Giant hiatus hernia presenting as a chronic cough masking a sinister diagnosis.

We present a case of an 82-year-old gentleman with an 18-month history of productive cough. Urgent CT scan of the thorax revealed type 1 hiatus hernia (HH). The patient was managed conservatively with lifestyle modifications to help his reflux symptomology. The patient subsequently presented with acute shortness of breath and vomiting. Repeat CT scan reported a giant incarcerated HH (15 cm). Endoscopy revealed an incidental finding of a 3 cm polypoid lesion in the oesophagus at the level of the carina and histology of biopsies reported an invasive adenocarcinoma. During admission, the patient unfortunately had a hospital acquired infection and cardiac complications which prevented surgical intervention. Patients with suspected HH should be investigated thoroughly with imaging studies including chest X-ray, CT or MRI alongside oesophageal manometry and gastroscopy. Endoscopic evaluation is particularly important as these patients are at higher risk of Barrett's oesophagus and invasive malignancy.

Adjuvant radiotherapy in oesophageal cancer with positive circumferential resection margins-recurrence and survival outcomes.

BACKGROUND: The role of adjuvant radiotherapy in patients with microscopically positive circumferential resection margins (CRM), R1 specimen, in oesophageal resections for cancer with curative intent remains unclear. However, R1 specimens are associated with poorer survival outcomes. The aim was to assess the benefit of adjuvant radiotherapy on recurrence and survival in these patients. METHODS: Patients were identified in a single centre between July 2000 and December 2016. Patient demographics, tumour characteristics and survival outcomes were assimilated and compared between those who received adjuvant therapy and those who did not. RESULTS: Sixty-eight patients were included in the study; 57 (83.8%) male and 11 (16.2%) female with a median age of 67 years. The adjuvant radiotherapy regimen used was 40-50 Gy in 25 fractions over 5 weeks. Median follow-up was 13 months (interquartile range, 6-27 months). Twenty-five (36.8%) patients received adjuvant radiotherapy. There was no statistically significant correlation between administration of adjuvant radiotherapy and local recurrence (P=0.148), distant metastases (P=0.605), overall disease progression (P=0.561), progression-free survival (P=0.663) and overall survival (P=0.538). CONCLUSIONS: This study detects no benefit to oncological outcomes with the use of adjuvant radiotherapy in patients with microscopically positive CRM. Larger randomized studies are needed to further confirm these results.

Optimum timing of emergency cholecystectomy for acute cholecystitis in England: population-based cohort study.

BACKGROUND: Cholecystectomy on index admission for acute cholecystitis is associated with improved patient outcomes. The timing of intervention is mainly driven by service provision. This population-based cohort study aimed to evaluate timing of emergency cholecystectomy in England. METHODS: Data from all consecutive patients undergoing surgery for acute cholecystitis on index admission in England from 1997 to 2012 were captured from the Hospital Episodes Statistics database. Data were analysed based on whether patients underwent surgery 0-3 days, 4-7 days or ≥ 8 days from admission. Outcome measures were rate of post-operative biliary complications, conversion to open and length of stay. RESULTS: Forty-three thousand eight hundred and seventy patients underwent emergency cholecystectomy. 64.6% of patients underwent surgery between days 0 and 3 of admission, 24.3% between days 4-7 and 11.0% had surgery after day 8. Patients undergoing early surgery had significantly reduced rates of intra-operative laparoscopic conversion to open (0-3 days: 3.6%; 4-7 days: 4.0%; ≥ 8 days 4.7%, p = 0.001), post-operative ERCP (0-3 days: 1.1%; 4-7 days: 1.5%; ≥ 8 days 1.9%, p < 0.001) and bile duct injury (0-3 days: 0.6%; 4-7 days: 1.0%; ≥ 8 days 1.8%, p < 0.001). Early cholecystectomy was also associated with a shorter post-operative length of stay (LOS) [0-3 days group: median post-operative LOS 3 days (IQR: 1-6); 4-7 days group: 3 days (IQR 2-6); ≥ 8 days group: 4 days (IQR 2-9) (p < 0.001)]. High-volume centres undertook a significantly greater proportion of cholecystectomies within 3 days of presentation (high-volume: 67.3%; medium-volume: 64.8%; low-volume: 61.2%). In multivariate analysis greater time to surgery was independently associated with increased risk of post-operative ERCP and bile duct injury. CONCLUSIONS: Early cholecystectomy within 3 days of admission reduces intra-operative conversion, post-operative biliary complications and length of stay. Centres undertaking the greatest numbers of emergency cholecystectomies perform a larger proportion within 3 days of admission.

Enrichment and Identification of Neural Stem Cells in Neurospheres Using Rigidity-Tunable Gels.

IMPACT STATEMENT: Neural stem cells (NCSs) are integral to establishing in vitro models and regenerative medicine. To this day, there is an unmet need to enrich these cells from a heterogeneous cell population for clinical applications without irreversible manipulation. We identified a method to propagate human NCSs via computational analysis of their mechanical signature. In this study, we report a novel analytical method for mechanical forces in three-dimensional cultures. Further, our results revealed that stemness may, in part, be mediated by physical properties of the extracellular matrix. In conclusion, our findings have potential implications in understanding stem cell mechanobiology for enrichment or differentiation.

Oesophageal adenocarcinoma following gastric band surgery in two patients.

Oesophageal adenocarcinoma following gastric band surgery has only been reported three times previously. The incidence is higher in morbidly obese patients, and its pathogenesis is correlated to reflux-induced microenvironmental changes. Bariatric surgery is transformative and its potential benefit for a substantial population is huge. Although no causal relationship with bariatric procedures has been evidenced to date, symptoms of adenocarcinoma-particularly anorexia, weight loss and dysphagia-can easily be overshadowed by alterations in eating patterns associated with weight-loss procedures. We report two cases of oesophageal adenocarcinoma in patients who had undergone a gastric banding procedure, and invite readers to consider the role that pre- and post-operative acid reflux dynamics may have precipitating neoplastic disease, and how endoscopic surveillance may play a role in prevention.

The definition and management of Barrett's oesophagus: a case report, review of the literature and a suggestion for the future.

The definition of Barrett's oesophagus continues to evolve and there has been divergence in the diagnostic criteria internationally, which has implications for surveillance practices and research inclusion criteria. Here we describe the case of a 69-year-old female with 10 cm of gastric-type columnar-lined oesophagus confirmed on histochemical staining. Surveillance biopsies, performed according to protocol, revealed an intramucosal adenocarcinoma. The patient was successfully treated with a transhiatal oesophagectomy and a detailed examination of the entire surgical specimen confirmed that the columnar oesophagus was lined by gastric villiform mucosa complicated by intramucosal carcinoma, on the background of dysplasia with no intestinal metaplasia. This highlights the spectrum of metaplastic epithelia that can harbour malignant potential. There is a need for an international consensus on the classification of Barrett's oesophagus to aid research progress. Therefore, we propose a new classification for Barrett's oesophagus based on a combination of endoscopic and histopathological features.

Free digital artery flap: an ideal flap for large finger defects in situations where local flaps are precluded.

The heterodigital arterialized flap is increasingly accepted as a flap of choice for reconstruction of large finger wounds. However, in situations where the adjacent fingers sustained concomitant injuries, the use of this flap as a local flap is precluded. This paper describes our experience with the free digital artery flap as an evolution of the heterodigital arterialized flap. Four patients with large finger wounds were reconstructed with free digital artery flap. Our indications for digital artery free flap were concomitant injuries to adjacent fingers that precluded their use as donor sites. The arterial supply of the flap was from the digital artery and the venous drainage was from the dominant dorsal vein of the finger. The flap was harvested from the ulnar side of the finger. The digital nerve was left in situ to minimize donor morbidity. The donor site was covered with a full-thickness skin graft and secured with bolster dressings. Early intensive mobilization was implemented for all patients. All flaps survived. No venous congestion was noted and primary healing was achieved in all flaps. In addition to providing well-vascularized tissue for coverage of vital structures, the digital artery was also used as a flow-through flap for finger revascularization in one patient. Donor-site morbidity was minimal, with all fingers retaining protective pulp sensation and the distal and proximal interphalangeal joints retaining full ranges of motion. In conclusion, the free digital artery flap is a versatile flap that is ideal for coverage of large-sized finger defects in situations where local flaps are unavailable. Donor-site morbidity can be minimized by preservation of the digital nerve, firmly securing the skin graft with bolster dressings, and early mobilization of the donor finger.

Cep97 and CP110 suppress a cilia assembly program.

Mammalian centrioles play a dynamic role in centrosome function, but they also have the capacity to nucleate the assembly of cilia. Although controls must exist to specify these different fates, the key regulators remain largely undefined. We have purified complexes associated with CP110, a protein that plays an essential role in centrosome duplication and cytokinesis, and have identified a previously uncharacterized protein, Cep97, that recruits CP110 to centrosomes. Depletion of Cep97 or expression of dominant-negative mutants results in CP110 disappearance from centrosomes, spindle defects, and polyploidy. Remarkably, loss of Cep97 or CP110 promotes primary cilia formation in growing cells, and enforced expression of CP110 in quiescent cells suppresses their ability to assemble cilia, suggesting that Cep97 and CP110 collaborate to inhibit a ciliogenesis program. Identification of Cep97 and other genes involved in regulation of cilia assembly may accelerate our understanding of human ciliary diseases, including renal disease and retinal degeneration.

Laparoscopic approach to an endometriotic vault fistula causing posthysterectomy "menstruation".

Endometriosis is a commonly prevalent disease but can include rare complaints posing a challenge to surgical treatment. We describe an unreported cause of menstruation after hysterectomy, which was revealed as an endometriotic tubo-ovarian mass that fistulated into the vaginal vault. A 37-year-old woman experienced monthly vaginal bleeding after hysterectomy. At laparoscopy a tubo-ovarian endometriotic mass was revealed with a fistula into the vaginal vault. The mass was adherent to the left ureter and the sigmoid colon. Laparoscopic excision of the mass and fistula after ureterolysis and bowel dissection was performed. This case describes an unreported cause of posthysterectomy menstruation. The management outlines the optimal surgical management of laparoscopic techniques combined with vaginal access to achieve complete excision with minimal patient morbidity.

Identification of a lytic-cycle Epstein-Barr virus gene product that can regulate PKR activation.

The Epstein-Barr virus (EBV) SM protein is a posttranscriptional regulator of viral gene expression. Like many transactivators encoded by herpesviruses, SM transports predominantly unspliced viral mRNA cargo from the nucleus to the cytosol, where it is subsequently translated. This activity likely involves a region of the protein that has homology to the herpes simplex virus type 1 (HSV-1) ICP27 gene product, the first member of this class of regulators to be discovered. However, SM also contains a repetitive segment rich in arginine and proline residues that is dispensable for its effects on RNA transport and splicing. This portion of SM, comprised of RXP triplet repeats, shows homology to the carboxyl-terminal domain of Us11, a double-stranded RNA (dsRNA) binding protein encoded by HSV-1 that inhibits activation of the cellular PKR kinase. To evaluate the intrinsic ability of SM to regulate PKR, we expressed and purified several SM protein derivatives and examined their activity in a variety of biochemical assays. The full-length SM protein bound dsRNA, associated physically with PKR, and prevented PKR activation. Removal of the 37-residue RXP domain significantly compromised all of these activities. Furthermore, the SM RXP domain was itself sufficient to inhibit PKR activation and interact with the kinase. Relative to its Us11 counterpart, the SM RXP segment bound dsRNA with reduced affinity and responded differently to single-stranded competitor polynucleotides. Thus, SM represents the first EBV gene product expressed during the lytic cycle that can prevent PKR activation. In addition, the RXP repeat segment appears to be a conserved herpesvirus motif capable of associating with dsRNA and modulating activation of the PKR kinase, a molecule important for the control of translation and the cellular antiviral response.

Characterization of RNA determinants recognized by the arginine- and proline-rich region of Us11, a herpes simplex virus type 1-encoded double-stranded RNA binding protein that prevents PKR activation.

The herpes simplex virus Us11 gene product inhibits activation of the cellular PKR kinase and associates with a limited number of unrelated viral and cellular RNA molecules via a carboxyl-terminal 68-amino-acid segment rich in arginine and proline. To characterize the determinants underlying the recognition of an RNA target by Us11, we employed an in vitro selection technique to isolate RNA ligands that bind Us11 with high affinity from a population of molecules containing an internal randomized segment. Binding of Us11 to these RNA ligands is specific and appears to occur preferentially on conformational isoforms that possess a higher-order structure. While the addition of unlabeled poly(I. C) reduced binding of Us11 to a selected radiolabeled RNA, single-stranded homopolymers were not effective competitors. Us11 directly associates with poly(I. C), and inclusion of an unlabeled selected RNA in the reaction reduces poly(I. C) binding, while single-stranded RNA homopolymers have no effect. Finally, Us11 binds to defined, double-stranded RNA (dsRNA) molecules that exhibit greater sequence complexity. Binding to these dsRNA perfect duplexes displays a striking dependence on length, as 39-bp or shorter duplexes do not bind efficiently. Furthermore, this interaction is specific for dsRNA as opposed to dsDNA, implying that the Us11 RNA binding domain can distinguish nucleic acid duplexes containing 2' hydroxyl groups from those that do not. These results establish that Us11 is a dsRNA binding protein. The arginine- and proline-rich Us11 RNA binding domain is unrelated to known dsRNA binding elements and thus constitutes a unique recognition motif that interacts with dsRNA. The ability of Us11 to bind dsRNA may be important for inhibiting activation of the cellular PKR kinase in response to dsRNA.

Inhibition of PACT-mediated activation of PKR by the herpes simplex virus type 1 Us11 protein.

PACT, a protein activator of PKR, can cause inhibition of cellular protein synthesis and apoptosis. Here, we report that the Us11 protein of herpes simplex virus type 1 can block PKR activation by PACT both in vitro and in vivo. Although Us11 can bind to both PKR and PACT, mutational analyses revealed that the binding of Us11 to PKR, and not to PACT, was essential for its inhibitory action. Similar analyses also revealed that the inhibitory effect was mediated by an interaction between the C-terminal half of Us11 and the N-terminal domain of PKR. The binding of Us11 to PKR did not block the binding of PKR to PACT but prevented its activation. Us11 is the first example of a viral protein that can inhibit the action of PACT on PKR.