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Fadi Abu Baker,1 Amir Mari,1 Kamal Aamarney,2 Abu Ras Hakeem,3 Barouch Ovadia,1 Yael Kopelman,11Gastroenterology and Hepatology Department, Hillel Yaffe Medical Center, affiliated to the Ruth and Rappaport Faculty of Medicine, Haifa, Israel; 2Pharmacy Services Department, Hillel Yaffe Medical Center, affiliated to the Ruth and Rappaport Faculty of Medicine, Haifa, Israel; 3Anesthesiology Department, Hillel Yaffe Medical Center, affiliated to the Ruth and Rappaport Faculty of Medicine, Haifa, Israel Background: Propofol-mediated sedation is safe and clearly associated with increased patient satisfaction. However, whether it results in a favorable effect on colonoscopy outcomes and performance compared to standard sedation with benzodiazepines/opiates remains unclear.Objectives: To determine the effect of propofol-mediated sedation on colonoscopy-quality measures compared to traditional sedation.Methods: A large cohort of 44,794 patients who had undergone sedated colonoscopies were included. Colonoscopy-quality indicators were examined in benzodiazepine/opiate-sedated patients and compared with a propofol-mediated sedation group. Adjustment for potential confounders, such as age, sex, quality of bowel preparation, procedural setting, and indication was performed.Results: Patients who received propofol-mediated sedation were more likely, and in a dose-dependent manner, to have an enhanced polyp-detection rate (22.8% vs 20.9%, P

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a tumour target currently used for the development of novel therapeutic modalities, such as antibody-drug conjugates, chimeric antigen receptor T-cell therapies, and others. Success of these new drugs depends on the selection of relevant indications based on ROR1 tumour prevalence, staining heterogeneity, and subcellular localization, among other parameters. We investigated ROR1 immunophenotype using validated antibody clones for immunohistochemistry (IHC) and flow cytometry (FC), analyzing 292 tumour specimens from 7 haematological malignancies and triple negative breast cancer (TNBC) as a reference solid tumour indication. ROR1 prevalence varied significantly across distinct tumour types, showing 100% of ROR1 positivity in all chronic lymphocytic leukaemia (n = 48) and hairy cell leukaemia (n = 14) specimens analyzed via FC with ranges between 1.1-99.8% and 0.8-62.1%, respectively. Samples analysed via IHC showed ROR1 membrane/cytoplasmic positivity in 44% of mantle cell lymphoma tumour samples (n = 27; H-score range: 10-285 in positive cases); 30% in TNBC (n = 46; H-score range: 1-200); 15% in diffuse large B-cell lymphoma (n = 45; H-score: 40-250); and 11% in follicular lymphoma (n = 34; H-score: 2-300). Finally, all acute myeloid leukaemia (n = 52) and most T-cell non-Hodgkin lymphoma (n = 31/32) tested samples were negative for ROR1 via IHC. In conclusion, ROR1 shows a heterogeneous tumour cell expression profile across multiple leukaemias and lymphomas, making it a tumour target that would require different patient selection strategies to develop novel therapeutic modalities., Competing Interests: This work was funded by Boehringer-Ingelheim GmbH, the employer of Manuel A. Silva, Lorenz Waldmeier and Yarúa Jaimes. Shuntae Williams, Sylvie Hauert, and Hytham Al-Masri are employed by Hematogenix. Benjamin Ovadia and Indu Gupta are employed by NeoGenomics. There are no patents, products in development or marketed products to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Silva et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Society guidelines on colorectal dysplasia screening, surveillance, and endoscopic management in inflammatory bowel disease (IBD) are complex, and physician adherence to them is suboptimal. We aimed to evaluate the use of ChatGPT, a large language model, in generating accurate guideline-based recommendations for colorectal dysplasia screening, surveillance, and endoscopic management in IBD in line with European Crohn's and Colitis Organization (ECCO) guidelines., Methods: 30 clinical scenarios in the form of free text were prepared and presented to three separate sessions of ChatGPT and to eight gastroenterologists (four IBD specialists and four non-IBD gastroenterologists). Two additional IBD specialists subsequently assessed all responses provided by ChatGPT and the eight gastroenterologists, judging their accuracy according to ECCO guidelines., Results: ChatGPT had a mean correct response rate of 87.8%. Among the eight gastroenterologists, the mean correct response rates were 85.8% for IBD experts and 89.2% for non-IBD experts. No statistically significant differences in accuracy were observed between ChatGPT and all gastroenterologists ( P =0.95), or between ChatGPT and the IBD experts and non-IBD expert gastroenterologists, respectively ( P =0.82)., Conclusions: This study highlights the potential of language models in enhancing guideline adherence regarding colorectal dysplasia in IBD. Further investigation of additional resources and prospective evaluation in real-world settings are warranted., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: With age, colorectal cancer (CRC) prevalence rises. The elderly (> 75 years), and the very elderly (> 85 years) are especially vulnerable. The advantages of screening must be assessed in the context of diminished life span and co-morbidities., Objectives: To compare CRC findings in colonoscopies that were performed following a positive fecal occult blood test/fecal immunochemical test (FOBT/FIT) in both elderly and very elderly age groups with those of younger patients., Methods: We identified colonoscopies conducted between 1998 and 2019 following a positive stool test for occult blood in asymptomatic individuals. A finding of malignancy was compared between the two patient age groups. Furthermore, a sub-analysis was performed for positive malignancy findings in FOBT/FIT among patients > 85 years compared to younger than < 75 years., Results: We compared the colonoscopy findings in 10,472 patients: 40-75 years old (n=10,146) vs. 76-110 years old (n=326). There was no significant difference in prevalence of CRC detection rate between the groups following positive FOBT/FIT (2.1% vs. 2.7%, P = 0.47). Similar results for non-significant differences were obtained in the sub-analysis compared to malignancy detection rates in the very elderly 0% (n=0) vs. 2.1% for < 75 years old (n=18), P = 0.59., Conclusions: Although the prevalence of CRC increases with age, no significant increase in the detection rate of CRC by FOBT was found in either the elderly or very elderly age groups. Screening colonoscopies in elderly patients should be performed only after careful consideration of potential benefits, risks, and patient preferences.

Background: Polyp detection rate (PDR) is a convenient quality measure indicator. Many factors influence PDR, including the patient's background, age, referral (ambulatory or hospitalized), and bowel cleansing., Objectives: To evaluate whether years of professional experience have any effect on PDR., Methods: A multivariate analysis of a retrospective cohort was performed, where both patient- and examiner-related variables, including the experience of doctors and nurses, were evaluated. PDR, as the dependent variable was calculated separately for all (APDR), proximal (PPDR), and small (SPDR) polyps., Results: Between 1998 and 2019, 20,996 patients underwent colonoscopy at a single center. After controlling for covariates, the experience of both doctors and nurses was not found to be associated with APDR (odds ratio [OR] 0.99, 95% confidence interval [95%CI] 0.98-1.00, P = 0.15 and OR 1.03, 95%CI 1.02-1.04, P < 0.0001, respectively). However, after 2.4 years of colonoscopy experience for doctors, and 9.5 years of experience for nurses, a significant increase in APDR was observed. Furthermore, results revealed no association for PPDR and SPDR, as well., Conclusions: Years of colonoscopy experience for both doctors and assisting nurses were not associated with APDR, PPDR, and SPDR. In doctors with 2.4 years of experience and nurses with 9.5 years of experience, a significant increase in APDR was observed.

Patients with inflammatory bowel disease (IBD) treated with anti-tumor-necrosis factor-alpha (TNFα) exhibited lower serologic responses one-month following the second dose of the COVID-19 BNT162b2 vaccine compared to those not treated with anti-TNFα (non-anti-TNFα) or to healthy controls (HCs). We comprehensively analyzed long-term humoral responses, including anti-spike (S) antibodies, serum inhibition, neutralization, cross-reactivity and circulating B cell six months post BNT162b2, in patients with IBD stratified by therapy compared to HCs. Subjects enrolled in a prospective, controlled, multi-center Israeli study received two BNT162b2 doses. Anti-S levels, functional activity, specific B cells, antigen cross-reactivity, anti-nucleocapsid levels, adverse events and IBD disease score were detected longitudinally. In total, 240 subjects, 151 with IBD (94 not treated with anti-TNFα and 57 treated with anti-TNFα) and 89 HCs participated. Six months after vaccination, patients with IBD treated with anti-TNFα had significantly impaired BNT162b2 responses, specifically, more seronegativity, decreased specific circulating B cells and cross-reactivity compared to patients untreated with anti-TNFα. Importantly, all seronegative subjects were patients with IBD; of those, >90% were treated with anti-TNFα. Finally, IBD activity was unaffected by BNT162b2. Altogether these data support the earlier booster dose administration in these patients.

Background: Crohn's disease (CD) and ulcerative colitis (UC) are chronic, immune-mediated inflammatory bowel diseases (IBD) affecting millions of people worldwide. IBD therapies, designed for continuous immune suppression, often render patients more susceptible to infections. The effect of the immune suppression on the risk of coronavirus disease-19 (COVID-19) is not fully determined yet., Objective: To describe COVID-19 characteristics and outcomes and to evaluate the association between IBD phenotypes, infection outcomes and immunomodulatory therapies., Methods: In this multi-center study, we prospectively followed IBD patients with proven COVID-19. De-identified data from medical charts were collected including age, gender, IBD type, IBD clinical activity, IBD treatments, comorbidities, symptoms and outcomes of COVID-19. A multivariable regression model was used to examine the effect of immunosuppressant drugs on the risk of infection by COVID-19 and the outcomes., Results: Of 144 IBD patients, 104 (72%) were CD and 40 (28%) were UC. Mean age was 32.2 ± 12.6 years. No mortalities were reported. In total, 94 patients (65.3%) received biologic therapy. Of them, 51 (54%) at escalated doses, 10 (11%) in combination with immunomodulators and 9 (10%) with concomitant corticosteroids. Disease location, behavior and activity did not correlate with the severity of COVID-19. Biologics as monotherapy or with immunomodulators or corticosteroids were not associated with more severe infection. On the contrary, patients receiving biologics had significantly milder infection course ( p = 0.001) and were less likely to be hospitalized ( p = 0.001). Treatment was postponed in 34.7% of patients until recovery from COVID-19, without consequent exacerbation., Conclusion: We did not witness aggravated COVID-19 outcomes in patients with IBD. Patients treated with biologics had a favorable outcome.

Background & Aim: Patients with inflammatory bowel diseases (IBD), specifically those treated with anti-tumor necrosis factor (TNF)α biologics, are at high risk for vaccine-preventable infections. Their ability to mount adequate vaccine responses is unclear. The aim of the study was to assess serologic responses to messenger RNA-Coronavirus Disease 2019 vaccine, and safety profile, in patients with IBD stratified according to therapy, compared with healthy controls (HCs)., Methods: Prospective, controlled, multicenter Israeli study. Subjects enrolled received 2 BNT162b2 (Pfizer/BioNTech) doses. Anti-spike antibody levels and functional activity, anti-TNFα levels and adverse events (AEs) were detected longitudinally., Results: Overall, 258 subjects: 185 IBD (67 treated with anti-TNFα, 118 non-anti-TNFα), and 73 HCs. After the first vaccine dose, all HCs were seropositive, whereas ∼7% of patients with IBD, regardless of treatment, remained seronegative. After the second dose, all subjects were seropositive, however anti-spike levels were significantly lower in anti-TNFα treated compared with non-anti-TNFα treated patients, and HCs (both P < .001). Neutralizing and inhibitory functions were both lower in anti-TNFα treated compared with non-anti-TNFα treated patients, and HCs (P < .03; P < .0001, respectively). Anti-TNFα drug levels and vaccine responses did not affect anti-spike levels. Infection rate (∼2%) and AEs were comparable in all groups. IBD activity was unaffected by BNT162b2., Conclusions: In this prospective study in patients with IBD stratified according to treatment, all patients mounted serologic response to 2 doses of BNT162b2; however, its magnitude was significantly lower in patients treated with anti-TNFα, regardless of administration timing and drug levels. Vaccine was safe. As vaccine serologic response longevity in this group may be limited, vaccine booster dose should be considered., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Electroless deposition on zinc and its alloys is challenging because of the negative standard potential of zinc, the formation of poor surface layers during oxidation in aqueous solutions, and extensive hydrogen evolution. Therefore, there are only few reports of electroless deposition on Zn and its alloys, neither of them on micro/nano powders. Here, we propose a two-step process that allows the formation of compact, uniform, and conformal Ni/NiP shell on Zn-based alloy microparticles without agglomeration. The process utilizes controlled galvanic displacement of Ni deposition in ethanol-based bath, followed by NiP autocatalytic deposition in an alkaline aqueous solution. The mechanism and effect of deposition conditions on the shell formation are discussed. Thermal stability and functional analysis of core-shell powder reveal a thermal storage capability of 98.5% with an encapsulation ratio of 66.5%. No significant morphological change of the core-shell powder and no apparent leakage of the ZnAl alloy through the Ni shell are evident following differential scanning calorimetry tests. Our two-step process paves the way to utilize electroless deposition for depositing metallic-based functional coatings on Zn-based bulk and powder materials.

Background: The implication of microscopic ileitis finding in patients referred for ileocolonoscopy for clinically suspected inflammatory bowel disease (IBD) is not well defined, and its correlation with clinical outcome has not been fully studied. The current study aims to determine the prognostic yield of biopsies in this setting, and to evaluate the correlation of microscopic ileitis with long-term clinical outcome., Methods: We reviewed endoscopic reports of patients referred to our department for ileocolonoscopy in the years 2010-2016, as part of a diagnostic work-up for suspected IBD. Patients whose ileocolonoscopies proved normal were included, provided that terminal ileum biopsies had been performed. Accordingly, patients were divided into groups classified as normal (normal or reactive changes) and microscopic ileitis (inflammation or ileitis of any severity). Both groups were followed prospectively to determine clinical outcome., Results: A total of 439 patients met the inclusion criteria. Sixty-four (14.6%) showed inflammation on biopsy and were included in the microscopic ileitis group. Age range and gender figures did not differ significantly between the groups. Overall follow-up period was 6.1 ± 2.3 years. Patients in the microscopic ileitis group were significantly associated with Crohn's diagnosis during the follow-up period compared with the normal group (19% vs 2%, OR = 11.98, 95%CI = 4.48-32.01; p < 0.01). Patients with granuloma or moderate-severe ileitis on biopsy were significantly associated with Crohn's development (100% vs 11%; P < 0.01) compared with mild or nonspecific inflammation., Conclusion: The discovery of microscopic ileitis in clinically suspected IBD is associated with increased risk of future diagnosis of Crohn's disease.

A 54-year-old female patient complained of right upper quadrant abdominal pain 11 years following a laparoscopic cholecystectomy. A CT scan demonstrated a collection in the surgical bed and a surgical clip in the proximal bile duct. Cholangitis developed a few days later. Another CT showed that the surgical clip migrated to the distal common bile duct. The clip was removed by endoscopic retrograde cholangiography and the cholangitis was resolved., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Inadequate bowel preparation is still the main obstacle to a complete colonoscopy in many patients and necessitates many repeated procedures. We aimed to identify risk factors associated with inadequate bowel preparation and to better characterize these patients., Methods: This was a retrospective study that reviewed electronic reports of colonoscopy procedures over a 10-year period. Patients were divided into 2 groups: adequate vs. non-adequate bowel preparation. A multivariate analysis was performed to identify variables associated with inadequate bowel preparation, including age, sex, setting (inpatient/outpatient), preparation regimen and procedures' indications. We examined the effect of inadequate preparation on colonoscopy quality indicators., Results: Of the 28,725 patients included in the study, 6,702 (23.3%) had inadequate bowel preparation. In the multivariate analysis, advanced age (odds ratio [OR] 1.015, 95% confidence interval [CI] 1.013-1.017; P<0.01), male sex (OR 1.353, 95%CI 1.286-1.423; P<0.01) and a minority population (OR 1.635, 95%CI 1.531-1.746; P<0.01) were significantly associated with inadequate bowel preparation. The inpatient setting was among the most prominent factors associated with inadequate bowel preparation (OR 2.018, 95%CI 1.884-2.163; P<0.01). Adequate bowel preparation was associated with a higher polyp detection rate (26.8% vs. 23.6%; OR 1.22, 95%CI 1.109-1.347; P<0.01) and colorectal cancer (2.8% vs. 2.4%; OR 1.402, 95%CI 1.146-1.716; P<0.01), and higher frequencies of cecal (96.4% vs. 73.5%; OR 2.243, 95%CI 2.095-2.403; P<0.01) and terminal ileum intubation (8.1% vs. 5.4%; OR 1.243, 95%CI 1.088-1.434; P<0.01)., Conclusion: We outlined various factors associated with inadequate bowel preparation and confirmed its adverse effect on colonoscopy quality indicators., Competing Interests: Conflict of Interest: None

Background: Adenoma/polyp detection rates are considered to be among the most important quality indicators of colonoscopy and are key measures of a quality procedure. However, they are designed for use in the screening setting and are not amenable to other colonoscopy indications. Little is known about their significance in other colonoscopy indications. We aimed to evaluate the impact of the various indications on polyp detection rate (PDR)., Methods: This was a retrospective, single-center study. Electronic reports of index colonoscopy procedures with adequate bowel preparation over a 10-year period were reviewed. Patients were divided into 7 groups based on the study indication. PDR was determined for each group and was compared to that of a control group, the screening indication group. Adjustment was made for potential confounders such as age, sex, and procedural setting., Results: A total of 13,054 patients were considered suitable for the study. PDR was greatest in the positive fecal occult blood test group, with a value of 33.1% (P<0.01). Overall, the remaining groups showed similar PDRs compared with screening (22.1% vs. 20.4%; P=0.15). This trend persisted in a multivariate analysis, which showed the odds ratio in the positive fecal occult blood test group to be significantly higher, with a value of 1.955 (1.759-2.172, P<0.001) compared with the screening group., Conclusion: PDR was highest for the positive fecal occult blood test indication, but was not affected significantly by most indications. Further randomized studies are warranted to confirm these findings and help calculate recommended thresholds for "overall" PDR., Competing Interests: Conflict of Interest: None

The three-component free-radical carbo-alkenylation of electron-rich olefins has been studied, varying the substitution pattern in the alkene, in the radical precursor and in the final acceptor. New vinylsulfones were also prepared and their reactivity investigated. The scope and limitations of the process was established, and the reaction mechanism clarified using selected dienes as radical clocks. It was thus recognised that the reversible addition onto the olefin of the released sulfonyl group is an important event, which should not be overlooked when using such multicomponent carbo-alkenylation reactions., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

This review provides an overview of the recent progress made in the area of free-radical additions across the π-system of olefins, with a focus on the role of sulfonyl derivatives as one of the reaction partners in multicomponent processes. The mechanism and utility in organic synthesis of carbo-alkenylation, alkynylation, oximation and azidation of olefins are thus discussed and illustrated with some applications in total synthesis of natural products.

New bifunctional reagents for free-radical carbo-oximation of olefins have been developed. In this process, a single reagent can act both as a trap for nucleophilic radicals as well as a source of electrophilic radical via an α-scission of an alkylsulfonyl radical. This strategy involving the addition of a C-centered electrophilic radical and an oxime across the double bond of an electron-rich alkene is initiated with a t-BuO radical following an unusual mechanism, supported by both experiments and density functional theory calculations.

Hyperplastic polyps of the stomach are regarded as benign. However, in rare cases they may contain incipient primary carcinomas. To our knowledge, breast carcinoma metastatic to a gastric hyperplastic polyp has not yet been reported. We describe the case of a 69-year-old woman to whom a gastric polyp was endoscopically excised. The patient had previously undergone a right mastectomy for mixed, invasive ductal and lobular carcinoma 5 years earlier. Histological sections from the gastric lesion showed typical features of hyperplastic polyp with foci of poorly differentiated adenocarcinoma including signet ring cells infiltrating the lamina propria. The histologic findings were consistent with a primary gastric cancer. However, the carcinoma cells were immunopositive for estrogen and progesterone receptors and GATA3 and negative for CDX2, Hep Par 1, and MUC5AC. E-cadherin showed membranous reactivity in some of the carcinoma cells while in others it was negative. Accordingly, metastatic mixed, lobular and ductal breast carcinoma was diagnosed. We conclude that metastatic adenocarcinoma mimicking primary gastric cancer can be rarely encountered in hyperplastic gastric polyps.

Aim: To compare small bowel (SB) cleanliness and capsule endoscopy (CE) image quality following Ensure(®), polyethylene glycol (PEG) and standard preparations., Methods: A preparation protocol for CE that is both efficacious and acceptable to patients remains elusive. Considering the physiological function of the SB as a site for the digestion and absorption of food and not as a stool reservoir, preparation consisting of a liquid, fiber-free formula ingested one day before a CE study might have an advantage over other kinds of preparations. We conducted a prospective, blind-to-preparation, two-center study that compared four types of preparations. The participants' demographic and clinical data were collected. Gastric and SB transit times were calculated. The presence of bile in the duodenum was scored by a single, blinded-to-preparation gastroenterologist expert in CE, as was cleanliness within the proximal, middle and distal part of the SB. A four-point scale was used (grade 1 = no bile or residue, grade 4 ≥ 90% of lumen full of bile or residual material)., Results: The 198 consecutive patients who were referred to CE studies due to routine medical reasons were divided into four groups. They all observed a 12-h overnight fast before undergoing CE. Throughout the 24 h preceding the fast, control group 1 (n = 45 patients) ate light unrestricted meals, control group 2 (n = 81) also ate light meals but free of fruits and vegetables, the PEG group (n = 50) ate unrestricted light meals and ingested the PEG preparation, and the Ensure group (n = 22) ingested only the Ensure formula. Preparation with Ensure improved the visualization of duodenal mucosa (a score of 1.76) by decreasing the bile content compared to preparation with PEG (a score of 2.9) (P = 0.053). Overall, as expected, there was less residue and stool in the proximal part of the SB than in the middle and distal parts in all groups. The total score of cleanliness throughout the length of the SB showed some benefit for Ensure (a score of 1.8) over control group 2 (a score of 2) (P = 0.06). The cleanliness grading of the proximal and distal parts of the SB was similar in all four groups (P = 0.6 for both). The cleanliness in the middle part of the SB in the PEG (a score of 1.8) and Ensure groups (a score of 1.7) was equally better than that of control group 2 (a score of 2.1) (P = 0.057 and P = 0.07, respectively). All 50 PEG patients had diarrhea as an anticipated side effect, compared with only one patient in the Ensure group., Conclusion: Preparation with Ensure, a liquid, fiber-free formula has advantages over standard and PEG preparations, with significantly fewer side effects than PEG.

Previous in vivo studies indicate that inhaled nitric oxide (NO) decreases nitric oxide synthase (NOS) activity and that this decrease is associated with significant increases in pulmonary vascular resistance (PVR) upon the acute withdrawal of inhaled NO (rebound pulmonary hypertension). In vitro studies suggest that superoxide and peroxynitrite production during inhaled NO therapy may mediate these effects, but in vivo data are lacking. The objective of this study was to determine the role of superoxide in the decrease in NOS activity and rebound pulmonary hypertension associated with inhaled NO therapy in vivo. In control lambs, 24 h of inhaled NO (40 ppm) decreased NOS activity by 40% (P<0.05) and increased endothelin-1 levels by 64% (P<0.05). Withdrawal of NO resulted in an acute increase in PVR (60.7%, P<0.05). Associated with these changes, superoxide and peroxynitrite levels increased more than twofold (P<0.05) following 24 h of inhaled NO therapy. However, in lambs treated with polyethylene glycol-conjugated superoxide dismutase (PEG-SOD) during inhaled NO therapy, there was no change in NOS activity, no increase in superoxide or peroxynitrite levels, and no increase in PVR upon the withdrawal of inhaled NO. In addition, endothelial NOS nitration was 18-fold higher (P<0.05) in control lambs than in PEG-SOD-treated lambs following 24 h of inhaled NO. These data suggest that superoxide and peroxynitrite participate in the decrease in NOS activity and rebound pulmonary hypertension associated with inhaled NO therapy. Reactive oxygen species scavenging may be a useful therapeutic strategy to ameliorate alterations in endogenous NO signaling during inhaled NO therapy.

Objective: To investigate the hemodynamic effects of tezosentan in the intact lamb both at rest and during acute and chronic pulmonary hypertension., Design: Prospective, randomized experimental study., Setting: University-based research laboratory., Subjects: Lambs with and without pulmonary hypertension., Interventions: Six newborn lambs were instrumented to measure vascular pressures and left pulmonary blood flow. The hemodynamic effects of tezosentan (0.5, 1.0, 5.0 mg/kg, intravenously) were studied at rest and during U46619-induced pulmonary hypertension. Following in utero placement of an aortopulmonary vascular graft, nine additional lambs with increased pulmonary blood flow and chronic pulmonary hypertension (shunt) were also studied at 1 wk (n = 5) and 8 wks (n = 4) of age., Measurements and Main Results: At rest, tezosentan had no significant effect on any of the variables. During acute U46619-induced pulmonary hypertension, tezosentan caused a dose-dependent decrease in pulmonary arterial pressure (from 5.9% +/- 4.7 to 16.0% +/- 10.7; p < .05) and pulmonary vascular resistance (from 6.2% +/- 8.0 to 21% +/- 8.8; p < .05). Mean systemic arterial pressure was unchanged. In 1- and 8-wk-old shunt lambs with increased pulmonary blood flow, tezosentan (1 mg/kg) produced potent nonselective pulmonary vasodilation., Conclusions: Tezosentan, a combined endothelin receptor antagonist optimized for parenteral use, induces potent selective pulmonary vasodilation during acute U46619-induced pulmonary hypertension and potent nonselective vasodilation in chronic pulmonary hypertension secondary to increased pulmonary blood flow. In general, the hemodynamic effects of bolus doses of tezosentan occurred within 60 secs of administration and lasted approximately 5-10 mins. The hemodynamic profile of intravenous tezosentan may make it a useful adjunct therapy for acute pulmonary hypertensive disorders and warrants further study.

Endothelin receptor blockade is an emerging therapy for pulmonary hypertension. However, hemodynamic and structural effects and potential changes in endogenous nitric oxide (NO)-cGMP and endothelin-1 signaling of chronic endothelin A receptor blockade in pulmonary hypertension secondary to congenital heart disease are unknown. Therefore, the objectives of this study were to determine hemodynamic and structural effects and potential changes in endogenous NO-cGMP and endothelin-1 signaling of chronic endothelin A receptor blockade in a lamb model of increased pulmonary blood flow following in utero placement of an aortopulmonary shunt. Immediately after spontaneous birth, shunt lambs were treated lifelong with either an endothelin A receptor antagonist (PD-156707) or placebo. At 4 wk of age, PD-156707-treated shunt lambs (n = 6) had lower pulmonary vascular resistance and right atrial pressure than placebo-treated shunt lambs (n = 8, P < 0.05). Smooth muscle thickness or arterial number per unit area was not different between the two groups. However, the number of alveolar profiles per unit area was increased in the PD-156707-treated shunt lambs (190.7 +/- 5.6 vs. 132.9 +/- 10.0, P < 0.05). Plasma endothelin-1 and cGMP levels and lung NOS activity, cGMP, eNOS, preproendothelin-1, endothelin-converting enzyme-1, endothelin A, and endothelin B receptor protein levels were similar in both groups. We conclude that chronic endothelin A receptor blockade attenuates the progression of pulmonary hypertension and augments alveolar growth in lambs with increased pulmonary blood flow.

Neonates and infants with congenital heart disease with increased pulmonary blood flow suffer morbidity from poor oxygenation and decreased lung compliance. In a previous experiment involving 4-wk-old lambs with pulmonary hypertension secondary to increased pulmonary blood flow following an in utero placement of an aortopulmonary vascular graft, we found a decrease in surfactant protein (SP)-A gene expression as well as a decrease in SP-A and SP-B protein contents. To determine the timing of these changes, the objective of the present study was to characterize the effect of increased pulmonary blood flow and pulmonary hypertension on SP-A, -B, and -C gene expressions and protein contents within the first week of life. Of eight fetal lambs that underwent the in utero placement of the shunt, there was no difference in the expression of SP-A, -B, and -C mRNA levels or SP-A and -B protein contents compared with age-matched controls. The results showed that, in this model of congenital heart disease with pulmonary hypertension and increased pulmonary blood flow, the effect of the shunt on SP gene expression and protein content was not apparent within the first week of life.

Objectives: To determine the effects of inhaled nitric oxide on endogenous cyclic adenosine monophosphate in the intact lamb, and to determine the potential role of cyclic adenosine monophosphate in the rebound pulmonary hypertension associated with nitric oxide withdrawal., Design: Prospective, placebo-controlled experimental study., Setting: University-based basic science research laboratory., Subjects: One-month-old lambs., Interventions: Six 1-month-old control lambs, and 6 milrinone- (phosphodiesterase-3 inhibitor) treated lambs, were mechanically ventilated. Inhaled nitric oxide (40 ppm) was administered for 24 hrs and then acutely withdrawn. Sequential peripheral lung biopsies were obtained before, during, and 2 hrs after withdrawing inhaled nitric oxide therapy., Measurements and Main Results: In control lambs, initiation of nitric oxide decreased left pulmonary vascular resistance by 29.6%, and withdrawal rapidly increased pulmonary vascular resistance by 77.1% (p <.05). Lung tissue cyclic adenosine monophosphate concentrations decreased by 25.3% during nitric oxide therapy (p <.05). In milrinone-treated lambs, nitric oxide decreased pulmonary vascular resistance by 26.6% (p <.05), but pulmonary vascular resistance was unchanged after acute withdrawal. Lung tissue cyclic adenosine monophosphate concentrations were preserved during nitric oxide therapy., Conclusions: Inhaled nitric oxide produces potent pulmonary vasodilation by activating soluble guanylate cyclase and increasing smooth muscle cell concentrations of guanosine-3',5'-cyclic monophosphate. However, alterations in endogenous nitric oxide/guanosine-3',5'-cyclic monophosphate during inhaled nitric oxide have been implicated in the clinically significant increases in pulmonary vascular resistance noted upon its acute withdrawal. Previous in vitro data suggest that exogenous nitric oxide/guanosine-3',5'-cyclic monophosphate can also alter cyclic adenosine monophosphate concentrations via their effect on cyclic adenosine monophosphate production and metabolism. The current in vivo study demonstrates that lung tissue cyclic adenosine monophosphate concentrations are decreased during inhaled nitric oxide and suggests a role for decreased cyclic adenosine monophosphate in the rebound pulmonary hypertension noted upon inhaled nitric oxide withdrawal. Milrinone may be a useful adjunct therapy during inhaled nitric oxide to preserve cyclic adenosine monophosphate concentrations and prevent rebound pulmonary hypertension.

Background: Inhaled nitric oxide produces potent pulmonary vasodilation by activating soluble guanylate cyclase and increasing smooth muscle cell concentrations of cyclic guanosine monophosphate. However, responses are often nonsustained, and clinically significant increases in pulmonary vascular resistance have been noted on its acute withdrawal. In vitro and in vivo data suggest that inhaled nitric oxide decreases endogenous nitric oxide synthase activity. The effects of inhaled nitric oxide on the downstream mediators of the nitric oxide/cyclic guanosine monophosphate cascade, soluble guanylate cyclase and phosphodiesterase 5, have not been investigated. We sought to determine the effects of inhaled nitric oxide on endogenous cyclic guanosine monophosphate levels, soluble guanylate cyclase, and phosphodiesterase 5 protein levels in the intact lamb., Methods: Eleven 1-month-old lambs were mechanically ventilated. In 7 lambs, inhaled nitric oxide (40 ppm) was administered for 24 hours and then acutely withdrawn. Intermittent lung biopsy samples were obtained for cyclic guanosine monophosphate concentrations and soluble guanylate cyclase and phosphodiesterase 5 protein levels (Western blot analysis)., Results: Initiation of nitric oxide decreased left pulmonary vascular resistance by 26.2%, and withdrawal rapidly increased pulmonary vascular resistance by 77.8% (P <.05). Tissue cyclic guanosine monophosphate concentrations initially increased during nitric oxide therapy but were not maintained during the 24-hour exposure. In addition, cyclic guanosine monophosphate concentrations rapidly decreased after nitric oxide withdrawal (P <.05). The alpha soluble guanylate cyclase (-45.7%) and beta soluble guanylate cyclase (-48.4%) protein levels decreased during nitric oxide therapy (P <.05), whereas phosphodiesterase 5 proteins levels were unchanged., Conclusions: These data suggest a role for decreased soluble guanylate cyclase and its resulting decrease in cyclic guanosine monophosphate concentrations in the nonsustained response to nitric oxide and the rebound pulmonary hypertension noted on its acute withdrawal. Phosphodiesterase 5 inhibitors may be a useful adjunct therapy during inhaled nitric oxide to preserve cyclic guanosine monophosphate levels and thereby preserve nitric oxide responsiveness and prevent rebound pulmonary hypertension.

Background: Endothelin-1 (ET-1) has been implicated in the pathophysiology of pulmonary hypertension. In 1-month-old lambs with increased pulmonary blood flow, we have demonstrated early alterations in the ET-1 cascade. The objective of this study was to investigate the role of potential later alterations of the ET cascade in the pathophysiology of pulmonary hypertension secondary to increased pulmonary blood flow., Methods and Results: Eighteen fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt) and were studied 8 weeks after spontaneous delivery. Compared with age-matched control lambs, lung tissue ET-1 levels were increased in shunt lambs (317.2+/-113.8 versus 209.8+/-61.8 pg/g, P<0.05). In shunt lambs (n=9), exogenous ET-1 induced potent pulmonary vasoconstriction, which was blocked by the ETA receptor antagonist PD 156707 (n=3). This pulmonary vasoconstriction was mimicked by exogenous Ala1,3,11,15 ET-1 (4 Ala ET-1), the ETB receptor agonist, and was blocked by the ETB receptor antagonist BQ 788 (n=3). However, in control lambs (n=7), ET-1 and 4 Ala ET-1 did not change pulmonary vascular tone. In contrast to 4-week-old shunt lambs, immunohistochemistry revealed the emergence of ETB receptors on smooth muscle cells in the vasculature of 8-week-old shunt lambs., Conclusions: Over time, increased pulmonary blood flow and/or pressure results in the emergence of ETB-mediated vasoconstriction, which coincides with the emergence of ETB receptors on smooth muscle cells. These data suggest an important role for ETB receptors in the pathophysiology of pulmonary hypertension in this animal model of increased pulmonary blood flow.

Inhaled nitric oxide (iNO) is used to treat a number of disease processes. Although in vitro data suggest that nitric oxide (NO) alters surfactant protein gene expression, the effects in vivo have not been studied. The objective of this study was to evaluate the effects of iNO on surfactant protein (SP)-A, -B, and -C gene expression in the intact lamb. Thirteen 4-wk-old lambs were mechanically ventilated with 21% oxygen and received iNO at 40 ppm (n = 7) or vehicle gas (n = 6) for 24 h. Peripheral lung biopsies were obtained at 0, 12, and 24 h and analyzed for surfactant mRNA, protein, and total DNA content. Inhaled NO increased SP-A and SP-B mRNA content by 80% from 0 to 12 h and by 78 and 71%, respectively, from 0 to 24 h. There was an increase in SP-A and SP-B protein content by 45% from 0 to 12 h, and a decrease by 70 and 65%, respectively, from 0 to 24 h. DNA content was unchanged. The mechanisms and physiological effects of these findings warrant further investigation.

Altered pulmonary vascular reactivity is a source of morbidity and mortality for children with congenital heart disease and increased pulmonary blood flow. Nitric oxide (NO) and endothelin (ET)-1 are important mediators of pulmonary vascular reactivity. We hypothesize that early alterations in endothelial function contribute to the altered vascular reactivity associated with congenital heart disease. The objective of this study was to characterize endothelial function in our lamb model of increased pulmonary blood flow at 1 wk of life. Eleven fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt) and were studied 7 days after delivery. The pulmonary vasodilator response to both intravenous ACh (endothelium dependent) and inhaled NO (endothelium independent) was similar in shunted and control lambs. In addition, tissue NO(x), NO synthase (NOS) activity, and endothelial NOS protein levels were similar. Conversely, the vasodilator response to both ET-1 and 4Ala-ET-1 (an ET(B) receptor agonist) were attenuated in shunted lambs, and tissue ET-1 concentrations were increased (P < 0.05). Associated with these changes were an increase in ET-converting enzyme-1 protein and a decrease in ET(B) receptor protein levels (P < 0.05). These data demonstrate that increased pulmonary blood flow induces alterations in ET-1 signaling before NO signaling and suggest an early role for ET-1 in the altered vascular reactivity associated with increased pulmonary blood flow.

Nitric oxide (NO) is an important mediator of pulmonary vascular reactivity, and decreased NO synthase expression has been demonstrated in children with advanced pulmonary hypertension secondary to congenital heart disease and increased pulmonary blood flow. Using aortopulmonary vascular graft placement in the fetal lamb, we have established a unique animal model of pulmonary hypertension with increased pulmonary blood flow. At 4 wk of age, these lambs display an early, selective impairment in agonist-induced NO responses, but an up-regulation of basal NO activity and gene expression. We hypothesized that further exposure to increased flow and/or pressure results in progressive endothelial dysfunction and a subsequent decrease in basal NO production. The objective of this study was to characterize potential later alterations in agonist-induced NO responses and basal NO activity and gene expression induced by 8 wk of increased pulmonary blood flow and pulmonary hypertension. Twenty-two fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt), and were studied 8 wk after delivery. Both in vivo and in isolated pulmonary arteries, the pulmonary vasodilating response to endothelium-dependent agents was attenuated in shunted lambs (p < 0.05), whereas the response to endothelium-independent agents was unchanged. The pulmonary vasoconstricting responses to Nomega-nitro-L-arginine, and lung tissue endothelial NO synthase mRNA, endothelial NO synthase protein, NO synthase activity, and NO(X) levels were all unchanged. These data suggest that the increase in basal NO activity demonstrated after 4 wk of increased pulmonary blood flow is lost by 8 wk of age, whereas the attenuation of agonist-induced responses persists. We speculate that the progressive decrease in basal NO activity participates in the development of pulmonary hypertension secondary to increased pulmonary blood flow.

Acute partial compression of the fetal ductus arteriosus (DA) results in an initial increase in pulmonary blood flow (PBF) that is followed by acute vasoconstriction. The objective of the present study was to determine the role of nitric oxide (NO)-endothelin-1 (ET-1) interactions in the acute changes in pulmonary vascular tone after in utero partial constriction of the DA. Twelve late-gestation fetal lambs (132-140 days) were instrumented to measure vascular pressures and left PBF. After a 24-h recovery period, acute constriction of the DA was performed by partially inflating a vascular occluder, and the hemodynamic variables were observed for 4 h. In control lambs (n = 7), acute ductal constriction initially increased PBF by 627% (P < 0.05). However, this was followed by active vasoconstriction, such that PBF was restored to preconstriction values by 4 h. This was associated with a 43% decrease in total NO synthase (NOS) activity (P < 0.05) and a 106% increase in plasma ET-1 levels (P < 0.05). Western blot analysis demonstrated no changes in lung tissue endothelial NOS, preproET-1, endothelin-converting enzyme-1, or ET(B) receptor protein levels. The infusion of PD-156707 (an ET(A) receptor antagonist, n = 5) completely blocked the vasoconstriction and preserved NOS activity. These data suggest that the fetal pulmonary vasoconstriction after acute constriction of the DA is mediated by NO-ET-1 interactions. These include an increase in ET(A) receptor-mediated vasoconstriction and an ET(A) receptor-mediated decrease in NOS activity. The mechanisms of these NO-ET-1 interactions, and their role in mediating acute changes in PBF, warrant further studies.

Objective: To review the incidence, diagnosis, and management of septic emboli caused by vascular catheters after surgery for congenital heart disease., Design: Retrospective clinical review. All patients were computer registered. Our database includes daily follow-up and every sign of infection registered., Setting: Pediatric cardiac surgery intensive care unit in a university hospital., Patients: A total of 720 consecutive pediatric cardiac operations performed in 108 neonates and 612 older children from 1995 to 1997 are reviewed., Measurements and Main Results: Septic emboli were defined as erythematous non-tender papulonodular hemorrhagic lesions restricted to the limb and distal to the monitoring catheter. Four patients (0.55%) with catheter-related septic emboli after congenital heart surgery were identified, three neonates (0.41%) and one older infant (0.14%). The incidence of catheter-related septic emboli in our patients was significantly higher in the neonatal group compared with older infants (p = .0076; odds ratio=17.45). All infants with catheter-associated septic emboli were severely ill and required prolonged intensive care management postoperatively for periods ranging from 27 to 90 days (mean, 50 days). The catheters involved were in place for periods ranging from 5 to 7 days. All patients were treated by catheter removal and intravenous antibiotics without surgical intervention in the vascular access area. The affected limbs healed well without residual damage., Conclusions: Septic emboli are a rare complication of infected vascular catheters in neonates and small infants undergoing prolonged postoperative intensive care management (0.55%). They may indicate the source of unexplained sepsis involving mainly Gram-negative bacilli. Generally, treatment consists of removal of the offending catheter and antibiotic administration with no need for surgical intervention.

During a 4 year period (January 1988 to December 1991), 237 pediatric patients (mean age +/- SD, 9.75 +/- 5.17 years) underwent 289 upper gastrointestinal endoscopies. Premedication was used in only 102 of the endoscopic examinations, mostly in children between 2 and 10 years of age. Patients who were examined without sedation tolerated the procedure well. Abdominal pain was the most frequent indication, accounting for 57.4% of all procedures. Gastritis, esophagitis, duodenitis and duodenal ulcer were the most common endoscopic findings. Seventy-five endoscopies were performed to obtain small bowel biopsies. We found this procedure to be easy and safe and preferable to capsule biopsies. In our experience, upper gastrointestinal endoscopy with or without sedation is a safe and effective diagnostic procedure in the pediatric age group.

When patients in treatment do not comply with medical directives, the most competent health care may go for naught and patients' well-being may be jeopardized. By focusing on the links between assertiveness and coping skills and compliant behavior, the group program described here increased compliance as well as self-confidence in diabetic group members.