Abdominal obesity and metabolic syndrome: exercise as medicine?

Background: Metabolic syndrome is defined as a cluster of at least three out of five clinical risk factors: abdominal (visceral) obesity, hypertension, elevated serum triglycerides, low serum high-density lipoprotein (HDL) and insulin resistance. It is estimated to affect over 20% of the global adult population. Abdominal (visceral) obesity is thought to be the predominant risk factor for metabolic syndrome and as predictions estimate that 50% of adults will be classified as obese by 2030 it is likely that metabolic syndrome will be a significant problem for health services and a drain on health economies.Evidence shows that regular and consistent exercise reduces abdominal obesity and results in favourable changes in body composition. It has therefore been suggested that exercise is a medicine in its own right and should be prescribed as such. Purpose of this review: This review provides a summary of the current evidence on the pathophysiology of dysfunctional adipose tissue (adiposopathy). It describes the relationship of adiposopathy to metabolic syndrome and how exercise may mediate these processes, and evaluates current evidence on the clinical efficacy of exercise in the management of abdominal obesity. The review also discusses the type and dose of exercise needed for optimal improvements in health status in relation to the available evidence and considers the difficulty in achieving adherence to exercise programmes. Conclusion: There is moderate evidence supporting the use of programmes of exercise to reverse metabolic syndrome although at present the optimal dose and type of exercise is unknown. The main challenge for health care professionals is how to motivate individuals to participate and adherence to programmes of exercise used prophylactically and as a treatment for metabolic syndrome

Loss of heterozygosity as a marker of homologous repair deficiency in multiple myeloma: a role for PARP inhibition?

PARP inhibitors can induce synthetic lethality in tumors characterized by homologous recombination deficiency (HRD), which can be detected by evaluating genome-wide loss of heterozygosity (LOH). Multiple myeloma (MM) is a genetically unstable tumor and we hypothesized that HRD-related LOH (HRD-LOH) could be detected in patient samples, supporting a potential role for PARP inhibition in MM. Using results from targeted next-generation sequencing studies (FoundationOne® Heme), we analyzed HRD-LOH in patients at all disease stages (MGUS (n = 7), smoldering MM (SMM, n = 30), newly diagnosed MM (NDMM, n = 71), treated MM (TRMM, n = 64), and relapsed MM (RLMM, n = 234)) using an algorithm to identify HRD-LOH segments. We demonstrated HRD-LOH in MM samples, increasing as disease progresses. The extent of genomic HRD-LOH correlated with high-risk disease markers. Outcome of RLMM patients, the biggest clinical group, was analyzed and patients with HRD-LOH above the third quartile (≥5% HRD-LOH) had significantly worse progression-free and overall survival than those with lower levels (p < 0.001). Mutations in key homologous recombination genes account for some, but not all, of the cases with an excess of HRD-LOH. These data support the further evaluation of PARP inhibitors in MM patients, particularly in the relapsed setting with a high unmet need for new treatments

Expense and benefit of neoadjuvant treatment in squamous cell carcinoma of the esophagus

BACKGROUND: The effectiveness of neoadjuvant treatment (NT) prior to resection of squamous cell carcinoma of the esophagus (SCCE) in terms of prolonged survival has not been proven by randomized trials. Facing considerable financial expenses and with concerns regarding the consumption of the patient's remaining survival time, this study aims to provide rationales for pretreating resection candidates. METHODS: From March 1986 to March 1999, patients undergoing resection for SCCE were documented prospectively. Since 1989, NT was offered to patients with mainly upper and middle third T3 or T4 tumors or T2 N1 stage who were fit for esophagectomy. Until 1993, NT consisted of chemotherapy. Since that time chemoradiation has also been applied. The parameters for expense and benefit of NT are costs, pretreatment time required, postoperative morbidity and mortality, clinical and histopathological response, and actuarial survival. RESULTS: Two hundred and three patients were treated, 170 by surgery alone and 33 by NT + surgery. Postoperative morbidity and mortality were 52% to 30% and 12% to 6%, respectively (p = n.s.). The response to NT was detected in 23 patients (70%). In 11 instances (33%), the primary tumor lesion was histopathologically eradicated. Survival following NT + surgery was significantly prolonged in node-positive patients with a median survival of 12 months to 19 months (p = 0.0193). The average pretreatment time was 113 ± 43 days, and reimbursement for NT to the hospital amounted to Euro 9.834. CONCLUSIONS: NT did not increase morbidity and mortality. Expenses for pretreatment, particularly time and costs, are considerable. However, taking into account that the results are derived from a non-randomized study, patients with regionally advanced tumor stages seem to benefit, as seen by their prolonged survival

Retinotopic Maps, Spatial Tuning, and Locations of Human Visual Areas in Surface Coordinates Characterized with Multifocal and Blocked fMRI Designs

The localization of visual areas in the human cortex is typically based on mapping the retinotopic organization with functional magnetic resonance imaging (fMRI). The most common approach is to encode the response phase for a slowly moving visual stimulus and to present the result on an individual's reconstructed cortical surface. The main aims of this study were to develop complementary general linear model (GLM)-based retinotopic mapping methods and to characterize the inter-individual variability of the visual area positions on the cortical surface. We studied 15 subjects with two methods: a 24-region multifocal checkerboard stimulus and a blocked presentation of object stimuli at different visual field locations. The retinotopic maps were based on weighted averaging of the GLM parameter estimates for the stimulus regions. In addition to localizing visual areas, both methods could be used to localize multiple retinotopic regions-of-interest. The two methods yielded consistent retinotopic maps in the visual areas V1, V2, V3, hV4, and V3AB. In the higher-level areas IPS0, VO1, LO1, LO2, TO1, and TO2, retinotopy could only be mapped with the blocked stimulus presentation. The gradual widening of spatial tuning and an increase in the responses to stimuli in the ipsilateral visual field along the hierarchy of visual areas likely reflected the increase in the average receptive field size. Finally, after registration to Freesurfer's surface-based atlas of the human cerebral cortex, we calculated the mean and variability of the visual area positions in the spherical surface-based coordinate system and generated probability maps of the visual areas on the average cortical surface. The inter-individual variability in the area locations decreased when the midpoints were calculated along the spherical cortical surface compared with volumetric coordinates. These results can facilitate both analysis of individual functional anatomy and comparisons of visual cortex topology across studies

Multishot versus Single-Shot Pulse Sequences in Very High Field fMRI: A Comparison Using Retinotopic Mapping

High-resolution functional MRI is a leading application for very high field (7 Tesla) human MR imaging. Though higher field strengths promise improvements in signal-to-noise ratios (SNR) and BOLD contrast relative to fMRI at 3 Tesla, these benefits may be partially offset by accompanying increases in geometric distortion and other off-resonance effects. Such effects may be especially pronounced with the single-shot EPI pulse sequences typically used for fMRI at standard field strengths. As an alternative, one might consider multishot pulse sequences, which may lead to somewhat lower temporal SNR than standard EPI, but which are also often substantially less susceptible to off-resonance effects. Here we consider retinotopic mapping of human visual cortex as a practical test case by which to compare examples of these sequence types for high-resolution fMRI at 7 Tesla. We performed polar angle retinotopic mapping at each of 3 isotropic resolutions (2.0, 1.7, and 1.1 mm) using both accelerated single-shot 2D EPI and accelerated multishot 3D gradient-echo pulse sequences. We found that single-shot EPI indeed led to greater temporal SNR and contrast-to-noise ratios (CNR) than the multishot sequences. However, additional distortion correction in postprocessing was required in order to fully realize these advantages, particularly at higher resolutions. The retinotopic maps produced by both sequence types were qualitatively comparable, and showed equivalent test/retest reliability. Thus, when surface-based analyses are planned, or in other circumstances where geometric distortion is of particular concern, multishot pulse sequences could provide a viable alternative to single-shot EPI

Neoadjuvant continuous infusion of weekly 5-fluorouracil and escalating doses of oxaliplatin plus concurrent radiation in locally advanced oesophageal squamous cell carcinoma: results of a phase I/II trial

Oxaliplatin and 5-fluorouracil have a significant activity in locally advanced oesophageal squamous cell cancer (OSCC). However, their optimal dosage and efficacy when combined with concurrent radiotherapy as neoadjuvant treatment are unknown. This non-randomised, phase I/II study aimed to define the maximum tolerated dose (MTD) and assessed the histopathological tumour response rate to neoadjuvant oxaliplatin in weekly escalating doses (40, 45, 50 mg m−2) and continuous infusional 5-fluorouracil (CI-5FU; 225 mg m−2) plus concurrent radiotherapy. Patients had resectable OSCC. Resection was scheduled for 4–6 weeks after chemoradiotherapy. During phase I (dose escalation; n=19), weekly oxaliplatin 45 mg m−2 plus CI-5FU 225 mg m−2 was established as the MTD and was the recommended dosage for phase II. Oesophageal mucositis was the dose-limiting toxicity at higher doses. During phase II, histopathological responses (<10% residual tumour cells within the specimen) were observed in 10 of 16 patients (63%; 95% confidence interval: 39–82%). Overall, 16 of the 25 patients (64%) who underwent resection had a histopathological response; tumour-free resection (R0) was achieved in 80%. Neoadjuvant weekly oxaliplatin 45 mg m−2 plus CI-5FU 225 mg m−2 with concurrent radiotherapy provides promising histological response rates and R0 resection rates in locally advanced OSCC

Modeling autosomal dominant Alzheimer's disease with machine learning

INTRODUCTION: Machine learning models were used to discover novel disease trajectories for autosomal dominant Alzheimer's disease. METHODS: Longitudinal structural magnetic resonance imaging, amyloid positron emission tomography (PET), and fluorodeoxyglucose PET were acquired in 131 mutation carriers and 74 non-carriers from the Dominantly Inherited Alzheimer Network; the groups were matched for age, education, sex, and apolipoprotein ε4 (APOE ε4). A deep neural network was trained to predict disease progression for each modality. Relief algorithms identified the strongest predictors of mutation status. RESULTS: The Relief algorithm identified the caudate, cingulate, and precuneus as the strongest predictors among all modalities. The model yielded accurate results for predicting future Pittsburgh compound B (R2  = 0.95), fluorodeoxyglucose (R2  = 0.93), and atrophy (R2  = 0.95) in mutation carriers compared to non-carriers. DISCUSSION: Results suggest a sigmoidal trajectory for amyloid, a biphasic response for metabolism, and a gradual decrease in volume, with disease progression primarily in subcortical, middle frontal, and posterior parietal regions

Soluble TREM2 in CSF and its association with other biomarkers and cognition in autosomal-dominant Alzheimer's disease: a longitudinal observational study

BACKGROUND: Therapeutic modulation of TREM2-dependent microglial function might provide an additional strategy to slow the progression of Alzheimer's disease. Although studies in animal models suggest that TREM2 is protective against Alzheimer's pathology, its effect on tau pathology and its potential beneficial role in people with Alzheimer's disease is still unclear. Our aim was to study associations between the dynamics of soluble TREM2, as a biomarker of TREM2 signalling, and amyloid β (Aβ) deposition, tau-related pathology, neuroimaging markers, and cognitive decline, during the progression of autosomal dominant Alzheimer's disease. METHODS: We did a longitudinal analysis of data from the Dominantly Inherited Alzheimer Network (DIAN) observational study, which includes families with a history of autosomal dominant Alzheimer's disease. Participants aged over 18 years who were enrolled in DIAN between Jan 1, 2009, and July 31, 2019, were categorised as either carriers of pathogenic variants in PSEN1, PSEN2, and APP genes (n=155) or non-carriers (n=93). We measured amounts of cleaved soluble TREM2 using a novel immunoassay in CSF samples obtained every 2 years from participants who were asymptomatic (Clinical Dementia Rating [CDR]=0) and annually for those who were symptomatic (CDR>0). CSF concentrations of Aβ40, Aβ42, total tau (t-tau), and tau phosphorylated on threonine 181 (p-tau) were measured by validated immunoassays. Predefined neuroimaging measurements were total cortical uptake of Pittsburgh compound B PET (PiB-PET), cortical thickness in the precuneus ascertained by MRI, and hippocampal volume determined by MRI. Cognition was measured using a validated cognitive composite (including DIAN word list test, logical memory delayed recall, digit symbol coding test [total score], and minimental status examination). We based our statistical analysis on univariate and bivariate linear mixed effects models. FINDINGS: In carriers of pathogenic variants, a high amyloid burden at baseline, represented by low CSF Aβ42 (β=–4·28 × 10^{–2} [SE 0·013], p=0·0012), but not high cortical uptake in PiB-PET (β=–5·51 × 10^{–3} [0·011], p=0·63), was the only predictor of an augmented annual rate of subsequent increase in soluble TREM2. Augmented annual rates of increase in soluble TREM2 were associated with a diminished rate of decrease in amyloid deposition, as measured by Aβ42 in CSF (r=0·56 [0·22], p=0·011), in presymptomatic carriers of pathogenic variants, and with diminished annual rate of increase in PiB-PET (r=–0·67 [0·25], p=0·0060) in symptomatic carriers of pathogenic variants. Presymptomatic carriers of pathogenic variants with annual rates of increase in soluble TREM2 lower than the median showed a correlation between enhanced annual rates of increase in p-tau in CSF and augmented annual rates of increase in PiB-PET signal (r=0·45 [0·21], p=0·035), that was not observed in those with rates of increase in soluble TREM2 higher than the median. Furthermore, presymptomatic carriers of pathogenic variants with rates of increase in soluble TREM2 above or below the median had opposite associations between Aβ42 in CSF and PiB-PET uptake when assessed longitudinally. Augmented annual rates of increase in soluble TREM2 in presymptomatic carriers of pathogenic variants correlated with decreased cortical shrinkage in the precuneus (r=0·46 [0·22]), p=0·040) and diminished cognitive decline (r=0·67 [0·22], p=0·0020). INTERPRETATION: Our findings in autosomal dominant Alzheimer's disease position the TREM2 response within the amyloid cascade immediately after the first pathological changes in Aβ aggregation and further support the role of TREM2 on Aβ plaque deposition and compaction. Furthermore, these findings underpin a beneficial effect of TREM2 on Aβ deposition, Aβ-dependent tau pathology, cortical shrinkage, and cognitive decline. Soluble TREM2 could, therefore, be a key marker for clinical trial design and interpretation. Efforts to develop TREM2-boosting therapies are ongoing