Combined D1/D2 receptor stimulation under conditions of dopamine depletion impairs spatial working memory performance in humans

Rationale The mesocortical dopamine system is regarded as an important modulator of working memory. While it has been established that stimulation of the D₁/D₂ receptor in primates can improve spatial working memory performance, findings in humans are less consistent. Recent studies in humans suggest that global depletion of dopamine via tyrosine/phenylalanine depletion may impair spatial working memory performance, although these results are also inconsistent, and it has been suggested that task differences may partly underlie the inconsistent findings. Objectives This study had two aims: (1) to investigate the effects of acute tyrosine depletion (TPD) on a number of working memory tasks and (2) to examine whether stimulation of D₁/D₂ receptors under conditions of TPD can attenuate or “reverse” TPD-induced working memory impairments. Methods Eighteen healthy male participants performed a spatial working memory delayed-recognition task, non-spatial working memory task and spatial n-back task on three separate occasions, after TPD, TPD and pergolide (D₁/D₂ agonist), and placebo. Results TPD did not impair working memory performance on any of the tasks administered. However, stimulation of D₁/D₂ receptors under TPD conditions caused a subtle impairment in spatial working memory performance. Conclusions The finding that D₁/D₂ stimulation under TPD conditions impairs working memory highlights the complexity of functional effects of augmenting dopaminergic transmission within a dopamine-depleted state. The lack of TPD-related effects on a range of working memory tasks questions the reliability of TPD as a modulator of dopamine function and working memory performance in humans.     

Methylphenidate effects in attention deficit/hyperactivity disorder: electrodermal and ERP measures during a continuous performance task

Rationale Previous research investigating the effects of stimulants, such as methylphenidate (MPH), on children with attention deficit/hyperactivity disorder (AD/HD) has rarely included autonomic measures of arousal.Objective Our aim was to clarify the effects of MPH on central and autonomic measures in AD/HD children during a continuous performance task (CPT) using a naturalistic open-label study.Method Thirty-six boys (18 AD/HD and 18 control) participated in a CPT over two trial periods, allowing a more valid estimate of the effects of medication, rather than assuming that retesting per se has no substantial impact. MPH was administered to the AD/HD group 1 h prior to the second trial. Errors and reaction time (RT) were recorded as measures of performance, electrodermal activity as an autonomic nervous system measure and event-related potentials (ERPs) as an index of central nervous system activity.Results AD/HD children made more errors than controls in the first session, but no group differences were found after medication. No significant differences were observed for RT. Skin conductance level was found to be lower in AD/HD children than controls, but this difference was also ameliorated after medication. Conversely, mean skin conductance response to target stimuli was found not to differ between groups during the initial test phase but became significantly different in phase 2. ERP data showed topographic differences between groups in N1, P2, N2 and P3 at the initial test phase, which were reduced at the second test.Conclusion Stimulant medication ameliorated some of the dysfunctions in AD/HD children, which are reflected in behavioural and ERP measures. These results, in combination with general differences in electrodermal activity, support a hypoarousal model of AD/HD, which can explain the action of MPH in these children.     

Vascular endothelial cell cyclic nucleotide phosphodiesterases and regulated cell migration: implications in angiogenesis

Angiogenesis is necessary during embryonic development and wound healing but can be detrimental in pathologies, including cancer. Because initiation of angiogenesis involves migration and proliferation of vascular endothelial cells (VECs) and cAMP-elevating agents inhibit these events, such agents may represent a novel therapeutic avenue to controlling angiogenesis. Intracellular cAMP levels are regulated by their synthesis by adenylyl cyclases and hydrolysis by cyclic nucleotide phosphodiesterases (PDEs). In this report, we show that human VECs express variants of PDE2, PDE3, PDE4, and PDE5 families and demonstrate that the levels of these enzymes differ in VECs derived from aorta, umbilical vein, and microvascular structures. Selective inhibition of PDE2 did not increase cAMP in any VECs, whether in the absence or presence of forskolin, but it did inhibit migration of all VECs studied. Inhibition of PDE4 activity decreased migration, and in conjunction with forskolin, increased cAMP in all VECs studied. PDE3 inhibition potentiated forskolin-induced increases in cAMP and inhibited migration in VECs derived from aorta and umbilical vein but not in microvascular VECs. In experiments with combinations of PDE2, PDE3, and PDE4 inhibitors, a complex interaction between the abilities of these agents to limit human VEC migration was observed. Overall, our data are consistent with the hypothesis that PDE subtype inhibition allows different effects in distinct VEC populations and indicate that these agents may represent novel therapeutic agents to limit angiogenesis in complex human diseases.     

DNA vaccines for biodefence

The advantages associated with DNA vaccines include the speed with which they may be constructed and produced at large-scale, the ability to produce a broad spectrum of immune responses, and the ability for delivery using non-invasive means. In addition, DNA vaccines may be manipulated to express multiple antigens and may be tailored for the induction of appropriate immune responses. These advantages make DNA vaccination a promising approach for the development of vaccines for biodefence. In this review, the potential of DNA vaccines for biodefence is discussed.     

Concepts in the prevention of adenocarcinoma of the distal esophagus and proximal stomach

For decades, the incidence rates for squamous cell carcinoma of the esophagus and adenocarcinoma of the distal stomach have been declining while the rates for adenocarcinomas of the esophagus and gastric cardia have increased profoundly. Recent studies have shown that the gastroesophageal junction (GEJ) is regularly exposed to concentrated gastric acid and to a variety of nitrosating species, noxious agents that may contribute to carcinogenesis in this region. For adenocarcinomas that straddle the GEJ, it can be difficult to determine whether the tumor originated in the esophagus or in the gastric cardia. This classification problem hampers studies on the epidemiology and pathogenesis of GEJ tumors. Current concepts in the prevention of cancers of the distal esophagus and proximal stomach have emerged from advances in our understanding of the specific molecular events that occur during the evolution of these tumors. This report reviews those events and focuses on current concepts in the prevention of adenocarcinomas at the GEJ. The similarities and differences in risk factors, molecular pathogenesis, and in preventive strategies for adenocarcinomas of the esophagus and gastric cardia are highlighted.     

Preferences of Women Evaluating Risks of Tamoxifen (POWER) study of preferences for tamoxifen for breast cancer risk reduction

BACKGROUND: The objective of this study was to understand the attitudes and preferences of risk-eligible women regarding use of tamoxifen for breast cancer risk reduction. METHODS: A cross-sectional, mixed-methods interview study was conducted at a university medical center and at community sites. Participants were women who had an estimated 5-year breast cancer risk > or = 1.7% and no prior breast cancer. Interviews were conducted in English or Spanish. The interview included a 15-minute, standardized educational session on the potential benefits and harms of tamoxifen followed by close-ended and open-ended questions about participants' inclinations to take tamoxifen and factors important to their decision. A demographic questionnaire, a test on knowledge of potential benefits and harms of tamoxifen, and an interview evaluation were included. RESULTS: Two hundred fifty-five women completed interviews. Their estimated mean 5-year breast cancer risk was 2.8%; and their mean self-perceived 5-year risk was 32.7%. After the educational intervention, 45 women (17.6%) were inclined to take tamoxifen. Very high risk women (> 3.5%) were no more inclined to take it than women with lower risk (1.7-3.5%). In a multivariable analysis, lower income, confidence in the effectiveness of tamoxifen, and concern about fractures were associated with being inclined to take it; concern about pulmonary embolism, dyspareunia, cataracts, and low self-perceived breast cancer risk were associated negatively with taking tamoxifen. Participants expressed concerns about adverse effects. CONCLUSIONS: Less than 20% of women were interested in tamoxifen after education about potential benefits and harms, despite a very high self-perceived breast cancer risk. Candidate chemoprevention agents must have few potential adverse effects to achieve widespread acceptance.     

Simultaneous pancreas-kidney transplantation from donation after cardiac death: successful long-term outcomes

OBJECTIVE: The outcomes of simultaneous pancreas-kidney (SPK) transplantation with donor organs procured from donation after cardiac death (DCD) are compared with transplants performed with donor organs recovered from donation after brain death (DBD). SUMMARY BACKGROUND DATA: Concerns exist regarding the utilization of pancreata obtained from DCD donors. While it is known that DCD kidneys will have a higher rate of DGF, long-term functional graft survival data for DCD pancreata have not been reported. METHODS: A retrospective review of all DCD SPK transplants performed at a single center was undertaken. RESULTS: Patient, pancreas, and kidney survival at 5 years were similar between DCD and DBD organs. Pancreas function and outcomes were indistinguishable between the 2 modes of procurement. As expected, the DCD kidneys had an elevated rate of DGF, which had no significant long-term clinical impact. CONCLUSION: SPK transplantation using selected DCD donors is a safe and viable method to expand the organ pool for transplantation.     

Quality-of-life outcome following hemiarthroplasty or total shoulder arthroplasty in patients with osteoarthritis. A prospective, randomized trial

BACKGROUND: Both total shoulder arthroplasty and hemiarthroplasty have been used commonly to treat severe osteoarthritis of the shoulder; however, their effect on disease-specific quality-of-life outcome is unknown. The purpose of this study was to compare the quality-of-life outcome following hemiarthroplasty with that following total shoulder arthroplasty in patients with osteoarthritis of the shoulder. METHODS: Forty-two patients with a diagnosis of osteoarthritis of the shoulder were randomized to receive a hemiarthroplasty or a total shoulder arthroplasty. One patient died, and all others were evaluated preoperatively and at six weeks and three, six, twelve, eighteen, and twenty-four months postoperatively with use of a standardized format including a disease-specific quality-of-life measurement tool (Western Ontario Osteoarthritis of the Shoulder [WOOS] index), general shoulder rating scales (University of California at Los Angeles [UCLA] shoulder scale, Constant score, and American Shoulder and Elbow Surgeons [ASES] evaluation form), general pain scales (McGill pain score and visual analogue scale), and a global health measure (Short Form-36 [SF-36]). When a patient required revision of a hemiarthroplasty to a total shoulder arthroplasty, the last score before he or she "crossed over" was used for the analysis. RESULTS: Significant improvements in disease-specific quality of life were seen two years after both the total shoulder arthroplasties and the hemiarthroplasties. There were no significant differences in quality of life (WOOS score) between the group treated with total shoulder arthroplasty and that treated with hemiarthroplasty (90.6 +/- 13.2 and 81.5 +/- 24.1 points, respectively; p = 0.18). The other outcome measures demonstrated similar findings. Two patients in the hemiarthroplasty group crossed over to the other group by undergoing a revision to a total shoulder arthroplasty because of glenoid arthrosis. CONCLUSIONS: Both total shoulder arthroplasty and hemiarthroplasty improve disease-specific and general quality-of-life measurements. With the small number of patients in our study, we found no significant differences in these measurements between the two treatment groups. LEVEL OF EVIDENCE: Therapeutic Level I.     

Surgical sphincteroplasty in 446 patients

HYPOTHESIS: Pancreaticobiliary sphincter disease is reliably diagnosed by endoscopic and intraoperative manometry. DESIGN: Retrospective review of prospectively collected data. SETTING: A 400-bed urban university hospital. PATIENTS: Between May 1, 1978, and March 27, 2002, 446 patients were treated surgically for dysfunction of the pancreaticobiliary sphincters. There were 376 females and 70 males (mean +/- SD age, 41.6 +/- 12.5 years). There were 372 patients with sphincter of Oddi dysfunction, and 74 with pancreas divisum. Symptoms included abdominal pain (100.0%), nausea/vomiting (80.5%), back pain (57.2%), and pancreatitis (22.4%). INTERVENTIONS: Perfusion manometry has evolved as the gold standard for diagnosis, and intraoperative manometry was done in 214 patients. All patients underwent transduodenal sphincteroplasty and biopsies of the ampullae and transampullar septa. RESULTS: Excellent or good results were seen in 86.8% of the patients with sphincter of Oddi dysfunction and in 63.5% of the patients with pancreas divisum. Common duct and sphincter of Oddi pressures were 0 mm Hg in all patients after sphincteroplasty. Pancreatic duct and pancreatic sphincter manometry results were improved in 82.4% of the patients. Biopsy results of the main and accessory sphincters demonstrated inflammation and/or fibrosis in 33.9% of ampullae and 43.5% of transampullar septa, but this did not correlate with outcome. There was 1 death from a duodenal leak. Complications occurred in 34.8% of patients, with pancreatitis (8.8%), asymptomatic hyperamylasemia (6.0%), and wound/abdominal infection (7.1%) the most common. Predictive factors for good outcome were reduction in pancreatic duct and sphincter pressures following sphincteroplasty. CONCLUSION: Good to excellent results may be achieved by surgical sphincteroplasty when careful patient selection by manometry is used.     

Neuroendocrine hepatic metastases: does aggressive management improve survival?

OBJECTIVE: The aim of this study was to determine whether aggressive management of neuroendocrine hepatic metastases improves survival. SUMMARY BACKGROUND DATA: Survival in patients with carcinoid and pancreatic neuroendocrine tumors is significantly better than adenocarcinomas arising from the same organs. However, survival and quality of life are diminished in patients with neuroendocrine hepatic metastases. In recent years, aggressive treatment of hepatic neuroendocrine tumors has been shown to relieve symptoms. Minimal data are available, however, to document improved survival with this approach. METHODS: The records of patients with carcinoid (n = 84) and pancreatic neuroendocrine tumors (n = 69) managed at our institution from January 1990 through July 2004 were reviewed. Eighty-four patients had malignant tumors, and hepatic metastases were present in 60 of these patients. Of these 60 patients, 23 received no aggressive treatment of their liver metastases, 19 were treated with hepatic resection and/or ablation, and 18 were managed with transarterial chemoembolization (TACE) frequently (n = 11) in addition to resection and/or ablation. These groups did not differ with respect to age, gender, tumor type, or extent of liver involvement. RESULTS: Median and 5-year survival were 20 months and 25% for the Nonaggressive group, >96 months and 72% for the Resection/Ablation group, and 50 months and 50% for the TACE group. The survival for the Resection/Ablation and the TACE groups was significantly better (P < 0.05) when compared with the Nonaggressive group. Patients with more than 50% liver involvement had a poor outcome (P < 0.001). CONCLUSIONS: These data suggest that aggressive management of neuroendocrine hepatic metastases does improve survival, that chemoembolization increases the patient population eligible for this strategy, and that patients with more than 50% liver involvement may not benefit from an aggressive approach.