Common and Dissociable Dysfunction of the Reward System in Bipolar and Unipolar Depression

Unipolar and bipolar depressive episodes have a similar clinical presentation that suggests common dysfunction of the brain’s reward system. Here, we evaluated the relationship of both dimensional depression severity and diagnostic category to reward system function in both bipolar and unipolar depression. In total, 89 adults were included, including 27 with bipolar depression, 25 with unipolar depression, and 37 healthy comparison subjects. Subjects completed both a monetary reward task and a resting-state acquisition during 3T BOLD fMRI. Across disorders, depression severity was significantly associated with reduced activation for wins compared with losses in bilateral ventral striatum, anterior cingulate cortex, posterior cingulate cortex, and right anterior insula. Resting-state connectivity within this reward network was also diminished in proportion to depression severity, most notably connectivity strength in the left ventral striatum. In addition, there were categorical differences between patient groups: resting-state connectivity at multiple reward network nodes was higher in bipolar than in unipolar depression. Reduced reward system task activation and resting-state connectivity therefore appear to be a brain phenotype that is dimensionally related to depression severity in both bipolar and unipolar depression. In contrast, categorical differences in reward system resting connectivity between unipolar and bipolar depression may reflect differential risk of mania. Reward system dysfunction thus represents a common brain mechanism with relevance that spans categories of psychiatric diagnosis.     

Usefulness of hypertensive blood pressure response during a single-stage exercise test to predict long-term outcome in patients with peripheral arterial disease

The prognostic value of a hypertensive blood pressure (BP) response is still unclear. Therefore, the prognostic value of a hypertensive BP response in patients during single-stage exercise testing for peripheral arterial disease (PAD) on long-term mortality and major adverse cerebrovascular and cardiac events (MACCEs) was investigated. In addition, effects of statin, beta-blocker, and aspirin use in patients with known or suspected PAD were studied. A total of 2,109 patients were enrolled in an observational prospective study from 1993 to 2005. Hypertensive BP response was defined as an increase in systolic BP >/=55 mm Hg (95(th) percentile within our population) after a single-stage treadmill exercise test. The outcome was obtained by using the civil registries, and a questionnaire about cardiac events was sent to all survivals. Hypertensive BP response was associated with increased risk of long-term mortality (hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.12 to 1.80) and MACCEs (HR 1.47, 95% CI 1.09 to 1.97). After adjustments for clinical risk factors and propensity score, baseline statin use was associated with reduced risk of long-term mortality (HR 0.59, 95% CI 0.44 to 0.79), and statin, beta-blocker, and aspirin use were associated with reduced risk of MACCEs (HR 0.59, 95% CI 0.43 to 0.81; HR 0.75, 95% CI 0.60 to 0.95; HR 0.73, 95% CI, 0.57 to 0.92, respectively). In conclusion, hypertensive BP response at exercise in patients with known or suspected PAD is an important independent risk factor for all-cause long-term mortality and MACCEs, whereas statin, beta-blocker, and aspirin use were associated with an improved outcome.     

Association between serum uric acid and perioperative and late cardiovascular outcome in patients with suspected or definite coronary artery disease undergoing elective vascular surgery

The role of uric acid as an independent marker of cardiovascular risk is unclear. Therefore, our aim was to assess the independent contribution of preoperative serum uric acid levels to the risk of 30-day and late mortality and major adverse cardiac event (MACE) in patients scheduled for open vascular surgery. In total, 936 patients (76% male, age 68 +/- 11 years) were enrolled. Hyperuricemia was defined as serum uric acid >0.42 mmol/l for men and >0.36 mmol/l for women, as defined by large epidemiological studies. Outcome measures were 30-day and late mortality and MACE (cardiac death or myocardial infarction). Multivariable logistic and Cox regression analysis were used, adjusting for age, gender, and all cardiac risk factors. Data are presented as odds ratios or hazard ratios, with 95% confidence intervals. Hyperuricemia was present in 299 patients (32%). The presence of hyperuricemia was associated with heart failure, chronic kidney disease, and the use of diuretics. Perioperatively, 46 patients (5%) died and 61 patients (7%) experienced a MACE. Mean follow-up was 3.7 years (range: 0 to 17 years). During follow-up, 282 patients (30%) died and 170 patients (18%) experienced a MACE. After adjustment for all clinical risk factors, the presence of hyperuricemia was not significantly associated with an increased risk of 30-day mortality or MACE, odds ratios of 1.5 (0.8 to 2.8) and 1.7 (0.9 to 3.0), respectively. However, the presence of hyperuricemia was associated with an increased risk of late mortality and MACE, with hazard ratios of 1.4 (1.1 to 1.7) and 1.7 (1.3 to 2.3), respectively. In conclusion, the presence of preoperative hyperuricemia in vascular patients is a significant predictor of late mortality and MACE.     

Single‐dose administration of clenbuterol is detectable in dried blood spots

Clenbuterol is a β₂‐agonist prescribed for asthmatic patients in some countries. Based on its anabolic and lipolytic effects observed in studies on rodents and in livestock destined for food production, clenbuterol is abused by bodybuilders and athletes seeking leanness. Urinary clenbuterol analysis is part of routine doping analysis. However, the collection of urine samples is time‐consuming and can be intimidating for athletes. Dried blood spot (DBS) appears attractive as an alternative matrix, but the detectability of clenbuterol in humans through DBS has not been investigated. This study evaluated if clenbuterol could be detected in DBS and urine collected from six healthy men after oral intake of 80 μg clenbuterol. The DBS and urine samples were collected at 0, 3, 8, 24, and 72 h post‐ingestion, with additional urine collections on days 7 and 10. Using LC–MS/MS, it was shown that clenbuterol could be detected in all DBS samples for 24 h post‐ingestion and with 50% sensitivity 3 days after ingestion. The DBS method was 100% specific. Evaluation of analyte stability showed that clenbuterol is stable in DBS for at least 365 days at room temperature when using desiccant and avoiding light exposure. In urine, clenbuterol was detectable for at least 7–10 days after ingestion. Urinary clenbuterol concentrations below 5 ng/mL were present in some subjects 24 h after administration. Collectively, these data indicate that DBS are suitable for routine doping control analysis of clenbuterol with a detection window of at least 3 days after oral administration of 80 μg.     

In vivo targeting of human DC‐SIGN drastically enhances CD8+ T‐cell‐mediated protective immunity

Vaccination is one of the oldest yet still most effective methods to prevent infectious diseases. However, eradication of intracellular pathogens and treatment of certain diseases like cancer requiring efficient cytotoxic immune responses remain a medical challenge. In mice, a successful approach to induce strong cytotoxic CD8⁺ T‐cell (CTL) reactions is to target antigens to DCs using specific antibodies against surface receptors in combination with adjuvants. A major drawback for translating this strategy into one for the clinic is the lack of analogous targets in human DCs. DC‐SIGN (DC‐specific‐ICAM3‐grabbing‐nonintegrin/CD209) is a C‐type lectin receptor with potent endocytic capacity and a highly restricted expression on human immature DCs. Therefore, DC‐SIGN represents an ideal candidate for DC targeting. Using transgenic mice that express human DC‐SIGN under the control of the murine CD11c promoter (hSIGN mice), we explored the efficacy of anti‐DC‐SIGN antibodies to target antigens to DCs and induce protective immune responses in vivo. We show that anti‐DC‐SIGN antibodies conjugated to OVA induced strong and persistent antigen‐specific CD4⁺ and CD8⁺ T‐cell responses, which efficiently protected from infection with OVA‐expressing Listeria monocytogenes. Thus, we propose DC targeting via DC‐SIGN as a promising strategy for novel vaccination protocols against intracellular pathogens.     

From classical sternotomy to truly endoscopic mitral valve surgery: a step by step procedure

Background: There is an increasing tendency towards minimally invasive valve surgery and various surgical techniques have been proposed to realise this goal. The aim of the present study was to describe our current surgical technique and clinical experience with respect to an endoscopic technique that allows the surgeon to perform an operation through a series of small intercostal ports.

Methods: After a learning experience with thoracoscopic left internal mammary to left anterior descending coronary artery bypass surgery, we adopted the endocardiopulmonary bypass technique to perform mitral valve surgery. The technique requires exclusive use of video-assisted surgery and control by transoesophageal echocardiography (TEE). Surgery requires long instruments and extra-corporeal knot tying. Between February 1997 and November 2001, 259 patients were operated on. Mitral valve repair was performed in 190 of them. One patient had a redo procedure using this approach to correct a paravalvular leak, but all other procedures were primary interventions.

Results: In all patients, surgery was performed using a 2 inch working port and two additional half-inch trocar-ports. Five patients required a conversion to median sternotomy: three because of inadequate size of the femoral vessels and two because of intraoperative aortic dissection. Hospital mortality included two patients, and seven patients required late reoperation (four of these were as a result of endocarditis).

Conclusions: Endoscopic mitral valve surgery is demanding, but feasible. Once the appropriate skills are acquired, both patient and surgeon can enjoy the benefits of this exciting new technique.     

Interleukin-1 receptor antagonist does not prevent endotoxin-induced inhibition of gastric acid secretion in rats

The underlying mechanisms involved in endotoxin-induced inhibition of gastric acid secretion were investigated in conscious rats with pylorus ligation for 2 hr. Intraperitoneal injection of endotoxin (0.1, 1, and 5 µg/rat) inhibited gastric acid output by 31%, 80%, and 84% respectively. Intraperitoneal endotoxin (1 µg/rat) -induced inhibition of gastric acid secretion was not altered by pretreatment with the interleukin-1 receptor antagonist, IL-1RA, indomethacin, naloxone, or capsaicin. Treatments were injected peripherally at doses previously shown to antagonize the antisecretory effect of exogenous interleukin-1, to inhibit prostaglandin synthesis in the stomach and brain, to block opiate receptors, and to alter functioning of unmyelinated afferent nerve fibers. These results indicate that the antisecretory effect of endotoxin can be expressed by factors other than interleukin-1, prostaglandins, or opioid peptides that do not require the integrity of capsaicin-sensitive afferent pathways.Supported by the National Institute of Arthritis Metabolism and Digestive Disease, grant DK-30110, and the Institute of Mental Health, grant MH-00663, a Research Grant from the Psychoneuroimmunology Program at UCLA, and the Direction General de Investigacion Cientificas Y Técnicas (DGICYT PM—0124 to Dr. E. Saperas).