Rome IV. Gallbladder and Sphincter of Oddi Disorders.

The concept that motor disorders of the gallbladder, cystic duct and sphincter of Oddi can cause painful syndromes is attractive and popular, at least in the USA. However, the results of commonly performed ablative treatments (cholecystectomy and sphincterotomy) are not uniformly good. The predictive value of tests that are often used to diagnose dysfunction (dynamic gallbladder scintigraphy and sphincter manometry) is controversial. Evaluation and management of these patients is made difficult by the fluctuating symptoms and the placebo effect of invasive interventions. A recent stringent study has shown that sphincterotomy is no better than sham treatment in patients with post-cholecystectomy pain and little or no objective abnormalities on investigation, so that the old concept of sphincter of Oddi dysfunction (SOD) type III is discarded. ERCP approaches are no longer appropriate in that context. There is a pressing need for similar prospective studies to provide better guidance for clinicians dealing with these patients. We need to clarify the indications for cholecystectomy in patients with Functional Gallbladder Disorder (FGBD) and the relevance of sphincter dysfunction in patients with some evidence for biliary obstruction (previously SOD type II, now called "Functional Biliary Sphincter Disorder - FBSD") and with idiopathic acute recurrent pancreatitis.

Serum amylase and C-reactive protein in risk stratification of pancreas-specific complications after pancreaticoduodenectomy.

BACKGROUND: Pancreas-specific complications (PSCs), comprising postoperative pancreatic fistula, haemorrhage and intra-abdominal collections, are drivers of morbidity and mortality after pancreaticoduodenectomy (PD). A serum amylase concentration of 130 units/l or more on postoperative day (POD) 0 has been shown to be an objective surrogate of pancreatic texture, a determinant of PSCs. This study evaluated serial measurements of C-reactive protein (CRP) to refine PSC risk stratification. METHODS: Consecutive patients undergoing PD between 2008 and 2014, with vascular resection if required and without preoperative chemoradiotherapy, had serum investigations from the day before operation until discharge. Receiver operating characteristic (ROC) curve analysis was used to identify a threshold value of serum CRP with clinically relevant PSCs for up to 30 days after discharge as outcome measure. RESULTS: Of 230 patients, 95 (41·3 per cent) experienced a clinically relevant PSC. A serum CRP level of 180 mg/l or higher on POD 2 was associated with PSCs, prolonged critical care stay and relaparotomy (all P < 0·050). Patients with a serum amylase concentration of 130 units/l or more on POD 0 who developed a serum CRP level of at least 180 mg/l on POD 2 had a higher incidence of morbidity. Patients were stratified into high-, intermediate- and low-risk groups using these markers. The low-risk category was associated with a negative predictive value of 86·5 per cent for development of clinically relevant PSCs. There were no deaths among 52 patients in the low-risk group, but seven deaths among 79 (9 per cent) in the high-risk group. CONCLUSION: A serum amylase level below 130 units/l on POD 0 combined with a serum CRP level under 180 mg/l on POD 2 constitutes a low-risk profile following PD, and may help identify patients suitable for early discharge.

Staged multidisciplinary step-up management for necrotizing pancreatitis.

BACKGROUND: Some 15 per cent of all patients with acute pancreatitis develop necrotizing pancreatitis, with potentially significant consequences for both patients and healthcare services. METHODS: This review summarizes the latest insights into the surgical and medical management of necrotizing pancreatitis. General management strategies for the treatment of complications are discussed in relation to the stage of the disease. RESULTS: Frequent clinical evaluation of the patient's condition remains paramount in the first 24-72 h of the disease. Liberal goal-directed fluid resuscitation and early enteral nutrition should be provided. Urgent endoscopic retrograde cholangiopancreatography is indicated when cholangitis is suspected, but it is unclear whether this is appropriate in patients with predicted severe biliary pancreatitis without cholangitis. Antibiotic prophylaxis does not prevent infection of necrosis and antibiotics are not indicated as part of initial management. Bacteriologically confirmed infections should receive targeted antibiotics. With the more conservative approach to necrotizing pancreatitis currently advocated, fine-needle aspiration culture of pancreatic or extrapancreatic necrosis will less often lead to a change in management and is therefore indicated less frequently. Optimal treatment of infected necrotizing pancreatitis consists of a staged multidisciplinary 'step-up' approach. The initial step is drainage, either percutaneous or transluminal, followed by surgical or endoscopic transluminal debridement only if needed. Debridement is delayed until the acute necrotic collection has become 'walled-off'. CONCLUSION: Outcome following necrotizing pancreatitis has improved substantially in recent years as a result of a shift from early surgical debridement to a staged, minimally invasive, multidisciplinary, step-up approach.

Exploiting inflammation for therapeutic gain in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy associated with <5% 5-year survival, in which standard chemotherapeutics have limited benefit. The disease is associated with significant intra- and peritumoral inflammation and failure of protective immunosurveillance. Indeed, inflammatory signals are implicated in both tumour initiation and tumour progression. The major pathways regulating PDAC-associated inflammation are now being explored. Activation of leukocytes, and upregulation of cytokine and chemokine signalling pathways, both have been shown to modulate PDAC progression. Therefore, targeting inflammatory pathways may be of benefit as part of a multi-target approach to PDAC therapy. This review explores the pathways known to modulate inflammation at different stages of tumour development, drawing conclusions on their potential as therapeutic targets in PDAC.

Treatment of mice with IL-12 DNA constructs leads to augmented NK activity in lungs but low IFN-gamma release -- implications for Bordetella pertussis infections following aerosol challenge.

Interleukin-12 protein has been widely used experimentally in therapeutic and adjuvant settings in the treatment of different diseases including intra-cellular bacterial infections. The in vivo clearance of Bordetella pertussis infections in naive mice and in animals vaccinated with whole cell vaccine is considered to be a Th-1 dependent mechanism. Furthermore, the addition of IL-12 protein to an acellular pertussis vaccine increases the efficacy of this vaccine. Whilst the use of IL-12 protein is often beneficial, a number of problems there are associated with this cytokine including toxicities and down regulation of normal immune functions. The use of DNA constructs encoding this cytokine may be a way of achieving maximum therapeutic benefit with minimum toxicity. The aims of this study were to optimise the effects of two IL-12 DNA constructs, especially with respect to augmenting pulmonary immune responsiveness and to compare the effect of IL-12 DNA and IL-12 protein on bacterial colonisation of lungs following aerosol challenge with B. pertussis. We found that IL-12 DNA constructs augmented the activity of pulmonary NK cells but had little effect on the course of B. pertussis infections in mice. In contrast to IL-12 protein, the DNA constructs had no immunosuppressive effects on splenic lymphocyte mitogen responses.

A randomized study of early nasogastric versus nasojejunal feeding in severe acute pancreatitis.

BACKGROUND: After 50 yr in which nasoenteric feeding was considered contraindicated in acute pancreatitis (AP), several clinical studies have shown that early nasojejunal (NJ) feeding can be achieved in most patients. A pilot study of early nasogastric (NG) feeding in patients with objectively graded severe AP proved that this approach was also feasible. A randomized study comparing NG versus NJ feeding has been performed. METHODS: A total of 50 consecutive patients with objectively graded severe AP were randomized to receive either NG or NJ feeding via a fine bore feeding tube. The end points were markers of the acute phase response APACHE II scores and C-reactive protein (CRP) measurements, and pain patterns by visual analogue score (VAS) and analgesic requirements. Complications were monitored and comparisons made of both total hospital and intensive-care stays. RESULTS: A total of 27 patients were randomized to NG feeding and 23 to NJ. One of those in the NJ group had a false diagnosis, thereby reducing the number to 22. Demographics were similar between the groups and no significant differences were found between the groups in APACHE II score, CRP measurement, VAS, or analgesic requirement. Clinical differences between the two groups were not significant. Overall mortality was 24.5% with five deaths in the NG group and seven in the NJ group. CONCLUSIONS: The simpler, cheaper, and more easily used NG feeding is as good as NJ feeding in patients with objectively graded severe AP. This appears to be a useful and practical therapeutic approach to enteral feeding in the early management of patients with severe AP.

Measurement of Vitamin D metabolites: an international perspective on methodology and clinical interpretation.

The International Quality Assessment Scheme for Vitamin D metabolites (DEQAS) was introduced in 1989. Initially, the aim was to improve the reliability of 25-hydroxyvitamin D (25-OHD) assays but the scheme was extended in 1997 to include 1,25-dihydroxyvitamin D (1,25(OH)(2)D). DEQAS has 95 members in 18 countries (January 2003). Five serum samples are distributed quarterly and participants are given up to 6 weeks to return their results for statistical analysis. The majority of participants use commercial kits for both analytes. A performance target was set by an advisory panel in 1997 and, at present, requires participants to get 80% or more of their results within +/-30% of the All-Laboratory Trimmed Mean (ALTM). The performance targets are under continual review. In 2003, 59% of participants met the target (cf. 52% in 2000). A questionnaire, distributed in January 2003, requested information on methods and the interpretation of results. Reference ranges varied but there was reasonable agreement on the 25-OHD concentrations below which Vitamin D supplementation was advised. A minority (22%) of respondents was unsure whether Vitamin D(3) or Vitamin D(2) was used to treat patients in their locality. The majority (52%) of assays for 1,25(OH)(2)D were done 'on demand' and others for apparently spurious reasons. Most respondents thought participation in DEQAS extremely important and the planned introduction of on-line reporting should enhance its value.

High dose interleukin-12 exacerbates Bordetella pertussis infection and is associated with suppression of cell-mediated immunity in a murine aerosol challenge model.

The in-vivo clearance of Bordetella pertussis infections in murine models in naive mice and animals vaccinated with whole-cell vaccine is considered to be via a Th-1-dependent mechanism in which interleukin-12 (IL)-12 may play a prominent role. It has also been demonstrated clearly that the treatment of animals with macrophage-derived IL-12 administered with an acellular vaccine can increase the efficacy of this vaccine preparation to levels seen with the whole-cell vaccine. However, the effects of exogenously added IL-12 on immune responses in non-vaccinated B. pertussis-challenged mice remain unclear, with two studies giving contradictory findings. In this study we have treated mice with escalating doses of mIL-12 (0.1-10 microg/mouse) prior to challenge with B. pertussis (using an aerosol challenge model of infection). The ability of mice to clear infection was assessed in IL-12 treated and in phosphate buffered saline (PBS) control animals at days 6 and 13 post-challenge. Lymphoid cells were isolated from spleen and cell-mediated immune responses assessed at days 1, 6 and 13 post-challenge. In addition, the direct effects of high-dose IL-12 on challenged mice was assessed by checking natural killer (NK) activity from isolated lung and spleen lymphoid cells as well as interferon-gamma (IFN-gamma) generation from isolated cells and serum at day 1 post-challenge. The results from this study show that bacterial colonization of the lungs is actually enhanced following treatment with high-dose IL-12. This is associated with impaired cellular immune responses. The mechanisms associated with the immunosuppressive effects of IL-12 are discussed.

Dynamic nature of early organ dysfunction determines outcome in acute pancreatitis.

BACKGROUND: All patients with organ dysfunction are currently classified as having severe acute pancreatitis. The aim of this study was to characterize the systemic inflammatory response syndrome (SIRS) and early organ dysfunction in patients with acute pancreatitis and the relationship with overall mortality. METHODS: Patients with predicted severe acute pancreatitis of less than 48 h duration had daily organ dysfunction scores and SIRS criteria calculated. These features were then correlated with outcome. RESULTS: Of 121 patients, 68 (56 per cent) did not develop organ dysfunction; only two of these patients died (mortality rate 3 per cent). Fifty-three (44 per cent) had early organ dysfunction, of whom 11 died (21 per cent). Organ dysfunction and persistent SIRS were both associated with an increased mortality rate, but on multivariate analysis only deteriorating organ dysfunction was an independent determinant of survival. CONCLUSION: Early organ dysfunction in acute pancreatitis usually resolves and in itself has no significant influence on mortality. In contrast, worsening organ dysfunction was associated with death in more than half of the patients (11 of 20); it is this group of patients who should be classified as having severe acute pancreatitis.

Mutational analysis and clinical correlation in Leber congenital amaurosis.

UNLABELLED: Leber congenital amaurosis (LCA, MIM 204001) is a clinically and genetically heterogeneous retinal disorder characterized by severe visual loss from birth, nystagmus, poor pupillary reflexes, retinal pigmentary or atrophic changes, and a markedly diminished electroretinogram (ERG). PURPOSE: To examine 100 consecutive patients with LCA in order to assess the relative burden of the three known genes involved in LCA, namely retinal guanylyl cyclase (GUCY2D), retinal pigment epithelium protein ( RPE65), and the cone-rod homeobox (CRX), and to define their clinical correlates. METHODS: Mutational analysis and detailed clinical examinations were performed in patients diagnosed with LCA at the Johns Hopkins Center for Hereditary Eye Diseases and the Montreal Children's Hospital. RESULTS: Mutations were identified in 11% of our patients: GUCY2D mutations accounted for 6%, while RPE65 and CRX gene mutations accounted for 3% and 2%, respectively. The clinical presentation was variable; however, the visual evolution in patients with mutations in GUCY2D and CRX remained stable, while individuals with mutations in the RPE65 gene showed progressive visual loss. CONCLUSIONS: This study suggests that molecular diagnosis of Leber congenital amaurosis could provide important information concerning prognosis and course of treatment.

Percutaneous necrosectomy and sinus tract endoscopy in the management of infected pancreatic necrosis: an initial experience.

OBJECTIVE: To describe the development of a minimally invasive technique aimed at surgical debridement in addition to simple drainage of the abscess cavity. SUMMARY BACKGROUND DATA: Surgical intervention for secondary infection of pancreatic necrosis is associated with a death rate of 25% to 40%. Although percutaneous approaches may drain the abscess, they have often failed in the long term as a result of inability to remove the necrotic material adequately. METHODS: Fourteen consecutive patients with infected necrosis secondary to acute pancreatitis were studied. The initial four patients underwent sinus tract endoscopy along a drainage tract for secondary sepsis after prior open necrosectomy. This technique was then modified to allow primary debridement for proven sepsis to be carried out percutaneously in a further 10 patients. The techniques and initial results are described. RESULTS: Additional surgery for sepsis was successfully avoided in the initial four patients managed by sinus tract endoscopy, and none died. Of the following 10 patients managed by percutaneous necrosectomy, 2 died. The median inpatient stay was 42 days. There was one conversion for intraoperative bleeding. Eight patients recovered and were discharged from the hospital after a median of three percutaneous explorations. Only 40% of patients required intensive care management after surgery. CONCLUSIONS: These initial results in an unselected group of patients are encouraging and show that unlike with percutaneous or endoscopic techniques, both resolution of sepsis and adequate necrosectomy can be achieved. The authors' initial impression of a reduction in postoperative organ dysfunction is particularly interesting; however, the technique requires further evaluation in a larger prospective series.

Effectiveness of screening instruments in detecting substance use disorders among prisoners.

This study examined the effectiveness of several screening instruments in detecting substance use disorders among prison inmates. A sample of 400 male inmates were administered eight different substance abuse screening instruments and the Structured Clinical Interview for DSM-IV (SCID-IV), Version 2.0, Substance Abuse Disorders module. The latter was used as a diagnostic criterion measure to determine the presence of substance use disorders. Based on positive predictive value, sensitivity, and overall accuracy, the Texas Christian University Drug Screen, the Simple Screening Instrument, and a combined instrument-Alcohol Dependence Scale/Addiction Severity Index-Drug Use section were found to be the most effective in identifying substance abuse and dependence disorders.

High early mortality rate from acute pancreatitis in Scotland, 1984-1995.

BACKGROUND: Death from acute pancreatitis within the first week after admission is usually a consequence of multiple organ dysfunction. Reports from specialist centres suggest that, with improvements in resuscitation and supportive care, such deaths are becoming uncommon but it is unclear if this is reflected in a decrease in early mortality rate from acute pancreatitis in the general population. METHODS: Data concerning patients discharged with a diagnosis of acute pancreatitis (International Classification of Disease-9 code 577.0) between 1984 and 1995 were obtained from the Information and Statistics Division, National Health Service in Scotland, and analysed on a computer database. RESULTS: The incidence of acute pancreatitis in Scotland continues to increase in both sexes. The in-hospital mortality rate (death from all causes) was 7.5 per cent and showed a slight but significant downward trend over the period of study. Death within 7 days of hospital admission accounted for 53.7 per cent of all deaths and the proportion of early deaths did not decline over the study interval. CONCLUSION: These results suggest that scope remains for considerable improvement in the early management of acute pancreatitis. There is an urgent need to improve the early recognition of severe pancreatitis coupled to a willingness on behalf of clinicians to transfer these patients at an early stage to a centre with high-dependency and intensive care facilities supervised by a multidisciplinary team with expertise in the endoscopic, radiological and surgical management of these patients.

Diagnosis of chronic pancreatitis and newer aspects of pain control.

The diagnosis of chronic pancreatitis in the UK largely rests on the combination of the clinical presentation which usually features pain which is often provoked by food and/or alcohol. There is usually a 30 to 40-min delay between the stimulus and the pain and, after exclusion of other causes of pain, an ERCP is performed. A minority of patients will have pancreatic function tests carried out while increasingly the diagnosis is being made by MR scanning. The control of pain is often the most important aspect of management to the patient. In those with large ducts due to compression of focal areas of the duct system surgical by-pass therapy is indicated. There is a bigger problem in patients with small ducts and chronic pancreatitis in whom extensive resection may be inappropriate. Our experience with minimally invasive thoracoscopic splanchnicectomy has been encouraging over the last three years. Having previously tried both percutaneous coeliac ganglion block and surgical excision of this nerve tissue, it is a great deal easier to carry out this procedure which usually takes only 15-20 min per side. Patients are usually only admitted for 48 h and the immediate beneficial effect usually results in opiate analgesia being discontinued with considerable improvement in the quality of life. While there is a slight drop-off in benefit between 6 and 12 months post-operatively, the clinical effectiveness of this approach is to be commended and the author's experience will be presented to support this view.

Prevalence of DSM-IV substance abuse and dependence disorders among prison inmates.

The study examined the 30-day and lifetime prevalence of DSM-IV alcohol and drug disorders among state prison inmates. A sample of 400 inmates consecutively admitted to a state prison reception center were assessed for alcohol and drug disorders using the Structured Clinical Interview for DSM-IV (SCID-IV). Test-retest reliabilities were calculated for the SCID-IV. Lifetime substance abuse or dependence disorders were detected among 74% of inmates, including over half who were dependent on alcohol or drugs. For the 30 days prior to incarceration, over half of the sample were diagnosed as having substance abuse or dependence disorders, including 46% who were dependent on alcohol or drugs. Black inmates were significantly less likely to be diagnosed as alcohol dependent than whites or Hispanics. The high rates of substance use disorders are consistent with previous findings from other studies conducted in correctional settings and reflect the need to expand treatment capacity in prisons.

The combination of laser recanalization and endoluminal intubation in the palliation of malignant dysphagia.

Laser recanalization and endoluminal intubation have been combined to optimize the palliation of malignant dysphagia in 37 patients. Nine patients with an endoluminal tube in situ presented with secondary dysphagia due to tumour overgrowth. Patency of the prosthesis was restored in all patients by laser recanalization with no complications. Twenty-eight patients treated initially by laser recanalization required subsequent intubation. The indications were dysphagia secondary to external compression (n = 3), significant angulation (n = 9), tracheo-oesophageal fistula (n = 3), failure of laser recanalization (n = 8), poor palliation (n = 3) or a combination of these (n = 2). There were no complications associated with the insertion of the tube and all patients subsequently reported improved swallowing. Laser recanalization or endoluminal intubation in isolation provide adequate palliation in the majority of patients with malignant dysphagia. We have shown that the appropriate timed combination of these two modalities may optimize the palliation of dysphagia in patients in whom the primary treatment modality fails.

Generation of antigenic peptides by lymphocyte granule serine proteases (granzymes).

We have examined the ability of several serine proteases (granzymes) isolated from the granules of the rat natural killer cell line, RNK, to generate antigenic peptides of ovalbumin (Ova) that are capable of being recognized by Ova-specific CD8+ T cells. The mouse MHC class I-restricted cytotoxic T-cell clone, GX-1, which recognizes a trypsinized fragment of Ova in the context of H-2b, was able to lyse EL4 (H-2b) target cells in the presence of Ova and the granzymes but not in the presence of Ova or granzymes alone. Similar results were obtained using the murine Ova-specific CD8+ T cell hybridomas, RF33.70 and CD8OVA. In all cases, the T cells' responses were MHC class I-restricted as Ova:granzyme mixtures failed to mediate the lysis of the MHC-disparate target cell, P815 (H-2d). The purified rat granzyme preparations contained three distinct enzymatic specificities: asp-ase met-ase, and tryptase. Aprotinin, a protease inhibitor that only inhibits tryptase activity in vitro, completely abolished the CD8+ T-cell responses to Ova. These results, along with peptide loading studies using the RMA-S cell line, suggest that the granzyme treatment of Ova can generate the proper antigenic fragments which facilitate class I-restricted CTL responses both in vivo and in vitro. We believe that enzymes produced and released by NK or cytotoxic T cells within a tissue microenvironment may enhance the cleavage of target cell antigens as well as soluble antigens resulting in the improved uptake and processing of soluble antigens.

Prospective comparison of laparoscopy, ultrasonography and computed tomography in the staging of gastric cancer.

A total of 103 consecutive patients with gastric adenocarcinoma was assessed for intra-abdominal spread of malignancy using ultrasonography, computed tomography (CT) and laparoscopy under general anaesthesia. Histologically proven metastases were to the liver in 27 patients, lymph nodes in 49 and directly to peritoneum in 13. All modalities showed a high specificity (92-100 per cent) for each type of metastasis. Laparoscopy was more sensitive in detecting hepatic, nodal and peritoneal metastases; the relative performance of laparoscopy was best with regard to hepatic metastases. Ultrasonography and CT were particularly poor at detecting nodal and peritoneal metastases. There was no significant morbidity and no mortality associated with laparoscopy, which was more accurate in preoperative staging of gastric cancer than ultrasonography or CT.