Reduced duodenal cytochrome P450 3A protein expression and catalytic activity in patients with cirrhosis.

The small intestine and liver express high levels of cytochrome P450 3A (CYP3A), an enzyme subfamily that contributes significantly to drug metabolism. In patients with cirrhosis, reduced metabolism of drugs is typically attributed to decreased liver function, but it is unclear whether drug metabolism in the intestine is also compromised. In this study, we compared CYP3A protein expression and in vitro midazolam hydroxylation in duodenal mucosal biopsies from subjects with normal liver function (controls; n = 20) and subjects with various levels of severity of cirrhosis (n = 23). In samples from subjects with cirrhosis, duodenal CYP3A expression and total midazolam hydroxylation were lower by 47 and 34%, respectively, as compared with samples from controls. Greater decreases in CYP3A expression were seen in subjects with more severe cirrhosis. Therefore, patients with advanced cirrhosis may have greater drug exposure following oral dosing as a result of both impaired liver function and decreased intestinal CYP3A expression and activity.

Toll-like receptor 2 is upregulated by hog confinement dust in an IL-6-dependent manner in the airway epithelium.

Hog confinement workers are at high risk to develop chronic bronchitis as a result of their exposure to organic dust. Chronic bronchitis is characterized by inflammatory changes of the airway epithelium. A key mediator in inflammation is Toll-like receptor 2 (TLR2). We investigated the role of TLR2 in pulmonary inflammation induced by hog confinement dust. Normal human bronchial epithelial cells (NHBE) were grown in culture and exposed to hog confinement dust extract. Hog confinement dust upregulated airway epithelial cell TLR2 mRNA in a concentration- and time-dependent manner using real-time PCR. There was a similar increase in TLR2 protein at 48 h as shown by Western blot. TLR2 was upregulated on the surface of airway epithelial cells as shown by flow cytometry. A similar upregulation of pulmonary TLR2 mRNA and protein was shown in a murine model of hog confinement dust exposure. Hog confinement dust is known to stimulate epithelial cells to produce IL-6. To determine whether TLR2 expression was being regulated by IL-6, the production of IL-6 was blocked using an IL-6-neutralizing antibody. This resulted in attenuation of the dust-induced upregulation of TLR2. To further demonstrate the importance of IL-6 in the regulation of TLR2, NHBE were directly stimulated with recombinant human IL-6. IL-6 alone was able to upregulate TLR2 in airway epithelial cells. Hog confinement dust upregulates TLR2 in the airway epithelium through an IL-6-dependent mechanism.

Hypersensitivity pneumonitis resulting from community exposure to Canada goose droppings: when an external environmental antigen becomes an indoor environmental antigen.

BACKGROUND: In the past, hypersensitivity pneumonitis has been attributed to occupational, agricultural, or home environmental exposure. OBJECTIVE: This report describes the first case of hypersensitivity pneumonitis due to community exposure to droppings from Canada geese migrating through a suburban environment. METHOD: Clinical and serologic information was used in making the diagnosis of hypersensitivity pneumonitis. RESULTS: Serologic analysis demonstrated precipitating antibodies against goose droppings and against an extract made from washings from a filter taken from the patient's office. These studies also showed that the antigens in the office filter were goose dropping antigens. CONCLUSION: Hypersensitivity pneumonitis can result from exposure to goose dropping antigens in the community that enter buildings through ventilation systems. This represents a new form of an old disease.

Succinylcholine does not change intracranial pressure, cerebral blood flow velocity, or the electroencephalogram in patients with neurologic injury.

The effect of succinylcholine (SCh) on intracranial pressure (ICP) was studied in 10 mechanically ventilated patients (Glasgow coma scale score 3-10, median 6) being treated for increased ICP in an intensive care unit. Mean arterial blood pressure (MAP), ICP, processed electroencephalogram (EEG), and mean middle cerebral artery blood flow velocity (V mca) were monitored. Baseline measurements after saline injection were obtained for 5 min. SCh (1 mg/kg) was administered intravenously and the above variables were monitored for 15 min. Neither saline nor SCh cause any significant change in cerebral perfusion pressure, MAP, V mca, EEG, or ICP. We conclude that in brain-injured patients, SCh did not alter cerebral blood flow velocity, cortical electrical activity, or ICP.

Nitrous oxide-isoflurane anesthesia causes more cerebral vasodilation than an equipotent dose of isoflurane in humans.

To compare the cerebral vascular and metabolic effect of an isoflurane-nitrous oxide mixture to an equipotent dose of isoflurane at 1.1 minimum alveolar anesthetic concentration (MAC), and to study the interaction between nitrous oxide and isoflurane anesthesia, we measured right middle cerebral artery blood flow velocity (V mca) and cerebral arteriovenous oxygen content difference (AVDO2) in six healthy patients during normocapnia and normothermia under the following sequence of steady-state anesthetic conditions: Condition A, 0.5 MAC of isoflurane, Condition B, 0.5 MAC of isoflurane + 0.6 MAC of N2O, Condition C, 1.1 MAC of isoflurane + 0.6 MAC of N2O, and Condition D, 1.1 MAC of isoflurane. The study entry sequence was randomized. V mca and AVDO2 during 1.1 MAC of isoflurane (Condition D) was 48 +/- 7 cm/s and 3.9 +/- 0.6 vol%, respectively. Substituting 0.6 MAC of isoflurane with an equipotent concentration of N2O (Condition B) resulted in an increase in both V mca and AVDO2 of approximately 20% (P < 0.05). These findings suggest that the increase in flow was accompanied by an even greater increase in metabolic rate. Adding 0.6 MAC of N2O to 1.1 MAC of isoflurane (Condition C) also increased V mca (P < 0.05). We conclude that N2O is a more potent cerebral vasodilator than an equipotent dose of isoflurane alone in humans.

Long-term outcome in patients who survive out of hospital ventricular fibrillation and undergo electrophysiologic studies: evaluation by electrophysiologic subgroups.

The long-term outcome of 241 survivors of out of hospital ventricular fibrillation who underwent programmed electrical stimulation was evaluated. Patients were categorized according to the rhythm induced at baseline drug-free electrophysiologic testing. Ventricular fibrillation was induced in 39 patients (16%) (Group 1), sustained ventricular tachycardia in 66 patients (27%) (Group 2) and nonsustained ventricular tachycardia in 34 patients (14%) (Group 3); 102 patients (42%) (Group 4) did not have an arrhythmia inducible at baseline electrophysiologic testing. Antiarrhythmic drugs were administered over the long term to 92% of patients in Group 2, 91% of patients in Group 1 and 47% of patients in Group 4. At a mean follow-up time of 30 +/- 15 months, recurrent sudden cardiac death or nonfatal ventricular fibrillation occurred in 11 (28%) of 39 patients with inducible ventricular fibrillation (Group 1), 14 (21%) of 66 patients with inducible sustained ventricular tachycardia (Group 2), 4 (12%) of 34 patients with inducible nonsustained ventricular tachycardia (Group 3) and 16 (16%) of 102 patients without inducible arrhythmias (Group 4). Actuarial analysis revealed a 2 year cumulative arrhythmia-free survival rate of 65% for patients in Group 2, 71% for patients in Group 1, 79% for patients in Group 3 and 81% for patients in Group 4 (p = 0.02). Actuarial survival of patients with inducible sustained ventricular tachycardia or ventricular fibrillation suppressed by electrophysiologically guided drug therapy was not significantly different from that in patients whose arrhythmia was not suppressed. Multivariate regression analysis revealed that only the presence of congestive heart failure was an independent predictor of outcome in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)