Long-term treatment with anti-alpha 4 integrin antibodies aggravates colitis in G alpha i2-deficient mice

Targeted deletion of the heterotrimeric G protein, Galphai2, in mice induces lethal colitis closely resembling ulcerative colitis. In chronic colitis, migration of circulating leukocytes into the intestinal mucosa is partially dependent on alpha4 integrins. In previous studies, short-term administration of anti-alpha4 integrin antibodies has been shown to attenuate intestinal inflammation, and here we elucidate the effect of long-term administration of anti-alpha4 integrin antibodies on colitis in Galphai2(-/- )mice. Long-term blockade of alpha4 integrin significantly increased the severity of colitis in Galphai2(-/-) mice. The inflammation was confined to the colon, associated with increased cancer in situ, destruction of crypt architecture, and increased production of IL-1beta, TNF-alpha and IFN-gamma. Blockade of alpha4 integrin reduced the recruitment of activated T cells to the small intestine. In strong contrast, there were significantly higher numbers of activated T cells in the colonic lamina propria and epithelium, most probably due to in situ proliferation. Furthermore, treatment with alpha4 integrin antibodies induced decreased levels of total IgA and IgG in sera, whereas total IgM levels were unchanged. These new findings may have implications in the understanding of the progression of chronic intestinal inflammation.     

Characterization of intestinal invasion by Salmonella typhimurium and Salmonella dublin and effect of a mutation in the invH gene.

The relative levels of invasiveness of two bovine isolates each of Salmonella typhimurium and Salmonella dublin and of invH mutants of S. typhimurium were determined in MDCK and Int 407 cultured-cell assays and in bovine ileal loops. S. dublin was found to be significantly less invasive in cultured cells than S. typhimurium, but this difference was not observed in bovine intestines. The invH mutants exhibited a significant reduction in invasion in both cultured cells and bovine intestines. The invasive phenotypes of the strains were confirmed by fluorescent microscopy and scanning and transmission electron microscopy. The wild-type strains were observed in the laminae propriae of the intestinal villi, while in contrast the invH mutants were generally associated with the enterocyte layer. The degree of damage in the bovine ileum was related to the magnitude of the invasion. There was no difference in the amount of S. typhimurium or S. dublin recovered from the bovine ileum either with or without Peyer's patches 3 h after inoculation of the loop.     

Adenosine triphosphate treatment for meconium aspiration-induced pulmonary hypertension in pigs

To investigate the pulmonary haemodynamic effects of meconium aspiration and subsequent adenosine triphosphate (ATP) treatment, 12 anaesthetized and ventilated pigs (wt 24-28 kg) received either ATP or an equal volume of saline into the right heart in doses of 0.02 to 0.80 lmol kg^-1 min^?1 after intratracheal administration of 2 mL kg^?1 of human meconium. Meconium instillation induced significant increases in pulmonary vascular pressures and total and postarterial resistances calculated from pulmonary artery occlusion studies, but did not affect the systemic haemodynamics, except for a fall in heart rate and increase in central venous pressure. Infusion of ATP at the lowest doses (0.02 and 0.08 µmol kg^?1 min^?1) selectively decreased the pulmonary arterial pressure and vascular resistance and at 0.32 and 0.80 µmol kg^?1 min^?1 reduced both the pulmonary and systemic resistances. In the lung circulation the increasing doses of ATP reduced preferably the arterial, but also the postarterial resistance. Withdrawal of ATP infusion led to a significant rebound effect especially in the postarterial segment of the lung circulation. Meconium aspiration thus induces an acute, predominantly postarterial obstruction in the lung circulation and infusion of ATP at low doses selectively dilates the pulmonary vascular bed and may help to preclude elevation of capillary pressures in meconium aspiration-induced pulmonary hypertension.     

Pneumococcus observatory data in the Rhône-Alps region. Results from 1996

Throughout 1996, 22 hospital-based laboratories in the Rh?ne-Alpes region of France collected pneumococcal strains and used a standardized protocol to record the following data; patient age and sex; type of specimen; and determination of susceptibility to at least the following antibiotics: oxacillin 1 microgram and 5 micrograms, erythromycin (Ery), tetracycline (Tet), chloramphenicol (Chl), rifampin (Rmp), and loracarbef. For penicillin-nonsusceptible strains (PNSSs), which were identified based on results with oxacillin, MICs for penicillin G, amoxicillin (Amx), and cefotaxime (Ctx) were determined using the E Test, at the study site and agar dilution at the coordinating center. Of the 1153 strains, 65.5% were from adults and 31.8% from children; patient age was unknown in 2.7% of cases. PNSPs (MIC > 0.06 mg/l) contributed 32.9% of strains (I: 23.3%; R: 9.6%) and were more common in children (41.1%) than in adults (28.1%). The frequency of PNSSs varied across specimen types: 27.9% in blood cultures (305 strains), 15.6% in cerebrospinal fluid (32), 38.7% in protected bronchopulmonary specimens (31), 31.5% in unprotected bronchopulmonary specimens (434), 50.8% in acute otitis media (118), and 34.4% in other specimens (221). Among PNSSs, nonsusceptibility (I + R) to other antibiotics was variable: Ery, 62.1%; Tet, 41.5%; Chl, 40.4%; Rmp, 1.1%. Corresponding figures for the overall strain population were Ery, 33.3%; Tet, 22.7%; Chl, 22.8%; Rmp, 0.9%. In addition, 56.5% of PNSSs exhibited multiple drug resistance. Resistance to amoxicillin (MIC > 2 mg/l) was demonstrated for only 5 strains. No strains were resistant to loracarbef or cefotaxime. Serotypes of the 379 PNSSs were as follows: 23F, 26.6%; 14 (25.6%); 9V (18.2%), 6 (8.7%), 15 (5%), 19 (4.5%).     

Mycobacterium chelonae causing otitis media in an ear-nose-and-throat practice

Seventeen cases of otitis media caused by Mycobacterium chelonae were detected among patients seen at a single ear-nose-and-throat (ENT) office (Office A) in Louisiana between May 5 and September 15, 1987. All the patients had a tympanotomy tube or tubes in place or had one or more tympanic-membrane perforations, with chronic otorrhea that was unresponsive to standard therapy with antimicrobial agents. Middle-ear exploration in six patients revealed abundant granulation tissue; multiple granulomas and acid-fast bacilli were demonstrated on a section of tissue from one patient with a nonhealing mastoidectomy incision. Thirteen of the 14 ear isolates obtained from patients seen in Office A had the same unusual pattern of high-level resistance to aminoglycosides. M. chelonae and other nontuberculous mycobacteria were recovered from several sources of water in Office A, as well as in another ENT office (Office B) in a neighboring city that was visited by the index patient. Only one additional case was detected in Office B during the same period. Otologic instruments in Office A were cleaned in an ultrasonic bath with tap water and a liquid detergent; the contents of the bath were changed only once weekly. Instruments in Office B were placed in boiling water between patient examinations. This outbreak establishes M. chelonae as an agent of otitis media and underscores the need for high-level disinfection or sterilization of ENT instruments between examinations to prevent the transmission of this organism to patients in the office setting.     

Comparison of midazolam and thiopental for rapid sequence anesthetic induction for elective cesarean section

Sixty healthy mothers undergoing elective cesarean section received at random either midazolam 0.2 mg/kg or thiopental 3.5 mg/kg with succinylcholine 1 mg/kg for rapid sequence intravenous anesthetic induction. Maintenance of anesthesia was identical in all patients: 50:50 N2O in oxygen, halothane 0.5% and pancuronium 0.05 mg/kg. Hemodynamic responses were similar, as were the biochemical status of mothers and infants, and maternal to fetal blood gas/acid base gradients. Correlation between maternal arterial and fetal (umbilical venous/arterial) pH, PCO2 and base excess values were statistically better with midazolam. However, 1-min Apgar minus color (A-C) scores less than 5/8 (representing "severe" neonatal depression) were recorded in five infants after midazolam, three of whom required tracheal intubation, and one whose mother was given thiopental. This difference reached statistical significance (P less than 0.05). It is concluded that midazolam is less suitable than thiopental for anesthetic induction in patients undergoing cesarean section.     

The role of glutamine in maintaining a healthy gut and supporting the metabolic response to injury and infection

In the critically ill surgical patient a variety of therapeutic maneuvers is required to maintain a "healthy gut." Provision of adequate amounts of glutamine to the gastrointestinal mucosa appears to be just one of these maneuvers. Other methods utilized to protect the gut from becoming a wound include: (a) minimizing additional systemic insults (such as hypotension, sepsis, multiple operative procedures); (b) aggressive pulmonary care; (c) the judicious use of antibiotics; and (d) aggressive enteral or parenteral feedings. The concept that the gut is an organ of quiescence following surgical stress merits reconsideration. The intestinal tract plays a central role in interorgan glutamine metabolism and is a key regulator of nitrogen handling following surgical stress. Critically ill patients are susceptible to developing gut-origin sepsis, the incidence of which will be diminished by instituting measures and providing treatments which support intestinal structure, function, and metabolism. Provision of glutamine-enriched diets to such patients may be one of these therapies.     

Short-term associations between emergency hospital admissions for respiratory and cardiovascular disease and outdoor air pollution in London

There are concerns about the possible short-term effects of outdoor air pollution on health in the United Kingdom. In a study conducted during the time period between 1987 and 1992, investigators determined that ozone had small, but significant effects on emergency respiratory admissions. In the current study, the authors investigated associations between emergency admissions and outdoor air pollution for the time period from 1992 to 1994, inclusive, and compared the results with those obtained in the earlier study. The authors also examined particulate matter less than 10 microm in diameter (PM10) and carbon monoxide in the current study. Appropriate confounding factors, such as seasonal patterns, temperature, and humidity, were controlled for, and the authors used Poisson regression to estimate the association between daily emergency admissions for respiratory and cardiovascular diseases and ozone, nitrogen dioxide, sulfur dioxide, carbon monoxide, particles measured as Black Smoke, and PM10. Significant positive associations were found between emergency hospital admissions for respiratory disease and PM10 and sulfur dioxide, but such an association did not exist for ozone. The results were not significantly different from earlier results from London and were comparable with those determined in North America and Europe. Cardiovascular disease was associated with carbon monoxide and Black Smoke, but weaker associations existed with the other pollutants studied.     

Mechanism of adrenal insufficiency following trauma and severe hemorrhage: role of hepatic 11beta-hydroxysteroid dehydrogenase

BACKGROUND: Although adrenal insufficiency may not occur with moderate hypotension, it does occur with severe hemorrhage. Since hepatocellular function is depressed following severe hemorrhage, it remains unknown whether the liver plays any role in regulating adrenal function after trauma and hemorrhagic shock. HYPOTHESIS: Hepatic 11beta-hydroxysteroid dehydrogenase (11beta-HSD), a microsomal enzyme responsible for the degradation of bioactive corticosterone, plays a major role in the development of adrenal insufficiency following trauma and severe hemorrhage. DESIGN, INTERVENTIONS, AND MAIN OUTCOME MEASURES: Male rats underwent laparotomy to induce trauma before hemorrhage. They were then bled to and maintained at a blood pressure of 40 mm Hg until 40% of the maximal bleed-out volume was returned in the form of Ringer lactate. The rats were then resuscitated with 4 times the volume of maximal bleed-out with Ringer lactate during a 60-minute period. Plasma levels of corticosterone and corticotropin were measured at various intervals. In additional groups, corticotropin-induced corticosterone release, adrenal contents of corticosterone and cyclic adenosine monophosphate (cAMP), hepatic 11beta-HSD activity, and plasma levels of corticosterone-binding globulin were determined at 1.5 hours after resuscitation. Moreover, a model of moderate hypotension (blood pressure, 80 mm Hg) was used to determine whether adrenal function is depressed under such conditions. RESULTS: At the time of maximal bleed-out, plasma corticosterone and corticotropin levels increased by 245% (P<.001) and 293% (P<.001), respectively. Despite corticotropin levels being similar to those of the animals undergoing sham operation after resuscitation, corticosterone levels in hemorrhaged animals remained elevated up to 4 hours after resuscitation (by 158%-207%; P<.001). In addition, corticotropin-induced corticosterone release decreased by 78% at 1.5 hours after resuscitation (P = .009). In contrast, moderate hypotension did not reduce corticotropin-induced corticosterone release. Adrenal corticosterone content and cAMP levels (i.e., the second messenger of corticotropin action) decreased by 55% (P<.001) and 25% (P = .03), respectively. Hepatic 11beta-HSD activity decreased significantly at 1.5 hours after resuscitation (P<.001). CONCLUSIONS: Sustained increase in plasma corticosterone levels following hemorrhage and resuscitation may be, in part, due to the decreased hepatic 11beta-HSD activity. The high level of corticosterone negatively regulates corticotropin release, further reducing adrenal responsiveness to corticotropin stimulation. Thus, the liver appears to play an important role in regulating adrenal function following trauma and severe hemorrhage.