Development and Testing of a New Simplified Endoscopic Mucosal Assessment for Crohn's Disease: The SEMA-CD.

OBJECTIVES: Endoscopic mucosal improvement is the gold standard for assessing treatment efficacy in clinical trials of Crohn's disease. Current endoscopic indices are not routinely used in clinical practice. The lack of endoscopic information in large clinical registries limits their use for research. A quick, easy, and accurate method is needed for assessing mucosal improvement for clinicians in real-world practice. We developed and tested a novel simplified endoscopic mucosal assessment for Crohn's disease (SEMA-CD). METHODS: We developed a 5-point scale for ranking endoscopic severity of ileum and colon based on Simple Endoscopic Score for Crohn's disease (SES-CD). Central readers were trained to perform SES-CD and SEMA-CD. Pediatric patients with Crohn's disease undergoing colonoscopy were enrolled. Video recordings of colonoscopies were de-identified and randomly assigned to blinded central readers. The SES-CD and SEMA-CD were scored for each video. The SES-CD was considered the validated standard for comparison. Correlation was assessed with Spearman rho, inter- and intrarater reliability with kappa statistics. RESULTS: Fifty-seven colonoscopies were read a total of 212 times. Correlation between SEMA-CD and SES-CD was strong (rho = 0.98, P < 0.0001). Inter-rater reliability for SEMA-CD was 0.80, and intrarater reliability was 0.83. Central readers rated SEMA-CD as easier than SES-CD. CONCLUSION: The SEMA-CD accurately and reproducibly correlates with the standard SES-CD. Central readers viewed SEMA-CD as easier than SES-CD. Use of SEMA-CD in practice should enable collecting mucosal improvement information in large populations of patients. This will improve the quality of research that can be conducted in clinical registries. External validation is needed.

Delayed Diagnosis of X-linked Lymphoproliferative Syndrome Type 2 in a 17-year-old Male With Severe Crohn's Disease and Recurrent Skin Infections.

X-linked lymphoproliferative syndrome type 2 (XLP2) is a rare genetic primary immunodeficiency disease caused by mutations in the XIAP gene that lead to deficiency of the X-linked inhibitor of apoptosis protein. XLP2 is characterized by dysregulated immune responses and can result in an inflammatory bowel disease (IBD)-like phenotype, a form of monogenic IBD. Patients with XLP2 often succumb to fulminant hemophagocytic lymphohistiocytosis or Epstein-Barr virus infections. Hematopoietic stem cell transplantation (HSCT) is currently the only definitive treatment for XLP2. We report an adolescent with a delayed diagnosis of XLP2 in the setting of severe Crohn's disease diagnosed at age 9 years and recurrent skin infections. He is under evaluation for HSCT. Gastroenterologists must recognize monogenic IBD in patients of all ages with severe disease and signs of an underlying primary immunodeficiency disease. Patients with suspected monogenic IBD should undergo immunologic and genetic analysis at diagnosis to initiate potentially life-saving treatment.

Protonation of Nucleobases in Single- and Double-Stranded DNA.

Single-stranded model oligodeoxyribonucleotides, each containing a single protonatable base-cytosine, adenine, guanine, or 5-methylcytosine-centrally located in a background of non-protonatable thymine residues, were acid-titrated in aqueous solution, with UV monitoring. The basicity of the central base was shown to depend on the type of the central base and its nearest neighbours and to rise with increasing oligonucleotide length and decreasing ionic strength of the solution. More complex model oligonucleotides, each containing a centrally located 5-methylcytosine base, were comparatively evaluated in single-stranded and double-stranded form, by UV spectroscopy and high-field NMR. The N3 protonation of the 5-methylcytosine moiety in the double-stranded case occurred at much lower pH, at which the duplex was already experiencing general dissociation, than in the single-stranded case. The central guanine:5-methylcytosine base pair remained intact up to this point, possibly due to an unusual alternative protonation on O2 of the 5-methylcytosine moiety, already taking place at neutral or weakly basic pH, as indicated by UV spectroscopy, thus suggesting that 5-methylcytosine sites in double-stranded DNA might be protonated to a significant extent under physiological conditions.

Safety of Secretin Administration in Children.

OBJECTIVE: The aim of this study was to compare the hemodynamic parameters from the anesthesia records of children who underwent upper gastrointestinal endoscopy (esophagogastroduodenoscopy [EGD]) with and without secretin pancreatic function tests (sPFTs). METHODS: The hemodynamic parameters were retrieved from an electronic anesthesia database. The secretin group consisted of 186 children, and the age- and sex-matched control group included 136 patients who did not have sPFTs. RESULTS: There was no difference in the demographic parameters (age and sex) between the 2 groups. The secretin group had a lower height and body mass index. The sPFT resulted in an average 3-minute extension of the endoscopic procedure. The heart rate increased during the EGD in both groups and was higher (averaged 7 beats per minute) in the secretin group than the EGD-only group. There were mild elevations on the systolic and diastolic blood pressures. None of these changes were clinically significant. There were no complications reported during the anesthesia and procedures in the 2 groups. CONCLUSIONS: Secretin PFT is a safe procedure. It only slightly prolongs the total procedure and anesthesia time. There were no clinically significant changes in the vital parameters in the secretin group, and there were no adverse effects recorded.

Bioseguridad ambiental en un hospital con grandes obras. Medidas correctoras y organización de control / Environmental biosafety in a hospital undergoing renovation work: corrective measures and control organisation

El objetivo de este trabajo es el de valorar la efectividad de las medidas organizativas en el control de la Bioseguridad Ambiental en un hospital de tercer nivel con grandes obras. Se describen las medidas de carácter organizativo puestas en marcha en abril de 2000 en un complejo hospitalario con grandes obras y reformas; se valoran los resultados del muestreo ambiental y su repercusión en la actividad clínica diaria. La mayoría de los controles efectuados mostraron resultados satisfactorios, pero durante el período de seguimiento hemos detectado situaciones de bioseguridad inadecuada que nos ha obligado a cancelar temporalmente las prestaciones y a someter a las zonas a profundas remodelaciones de mejora (en el caso de Oncohematología Infantil) o a un cambio de la estructura organizativa (Qui´rofanos del H. Materno-Infantil, Oncohematología de adultos). El bloque quirúrgico de adultos (sometido a remodelación en período previo al inicio de la vigilancia) ha sido el área que mejores resultados ha presentado. No se han detectado brotes de aspergilosis ni de legionelosis nosocomiales, ni aumento en la incidencia de estos procesos en el período de vigilancia. La puesta en funcionamiento de la Comisión de Obras y de una política proactiva de prevención en esta materia se ha mostrado eficaz en cuanto a la detección y control de la bioseguridad ambiental y nos ha permitido la coexistencia de la asistencia con grandes obras dentro y alrededor de lo dos hospitales

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Health-related quality of life in the first year after a diagnosis of pediatric inflammatory bowel disease.

BACKGROUND AND AIMS: Assessment of health-related quality of life (HRQOL) is of increasing importance in the evaluation of new therapies for inflammatory bowel disease (IBD). Available data concerning HRQOL in pediatric patients are sparse and uniformly cross-sectional. The aim of this study was to describe HRQOL and influential factors in newly diagnosed pediatric patients with Crohn's disease and ulcerative colitis during the first 12 months after diagnosis. MATERIALS AND METHODS: Participants were drawn from a large, prospectively derived observational IBD registry of pediatric patients studied through 18 U.S. and Canadian centers. Patients who had completed a baseline IMPACT questionnaire and for whom there were 12 months of follow-up data available were included. In addition to description of cohort, factors that were believed to influence HLQOL were assessed during the course of the year from diagnosis. RESULTS: Two hundred eighteen children met inclusion criteria (77% Crohn's disease, 23 % ulcerative colitis, mean age 12.7 +/- 1.9 years). Mean total IMPACT score at baseline was 154, 181 at 6 months, and 191 at 1 year (possible range 0-238, with increasing scores representing better quality of life). Repeated measures analysis showed that age and disease severity significantly negatively affected the IMPACT scores during the course of the year. CONCLUSIONS: In this large prospective pediatric IBD cohort, significant improvement in HRQOL is noted during the year from diagnosis. Mean IMPACT scores varied significantly depending on the disease severity and also decreased with increasing age.

Corticosteroid therapy in the age of infliximab: acute and 1-year outcomes in newly diagnosed children with Crohn's disease.

BACKGROUND & AIMS: The aim of this study was to describe 3-month and 1-year outcomes of children with Crohn's disease (CD) treated with corticosteroids within 30 days of diagnosis, with particular emphasis on the influence of infliximab on these outcomes. We also aimed to determine whether there are clinical or laboratory characteristics associated with corticosteroid therapy outcomes. METHODS: Data from 109 children were drawn from a multicenter observational registry that was started in 2002. Clinical characteristics and data on corticosteroid and other therapies were recorded prospectively. Corticosteroid therapy outcomes at 3 months were defined as complete acute response, partial response, or corticosteroid resistance. At 1 year, corticosteroid responsiveness, dependence, and surgical rates were determined. Infliximab's influence on short- and long-term outcomes also was investigated. RESULTS: At 3 months, 65 of 109 (60%) patients had a complete acute response to corticosteroids, 26 (24%) had a partial response, and 18 (17%) were corticosteroid resistant. At 1 year, 61% were corticosteroid responsive, 31% were corticosteroid dependent, and 8% required surgery. Irrespective of the duration of corticosteroid treatment, 16 of 24 of corticosteroid-dependent/resistant patients rapidly discontinued corticosteroids after starting infliximab. No clinical or laboratory characteristics at diagnosis predicted short-term outcome. Growth impairment at diagnosis increased risk for corticosteroid dependence or surgery at 1 year. CONCLUSIONS: At 3 months, 84% of children had a complete or partial response to corticosteroids. However, despite concomitant immunomodulators, at 1 year 31% were corticosteroid dependent and 8% required surgery. Infliximab improves outcomes of corticosteroid-dependent/resistant patients because the duration of corticosteroid use can be controlled by initiating treatment with infliximab.

Evaluation of the pediatric crohn disease activity index: a prospective multicenter experience.

BACKGROUND AND OBJECTIVES: Longitudinal assessment of disease activity is necessary for studies of therapeutic intervention in children with Crohn disease. The Pediatric Crohn Disease Activity Index (PCDAI) was developed a decade ago for such a purpose, but it function has only been examined in a small number of studies with a limited number of patients. The primary objectives of the present study were to develop cut scores reflecting disease activity as determined by physician global assessment (PGA) and to evaluate the responsiveness of the PCDAI to changes in patient condition after therapeutic interventions. METHODS: Data were derived from a prospective database of newly diagnosed children with inflammatory bowel disease established in 2002 at 18 pediatric gastroenterology centers in the United States and Canada. At diagnosis, at 30 days and 3 months after diagnosis, and quarterly thereafter, children (<16 years of age) with Crohn disease had disease assessment performed by PGA and PCDAI. Disease management was provided according to the dictates of the attending gastroenterologist and not by predetermined protocol. RESULTS: 181 patients had concomitant PGA and PCDAI performed at diagnosis, and 95 of these had similar assessment at short-term follow up. Mean +/- SD PCDAI scores for mild, moderate, and severe disease by PGA at diagnosis were 19.5 +/- 10.4, 32.2 +/- 12.7, and 47.8 +/- 14.9, respectively (P < 0.001 for all comparisons). Mean +/- SD PCDAI for inactive disease after treatment was 5.2 +/- 5.4. Receiver operating characteristic (ROC) curve analysis suggested that: 1) activity of moderate/severe disease was best reflected by a PCDAI of > or = 30 points, 2) clinical response (moderate/severe disease improving to mild/inactive) was best reflected by a decrease in PCDAI of > or = 12.5 points, and 3) a PCDAI < 10 best reflected inactive disease. CONCLUSIONS: PCDAI scores accurately reflect disease activity as assessed by physician global assessment. A PCDAI score of > or = 30 has acceptable sensitivity and specificity to indicate disease of moderate/severe activity. A PCDAI decrease of 12.5 points or greater following therapeutic intervention accurately reflects a clinically significant response. The PCDAI is an appropriate tool for intervention trials in Crohn disease in children.

[Thrombophlebitis of the lateral sinuses. A difficult diagnostic case for nine otorhinolaryngologists]. / Tromboflebitis del seno lateral. Un difícil diagnóstico para los nuevos otorrinolaringólogos.

Since the advent of antibiotic era lateral sinus thrombophlebitis has become an scarce complication in otology. The clinical picture can present under several aspects, specially if given a course of antibiotics previously, which complicates the diagnose. We report a case recently treated and compare ours with the classic symptomatology quoted in the literature.

[Giant cholesteatoma of the external ear canal after myringoplasty]. / Colesteatoma gigante del conducto auditivo externo posmiringoplastia.

Cholesteatoma are specially localized in middle ear and mastoid process, although sometimes is the external ear canal which shows the disorder. Usually its a appearance is spontaneous. We report a rare case of gigantic cholesteatoma which origin was the previous otologic surgery done because of the inclusion of a bit of epithelial tissue inside the surgical incision. Similar outcomes justify periodical checking after ear surgery with outlining a tympanomeatal flap.

Massive rectal bleeding following transrectal ultrasound-guided prostate biopsy.

BACKGROUND AND STUDY AIMS: Rectal bleeding is frequently seen in patients undergoing transrectal ultrasound (TRUS)-guided prostate biopsy, but is usually mild and stops spontaneously. We report five cases of life-threatening hemorrhage following this procedure, which were treated successfully by endoscopic injection. PATIENTS AND METHODS: A total of 550 consecutive patients underwent TRUS-guided prostate biopsy in an outpatient setting. TRUS was performed using a Sonolayer 140 A (Toshiba) unit with a 7-MHz biplane transrectal probe, which was covered with two prophylactic sheaths. Sextant prostatic biopsies were systematically performed with a 16-gauge or 18-gauge needle without antibiotic prophylaxis. RESULTS: Five patients (1%) presented rectal bleeding with hypovolemic symptoms shortly after the procedure. Emergency colonoscopy revealed active bleeding from biopsy sites in the anterior rectal wall. Endoscopic injection of epinephrine and polidocanol achieved control of bleeding and permanent hemostasis in all cases. The patients required hospitalization and a mean of 4 packed red blood cell units (range 2-7). The patients were discharged, with uneventful recoveries. CONCLUSIONS: Colonoscopy should be carried out in patients presenting severe rectal bleeding after TRUS-guided prostate biopsy. Endoscopic treatment can be used to deal with this rare complication.

Frequency of restenosis after balloon pulmonary arterioplasty and its causes.

Restenosis has been described after balloon pulmonary arterioplasty (BPA), but litte is known about its frequency, settings, and time course. We undertook this study to (1) determine the incidence of restenosis after BPA, and (2) identify its potential determinants. We reviewed clinical data and measured pulmonary artery diameters from angiograms of 134 dilations on 75 patients (median 2.1 years, range 0.3 to 32) who had BPA from January 1990 to June 1998. Successful BPA was defined as a > or = 50% increase in predilation diameter, whereas restenosis was said to occur if there was a > or = 50% loss in initial diameter gain. The success rate after BPA by angiographic criteria was 64% (95% confidence interval 56% to 73%). Seventy-four percent of BPAs were successful by published standard criteria (angiographic criteria or > or = 20% change in right ventricular/aortic pressure). Baseline demographic variables and predilation parameters were not predictive of initial dilation success. Restenosis occurred in 35% (95% confidence interval 22% to 49%) of successfully dilated vessels. Only weight at follow-up (p = 0.02) was associated with an increased likelihood of restenosis. Predilation parameters, technical aspects of dilation, or immediate results of BPA were not predictive of restenosis. We therefore conclude that restenosis is unpredictable and more common after BPA than previously recognized.

[Inflammatory pseudotumor of the lymph nodes. A case report]. / Seudotumor inflamatorio de ganglios linfáticos. A propósito de un caso.

Inflammatory pseudotumor of the lymph nodes is a little-known condition characterized mainly by cervical lymph node enlargement, hematological manifestations, and major constitutional symptoms in most patients. The diagnosis is histological, after surgical removal of an involved lymph node. Histologically, stromal proliferation and neovascularity are present, as well as lymphocytic infiltration. This disease is considered benign because of its tendency toward spontaneous resolution, even though symptoms are usually intense. A male patient presented cervical lymph node enlargement, constitutional syndrome, and hematological manifestations, including oscillating thrombocytopenia, leukopenia, and increased ESR. The diagnosis was inflammatory pseudotumor of the lymph nodes, a rare disease. The evolution is torpid but the prognosis is good. This disease should be considered in the differential diagnosis of tumors of the neck region.

[Otogenic cerebral abscess: a persistent problem]. / Absceso cerebral otógeno: un problema persistente.

A young man with otitis media and cholesteatoma of the left ear developed secondary cerebral abscess. The clinical debut was non-specific, with headache, mild fever, and mild persistent otalgia in spite of early antibiotic treatment. Studies revealed a cerebral abscess, so ENT surgery in collaboration with the neurosurgery department was decided. This case illustrates that clinical manifestations in such cases can be mild and highlights the need to exclude this type of serious pathology.

Seudotumor inflamatorio de ganglios linfáticos. A propósito de un caso / Inflammatory pseudoturnor of the lymph nodes. A case report

El seudotumor inflamatorio de ganglios linfáticos es una entidad poco conocida que se caracteriza por cursar con adenopatías de localización fundamentalmente cervical, manifestaciones hematológicas y una importante sintomatología constitucional. El diagnóstico se hace mediante el examen anatomopatológico, previa excisión quirúrgica, de una adenopatía. El patrón histológico consiste básicamente en proliferación estromal, neoformación de vasos, e infiltrado linfocitario. La enfermedad se considera benigna dada su evolución autorresolutiva a pesar de la intensidad de su sintomatología. Presentamos el caso clínico de un paciente con adenopatías cervicales, síndrome constitucional y manifestaciones hematológicas, entre las que destacó una trombocitopenia de carácter oscilante, leucopenia y aumento de la VSG. El diagnóstico fue seudotumor inflamatorio de ganglios linfáticos: una enfermedad rara, de evolución confusa y de pronóstico bueno y que es necesario tener en cuenta en el diagnóstico diferencial de las masas de localización cervical (AU)

Inflammatory pseudotumor of the lymph nodes is a little-known condition characterized mainly by cervical lymph node enlargement, hematological manifestations, and major constitutional symptoms in most patients. The diagnosis is histological, after surgical removal of an involved lymph node. Histologically, stromal proliferation and neovascularity are present, as well as lymphocytic infiltration. This disease is considered benign because of its tendency toward spontaneous resolution, even though symptoms are usually intense. A male patient presented cervical lymph node enlargement, constitutional syndrome, and hematological manifestations, including oscillating thrombocytopenia, leukopenia, and increased ESR. The diagnosis was inflammatory pseudotumor of the lymph nodes, a rare disease. The evolution is torpid but the prognosis is good. This disease should be considered in the differential diagnosis of tumors of the neck region (AU)

Identification of pharmacokinetically stable 3, 10-dibromo-8-chlorobenzocycloheptapyridine farnesyl protein transferase inhibitors with potent enzyme and cellular activities.

Farnesyl protein transferase (FPT) is a promising target for the development of cancer chemotherapeutics because it is responsible for the farnesylation of oncogenic p21 Ras proteins which are found in nearly 30% of all human cancers and necessary for cellular development and growth. The recent discovery and progression to phase II clinical trials of trihalobenzocycloheptapyridine Sch-66336 as a potent inhibitor of FPT with oral, in vivo efficacy in mice have spawned extensive structure-activity relationship studies (SAR) of this class of compounds. Of the many trihalobenzocycloheptapyridine analogues prepared, we have identified several which inhibit FPT and cellular proliferation at single-digit nanomolar concentrations and which have good pharmacokinetic properties in mice.

Tricyclic farnesyl protein transferase inhibitors: crystallographic and calorimetric studies of structure-activity relationships.

Crystallographic and thermodynamic studies of farnesyl protein transferase (FPT) complexed with novel tricyclic inhibitors provide insights into the observed SAR for this unique class of nonpeptidic FPT inhibitors. The crystallographic structures reveal a binding pattern conserved across the mono-, di-, and trihalogen series. In the complexes, the tricycle spans the FPT active site cavity and interacts with both protein atoms and the isoprenoid portion of bound farnesyl diphosphate. An amide carbonyl, common to the tricyclic compounds described here, participates in a water-mediated hydrogen bond to the protein backbone. Ten high-resolution crystal structures of inhibitors complexed with FPT are reported. Included are crystallographic data for FPT complexed with SCH 66336, a compound currently undergoing clinical trials as an anticancer agent (SCH 66336, 4-[2-[4-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5, 6]cyclohepta[1, 2-b]pyridin-11-yl)-1-piperidinyl]-2-oxoethyl]-1-piperidinecarbo xamide ). Thermodynamic binding parameters show favorable enthalpies of complex formation and small net entropic contributions as observed for 4-[2-[4-(3,10-dibromo-8-chloro-6,11-dihydro-11H-benzo[5, 6]cyclohepta[1, 2-b]pyridin-11-ylidene)-1-piperidinyl]-2-oxoethyl]pyridine N-oxide where DeltaH degrees bind = -12.5 kcal/mol and TDeltaS degrees bind = -1.5 kcal/mol.

Interaction of a novel GDP exchange inhibitor with the Ras protein.

Mutated, tumorigenic Ras is present in a variety of human tumors. Compounds that inhibit tumorigenic Ras function may be useful in the treatment of Ras-related tumors. The interaction of a novel GDP exchange inhibitor (SCH-54292) with the Ras-GDP protein was studied by NMR spectroscopy. The binding of the inhibitor to the Ras protein was enhanced at low Mg2+ concentrations, which enabled the preparation of a stable complex for NMR study. To understand the enhanced inhibitor binding and the increased GDP dissociation rates of the Ras protein, the conformational changes of the Ras protein at low Mg2+ concentrations was investigated using two-dimensional 1H-15N HSQC experiments. The Ras protein existed in two conformations in slow exchange on the NMR time scale under such conditions. The conformational changes mainly occurred in the GDP binding pocket, in the switch I and the switch II regions, and were reversible. The Ras protein resumed its regular conformation after an excess amount of Mg2+ was added. A model of the inhibitor in complex with the Ras-GDP protein was derived from intra- and intermolecular NOE distance constraints, and revealed that the inhibitor bound to the critical switch II region of the Ras protein.

Use of technetium-tagged white blood cells in patients with Crohn's disease and ulcerative colitis: is differential diagnosis possible?

BACKGROUND: Studies have suggested that scans with technetium-tagged white blood cells (WBC-Tc99m) may be equal to endoscopy in the assessment of extent and activity of inflammatory bowel disease (IBD). OBJECTIVE: We have retrospectively examined the accuracy of WBC-Tc99m scans in differentiating continuous from discontinuous colitis in pediatric IBD. MATERIALS AND METHODS: There were 207 children in the study (96 boys, 111 girls, median age 13 years). This included 29 controls - children with no gastrointestinal disease (NL) who underwent WBC-Tc99m scans for other medical problems. Scans were obtained at 30 minutes and 2-4 hours following injection. Scans were interpreted as showing continuous colitis, discontinuous colitis, or no colitis. RESULTS: In the 77 children with active Crohn's disease (CD) of the colon, the scans revealed discontinuous uptake in 63 children and continuous uptake in 14. In the 29 children with ulcerative colitis (UC), 23 scans showed continuous uptake and 6 revealed discontinuous uptake. Two of these 6 showed focal activity near the appendix, and subclinical appendicitis could not be excluded. Another child was bleeding and the scan could have been misinterpreted as showing small- bowel inflammation. In the last three patients, skip areas were clearly identifiable. In none of these last three patients were the biopsies typical of CD (i. e., no granuloma was identified) nor was inflammation patchy. In summary, of the 106 scans showing inflammation, 6 were classified into the wrong group. CONCLUSION: These data show that WBC-Tc99m scanning can be useful in distinguishing discontinuous from continuous colitis.