Contrast-enhanced ultrasound evaluation of hepatic microvascular changes in liver diseases

AIM： To assess if software assisted-contrast-enhanced ultrasonography （CEUS） provides reproducible perfu- sion parameters of hepatic parenchyma in patients af- fected by chronic liver disease. METHODS： Forty patients with chronic viral liver dis- ease, with （n = 20） or without （n = 20） cirrhosis, and 10 healthy subjects underwent CEUS and video re- cordings of each examination were then analysed with Esaote＇s Qontrast software. CEUS dedicated software Qontrast was used to determine peak （the maximum signal intensity）, time to peak （TTP）, region of blood value （RBV） proportional to the area under the time- intensity curve, mean transit time （MTT） measured in seconds and region of blood flow （RBF）. RESULTS： Qontrast-assisted CEUS parameters dis- played high inter-observer reproducibility （κ： coefficients of 0.87 for MTT and 0.90 TTP）. When the region of in-terest included a main hepatic vein, Qontrast-calculated TTP was significantly shorter in cirrhotic patients （vs non-cirrhotics and healthy subjects） （71.0 ± 11.3 s vs 82.4±15.6 s, 86.3±20.3 s, P 〈 0.05）. MTIs in the patients with liver cirrhosis were significantly shorter than those of controls （111.9±22.0 s vs 139.4±39.8 s, P 〈 0.05）, but there was no significant difference between the cirrhotic and non-cirrhotic groups （111.9± 22.0 s vs 110.3 ±14.6 s）. Peak enhancement in the patients with liver cirrhosis was also higher than that observed in controls （23.9± 5.9 vs 18.9±7.1, P = 0.05）. There were no significant intergroup differences in the RBVs and RBFs. CONCLUSION： Qontrast-assisted CEUS revealed re- producible differences in liver perfusion parameters during the development of hepatic fibrogenesis.

New era of colorectal cancer screening

Colorectal cancer(CRC) is the 2^(nd) most common cancer in women and 3^(rd) most common cancer in men worldwide. Most CRCs develop from adenomatous polyps arising from glandular epithelium. Tumor growth is initiated by mutation of the tumor suppressor gene APC and involves other genetic mutations in a stepwise process over years. Both hereditary and environmental factors contribute to the development of CRC. Screening has been proven to reduce the incidence of CRC. Screening has also contributed to the decrease in CRC mortality in the United States. However,CRC incidence and/or mortality remain on the rise in some parts of the world(Eastern Europe,Asia,and South America),likely due to factors including westernized diet,lifestyle,and lack of healthcare infrastructure. Multiple screening options are available,ranging from direct radiologic or endoscopic visualization tests that primarily detect premalignant or malignant lesions such as flexible sigmoidoscopy,optical colonoscopy,colon capsule endoscopy,computed tomographic colonography,and double contrast barium enema- to stool based tests which primarily detect cancers,including fecal DNA,fecal immunochemical test,and fecal occult blood test. The availability of some of these tests is limited to areas with high economic resources. This article will discuss CRC epidemiology,pathogenesis,risk factors,and screening modalities with a particular focus on new technologies.

Optimal management of biopsy-proven low-grade gastric dysplasia

Gastric adenocarcinoma generally culminates via the inflammation-metaplasia-dysplasia-carcinoma sequence progression. The prevalence of gastric adenomas shows marked geographic variation. Recently, the rate of diagnosis of low-grade dysplasia(LGD) has increased due to increased use of upper endoscopy. Many investigators have reported that gastric highgrade dysplasia has high potential for malignancy and should be removed; however, the treatment for gastric LGD remains controversial. Although the risk of LGD progression to invasive carcinoma has been reported to be inconsistent, progression has been observed during follow-up. Additionally, the rate of upgraded diagnosis in biopsy-proven LGD is high. Therefore, endoscopic resection(ER) may be useful in the treatment and diagnosis of LGD, especially if lesions are found to have risk factors for upgraded histology after ER, such as large size, surface erythema or depressed morphology. Fatal complications in endoscopic submucosal dissection(ESD) are extremely low and its therapeutic and diagnostic outcomes are excellent. Therefore, ESD should be applied preferentially instead of endoscopic mucosal resection.

Is acute recurrent pancreatitis a chronic disease?

Whether acute recurrent pancreatitis is a chronic disease is still debated and a consensus is not still reached as demonstrated by differences in the classification of acute recurrent pancreatitis. There is major evidence for considering alcoholic pancreatitis as a chronic disease ab initio while chronic pancreatitis lesions detectable in biliary acute recurrent pancreatitis (ARP) seem a casual association. Cystic fibrosis transmembrane con-ductance regulator (CFTR) gene mutation, hereditary and obstructive pancreatitis seem an acute disease that progress to chronic pancreatitis, likely as a consequence of the activation and proliferation of pancreatic stellate cells that produce and activate collagen and therefore fibrosis. From the diagnostic point of view, in patients with acute recurrent pancreatitis Endoscopic ultrasound (EUS) seems the more reliable technique for an accurate evaluation and follow-up of some ductal and parenchymal abnormalities suspected for early chronic pancreatitis.

Endoscopic closure of a gastrocolic fistula using the over-the-scope-clip-system

Gastrointestinal (GI) defects such as fistulas and leaks can be potentially closed endoscopically using hemo-clips and loops. However, hemoclips may not allow for closure of large defects and they do not exert enough tensile force to keep fibrotic defects larger than 5 mm approximated. Herein we present a case of successful endoscopic closure of a gastrocolic fistula in a severely malnourished patient with complex post-surgical upper GI anatomy. We strongly believe that this device is a major breakthrough for the management of various types of discontinuity defects or fistulas. In addition, we show the usefulness of placing a direct jejunostomy using the double balloon enteroscopy (DBE) technique during the same procedure. The concept of providing direct jejunal feedings while allowing for upper gas-trointestinal bowel rest to promote the healing of the minimally invasive endoscopic operation is novel. Thus, our case is unique and exemplifies the utility of mini-mally invasive endoscopic endoluminal surgery.

Pharmacotherapy for the management of achalasia: Current status, challenges and future directions

This article reviews currently available pharmacological options available for the treatment of achalasia, with a special focus on the role of botulinum toxin(BT) injection due to its superior therapeutic effect and side effect profile. The discussion on BT includes the role of different BT serotypes, better pharmacological formulations, improved BT injection techniques, the use of sprouting inhibitors, designer recombinant BT formulations and alternative substances used in endoscopic injections. The large body of ongoing research into achalasia and BT may provide a stronger role for BT injection as a form of minimally invasive, cost effective and efficacious form of therapy for patients with achalasia. The article also explores current issues and future research avenues that may prove beneficial in improving the efficacy of pharmacological treatment approaches in patients with achalasia.

Heterogeneity of endoscopy negative heartburn:Epidemiology and natural history

It has now become clear that only about 40% or less of patients with heartburn and/or regurgitation have esophagitis, and that the majority of them lack visible distal esophageal mucosa breaks. These subjects are referred to as non-erosive gastroesophageal reflux disease (NERD) patients. It has been estimated that in the Western world at least one tenth of the general population has at least weekly heartburn. This proportion seems to be lower in Asia, while prevalence is rapidly increasing. Although it would be extremely useful to have prospective information regarding the fate of such patients, the natural history of NERD is largely unknown, and very few studies in the literature have addressed this issue. These studies are for the greater part old, not well conducted, and suffer from methodological drawbacks including ill-defined entry criteria. However, a review of these studies indicates that a consistent minority of NERD patients may develop erosive disease at an approximate rate of about 10% per year.

Inhibition of gastric perception of mild distention by omeprazole in volunteers

AIM： To evaluate the effects of omeprazole on gastric mechanosensitivity in humans. METHODS： A double lumen polyvinyl tube with a plas- tic bag was introduced into the stomach of healthy volunteers under fluorography and connected to a barostat device. Subjects were then positioned so they were sitting comfortably, and the minimal distending pressure （MDP） was determined after a 30-rain adap- tation period. Isobaric distensions were performed in stepwise increments of 2 mmHg （2 min each） starting from the MDR Subjects were instructed to score feel- ings at the end of every step using a graphic rating scale： 0, no perception; 1, weak/vague; 2, weak but significant; 3, moderate/vague; 4, moderate but signifi- cant; 5, severe discomfort; and 6, unbearable pain. Af- ter this first test, subjects received omeprazole （20 mg, after dinner） once daily for 1 wk. A second test was performed on the last day of treatment. RESULTS： No adverse effects were observed. Mean MDP before and after treatment was 6.3 - 0.3 mmHg and 6.2：1：0.5 mmHg, respectively. One subject before and 2 after treatment did not reach a score of 6 at the maximum bag volume of 750 mL. After omeprazole, there was a significant increase in the distension pres- sure required to reach scores of 1 （P = 0.019） and 2 （P = 0.017） as compared to baseline. There were no changes in pressure required to reach the other scores after treatment. Two subjects before and one after omeprazole rated their abdominal feeling 〈 1 at MDP, and mean （±SE） abdominal discomfort scores at MDP were 0.13±0.09 and 0.04±0.04, respectively. Mean scores induced by each MDP ＋ 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20 （mmHg） were 1.1±0.3, 2.0±0.4, 2.9±0.5, 3.3±0.4, 4.6±0.3, 5.2±0.3, 5.5±0.2, 5.5±0.3, 5.7±0.3, and 5.4, respectively. After omepra- zole, abdominal feeling scores for the same incremen- tal pressures over MDP were 0.3±0.1, 0.8±0.1, 2.0±0.4, 2.8±0.4, 3.8±0.4, 4.6±0.4, 4.9±0.3, 5.4±0.4, 5.2±0.6, and 5.0±1.0, respectively. A signif- icant decrease in feeling score was observed at intra- bag pressures of MDP ＋ 2 mmHg （P = 0.028） and ＋ 4 mmHg （P = 0.013）, respectively, after omeprazole. No significant score changes were observed at pres- sures ≥ MDP ＋ 6 mmHg. CONCLUSION： Although the precise mechanisms are undetermined, the present study demonstrated that omeprazole decreases mechanosensitivity to mild gas- tric distension.

Treatment of severe steroid refractory ulcerative colitis

Although systemic steroids are highly efficacious in ulcerative colitis (UC), failure to respond to steroids still poses an important challenge to the surgeon and physician alike. Even if the life time risk of a fulminant UC flare is only 20%, this condition is potentially life threatening and should be managed in hospital. If patients fail 3 to 5 d of intravenous corticosteroids and optimal supportive care, they should be considered for any of three options: intravenous cyclosporine (2 mg/kg for 7 d, and serum level controlled), infliximab (5 mg/kg Ⅳ, 0-2-6 wk) or total colectomy. The choice between these three options is a medical- surgical decision based on clinical signs, radiological and endoscopic findings and blood analysis (CRP, serum albumin). Between 65 and 85% of patients will initially respond to cyclosporine and avoid colectomy on the short term. Over 5 years only 50% of initial responders avoid colectomy and outcomes are better in patients naive to azathioprine (bridging strategy). The data on infliximab as a medical rescue in fulminant colitis are more limited although the efficacy of this anti tumor necrosis factor (TNF) monoclonal antibody has been demonstrated in a controlled trial. Controlled data on the comparative efficacy of cyclosporine and infliximab are not available at this moment. Both drugs are immunosuppressants and are used in combination with steroids and azathioprine, which infers a risk of serious, even fatal, opportunistic infections. Therefore, patients not responding to these agents within 5-7 d should be considered for colectomy and responders should be closely monitored for infections.

Urinary metabolites as noninvasive biomarkers of gastrointestinal diseases:A clinical review

The diagnosis of gastrointestinal(GI) disorders is usually based on invasive techniques such as endoscopy.A key important factor in GI cancer is early diagnosis which warrants development of non-or lessinvasive diagnostic techniques.In addition,monitoring and surveillance are other important parts in the management of GI diseases.Metabolomics studies with nuclear magnetic resonance and mass spectrometry can measure the concentration of more than 3000 chemical compounds in the urine providing possible chemical signature in different diseases and during health.In this review,we discuss the urinary metabolomics signature of different GI diseases including GI cancer and elaborate on how these biomarkers could be used for the classification,early diagnosis and the monitoring of the patients.Moreover,we discuss future directions of this still evolving field of research.

Acute cytomegalovirus infection in liver transplant recipients:An independent risk for venous thromboembolism

Acute cytomegalovirus(CMV) infection is a commonly encountered complication in the post liver transplant setting. We present a case of a 71-year-old male with acute CMV infection, initially presenting with a gastro- intestinal bleed due to acute CMV gastritis and later on complicated by acute venous thromboembolism occur- ring as an unprovoked event in the post liver transplant period. Traditional risk factors for venous thromboem- bolism have been well described in the medical litera- ture. Sporadic cases of thromboembolism due to CMV infection in the immune compromised patients have been described, especially in the post kidney transplant patients. Liver transplant recipients are equally prone to CMV infection particularly in the first year after suc- cessful transplantation. Venous thromboembolism in this special population is particularly challenging due to the fact that these patients may have persistent throm- bocytopenia and anticoagulation may be a challenge for the treating physician. Since liver transplantation is severely and universally limited by the availability of donor organs, we feel that this case report will provide valuable knowledge in the day to day management of these patients, whose clinical needs are complex and require a multidisciplinary approach in their care and management. Evidence and pathophysiology link- ing both the conditions is presented along with a brief discussion on the management, common scenarios en- countered and potential impact in this special group of patients.

Uncoupling protein 2 deficiency reduces proliferative capacity of murine pancreatic stellate cells

BACKGROUND： Uncoupling protein 2 （UCP2） has been suggested to inhibit mitochondrial production of reactive oxygen species （ROS） by decreasing the mitochondrial membrane potential. Experimental acute pancreatitis is associated with increased UCP2 expression, whereas UCP2 deficiency retards regeneration of aged mice from acute pancreatitis. Here, we have addressed biological and molecular functions of UCP2 in pancreatic stellate cells （PSCs）, which are involved in pancreatic wound repair and fibrogenesis. METHODS： PSCs were isolated from 12 months old （aged） UCP2^-/- mice and animals of the wild-type （WT） strain C57BL/6. Proliferation and cell death were assessed by em- ploying trypan blue staining and a 5-bromo-2＇-deoxyuridine incorporation assay. Intracellular fat droplets were visualized by oil red O staining. Levels of mRNA were determined by RT-PCR, while protein expression was analyzed by immunoblotting and immunofluorescence analysis. Intracellular ROS levels were measured with 2＇,7＇-dichlorofluorescin diacetate. Expression of senescence-associated β-galactosidase （SA β-Gal） was used as a surrogate marker of cellular senescence. RESULTS： PSCs derived from UCP2^-/- mice proliferated at a lower rate than cells from WT mice. In agreement with this observation, the UCP2 inhibitor genipin displayed dose- dependent inhibitory effects on WT PSC growth. Interestingly, ROS levels in PSCs did not differ between the two strains, and PSCs derived from UCP2^-/- mice did not senesce faster than those from corresponding WT cells. PSCs from UCP2^-/- mice and WT animals were also indistinguishable with respect to the activation-dependent loss of intracellular fat droplets, expression of the activation marker α-smooth muscle actin, type I collagen and the autocrine/paracrine mediators interleukin-6 and transforming growth factor-I~ 1. CONCLUSIONS： A reduced proliferative capacity of PSC from aged UCP2^-/- mice may contribute to the retarded regeneration after acute pancreatitis. Apart from their slower growth, PSC of UCP2^-/- mice displayed no functional abnormalities. The antifibrotic potential of UCP2 inhibitors deserves further attention.

＂LOCK＂ing up allergic responses with a Polish probiotic

Three relatively new lactobacillus species that were developed from fecal samples of a 26-year-old woman （LOCK0900）, a 6-year-old girl （LOCK 0908）, and a 5-year-old boy （LOCK 0919） have been studied by Kozakova et al.a in an attempt to define the mechanism by which the probiotics modify the allergic response.