The threatened stomach: management of the acute gastric volvulus.

INTRODUCTION: Acute presentation of gastric volvulus is a rare condition with a high mortality for acute ischaemia. This study was undertaken to investigate the acute management, diagnosis, and long-term outcomes of patients presenting with acute gastric volvulus. METHODS: Cases were reviewed retrospectively from 2004 to 2014. Patients presenting as an emergency admission with acute gastric volvulus were included. RESULTS: Thirty-six patients were included, five of whom had previous surgery. The mean age was 71 years old. All patients presented with vomiting and chest/epigastric pain. CT was diagnostic in all 26 patients. Barium swallow was diagnostic in two/four patients. OGD was diagnostic in 9 of 20 patients. All patients had an NG tube placed, and eight patients were treated conservatively and made a full recovery. Twenty-nine patients proceeded to surgery. Nine had a laparoscopic repair with two open conversions. Four patients had gastric necrosis, and all had open surgery with resection. Three patients had a mediastinal perforation, and one patient required an additional thoracotomy. All patients with viable stomach had a hiatal repair (where appropriate), 11 had a gastropexy, and 11 had a fundoplication. Mortality for gastric necrosis/perforation was 30 %. Mean postoperative stay was 4 days for laparoscopic repair and 8 days for uncomplicated open surgery. Nine of twenty-nine had transient dysphagia postoperatively. Three of eight patients treated conservatively had an elective procedure subsequently. CONCLUSIONS: Acute paraoesophageal hiatus hernia requires early resuscitation and diagnosis. CT should be favoured in assessment, and an NG tube placed promptly. A conservative management may be considered safely in stable patients. Surgical management should be prompt for unstable patients. Gastric ischaemia or perforation has a mortality of 30 %. Laparoscopic repair has a shorter postoperative stay, but has a higher recurrence rate. Surgery for patients without gastric ischaemia has good long-term outcomes with minimal morbidity.

Diaphragmatic disease of the colon: systematic review.

AIM: Diaphragmatic disease is rare. This review aims to increase awareness of this condition and its management. METHOD: A literature search was conducted using the key terms 'colon' or 'colonic' in combination with 'diaphragm' or 'diaphragm disease' for publications until August 2012. All cases of colonic diaphragm syndrome were identified and the required data were collected. RESULTS: Forty-five cases of colon diaphragm disease were included. The highest incidence was in the seventh decade of life, with a female preponderance (40F:5M). Most patients presented with chronic (median 3 months) and multiple symptoms. The median use of nonsteroidal anti-inflammatory drugs (NSAIDs) was 5 years including diclofenac as the most commonly used NSAID. Colonoscopy was the most informative investigation and the ascending colon was the most common site of diaphragm disease. Nearly two-thirds of the patients were treated by discontinuing NSAID treatment combined with other forms of treatment, mostly surgery. CONCLUSION: Diaphragm disease of the colon is a rare condition associated with long-term use of NSAIDs with a range of presentations and symptoms. Based on this review, when colon diaphragm disease is diagnosed we would recommend a trial cessation of NSAIDs. Therapeutic endoscopic techniques should be considered but surgery may be required for definitive treatment.

A modified Delphi process to establish research priorities in hernia surgery.

BACKGROUND: Abdominal wall hernia repair is one of the most commonly performed surgical procedures worldwide, yet despite this, there remains a lack of high-quality evidence to support best management. The aim of the study was to use a modified Delphi process to determine future research priorities in this field. METHODS: Stakeholders were invited by email, using British Hernia Society membership details or Twitter, to submit individual research questions via an online survey. In addition, questions obtained from a patient focus group (PFG) were collated to form Phase I. Two rounds of prioritization by stakeholders (phases II and III) were then completed to determine a final list of research questions. All questions were analyzed on an anonymized basis. RESULTS: A total of 266 questions, 19 from the PFG, were submitted by 113 stakeholders in Phase I. Of these, 64 questions were taken forward for prioritization in Phase II, which was completed by 107 stakeholders. Following Phase II analysis, 97 stakeholders prioritized 36 questions in Phase III. This resulted in a final list of 14 research questions, 3 of which were from the PFG. Stakeholders included patients and healthcare professionals (consultant surgeons, trainee surgeons and other multidisciplinary members) from over 27 countries during the 3 phases. CONCLUSION: The study has identified 14 key research priorities pertaining to abdominal wall hernia surgery. Uniquely, these priorities have been determined from participation by both healthcare professionals and patients. These priorities should now be addressed by well-designed, high-quality international collaborative research.

Management of the uncomplicated primary inguinal hernia in 2019: the practice amongst members of the British Hernia Society.

INTRODUCTION: The aim of this study was to survey the current practice of UK-based hernia surgeons in elective inguinal hernia repair. MATERIALS AND METHODS: A questionnaire was created using SurveyMonkey™ and sent electronically to registered members of the British Hernia Society. RESULTS: A total of 368 responses were obtained (a response rate of 55%); 83% were consultant surgeons, 91% were male and 91% stated that they had an interest in laparoscopic surgery. For an uncomplicated inguinal hernia in a male patient, 60% would perform an open Lichtenstein repair, 20% trans-abdominal pre-peritoneal repair and 20% totally extra-peritoneal repair. In a female patient, 54% would perform an open Lichtenstein repair, 25% trans-abdominal pre-peritoneal repair and 21% totally extra-peritoneal repair. 90% always use mesh in inguinal hernia repair. 93% of surgeons rarely or never perform a tissue repair. CONCLUSIONS: Despite recent controversy, UK surgeons support the use of mesh in the repair of inguinal hernias with an open Lichtenstein repair being the most common choice. There has only been a modest increase in the use of laparoscopic surgery over the past 20 years.

Atrial natriuretic peptide inhibits a cation channel in renal inner medullary collecting duct cells.

The patch-clamp technique was used to examine the effects of atrial natriuretic peptide (ANP) and its second messenger guanosine 3',5'-monophosphate (cGMP) on an amiloride-sensitive cation channel in the apical membrane of renal inner medullary collecting duct cells. Both ANP (10(-11) M) and dibutyryl guanosine 3',5'-monophosphate (10(-4) M) inhibited the channel in cell-attached patches, and cGMP (10(-5) M) inhibited the channel in inside-out patches. The inner medullary collecting duct is the first tissue in which ANP, via its second messenger cGMP, has been shown to regulate single ion channels. The results suggest that the natriuretic action of ANP is related in part to cGMP-mediated inhibition of electrogenic Na+ absorption by the inner medullary collecting duct.

Production of 2-Keto-L-Gulonate, an Intermediate in L-Ascorbate Synthesis, by a Genetically Modified Erwinia herbicola.

A new metabolic pathway has been created in the microorganism Erwinia herbicola that gives it the ability to produce 2-keto-L-gulonic acid, an important intermediate in the synthesis of L-ascorbic acid. Initially, a Corynebacterium enzyme that could stereoselectively reduce 2,5-diketo-D-gluconic acid to 2-keto-L-gulonic acid was identified and purified. DNA probes based on amino acid sequence information from 2,5-diketo-D-gluconic acid reductase were then used to isolate the gene for this enzyme from a Corynebacterium genomic library. The 2,5-diketo-D-gluconic acid reductase coding region was fused to the Escherichia coli trp promoter and a synthetic ribosome binding site and was then introduced into E. herbicola on a multicopy plasmid. Erwinia herbicola naturally produces 2,5-diketo-D-gluconic acid via glucose oxidation, and when recombinant cells expressing the plasmid-encoded reductase were grown in the presence of glucose, 2-keto-L-gulonic acid was made and released into the culture medium. The data demonstrate the feasibility of creating novel in vivo routes for the synthesis of important specialty chemicals by combining useful metabolic traits from diverse sources in a single organism.

Is sharing speaker's slides from conference presentations on social media a breach of intellectual property or a delegate's right? Depends who you ask.

BACKGROUND: The contemporary practice of the sharing of speaker's slides from medical conference presentations is common but raises a number of complex ethical and legal questions. We investigated the views of a large group of international hernia surgeons to evaluate the comtemporary view on this topic. METHODS: A questionnaire was widely promoted on Twitter and distributed by email to target the membership of the British and European Hernia Societies. Demographics and responses were recorded. RESULTS: There were 185 respondents; 68 BHS email (37%), 76  EHS email (41%) and 41 respondents via Twitter (22%). 49 (34%) society members used social media for professional communication. 23 (56%) of Twitter respondents had posted speakers slides versus 5 (12%) from society members email respondents. A majority of respondents held the view that either the specific congress (37%) or individual speakers (24%) should set the rules on the distribution of speakers slides explicitly. 10 (24%) of Twitter respondents felt that sharing content violated intellectual property compared to 88 (61%) of email respondents. CONCLUSION: Contemporary opinion regarding this subject differs depending on the modality of questionnaire and population interrogated. Respondents who use social media in their professional practice are more comfortable with the practice of sharing speaker's slides. Whilst, the sharing of speaker's slides is legal in Europe, but it may be good practice to seek consent and acknowledge the author in any communication.

Guanine nucleotide-binding protein, alpha i-3, directly activates a cation channel in rat renal inner medullary collecting duct cells.

We examined whether GTP binding proteins (G proteins) regulate sodium conducting channels in the apical membrane of renal inner medullary collecting duct (IMCD) cells and thereby modulate sodium absorption. Patch clamp studies were conducted on inside-out patches of the apical membrane of IMCD cells grown in primary culture. Guanosine 5'-triphosphate (GTP) and the nonhydrolyzable GTP analogue, GTP gamma S, which activate G proteins, increased the open probability of the cation channel. In contrast, the nonhydrolyzable GDP analogue, GDP beta S, which decreases G protein activity, inhibited the channel. Pertussis toxin also reduced the open probability of the channel. Addition of the alpha *i-3 subunit of Gi to the solution bathing the cytoplasmic surface of the membrane increased the open probability in a dose-dependent manner (2-200 pM). The threshold concentration for activation by alpha *i-3 was 2 pM. Activation of the cation channel by alpha *i-3 was not mediated via a protein kinase. The IMCD is the first polarized epithelium in which an ion channel has been shown to be directly regulated by a G protein. Thus, G proteins are important elements in regulating sodium absorption by the IMCD.

Oxidation of a specific methionine in thrombomodulin by activated neutrophil products blocks cofactor activity. A potential rapid mechanism for modulation of coagulation.

Endothelial thrombomodulin (TM) plays a critical role in hemostasis as a cofactor for thrombin-dependent formation of activated protein C, a potent anticoagulant. Chloramine T, H2O2, or hypochlorous acid generated from H2O2 by myeloperoxidase rapidly destroy 75-90% of TM cofactor activity. Activated PMN, the primary in vivo source of biological oxidants, also rapidly inactivate TM. Oxidation of TM by PMN is inhibited by diphenylene iodonium, an inhibitor of NADPH oxidase. Both Met291 and Met388 in the six epidermal growth factor-like repeat domain are oxidized; however, only substitutions of Met388 lead to TM analogues that resist oxidative inactivation. We suggest that in inflamed tissues activated PMN may inactivate TM and demonstrate further evidence of the interaction between the inflammatory process and induction of thrombotic potential.

Outcomes of an innovative training course in laparoscopic hernia repair.

Introduction The Ethicon™ laparoscopic inguinal groin hernia training (LIGHT) course is an educational course based on three days of teaching on laparoscopic hernia surgery. The first day involves didactic lectures with tutorials. The second day involves practical cadaveric procedures in laparoscopic hernia surgery. The third day involves direct supervision by a consultant surgeon during laparoscopic hernia surgery on a real patient. We reviewed our outcomes for procedures performed on real patients on the final day of the course for early complications and outcomes. Methods A retrospective study was undertaken of patients who had laparoscopic hernia surgery as part of the LIGHT course from 2013 to 2015. A matched control cohort of patients who had elective laparoscopic hernia surgery over the study period was identified. These patients had their surgery performed by the same consultant general surgeons involved in delivering the course. All patients were followed up at 6 weeks postoperatively. Results A total of 60 patients had a laparoscopic inguinal hernia repair and 23 patients had a laparoscopic ventral hernia repair during the course. The mean operative time for laparoscopic inguinal hernia repair was 48 minutes for trainees (range 22-90 minutes) and 35 minutes for consultant surgeons (range 18-80 minutes). There were no intraoperative injuries or returns to theatre in either group. All the patients operated on during the course were successfully performed as daycase procedures. The mean operative time for laparoscopic ventral hernia repair was 64 minutes for trainees (range 40-120 minutes) and 51 minutes for consultant surgeons (range 30-130 minutes). Conclusions The outcomes of patients operated on during the LIGHT course are comparable to procedures performed by a consultant. Supervised operating by trainees is a safe and effective educational model in hernia surgery.

The impact of medical school on future psychiatrists.

Although psychiatry and clinical medicine share ideals about what distinguishes a good practitioner, medical schools do not select students on the basis of these qualities. Moreover, they seem to discourage many interested students from choosing psychiatry. Part of the problem is that psychiatry is poorly taught. Research suggests that psychiatry can be better taught and that medical students will be receptive. However, the clash between the values of technological medicine and psychiatry has created discouragement, with the ironic result that medical students rate psychiatrists poorly because they embody the very qualities that distinguish the good clinician.

Finding psychiatric diagnosis-related groups that work: a call for research.

Diagnosis-related groups (DRGs) are under consideration as a way to pay hospitals for psychiatric care. Yet psychiatric DRGs account for only 3% of the variation in how long patients stay in the hospital. This nearly random variation means that psychiatrists may be working under a payment system that will have little relation to clinical reality. The authors identify important flaws in the current psychiatric DRGs and describe an alternative approach that promises to reflect clinical reality much more accurately.

Effect of vascular injury on inhibition of venous thrombosis with ZK-807834, a direct inhibitor of factor Xa.

Inhibition of factor Xa with the small molecule inhibitor ZK-807834 (Mr 527 Da, Ki 0.11 nM) attenuates progression of thrombosis, but the ED50 is substantially lower for venous compared with arterial thrombosis in experimental animals. To determine whether this reflects differences in the extent of vascular injury, we compared the dose-response of ZK-807834 for inhibition of venous thrombosis induced with a cotton thread and copper wire device in the presence and absence of balloon catheter-induced injury to the vena cava in rabbits. ZK-807834 administration over 2 h (total dosages of 0.0023-2.3 micro mol kg-1, n = 6/group) resulted in dose-dependent reductions in clot weight compared with vehicle controls, but the ED50 was 0.03 micro mol kg-1 for non-injured veins and 0.42 micro mol kg-1 for injured veins. We conclude that vascular injury invokes a tissue factor-mediated response that increases the dose requirements for inhibition of venous thrombosis with ZK-807834.

Discovery of the factor Xa inhibitor, ZK 807834 (CI-1031).

Discoveries that lead to ZK 807834 (CI-1031, 2a), a potent and selective factor Xa (fXa) inhibitor currently in clinical testing as an intravenous antithrombotic, were initiated by the identification of the potent (Z,Z)-isomer of BABCH (1c). A structure-activity relationship (SAR) was established with a series of analogues of BABCH. This SAR database, combined with computer modeling, demonstrated that binding of the second basic group in the S3/S4 pocket provided fXa potency and that a carboxylic acid group on the opposite side of the molecule resulted in selectivity versus thrombin. Simple substitution of a cyclic urea for the unsaturated ketone structure of BABCH gave disappointing results, but discovery of the bisphenoxy-pyridine analogues provided a template that could be readily optimized. The SAR established for this template is described and compared with computer modeling, REDOR NMR and X-ray crystallography studies. Inhibitor binding to fXa was increased by the introduction of a hydroxyl group on the proximal phenylamidine ring and by the introduction of fluorine atoms at C-3 and C-5 of the pyridine ring. Pharmacokinetic parameters were improved by balancing the contributions from the substituents on the distal ring and the central pyridine ring. The optimal combination was a methyl-(2H)-imidazoline group on the distal ring and a sarcosine at C-4 of the pyridine ring. The promising preclinical database for CI-1031 is described. This review relates the SAR leading to the discovery of the clinical candidate, CI-1031 directly to our best understanding of how this potent inhibitor interacts with the fXa active site.

Conformations of trypsin-bound amidine inhibitors of blood coagulant factor Xa by double REDOR NMR and MD simulations.

Double rotational-echo double resonance (double REDOR) has been used to investigate the bound conformations of (13)C,(15)N,(19)F-labeled factor Xa inhibitors to bovine trypsin. Carbon-fluorine dipolar couplings were measured by (13)C{(19)F} REDOR with natural-abundance background interferences removed by (13)C{(15)N} REDOR. The conformations of the bound inhibitors were characterized by molecular dynamics (MD) simulations of binding restrained by double REDOR-determined intramolecular C-F distances. A symmetrical bisamidine inhibitor and an asymmetrical monoamidine-monoamine inhibitor of the same general shape had distinctly different conformations in the bound state. According to the MD models, these differences arise from specific interactions of the amidine and amine groups with the active-site residues of trypsin and nearby water molecules.

Synthesis, characterization, and structure-activity relationships of amidine-substituted (bis)benzylidene-cycloketone olefin isomers as potent and selective factor Xa inhibitors.

Factor Xa (FXa) is a trypsin-like serine protease that plays a key role in blood coagulation linking the intrinsic and extrinsic pathways to the final common pathway of the coagulation cascade. During our initial studies, we observed facile photochemical conversion of the known FXa/tPA inhibitor, BABCH ¿(E,E)-2, 7-bis(4-amidinobenzylidene)cycloheptan-1-one, 1a, to the corresponding (Z,Z) olefin isomer, 1c (FXa K(i) = 0.66 nM), which was over 25,000 times more potent than the corresponding (E,E) isomer (1a, FXa K(i) = 17 000 nM). In order to determine the scope of this observation, we expanded on our initial investigation through the preparation of the olefin isomers in a homologous series of cycloalkanone rings, 4-substituted cyclohexanone analogues, and modified amidine derivatives. In most cases the order of potency of the olefin isomers was (Z,Z) > (E,Z) > (E,E) with the cycloheptanone analogue (1c) showing the most potent factor Xa inhibitory activity. In addition, we found that selectivity versus thrombin (FIIa) can be dramatically improved by the addition of a carboxylic acid group to the cycloalkanone ring as seen with 8c (FXa K(i) = 6.9 nM, FIIa K(i) > 50,000 nM). Compounds with one or both of the amidine groups substituted with N-alkyl substituents or replaced with amide groups led to a significant loss of activity. In this report we have demonstrated the importance of the two amidine groups, the cycloheptanone ring, and the (Z,Z) olefin configuration for maximum inhibition of FXa within the BABCH template. The results from this study provided the foundation for the discovery of potent, selective, and orally active FXa inhibitors.

The effect of the surface finish of alumina and stainless steel on the wear rate of UHMW polyethylene.

The effect of the surface finish of medical grade alumina and stainless steel on the wear rate of ultra-high molecular weight (UHMW) polyethylene was studied in a six station pin-on-plate wear screening device using bovine serum as lubricant. The wear rate decreased as the surface finish of alumina improved from 0.10 to 0.015 micron Ra, with no evidence of an increasing wear rate below a particular value of surface finish. Tests with surgical grade stainless steel showed a similar polyethylene wear rate around the 0.025 micron Ra level, but there was evidence of a higher wear rate with stainless steel than with alumina between approx. 0.035 and 0.075 micron Ra.

A comparison of RCH 1000 and Hi-Fax 1900 ultra-high molecular weight polyethylenes.

Hoechst RCH 1000 and Hercules Hi-Fax 1900 ultra-high molecular weight (UHMW) polyethylenes have been compared, for the first time, in tests, including wear, fatigue and creep, relevant to artificial human joints. In none of the tests was the behaviour of the Hercules material inferior to that of RCH 1000, and in the wear and creep tests it was superior.

FXa-induced responses in vascular wall cells are PAR-mediated and inhibited by ZK-807834.

During thrombosis, vascular wall cells are exposed to clotting factors, including the procoagulant proteases thrombin and factor Xa (FXa), both known to induce cell signaling. FXa shows dose-dependent induction of intracellular Ca(2+) transients in vascular wall cells that is active-site-dependent, Gla-domain-independent, and enhanced by FXa assembly into the prothrombinase complex. FXa signaling is independent of prothrombin activation as shown by the lack of inhibition by argatroban, hirudin and the sulfated C-terminal peptide of hirudin (Hir(54-65)(SO3(-))). This peptide binds to both proexosite I in prothrombin and exosite I in thrombin. In contrast, signaling is completely blocked by the FXa inhibitor ZK-807834 (CI-1031). No inhibition is observed by peptides which block interaction of FXa with effector cell protease 1 receptor (EPR-1), indicating that this receptor does not mediate signaling in the cells assayed. Receptor desensitization studies with thrombin or peptide agonists (PAR-1 or PAR-2) and experiments with PAR-1-blocking antibodies indicate that signaling by FXa is mediated by both PAR-1 and PAR-2. Potential pathophysiological responses to FXa include increased cell proliferation, increased production of the proinflammatory cytokine IL-6 and increased production of prothrombotic tissue factor. These cellular responses, which may complicate vascular disease, are inhibited by ZK-807834.

Recombinant soluble human thrombomodulin: a randomized, blinded assessment of prevention of venous thrombosis and effects on hemostatic parameters in a rat model.

UNLABELLED: Thrombomodulin is an endothelial surface receptor that binds thrombin and accelerates the activation of protein C. We compared the effects of a recombinant thrombomodulin analog (TME), recombinant hirudin (r-HIR), heparin sodium (HEP), and normal saline (Control) on thrombus formation, activated partial thromboplastin time (APTT), thrombin time (TT), platelet aggregation and tail transection bleeding time (BT) in a rat model of vena cava thrombosis. RESULTS: TME, r-HIR and HEP prevented venous thrombosis in this model in a dose-dependent manner. At the dose required to reduce vena cava thrombosis by 50% (ED50), TME did not prolong the APTT or TT as did HEP and r-HIR. Platelet aggregation in response to thrombin was not effected by TME but was inhibited by both r-HIR and HEP. BT did not differentiate the agents tested. CONCLUSION: TME inhibited venous thrombosis in a rat vena cava model with less effect on hemostatic variables than HEP or r-HIR.