Small bowel intussusception and concurrent jejunal polyp with neoplastic transformation: a new diagnosis of Peutz-Jeghers syndrome.

Peutz-Jeghers syndrome (PJS) is a rare hereditary disease characterised by hyperpigmentation of the oral mucosa and gastrointestinal hamartomatous polyps. We report a case of a 27-year-old man who presented with a 5-day history of epigastric pain and rectal bleeding. Computed tomography suggested small bowel obstruction secondary to ileocolic intussusception and an incidental polyp in the mid jejunum. The patient underwent exploratory laparotomy during which right hemicolectomy and small bowel resection were performed. Histology from surgical specimens revealed Peutz-Jeghers polyps, one of which had low-grade dysplasia. This case emphasises that although rare, adults with PJS can present with intussusception. Also illustrated is the extremely rare possibility of concurrent polyps occurring in different parts of the bowel with neoplastic transformation. Intussusception is a challenge to diagnose because the presentation is often non-specific. Clinical history-taking and physical examination along with prompt axial imaging is important for the diagnosis. Careful examination of the bowel and polypectomy during laparotomy may prevent neoplastic transformation and short bowel syndrome.

A single centre evaluation of risk prediction models and imaging modalities in acute appendicitis.

INTRODUCTION: Patients with suspected appendicitis remain a diagnostic challenge. The aim of this study was to validate risk prediction models, and to investigate diagnostic accuracy of ultrasonography and computed tomography (CT) in adults undergoing appendicectomy. METHODS: A retrospective case review was performed of patients aged 16-45 years having an appendicectomy between January 2019 and January 2020 at a tertiary referral centre. Primary outcomes were the accuracy of a high risk appendicitis risk score and ultrasonography and CT imaging modalities compared with histological reports following appendicectomy. RESULTS: A total of 206 patients (52% female) were included in the study. Removal of a histologically normal appendix was equally likely in men and women (13.1% vs 11.2% respectively, relative risk: 1.17, 95% confidence interval: 0.56-2.44, p=0.674). A high risk appendicitis score correctly identified 84.0% (79/94) of cases in men and 85.9% (67/78) of cases in women. Ultrasonography was reported as equivocal in 85.7% (18/21) of low risk women and 59.0% (23/39) of high risk women. CT correctly detected or excluded appendicitis in 75.0% (6/8) of low risk women and 88.5% (23/26) of high risk women. CONCLUSIONS: This study suggests that risk prediction models may be useful in both women and men to identify appendicitis. Ultrasonography gave high rates of equivocal results and should not be relied on for the diagnosis of appendicitis. CT is a highly accurate diagnostic tool and could be considered in those at low risk where clinical suspicion remains to reduce negative appendicectomy rates.

Infiltrating macrophages contribute to age-related neuroinflammation in C57/BL6 mice.

The recognized role of neuroinflammation in the age-related deterioration of neuronal function highlights the importance of understanding the factors that control microglial activation. Microglia, as the immune cells of the brain, are the arbiters of the inflammatory profile in the brain. Normally they are maintained in a quiescent state by means of ligand-receptor interactions with neurons, within a prevailing anti-inflammatory microenvironment. The evidence indicates that, as the ageing process continues, microglia become activated, shift towards an inflammatory phenotype and alter the milieu in the brain. Although there has been progress in identifying factors that contribute to age-related microglial activation, our understanding remains incomplete. Here we report that there was an age-related increase in circulating inflammatory cytokines, accompanied by microglial activation. Neutrophils, and to a greater extent, macrophages, infiltrate the brain with age, perhaps as a result of increased chemokine expression in the brain, specifically CXCL1 and CCL2. We sought to determine whether macrophages might trigger microglial activation and the evidence shows that conditioned medium obtained from interferon-γ (IFNγ)-stimulated macrophages potently activated microglia. The data suggest that infiltrating macrophages may be one factor that contributes to age-related microglial activation.

Effect of Valvular Surgery in Carcinoid Heart Disease: An Observational Cohort Study.

CONTEXT: Carcinoid heart disease (NET-CHD) is associated with the development of symptom-limited exercise capacity and high rates of morbidity and mortality. OBJECTIVE: This study sought to determine the survival, cardiac function, and functional class following surgery. DESIGN AND SETTING, AND PATIENTS: This was a retrospective observational cohort study between 2005 and 2015 at a European Centre of Excellence for Neuroendocrine Tumours, Queen Elizabeth Hospital Birmingham. England consisting of 62 consecutive patients referred to the NET-Cardiology Service. INTERVENTIONS: Subjects were assessed at referral using transthoracic echocardiography (with saline contrast) and transesophageal echocardiography, and 77% with confirmed NET-CHD underwent cardiovascular magnetic resonance imaging. Symptomatic patients with concomitant severe valvular dysfunction were referred for surgery with stable NET disease. MAIN OUTCOME MEASURE: Survival of patients with proven NET-CHD following medical and surgical treatments was measure. RESULTS: In total, 47/62 patients were diagnosed with NET-CHD. Thirty-two patients (68%) underwent surgery with bioprosthetic valve replacements in all subjects; tricuspid, n = 31; pulmonary, n = 30; mitral, n = 3; and aortic, n = 3. Four patients underwent concomitant coronary artery bypass grafting. There were 4 (13%) early post-operative deaths. One- and 2-y survival rates after surgery were 75 and 69% compared with 45 and 15% in un-operated patients. Post-operatively, functional class was improved (pre-New York Heart Association Classification [NYHA], 2.6 [0.5] vs post-NYHA, 1.7 [1.1]), P < .05, right-ventricular (RV) size was reduced (136 ml/m(2) [25] vs 71 ml/m(2) [7]; P < .01) with preserved RV ejection fraction (61% ± 9 vs 55% ± 10; P = .26). CONCLUSION: Valve surgery improved functional class and resulted in RV reverse remodelling with improved survival rates at 2 y compared with those not proceeding to operation. These data highlight the importance of close collaboration between NET clinicians, cardiology, and cardiothoracic surgery teams. Early referral can improve functional capacity but more research is needed to define the selection of appropriate candidates and randomized data are needed to define the effect of surgery on prognosis.

Screening and confirmation of hereditary spherocytosis in children using a CELL-DYN Sapphire haematology analyser.

INTRODUCTION: Multidimensional optical scatter of sphered erythrocytes can identify and enumerate hyperchromic erythrocytes, which might be used for hereditary spherocytosis (HS) screening. The flow cytometric eosin-5'-maleimide test (EMA) is highly sensitive and specific for HS as a confirmatory method. The aims of this study were to assess the utility of hyperchromic erythrocytes in HS screening and to evaluate the EMA test performed on CELL-DYN Sapphire analyser compared with the reference method. METHODS: Blood from 740 paediatric patients presenting at our institution was analysed in reticulocyte mode of the CELL-DYN Sapphire haematology analyser (Abbott Diagnostics) to obtain hyperchromic erythrocyte counts. The EMA test was performed using a flow cytometer as a reference, as well as CELL-DYN Sapphire as an investigational method. RESULTS: Hyperchromic erythrocytes were the highest in patients with HS (median 11.5%; range 5.1-29.2%). Patients with autoimmune haemolytic disease had significantly less hyperchromic erythrocytes (median 4.9%; range 0.0-18.3%). Hyperchromic erythrocytes showed a high area under the ROC curve: 0.972. At 4.9% cut-off, hyperchromic erythrocytes detected HS with 96.4% sensitivity and 99.1% specificity. The EMA test on CELL-DYN Sapphire correlated strongly with the reference test and had identical diagnostic power. Stability studies with blood from HS patients showed a significant decrease in hyperchromic erythrocytes after 6 h storage. CONCLUSIONS: Measurement of hyperchromic erythrocytes is highly sensitive and specific for detecting HS and can be used for rapid and inexpensive screening. If required, the EMA test can be performed on CELL-DYN Sapphire or a standard flow cytometer for confirmation of HS.

Numerical method for the stochastic projected Gross-Pitaevskii equation.

We present a method for solving the stochastic projected Gross-Pitaevskii equation (SPGPE) for a three-dimensional weakly interacting Bose gas in a harmonic-oscillator trapping potential. The SPGPE contains the challenge of both accurately evolving all modes in the low-energy classical region of the system, and evaluating terms from the number-conserving scattering reservoir process. We give an accurate and efficient procedure for evaluating the scattering terms using a Hermite-polynomial based spectral-Galerkin representation, which allows us to precisely implement the low-energy mode restriction. Stochastic integration is performed using the weak semi-implicit Euler method. We extensively characterize the accuracy of our method, finding a faster-than-expected rate of stochastic convergence. Physical consistency of the algorithm is demonstrated by considering thermalization of initially random states.

Cost-effectiveness of transcatheter aortic valve implantation (TAVI) for aortic stenosis in patients who are high risk or contraindicated for surgery: a model-based economic evaluation.

BACKGROUND: Calcific aortic stenosis (AS) is a common valvular heart disease. Patients with severe symptomatic AS typically survive less than 3 years. In such patients, intervention with surgical aortic valve replacement (SAVR) may increase survival. However, in some patients SAVR is associated with a high operative risk and medical management is considered appropriate. Transcatheter aortic valve implantation (TAVI) is a relatively recent technique to avoid the invasiveness of open surgery. This procedure has been used for the treatment of patients with severe AS who are unsuitable for SAVR (because it is too high risk and/or for other reasons such as suffering from porcelain aorta) and is increasingly being considered for other patients. OBJECTIVES: To determine the cost-effectiveness of TAVI being made available for patients who are high risk or contraindicated for SAVR through a review of existing economic evaluations and development of a model. DATA SOURCES AND REVIEW METHODS: Bibliographic databases [MEDLINE, EMBASE, The Cochrane Library, Health Technology Assessment (HTA), Database of Abstracts of Reviews of Effects (DARE) and NHS Economic Evaluation Database (EED), Centre for Reviews and Dissemination HTA, DARE and NHS EED], guideline resources, current trials registers, websites/grey literature and manufacturers' websites, and consultation with clinical experts were used to identify studies for the review and information for the model. Databases were searched from 2007 to November 2010. A model was built to assess the cost-effectiveness of TAVI separately in patients suitable and unsuitable for SAVR, together with overall results for the effect of making TAVI available. Substantial deterministic sensitivity analysis was carried out together with probabilistic sensitivity analysis. RESULTS: No fully published cost-effectiveness studies were found. Modelling patients not suitable for SAVR, the base-case results show TAVI as more costly but more effective than medical management, with an incremental cost-effectiveness ratio (ICER) of £12,900 per quality-adjusted life-year (QALY). The ICER was below £20,000 per QALY for over 99% of model runs in the probabilistic sensitivity analysis. For patients suitable for SAVR, the comparator with TAVI is a mixture of SAVR and medical management. TAVI is both more costly and less effective than this comparator assuming that most patients would receive SAVR in the absence of TAVI. This is robust to a number of assumption changes about the effects of treatment, but sensitive to assumptions about the proportion of patients receiving SAVR in the comparator. If the use of TAVI is extended to include more patients suitable for SAVR, the overall results from the model become less favourable for TAVI. LIMITATIONS: The modelling involves extrapolation of short-term data and the comparison between TAVI and SAVR is not based on randomised data. More trial data on the latter have been published since the modelling was undertaken. CONCLUSIONS: The results for TAVI compared with medical management in patients unsuitable for surgery are reasonably robust and suggest that TAVI is likely to be cost-effective. For patients suitable for SAVR, TAVI could be both more costly and less effective than SAVR. The overall results suggest that, if a very substantial majority of TAVI patients are those unsuitable for SAVR, the cost-effectiveness of a broad policy of introducing TAVI may fall below £20,000 per QALY. Future work required includes the incorporation of new data made available after completion of this work. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

In search of Pinkel's children: unravelling the biological heterogeneity of childhood acute lymphoblastic leukaemia by genotype and treatment molecular response.

BACKGROUND: Acute lymphoblastic leukaemia (ALL), the commonest childhood malignancy has seen remarkable progress since the 1960s with cure rates now approaching 85%. To achieve this patients undergo intensive treatment that usually takes 2.5-3.5 years involving on average 15 different chemotherapeutic drugs. In 1971, Donald Pinkel reported Total Therapy-Protocol V that used 5 drugs and cranial radiation therapy over a similar time period. Today, one half of these patients (Pinkel's children) remain alive and free of leukaemia. AIM: The aim of this study was to evaluate the impact post-induction minimal residual disease (MRD) levels had on survival and its relationship with the more established clinical and biological prognostic predictors of outcome in the hope of identifying a subgroup of patients that are at very low risk of failure. METHODS: A retrospective review of 250 Irish children with ALL was carried out. MRD status after 28 days of induction chemotherapy and other known predictors of outcome were correlated with 5 year event-free survival (EFS). RESULTS: MRD status was the strongest predictor of outcome with 5 year EFS rates greater that 90% seen in those patients with low-risk MRD and this was associated with TEL/AML1 rearrangement, high hyperdiploidy (HH) karyotype and female gender. CONCLUSION: Both MRD and karyotype are powerful determinants of outcome in childhood ALL. Therefore, it is reasonable to conclude that the majority of children cured by Pinkel et al. in the late 1960s were most likely composed of low-risk MRD, TEL/AML1 and HH patients.

Characteristics of two-dimensional quantum turbulence in a compressible superfluid.

Fluids subjected to suitable forcing will exhibit turbulence, with characteristics strongly affected by the fluid's physical properties and dimensionality. In this work, we explore two-dimensional (2D) quantum turbulence in an oblate Bose-Einstein condensate confined to an annular trapping potential. Experimentally, we find conditions for which small-scale stirring of the condensate generates disordered 2D vortex distributions that dissipatively evolve toward persistent currents, indicating energy transport from small to large length scales. Simulations of the experiment reveal spontaneous clustering of same-circulation vortices and an incompressible energy spectrum with k(-5/3) dependence for low wave numbers k. This work links experimentally observed vortex dynamics with signatures of 2D turbulence in a compressible superfluid.

Comparison of three cuffed emergency percutaneous cricothyroidotomy devices to conventional surgical cricothyroidotomy in a porcine model.

BACKGROUND: Emergency cricothyroidotomy is a potentially life-saving procedure in the 'cannot intubate cannot ventilate (CICV)' scenario. Although surgical cricothyroidotomy remains the technique recommended in many 'CICV' algorithms, the insertion of a tracheostomy as a cannula over a trocar, or using the Seldinger method, may have advantages as they are more familiar to the anaesthetist. We compared the utility of three cuffed cricothyroidotomy devices: cuffed Melker®, Quicktrach 2®, and PCK® devices, with surgical cricothyroidotomy. METHODS: After ethical committee approval and written informed consent, 20 anaesthetists performed cricothyroidotomy with all four devices in random order, in a pig larynx and trachea model covered in cured pelt. The primary endpoints were the rate of successful placement of the cricothyroidotomy device into the trachea and the duration of the insertion attempt. RESULTS: The Melker® and Quicktrach 2® devices possessed advantages over the surgical approach, in contrast to the PCK® device, which performed less well. All 20 participants inserted the Melker®, with 19 being successful using the surgical approach and the Quicktrach 2®, whereas only 12 successfully inserted the PCK® device (PCK® vs surgical, P=0.02). The Quicktrach 2® had the fastest insertion times and caused least trauma to the posterior tracheal wall. The Melker® was rated highest by the participants and was the only device rated higher than the surgical technique. CONCLUSIONS: The Melker® and Quicktrach 2® devices appear to hold particular promise as alternatives to surgical cricothyroidotomy. Further studies, in more clinically relevant models, are required to confirm these initial positive findings.

Platelets in the paediatric population: the influence of age and the limitations of automation.

Accurate and precise platelet counting is important for the clinical management of children with platelet disorders. Current automated technologies are often unable to discriminate platelets from non-platelet particles particularly in circumstances where platelet anisocytosis is common. This study compares manual methodology and the automated technologies; impedance, optical density and CD61 immunoplatelet method (available on the Cell Dyn 4000) with the reference method of flow cytometric analysis in a paediatric population. A total of 141 samples were analysed and divided into specific age related groups and groups with thrombocytopenia and thrombocytosis. Data analysis showed that the CD61 method compared best with the reference method and this was evident in all the specified groups. The mean platelet count obtained by optical and manual methods were lower, suggesting that these methods are less reliable. The impedance count method was accurate despite its limitations. Strong correlations were observed in the 2-14 year age group but there was greater variation in the <1 month group supporting the theory that there is a greater variation in platelet characteristics in neonates. The CD61 method is the automated method of choice and would be particularly useful in the problem groups (platelet counts <50 x 10(9)/l and neonates <1 month old).

Proceso para conseguir una evaluación basal de la dirección clínica en seis meses

Se presenta el proceso para conseguir la evaluación de la situación basal de la organización, antes de iniciar un proceso de dirección clínica. Este proyecto engloba el gobierno de los servicios sociales y sanitarios, los organizacionales y los financieros de un trust de servicios sociales y comunitarios de Belfast. Se desarrolló una estructura de gestión del proyecto que engloba a profesionales de las distintas áreas implicadas. Las etapas del proyecto son:1. Plan de comunicación.2. Empleo del modelo EFQM para realizar la parte inicial de la evaluación basal.3. Identificación de las áreas críticas, clasificando los riesgos corporativos.4. Informes externos.5. Informes internos.6. Contratos clave.7. Informe final; su objetivo es resumir los puntos clave de la evaluación basal de gobierno y presentar las recomendaciones en las 6 etapas previas. Este proyecto en 7 etapas ya se ha puesto en marcha con éxito en un gran trust de servicios sociales y sanitarios y puede utilizarse en cualquier otra organización (AU)

Glucocorticoids regulate expression of the fatty acid synthase gene in fetal rat type II cells.

Fatty acids are integral components of pulmonary surfactant, a mixture of phospholipids and specific proteins that lines the alveolar surface and is essential for normal lung function. There are developmental increases in fatty acid biosynthesis and surfactant production in late-gestation fetal lung, and both processes are accelerated by glucocorticoids. Fatty acid synthase (FAS) is a key enzyme in de novo fatty acid biosynthesis, and increased FAS activity is responsible for the developmental and hormone-induced increases in fatty acid biosynthesis in fetal lung. Using cultured fetal lung explants, it has been reported that dexamethasone (Dex) increases FAS activity, protein content, mRNA content and rate of transcription. However, FAS expression has not been measured in isolated type II cells, the cellular source of surfactant within the lung. In the present study we measured parameters of FAS expression in type II cells isolated from the lungs of Dex-treated rats. Pregnant rats were injected with Dex or saline on days 18 and 19 of gestation and the fetuses delivered on day 20. Type II cells and fibroblasts were then isolated from the fetal lungs. Dex increased FAS activity, protein content, mRNA content and rate of transcription in the type II cells but not in the fibroblasts. Increased FAS expression in fetal type II cells in response to Dex is consistent with a critical role for FAS in the biosynthesis of lung surfactant.

Regulation of SP-B and SP-C secretion in rat type II cells in primary culture.

Secretion of lung surfactant phospholipids is a highly regulated process. A variety of physiological and pharmacological agents stimulate surfactant phospholipid secretion in isolated type II cells. Although the lipid and hydrophobic protein components of surfactant are believed to be secreted together by exocytosis of lamellar body contents, regulation of surfactant protein (SP) B and SP-C secretion has not previously been examined. To address the question of whether secretion of SP-B and SP-C is stimulated by the same agonists that stimulate phospholipid secretion, we measured secretion of all four SPs under the same conditions used to measure phosphatidylcholine secretion. Freshly isolated rat type II cells were cultured overnight and exposed to known surfactant phospholipid secretagogues for 2.5 h, after which the amounts of SP-A, SP-B, SP-C, and SP-D in the medium were measured with immunoblotting. Secretion of SP-B and SP-C was stimulated three- to fivefold by terbutaline, 5'-(N-ethylcarboxyamido)adenosine, ATP, 12-O-tetradecanoylphorbol 13-acetate, and ionomycin. Similar to their effects on phospholipid secretion, the stimulatory effects of the agonists were abolished by Ro 31-8220. Secretion of SP-A and SP-D was not stimulated by the secretagogues tested. We conclude that secretion of the phospholipid and hydrophobic protein components of surfactant is similarly regulated, whereas secretion of the hydrophilic proteins is regulated differently.

Transcriptional regulation of the lung fatty acid synthase gene by glucocorticoid, thyroid hormone and transforming growth factor-beta 1.

Fatty acid synthase (FAS) is a key enzyme in the biosynthesis of lung surfactant. FAS expression in fetal lungs is increased by glucocorticoids and this effect is largely due to increased transcription. The stimulatory effect of glucocorticoid on FAS expression is antagonized by thyroid hormone and transforming growth factor-beta 1 (TGF-beta 1). To determine the glucocorticoid responsive regions of the FAS gene we employed deletion analysis and reporter gene assays. A549 cells were transfected with various FAS gene constructs ligated to the firefly luciferase gene and cultured with dexamethasone (Dex) for 24 h after which luciferase activity was measured. Dex increased luciferase expression in response to a fragment in the promoter and 5'-flanking region of the FAS gene, from -1592 to +65 bp. This increase was antagonized by triiodothyronine (T(3)) and TGF-beta 1. Serial deletions showed that the full response to Dex and T(3) were retained in the 89 bp -33/+56 bp fragment whereas the response to TGF was mediated by the immediately upstream -104/-34 bp sequence. The Dex responsive region of the FAS gene could not be separated from the minimal promoter showing that they are intimately associated. The extents of Dex stimulation and antagonism by T(3) and TGF in A549 cells were similar to those noted on parameters of FAS expression in fetal lung explants. These data show that the effects of Dex, T(3) and TGF on FAS expression are mediated by DNA sequences in the promoter region of the gene.

Regulation of surfactant secretion.

Lung surfactant is synthesized in the alveolar type II cell. Its lipids and hydrophobic proteins (SP-B and SP-C) are stored in lamellar bodies and secreted by regulated exocytosis. In contrast, the hydrophilic proteins (SP-A and SP-D) appear to be secreted independently of lamellar bodies. Regulation of surfactant secretion is mediated by at least three distinct signaling mechanisms: activation of adenylate cyclase with formation of cAMP and activation of cAMP-dependent protein kinase; activation of protein kinase C; and a Ca(2+)-regulated mechanism that likely results in the activation of Ca(2+)-calmodulin-dependent protein kinase. These signaling mechanisms are activated by a variety of agonists, some of which may have a physiological role. ATP is one such agent and it activates all three signaling mechanisms. There is increasing information on the identity of several of the signaling proteins involved in surfactant secretion although others remain to be established. In particular the identity of the phospholipase C, protein kinase C and phospholipase D isomers expressed in the type II cell and/or involved in surfactant secretion has been established. Distal steps in the secretory pathway beyond protein kinase activation as well as the physiological regulation of surfactant secretion, are major issues that need to be addressed.

Glucocorticoid enhances the response of type II cells from newborn rats to surfactant secretagogues.

There is a developmental increase in agonist-induced surfactant secretion in type II cells. The response to the P2Y(2) agonist UTP is negligible in early newborn cells but increases with age. The response to terbutaline, N-ethylcarboxyamidoadenosine (NECA), and ATP also increases with age. As glucocorticoids are known to accelerate several aspects of lung maturation we examined the effect of dexamethasone (Dex) on the response of 1-day-old rat type II cells to surfactant secretagogues. Freshly isolated cells were cultured +/-10(-6) M Dex for 18--20 h after which phosphatidylcholine secretion was measured. Dex slightly decreased the basal secretion rate. However, it significantly increased the response to terbutaline, NECA, ATP and UTP. This effect was dependent on Dex concentration (EC(50)=2-6 x 10(-9) M) and blocked by the glucocorticoid receptor antagonist RU-486. It is unlikely to be due to increased receptor content as Dex had no effect on adenylate cyclase, phospholipase C or phospholipase D activation and the response to cAMP, forskolin and phorbol ester, secretagogues acting downstream from receptors, was also increased by Dex. These data show that Dex acts directly on the type II cell to enhance the response to surfactant secretagogues, that the effect of the hormone is mediated by the glucocorticoid receptor and suggest induction of a common downstream signaling step(s). Regulation of surfactant secretion may be an important function of glucocorticoids in the developing lung.