Bariatric surgery and brain health: A longitudinal observational study investigating the effect of surgery on cognitive function and gray matter volume

Dietary modifications leading to weight loss have been suggested as a means to improve brain health. In morbid obesity, bariatric surgery (BARS)—including different procedures, such as vertical sleeve gastrectomy (VSG), gastric banding (GB), or Roux-en-Y gastric bypass (RYGB) surgery—is performed to induce rapid weight loss. Combining reduced food intake and malabsorption of nutrients, RYGB might be most effective, but requires life-long follow-up treatment. Here, we tested 40 patients before and six months after surgery (BARS group) using a neuropsychological test battery and compared them with a waiting list control group. Subsamples of both groups underwent structural MRI and were examined for differences between surgical procedures. No substantial differences between BARS and control group emerged with regard to cognition. However, larger gray matter volume in fronto-temporal brain areas accompanied by smaller volume in the ventral striatum was seen in the BARS group compared to controls. RYGB patients compared to patients with restrictive treatment alone (VSG/GB) had higher weight loss, but did not benefit more in cognitive outcomes. In sum, the data of our study suggest that BARS might lead to brain structure reorganization at long-term follow-up, while the type of surgical procedure does not differentially modulate cognitive performance

Weight loss reduces head motion: Re-visiting a major confound in neuroimaging

Head motion during magnetic resonance imaging (MRI) induces image artifacts that affect virtually every brain measure. In parallel, cross‐sectional observations indicate a correlation of head motion with age, psychiatric disease status and obesity, raising the possibility of a systematic artifact‐induced bias in neuroimaging outcomes in these conditions, due to the differences in head motion. Yet, a causal link between obesity and head motion has not been tested in an experimental design. Here, we show that a change in body mass index (BMI) (i.e., weight loss after bariatric surgery) systematically decreases head motion during MRI. In this setting, reduced imaging artifacts due to lower head motion might result in biased estimates of neural differences induced by changes in BMI. Overall, our finding urges the need to rigorously control for head motion during MRI to enable valid results of neuroimaging outcomes in populations that differ in head motion due to obesity or other conditions

How much of Me do I see in You: Neural correlates of self-other distinction in the affective domain

When inferring mental states of others, individuals’ judgments are influenced by their own state of mind, which has been referred to as egocentric bias. Especially in situations where one holds a different mental state than another person to be interpreted, self-other differentiation is key for an accurate interpretation on the other person’s mind. It has been suggested that the right supramarginal gyrus (rSMG) is involved in self-other differentiation and overcoming egocentric bias in the affective domain. In a double-blind, randomized study 47 healthy adults received active or sham anodal tDCS (1mA, 20min) or a sham stimulation to the rSMG prior to performing a newly developed emotional egocentricity paradigm (SOFE, Self-Other Facial Emotion Judgment Task). In SOFE, subjects are presented with emotionally ambiguous situations (happy or fearful) in which they have to continuously rate 1) their own emotion and 2) the emotion of another person whose facial expression is either congruent or incongruent to the subject’s emotion. Analyses confirmed the presence of an emotional egocentric bias in incongruent trials. We furthermore found that active tDCS applied to the rSMG increased subjects’ ability to overcome egocentric judgments. This effect was valence dependent with significant effects when inferring affective states of happy faces right after imagining oneself in a fear-evoking situation (p<0.05). Our findings extend previous research showing a causal role of the rSMG for emotional self-other distinction to the inferring of emotional states from pictorial stimuli. They additionally point towards valence-specific patterns of rSMG functionality. In a next step the SOFE task will be applied in autism spectrum disorder to characterize egocentric bias suppression and SMG network integrity in an effort to elucidate social cognitive dysfunction in affected individuals

Increased amino acids levels and the risk of developing of hypertriglyceridemia in a 7-year follow-up

BACKGROUND: Recently, five branched-chain and aromatic amino acids were shown to be associated with the risk of developing type 2 diabetes (T2D). AIM: We set out to examine whether amino acids are also associated with the development of hypertriglyceridemia. MATERIALS AND METHODS: We determined the serum amino acids concentrations of 1,125 individuals of the KORA S4 baseline study, for which follow-up data were available also at the KORA F4 7 years later. After exclusion for hypertriglyceridemia (defined as having a fasting triglyceride level above 1.70 mmol/L) and diabetes at baseline, 755 subjects remained for analyses. RESULTS: Increased levels of leucine, arginine, valine, proline, phenylalanine, isoleucine and lysine were significantly associated with an increased risk of hypertriglyceridemia. These associations remained significant when restricting to those individuals who did not develop T2D in the 7-year follow-up. The increase per standard deviation of amino acid level was between 26 and 40 %. CONCLUSIONS: Seven amino acids were associated with an increased risk of developing hypertriglyceridemia after 7 years. Further studies are necessary to elucidate the complex role of these amino acids in the pathogenesis of metabolic disorders

Low levels of Caspase-3 predict favourable response to 5FU-based chemotherapy in advanced colorectal cancer: Caspase-3 inhibition as a therapeutic approach.

Colorectal cancer (CRC) is one of the most common cancers in the Western world. 5-Fluorouracil (5FU)-based chemotherapy (CT) remains the mainstay treatment of CRC in the advanced setting, and activates executioner caspases in target cells. Executioner caspases are key proteins involved in cell disassembly during apoptosis. Activation of executioner caspases also has a role in tissue regeneration and repopulation by stimulating signal transduction and cell proliferation in neighbouring, non-apoptotic cells as reported recently. Tissue microarrays (TMAs) consisting of tumour tissue from 93 stage II and III colon cancer patients were analysed by immunohistochemistry. Surprisingly, patients with low levels of active Caspase-3 had an increased disease-free survival time. This was particularly pronounced in patients who received 5FU-based adjuvant CT. In line with this observation, lower serum levels of active Caspase-3 were found in patients with metastasised CRC who revealed stable disease or tumour regression compared with those with disease progression. The role of Caspase-3 in treatment responses was explored further in primary human tumour explant cultures from fresh patient tumour tissue. Exposure of explant cultures to 5FU-based CT increased the percentage of cells positive for active Caspase-3 and Terminal Deoxynucleotidyl Transferase dUTP Nick end Labelling (TUNEL), but also the expression of regeneration and proliferation markers β-Catenin and Ki-67, as well as cyclooxygenase-2 (COX-2). Of note, selective inhibition of Caspase-3 with Ac-DNLD-CHO, a selective, reversible inhibitor of Caspase-3, significantly reduced the expression of proliferation markers as well as COX-2. Inhibition of COX-2 with aspirin or celecoxib did not affect Caspase-3 levels but also reduced Ki-67 and β-Catenin levels, suggesting that Caspase-3 acted via COX-2 to stimulate cell proliferation and tissue regeneration. This indicates that low levels of active Caspase-3 may represent a new predictor of CT responsiveness, and inhibition of Caspase-3, or antagonising downstream effectors of Caspase-3 paracrine signalling, such as COX-2 may improve patient outcomes following CT in advanced CRC

Sisyphus Cooling of Electrically Trapped Polyatomic Molecules

The rich internal structure and long-range dipole-dipole interactions establish polar molecules as unique instruments for quantum-controlled applications and fundamental investigations. Their potential fully unfolds at ultracold temperatures, where a plethora of effects is predicted in many-body physics, quantum information science, ultracold chemistry, and physics beyond the standard model. These objectives have inspired the development of a wide range of methods to produce cold molecular ensembles. However, cooling polyatomic molecules to ultracold temperatures has until now seemed intractable. Here we report on the experimental realization of opto-electrical cooling, a paradigm-changing cooling and accumulation method for polar molecules. Its key attribute is the removal of a large fraction of a molecule's kinetic energy in each step of the cooling cycle via a Sisyphus effect, allowing cooling with only few dissipative decay processes. We demonstrate its potential by reducing the temperature of about 10^6 trapped CH_3F molecules by a factor of 13.5, with the phase-space density increased by a factor of 29 or a factor of 70 discounting trap losses. In contrast to other cooling mechanisms, our scheme proceeds in a trap, cools in all three dimensions, and works for a large variety of polar molecules. With no fundamental temperature limit anticipated down to the photon-recoil temperature in the nanokelvin range, our method eliminates the primary hurdle in producing ultracold polyatomic molecules. The low temperatures, large molecule numbers and long trapping times up to 27 s will allow an interaction-dominated regime to be attained, enabling collision studies and investigation of evaporative cooling toward a BEC of polyatomic molecules

Modulation of Mcl-1 sensitizes glioblastoma to TRAIL-induced apoptosis

Glioblastoma (GBM) is the most aggressive form of primary brain tumour, with dismal patient outcome. Treatment failure is associated with intrinsic or acquired apoptosis resistance and the presence of a highly tumourigenic subpopulation of cancer cells called GBM stem cells. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has emerged as a promising novel therapy for some treatment-resistant tumours but unfortunately GBM can be completely resistant to TRAIL monotherapy. In this study, we identified Mcl-1, an anti-apoptotic Bcl-2 family member, as a critical player involved in determining the sensitivity of GBM to TRAIL-induced apoptosis. Effective targeting of Mcl-1 in TRAIL resistant GBM cells, either by gene silencing technology or by treatment with R-roscovitine, a cyclin-dependent kinase inhibitor that targets Mcl-1, was demonstrated to augment sensitivity to TRAIL, both within GBM cells grown as monolayers and in a 3D tumour model. Finally, we highlight that two separate pathways are activated during the apoptotic death of GBM cells treated with a combination of TRAIL and R-roscovitine, one which leads to caspase-8 and caspase-3 activation and a second pathway, involving a Mcl-1:Noxa axis. In conclusion, our study demonstrates that R-roscovitine in combination with TRAIL presents a promising novel strategy to trigger cell death pathways in glioblastoma. Electronic supplementary material The online version of this article (doi:10.1007/s10495-013-0935-2) contains supplementary material, which is available to authorized users

Further investment in Aboriginal and Torres Strait Islander men's health research funding is urgently required

Kootsy Canuto, Jacob Prehn, Karla Canuto, Rosie Neate, Graham Gee, Corey Kennedy, Celina Gaweda, Oliver Black, James Smith, Alex Brow

New hints towards a precision medicine strategy for IDH wild-type glioblastoma.

Glioblastoma represents the most common primary malignancy of the central nervous system in adults and remains a largely incurable disease. The elucidation of disease subtypes based on mutational profiling, gene expression and DNA methylation has so far failed to translate into improved clinical outcomes. However, new knowledge emerging from the subtyping effort in the IDH-wild-type setting may provide directions for future precision therapies. Here, we review recent learnings in the field, and further consider how tumour microenvironment differences across subtypes may reveal novel contexts of vulnerability. We discuss recent treatment approaches and ongoing trials in the IDH-wild-type glioblastoma setting, and propose an integrated discovery stratagem incorporating multi-omics, single-cell technologies and computational approaches

Remarkable change in age-specific breast cancer incidence in the Swiss canton of Geneva and its possible relation with the use of hormone replacement therapy

BACKGROUND: This article aims to explain the reasons for the remarkable change in age of breast cancer occurrence in the Swiss canton of Geneva. METHODS: We used population-based data from the Geneva cancer registry, which collects information on method of detection, stage and tumour characteristics since 1975. For patients diagnosed between 1997–2003, we obtained additional information on use of hormone replacement therapy from a large prospective study on breast cancer. Using generalized log linear regression analysis, we compared age-specific incidence rates with respect to period, stage, oestrogen receptor status, method of detection and use of hormone replacement therapy. RESULTS: In the periods 1975–1979 and 1985–1989, breast cancer risk increased with age, showing the highest incidence rates among women aged ≥ 85 years. From 1997, the age-specific incidence curve changed completely (p < 0.0001), showing an incidence peak at 60–64 years and a reduced incidence among elderly women. This incidence peak concerned mainly early stage and oestrogen positive cancers and was exclusively observed among women who ever used hormone replacement therapy, regardless whether the tumour was screen-detected or not. CONCLUSION: The increasing prevalence of hormone replacement therapy use during the 1990s could explain the important change in age-specific breast cancer incidence, not only by increasing breast cancer risk, but also by revealing breast cancer at an earlier age