Video Capsule Endoscopy in Patients with Muir-Torre Syndrome

Introduction: Muir-Torre Syndrome (MTS) is a rare, primarily autosomal dominant disorder that is distinguished by having sebaceous skin malignancies in addition to visceral malignancies. The most common form of MTS is a variant of HNPCC. Our aim is to demonstrate the utilization of VCE in patients with MTS as the first line screening method. Methods: Single center, retrospective chart review study of outpatients with MTS who underwent a video capsule endoscopy study between January 2006 and January 2016. Results: Four patients, all women and mean age of 57 years old, with MTS underwent a video capsule endoscopy at our institution. In 75% of the patients, VCE detected polyps at a point in the small bowel which upper endoscopy and colonoscopy did not visualize. Two patients had large jejunal polyps, approximately 20mm in diameter. One patient had multiple 3-20mm sessile polyps from the duodenum to the ileum. On endoscopy, only one of the patients had a polyp detected and it was a 10mm polyp in the stomach which was positive for GIST. With regards to colonoscopy, 2 of the patients had critical findings of colonic mucosa with focal adenomatous changes and cryptitis (high grade dysplasia) and T1 poorly differentiated signet cell carcinoma respectively. Both of these patients underwent total colectomies. Cumulatively, all four of these patients have undergone 17 endoscopies/colonoscopies. Conclusion: MTS is a disorder that needs to be monitored closely as patients have a high propensity of developing gastrointestinal malignancies. Current recommendations are colonoscopies annually starting at ages 20-25 and endoscopies with gastric antrum biopsies starting at ages 30-35. 75% of the patients had lesions in the small bowel that were only picked up by VCE. Failure to detect asymptomatic advanced lesions in the small bowel may have serious consequences. We therefore recommend pan-endoscopy in this rare syndrome

The Acute Physiological and Perceptual Responses to Blood-flow Restriction Applied During Un-resisted Knee Exercise: A Potential Treatment Adjunct for Physiotherapists

Purpose: Blood-flow restriction [BfR] training involves the temporary, artificial reduction of blood flow through a limb. Evidence suggests that BfR combined with low-intensity resistance exercise can minimise the loss of thigh muscle size and strength during periods of impaired weight-bearing. However, evidence is scarce as to the specific utility of adding BfR to un-resisted or ‘no-load’ exercise during injury rehabilitation. Therefore, this case series examined the effects of applying BfR during a no-load lower-limb knee exercise completed by athletes recovering from significant lower limb injuries. Methods: Three professional rugby players provided consent to incorporate BfR training into their injury rehabilitation programmes. (Case one; four weeks post tibia and fibula fracture. Case two; five weeks post Achilles tendon rupture. Case three; immediately following MRI diagnosis of an osseous stress injury of the knee). During the control exercise session, players performed three sets of a seated, un-resisted, single-leg knee-extension exercise. At subsequent sessions, a 21.5 cm wide blood-pressure cuff was used to superimpose BfR over the same exercise. BfR was applied intermittently or continuously across the upper thigh via 100 mmHg or 120 mmHg cuff pressure. Near infra-red spectroscopy [NIRS] monitored tissue oxygen saturation [SmO2] and total haemoglobin mass [tHb] of the vastus lateralis muscle before and during the exercise of each lower-limb. The relative change in SmO2 and tHb generated during each exercise session was then calculated. Session rate of perceived exertion [RPE] was monitored via a 10-point visual scale. Descriptive statistics were then used to indicate trends among these variables. Results: BfR training was delivered four to five times per week for periods of 4 to 12 weeks. NIRS data from thirty BfRT sessions (five sessions per leg, per player) were obtained. Mean resting values for vastus lateralis SmO2 and tHb were 54.3% and 12.72 g/dL respectively. During the control exercise session, SmO2 increased by a mean of 4.68 points, whilst tHb decreased slightly (-0.04 g/dL). In contrast, the addition of continuous BfR at 120 mmHg generated a mean drop in SmO2 of 22.31 points, whilst tHb increased (+0.23 g/dL). No adverse events or pain occurred during any exercise session. The control session generated a mean session RPE of 0.94 out of 10. Session RPE during BfR training ranged between 3.6 and 4.9. Conclusion(s): In a case series of injured athletes, data indicated that adding BfR to a ‘no-load’ knee extension exercise generated oxygen desaturation of the vastus lateralis muscle and increased perceptual exertion. Lower-limb BfR training was delivered in a safe, tolerable way as part of a multi-modal, intensive injury rehabilitation programme. Implications: BfR training may provide Physiotherapists with a novel Method of generating exercise-induced physiological stress within muscle tissue during exercise, without the need to add any external resistance. Achieving sufficient physiological stress during the very early stages of injury rehabilitation via no-load BfR training may promote a muscular response that limits the longitudinal muscle disuse atrophy seen during periods of impaired weight-bearing. Further research is warranted to substantiate this and to explore the utility of no-load BfR training within non-athletic, clinical populations. Funding acknowledgements: This study was funded via a PhD studentship awarded by Manchester Metropolitan University

Transcriptomic Analysis of Age-Associated Periventricular Lesions Reveals Dysregulation of the Immune Response.

White matter lesions (WML) are a common feature of the ageing brain associated with cognitive impairment. The gene expression profiles of periventricular lesions (PVL, n = 7) and radiologically-normal-appearing (control) periventricular white matter cases (n = 11) obtained from the Cognitive Function and Ageing Study (CFAS) neuropathology cohort were interrogated using microarray analysis and NanoString to identify novel mechanisms potentially underlying their formation. Histological characterisation of control white matter cases identified a subgroup (n = 4) which contained high levels of MHC-II immunoreactive microglia, and were classified as "pre-lesional." Microarray analysis identified 2256 significantly differentially-expressed genes (p ≤ 0.05, FC ≥ 1.2) in PVL compared to non-lesional control white matter (1378 upregulated and 878 downregulated); 2649 significantly differentially-expressed genes in "pre-lesional" cases compared to PVL (1390 upregulated and 1259 downregulated); and 2398 significantly differentially-expressed genes in "pre-lesional" versus non-lesional control cases (1527 upregulated and 871 downregulated). Whilst histological evaluation of a single marker (MHC-II) implicates immune-activated microglia in lesion pathology, transcriptomic analysis indicates significant downregulation of a number of activated microglial markers and suggests established PVL are part of a continuous spectrum of white matter injury. The gene expression profile of "pre-lesional" periventricular white matter suggests upregulation of several signalling pathways may be a neuroprotective response to prevent the pathogenesis of PVL

Internal Mammary Arteries as a Model to Demonstrate Restoration of the Impaired Vasodilation in Hypertension, Using Liposomal Delivery of the CYP1B1 Inhibitor, 2,3′,4,5′-Tetramethoxystilbene

A significant number of patients with severe cardiovascular disease, undergoing coronary artery bypass grafting (CABG), present with hypertension. While internal mammary arteries (IMAs) may be a better alternative to vein grafts, their impaired vasodilator function affects their patency. Our objectives were to (1) determine if inhibition of the cytochrome P450 enzyme CYP1B1, using liposome-encapsulated 2,3′,4,5′-tetramethoxystilbene (TMS), can potentiate vasodilation of IMAs from CABG patients, and (2) assess mechanisms involved using coronary arteries from normal rats, in an ex vivo model of hypertension. PEGylated liposomes were synthesized and loaded with TMS (mean diameter 141 ± 0.9 nm). Liposomal delivery of TMS improved its bioavailability Compared to TMS solution (0.129 ± 0.02 ng/mL vs. 0.086 ± 0.01 ng/mL at 4 h; p < 0.05). TMS-loaded liposomes alleviated attenuated endothelial-dependent acetylcholine (ACh)-induced dilation in diseased IMAs (@ACh 10−4 M: 56.9 ± 5.1%; n = 8 vs. 12.7 ± 7.8%; n = 6; p < 0.01) for TMS-loaded liposomes vs. blank liposomes, respectively. The alleviation in dilation may be due to the potent inhibition of CYP1B1 by TMS, and subsequent reduction in reactive oxygen species (ROS) moieties and stimulation of nitric oxide synthesis. In isolated rat coronary arteries exposed to a hypertensive environment, TMS-loaded liposomes potentiated nitric oxide and endothelium-derived hyperpolarization pathways via AMPK. Our findings are promising for the future development of TMS-loaded liposomes as a promising therapeutic strategy to enhance TMS bioavailability and potentiate vasodilator function in hypertension, with relevance for early and long-term treatment of CABG patients, via the sustained and localized TMS release within IMA

Connection between Telomerase Activity in PBMC and Markers of Inflammation and Endothelial Dysfunction in Patients with Metabolic Syndrome

Metabolic syndrome (MS) is a constellation of metabolic derangements associated with vascular endothelial dysfunction and oxidative stress and is widely regarded as an inflammatory condition, accompanied by an increased risk for cardiovascular disease. The present study tried to investigate the implications of telomerase activity with inflammation and impaired endothelial function in patients with metabolic syndrome. Telomerase activity in circulating peripheral blood mononuclear cells (PBMC), TNF-α, IL-6 and ADMA were monitored in 39 patients with MS and 20 age and sex-matched healthy volunteers. Telomerase activity in PBMC, TNF-α, IL-6 and ADMA were all significantly elevated in patients with MS compared to healthy volunteers. PBMC telomerase was negatively correlated with HDL and positively correlated with ADMA, while no association between TNF-α and IL-6 was observed. IL-6 was increasing with increasing systolic pressure both in the patients with MS and in the healthy volunteers, while smoking and diabetes were positively correlated with IL-6 only in the patients' group. In conclusion, in patients with MS characterised by a strong dyslipidemic profile and low diabetes prevalence, significant telomerase activity was detected in circulating PBMC, along with elevated markers of inflammation and endothelial dysfunction. These findings suggest a prolonged activity of inflammatory cells in the studied state of this metabolic disorder that could represent a contributory pathway in the pathogenesis of atherosclerosis

Chemokines and their role in airway hyper-reactivity

Airway hyper-reactivity is a characteristic feature of many inflammatory lung diseases and is defined as an exaggerated degree of airway narrowing. Chemokines and their receptors are involved in several pathological processes that are believed to contribute to airway hyper-responsiveness, including recruitment and activation of inflammatory cells, collagen deposition and airway wall remodeling. These proteins are therefore thought to represent important therapeutic targets in the treatment of airway hyper-responsiveness. This review highlights the processes thought to be involved in airway hyper-responsiveness in allergic asthma, and the role of chemokines in these processes. Overall, the application of chemokines to the prevention or treatment of airway hyper-reactivity has tremendous potential

MicroRNA Involvement in Immune Activation During Heart Failure

Heart failure is one of the common end stages of cardiovascular diseases, the leading cause of death in developed countries. Molecular mechanisms underlying the development of heart failure remain elusive but there is a consistent observation of chronic immune activation and aberrant microRNA (miRNA) expression that is present in failing hearts. This review will focus on the interplay between the immune system and miRNAs as factors that play a role during the development of heart failure. Several studies have shown that heart failure patients can be characterized by a sustained innate immune activation. The role of inflammatory signaling is discussed and TLR4 signaling, IL-1β, TNFα and IL-6 expression appears to coincide with the development of heart failure. Furthermore, we describe the implication of the renin angiotensin aldosteron system in immunity and heart failure. In the past decade microRNAs (miRNAs), small non-coding RNAs that translationally repress protein synthesis by binding to partially complementary sequences of mRNA, have come to light as important regulators of several kinds of cardiovascular diseases including cardiac hypertrophy and heart failure. The involvement of differentially expressed miRNAs in the inflammation that occurs during the development of heart failure is still subject of investigation. Here, we summarize and comment on the first studies in this field and hypothesize on the putative involvement of certain miRNAs in heart failure. MicroRNAs have been shown to be critical regulators of cardiac function and inflammation. Future research will have to point out if dampening the immune response, and the miRNAs associated with it, during the development of heart failure is a therapeutically plausible route to follow