Influence of repetitive transcranial magnetic stimulation on psychomotor symptoms in major depression

Psychomotor symptoms related to an impairment of the nigrostriatal dopaminergic system are frequent in major depression (MD). Repetitive transcranial magnetic stimulation (rTMS) has been discussed as a new treatment option for MD. In neurobiological terms, an influence of high-frequency rTMS on dopaminergic neurotransmission has previously been shown by several studies in animals and humans. Therefore, an improvement of psychomotor symptoms by rTMS could be assumed. The aim of this pilot study was to investigate the effect of high-frequency rTMS on psychomotor retardation and agitation in depressive patients. We investigated the effect of left prefrontal 10 Hz rTMS on psychomotor retardation and agitation in 30 patients with MD. Patients were randomly assigned to real or sham rTMS in addition to a newly initiated standardized antidepressant medication. We found a trend in the reduction of agitation (t ₂₈ = 1.76, p = 0.09, two-tailed), but not in the reduction of retardation. Furthermore, no general additional antidepressant effect of rTMS was observed. Although there was no statistical significant influence of high-frequency rTMS on psychomotor symptoms in depressive patients, the results showed a trend in the reduction of psychomotor agitation in MD. This effect should be systematically investigated as the primary end point in further studies with larger sample sizes.     

Tauroursodeoxycholic Acid May Improve Liver and Muscle but Not Adipose Tissue Insulin Sensitivity in Obese Men and Women

OBJECTIVE

Insulin resistance is commonly associated with obesity. Studies conducted in obese mouse models found that endoplasmic reticulum (ER) stress contributes to insulin resistance, and treatment with tauroursodeoxycholic acid (TUDCA), a bile acid derivative that acts as a chemical chaperone to enhance protein folding and ameliorate ER stress, increases insulin sensitivity. The purpose of this study was to determine the effect of TUDCA therapy on multiorgan insulin action and metabolic factors associated with insulin resistance in obese men and women.

RESEARCH DESIGN AND METHODS

Twenty obese subjects ([means ± SD] aged 48 ± 11 years, BMI 37 ± 4 kg/m²) were randomized to 4 weeks of treatment with TUDCA (1,750 mg/day) or placebo. A two-stage hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotopically labeled tracer infusions and muscle and adipose tissue biopsies were used to evaluate in vivo insulin sensitivity, cellular factors involved in insulin signaling, and cellular markers of ER stress.

RESULTS

Hepatic and muscle insulin sensitivity increased by ∼30% (P < 0.05) after treatment with TUDCA but did not change after placebo therapy. In addition, therapy with TUDCA, but not placebo, increased muscle insulin signaling (phosphorylated insulin receptor substrate^Tyr and Akt^Ser473 levels) (P < 0.05). Markers of ER stress in muscle or adipose tissue did not change after treatment with either TUDCA or placebo.

CONCLUSIONS

These data demonstrate that TUDCA might be an effective pharmacological approach for treating insulin resistance. Additional studies are needed to evaluate the target cells and mechanisms responsible for this effect.The ability of insulin to decrease hepatic glucose production, suppress adipose tissue lipolytic rate, and stimulate skeletal muscle glucose uptake is critical for normal metabolic function. Obesity is an important cause of multiorgan insulin resistance (1–3), and insulin sensitivity decreases linearly with increasing BMI (4,5). Insulin resistance has important clinical implications because it is involved in the pathogenesis of many of the metabolic complications associated with obesity. The precise mechanisms responsible for the link between obesity and insulin resistance are not known but likely involve alterations in fatty acid metabolism, excess triglyceride accumulation in the liver and muscle (6–11), and systemic low-grade inflammation (12–14).Recently, endoplasmic reticulum (ER) stress has been identified as a contributor to insulin resistance associated with obesity in experimental models (15,16). The ER is responsible for the synthesis, folding, and trafficking of secretory and membrane proteins. Disruption of ER homeostasis results in an adaptive unfolded protein response (UPR), which aims to restore ER folding capacity and mitigate stress. ER stress can also inhibit insulin signaling, at least in part, by activating the c-Jun NH₂-terminal kinase (JNK) pathway through inositol-requiring enzyme (IRE)-1 (15,17–20) or RNA-dependent protein kinase (PKR)-mediated mechanisms (21). Increased ER stress is associated with impaired insulin action in obese mice (15), and chemical or genetic amelioration of this stress improves insulin sensitivity and glucose homeostasis (18). Increased ER stress in liver and adipose tissue and insulin resistance are also associated with obesity in humans (22,23), whereas weight loss decreases ER stress and improves insulin sensitivity (22).Tauroursodeoxycholic acid (TUDCA) is a bile acid derivative that has been used in Europe to treat cholelithiasis and cholestatic liver disease. TUDCA can also act as a chemical chaperone to enhance protein folding and protect cells against ER stress (18). In obese mice, parenteral TUDCA treatment reduces ER stress, improves systemic insulin resistance, and decreases intrahepatic triglyceride (IHTG) content (18). Although data from studies conducted in animal models and cell systems demonstrate beneficial metabolic effects, the effect of TUDCA on insulin action has not been studied in human subjects.The purpose of the present study was to determine whether chemical interventions targeting the ER stress pathway results in metabolic benefits in people. Accordingly, we conducted a randomized controlled trial in insulin-resistant, obese subjects to evaluate the effect of treatment with TUDCA on insulin sensitivity in the liver (glucose production), muscle (glucose uptake), and adipose tissue (lipolysis). We hypothesized that treatment with TUDCA would improve multiorgan insulin signaling and sensitivity and other metabolic factors associated with insulin resistance. The hyperinsulinemic-euglycemic clamp procedure, in conjunction with stable isotopically labeled tracer infusions, was used to determine in vivo insulin sensitivity, and adipose tissue and skeletal muscle biopsies were obtained to assess ER stress markers, phosphorylation of JNK, and components of the insulin-signaling pathway before and after 4 weeks of treatment with TUDCA or placebo.     

Studies on p53, BAX and Bcl-2 protein expression and microsatellite instability in stage III (UICC) colon cancer treated by adjuvant chemotherapy: major prognostic impact of proapoptotic BAX

We evaluated the expression patterns of proapoptotic BAX, antiapoptotic Bcl-2 and p53, the proposed upstream effector of these molecules, as potential prognostic markers in UICC stage III colon cancer by immunohistochemical staining. To identify high-frequency microsatellite instability (MSI+) individuals, we performed single-strand conformation polymorphism-based analysis for BAT26. A total of 188 patients who had received 5-fluorouracil (5-FU)-based adjuvant chemotherapy (5-FU/folinic acid or 5-FU/levamisole) were enrolled. Median follow-up was 84.5 months. We found that BAX, Bcl-2 and p53 protein expressions were high or positive in 59, 70 and 50% of 188 cases, respectively. MSI+ tumours were detected in 9% of 174 evaluable patients. BAX or Bcl-2 was correlated with a higher degree of differentiation or left-sided tumours (P=0.01 or P=0.03, respectively); MSI was correlated with right-sided tumours (P<0.0001). In contrast to p53, Bcl-2, or MSI, low BAX, advanced pN category, low grade of differentiation and treatment with 5-FU/levamisole were univariately associated with poorer disease-free survival (DFS) (P=0.0005, P=0.001, P=0.005 and P=0.01, respectively) and poorer overall survival (OS) (P=0.002, P=0.0001, P=0.003 and P=0.02, respectively). Besides pN category and treatment arm, BAX was an independent variable related to both OS and DFS (P=0.003 and P=0.001, respectively). In both univariate and multivariate analysis, the p53-/BAX high in comparison with the p53+/BAX high subset conferred a significantly improved DFS (P=0.03 and P=0.03, respectively) as well as a marginally improved OS (P=0.07 and P=0.08, respectively). BAX protein expression may be of central significance for clinical outcome to 5-FU-based adjuvant chemotherapy in stage III colon cancer, and bivariate analysis of p53/BAX possibly may provide further prognostic evidence.     

Anticipation of monetary and social reward differently activates mesolimbic brain structures in men and women

Motivation for goal-directed behaviour largely depends on the expected value of the anticipated reward. The aim of the present study was to examine how different levels of reward value are coded in the brain for two common forms of human reward: money and social approval. To account for gender differences 16 male and 16 female participants performed an incentive delay task expecting to win either money or positive social feedback. fMRI recording during the anticipation phase revealed proportional activation of neural structures constituting the human reward system for increasing levels of reward, independent of incentive type. However, in men activation in the prospect of monetary rewards encompassed a wide network of mesolimbic brain regions compared to only limited activation for social rewards. In contrast, in women, anticipation of either incentive type activated identical brain regions. Our findings represent an important step towards a better understanding of motivated behaviour by taking into account individual differences in reward valuation.     

Liver resection using heat coagulative necrosis: indications and limits of a new method

Background: A new approach towards achieving bloodless liver resection is the use of heat coagulative necrosis. The latest stage of this technique is a four‐probe device (Habib Sealer), which we used for a variety of resections to find the best indications for the method. Methods: Between 2005 and 2006 we performed 28 liver resections in 20 consecutive patients. The most common indication was metastatic colorectal cancer (75%). We treated a heterogeneous patient collective in terms of tumour localization and extent of resection. Resection was performed after creating a necrotic zone. The device achieved an area of coagulation of 1‐cm width in which even larger vessels and bile ducts were safely sealed. Results: Operative spectrum covered atypical resections (8), one‐ or bisegmentectomies at different locations (15), hemihepatectomies (4) and one extended right hepatectomy. With one exception intra‐operative blood loss was lower than 100 mL. Four patients (20%) developed operation‐related complications comprising abscess formation at the resection site. Follow‐up shows tumour‐free survival for 13 of 18 patients 12 months after resection. Conclusion: Liver resection using the sealer device seems safe. In proximity of hilar structures or large vessels the method is not favourable for the fear of thermal damage. Extended resections are possible but not parenchyma saving. Good indications are atypical (deep) resections – especially in Segment IVb.     

Contrast‐enhanced ultrasonography using cadence‐contrast pulse sequencing technology for targeted biopsy of the prostate

OBJECTIVE

To evaluate contrast‐enhanced ultrasonography (US) using cadence‐contrast pulse sequencing (CPS) technology, compared with systematic biopsy for detecting prostate cancer, as grey‐scale US has low sensitivity and specificity for detecting prostate cancer.

PATIENTS AND METHODS

In all, 44 men with suspicious prostate‐specific antigen (PSA) levels and CPS findings were assessed; all had CPS‐targeted and systematic biopsy. Transrectal CPS images were taken with a low mechanical index (0.14). A microbubble contrast agent (SonoVue, Bracco International BV, Amsterdam, the Netherlands) was administered as a bolus, with a maximum dose of 4.8 mL. CPS was used to assess prostatic vascularity. Areas with a rapid and increased contrast enhancement within the peripheral zone were defined as suspicious for prostate cancer. Up to five CPS targeted biopsies were taken and subsequently a 10‐core systematic biopsy was taken. Cancer detection rates for the two techniques were compared.

RESULTS

Overall, cancer was detected in 35 of 44 patients (80%), with a mean PSA level of 3.8 ng/mL. Lesions suspicious on CPS showed cancer in 35 of 44 patients (80%) and systematic biopsy detected cancer in 15 of 44 patients (34%). CPS‐targeted cores were positive in 105 of 220 cores (47.7%) and in 41 of 440 systematic biopsy cores (9.3%) (P < 0.001). Lesions suspicious on CPS were false‐positive in nine of 44 patients (20%). The mean Gleason score for systematic biopsy was 6.7 and for CPS‐targeted biopsy 6.8 (P > 0.05). The sensitivity of CPS for detecting cancer was 100% (confidence interval, 95%). However, limitations in the series included that only CPS‐positive cases were investigated, and CPS‐targeted biopsy should be evaluated in a more extended biopsy scheme.

CONCLUSIONS

Contrast‐enhanced US using CPS enables excellent visualization of the microvasculature associated with prostate cancer, and can improve the detection of prostate cancer compared with systematic biopsy.