DNA demethylation and tri-methylation of H3K4 at the TACSTD2 promoter are complementary players for TROP2 regulation in colorectal cancer cells.

TROP2 is a powerful cancer driver in colorectal cancer cells. Divergent epigenetic regulation mechanisms for the corresponding TACSTD2 gene exist such as miRNAs or DNA methylation. However, the role of TACSTD2 promoter hypermethylation in colorectal cancer has not been investigated yet. In this study, TROP2 expression strongly correlated with promoter methylation in different colorectal tumor cell lines. Treatment with 5-Azacytidine, a DNMT1 inhibitor, led to demethylation of the TACSTD2 promoter accompanied by an increase in TROP2 protein expression. TROP2 expression correlated with promoter methylation in vivo in human colon tumor tissue, thereby verifying promoter methylation as an important factor in the regulation of TROP2 expression in colorectal cancer. When performing a ChIP-Seq analysis in HCT116 and HT29 cells, we found that TACSTD2 promoter demethylation was accompanied by tri-methylation of H3K4. In silico analysis of GSE156613 data set confirmed that a higher binding of histone mark H3K4me3 around the TACSTD2 promoter was found in TACSTD2 high expressing tumors of colon cancer patients compared to the corresponding adjacent tumor tissue. Moreover, the link between TROP2 and the H3K4me3 code was even evident in tumors showing high intratumoral heterogeneity for TROP2 staining. Our data provide novel evidence for promoter demethylation and simultaneous gains of the active histone mark H3K4me3 across CpG-rich sequences, both being complementary mechanisms in the transcriptional regulation of TACSTD2 in colon cancer. The functional consequences of TROP2 loss in colorectal cancer needs to be further investigated.

Muc2-dependent microbial colonization of the jejunal mucus layer is diet sensitive and confers local resistance to enteric pathogen infection.

Intestinal mucus barriers normally prevent microbial infections but are sensitive to diet-dependent changes in the luminal environment. Here we demonstrate that mice fed a Western-style diet (WSD) suffer regiospecific failure of the mucus barrier in the small intestinal jejunum caused by diet-induced mucus aggregation. Mucus barrier disruption due to either WSD exposure or chromosomal Muc2 deletion results in collapse of the commensal jejunal microbiota, which in turn sensitizes mice to atypical jejunal colonization by the enteric pathogen Citrobacter rodentium. We illustrate the jejunal mucus layer as a microbial habitat, and link the regiospecific mucus dependency of the microbiota to distinctive properties of the jejunal niche. Together, our data demonstrate a symbiotic mucus-microbiota relationship that normally prevents jejunal pathogen colonization, but is highly sensitive to disruption by exposure to a WSD.

The significance of the pharyngeal veins during carotid endarterectomy: description of an anatomical triangle.

Injuries to the hypoglossal and vagus nerves are the most commonly reported injuries during carotid endarterectomy. While unilateral single nerve injury is usually well tolerated, bilateral or combined nerve injuries can pose a serious threat to life. This study aims to increase awareness of the inferior pharyngeal vein, which usually passes posterior to the internal carotid artery but sometimes crosses anterior to it. Injury to either or both hypoglossal and vagus nerves can occur during control of unexpected haemorrhage from the torn and retracted edges of the inferior pharyngeal vein. We recommend careful ligation and division of this vein. In addition, we observed in 9 (17.3%) of the 52 operations that the pharyngeal vein formed a triangle with the vagus and hypoglossal nerves when it passes anterior to the internal carotid artery.

Right colic artery anatomy: a systematic review of cadaveric studies.

BACKGROUND: Complete mesocolic excision for right-sided colon cancer may offer an oncologically superior excision compared to traditional right hemicolectomy through high vascular tie and adherence to embryonic planes during dissection, supported by preoperative scanning to accurately define the tumour lymphovascular supply and drainage. The authors support and recommend precision oncosurgery based on these principles, with an emphasis on the importance of understanding the vascular anatomy. However, the anatomical variability of the right colic artery (RCA) has resulted in significant discord in the literature regarding its precise arrangement. METHODS: We systematically reviewed the literature on the incidence of the different origins of the RCA in cadaveric studies. An electronic search was conducted as per Preferred Reporting Items for Systematic Reviews and Meta-analyses recommendations up to October 2016 using the MESH terms 'right colic artery' and 'anatomy' (PROSPERO registration number CRD42016041578). RESULTS: Ten studies involving 1073 cadavers were identified as suitable for analysis from 211 articles retrieved. The weighted mean incidence with which the right colic artery arose from other parent vessels was calculated at 36.8% for the superior mesenteric artery, 31.9% for the ileocolic artery, 27.7% for the root of the middle colic artery and 2.5% for the right branch of the middle colic artery. In 1.1% of individuals the RCA shared a trunk with the middle colic and ileocolic arteries. The weighted mean incidence of 2 RCAs was 7.0%, and in 8.9% of cadavers the RCA was absent. CONCLUSIONS: This anatomical information will add to the technical nuances of precision oncosurgery in right-sided colon resections.

The right colic artery: An anatomical demonstration and its relevance in the laparoscopic era.

INTRODUCTION Hemicolectomies are not tailored in right-sided colon cancer resections, despite significant variation in the incidence and origin of the right colic artery (RCA). Early evidence suggests that removal of the relevant lymphovascular package and associated cancer as part of complete mesocolic excision (CME), rather than the entire right colon, may produce better outcomes. Advancing laparoscopic techniques are making this possible, and so it is increasingly important to more precisely define the anatomy of the RCA. METHODS To demonstrate the incidence and variation of the RCA, 25 formalin embalmed cadavers were dissected. Consent to dissection and photography was obtained under Human Tissue Act regulations. RESULTS Eleven female and 14 male cadavers (mean age 79.7 years, range 41-95 years) were included. The RCA originated from the right branch of the middle colic artery in nine cadavers (36%), while it arose from the superior mesenteric artery in eight cases (32%) and from the ileocolic or root of the middle colic artery in a smaller number of specimens. The RCA was absent in two individuals. CONCLUSIONS The RCA arises from the right branch of the middle colic artery in a considerable number of cases. The literature to date does not reflect the precision of anatomical understanding required for CME; hence, a new definition for the right colic vessel is proposed.

Macitentan treatment retards the progression of established pulmonary arterial hypertension in an animal model.

BACKGROUND: Macitentan is a new endothelin receptor antagonist that is used to treat pulmonary arterial hypertension in humans. Treatment of established pulmonary hypertension with macitentan was studied using the monocrotaline model of pulmonary hypertension. METHODS: Three groups of rats were created (n=12): control (CON: macitentan only), monocrotaline (MCT: monocrotaline only) and macitentan (MACI: macitentan and monocrotaline). Monocrotaline (60 mg/kg) was injected in the MCT and MACI groups on day 0; volume matched saline was injected in the CON groups. Macitentan therapy (30 mg/kg/day) was commenced on day 11 in the CON and MACI groups. Serial echocardiography and ECGs were performed. The rats were sacrificed if they showed clinical deterioration. RESULTS: The MCT and MACI rats showed signs of pulmonary hypertension by day 7 (maximum pulmonary velocity, CON 1.15 ± 0.15m/s vs MCT 1.04 ± 0.10 m/s vs MACI 0.99 ± 0.18 m/s; p<0.05). Both the MCT and MACI groups developed pulmonary hypertension, but this was less severe in the MACI group (day 21 pulmonary artery acceleration time, MCT 17.55 ± 1.56 ms vs MACI 22.55 ± 1.00 ms; pulmonary artery deceleration, MCT 34.72 ± 3.72 m/s(2) vs MACI 17.30 ± 1.89 m/s(2); p<0.05). Right ventricular hypertrophy and QT interval increases were more pronounced in MCT than MACI (right ventricle wall thickness, MCT 0.13 ± 0.1cm vs MACI 0.10 ± 0.1cm; QT interval, MCT 85 ± 13 ms vs MACI 71 ± 14 ms; p<0.05). Survival benefit was not seen in the MACI group (p=0.50). CONCLUSIONS: Macitentan treatment improves haemodynamic parameters in established pulmonary hypertension. Further research is required to see if earlier introduction of macitentan has greater effects.

The surgical anatomy of the perineum.

The anatomy of the perineum and pelvis is complex. Those outside the specialist fields of colorectal surgery, urology and gynaecological surgery often have a less-than-complete understanding of the anatomical details of this region. The recent increase in complicated pelvic and perineal injuries caused by the detonation of Improvised Explosive Devices has brought into sharp focus, the importance of this area of surgical anatomy. The following article describes, in a systematic and detailed manner, the anatomy of the urogenital and anal regions of the perineum. The terminology in relation to the fascial layers and structures encountered in the perineum is elucidated. In addition, the surgical anatomy of the scrotum and its contents and the ligamentous support of the penis are described, with clear illustrations throughout. It is intended that this article will go some way towards clarifying the anatomy underlying the surgical management of complex perineal/pelvic injuries, and benefit both the specialist and non-specialist military surgeon.

A guide for identification and continuing care of adult congenital heart disease patients in primary care.

BACKGROUND: Surgical and other advances in the treatment and care of congenital heart disease have resulted in a significant increase in the number of adults with congenital heart disease (ACHD), many of whom have no regular cardiology follow-up. Optimised care for ACHD patients requires continuity of specialist and shared care and education of practitioners and patients. The challenges for managing ACHD were identified by a Health Needs Assessment in the North West and are addressed within the UK Department of Health's ACHD Commissioning Guide. MATERIALS AND METHODS: An ACHD model of care was recommended in the North West of England and developed by the three North West Cardiac & Stroke Networks. Within this, a Task Group focused on the role of primary care in the identification and continuing care of ACHD patients. A feasibility study demonstrated that existing diagnostic Read Codes can identify ACHD patients on general practice registers. An ACHD Toolkit was developed to provide algorithms to guide the appropriate management of ACHD patients through primary, secondary and/or specialist ACHD care and to improve education/knowledge amongst primary care staff about ACHD and its wider implications. RESULTS: Early findings during the development of this Toolkit illustrate a wide disparity of provision between current and optimal management strategies. Patients lost to follow-up have already been identified and their management modified. CONCLUSIONS: By focusing on identifying ACHD patients in primary care and organising/delivering ACHD services, the ACHD Toolkit could help to improve quality, timeliness of care, patient experience and wellbeing.

Injury to the lateral cutaneous nerve of forearm after venous cannulation: a case report and literature review.

Venepuncture may be associated with nerve injuries and is commonly performed at the median cubital vein (MCV). Injuries to the superficial radial nerve at the wrist and to the median nerve, anterior and posterior interosseus nerves and medial and lateral cutaneous nerves (LCN) of the forearm at the cubital fossa have been reported. The LCN is a sensory branch of the musculocutaneous nerve and the position of the nerve in relation to the MCV is variable within the cubital fossa. The LCN supplies sensory innervation to the C6 dermatome corresponding to an area of skin overlying the radial border of the forearm. We report the case of a 30-year-old right-handed woman who presented with loss of sensation in the left forearm after donating blood at a transfusion centre. This was due to an injury of the LCN. After 3, 18 and 36 months of follow-up, the sensory deficit had only improved minimally. The lack of recovery of the sensation after 36 months indicates a permanent nerve injury such as neurotmesis rather than neurapraxia of the LCN. A thorough knowledge of the clinical anatomy of the MCV and the LCN, which is highlighted, is essential in preventing venepuncture-associated nerve injury.

Pre-closure of femoral venous access sites used for large-sized sheath insertion with the Perclose device in adults undergoing cardiac intervention.

BACKGROUND: Interventional procedures in adults with congenital cardiac conditions often require insertion of large-sized sheaths into the femoral veins. Data on the use of suture-mediated devices for femoral venous access site closure are scant and no data are available regarding venous patency after device use. OBJECTIVE: To assess the efficacy of the 6Fr Perclose (Abbott Vascular Devices, CA, USA) suture-mediated device in achieving haemostasis and venous patency after closure. DESIGN AND SETTING: 146 consecutive patients (80 women, mean (SD) age 45 (14) years) undergoing closure of 205 femoral venous access sites in a tertiary cardiac centre were studied. All received heparin and were taking concomitant aspirin or clopidogrel, or both. The majority (98%) had a >or=10Fr sheath inserted. RESULTS: Immediate haemostasis was achieved in 202 (99%) sites. Two patients (1.4%) had a major complication. On follow-up (111 patients, mean (SD) 71 (33) days) there was no evidence of haematoma or fistula formation. Doppler studies from a subgroup of 43 (29%) patients (mean (SD) age 45 (15) years, mean (SD) follow-up 47 (18) days) showed a common femoral venous diameter of 11.6 (2.7) mm on the device closed right and 12.2 (2.5) mm on the left vein (p>0.05). All accessed veins were patent with no pseudoaneurysm or arteriovenous fistula formation. CONCLUSION: Pre-closure of large-size sheath femoral venous access sites using the suture-mediated Perclose device is efficacious in achieving rapid haemostasis in the presence of anticoagulation. Doppler follow-up shows no loss of venous patency or luminal venous diameter as compared with the contralateral side.

Open access echocardiography has diagnostic yield similar to outpatient echocardiography and is highly rated by general practitioners and patients.

BACKGROUND: Open access echocardiography is widely available to General Practitioners (GP). There is little data comparing the proportion of echocardiographic studies which are abnormal in open access series with that in hospital outpatient practice. This study compares the diagnostic yield from echocardiograms performed for similar indications by open access and hospital out patient requested groups and assesses the attitudes of GPs and patients to open access echocardiography. METHODS: The reports of 151 consecutive patients who had open access echocardiograms were analysed using predefined criteria for an abnormal study. The reports of 100 consecutive patients who had a new outpatient requested echocardiograms for similar indications were used as the control group. The attitudes of GPs and patients to the open access service were also assessed. RESULTS: Fifty seven percent of patients in the open access group and 51% in the hospital requested group had abnormal studies (p>0.05). 92% of GPs who responded to the questionnaire thought the report was easy to understand while 69% thought it led to a change in patient management. 74% said a clinic referral would have been made without this service and 79% preferred a management strategy to be included in the report. 90% of patients had been informed of the result by their GP. CONCLUSIONS: Open access echocardiography has a diagnostic yield similar to echocardiograms requested on new hospital outpatients in a district general hospital setting. GPs and patients report high levels of satisfaction with this service.

Effect of microwave pretreatment of coal for improvement of rheological characteristics of coal-water slurries.

Indian high-ash coal contains alpha-silica components of the mineral matter. When coal is transported in the form of a slurry, alpha-silica adds to the settling properties of coal and enhances erosion of pipelines. As such any technique that will contribute to changing the characteristics of mineral matter by selective demineralization is bound to supplement the knowledge of coal slurries in the science of rheology. One such method is the use of a novel microwave technology, which changes the alpha-silica to less harmful beta-silica. Thus microwave-treated coal slurry facilitates enhanced flow characteristics and abates the erosion problem in pipeline transport as well as in coal-slurry injection furnaces. This paper reports on the rheological study of closely sized coal particles of medium-volatile, low-ash, low-moisture cleans and high-ash rejects with and without microwave treatment. Viscosity of suspensions of microwave-treated coal was found to be less than that of untreated coal, in the case of both cleans and rejects. Microwave pretreatment thus reduces the viscosity and the pumping cost and opens a new outlook for pipeline transport. An attempt has been made to quantify the improvement of rheological characteristics due to microwave pretreatment.

The evaluation of bone damage in rheumatoid arthritis with magnetic resonance imaging.

Magnetic resonance imaging (MRA) greatly improves the early detection and visualization of osseous and non-osseous joint changes over conventional x-rays of involved joints in patients with rheumatoid arthritis (RA). However, the "pathophysiological correlate" of these MR imaging changes remains poorly defined. Careful validation of MRI findings and the evaluation of MRI as a tool to follow the effect of therapy remain to be performed before MRI may be used as a clinical tool to follow therapy or as a surrogate for evaluating osseous changes over time.

Glue aortoplasty repair of aortic dissection after coronary angioplasty.

Aortic dissection complicating percutaneous transluminal coronary angioplasty is rare. We report the case of a 45-year-old man who after right coronary artery angioplasty with stenting, dissected that vessel to involve the aorta to the bifurcation. Surgical repair with Gelatin-Resorcinol-Formaldehyde (GRF) glue as opposed to prosthetic graft replacement of the ascending aorta was successful. The use of GRF glue is effective in the surgical treatment of aortic dissection after coronary angioplasty.

Bedside tracer gas technique accurately predicts outcome in aspiration of spontaneous pneumothorax.

BACKGROUND: There is no technique in general use that reliably predicts the outcome of manual aspiration of spontaneous pneumothorax. We have hypothesised that the absence of a pleural leak at the time of aspiration will identify a group of patients in whom immediate discharge is unlikely to be complicated by early lung re-collapse and have tested this hypothesis by using a simple bedside tracer gas technique. METHODS: Eighty four episodes of primary spontaneous pneumothorax and 35 episodes of secondary spontaneous pneumothorax were studied prospectively. Patients breathed air containing a tracer (propellant gas from a pressurised metered dose inhaler) while the pneumothorax was aspirated percutaneously. Tracer gas in the aspirate was detected at the bedside using a portable flame ioniser and episodes were categorised as tracer gas positive (>1 part per million of tracer gas) or negative. The presence of tracer gas was taken to imply a persistent pleural leak. Failure of manual aspiration and the need for a further intervention was based on chest radiographic appearances showing either failure of the lung to re-expand or re-collapse following initial re-expansion. RESULTS: A negative tracer gas test alone implied that manual aspiration would be successful in the treatment of 93% of episodes of primary spontaneous pneumothorax (p<0.001) and in 86% of episodes of secondary spontaneous pneumothorax (p=0.01). A positive test implied that manual aspiration would either fail to re-expand the lung or that early re-collapse would occur despite initial re-expansion in 66% of episodes of primary spontaneous pneumothorax and 71% of episodes of secondary spontaneous pneumothorax. Lung re-inflation on the chest radiograph taken immediately after aspiration was a poor predictor of successful aspiration, with lung re-collapse occurring in 34% of episodes by the following day such that a further intervention was required. CONCLUSIONS: National guidelines currently recommend immediate discharge of patients with primary spontaneous pneumothorax based primarily on the outcome of the post-aspiration chest radiograph which we have shown to be a poor predictor of early lung re-collapse. Using a simple bedside test in combination with the post-aspiration chest radiograph, we can predict with high accuracy the success of aspiration in achieving sustained lung re-inflation, thereby identifying patients with primary spontaneous pneumothorax who can be safely and immediately discharged home and those who should be observed overnight because of a significant risk of re-collapse, with an estimated re-admission rate of 1%.