); time of analysis, 0.89 mg/dl (0.4-2); highest level, 1.0 mg/dl (0.5-2). A notable SCr increase was observed in seven patients (12.2%; all grade 1). Twenty-six patients (45.6%) experienced SREs after starting BP treatment. The median time to first SRE was 911 days (95% confidence interval, 731; 1,023). The SMR was 0.20 events per year. Ten patients ceased treatment because of: an SCr level of 2 mg/dl (n = 1) physician decision (n = 6) and jaw osteonecrosis (n = 3). Ten patients died of progressive disease. Conclusion: i.v. BPs are safe and active during prolonged treatment administration, and renal function is maintained in patients receiving multiple cytotoxic therapies. Jaw osteonecrosis occurred in 5% of the study population, and its causal relationship with BP treatment requires further observation and study.     

Predictive value of biologic parameters for primary chemotherapy in operable breast cancer

Primary chemotherapy represents an ideal model to evaluate the relationships between treatments and the prognostic and predictive parameters provided by the new technologies. First- and second-generation trials have shown that primary chemotherapy significantly improves the rate of breast conservation without increasing the risk of ipsilateral recurrence and while assuring survival rates comparable with those achieved with postoperative chemotherapy. Moreover, patients who exhibited a pathologic complete response (pCR) showed better progression-free survival and overall survival. The third-generation trials were aimed at improving the percentage of pCR, identifying and validating gene and protein biomarkers of chemotherapy sensitivity, and better defining the individual risk of relapse. Several parameters, such as index of proliferation and apoptosis, expression of proteins (eg, p53 and Bcl-2), and hormone receptor and epidermal growth factor family receptors, have been related to response to primary chemotherapy. Negative hormone receptors and greater proliferative activity seem to be the only parameters more consistently associated with greater chemotherapy sensitivity. However, the strength of this association is not sufficient to differentiate patients at different degrees of risk and does not allow for an individualized therapeutic choice. Newer technologies offer the possibility of evaluating thousands of genes and identifying clusters of gene expression associated with significantly different risks of relapse and patterns of sensitivity/resistance to specific drugs. The primary chemotherapy model is the ideal clinical setting in which to validate the relationship between tumor molecular profiling and treatment outcomes and to design tailored therapies based on observed effects on individual tumors.     

Perioperative stress response to carotid endarterectomy: the impact of anesthetic modality

OBJECTIVE: Surgery for extracranial carotid artery disease has been challenged by carotid angioplasty stenting because the latter is less invasive and avoids surgical trauma. In fact, the magnitude of the perioperative stress response evoked by carotid endarterectomy (CEA) has never been evaluated. Our aim was to determine the degree of surgical trauma caused by CEA and to define differences related to the use of locoregional or general anesthesia. METHODS: We prospectively studied 113 consecutive CEAs performed on 109 patients admitted at a community institutional center. Patients were stratified for demographics and risk factors and operated on under locoregional (LA) or general anesthesia (GA) depending on both the surgeon preference and patient's compliance. Selective carotid shunting was performed for patients who manifested neurologic deficits under LA or had stump pressure values 120 minutes. Three patients experienced an intraoperative neurologic event and had higher post-CACC cortisol values as compared to asymptomatic patients. CONCLUSIONS: Intraoperative surgical stress was higher under LA and was blunted by carotid shunting under both LA and GA. Within 2 hours after surgery the anesthetic modality no longer had any impact on surgical trauma. The stress response to CEA, regardless of the type of anesthesia, was abolished within 24 hours. Intraoperative stress response, namely hypercortisolemia, directly correlated with subclinical and clinical cerebral hypoperfusion/ischemia during CACC. Hence, attenuation of the stress response to CEA might decrease the incidence of cerebral ischemic events.     

Association of long QT syndrome loci and cardiac events among patients treated with beta-blockers

Context  Data on the efficacy of -blockers in the 3 most common genetic long QT syndrome (LQTS) loci are limited. Objective  To describe and assess outcome in a large systematically genotyped population of -blocker–treated LQTS patients. Design, Setting, and Patients  Consecutive LQTS-genotyped patients (n = 335) in Italy treated with -blockers for an average of 5 years. Main Outcome Measures  Cardiac events (syncope, ventricular tachycardia/torsades de pointes, cardiac arrest, and sudden cardiac death) while patients received -blocker therapy according to genotype. Results  Cardiac events among patients receiving -blocker therapy occurred in 19 of 187 (10%) LQT1 patients, 27 of 120 (23%) LQT2 patients, and 9 of 28 (32%) LQT3 patients (P<.001). The risk of cardiac events was higher among LQT2 (adjusted relative risk, 2.81; 95% confidence interval [CI], 1.50-5.27; P = .001) and LQT3 (adjusted relative risk, 4.00; 95% CI, 2.45-8.03; P<.001) patients than among LQT1 patients, suggesting inadequate protection from -blocker therapy. Other important predictors of risk were a QT interval corrected for heart rate that was more than 500 ms in patients receiving therapy (adjusted relative risk, 2.01; 95% CI, 1.16-3.51; P = .01) and occurrence of a first cardiac event before the age of 7 years (adjusted RR, 4.34; 95% CI, 2.35-8.03; P<.001). Conclusion  Among patients with genetic LQTS treated with -blockers, there is a high rate of cardiac events, particularly among patients with LQT2 and LQT3 genotypes.      

The grafted kidney takes over: disappearance of the nephrotic syndrome after preemptive pancreas-kidney and kidney transplantation in diabetic nephropathy

This report describes the rapid and complete reversal of proteinuria after preemptive transplantation in diabetic nephropathy. Case 1 was a 42-year-old woman with type 1 diabetes (before pancreas-kidney graft: serum creatinine 1.6 mg/dL and proteinuria 9.1 g/day; 1 month after pancreas-kidney graft: proteinuria 0.3 g/day and creatinine 1.3 mg/dL). Case 2 was a 48-year-old man with type 2 diabetes (before kidney graft: creatinine 2 mg/dL and proteinuria 5.9 g/day; 1 month after: proteinuria 0.7 g/day and creatinine 1.1 mg/dL). The proteinuria pattern changed (pre: glomerular nonselective, tubular complete; post: physiologic). Renal scintiscan (99mTC-MAG3) demonstrated functional exclusion of the native kidneys, despite high pretransplant clearance (> 50 mL/min). The effect was not linked to euglycemia or readily explainable by pharmacologic effects (no difference in renal parameters after pancreas transplantation with the same protocols). These data confirm the efficacy of preemptive kidney and kidney-pancreas transplantation in diabetic nephrotic syndrome and indicate that a regulatory hemodynamic effect should be investigated.     

Real-time transrectal ultrasonography during laparoscopic radical prostatectomy

PURPOSE: We describe the technical aspects of real-time transrectal ultrasound (TRUS) monitoring and guidance during laparoscopic radical prostatectomy (LRP). Furthermore, we describe the TRUS visualized anatomy of periprostatic structures during LRP. MATERIALS AND METHODS: In 25 consecutive patients undergoing transperitoneal LRP, baseline preoperative, real-time intraoperative and immediate postoperative TRUS evaluations were performed. To define periprostatic anatomy precisely TRUS measurements were obtained with specific reference to the neurovascular bundle (NVB), prostate apex, membranous urethra, bladder neck, rectal wall and any cancer nodule. Conventional gray scale, power Doppler, harmonic imaging and 3-dimensional ultrasound functions were used. RESULTS: Real-time TRUS navigation facilitated 3 technical aspects of LRP. 1) It identified the correct plane between the posterior bladder neck and prostate base, allowing quick laparoscopic identification of the vasa and seminal vesicles. 2) It identified the occasional, difficult to see distal protrusion of the prostate apex posterior to the membranous urethra, thus enhancing apical dissection with negative margins. 3) It provided visualization of any hypoechoic nodule abutting the prostate capsule, alerting the laparoscopic surgeon to perform wide dissection at that location. TRUS measured various anatomical parameters including i) the mean distance +/-SD between the NVB and the lateral edge of the prostate a) at apex (1.9 +/- 0.9 mm), b) base (2.5 +/- 0.8 mm) and c) tip of seminal vesicle (4.0 +/- 1.6 mm), ii) the dimensions of the NVB a) before (4.5 x 3.9 mm), b) after (4.2 x 3.6 mm) nerve sparing LRP and c) after nonnerve sparing LRP (0.9 x 0.9 mm), iii) arterial blood flow resistive index within NVB a) before (0.83 +/- 0.04), b) after (0.84 +/- 0.03) nerve sparing LRP and c) after nonnerve sparing LRP (0), iv) and the length of membranous urethra a) before (12.2 +/- 1.1 mm) and b) after (11.7 +/- 1.0 mm) surgery. Focal distortion of the prostate surface by an exophytic nodule was visualized on TRUS in 3 patients, necessitating ipsilateral nerve resection at LRP and contributing to negative surgical margins. CONCLUSIONS: This initial experience suggests that real-time intraoperative TRUS guidance may enhance anatomical performance of LRP. This improved understanding of periprostatic anatomy has the potential to improve functional and oncological outcomes. Such corroboration is awaited.