Electron Signatures of Reconnection in a Global eVlasiator Simulation.

Geospace plasma simulations have progressed toward more realistic descriptions of the solar wind-magnetosphere interaction from magnetohydrodynamic to hybrid ion-kinetic, such as the state-of-the-art Vlasiator model. Despite computational advances, electron scales have been out of reach in a global setting. eVlasiator, a novel Vlasiator submodule, shows for the first time how electromagnetic fields driven by global hybrid-ion kinetics influence electrons, resulting in kinetic signatures. We analyze simulated electron distributions associated with reconnection sites and compare them with Magnetospheric Multiscale (MMS) spacecraft observations. Comparison with MMS shows that key electron features, such as reconnection inflows, heated outflows, flat-top distributions, and bidirectional streaming, are in remarkable agreement. Thus, we show that many reconnection-related features can be reproduced despite strongly truncated electron physics and an ion-scale spatial resolution. Ion-scale dynamics and ion-driven magnetic fields are shown to be significantly responsible for the environment that produces electron dynamics observed by spacecraft in near-Earth plasmas.

Diagnostic yield of capsule endoscopy in ulcerative colitis and inflammatory bowel disease of unclassified type (IBDU).

BACKGROUND AND STUDY AIMS: Capsule endoscopy is increasingly reported as an important diagnostic procedure in patients with known or suspected Crohn's disease, but its clinical utility in patients with ulcerative colitis or unclassified type inflammatory bowel disease (IBDU) is unclear. The aim of our study was to determine the diagnostic yield of capsule endoscopy for small-bowel disease in patients with ulcerative colitis and IBDU. PATIENTS AND METHODS: All data from patients with a history of ulcerative colitis or IBDU who underwent capsule endoscopy between October 2001 and August 2005 were analyzed for procedure indications and findings. Images were reviewed by an experienced capsule endoscopist. The finding of multiple ulcerations (three or more) on capsule endoscopy was classified as diagnostic of small-bowel Crohn's disease. RESULTS: 120 patients had undergone 122 capsule endoscopy procedures. Overall, 19 of 120 patients (15.8 %) had capsule endoscopy findings consistent with the diagnosis of Crohn's disease. The proportion of patients with small-bowel disease was significantly higher among patients with a history of colectomy (7 of 21 patients, 33 %) compared with those without colectomy (12/99, 12 %) ( P = 0.04). Among patients with positive findings on capsule endoscopy, 18 had also previously undergone a small-bowel follow-through study and only one showed findings consistent with Crohn's disease. CONCLUSIONS: Many patients with a diagnosis of ulcerative colitis and atypical features or IBDU may have small-bowel findings on capsule endoscopy that are consistent with Crohn's disease. Capsule endoscopy should be considered in ulcerative colitis patients with atypical clinical features particularly after colectomy.

Apolipoprotein A-I inhibits experimental colitis and colitis-propelled carcinogenesis.

In both humans with long-standing ulcerative colitis and mouse models of colitis-associated carcinogenesis (CAC), tumors develop predominantly in the distal part of the large intestine but the biological basis of this intriguing pathology remains unknown. Herein we report intrinsic differences in gene expression between proximal and distal colon in the mouse, which are augmented during dextran sodium sulfate (DSS)/azoxymethane (AOM)-induced CAC. Functional enrichment of differentially expressed genes identified discrete biological pathways operating in proximal vs distal intestine and revealed a cluster of genes involved in lipid metabolism to be associated with the disease-resistant proximal colon. Guided by this finding, we have further interrogated the expression and function of one of these genes, apolipoprotein A-I (ApoA-I), a major component of high-density lipoprotein. We show that ApoA-I is expressed at higher levels in the proximal compared with the distal part of the colon and its ablation in mice results in exaggerated DSS-induced colitis and disruption of epithelial architecture in larger areas of the large intestine. Conversely, treatment with an ApoA-I mimetic peptide ameliorated the phenotypic, histopathological and inflammatory manifestations of the disease. Genetic interference with ApoA-I levels in vivo impacted on the number, size and distribution of AOM/DSS-induced colon tumors. Mechanistically, ApoA-I was found to modulate signal transducer and activator of transcription 3 (STAT3) and nuclear factor-κB activation in response to the bacterial product lipopolysaccharide with concomitant impairment in the production of the pathogenic cytokine interleukin-6. Collectively, these data demonstrate a novel protective role for ApoA-I in colitis and CAC and unravel an unprecedented link between lipid metabolic processes and intestinal pathologies.

Stenotrophomonas (Xanthomonas) maltophilia urinary tract infection. A disease that is usually severe and complicated.

BACKGROUND: Stenotrophomonas (Xanthomonas) maltophilia has emerged as a causative agent of serious nosocomial infections. However, well-documented cases of urinary tract infection with this organism have rarely been reported. METHODS: review of the medical records of patients admitted to a large cancer center with cultures yielding S maltophilia from urinary sources during a 15-month period. RESULTS: All urinary tract infections were serious: 13 were complicated and two were acute uncomplicated pyelonephritis. The urinary tracts of 13 other patients were colonized with S maltophilia. Most of the colonized and infected patients were hospitalized with genitourinary malignancy, underwent urinary catheterization, and were receiving antibiotics inactive against S maltophilia. Neutropenia and urinary structural abnormalities were significantly associated with infection. The clinical course of infection was usually severe: fever (100%), sepsis disorder (47%), neutrophilia (70% of patients without neutropenia), bacteremia (13%) and death (7%). Still, response to treatment was prompt. CONCLUSIONS: Stenotrophomonas maltophilia urinary tract infection is usually associated with a severe clinical course. Risk factors for urinary colonization by this organism include hospitalization, urinary catheterization, and administration of inactive antibiotics. Risk factors for urinary tract infection include neutropenia and urinary structural abnormalities. In the presence of these risk factors, treatment of S maltophilia should be considered in patients with urinary colonization by the organism or in those with nosocomial urinary tract infection caused by an unknown pathogen and that is unresponsive to therapy with the antibiotics that are used to treat the common uropathogens.

Descending phlebography in patients with venous ulceration: hemodynamic implications.

AIM: The aim of this paper is to report on the hemodynamic significance of the various degrees reflux as demonstrated on descending phlebography, by comparing the phlebographic findings with ambulatory venous pressure (AVP) measurements. METHOD: Thirty-two patients (45 affected limbs) with active or healed venous ulceration were admitted to the study. Descending phlebography with grading of reflux (0-4 using Herman's grading), AVP and refilling time 90 (RT90) were performed in all patients. In addition, the presence of deep to superficial reflux into the great saphenous vein at the sapheno-femoral junction, thigh incompetent perforating veins, small saphenous vein at the saphenopopliteal junction and incompetent calf perforating veins was recorded using ascending functional phlebography. The examined limbs were separated into two groups according to the Grade of reflux. Group I consisted of limbs in which popliteal valve incompetence was not demonstrated on descending phlebography, i.e., Grades 0-2 (18 limbs). Group II consisted of limbs with popliteal reflux as demonstrated by descending venography, i.e., grades 3 and 4 (27 limbs). RESULTS: In Group I the mean AVP ± SD was 47.2 ± 9.3 mmHg (range 31-67 mmHg). After the application of the ankle tourniquet to exclude the effects of the superficial venous incompetence on the pressure recordings, the mean AVP ± SD became 28.1 ± 9.9 mmHg (range 11-44) (paired t test: P < 0.001). In Group II (limbs with incompetent popliteal valves) the mean AVP ± SD was 71.6 ± 12.7 mmHg (range 49-95 mmHg) before the tourniquet. This was significantly higher than in Group I (t test: P < 0.001). The application of the ankle tourniquet in this group produced a small but significant decrease in the AVP (mean AVP ± SD: 66 ± 14.5 mmHg) (paired t test: P < 0.001). CONCLUSION: Incompetence of the femoral valves in the presence of competent popliteal valves adds very little to the hemodynamic abnormality produced by superficial venous reflux. In the majority of these patients, there is co-existing reflux from deep to superficial veins with associated superficial valve incompetence which is responsible for the venous hypertension, skin changes and ulceration. The hemodynamic changes which in the past had been associated with deep venous insufficiency (AVP >45 mmHg and RT90 < 14 seconds despite the application of an ankle tourniquet) occur only when there is popliteal incompetence.

Fluconazole versus amphotericin B in the treatment of hematogenous candidiasis: a matched cohort study.

PURPOSE: To compare the efficacy and toxicity of fluconazole and amphotericin B in the treatment of hematogenous candidiasis in cancer patients. PATIENTS AND METHODS: A matched cohort study of cancer patients with hematogenous candidiasis was conducted. Forty-five patients with hematogenous candidiasis who received fluconazole (200 to 600 mg/day) in an open-label trial at the University of Texas M. D. Anderson Cancer Center, Houston, Texas, between February 1990 and June 1992 were matched to 45 patients treated with amphotericin B (0.3 to 1.2 mg/kg/day) for the same diagnosis. Criteria for matching included the following prognostic variables at the initiation of therapy: pneumonia, neutropenia (< 1,000 cells/mm3), number of positive blood cultures before therapy, infecting Candida species, underlying disease, and the simplified acute physiology score. Response and survival at 48 hours, after 5 days of therapy, and at the end of therapy, as well as toxicity rates were obtained. Other post hoc analyses were performed. Differences in outcomes were assessed by the McNemar, the sign, and the log rank tests. RESULTS: Patients were similar with respect to the matching criteria, age, sex, status of underlying disease, use of antibiotics and growth factors, duration of treatment, presence and removal of central venous catheters, disseminated disease, and concomitant infections. Response rates at 48 hours and 5 days were similar between the two study groups. Overall response rates at the end of therapy were 73% for patients treated with fluconazole and 71% for patients treated with amphotericin B (P = 0.78). There were no differences in survival rates or causes of death. Toxicity was observed in 9% of patients treated with fluconazole and in 67% of patients treated with amphotericin B (P < 0.0001). Toxic effects of amphotericin B included nephrotoxicity, hypokaliemia, and fever and chills. CONCLUSION: Fluconazole is effective and better tolerated than amphotericin B for the treatment of hematogenous candidiasis in cancer patients.

The role of chemokines and chemokine receptors in mucosal inflammation.

Chemokines represent a large family of small cytokines, the main function of which is the attraction of leukocytes to different tissues. Several chemokines and their receptors have been shown to play a critical role in lymphoid development, mucosal immunity, and inflammation. In this article we review recent advances in chemokine physiology and their potential role in the pathogenesis of mucosal inflammation. We also discuss the potential for the use of chemokine or chemokine receptor antagonists as novel therapies for inflammatory bowel disease.

Infliximab in the treatment of medically refractory indeterminate colitis.

AIM: To examine the outcome of infliximab intervention in refractory indeterminate colitis. METHODS: Twenty patients with severe, medically refractory indeterminate colitis were treated with infliximab. All patients initially received infliximab, 5 mg/kg, intravenously and, in some patients, the dose was subsequently increased to 10 mg/kg. The number of infusions ranged from one to 16 per patient. Indeterminate colitis was defined as colitis that could not be classified with certainty as Crohn's disease or ulcerative colitis based on traditional clinical, endoscopic and histopathological criteria. The clinical response to infliximab was classified as complete response, partial response or non-response. RESULTS: Fourteen of the 20 patients (70%) showed a complete response to infliximab treatment, two showed a partial response and four showed no response. The four non-responders underwent colectomy with ileal pouch-anal anastomosis. The resected colon specimen was consistent with ulcerative colitis in all four cases, although two were subsequently re-classified as Crohn's disease. Eight additional patients were subsequently re-classified as having Crohn's disease on longer follow-up evaluation, whilst eight continued to have features of indeterminate colitis. The response rate to infliximab treatment was similar in both groups. CONCLUSIONS: Infliximab is effective in approximately two-thirds of patients with indeterminate colitis, and thus may be considered for patients with refractory disease prior to colectomy. The follow-up time afforded by infliximab treatment may allow for more accurate classification of the disease in a significant proportion of patients whose colitis has indeterminate features at initial presentation.

Fate of the type II pneumocyte following tracheal occlusion in utero: a time-course study in fetal sheep.

Tracheal occlusion in utero has been shown to cause accelerated fetal lung growth and is now being considered as a therapeutic modality for pulmonary hypoplasia. We report the effects of tracheal ligation on the surfactant-producing type II pneumocyte population. Three groups of fetal lambs underwent tracheal ligation of 2 weeks', 4 weeks' and 6 weeks' duration, respectively, and all were sacrificed at 136 days' gestation (9 days pre-term). Nonoperated twins served as controls. The type II pneumocyte population was studied morphometrically using a combination of anti-surfactant protein B immunohistochemistry and computer-assisted stereologic morphometry at light and electron microscopic levels. Single-factor ANOVA was used for statistical analysis. Two weeks of tracheal ligation resulted in doubling of the total lung volume as a result of airspace distension and, to lesser extent, growth of the tissue compartment. With increasing duration of tracheal ligation, there was no additional lung growth. However, more prolonged tracheal occlusion was found to result in significant reduction of the surfactant system, as reflected in the marked decrease of total pneumocyte type II volume (3.14 cm3, 0.95 cm3, and 0.46 cm3, after 2, 4, and 6 weeks of ligation, compared with 5.96 cm3 for controls) and total pneumocyte type II number (13.9 x 10(9), 3.8 x 10(9), and 2.4 x 10(9), compared with 53.2 x 10(9) for controls). Ultrastructural analysis of the type II cells in obstructed lungs showed vacuolar degenerative changes that, after 6 weeks of ligation, were apparently irreversible. In utero tracheal ligation causes fetal lung hyperplasia, but results in reduction of and injury to the surfactant-producing cell population. Before tracheal occlusion can find wide-spread clinical application, its pathophysiology needs to be further elucidated.

Stenotrophomonas maltophilia meningitis. Report of two cases and review of the literature.

The authors report two cases of meningitis caused by Stenotrophomonas maltophilia in cancer patients following placement of an Ommaya reservoir for treatment of meningeal carcinomatosis. In addition, they review eight other cases of S. maltophilia that have been reported to date. Stenotrophomonas maltophilia meningitis is often associated with neurosurgical procedures; however, spontaneous infection may also occur, mainly in neonates. The disease's clinical presentation is similar to that of other forms of meningitis caused by Gram-negative bacilli. The overall mortality rate of this disease is 20% and is limited to neonates with spontaneous meningitis in whom effective antibiotic therapy is delayed. Meningitis caused by S. maltophilia in the modern era should be considered in immunocompromised hosts with significant central nervous system disease who have undergone neurosurgical procedures and who do not readily respond to broad-spectrum antimicrobial coverage.

Double-bond patterns of fatty acids and alcohols in steer and human meibomian gland lipids.

Ozonolysis studies of the monoenes of the fatty chain types in lipids of steer meibomian gland excreta (meibum) have confirmed earlier structural assignments based on gas liquid chromatography (GLC) retention data and have assisted in assigning complete structures to a group of recently identified omega-hydroxy fatty acids. The omega-hydroxy acids include straight-chain monoenoic acids (85%), saturated anteiso and iso acids (13%), monoenoic acids of the latter group (1%) and, finally, saturates of the normal monoenoic acids (1%). All the fatty chains of meibum can be biosynthesized by a unified process of chain buildup to primary chain lengths of 12:0-20:0 for the straight evens, with 16:0 predominating, 13:0-21:0 for the straight odds with 17:0 predominating, i16:0 to i28:0 for the iso and ai17:0 to ai29:0 for the anteiso chain types; then delta 9 desaturation of each of these chain types: and finally chain elongation of 1-10 C2 units. Some chain degradation may also occur. The meibum lipid components involved are unsubstituted fatty acids, alpha-OH fatty acids, alpha-OH fatty acids, omega-OH fatty acids, fatty alcohols and some other lipid components incompletely characterized. The carbon skeletons are straight even, straight odd, iso and anteiso except that the alpha-OH fatty acids are only straight even and straight odd and these chains are not elongated. All fatty chains are almost entirely saturated and monoenoic, the polyenes occurring in only trace amounts. Biosynthesis of the fatty chains of human meibum evidently occurs similarly, except that considerably more 18:0 than 16:0 fatty acids are built up by the fatty acid synthetase, before desaturation and extension.

The occurrence of long chain alpha, omega-diols in the lipids of steer and human meibomian glands.

A group of long chain alpha, omega-diols (C29 to C34) has been identified in the lipids of steer and human meibomian gland excreta (meibum). These new lipids were isolated from the steer meibum unsaponifiables. Proof of structure was provided by 1) the column chromatographic behavior and TLC of the diols and their diacetates; 2) GLC on glass capillary columns; 3) fragmentation patterns in GC-MS; 4) NMR data, and 5) ozonolysis studies of the unsaturates. Chain types for the steer sample were 51% straight monoenes, 8.5% straight saturates, 39% iso and anteiso saturates and 1.5% iso and anteiso unsaturates. GC for the human sample gave straight monoenes 83%, straight saturates 8%, and iso plus anteiso saturates 9%. Close correspondence of the alpha, omega-diol chain lengths and types with meibum omega-hydroxy fatty acids suggests a biochemical precursor relationship.

Fetal lung growth after tracheal ligation is not solely a pressure phenomenon.

Fetal tracheal ligation increases lung growth in utero, making it potentially applicable for antenatal treatment of diaphragmatic hernia. This phenomenon has been ascribed to increased intratracheal pressure, which activates as yet unidentified pulmonary stretch receptors. The purpose of this study was to determine whether the composition of lung fluid has any effect on fetal lung development after tracheal obstruction. Six sets of fetal lamb twins underwent tracheal ligation with placement of intratracheal catheters at 122 days' gestation (term, 145 days). In group 1 (n = 6), tracheal fluid was aspirated daily, measured, and replaced with equal volumes of saline. Their respective twins (group 2, n = 6) had daily reinfusion of their own tracheal aspirates. Intratracheal pressure was recorded daily in both groups. Unobstructed fetal lambs (n = 7) were used as negative controls. Animals were killed on postoperative day 14 (136 days). Lungs were weighed, perfusion fixed at 25 cm H2O, and processed for standard morphometric analysis. Intratracheal pressure remained between 3 and 5 torr in both experimental groups throughout the entire postoperative period. In all 12 experimental fetuses, tracheal ligation resulted in an almost threefold increase in lung fluid volume by day 1; a slight decrease at a mean of 2.4 days; and a second surge from day 4 on. Lung fluid volume was significantly higher in group 2 than in group 1 at all measured time points (P < .05, Wilcoxon rank sum test) except on days 3, 4, and 8 (P = .06). Lung weight per body weight (LW/BW) at delivery was 0.045 +/- 0.008 in group 1, not significantly different from unobstructed controls (0.038 +/- 0.006). LW/BW in group 2 was 0.055 +/- 0.010, significantly larger than either group 1 or control (P < .05, single factor analysis of variance). Air space fraction was comparable between the three groups. Alveolar numerical density was significantly lower in groups 1 and 2 than in unobstructed controls (P < 0.05). Replacement of tracheal fluid with saline inhibits the lung hypertrophy seen after tracheal ligation. This phenomenon therefore appears more dependent on tracheal fluid growth factors than on increased intratracheal pressure after obstruction. The immediate decrease in net lung fluid production after saline exchange suggests that these humoral factors play an important role in the initiation of lung cell proliferation.

Predictive value of monitoring parameters in fetal surgery.

BACKGROUND/PURPOSE: The choice of monitoring parameters in fetal surgery has thus far been based on feasibility rather than on predictability. Ideally, monitoring should be noninvasive, have a rapid response time and high sensitivity, and be applicable to open and endoscopic techniques. Herein, the authors studied the response of several parameters to standardized episodes of fetal ischemia and stress. METHODS: Eight time-dated fetal lambs (110 days, term, 145 days) were used. Under general anesthesia, a balloon occluder was placed around the umbilical cord. Pulse oximetry (POx + heart rate, HR), electrocardiography (ECG), direct oximetry (DOx), and blood pressure (BP) were recorded continuously. After stabilization, the umbilical cord was completely occluded for 5 seconds, then released. False-negative recordings were defined as failure of a parameter to respond to umbilical occlusion; false-positive episodes were defined as 10% change in value over < or = 10 seconds during stabilization (baseline) period. RESULTS: The fetuses were monitored for an aggregate of 358 minutes. Baseline DOx was 64%+/-5%, POx, 66%+/-16%; HR, 141+/-18 beats per minute (bpm); systolic BP (SBP), 51+/-3 torr; and diastolic BP (DBP), 38+/-2 torr. During umbilical occlusion (n=15), SBP increased to 56+/-3 torr and DBP to 43+/-2 torr at 0.5 seconds, then returned to baseline at 8.0 seconds. A decrease was seen in DOx (start at 3.5s, maximum delta 9.9+/-1.5% at 10.5 seconds) and POx (start at 4.2 seconds, maximum delta 7.3+/-2.4% at 20.5 seconds). Heart rate showed <10% decrease (start at 8.5 seconds, nadir 131+/-14 bpm at 19.5 seconds). No ECG changes were noted. Sensitivity was 100% for DOx, POx, and BP, but only 14% for HR; specificity was 97% for DOx and 88% for POx; positive predictive value was 58% for DOx and 37% for POx; negative predictive value was 100% for DOx and POx. CONCLUSIONS: Direct intravascular oximetry and blood pressure provide a prompt and reliable response to acute fetal stress, but are too invasive for routine use. Bradycardia is an insensitive and late sign of fetal distress. Pulse oximetry has a rapid response time (<5 seconds), high sensitivity, and negative predictive value. In addition, its application is noninvasive and has proven to be feasible in open and endoscopic fetal surgical procedures. It therefore appears to be the monitoring parameter of choice for fetal surgery.

Temporary tracheal occlusion causes catch-up lung maturation in a fetal model of diaphragmatic hernia.

BACKGROUND: The lungs of infants born with diaphragmatic hernia are hypoplastic, immature, and surfactant-deficient. Tracheal occlusion in utero, which is being proposed as antenatal treatment of diaphragmatic hernia by promoting compensatory lung growth, decreases surfactant production as well, through loss of type II pneumocytes. The authors studied whether temporary tracheal occlusion might cause 'catch-up' lung growth and maturation, without negative effects of prolonged tracheal occlusion on the surfactant system. METHODS: Diaphragmatic hernia was created in time-dated fetal lambs (65 to 75 days). At 108 days, the trachea was occluded with an embolectomy catheter (DH + TO, n = 6). After day 14, the balloon was deflated. Six congenital diaphragmatic hernia (CDH) fetuses were left unobstructed (DH). For comparison, a group of fetuses without diaphragmatic hernia were subjected to prolonged tracheal ligation (TL; 4-week tracheal ligation, n = 3). Unoperated littermates (n = 8) were used as controls (CTR). All were killed near term. Lung tissue was processed for light and electron microscopy (computerized stereologic morphometry). Type II pneumocytes were identified with antisurfactant protein B antibody. RESULTS: Four animals in DH + TO and four in DH survived to term. Lung fluid volume (LFV) at 108 days was 5.2 +/- 4.4 mL in DH and 24.6 +/- 6.8 mL in controls (P < .05, Student t test). In DH + TO, LFV increased ninefold (to 48.3 +/- 13.3 mL) by 1 week postocclusion, suggesting accelerated lung growth. At term, lung weight to body weight ratio (LW/BW) was higher in TL (9.85% +/- 1.81%) than in CTR (3.55% +/- 0.56%; P < .05, analysis of variance); LW/BW and parenchymal volume tended to be greater in DH + TO than in DH, and air-exchanging parenchymal volume in DH + TO was similar to CTR (v a 50% reduction in DH), indicating some degree of hyperplasia after temporary occlusion. Pneumocyte II numerical density was decreased more than 10-fold in TL (60 +/- 22 v 826 +/- 324 in CTR, P < .001; it was slightly lower in DH + TO than in CTR, but individual type II pneumocyte cell volume was greater in the latter, and they appeared more mature than in DH (increased granulation by light microscopy, fewer glycogen granules, and abundant lamellar bodies by electron microscopy). Surfactant was also seen in the air spaces in DH + TO and CTR; it was absent in unobstructed CDH and in TL. CONCLUSIONS: Temporary tracheal occlusion in utero does not cause the dramatic decrease in type II pneumocytes seen after prolonged occlusion. Although only minimal increase in lung volume is seen in CDH, catch-up parenchymal growth and maturation occur, most notably in the surfactant-producing system.

Single-port tracheoscopic surgery in the fetal lamb.

BACKGROUND/PURPOSE: Endoscopic fetal surgery could help avoid many of the problems associated with open fetal surgery, but the use of multiple ports may be too traumatic to the membranes. The authors describe a single-port technique of tracheoscopic surgery in the fetus. METHODS: Time-dated pregnant ewes (95 to 105 days; term, 145 days) underwent midline laparotomy under general halothane anesthesia. A 5-mm-diameter balloon-tipped cannula was introduced in the uterus by Seldinger technique. A 1.2-mm semirigid mini-endoscope, fitted inside a 9F, 20 degrees curved sheath, was introduced under continuous, low-pressure irrigation, inside the fetus' mouth, and advanced into the trachea. RESULTS: Endotracheal procedures, including temporary (n = 11) and permanent balloon tracheal occlusion (n = 30) and placement of a barbed guide wire for endotracheal occlusion device insertion (n = 12), were performed by introducing a 1-mm diameter instrument alongside the telescope. These were successfully performed in 52 of the 53 fetuses. The rigidity of the telescope allowed controlled access to the pharynx; its curve allowed full tracheobronchial endoscopy with the fetus in utero. CONCLUSIONS: The present technique marries the control and optical quality of a rigid endoscope with the physiological curve only a flexible instrument could offer until now. The types of procedures performed with this technique illustrate its potential as a research tool; the size (1.2-mm diameter), shape, and optical qualities of the telescope should make clinical applications possible.

The role of apoptosis in normal and accelerated lung development in fetal rabbits.

BACKGROUND/PURPOSE: During fetal development, the mammalian lung undergoes progressive parenchymal involution. Intrauterine tracheal occlusion induces accelerated architectural maturation of the fetal lungs associated with depletion of the surfactant-producing type II cells. This study investigates the spatiotemporal pattern of apoptosis during normal fetal lung development and its modulation in tracheal occlusion-induced accelerated fetal lung growth. METHODS: Fetal rabbit lungs were studied at 25 to 31 days' gestational age (DGA; term, 31 DGA), corresponding to late pseudoglandular through terminal air sac stages of fetal lung development. Intrauterine tracheal ligation (TL) was performed at 24 DGA. TL fetuses were monitored until 29 DGA, a time-point previously shown to coincide with significant type II cell depletion. Apoptotic cells were identified by light and electron microscopy, as well as terminal deoxynucleotidyl transferase-mediated dUTP-FITC nick-end labeling (TUNEL). Epithelial (type I and II) cell apoptosis was studied by TUNEL labeling in conjunction with antisurfactant protein and anticytokeratin immunohistochemistry. DNA fragmentation was analyzed by gel electrophoresis. Sham-operated littermates served as controls. RESULTS: The number of apoptotic cells progressively increased with advancing lung growth and architectural maturation (apoptotic index [Al] 1.2 +/- 0.7 x 10(-3) at 25 DGA v 4.2 +/- 1.4 x 10(-3) at 31 DGA; P< .05, analysis of variance). In TL fetuses, the apoptotic rate was significantly higher than in non-TL fetuses from the third postligation day on, coinciding with the onset of significantly increased airspace distension (Al 4.9 +/- 1.3 x 10(-3) in TL v2.6 +/- 0.4 x 10(-3) in controls at 29 DGA; P< .05, Student's ttest). Apoptosis occurred in parenchymal cells and in isolated cells within the airspaces. The apoptotic activity of type II cells was significantly higher in TL fetuses than C fetuses at 29 DGA (type II Al 25.5 +/- 6.3 x 10(-3) in TL v2.3 +/- 0.8 x 10(-3) in C; P< .001). Electron microscopic studies confirmed the presence of apoptotic nuclei in interstitial macrophages and in degenerating intraluminal type II cells. DNA analysis showed nucleosomal bands. CONCLUSIONS: Normal fetal lung development is associated with a progressive increase of epithelial and interstitial apoptotic activity, a process enhanced by TL. Tracheal occlusion induces a significant increase of type II cell apoptosis, which likely contributes to the observed type II cell depletion after TL. We speculate that fetal type II cell apoptosis after TL may be induced by mechanical distension (stretch) of the airspaces.

Noninvasive detection of coronary artery disease in patients presenting with claudication.

ECG chest wall mapping with bicycle ergometry which can detect not only myocardial ischaemia but also individual coronary artery territories involved has been used to screen 100 consecutive patients presenting with claudication. Fifty-three had a positive history and/or evidence of ischaemic heart disease on a resting ECG. The test was positive in 38, negative in 38 and inconclusive in 24, the latter because of inadequate heart rate response. In 11 out of 38 (29%) with a positive test there was no history or evidence of myocardial ischaemia on a conventional resting ECG. ECG changes suggestive of three vessel coronary disease were found in three, single vessel coronary disease in 16 and two vessel disease in 19. Of the latter, eight had changes in the LAD/circumflex distribution, indicating left main stem or equivalent disease. These together with the three with triple vessel coronary disease constituted a subset of 11 (11%) high risk patients who merited coronary angiography with a view to confirming the presence of severe coronary disease.

The effect of enalapril on leg muscle blood flow in patients with claudication.

In the percent study the authors have demonstrated that the peripheral blood flow and resistance as measured by strain-gauge venous occlusion plethysmography were favourably altered by enalapril. The peripheral blood flow increased significantly and since there was no detectable change in ankle pressure this indicated a decrease in resistance during administration of the drug.

Treatment of experimental murine colitis with CD40 antisense oligonucleotides delivered in amphoteric liposomes.

BACKGROUND AND AIMS: CD40-CD40L interactions appear to play an important role in the pathogenesis of experimental colitis. We tested the effect and investigated the underlying mechanism of action of systemically administered antisense oligonucleotide (ASO) targeting CD40 formulated in amphoteric liposomes (nov038/CD40). The charge characteristics of the amphoteric liposomes (anionic surface charge at physiological pH that becomes cationic at low pH), facilitate efficient sequestration of the ASO inside the liposomes at low pH and the direction of the carriers towards macrophages and dendritic cells under physiological conditions. METHODS: Colitis was induced in Balb/c mice using 2,4,6-Trinitrobenzene sulphonic acid (TNBS) and treated with nov038/CD40. Disease was monitored by body weight, histology, cytokine profiling and changes in immune cell populations. CD40 expression on different cell subsets was analyzed by flow cytometry. An antigen challenge model was used to determine neoimmunity under CD40 modulation. RESULTS: Administration of nov038/CD40 inhibited the development of TNBS colitis as assessed by weight loss, histology and cytokine profiles; unformulated CD40 ASO or nov038 encapsulating an unrelated ASO (nov038/SCR) were ineffective. The novel agent is potent as it completely suppressed even established colitis with a single treatment and significantly reduced T-cell activation as well as levels of pro-inflammatory mediators in serum. The inhibition of CD40 specifically occurred in macrophages, but not in B-cells. In contrast to prednisolone, standard treatment for inflammatory bowel diseases (IBD) that is effective in a single administration and involves extensive immunosuppression, nov038/CD40 did not affect the number of B- or Treg cells. Eventually, we observed a largely intact neoimmunity under conditions of a CD40 inhibition. CONCLUSIONS: Administration of nov038/CD40, but neither naked CD40 ASO nor nov038/SCR, prevents the development and treats established colitis in mice. Delivery of CD40 ASO in nov038 is highly cell-specific as it selectively suppresses CD40 on macrophages, but not on B-cells; the novel agent has strong anti-inflammatory characteristics without being immunosuppressive.