OX40L blockade and allergen-induced airway responses in subjects with mild asthma.

BACKGROUND: The OX40/OX40L interaction contributes to an optimal T cell response following allergic stimuli and plays an important role in the maintenance and reactivation of memory T effector cells. OBJECTIVE: We tested whether treatment with an anti-OX40L monoclonal antibody (MAb) would inhibit allergen-induced responses in subjects with asthma. METHODS: Twenty-eight mild, atopic asthmatic subjects were recruited for a double-blind, randomized, placebo-controlled, parallel-group trial (ClinicalTrials.gov identifier NCT00983658) to compare blockade of OX40L using a humanized anti-OX40L MAb to placebo-administered intravenously in 4 doses over 3 months. Allergen inhalation challenges were carried out 56 and 113 days after the first dose of study drug. The primary outcome variable was the late-phase asthmatic response. Other outcomes included the early-phase asthmatic response, airway hyperresponsiveness, serum IgE levels, blood and sputum eosinophils, safety and tolerability. RESULTS: Treatment with anti-OX40L MAb did not attenuate the early- or late-phase asthmatic responses at days 56 or 113 compared with placebo. In the anti-OX40L MAb treatment group, total IgE was reduced 17% from pre-dosing levels, and sputum eosinophils decreased 75% by day 113 (both P = 0.04). There was no effect of anti-OX40L MAb on airway hyperresponsiveness or blood eosinophils. The frequency of AEs was similar in both groups. CONCLUSION AND CLINICAL RELEVANCE: Pharmacological activity of anti-OX40L MAb was observed by decreases in serum total IgE and airway eosinophils at 16 weeks post-dosing, but there was no effect on allergen-induced airway responses. It is possible that the treatment duration or dose of antibody was insufficient to impact the airway responses.

Asthma in primary care: making guidelines work.

OBJECTIVE: To determine the views of family physicians regarding selected asthma recommendations from a Canadian practice guideline and the supporting evidence, and to identify issues needing further development if family physicians are to find guideline recommendations to be truly useful clinical tools. SETTING: Four urban communities in Nova Scotia, Prince Edward Island and New Brunswick. PARTICIPANTS: Twenty community family physicians representing different practice settings, and varying according to age and sex, were recruited to participate. DATA COLLECTION: Four focus groups were held, each lasting 2 h, at which recommendations from a published asthma guideline were presented for discussion on the applicability to their practices. The data were analyzed using a grounded theory method. RESULTS: Physicians rely on clinical judgment in lieu of objective measures in diagnosing asthma and resist treating every exacerbation with steroids. They thought that the recommendations on smoking and patient education should have been stronger or more prominent. Patient noncompliance limits the usefulness of home peak flow measures. Topics such as allergy assessment and most pharmacological therapies triggered little discussion. DISCUSSION: Asthma guideline developers and those interested in enhancing compliance with recommendations will need to attend to factors such as physician attitudes and beliefs on a variety of issues, including the use of objective measures and the availability of adequate resources to conduct the tests. Similarly, negative patient attitudes toward an increased use of corticosteroids suggest that a public education program would be most helpful regarding that group of recommendations.

Bile duct diverticula and webs: nonspecific cholangiographic features of primary sclerosing cholangitis.

Biliary tree diverticula and webs are considered by several authors to be specific cholangiographic features of primary sclerosing cholangitis (PSC). Our experience suggested that these findings can be seen in patients without PSC. The purpose of this study was twofold: to establish whether diverticula and webs are indeed specific for PSC and to assess whether PSC can be accurately diagnosed without reference to diverticula or webs. We retrospectively reviewed 861 consecutive ERCP studies and found 32 cases of webs and/or diverticula. Using accepted cholangiographic, clinical, and histologic criteria, we diagnosed PSC in nine patients and excluded it in 21, with two instances of uncertain diagnoses. Webs and diverticula seen in PSC were cholangiographically indistinguishable from those in the group without PSC. All 21 patients without PSC had other biliary abnormalities, and were grouped by the predominant abnormality or finding believed to be associated with diverticulum or web formation: common duct stones or cholangitis (n = 11 patients), postoperative stricture (n = 4), bile duct stent and balloon dilatation (n = 3), malignant stricture (n = 2), and choledochoduodenostomy (n = 1). To assess cholangiographic diagnosis of PSC in these patients, a blinded reviewer studied the radiographs of the 30 patients with diverticula and/or webs who had confirmed diagnoses. By using established radiologic criteria alone (ignoring diverticula and webs), the correct diagnosis was made in 27, yielding a sensitivity of 89% and specificity of 91%. We conclude that the presence of diverticula and/or webs on a cholangiogram is a nonspecific finding and may be due to inflammation or trauma to the bile duct wall. Further, PSC can be distinguished from other abnormalities on the basis of findings other than diverticula and webs.

Endoscopic laser lithotripsy of large bile duct stones.

Experimental work has established that the Candela (Candela Laser Corporation, Wayland, MA) flashlamp excited dye laser (wavelength, 504 nm) is a highly effective method for fragmenting biliary stones and has minimal potential for injuring the bile duct wall. This technique was evaluated in 25 complex patients whose stones, usually because of large size, did not respond to standard nonoperative treatment. The laser imaging was applied through a quartz fiber and aimed either under direct vision with choledochoscopes passed percutaneously or through a special "mother" duodenoscope or under fluoroscopic guidance at standard duodenoscopy. Laser treatment resulted in some fragmentation of stones in 23 cases. Subsequently, it proved that it was possible to clear the bile duct of stones in 20 patients, 12 of them receiving successful treatment during the same endoscopic procedure. There were no significant complications. This endoscopic technique seems to be a useful new alternative to surgery in patients with large and difficult bile duct stones.

Inhibitory regulation of rat exocrine pancreas by peptide YY and pancreatic polypeptide.

Peptide YY (PYY) and pancreatic polypeptide (PP) have been shown to inhibit exocrine pancreatic secretion in vivo in a variety of species. This study evaluates the type of stimulation inhibited by PYY and PP by examining, in urethan-anesthetized rats, the inhibition of pancreatic secretion when stimulated to a comparable extent by cholecystokinin (CCK), 2-deoxy-D-glucose (2DG), bethanecol, and electrical vagal nerve stimulation. PYY at maximal infusion rates inhibited stimulation by CCK by 83%, bethanecol by 55%, and electrical nerve stimulation by 40%. The inhibition of CCK stimulation was half maximal at 250 pmol.kg-1.h-1. By contrast, PYY totally inhibited 2DG-stimulated secretion with half-maximal inhibition at 10 pmol. kg-1.h-1. PP acted similarly to PYY in inhibiting CCK and 2DG-stimulated pancreatic protein secretion but was fivefold weaker in each case. These findings indicate that PYY and PP have multiple actions but preferentially inhibit neurally mediated pancreatic secretion at a preacinar cell locus, possibly at a central site of action.

The hepatic extraction of gastric inhibitory polypeptide and insulin.

The hepatic extractions of gastric inhibitory polypeptide (GIP) and insulin were determined using in vitro and in vivo methods to assess the role of the liver in GIP metabolism and the possible effect of GIP on the hepatic extraction of insulin. During in vitro studies using the isolated perfused rat liver, infusion of GIP (2000 pg/ml) alone and in combination with porcine insulin (200 microU/ml) resulted in negligible hepatic extraction of immunoreactive GIP (IR-GIP) in both fed and fasted animals during either physiologically euglycemic or hyperglycemic perfusions. Hepatic extraction of insulin, however, ranged from 26-36% in fasted animals and from 7-25% in fed animals. Hepatic extraction of insulin and net hepatic glucose appearance were minimally affected by GIP. In vivo studies in awake dogs were then performed, in which simultaneous portal and peripheral venous levels of IR-GIP, immunoreactive insulin (IRI), and glucose were assessed after intraduodenal glucose administration. The portal to peripheral (PORT/PERI) venous ratio of endogenous IRI and IR-GIP reflected the findings of the in vitro studies; the PORT/PERI ratio of IRI levels rose from a basal value of 1.9 +/- 0.3 to a peak of 3.7 +/- 0.9, while the PORT/PERI ratio of IR-GIP levels rose from a basal value of 1.0 +/- 0.1 to a peak of 1.4 +/- 0.2, then rapidly returned to 1.0. The in vivo data are consistent with a continuous hepatic extraction of 40-50% of the insulin entering the liver and a negligible hepatic extraction of IR-GIP. We conclude that hepatic extraction of GIP in vitro or in vivo is minimal. In addition, while the fed state of the animal before infusion can result in changes in the in vitro hepatic extraction of insulin, GIP does not mediate these changes.

Insulin's effect on bile flow and lipid excretion during euglycemia and hypoglycemia.

Mongrel dogs were prepared by cholecystectomy, ligation of the lesser pancreatic duct, and insertion of modified Thomas cannulas into the stomach and duodenum. When the dogs had recovered from surgery, studies were performed on them, conscious and unanesthetized after an overnight fast. The common bile duct was catheterized through the opened duodenal cannula for collection of hepatic bile. Bile flow was stabilized by the intravenous infusion of sodium taurocholate. After 2 hr of taurocholate infusion, insulin was added to the infusion and continued for the duration of the experiment. Glucose was administered intravenously during the first 120 min of insulin administration to maintain euglycemia; then the glucose was discontinued. The intravenous infusion of insulin during euglycemia maintained by glucose infusion caused a significant increase in bile flow and a decrease in bile salt concentration, but no change in bile salt output. There was a decrease in cholesterol concentration and output and in phospholipid concentration, but no significant change in phospholipid output. When glucose infusion was discontinued and hypoglycemia occurred, there was a further significant increase in bile flow, but no other change. These studies demonstrate that the choleretic action of insulin is not dependent upon hypoglycemia and that intravenously administered insulin may cause increased bile secretion without increase in serum glucagon concentration. These experiments also confirm that insulin choleresis may be associated with a decline in cholesterol output.