The classical progesterone receptor associates with p42 MAPK and is involved in phosphatidylinositol 3-kinase signaling in Xenopus oocytes.

The induction of Xenopus laevis oocyte maturation by progesterone is a striking example of a steroid hormone-mediated event that does not require transcription. Here we have investigated the role of the classical progesterone receptor in this nongenomic signaling. The Xenopus progesterone receptor (XPR) was predominantly cytoplasmic; however, a significant fraction ( approximately 5%) of one form of the receptor (p82 XPR) was associated with the plasma membrane-containing P-10,000 fraction, compatible with the observation that membrane-impermeant derivatives of progesterone can induce maturation. XPR co-precipitated with active phosphatidylinositol 3-kinase. The phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin delayed progesterone-induced maturation and completely blocked the insulin-dependent maturation, indicating that the association of XPR with PI3-K could be functionally important. We also examined whether the nongenomic signaling properties of XPR can account for the ability of glucocorticoids and the progesterone antagonist RU486 to induce maturation. We found that none of these steroids cause XPR to become associated with active PI3-K; thus, association of XPR with active PI3-K is progesterone-specific. Finally, we showed that p42 mitogen-activated protein kinase (MAPK) associates with XPR after progesterone-induced germinal vesicle breakdown and that active recombinant MAPK is able to phosphorylate p110 XPR in vitro. These findings demonstrate that the classical progesterone receptor is involved in progesterone-induced nongenomic signaling in Xenopus oocytes and provide evidence that p42 MAPK and PI3-K activity are directly associated with the classical progesterone receptor.

Demonstration of a possible source of error with an electric pulp tester.

The purpose of this study was to determine whether electrical current can travel between adjacent teeth through contacting interproximal amalgam restorations. Twenty-two extracted human premolars were restored with class II amalgam restorations. They were then mounted in pairs in self-curing resin, simulating adjacent teeth. Only their restorations were allowed to contact. An electrical multimeter was used to supply electrical current and to measure any current passing through the mounted teeth. One current measurement was made from the buccal enamel of a tooth to the occlusal surface of the filling in that tooth. A second measurement was made from the buccal enamel of the same tooth to the occlusal surface of the adjacent filling. These two measurements were made for all 11 trials. Statistically, all current that entered the first tooth passed to the adjacent tooth. This finding suggests a potential source of error when using an electric pulp tester.

Pulmonary blastomycosis with acute respiratory failure as predominant clinical feature.

Two previously healthy young adults came to our community hospital with rapidly progressive respiratory failure. Investigation confirmed Blastomyces as the responsible etiologic agent. Despite adequate antifungal chemotherapy and intensive supportive care, both patients died, one within 24 hours and the other after 14 days. Overwhelming infection with Blastomyces dermatitidis can cause acute respiratory failure, possibly the adult respiratory distress syndrome, even in immunocompetent hosts.

Suppression of cell-mediated immunity in hypothyroidism.

A 71-year-old man had severe hypothyroidism, chronic autoimmune thyroiditis, and bacteremia due to Edwardsiella tarda. Review of the literature identified the hypothesis that E tarda infections may occur more frequently in immunocompromised patients. Previous animal studies have shown decreases in lymphocyte function during hypothyroidism, with return of normal lymphocyte function during euthyroid states. Therefore, lymphocyte transformation studies were obtained, demonstrating severe decreases in our patient's lymphocyte function. Except for chronic autoimmune thyroiditis, other immune system abnormalities were excluded. Serial lymphocyte transformation studies showed gradual improvement in lymphocyte function during gradual return to euthyroid state. Possible pathophysiologic mechanisms for these findings will be reviewed.

Drug susceptibility of Mycobacterium tuberculosis isolates from recent Haitian migrants: correlation with clinical response.

Between November 1991 and June 1993, approximately 11,000 Haitian migrants were screened for active tuberculosis and human immunodeficiency virus type 1 (HIV-1) infection at the U.S. Naval Base in Guantánamo Bay, Cuba. Cultures of specimens from 37 of these patients yielded Mycobacterium tuberculosis; eight (22%) of these isolates were resistant to standard medications, including isoniazid (22%), rifampin (0), ethambutol (3%), and streptomycin (3%). Two isolates (5.4%) were resistant to two drugs simultaneously. All but one of 340 patients who were treated for presumptive active tuberculosis and who were followed up for about 1 month had a favorable initial clinical response to a standard four-drug regimen. Among 259 HIV-1-infected patients who had normal findings on screening chest radiographs and who received prophylaxis with isoniazid, there were 1.8 incident cases of active tuberculosis per 100 person-years; this rate was 76% lower than that (reported by others) among HIV-1-infected Haitian patients who were not treated with isoniazid. No serious toxic effects due to standard four-drug regimens or to prophylaxis with isoniazid were observed. These data suggest that standard empirical therapeutic interventions for tuberculosis are adequate and well tolerated in Haitian migrants.

Involvement of intrahepatic innervation in caesium-induced haemodynamic oscillations in the rat liver.

1. Cs+ was used to study the mechanisms involved in the induction of haemodynamic and metabolic oscillations in the isolated rat liver perfused by the portal vein. 2. Cs+ (2.25 mM) in K(+)-free perfusate causes the appearance of periodic increases in portal pressure (3.87 +/- 0.6 mmHg, n = 24) and decreases in O2 uptake (111 +/- 26 microM) at a frequency of 0.013 +/- 0.002 Hz. A 19.8 +/- 1.2 min induction time occurs prior to the generation of periodicity. The oscillations are interspersed with low amplitude shoulders and peaks indicating multiple non-phasic components. 3. Cs+ concentrations higher or lower than 2.25 mM decrease oscillation amplitude and render them aperiodic. No oscillations are observed with 0.5 or 12.5 mM Cs+. 4. The oscillations are reversibly blocked by 1 mM K+, 1 mM EGTA, 5 microM verapamil or 0.17 microM tetrodotoxin. One micromolar chlorpheniramine, 10 microM propranolol, 12 microM phentolamine or 35 microM atropine also maximally inhibit the Cs(+)-induced vasoactivity. 5. The results show that the liver perfused by the portal vein has all of the components required to activate vascular synchrony including intrinsic neural input and responsive vasoactive cells.

Respiratory infections caused by Branhamella catarrhalis. Selected epidemiologic features.

PURPOSE: This work reviewed existing literature pertaining to the epidemiologic aspects of respiratory tract infections caused by Branhamella catarrhalis, examined certain epidemiologic features of B. catarrhalis infections occurring at this facility, and identified relevant areas in need of further study. PATIENTS AND METHODS: Literature dealing with the epidemiology of B. catarrhalis infections was reviewed. Records in this Veterans Administration hospital microbiology laboratory were reviewed and all B. catarrhalis isolates and pure cultures of Hemophilus influenzae and Streptococcus pneumoniae were noted for the January 1986 to June 1989 study period. RESULTS: B. catarrhalis is now recognized as a disease-causing pathogen that is particularly noted for its association with acute otitis media in children and lower respiratory tract infections in adults with underlying cardiopulmonary disease. It was recovered from 2.7 percent of all respiratory specimens submitted over a 42-month period at this Veterans hospital. When compared with H. influenzae and S. pneumoniae, B. catarrhalis was found to be the second most commonly isolated respiratory pathogen. It was frequently found in pure culture (53 percent) or in combination with H. influenzae, gram-negative bacilli, or S. pneumoniae. The seasonal recovery of B. catarrhalis was apparent for the November to May period compared with the June to October period (p less than 0.001). CONCLUSION: B. catarrhalis has emerged as a major respiratory pathogen in pediatric and adult patient populations. There is a distinct seasonal pattern associated with its recovery and reasons for this are unclear. Prevalence studies aimed at identifying colonization rates among "low" and "high" risk groups are needed. The availability of restriction endonuclease analysis as a typing system for B. catarrhalis should favorably impact upon future epidemiologic studies. Many B. catarrhalis isolates produce beta-lactamase, and therapeutic options must reflect this.

High-dose cisplatin for locally advanced or metastatic head and neck cancer. A phase II pilot study.

High-dose cisplatin (40 mg/m2 every day X5) was administered to 14 patients (11 men, three women) with locally advanced or metastatic head and neck cancer not curable by surgery or refractory to previous chemotherapy and/or radiation therapy. All 14 patients were evaluable for toxicity; one patient was inevaluable for response due to early death. A total of 24 courses of therapy were administered. The dose-limiting toxicity was myelosuppression with 73% of patients experiencing Grade III or IV neutropenia. Grade II or above thrombocytopenia occurred in 30% of the patients. Renal and neurologic toxicity was minimal. Two patients experienced laryngeal edema from vigorous hydration with one of them requiring a tracheostomy for respiratory compromise. Partial responses were seen in six patients (46%). Two of the six patients had received previous treatment with standard dose cisplatin. Two patients achieved long-term responses (54+, 44+ months, respectively). Both of these patients were previously untreated, inoperable (T4N3M0, T3N1M0), and subsequently received radiation therapy after two cycles of chemotherapy. Median duration of response in the remaining responders was 3 months (range, 3-10 months). High-dose cisplatin may benefit selected patients with inoperable, advanced head and neck tumors. However, further randomized trials need to be conducted before firm conclusions can be established.

Radioangiocardiogram monitoring in patients receiving bisantrene.

Due to the tricyclic structural similarity between the anthracyclines and a new anthracene bishydrazone derivative, bisantrene, changes in myocardial function as detected by radionuclide angiography were sought in early phase I-II trials of the drug. Overall, there appear to be no changes in ejection fraction when determined 24 hours postinfusion, or when determined after low cumulative doses of bisantrene.

Anaphylactoid reactions associated with bisantrene infusions.

Nine of ninety-three patients receiving Bisantrene on an every three week schedule developed an anaphylactoid reaction with a variety of symptoms. Most reactions occurred in patients who had multiple exposures to Bisantrene. Investigators utilizing Bisantrene in ongoing clinical trials should be aware of this life threatening toxicity.

Characterization of the pharmacokinetics of bisantrene (NSC-337766).

The pharmacokinetics of bisantrene, 9,10-anthracenedicarboxaldehyde bis [4,5-dihydro-1 H-imidazol-2-yl) hydrazone) dihydrochloride were evaluated during a Phase I clinical investigation. Bisantrene at doses of 20 to 280 mg/m2 was administered by variable infusion rates to nine patients with advanced metastatic cancer. Bisantrene's plasma clearance followed a triexponential pattern with a harmonic mean terminal half-life (t1/2 gamma) of 26 h. The steady state volume of distribution (Vdss) was large, averaging 627 l/m2. Plasma clearance averaged 42.6 +/- 6.7 l/h/m2. The cumulative urinary excretion of bisantrene was 3.6 +/- 1.6% at 48 h.