An expert consensus to standardise definitions, diagnosis and treatment targets for anti-fibrotic stricture therapies in Crohn's disease.

BACKGROUND: Fibrotic stricture is a common complication of Crohn's disease (CD) affecting approximately half of all patients. No specific anti-fibrotic therapies are available; however, several therapies are currently under evaluation. Drug development for the indication of stricturing CD is hampered by a lack of standardised definitions, diagnostic modalities, clinical trial eligibility criteria, endpoints and treatment targets in stricturing CD. AIM: To standardise definitions, diagnosis and treatment targets for anti-fibrotic stricture therapies in Chron's disease. METHODS: An interdisciplinary expert panel consisting of 15 gastroenterologists and radiologists was assembled. Using modified RAND/University of California Los Angeles appropriateness methodology, 109 candidate items derived from systematic review and expert opinion focusing on small intestinal strictures were anonymously rated as inappropriate, uncertain or appropriate. Survey results were discussed as a group before a second and third round of voting. RESULTS: Fibrotic strictures are defined by the combination of luminal narrowing, wall thickening and pre-stenotic dilation. Definitions of anastomotic (at site of prior intestinal resection with anastomosis) and naïve small bowel strictures were similar; however, there was uncertainty regarding wall thickness in anastomotic strictures. Magnetic resonance imaging is considered the optimal technique to define fibrotic strictures and assess response to therapy. Symptomatic strictures are defined by abdominal distension, cramping, dietary restrictions, nausea, vomiting, abdominal pain and post-prandial abdominal pain. Need for intervention (endoscopic balloon dilation or surgery) within 24-48 weeks is considered the appropriate endpoint in pharmacological trials. CONCLUSIONS: Consensus criteria for diagnosis and response to therapy in stricturing Crohn's disease should inform both clinical practice and trial design.

Soil Methane and Carbon Dioxide Fluxes from Cropland and Riparian Buffers in Different Hydrogeomorphic Settings.

Riparian buffers contribute to the mitigation of nutrient pollution in agricultural landscapes, but there is concern regarding their potential to be hot spots of greenhouse gas production. This study compared soil CO and CH fluxes in adjacent crop fields and riparian buffers (a flood-prone forest and a flood-protected grassland along an incised channel) and examined the impact of water table depth (WTD) and flood events on the variability of gas fluxes in riparian zones. Results showed significantly ( < 0.001) higher CO emission in riparian areas than in adjoining croplands (6.8 ± 0.6 vs. 3.6 ± 0.5 Mg CO-C ha yr; mean ± SE). Daily flux of CO and soil temperature were significantly related ( < 0.002), with Q values ranging between 1.75 and 2.53. Significant relationships ( < 0.05) were found between CH daily flux and WTD. Flood events resulted in enhanced CH emission (up to +44.5 mg CH-C m d in a swale) under warm soil conditions (>22°C), but the effect of flooding was less pronounced in early spring (emission <1.06 mg CH-C m d), probably due to low soil temperature. Although CH flux direction alternated at all sites, overall the croplands and the flood-affected riparian forest were CH sources, with annual emission averaging +0.04 ± 0.17 and +0.92 ± 1.6 kg CH-C ha, respectively. In the riparian forest, a topographic depression (<8% of the total area) accounted for 78% of the annual CH emission, underscoring the significance of landscape heterogeneity on CH dynamics in riparian buffers. The nonflooded riparian grassland, however, was a net CH sink (-1.08 ± 0.22 kg CH-C ha yr), probably due to the presence of subsurface tile drains and a dredged/incised channel at that study site. Although these hydrological alterations may have contributed to improvement in the CH sink strength of the riparian grassland, this must be weighed against the water quality maintenance functions and other ecological services provided by riparian buffers.

Timed barium esophagram in achalasia types.

Relationships of timed barium esophagram (TBE) findings to achalasia types defined by high-resolution manometry (HRM) have not been elucidated. Therefore, we correlated preoperative TBE and HRM measurements in achalasia types and related these to patient symptoms and prior treatments. From 2006 to 2013, 248 achalasia patients underwent TBE and HRM before Heller myotomy. TBE height and width were recorded at 1 and 5 minutes; HRM measured lower esophageal sphincter mean basal pressure, integrated relaxation pressure (IRP), and mean esophageal body contraction amplitude. Achalasia was classified into types I (25%), II (65%), and III (9.7%). TBE height at 5 minutes was higher for I (median 8 cm; interquartile range 6-12) and II (8 cm; 8-11) than for III (1 cm; 0-7). TBE width at 5 minutes was widest (3 cm; 2-4), narrower in II (2 cm; 2-3), and narrowest in I (1 cm; 0-2), P < 0.001. Volume remaining at 1 and 5 minutes was lower in III (1 m(2) ; 0-16) than I (42 m(2) ; 17-106) and II (39 m(2) ; 15-60), highlighting poorer emptying of I and II. Increasing TBE width correlated with deteriorating morphology and function from III to II to I. Symptoms poorly correlated with TBE and HRM. Prior treatment was associated with less regurgitation, faster emptying, and lower IRP. Although TBE and HRM are correlated in many respects, the wide range of their measurements observed in this study reveals a spectrum of morphology and dysfunction in achalasia that is best characterized by the combination of these studies.

Comparison of radiation dose and image quality from single-energy and dual-energy CT examinations in the same patients screened for hepatocellular carcinoma.

AIM: To compare radiation dose surrogates [volume CT dose index (CTDIvol), dose-length product (DLP), size-specific dose estimate (SSDE), and effective dose] and image noise in a cohort of patients undergoing hepatocellular carcinoma screening who underwent both single-energy CT (SECT) and dual-energy CT (DECT). MATERIALS AND METHODS: In this institutional review board-approved, Health Insurance Portability and Accountability Act-compliant retrospective study, 74 adults (mean age 59.5 years) underwent 64 section SECT (120 kVp and weight-based reference mAs) and 128 section dual-source DECT (100/Sn 140 kVp and CTDIvol, adjusted to match the CDTIvol of the SECT protocol) on different occasions. Noise levels were measured in the liver, inferior vena cava (IVC), retroperitoneal (RP) fat, and aorta. Generalized linear models were constructed to compare dose and noise, adjusting for effective diameter. RESULTS: The total DLP (1371.11 mGy-cm, SD = 527.91) and effective dose (20.57 mSv, SD = 7.92) with SECT were significantly higher than the DLP (864.84 mGy-cm, SD = 322.10) and effective dose (12.97 mSv, SD = 4.83) with DECT (p < 0.001). The differences between SECT and DECT increased as the patient's effective diameter increased (p < 0.001). Noise levels in the liver (22.4 versus 21.9 HU), IVC (22.3 versus 23.4 HU), and RP fat (23.5 versus 23 HU) were similar for DECT and SECT (p > 0.05) but were significantly lower in the aorta for DECT (25.3 versus 26.4 HU; p = 0.006). CONCLUSION: DECT imaging of the abdomen can achieve noise levels comparable to those seen with SECT imaging without a dose penalty to patients.

Nitrous oxide emission from cropland and adjacent riparian buffers in contrasting hydrogeomorphic settings.

Riparian buffers are important nitrate (NO) sinks in agricultural watersheds, but limited information is available regarding the intensity and control of nitrous oxide (NO) emission from these buffers. This study monitored (December 2009-May 2011) NO fluxes at two agricultural riparian buffers in the White River watershed in Indiana to assess the impact of land use and hydrogeomorphologic (HGM) attributes on emission. The study sites included a riparian forest in a glacial outwash/alluvium setting (White River [WR]) and a grassed riparian buffer in tile-drained till plains (Leary Weber Ditch [LWD]). Adjacent corn ( L.) fields were monitored for land use assessment. Analysis of variance identified season, land use (riparian buffer vs. crop field), and site geomorphology as major drivers of NO fluxes. Strong relationships between N mineralization and NO fluxes were found at both sites, but relationships with other nutrient cycling indicators (C/N ratio, dissolved organic C, microbial biomass C) were detected only at LWD. Nitrous oxide emission showed strong seasonal variability; the largest NO peaks occurred in late spring/early summer as a result of flooding at the WR riparian buffer (up to 27.8 mg NO-N m d) and N fertilizer application to crop fields. Annual NO emission (kg NO-N ha) was higher in the crop fields (WR: 7.82; LWD: 6.37) than in the riparian areas. A significant difference ( < 0.02) in annual NO emission between the riparian buffers was detected (4.32 vs. 1.03 kg NO-N ha at WR and LWD, respectively), and this difference was attributed to site geomorphology and flooding (WR is flood prone; no flooding occurred at tile-drained LWD). The study results demonstrate the significance of landscape geomorphology and land-stream connection (i.e., flood potential) as drivers of NO emission in riparian buffers and therefore argue that an HGM-based approach should be especially suitable for determination of regional NO budget in riparian ecosystems.

Coronary angiographic profile in bangladeshi patients with metabolic syndrome and ischemic heart disease.

The metabolic syndrome, which is characterized by a constellation of fasting hyperglycemia, hypertriglyceridemia, low HDL cholesterol, hypertension, and/or abdominal obesity, is a risk factor for the development of coronary artery disease (CAD) and cardiovascular events. We evaluated interrelationships between angiographic CAD and the metabolic syndrome, in 478 patients who were referred for coronary angiography to evaluate suspected myocardial ischemia in the department of cardiology of BSMMU between June 2007 and May 2008. We applied the criteria for the metabolic syndrome proposed by ATP III guideline. Study populations were divided into two groups on the basis of presence or absence of metabolic syndrome. Age was similar in both groups. Body mass index (BMI) was higher (26.22 ± 1.94 vs. 22.07 ± 1.55) in metabolic syndrome group (p ≤ 0.0001). All parameters, waist circumference (103.16 ± 10.21 vs. 91.45 ± 7.61) cm, blood pressure both systolic (141.34 ± 21.49 vs. 127.94 ± 13.01) and diastolic (86.8 5 ± 8.42 vs. 79.28 ± 7.77) mm of Hg, serum triglyceride (248.32 ± 77.88 vs. 128.35 ± 19.00)mg/dl, fasting blood glucose (125.40 ± 22.86 vs. 95.65 ± 10.63)mg/dl were significantly higher in metabolic syndrome group (p value=0.0001), whereas HDL (33.10 ± 6.55 vs. 39.30 ± 6.17)mg/dl was lower (p value = 0.0001). More subjects in metabolic syndrome were having type B (55.60% vs. 31.00%) and type C (9.50% vs. 2.70%) lesion as compared to non-metabolic syndrome group. Involvement of left main artery was more (4.80% vs. 0.90%) in metabolic syndrome group. Metabolic syndrome has primary predictive ability for CAD. A metabolic profile should form part of the risk assessment in all patients with coronary disease, not just those who are obese.

Biological effects of marine contaminated sediments on Sparus aurata juveniles.

Chemical analysis of the compounds present in sediment, although informative, often is not indicative of the downstream biological effects that these contaminants exert on resident aquatic organisms. More direct molecular methods are needed to determine if marine life is affected by exposure to sediments. In this study, we used an aquatic multi-species microarray and q-PCR to investigate the effects on gene expression in juvenile sea bream (Sparus aurata) of two contaminated sediments defined as sediment 1 and 2, respectively, from marine areas in Northern Italy. Both sediments affected gene expression as evidenced by aquatic multi-species microarray analysis and q-PCR. Exposure of S. aurata juveniles to sediment 1 and sediment 2 altered expression of genes that are biomarkers for endocrine disruption. There were differences between the effects of sediment 1 and sediment 2 on gene expression in S. aurata juveniles indicating that the chemicals in the two sediments had different physiological targets. These results suggest that the classification of sediment solely on the basis of specific chemical profiles is inadequate, and not a true indicator of its potential to cause harmful effects. Our data also indicate that integration of physiochemical analysis and bioassays for monitoring the downstream harmful effects on aquatic organisms are required to gain a complete understanding of the effects of sediment on aquatic life.

Variation of the genetic expression pattern after exposure to estradiol-17beta and 4-nonylphenol in male zebrafish (Danio rerio).

There is much concern about the increasing presence in the environment of synthetic chemicals that are able to disrupt the endocrine system. Among these compounds, 4-nonylphenol (4-NP) is one of the most studied xenoestrogens, due to its widespread accumulation in water sediment and consequent presence in fatty acid of aquatic organisms. Here, we have used a zebrafish microarray representing 16,399 genes to study the effects of 4-NP and estradiol-17beta (E2) in adult male zebrafish in order to elucidate the mechanism of action of 4-NP compared with that of E2. The microarray results showed that both 4-NP and E2 induced a strong expression of vitellogenin (VTG), the sex related precursor of the yolk proteins in oviparous vertebrates. Both treatments induced elevated protein turnover upregulating genes involved in proteolysis and those that are constituents of the ribosome. Many genes regulated by 4-NP and E2 are involved in energy metabolism, oxidative stress defense mechanisms, xenobiotic metabolism, and lipid metabolism. A different pattern of expression in the two treatments was found for genes involved in oxidative stress, since E2 seems to induce the mechanism of detoxification, while 4-NP seems to inhibit this protective mechanism of the cell. Overall, these findings demonstrate that the microarray approach can contribute significantly to the understanding of expression patterns induced by E2 and 4-NP in male zebrafish. The results also demonstrate that 4-NP is able to act through an alternative pattern to that of estradiol-17beta, modulating the expression of the same genes in a different manner.

Computer-aided detection (CAD) for CT colonography: a tool to address a growing need.

Colorectal cancer is the third most common cancer in both men and women. It is estimated that in 2004, nearly 147,000 cases of colon and rectal cancer will be diagnosed in the USA, and approximately 57,000 people would die from the disease; however, only 44% of the eligible population undergoes any type of colorectal cancer screening. Many reasons have been identified for non-compliance, with key ones being patient comfort, bowel preparation and cost. Virtual colonoscopy derived from computed tomography (CT) images is gaining broader acceptance as a screening method for colorectal neoplasia. Our research suggests that computer-aided detection (CAD) as a second reader has great potential in improving polyp detection. The ColonCAD prototype presented in this paper was developed and tested on cases representative of the variability and quality in true clinical practice. Results of this study with 150 patients demonstrate that: the developed algorithm generalises well: the sensitivity for polyps > or = 6 mm is on average 90%; and the median false positive rate is a manageable 3 per volume.

Albumin, steroid hormones and the origin of vertebrates.

Albumin, the major serum protein, binds a wide variety of lipophilic compounds including steroids, other lipophilic hormones and various phytochemicals and xenobiotics that bind to receptors for steroids and other lipophilic hormones. Despite albumin's low affinity (K(d) approximately 10(-4) M to 10(-6) M) for these lipophilic compounds, the high concentration of albumin in serum makes this protein a major carrier of steroids and lipophilic hormones and a regulator of their access to receptors. Albumin also functions as a sink for xenobiotics, diminishing the binding of xenobiotics to hormone receptors and other cellular proteins. This protects animals from endocrine disruption by xenobiotics. We propose that these properties of albumin were important in protochordates and primitive vertebrates, such as jawless fish, about 600 to 530 million years ago, just before and during the Cambrian period. It is at that time that the ancestral receptors of adrenal and sex steroids - androgens, estrogens, glucocorticoids, mineralocorticoids, and progestins - arose in multicellular animals. Albumin regulated access of steroids to their receptors, as well as protecting animals from endocrine disruptors, such as phytochemicals, fungal chemicals and phenolics, and other chemicals formed at hydrothermal vents by geochemical processes. Thus, animals in which albumin expression was high had a selective advantage in regulating the steroid response and avoiding endocrine disruption by xenobiotics.

Recent insights into the origins of adrenal and sex steroid receptors.

The recent cloning by Thornton (2001) of estrogen, progesterone and corticoid receptors from lamprey provides important insights into the early evolution of adrenal and sex steroid receptors and an opportunity to elucidate the ancient steroids that regulated gene transcription. Inclusion of lamprey sequences in a steroid receptor phylogeny indicates that the estrogen receptor is the most ancient of these receptors, followed by the progesterone receptor and the corticoid receptor. Thornton proposed that estradiol was the earliest of the steroids to activate a steroid receptor. An alternative hypothesis is that a steroid in the Delta(5) pathway activated the ancestral estrogen receptor.

Timed barium oesophagram: better predictor of long term success after pneumatic dilation in achalasia than symptom assessment.

BACKGROUND: Symptom relief post pneumatic dilation is traditionally used to assess treatment success in achalasia patients. Recently, we showed that symptom relief and objective oesophageal emptying are concordant in about 70% of patients, while up to 30% of achalasia patients report near complete symptom relief despite poor oesophageal emptying of barium. AIMS: We now report the results of long term clinical follow up in these two groups of achalasia patients, assessing differences in symptomatic remission rates. METHODS: Achalasia patients undergoing pneumatic dilation since 1995 were evaluated both symptomatically and objectively at regular intervals. Pre and post dilation symptoms were recorded. Barium column height was measured five minutes after ingesting a fixed volume of barium per patient to assess oesophageal emptying. Patients who initially reported near complete symptom relief were divided into two groups based on objective findings on barium study: (1) complete oesophageal emptying (concordant group), and (2) poor oesophageal emptying (discordant group). Patients were followed prospectively for symptom recurrence. RESULTS: Thirty four patients with complete symptom relief post pneumatic dilation were identified. In 22/34 (65%) patients, the degree of symptom and barium height improvements was similar (concordant group). In 10/34 (30%) patients, there was < 50% improvement in barium height (discordant group). Significantly (p<0.001) more discordant (9/10; 90%) than concordant (2/22; 9%) patients failed therapy at the one year follow up. Seventeen of 22 (77%) concordant patients were still in remission while all discordant patients had failed therapy by six years of follow up. Length of time in symptom remission (mean (SEM)) post pneumatic dilation was significantly (p=0.001) less for the discordant group (18.0 (3.6) months) compared with the concordant group (59.0 (4.8) months). CONCLUSIONS: (1) Poor oesophageal emptying is present in nearly 30% of achalasia patients reporting complete symptom relief post pneumatic dilation. (2) The majority (90%) of these patients will fail within one year of treatment. (3) Timed barium oesophagram is an important tool in the objective evaluation of achalasia patients post pneumatic dilation.

Radiologic evaluation of the esophagus: methods and value in motility disorders and GERD.

The barium esophagram is an essential component in the workup of a patient with dysphagia and gastroesophageal reflux disease, especially when considering antireflux surgery or after such surgery. The examination requires a flexible approach with an emphasis on the motility portion of the examination. When properly performed, the examination should identify the following: normal or impaired esophageal emptying; normal or abnormal motility; the presence and type of hiatal hernia; the presence of a distal stricture or mucosal ring; and in many instances, the presence of gastroesophageal reflux. In patients after antireflux surgery, the examination should identify the following: normal of impaired esophageal emptying; normal or abnormal motility; the location, tightness, and length of the fundoplication; the presence of a recurrent hernia; and the presence of gastroesophageal reflux.

Hydroxysteroid dehydrogenases: ancient and modern regulators of adrenal and sex steroid action.

The adrenal and sex steroids receptor clade arose from an ancestral nuclear receptor in a primitive vertebrate at least 540 million years ago during the early Cambrian. At that time, these receptors had less specificity for their canonical ligands than their descendents in mammals have, which raises the question of how specificity for responses to different steroids was regulated. We propose that hydroxysteroid dehydrogenases that metabolized functional groups at different sites on steroids (e.g. C3, C11, C17 and C20) had a key role in providing specificity for steroid regulation of gene transcription in primitive vertebrates. Later, with increased physiological complexity in land animals due to innovations such as the placenta, hydroxysteroid dehydrogenases were recruited for new roles in regulating steroid-mediated physiological responses. Hydroxysteroid dehydrogenases in fish, amphibia and mammals are likely have different affinities for some xenobiotics, which needs to be considered in evaluating their hazards as endocrine disruptors.

Adrenal and sex steroid receptor evolution: environmental implications.

The nuclear receptor family responds to a diverse group of ligands, including steroids, retinoids, thyroid hormone, prostaglandins and fatty acids. Previous sequence analyses of adrenal and sex steroid receptors indicate that they form a clade separate from other nuclear receptors. However, the relationships of adrenal and sex steroid receptors to each other and to their ancestors are not fully understood. We have used new information from androgen, estrogen, mineralocorticoid and progesterone receptors in fish to better resolve the phylogeny of adrenal and sex steroid receptors. Sequence divergence between fish and mammalian steroid receptors correlates with differences in steroid specificity, suggesting that phylogeny needs to be considered in evaluating the endocrine effects of xenobiotics. Among the vertebrate steroid receptors, the most ancient is the estrogen receptor. The phylogeny indicates that adrenal and sex steroid receptors arose in a jawless fish or a protochordate and that changes in the sequence of the hormone-binding domain have slowed considerably in land vertebrates. The retinoid X receptor clade is closest to the adrenal and sex steroid receptor clade. Retinoid X receptor is noteworthy for its ability to form dimers with other nuclear receptors, an important mechanism for regulating the action of retinoid X receptor and its dimerization partners. In contrast, the adrenal and sex steroid receptors bind to DNA as homodimers. Moreover, unliganded adrenal and sex steroid receptors form complexes with heat shock protein 90. Thus, the evolution of adrenal and sex steroid receptors involved changes in protein-protein interactions as well as ligand recognition.

Evolution of 17beta-hydroxysteroid dehydrogenases and their role in androgen, estrogen and retinoid action.

17beta-Hydroxysteroid dehydrogenases (17beta-HSDs) regulate androgen and estrogen concentrations in mammals. By 1995, four distinct enzymes with 17beta-HSD activity had been identified--17beta-HSD-types 1 and 3, which, in vivo, are NADPH-dependent reductases; and 17beta-HSD-types 2 and 4, which, in vivo, are NAD(+)-dependent oxidases. Since then, six additional enzymes with 17beta-HSD activity have been isolated from mammals. With the exception of 17beta-HSD-type 5, which belongs to the aldoketo-reductase (AKR) family, these 17beta-HSDs belong to the short chain dehydrogenase/reductase (SDR) family. Several 17beta-HSDs appear to be examples of convergent evolution. That is, 17beta-HSD activity arose several times from different ancestors. Some 17beta-HSDs share a common ancestor with retinoid oxido-reductases and have retinol dehydrogenase activity. 17beta-HSD-types 2, 6 and 9 appear to have diverged from ancestral retinoid dehydrogenases early in the evolution of deuterostomes during the Cambrian, about 540 million years ago. This coincided with the origin of nuclear receptors for androgens and estrogens suggesting that expression of 17beta-HSDs had an important role in the early evolution of the physiological response to androgens and estrogens.

Deletion of 12 carboxyl-terminal residues from pig 3alpha/beta,20beta-hydroxysteroid dehydrogenase affects steroid metabolism.

Pig 3alpha/beta,20beta-hydroxysteroid dehydrogenase (3alpha/beta,20beta-HSD) is 80-85% identical to human, rat, and mouse carbonyl reductases. However, pig 3alpha/beta,20beta-HSD contains an extra 12 amino acids at its COOH-terminus that these other mammalian carbonyl reductases lack. We constructed a pig 3alpha/beta,20beta-HSD mutant, G278opal, which lacks these amino acids and found that compared to wild-type 3alpha/beta,20beta-HSD, G278opal has a 10-fold lower catalytic efficiency for testosterone and progesterone. G278opal also has lower 3alpha- and 20beta-reductase and increased 3beta-reductase activity compared to wild-type 3alpha/beta,20beta-HSD. Binding of NADPH to G278opal was similar to that of wild-type 3alpha/beta,20beta-HSD. The recently determined three-dimensional structure of 3alpha/beta,20beta-HSD, without a steroid substrate, shows the 12 COOH-terminal amino acids in a random configuration. Our data indicate that the 12 COOH-terminal amino acids have a role in steroid metabolism suggesting that binding of steroid to wild-type 3alpha/beta,20beta-HSD induces a conformational change in which the 12 COOH-terminal amino acids interact with the steroid substrate.

Imaging strategies in the pregnant cancer patient.

This review summarizes the pertinent issues of radiation exposure to the developing fetus and the existing imaging techniques available to detect neoplastic disease spread of the common malignancies in women of reproductive age (breast cancer, cervical carcinoma, Hodgkin's disease, and melanoma). The standard radiologic work-up for assessing disease extent is reviewed and the pros and cons of these various imaging modalities are discussed with regard to the potential deleterious effects on the mother and fetus. Reasonable alternatives to the standard protocols for documenting extent of disease for these neoplasms are proposed. Usually a pregnant cancer patient can be safely and reasonably staged with imaging. Magnetic resonance (MR) imaging will most often be the procedure of choice because it does not use ionizing radiation. Specialized, focused questions such as sentinel lymph node detection may require limited exposure to ionizing radiation, which will not expose the fetus to a significant dose. While a standard chest x-ray does involve ionizing radiation, it does not expose the fetus to significant radiation.