Flecainide exerts paradoxical effects on sodium currents and atrial arrhythmia in murine RyR2-P2328S hearts.

AIMS: Cardiac ryanodine receptor mutations are associated with catecholaminergic polymorphic ventricular tachycardia (CPVT), and some, including RyR2-P2328S, also predispose to atrial fibrillation. Recent work associates reduced atrial Nav 1.5 currents in homozygous RyR2-P2328S (RyR2(S/S) ) mice with slowed conduction and increased arrhythmogenicity. Yet clinically, and in murine models, the Nav 1.5 blocker flecainide reduces ventricular arrhythmogenicity in CPVT. We aimed to determine whether, and how, flecainide influences atrial arrhythmogenicity in RyR2(S/S) mice and their wild-type (WT) littermates. METHODS: We explored effects of 1 µm flecainide on WT and RyR2(S/S) atria. Arrhythmic incidence, action potential (AP) conduction velocity (CV), atrial effective refractory period (AERP) and AP wavelength (λ = CV × AERP) were measured using multi-electrode array recordings in Langendorff-perfused hearts; Na(+) currents (INa ) were recorded using loose patch clamping of superfused atria. RESULTS: RyR2(S/S) showed more frequent atrial arrhythmias, slower CV, reduced INa and unchanged AERP compared to WT. Flecainide was anti-arrhythmic in RyR2(S/S) but pro-arrhythmic in WT. It increased INa in RyR2(S/S) atria, whereas it reduced INa as expected in WT. It increased AERP while sparing CV in RyR2(S/S) , but reduced CV while sparing AERP in WT. Thus, RyR2(S/S) hearts have low λ relative to WT; flecainide then increases λ in RyR2(S/S) but decreases λ in WT. CONCLUSIONS: Flecainide (1 µm) rescues the RyR2-P2328S atrial arrhythmogenic phenotype by restoring compromised INa and λ, changes recently attributed to increased sarcoplasmic reticular Ca(2+) release. This contrasts with the increased arrhythmic incidence and reduced INa and λ with flecainide in WT.

Atrial arrhythmia, triggering events and conduction abnormalities in isolated murine RyR2-P2328S hearts.

AIM: RyR2 mutations are associated with catecholaminergic polymorphic tachycardia, a condition characterized by ventricular and atrial arrhythmias. The present experiments investigate the atrial electrophysiology of homozygotic murine RyR2-P2328S (RyR2(S/S)) hearts for ectopic triggering events and for conduction abnormalities that might provide a re-entrant substrate. METHODS: Electrocardiograph recordings were made from regularly stimulated RyR2(S/S) and wild type (WT) hearts, perfused using a novel modified Langendorff preparation. This permitted the simultaneous use of either floating intracellular microelectrodes to measure action potential (AP) parameters, or a multielectrode array to measure epicardial conduction velocity (CV). RESULTS: RyR2(S/S) showed frequent sustained tachyarrhythmias, delayed afterdepolarizations and ectopic APs, increased interatrial conduction delays, reduced epicardial CVs and reduced maximum rates of AP depolarization ((dV/dt)(max)), despite similar effective refractory periods, AP durations and AP amplitudes. Effective interatrial CVs and (dV/dt)(max) values of APs following ectopic (S2) stimulation were lower than those of APs following regular stimulation and decreased with shortening S1S2 intervals. However, although RyR2(S/S) atria showed arrhythmias over a wider range of S1S2 intervals, the interatrial CV and (dV/dt)(max) of S2 APs provoking such arrhythmias were similar in RyR2(S/S) and WT. CONCLUSIONS: These results suggest that abnormal intracellular Ca(2+) homoeostasis produces both arrhythmic triggers and a slow-conducting arrhythmic substrate in RyR2(S/S) atria. A similar mechanism might also contribute to arrhythmogenesis in other conditions, associated with diastolic Ca(2+) release, such as atrial fibrillation.

Prospective study of neuropsychologic testing and quality-of-life assessment of adults with primary malignant brain tumors.

PURPOSE: To identify the characteristics of adult patients with newly diagnosed primary brain tumors associated with identifiable deficits in neuropsychologic function to target interventions to improve function and quality of life (QOL). MATERIALS AND METHODS: Adult patients with newly diagnosed primary brain tumors and their caregivers were enrolled and underwent a battery of standardized neuropsychologic tests, allowing for qualitative and quantitative assessment and sensitive to the effects of the brain tumor, QOL, or caregiver stress. RESULTS: We enrolled 68 patients with no prior radiotherapy. Patients with left hemisphere tumors reported significantly more memory problems and depressive symptoms. They also exhibited poorer attention and were more distractible, with poorer verbal fluency and poorer verbal learning. Patients with glioblastoma multiforme demonstrated poorer psychomotor speed and visual tracking than patients with non-glioblastoma multiforme histologic features. Patients and caregivers perceived QOL in a similar fashion, with significant correlation between patient and caregiver on hope testing and general QOL on the Linear Analog Self-Assessment Scale. CONCLUSIONS: Patients with left hemisphere tumors and glioblastoma multiforme histologic features demonstrated testable differences in neuropsychologic function and QOL that may be amenable to improvement with medical therapy or tailored rehabilitation programs. Caregiver assessments can predict patient QOL, which may be useful in patients with declining status.

Serum biochemical changes after laparoscopy may be indicators of bladder injury.

We evaluated the serum renal biochemical profile as an indicator of unrecognized laparoscopic bladder injury in four women. The patients were seen 24 to 56 hours postoperatively with elevated serum creatinine and urea levels, and electrolyte changes compatible with acute renal dysfunction. The mechanism responsible for these biochemical changes appears to be extravasation and reabsorption of urine. Biochemical values returned to normal within 24 hours after bladder repair.

Slow wave sleep rebound and REM rebound following the first night of treatment with CPAP for sleep apnea: correlation with subjective improvement in sleep quality.

Objective: The purpose of this study was to correlate changes in PSG parameters between the diagnostic polysomnogram (dPSG) and the first night of treatment with continuous positive airway pressure (CPAP) (cpapPSG) to subjective improvement in sleep quality.Background: In patients with obstructive sleep apnea syndrome (OSAS), therapy with CPAP results in reduction of sleep latency, stage 1 sleep, arousal index (Al) and respiratory disturbance index (RDI), and increase in stage 2 sleep, REM sleep and REM density. No data exists on the differences in polysomnographic (PSG) parameters in patients who have subjective improvement in sleep quality and those who do not.Methods: We retrospectively reviewed PSG studies of 44 patients with OSAS who presented to the Sleep Disorders Center at Duke University Medical Center. Patient's qualitative assessment of sleep was noted using a Likert-type scale administered the morning after the dPSG and cpapPSG. PSG indices of patients noting subjective improvement were compared to those with no improvement.Results: Patients noting a subjective improvement in sleep quality showed a decrease in the percentages of stage 1 sleep (P<0.001) and an increase in percentages of stages 3 and 4 sleep (slow wave sleep rebound; P<0.007) and stage REM sleep (REM rebound; P<0.008).

Optimization of inpatient warfarin therapy: impact of daily consultation by a pharmacist-managed anticoagulation service.

OBJECTIVE: To determine the effect of daily consultation by a team of hospital pharmacists on the accuracy and rapidity of optimizing warfarin therapy. DESIGN: Comparison of a historical control cohort with a prospective cohort matched for treatment indication. SETTING: A 400-bed university teaching hospital. PATIENTS: Sixty consecutive patients hospitalized in 1992 and starting warfarin for the first time, with anticoagulation therapy managed by physicians, were compared with 60 patients matched for warfarin indication hospitalized in 1995, but with anticoagulation therapy managed with pharmacy consultation. RESULTS: Pharmacist management of initial warfarin therapy resulted in a significant reduction in the length of hospitalization compared with physician dosing, from 9.5 +/- 5.6 days to 6.8 +/- 4.4 days (p = 0.009). The number of patients and patient-days with international normalized ratio (INR) values >3.5 were reduced by pharmacist dosing from 37 patients and 142 days to 16 patients and 29 days, respectively (p < 0.001). Similarly, the number of patients and patient-days with INR >6.0 were reduced from 20 patients and 50 days to two patients and six days, respectively (p < 0.001). There were six documented bleeding complications in 1992 compared with one in 1995 (p = 0.11). The mean INR at discharge was significantly lower in the pharmacy surveillance group, 2.6 +/- 0.58, compared with the physician cohort, 3.3 +/- 2.1 (p = 0.07). Readmissions after discharge due to bleeding or recurrent thrombosis were reduced from five (at 1 mo) and 10 (at 3 mo) to two and five readmissions, respectively, by pharmacist intervention (p = 0.43). The number of patients with concurrently prescribed drugs known to significantly interact with warfarin was significantly lower (6 vs. 13; p = 0.02) in the pharmacy surveillance group. CONCLUSIONS: Among patients starting warfarin for the first time, daily consultation by a pharmacist significantly decreased the length of hospital stay and the number of patients who received excessive anticoagulation therapy. These findings translate into improved quality of care and potentially significant cost savings.

Detecting simulated memory impairment with the Rey Auditory Verbal Learning Test: implications of base rates and study generalizability.

The accuracy of the Rey Auditory Verbal Learning Test (RAVLT) for detecting simulated neuropsychological impairment was investigated using discriminant function analyses and cross-validation procedures. In Study 1, a discriminant function analysis, using six RAVLT variables, correctly classified 80% of 50 simulating and 50 non-simulating participants. Base rates were changed and this discriminant function was tested in Study 2 with a 33% base rate of simulation. The discriminant function correctly classified 75% of 20 simulators and 90% of 40 non-simulators, yielding an overall classification rate of 85%. To determine the generalizability of this discriminant function to a clinical sample, Study 3 compared the RAVLT performance of 20 simulating participants to that of 40 motor vehicle accident (MVA) patients. The discriminant function from Study 1 incorrectly classified 60% of the MVA patients and yielded an overall correct classification rate of 48%. The limitations associated with generalizing from analog research and the implications of varying base rates on classification accuracy are discussed.

Computerized documentation of activities of Pharm.D. clerkship students.

A method for documenting the contributions of entry-level Pharm.D. clerkship students at a teaching hospital is described. Between mid-September 1995 and April 1996, students were asked to use a cost-accounting software program to document time spent on various activities associated with inpatient pharmacy services. The system was already being used for documenting the clinical activities of staff pharmacists; pharmacists entered activities in the same way that they entered medication orders, using a mnemonic for a clinical activity in place of a drug name and time spent on the activity in place of a dosage. Pharmacist preceptors verified the students' entries. Eleven students reported 3,466 clinical events. Thirty-five pharmacists reported 54,299 clinical events during the same period. Students were responsible for 42.5% of the initial patient work-ups reported, 34.0% of the patient information and education episodes, and 24.6% of the inservice programs for physicians. On the basis of documented student contributions to the clinical workload, the pharmacy department requested additional clerkship students. The following year, 16 clerkship students were assigned to the department and the program was expanded to year-round clerkships. Pharmacy clerkship students contributed to the productivity data of a teaching hospital. Documentation of the students' contributions led to an expansion of the clerkship program.

The detection of simulated malingering using a computerized category classification test.

A category classification test was used to differentiate between normal student control participants, students instructed to malinger a memory deficit, and amnesic patients. Controls (N = 44) and amnesic patients (N = 10) were instructed to do their best, while simulators of malingering (N = 43) were instructed to fake a memory deficit for credit and possible financial compensation. Participants studied a list of high distortions of a prototype dot pattern and were then asked to choose whether or not a new set of dot patterns (random patterns, high distortions, low distortions, and the prototype) belonged to the same category of dot patterns as studied. Malingerers performed significantly worse than normal controls and amnesic patients. A discriminant function analysis showed that the classification test can be used to correctly classify participants as simulated malingerers, controls, or amnesic patients significantly higher than chance. These results indicate that a category classification test can be used in the detection of simulated malingering and that some tests of implicit memory provide a potential supplement to standard forced choice tests in the detection of malingering.

The detection of simulated malingering using a computerized priming test.

A word completion priming test was used to differentiate between normal student control subjects and students instructed to malinger. Controls (n = 60) were instructed to do their best, while malingering subjects (n = 60) were instructed to fake a memory deficit for credit and possible financial compensation. Subjects initially rated and completed stems for words that had at least 10 possible completions. Thirty minutes later, subjects rated and completed stems for words that were either uniquely defined by the stem or could only be completed with a variation of the word. Simulated malingerers and controls differed significantly on response latencies (time to produce rated words-time to produce baseline words, 10 second time limit) and priming scores. Discriminant function analyses showed that as high as 92% of the controls could be correctly identified, and 73% of the malingerers could be correctly identified. These results indicate that priming tests can be used in the detection of malingering.

Experience with 800 hysteroscopic endometrial ablations.

STUDY OBJECTIVE: To determine the safety and efficacy of hysteroscopic endometrial ablation in women with menometrorrhagia. DESIGN: Retrospective record review. SETTING: A credentialing program in teaching and nonteaching hospitals. PATIENTS: Eight hundred women who underwent endometrial ablation in 54 hospitals, with indications of abnormal uterine bleeding disrupting lifestyle, postmenopausal bleeding during hormone replacement therapy, poor surgical risk for hysterectomy, or desire to preserve the uterus. INTERVENTIONS: Seventy percent of the patients were treated with danazol 100 to 600 mg/day for 6 to 12 weeks, 8% received gonadotropin-releasing hormone analogs, 7% received progestins, and 15% were given no preoperative treatment. Under appropriate anesthesia the cervix was dilated to 10 mm and the uterine cavity was distended with 1.5% glycine solution under gravity inflow of 80 to 100 cm water and outflow suction of 80 to 100 mm Hg pressure. Electrocoagulation with or without resection was completed using 100 and 125 W, respectively. MEASUREMENTS AND RESULTS: At 12 months 60% of patients reported amenorrhea, 29% hypomenorrhea, 6% eumenorrhea, and 5% no change. Repeat ablation was performed in 4% of patients. An additional 2% had hysterectomy for malignancy (endometrium 2, sarcoma 1, atypical hyperplasia 1), pelvic pain (4), fibroids (4), persistent bleeding (3), and endometritis (2). The complication rate was 3.9%: false passage during cervical dilatation (6), uterine perforation (dilator 4, resectoscope 2, Laminaria 1), fluid absorption greater than 1500 ml (8), minor bleeding (5), endomyometritis (4), and intrauterine pregnancy (1). CONCLUSIONS: Hysteroscopic endometrial ablation is a safe and effective treatment for women with menometrorrhagia.

The relationship between antecedent antibiotic use and resistance to extended-spectrum cephalosporins in group I beta-lactamase-producing organisms.

Gram-negative pathogens are increasingly resistant to extended-spectrum cephalosporins (ESCs). Using a prospective, case-controlled observational study, we examined the prevalence and the risk factors for development of resistance to ESCs in group I beta-lactamase-producing organisms. Of the 386 isolates of Enterobacter species, Pseudomonas aeruginosa, Citrobacter species, and Serratia marsescens from 340 consecutive patients, 70 (18.1%) were resistant to ESCs; the highest rates of resistance were found among Citrobacter freundii (40.9%), Enterobacter cloacae (31.1%), and Enterobacter aerogenes isolates (18.9%). Patients' prior antibiotic use and the mean number of antibiotics used were significantly greater in association with resistant vs. susceptible isolates. Resistance was associated with prior use of ceftizoxime or cefotaxime (P = .008), ceftazidime (P = .004), and piperacillin (P = .001). Other antibiotics were not associated with resistance. Resistance was less frequent in patients receiving ESCs and an aminoglycoside. We conclude that prior use of ESCs is associated with the isolation of resistant group I beta-lactamase-producing organisms. Concomitant use of an aminoglycoside may decrease this risk.

Successful use of higher-than-recommended dosage of imipenem in Pseudomonas aeruginosa endocarditis.

OBJECTIVE: To report a case of Pseudomonas aeruginosa endocarditis that was successfully treated with high-dose imipenem/cilastatin and to discuss dosage modification based on individual pharmacokinetic parameters. DATA SOURCES: Clinical studies, review articles, and relevant laboratory and pharmacokinetic information. CASE SUMMARY: A 27-year-old man with right-sided P. aeruginosa endocarditis was successfully treated with long-term imipenem/cilastatin and tobramycin. The imipenem dose required to achieve therapeutic serum concentrations and cidal activity was 6 g/d. The manufacturer's recommended maximum dose is 4.0 g/d or 50 mg/kg/d. Because of the patient's large apparent volume of distribution, low serum imipenem concentrations, and lack of serum cidal activity, the clinical decision was made to increase the dose to 6 g/d or 54 mg/kg/d. Treatment was tolerated for seven weeks without any adverse effects. The patient remains free of symptoms 24 months after the diagnosis. CONCLUSIONS: Careful and discriminate use of larger-than-recommended doses of imipenem may be indicated in certain clinical situations. Dosage may need to be adjusted to body size in order to obtain optimal serum concentrations and activity.

The effect of acetaminophen on zidovudine metabolism in HIV-infected patients.

The concomitant administration of acetaminophen to HIV-positive patients receiving zidovudine (AZT) therapy has previously been thought to increase the likelihood of the toxicity of AZT due to increased serum levels, resulting from hypothesized metabolic competition. We measured serum AZT and metabolite levels by HPLC in HIV-infected patients taking regular doses of AZT with and without acetaminophen administration. In all patients, serum levels of AZT and the glucuronidated metabolite (GAZT) were similar with and without acetaminophen administration. AZT serum levels were not increased (p less than 0.05). We believe that the rationale for withholding acetaminophen from patients receiving AZT should be re-evaluated.

The early growth of cancer.

In this paper, we compare two types of stochastic models for the initial growth of cancerous tumors. In one type, the random element enters via the initial time of growth or via the initial size of the growth clone. In the other type, tumors differ from one another essentially via their growth rates. We present a simple test to distinguish between the two types when tumor size distributions are available from several time points. Size distributions are the key elements of such kinetic analysis given the limitation that an individual tumor can be measured only once, at the time of sacrifice of an experimental animal. We discuss these concepts in connection with data from particular experiments on carcinogenic growth in the livers of mice.

Optimal use of sampled tissue sections for estimating the number of hepatocellular foci.

Statistical techniques were applied to computer-simulated data to evaluate the importance of various factors that may affect the estimation of the number of hepatocellular foci from foci transections. The simulations were modeled after mouse foci for which three-dimensional size distributions and densities were determined from serial section reconstructions. The foci had been induced in male C57BL/6 X C3H F1 mice at 20 and 28 weeks after a single injection, in infancy, of diethylnitrosamine. In an earlier report, we had shown that the number of foci per cu cm could be accurately estimated from profiles using a conditional estimator when the investigator is unable to identify profiles smaller than a certain size (epsilon). In the present study, emphasis was placed on assessing the value of step serial sections in order to make optimal use of the small tissue samples in mouse liver. Since all mathematical estimators of N3 are based on measurement of sampled profiles (n2') and ultimately derive from the fundamental relationship. N3' = N2'/2mu, (where N3' is the number of foci per cu cm, N2' is the number of profiles per sq cm, and mu, is the average adjusted focus radius), the relative importance of N2' and mu, on the conditional estimator was evaluated. This was accomplished by comparing the errors resulting from use of the conditional estimator with those resulting from use of two other estimators. The latter two estimators consisted of a "sampled focus estimator," which used sampled intact foci to estimate N3, and a "reference estimator," which used profiles from foci with a mu, that was known. Additionally, in order to provide a stable variance for the conditional estimator, we adopted a simple smoothing procedure. As expected, none of the estimators showed any significant bias. However, somewhat surprising was the finding that the standard deviations from use of all three estimators were almost identical. Consequently, it appears that the variance resulting from application of the smoothed conditional estimator to large sets of profile data is not due to difficulty in estimating mu epsilon. In these instances, the faulty estimates of N2' resulted almost entirely from the variability in sampling foci from tissue blocks which constituted only about 1/25 of the liver volume. In addition, the ability to reduce the error in estimating the number of foci by increasing the number of profiles was also evaluated. We simulated a sectioning protocol for the 28-week mouse livers in which the distances between the 5-micron-thick step sections in a 1-mm block of liver were progressively decreased from 1000 to 50 micron.(ABSTRACT TRUNCATED AT 400 WORDS)