Complex temporal patterns of spontaneous initiation and termination of reentry in a loop of cardiac tissue.

A two-component model is developed consisting of a discrete loop of cardiac cells that circulates action potentials as well as a pacing mechanism. Physiological properties of cells such as restitutions of refractoriness and of conduction velocity are given via experimentally measured functions. The dynamics of circulating pulses and the pacer's action are regulated by two threshold relations. Patterns of spontaneous initiations and terminations of reentry (SITR) generated by this system are studied through numerical simulations and analytical observations. These patterns can be regular or irregular; causes of irregularities are identified as the threshold bistability (T-bistability) of reentrant circulation and in some cases, also phase-resetting interactions with the pacer.

Expression of classic cadherins type I in urothelial neoplastic progression.

Loss or reduced expression of E-cadherin has been shown to be associated with poor survival in patients with bladder cancer. In numerous cases, loss of E-cadherin expression in bladder tumors has been accompanied by continued association of catenins with the membrane, suggestive of the expression of an alternative cadherin member. In this study we examined 75 bladder tumors using immunohistochemistry for the expression of E-, P-cadherin, and alpha-, beta-, and gamma-catenins. As reported previously, loss or reduced E-cadherin expression is a frequent event in late stage bladder cancer, accompanied by less frequent alterations associated with different catenin family members. Analysis of 51 tumors for expression of E-, P-, and N-cadherin showed P-cadherin localized to the basal cell layers of normal urothelium, with retention of expression in the majority of tumors. In low-grade tumors P-cadherin was found localized to an expanded basal cell compartment, contrasting with the more extensive staining observed in late stage tumors. Membranous P-cadherin staining was often found in the absence of E-cadherin staining. N-cadherin is not expressed in normal bladder mucosa, but detection of this cadherin member was recorded in 39% (20/51) of bladder tumors. Unlike P-cadherin, membranous N-cadherin was detected in focal regions within tumors, representing novel expression in urothelial neoplastic progression. Although focal N-cadherin staining was observed in 3 noninvasive lesions, the majority of tumors expressing N-cadherin were invasive (17/20). Coexpression of E-, P-, and N-cadherin was recorded in 5 grade 2 bladder tumors. Expression of P-cadherin is maintained throughout bladder tumorigenesis, accompanied by aberrant expression of N-cadherin. Clearly, neither P- nor N-cadherin act in an invasive-suppressor mode in bladder cancer, but whether they have a primary role to play in urothelial neoplastic progression has yet to be established.

Somatic mutation of PTEN in vulvar cancer.

PTEN, a candidate tumor suppressor gene located at chromosome 10q23.3, has been shown to be mutated in approximately 40% of endometrial cancers. Such mutations have also been identified in endometrial hyperplasia, indicating that inactivation of the PTEN tumor suppressor gene is an early event in the genesis of some endometrial cancers. In this study, we have extended the analysis of PTEN in gynecological cancer to include adenocarcinoma of the cervix and vulvar carcinomas. Microdissected tissue (including normal tissues), preneoplastic, and neoplastic lesions were analyzed from 9 patients with cervical cancer and 10 patients with vulvar cancer. Only 1 cervical adenocarcinoma displayed a PTEN mutation. In contrast, five of eight vulvar carcinomas studied harbored PTEN mutations. Alterations were identified in carcinoma in situ as well as squamous cell carcinoma of the vulva. In two patients, PTEN mutations were identified in mucosal regions with mild or focal dysplasia. These results suggest that PTEN is frequently altered in vulvar carcinomas and can be found associated with early dysplastic changes in vulvar mucosa.

Resistance to the insecticides lufenuron and propoxur in natural populations of Drosophila melanogaster (Diptera: Drosophilidae).

Lufenuron is a newly marketed benzoylphenyl urea chitin-synthesis inhibitor insecticide that is effective against certain insects, including Drosophila melanogaster (Meigen). Resistance to this class of insecticides is not widespread in pest insect populations and, for the resistance that has been reported, the genetic basis is not understood. In previous work, natural population strains of D. melanogaster from 2 widely separated locations in the United States were found to be as much as 100 times more resistant to lufenuron when compared with laboratory strains. It was postulated that this resistance is the result of cross-resistance that evolved to an earlier, widely used insecticide. In the current study we examined cross-resistance of selected D. melanogaster strains to propoxur, a likely candidate carbamate insecticide that has been extensively used during the past 3 decades. However, no correlation between resistance to lufenuron and propoxur was found. Strains were selected to represent a range of dates of establishment (1936-1996) from natural populations to laboratory culture. Examination of these strains showed susceptibility to propoxur in long-established laboratory strains, but resistance in recently established strains. Susceptibility to lufenuron was also high in long-established strains and apparently slowly decreased in natural populations until approximately equal to 5 yr ago, when it decreased more rapidly. These results suggest that if this loss in susceptibility results from agricultural chemical usage, then these chemicals can significantly affect a non-target insect.

Moclobemide in social phobia: a controlled dose-response trial.

Although the monoamine oxidase inhibitor phenelzine has proven efficacious in social phobia, the risk of hypertensive crises has reduced its acceptability. The reversible monoamine oxidase inhibitor moclobemide has less potential for such reactions, but its efficacy in this disorder remains unproven. A double-blind, placebo-controlled study was undertaken to assess the efficacy and safety of fixed doses of moclobemide. After a 1-week placebo run-in, subjects with social phobia were randomly assigned to placebo or one of five doses (75 mg, 150 mg, 300 mg, 600 mg, or 900 mg daily) of moclobemide for 12 weeks. Although a trend toward greater efficacy of higher doses of moclobemide was observed at 8 weeks, no differences in response to various doses of the drug and placebo were observed at 12 weeks. At 12 weeks, 35% of subjects on 900 mg of moclobemide and 33% of those on placebo were at least much improved. Moclobemide was well tolerated, insomnia being the only dose-related adverse event observed with the drug. In this dose-response trial, moclobemide did not demonstrate efficacy at 12 weeks. Some other controlled studies have found moclobemide and brofaromine, another reversible monoamine oxidase inhibitor, efficacious in social phobia. Possible reasons for inconsistent findings are discussed.

Are fluoxetine plasma levels related to outcome in obsessive-compulsive disorder?

OBJECTIVE: In obsessive-compulsive disorder, the relationship between blood levels of serotonin reuptake inhibitors and clinical outcome is unclear. In a multicenter trial, the authors examined the relationship between steady state plasma levels of fluoxetine and norfluoxetine (determined after 7 weeks of treatment), and their sum, and clinical outcome. METHOD: Ratings of symptom severity of obsessive-compulsive disorder (Yale-Brown Obsessive Compulsive Scale scores) were obtained at baseline and after 13 weeks for 200 adult outpatients with moderately severe obsessive-compulsive disorder treated with fluoxetine doses of 20 mg/day (N = 68), 40 mg/day (N = 64), and 60 mg/day (N = 68). RESULTS: Mean plasma levels of fluoxetine and norfluoxetine were statistically significantly higher with higher dose. Statistical analyses revealed no significant relationship for plasma level of either molecule or their sum in predicting endpoint percent change in obsessive-compulsive scores. Plasma levels of patients with a marked response (decrease of 50% or more in obsessive-compulsive score) did not differ significantly from those of nonresponders (less than a 25% decrease in obsessive-compulsive score). No hint was seen of a therapeutic window or of a relationship limited to one gender or within the lowest dose group (20 mg/day). However, since S-norfluoxetine is a much more potent serotonin reuptake inhibitor than R-norfluoxetine, the absence of chiral (stereospecific) assays in this study limits the results. CONCLUSIONS: Steady state plasma levels of fluoxetine and norfluoxetine are not related to clinical outcome in patients with obsessive-compulsive disorder. Individual patients can be told only that the optimum dose of fluoxetine for them will be the dose that produces the largest therapeutic effect with the smallest side effect burden. Future studies should examine the predictive utility of measures of serotonergic neuronal function and, if plasma levels of norfluoxetine are examined, the use of chiral assays.

Ifosfamide-induced neurotoxicity: associated symptoms and nursing implications.

PURPOSE/OBJECTIVES: To review current understanding of the neurotoxicity associated with ifosfamide administration. DATA SOURCES: Published studies of ifosfamide-induced neurotoxicity, published literature on other causes of neurotoxicity associated with cancer, and a case study. DATA SYNTHESIS: Ifosfamide-induced neurotoxicity has not been well-described in the nursing literature. To correctly identify ifosfamide-induced neurotoxicity, nurses need to assess the patient's history and neurologic, affective, and cognitive status and implement appropriate nursing interventions. CONCLUSIONS: Research aimed at accurate identification of ifosfamide-induced neurotoxicity and the most effective nursing interventions is needed. IMPLICATIONS FOR NURSING PRACTICE: Judicious nursing assessment will facilitate differentiation of ifosfamide-induced neurotoxicity from other neurotoxicities associated with cancer and its treatment.

The effects of fluoxetine on the polysomnogram of depressed outpatients: a pilot study.

The effects of fluoxetine (FLU) and its active metabolite, norfluoxetine (NFLU), on the polysomnogram (PSG) of nine depressed outpatients (eight with major depression; one with bipolar II, depressed phase disorder) were investigated by contrasting PSG values prior to treatment and during administration of FLU. The PSG changes were correlated with daily dose, cumulative dosage, single serum concentrations, and the total area under the serum concentration curve (AUC) of both FLU and NFLU. Fluoxetine clearly increased both stage 1 sleep time and rapid-eye-movement (REM) latency and decreased both percent REM and REM density. With a few exceptions, the cumulative dosage of FLU and the AUC of FLU and NFLU were better predictors of the changes in awake and movement time in the PSG than single-sample concentrations of FLU and NFLU taken at the time of PSG assessment.

Poor response to fluoxetine: underlying depression, serotonergic overstimulation, or a "therapeutic window"?

BACKGROUND: Symptoms of serotonergic overstimulation may resemble depressive symptoms. Postulating that overmedication with fluoxetine can appear as response failure (as norfluoxetine accumulates), systematic trials of lower doses were conducted in patients who failed to respond despite apparent initial improvements. METHOD: Of 23 consecutive outpatients treated with fluoxetine 20 mg/day for DSM-III-R major depression, 4 failed to sustain initial improvements during 4-8 weeks of treatment (in the absence of apparent side effects). In these 4 patients, fluoxetine was withdrawn for 2 weeks, then reinstituted at 20 mg q.o.d. All patients were followed up weekly to monthly (for up to 17 months) and administered the 17-item Hamilton Rating Scale for Depression. RESULTS: Four of 4 patients improved during washout and went on to respond to the lower dose. All 4 cases are presented. On review of the literature, fluoxetine fixed-dose studies reveal increased adverse effects with no increase in efficacy at dosages above 5 mg/day and decreased efficacy at dosages above 40 mg/day. Special issues inherent in the study and use of an antidepressant with a 1- to 3-week active half-life are discussed. CONCLUSION: Even in the apparent absence of side effects, nonresponse to fluoxetine may be due to overmedication in some patients. Standard doses of fluoxetine may be higher than "optimum." The apparent difficulty distinguishing fluoxetine's adverse effects/toxicity (or a "therapeutic window" effect) from underlying depressive symptoms, taken in conjunction with the 3-9 weeks required to approach steady state, may suggest the option of lowering the dose in some cases of nonresponse or "relapse."

Hypertension associated with oral administration of physostigmine in a patient with Alzheimer's disease.

The hemodynamic effects of physostigmine, a cholinomimetic drug used in the experimental treatment of Alzheimer's disease, are largely unknown. The author describes the development of episodes of hypertension in an elderly patient with Alzheimer's disease following treatment with oral physostigmine.