Endoscopic histology: the start of a new era?
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Endoscopes, Gastrointestinal↗
Biomedical subjects
P Sharma
Publications and source records attributed to P Sharma.
A free energy based computational pathway from chemical templates to lead compounds: a case study of COX-2 inhibitors.
Automation of lead compound design in silico given the structure of the protein target and a definition of its active site vies for the top of the wish list in any drug discovery programme. We present here an enumeration of steps starting from chemical templates and propose a solution at the state of the art, in the form of a system independent comprehensive computational pathway. This methodology is illustrated with cyclooxygenase-2 (COX-2) as a target. We built candidate molecules including a few Non Steroidal Anti-inflammatory Drugs (NSAIDs) from chemical templates, passed them through empirical filters to assess drug-like properties, optimized their geometries, derived partial atomic charges via quantum calculations, performed Monte Carlo docking, carried out molecular mechanics and developed free energy estimates with Molecular Mechanics Generalized Born Solvent Accessibility (MMGBSA) methodology for each of the candidate molecules. For the case of aspirin, we also conducted molecular dynamics on the enzyme, the drug and the complex with explicit solvent followed by binding free energy analysis. Collectively, the results obtained from the above studies viz. sorting of drugs from non-drugs, semi-quantitative estimates of binding free energies, amply demonstrate the viability of the strategy proposed for lead selection/design for biomolecular targets.
Anti-Inflammatory Agents, Non-Steroidal↗
Review article: approaches to Barrett's oesophagus treatment-the role of proton pump inhibitors and other interventions.
Despite implementation of screening and surveillance strategies, a significantly large number of patients with Barrett's oesophagus remain undiagnosed. In those who are identified, the management options include acid reduction therapies with proton pump inhibitors or anti-reflux surgery. Endoscopic ablative therapies have also been attempted. In addition to having inherent procedure-related risks with ablative therapies, these alternatives may be limited by high rates of failure, need for continued acid suppressive therapy, metaplasia persistence under otherwise normal appearing tissue, need for procedural expertise, and continued risk for adenocarcinoma development. Therefore, a widely applicable chemoprevention strategy that cost-effectively reduces the rate of progression from oesophagitis to adenocarcinoma in high-risk patients and perhaps those at lower rates of risk is highly desirable. The AspECT trial currently underway is seeking to determine the effects of high- and low-dose proton pump inhibitor therapy with and without low-dose aspirin as Barrett's oesophagus chemoprevention.
Adenocarcinoma↗
Review article: emerging techniques for screening and surveillance in Barrett's oesophagus.
The incidence of oesophageal adenocarcinoma continues to increase in the US and the Western world, with the 5-year survival rate for this cancer still being very dismal. The diagnosis of Barrett's metaplasia and dysplasia (i.e. screening and surveillance) currently requires endoscopy with biopsy of the abnormally appearing distal oesophagus. Surveillance endoscopy in patients with Barrett's oesophagus relies on the performance of random biopsies from the metaplastic segment, with the aim of identifying dysplasia and/or cancer. However, intestinal metaplasia and dysplasia are not uniformly distributed within the columnar-lined mucosa in the distal oesophagus, and the sensitivity of standard endoscopy with biopsy for the detection of these lesions is low. New techniques to improve the accuracy of endoscopic diagnosis, as well as to identify patients at high risk for neoplasia development, have recently been developed and most are currently being evaluated in clinical studies. The results with these techniques, although promising, are still preliminary. They hold promise for the improved detection of dysplasia and neoplasia at an early stage of development, with a greater chance for early treatment, and therefore a greater likelihood of either cure of adenocarcinoma or prevention of its development from dysplasia.
Barrett Esophagus↗
Review article: prevalence of Barrett's oesophagus and metaplasia at the gastro-oesophageal junction.
Barrett's oesophagus, a complication of chronic gastro-oesophageal reflux disease, is the premalignant lesion for oesophageal and gastro-oesophageal junction adenocarcinoma. Described in the 1950s by Norman Barrett, the diagnostic criterion for this lesion has evolved significantly over the last three decades. Endoscopic Barrett's oesophagus requires the recognition of columnar mucosa in the distal oesophagus; documentation of metaplastic tissue is confirmed by random biopsies. Given this changing definition of Barrett's metaplasia, the prevalence rates vary in the literature depending on the diagnostic criteria applied. However, it is generally accepted that approximately 10% of patients with chronic gastro-oesophageal reflux disease will be diagnosed with this condition. There are no population-based studies on the prevalence of Barrett's oesophagus, but emerging data indicate that it may be equally prevalent in asymptomatic individuals. These studies require confirmation. Although the incidence of oesophageal adenocarcinoma is increasing rapidly, it is unclear whether the true incidence of Barrett's oesophagus is increasing at the same time. On the other hand, metaplasia at the gastro-oesophageal junction appears to be distinct from Barrett's oesophagus, is probably not related to chronic gastro-oesophageal reflux disease and is a common finding if routine biopsies are obtained at the gastro-oesophageal junction. This article reviews our current understanding of the diagnosis, definition and prevalence of both of these lesions.
Barrett Esophagus↗
Review article: oesophageal complications and consequences of persistent gastro-oesophageal reflux disease.
The major oesophageal complications associated with persistent gastro-oesophageal reflux disease (GERD) include erosive oesophagitis, ulceration, strictures and gastrointestinal (GI) bleeding. Although the causes of these complications are uncertain, studies indicate that erosive oesophagitis may progress to the development of ulcers, strictures and GI bleeding. Pharmacological treatment with proton pump inhibitors is favoured over that with H(2)-receptor antagonists for the treatment of strictures. The treatment of strictures is accomplished with dilation and many favour the concomitant use of proton pump inhibitors. Most gastroenterologists are seeing far fewer oesophageal strictures these days since the introduction of proton pump inhibitors. In addition, research has shown that oesophageal complications have a greater impact on patients suffering from night-time GERD than on those suffering from daytime GERD. Barrett's oesophagus is a significant complication associated with persistent GERD and those at risk generally experience a longer duration of symptoms, especially those with a high degree of severity. In addition, there is a strong relationship between Barrett's oesophagus and oesophageal adenocarcinoma. This is in part due to the association of obesity and the development of hiatal hernias. Furthermore, endoscopic screening is being used to detect Barrett's oesophagus and oesophageal adenocarcinoma in persons suffering from chronic GERD, even though screening may not have an impact on outcomes (Sharma P, McQuaid K, Dent J, et al. A critical review of the diagnosis and management of Barrett's esophagus: The AGA Chicago Workshop. Gastroenterology 2004; 127: 310-30.).
Adenocarcinoma↗
Neutrophil-free radical generation and enzymatic antioxidants in migraine patients.
The present study was undertaken to elucidate the role of circulating neutrophils if any in oxidative stress in migraine by evaluating free radical generation and activities of enzymatic antioxidants in the blood in 55 patients with migraine and 60 healthy controls. Free radical generation was assessed by flow cytometry, while activity of catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPx) was estimated in blood polymorphonuclear neutrophils (PMNs) by standard procedures. Platelet SOD was also measured. No significant change was found in free radical generation and in the activity of catalase, SOD and GPx in migraine patients. Univariate analysis of PMN catalase level revealed that migraineurs with a positive family history had significantly lower catalase activity compared with those with a negative family history. No correlation was found in the activity of antioxidant enzymes with age, duration of disease, time since last attack and headache index. The platelet SOD also did not show any significant change in patients of migraine without aura. Platelet aggregation in the presence or absence of PMNs was also not altered significantly. Thus the findings of the present study suggest that neutrophils are not the cause of oxidative stress observed in migraine patients.
Adult↗
What is the best management strategy for high grade dysplasia in Barrett's oesophagus? A cost effectiveness analysis.
BACKGROUND: Multiple treatment strategies for subjects with high grade dysplasia (HGD) in Barrett's oesophagus (BO) have been suggested. However, it is unclear which of these strategies provides the greatest life expectancy, and the costs associated with the management strategies are unknown. AIM: To compare the efficacy and cost effectiveness of competing management strategies for BO with HGD. METHODS: We created a decision analysis model in Data 4.0 to assess possible treatment strategies for BO with HGD. The strategies included: (1) no preventative strategy, (2) elective surgical oesophagectomy, (3) endoscopic ablation, and (4) surveillance endoscopy. The base case was a healthy 50 year old White male with an initial diagnosis of BO with HGD. The model allowed for complications of surgery, including death. Ablative therapy could cause stricture or perforation. Pathological misinterpretation was allowed, and modelled after reported rates. Estimates were derived from the literature for the rate of progression of HGD to cancer and for complication rates for the various treatment modalities. The endoscopic ablation arm was modelled as photodynamic therapy. Sensitivity analyses were performed over a wide range of cancer incidences, complication rates, and procedure costs. RESULTS: Endoscopic ablation was the most effective strategy, yielding 15.5 discounted quality adjusted life years (dQALY), compared with 15.0 for endoscopic surveillance and 14.9 for oesophagectomy. No preventative strategy was the most inexpensive option, yielding an average cost per quality adjusted life year of US dollars 54 (44) per dQALY, but resulted in high rates of cancer. Endoscopic surveillance dominated oesophagectomy, being both less costly and more effective. The condition of extended dominance occurred when comparing endoscopic ablation to endoscopic surveillance because, although the total costs of ablation were greater than those of surveillance, it was less expensive to buy an additional life year using endoscopic ablation than endoscopic surveillance. The incremental cost effectiveness ratio when moving from no therapy to ablative therapy was a reasonable US dollars 25 621/dQALY (21 009/dQALY). Sensitivity analysis demonstrated that when yearly rates of progression to cancer from HGD exceeded 30%, oesophagectomy became the most cost effective option. CONCLUSIONS: A strategy of endoscopic ablation provided the longest quality adjusted life expectancy for BO with HGD. Although endoscopic surveillance was less expensive than endoscopic ablation, it was associated with shorter survival. Optimal utilisation of healthcare resources may be achieved with endoscopic ablative therapy for BO with HGD.
Barrett Esophagus↗
Breathing circuit obstruction by a foreign body.
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Adult↗
Clostridium difficile-associated diarrhoea after internal fixation of intertrochanteric femoral fractures.
The aim of the study presented here was to record the incidence and outcome of Clostridium difficile-associated diarrhoea in patients undergoing surgery for intertrochanteric femoral fractures. Between January 2000 and June 2001, a total of 239 patients who underwent surgery after sustaining an intertrochanteric femoral fracture were included in the study. Seventeen patients developed Clostridium difficile-associated diarrhoea (incidence risk, 7.1%), and six patients died after developing the condition (case fatality rate, 35%). Thus, Clostridium difficile-associated diarrhoea was found to cause significant morbidity and mortality after surgery for intertrochanteric femoral fractures, and antibiotics should be used judiciously in this group of patients.
Age Distribution↗
Review article: endoscopic treatments for gastro-oesophageal reflux disease.
A number of endoscopic techniques have been described for the treatment of reflux disease. These include endoscopic plicators, which place submucosal or transmural sutures around the lower oesophageal sphincter, the Stretta procedure, which places minute areas of thermal injury in the muscle of the lower oesophageal sphincter and cardia, and injection techniques, in which inert substances are injected into the mucosa or the muscle of the lower oesophagus. The mechanism of action of these procedures has been studied to varying degrees. The Stretta procedure is the only endoscopic technique that has been shown to be effective in a sham-controlled trial. Complication rates are generally low, but serious complications have been reported in some cases. The results with some of these techniques are promising, but all procedures described to date are limited by the absence of large, rigorously controlled trials against a form of treatment that has been proven to be both safe and effective (medical therapy). Future studies will need to use controls, validated outcome measures and pre-determined end-points and to provide comparative and long-term data.
Biomarkers↗
Role of ascorbic acid in the modulation of inhibition of platelet aggregation by polymorphonuclear leukocytes.
OBJECTIVES: We investigated the modulatory effect of ascorbate on the inhibition of platelet aggregation response by polymorphonuclear leukocytes (PMNs) and characterized the mechanism of the inhibitory response. BACKGROUND: PMNs have been reported to play a significant role in vascular homeostasis by releasing various factors including short-lived reactive oxygen species (ROS) and nitric oxide (NO). NO prevents the activation of circulating platelets and plays a significant role in hemostasis. In addition, PMNs also have the capacity to store very high concentrations of ascorbate. The physiological implications of storing such high concentrations of an antioxidant by a cell-releasing free radicals is unknown, viz. a viz. hemostatic regulation. METHODS: ADP-induced aggregation in human, monkey and rat platelet-rich plasma (PRP) was monitored in the presence of PMNs treated with varying concentrations of ascorbate/dehydroascorbate. NO generation from rat and human PMNs treated with ascorbate was monitored on a FACS Calibur flow cytometer and intraplatelet cyclic guanosine 3',5'-monophosphate (cGMP) levels was also measured. RESULTS: PMNs induced a cell number and time-dependent inhibition of ADP-induced aggregation. The PMNs dependent inhibition was enhanced significantly at 30 min by ascorbate (300 microM). Ascorbate seemed to exert its effects through its oxidized product, dehydroascorbate, as the effects was prevented in the presence of D-glucose (10 mM). Dehydroascorbate elicited significant potentiation of the PMNs induced inhibitory responses and these effects were mediated by the release of NO and subsequent activation of platelet guanylyl cyclase. Flow cytometry experiments with human and rat PMNs confirmed the release of NO and the elevated platelet cGMP levels confirmed NO-mediated activation of guanylyl cyclase. CONCLUSIONS: Ascorbate in circulation seems to prevent the activation of platelets by enhancing the release of antiaggregatory NO, from neighbouring or cohabitant PMNs. The ascorbate effect is mediated through its conversion to dehydroascorbate, subsequently, gets taken up by the cell and converted back to ascorbate. Intracellular ascorbate potentiates the release of NO from the PMNs and subsequently activates guanylyl cyclase in the platelets.
Adenosine Diphosphate↗
Hypodiploidy of 37 chromosomes in an adult patient with acute lymphoblastic leukemia.
We present a 42-year-old man with acute lymphoblastic leukemia and hypodiploidy at diagnosis. Chromosome count was 37, with a mixture of numerical and structural abnormalities. The patient died 9 months post diagnosis, during which time three further cytogenetic tests were performed. The core abnormalities seen upon diagnosis were present at 7 and 9 months after diagnosis, with a duplication of the abnormal hypodiploid karyotype on the last specimen. While considerable imbalances were present as a result of whole chromosome aneuploidy, no region was obviously nullisomic.
Adult↗
Prophylactic potential of autoclaved Leishmania donovani with BCG against experimental visceral leishmaniasis.
The prophylactic efficacy of autoclaved Leishmania donovani (ALD) and autoclaved L. major (ALM)--a heterologous vaccine developed against cutaneous leishmaniasis (used as a reference vaccine), along with BCG--was evaluated against L. donovani in hamsters (Mesocricetus auratus). Animals were immunized with triple doses (21 days apart) of either ALD or ALM (1.0 mg) with or without BCG (0.1 mg) and challenged 21 days later with 1 x 10(6) L. donovani amastigotes intracardially. Animals immunized with ALM + BCG and ALD + BCG yielded 94.3% and 86.1% parasite inhibition respectively in comparison to the BCG only and unvaccinated controls. Fifty and 33.3% of the vaccinated animals (ALM + BCG and ALD + BCG respectively) were completely devoid of parasites when tested on day 45 post-challenge (p.c.) and survived till the experiment was terminated. The mean survival of ALM + BCG and ALD + BCG groups (animals harbouring parasites) was longest (168 and 139 days respectively). No significant increase in anti-leishmanial antibody level (ELISA) was noticed in ALD + BCG and ALM + BCG groups whereas it increased progressively in the rest of the experimental groups. The lymphoproliferative responses to PHA and Con A, of the 2 vaccinated groups were comparable to that of normal controls on day 45 p.c. The study suggests that ALD along with BCG can offer substantial protection against visceral leishmaniasis in hamsters.
Animals↗
Review article: Helicobacter pylori and reflux disease.
The falling prevalence of Helicobacter pylori infection and related diseases (peptic ulcer disease, gastric cancer) in developed countries has been paralleled by an increased recognition of gastro-oesophageal reflux and its complications. These epidemiological data do not support a role for H. pylori in the pathogenesis of reflux disease, but suggest a negative association with the increasing incidence of oesophageal diseases. This has led some investigators to propose a 'protective' role of H. pylori infection against the development of oesophageal diseases. In these patients, pre-existing lower oesophageal sphincter dysfunction, susceptibility to reflux, unmasking of latent reflux and the patterns and severity of gastritis are probably important factors contributing to the development of oesophageal diseases. The most likely mechanism by which H. pylori infection may protect against reflux is by decreasing the potency of the gastric refluxate in patients with corpus-predominant gastritis. The prevalence of H. pylori infection in patients with reflux disease is probably no greater than that in those without reflux, and there are conflicting data indicating that reflux symptoms or erosive oesophagitis develop after H. pylori eradication. It is also unclear whether H. pylori augments the antisecretory effects of proton pump inhibitors or accelerates the development of atrophic gastritis.
Adenocarcinoma↗
Intracellular expression of Mycobacterium tuberculosis-specific 10-kDa antigen down-regulates macrophage B7.1 expression and nitric oxide release.
To explore the role of the 10-kDa Mycobacterium tuberculosis-specific secreted antigen (MTSA-10 or CFP-10) in modulation of macrophage function, J774 macrophages were transfected stably with DNA encoding MTSA-10. Compared to normal or mock-transfected controls, MTSA-10-expressing macrophages had markedly lower levels of co-stimulatory molecule B7.1 on their surface, while the expression of B7.2 and ICAM-1 was not affected. MTSA-transfected cells also produced significantly less microbicidal free radical nitric oxide (NO) upon stimulation with interferon (IFN)-gamma, lipopolysaccharide or M. tuberculosis cell lysate. Western blot analysis revealed the absence of tyrosine-phosphorylated protein slightly larger than 112 kDa in MTSA-transfected macrophages. Moreover, the treatment of control J774 cells with protein tyrosine kinase inhibitor genistein completely mimicked the effects of transfection with MTSA-10, selectively down-regulating NO and B7.1, but not B7.2 or ICAM-1 expression. The observed MTSA-10-mediated block of B7.1 expression and NO release might contribute to the suppression of antimycobacterial response in tuberculosis.
Animals↗
Magnification chromoendoscopy for the detection of intestinal metaplasia and dysplasia in Barrett's oesophagus.
BACKGROUND: The presence of intestinal metaplasia (IM) in the columnar lined distal oesophagus defines Barrett's oesophagus with the risk of future malignant transformation. The distribution of both IM and dysplasia (low grade (LGD) and high grade (HGD)) within the columnar lined oesophagus is patchy and mosaic requiring random biopsies. Techniques that could help target areas of high yield within Barrett's mucosa would be helpful. AIM: To study the utility of high magnification chromoendoscopy (MCE) in the detection of IM, LGD, and HGD in patients with Barrett's oesophagus. METHODS: Consecutive patients detected with columnar mucosa in the distal oesophagus were studied using an Olympus magnification endoscope (GIF-Q16OZ, 115x). The distal oesophagus was sprayed with indigo carmine solution and the oesophageal columnar mucosa patterns were noted under high magnification and targeted for biopsy. All biopsies were read by pathologists blinded to the endoscopic findings. RESULTS: Eighty patients with suspected Barrett's oesophagus (that is, columnar lined distal oesophagus) were studied: mean age 62.7 years (range 35-81). Mean length of columnar mucosa was 3.7 cm (range 0.5-17). Three types of mucosal patterns were noted within the columnar mucosa after spraying indigo carmine and using MCE: ridged/villous pattern, circular pattern, and irregular/distorted pattern. The yield of IM on target biopsies according to the patterns was: ridged/villous 57/62 (97%) and circular 2/12 (17%). Six patients had an irregular/distorted pattern and all had HGD on biopsy (6/6 (100%)). Eighteen patients had LGD on target biopsies; all had the ridged/villous pattern. All patients with long segment Barrett's were identified using MCE whereas 23/28 patients (82%) with short segment Barrett's had the ridged/villous pattern. CONCLUSIONS: MCE helps visually identify areas with IM and HGD having specific patterns but not patients with LGD (appear similar to IM). MCE may be a useful clinical tool for the increased detection of patients with IM as well as for surveillance of patients for the detection of HGD. If these preliminary results are validated, MCE would help identify high yield areas, potentially eliminating the need for random biopsies.
Adult↗
Presumptive artemether resistance in a patient with mixed malarial infection.
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Animals↗