Permanent molars: delayed development and eruption.

Delayed development and eruption of all the permanent molars is a rare phenomenon, which can cause disturbance in the developing occlusion. The eruption of permanent first and second molars is very important for the coordination of facial growth and for providing sufficient occlusal support for undisturbed mastication. In the case described, the first permanent molars were delayed in their development and were seen erupting at the age of nine and a half years. Severe disparity between the left and the right side of the dentition with respect to the rate of development of molars were also present.

Ankylosis of primary molar along with congenitally missing first permanent molar.

Ankylosis of primary mandibular molars has been routinely found to be associated with various developmental disturbances in permanent dentition such as aplasia of the succedaneous tooth, ectopic eruption of the premolar, infraoclusion of the ankylosed tooth leading to tipping of the first permanent molar etc. This article describes a rare case where there was ankylosis of a mandibular second primary molar along with congenitally missing first permanent molar which resulted in the transposition of second premolar. Treatment options and prognosis of the case are discussed.

Population pharmacokinetics of temozolomide in cancer patients.

PURPOSE: To evaluate covariate effects on the pharmacokinetics of temozolomide in cancer patients, and to explore the dose-pharmacokinetics-toxicity relationship of temozolomide. METHODS: Non-linear mixed-effects modeling approach was used to analyze the data from 445 patients enrolled in eleven Phase I and Phase II clinical trials. All patients in the phase I trials had advanced cancer. Patients in the phase II trials had anaplastic astrocytoma (AA), glioblastoma multiforme (GBM) or malignant melanoma (MM). A sparse sampling scheme was prospectively developed using Phase I data and was successfully implemented in Phase II trials. Population factors included age, gender, height (HT), weight (WT), body surface area (BSA), serum creatinine (Sr.Cr.), estimated creatinine clearance, serum chemistry data as indices of hepatic function and disease, smoking status, and selected concomitant medications. Descriptive statistics were used to summarize the toxicity and temozolomide dose and exposure relationship. RESULTS: The pharmacokinetics of temozolomide follows a one-compartment model with first order absorption and elimination. Temozolomide clearance (CL) increased with BSA for both genders. The population mean clearance for GBM or AA patients was 11.2 L/hr for male with BSA equal to 2.0 m2, and 8.8 L/hr for female with BSA equal to 1.7 m2. The mean clearance for MM patients was slightly higher. The inter-subject variability in clearance was 15%, and the residual variability was 26%. Other factors investigated in this analysis had little effect on clearance. The overall incidence of neutropenia and thrombocytopenia were 5-8%. Temozolomide dose and AUC did not predict nadir neutrophil and platelet counts due to large variability in counts. CONCLUSIONS: The current dose regimen is administered according to BSA which is the most important factor influencing temozolomide clearance. No further dose adjustment is required.

QT dispersion as a noninvasive predictor of inducible ventricular tachycardia.

The QT dispersion (QTD) on the surface electrocardiogram is a noninvasive marker of heterogeneity of ventricular repolarization. An increased QTD has been associated with spontaneous ventricular arrhythmias. We investigated the relationship of QTD to inducible reentrant sustained ventricular tachycardia (VT) in 66 patients who underwent programmed electrical stimulation. Thirty-three patients had inducible VT and 33 had noninducible VT with up to three extra stimuli. The QTD was significantly longer in patients with inducible VT (79+/-30 ms) compared with those in whom VT was noninducible (50+/-20 ms, P < .0001). QTD of > or =70 ms had a sensitivity of 67%, a specificity of 94%, a positive predictive value of 92%, and a negative predictive value of 74% for inducible VT. We conclude that QTD is an easily measurable electrocardiographic index that is increased in patients with inducible VT, and a QTD of > or =70 ms is highly predictive of VT inducibility.

A rare case of inferior venacaval type of atrial septal defect in an adult: echocardiographic features.

We report a rare type of atrial septal defect with communication between the left atrium and the inferior vena cava. This type of defect has been referred to as a low sinus venous type of atrial septal defect because of its developmental origin, and possibly is caused by defective absorption of the left venous valve of the sinus venosus into the septum secundum. Detailed echocardiographic features are discussed.

Characterization of AUCs from sparsely sampled populations in toxicology studies.

PURPOSE: The objective of this work was to develop and validate blood sampling schemes for accurate AUC determination from a few samples (sparse sampling). This will enable AUC determination directly in toxicology studies, without the need to utilize a large number of animals. METHODS: Sparse sampling schemes were developed using plasma concentration-time (Cp-t) data in rats from toxicokinetic (TK) studies with the antiepileptic felbamate (F) and the antihistamine loratadine (L); Cp-t data at 13-16 time-points (N = 4 or 5 rats/time-point) were available for F, L and its active circulating metabolite descarboethoxyloratadine (DCL). AUCs were determined using the full profile and from 5 investigator designated time-points termed "critical" time-points. Using the bootstrap (re-sampling) technique, 1000 AUCs were computed by sampling (N = 2 rats/point, with replacement) from the 4 or 5 rats at each "critical" point. The data were subsequently modeled using PCNONLIN, and the parameters (ka, ke, and Vd) were perturbed by different degrees to simulate pharmacokinetic (PK) changes that may occur during a toxicology study due to enzyme induction/inhibition, etc. Finally Monte Carlo simulations were performed with random noise (10 to 40%) applied to Cp-t and/or PK parameters to examine its impact on AUCs from sparse sampling. RESULTS: The 5 time-points with 2 rats/point accurately and precisely estimated the AUC for F, L and DCL; the deviation from the full profile was approximately 10%, with a precision (%CV) of approximately 15%. Further, altered kinetics and random noise had minimal impact on AUCs from sparse sampling. CONCLUSIONS: Sparse sampling can accurately estimate AUCs and can be implemented in rodent toxicology studies to significantly reduce the number of animals for TK evaluations. The same principle is applicable to sparse sampling designs in other species used in safety assessments.

Severe bioprosthetic tricuspid valve stenosis with systolic antegrade flow across the tricuspid valve.

We report the anatomic and hemodynamic details of severe stenosis of a bioprosthetic tricuspid valve studied by transthoracic and transesophageal echocardiography. This patient also had antegrade systolic flow across the tricuspid valve due to a combination of severe tricuspid valve stenosis and poor right ventricular systolic function.

Septic arthritis due to Actinobacillus actinomycetemcomitans.

Actinobacillus actinomycetemcomitans, a gram-negative aerobic bacillus of the family Parvobacteriaceae which is a normal inhabitant of the oral flora, is a rare cause of human infection. We report a case of septic arthritis caused by this organism in an uncompromised child.

Effect of respiration on the QT interval.

This clinical study was undertaken to investigate the effect of respiration on the QT interval. The QT interval is affected by a variety of factors, including steady changes in heart rate, instantaneous changes in heart rate as in atrial fibrillation, and changes in autonomic tone. Respiration gives rise to cyclical changes in the instantaneous heart rate and autonomic tone. The effect of respiration on the QT interval was analyzed in 25 subjects in sinus rhythm. Cosinor analysis was used to estimate the amplitude of its change from the mean value, its statistical significance, and the timing of the maximum change. Thirteen (52%) subjects revealed significant respiratory change in the QT interval, being the shortest during inspiration in 10 of them. Its amplitude correlated positively with respiratory cycle length (r = .58, P < .01), but not with age, mean heart rate, or the amplitude of change in the RR interval. The mean amplitude of change in the QT interval was 0.8% compared to a change of 2.6% in the RR interval. There is a respiratory variation in the QT interval in subjects in sinus rhythm that is more prominent during slower respirations. However, the amplitude of change in the QT interval is small compared to the change in the RR interval.

Atrial fibrillation: new management strategies.

The main goal of therapy in atrial fibrillation is to restore sinus rhythm, if this is possible, to avoid adverse hemodynamic, electrical, and embolic consequences. The restoration of sinus rhythm is urgent if the patient is unstable. In a stable patient, if the duration is shorter than 48 hours and an atrial thrombus is unlikely, then sinus rhythm can be restored after initial rate control. If the duration of atrial fibrillation is more than 48 hours, the embolic risk may be significant, and anticoagulation will be required for 2 to 4 weeks before an attempt at cardioversion. In patients in whom sinus rhythm cannot be restored or maintained, the goal of therapy is rate control and reduction of embolic risk unless the risk of anticoagulation outweighs its benefit. In difficult cases, rate control may be accomplished with AV nodal ablation and pacemaker implantation or with one of the surgical procedures described above with varying degrees of normalization of the physiology. Although not included in this flow chart, we do not advocate episodic intermittent therapy for patients with infrequent episodes of atrial fibrillation because this could be potentially dangerous and may place the patient at a higher risk for developing proarrhythmia.

Population pharmacokinetic analysis of didanosine (2',3'-dideoxyinosine) plasma concentrations obtained in phase I clinical trials in patients with AIDS or AIDS-related complex.

Plasma didanosine concentration data from 36 patients receiving once-a-day therapy and from 33 patients receiving twice-a-day therapy were subject to population pharmacokinetic analysis with the computer program NONMEM. Once- or twice-a-day regimens of didanosine were administered intravenously (i.v.) (dose: 0.8-33 mg/kg) during the first 2 weeks of therapy, and orally (dose: 1.6-66 mg/kg) for the remaining 4 weeks of therapy. Plasma pharmacokinetics were determined after the first and last (steady-state) i.v. and oral doses. Population pharmacokinetic parameters for the combined i.v. and oral steady-state data were (mean [%CV]): systemic clearance, CL, 0.70 (5.2) L/h/kg; central compartment volume, Vc, 0.18 (32) L/kg; steady-state distribution volume, Vdss, 0.84 (6.8) L/kg; first-order absorption rate constant, Ka, 1.3 (9.5) hr-1; and bioavailable fraction, F, 0.34 (8.5). Interindividual variability (omega) was (%CV) 22.3 and 71.0 for CL and Vc, respectively. Intraindividual (residual) variability (sigma) in plasma concentrations (%CV) was 50.2. Body weight, sex, and age did not account for the variability in either CL or Vc, and the use of alternate pharmacokinetic models did not reduce the value of intraindividual variability. Population parameters for the combined i.v. and oral first-dose data were generally similar to those for the steady-state data. The parameters can be used to design dosing regimens in patients using the Bayesian feedback approach.

Kinetics of aluminum in rats. II: Dose-dependent urinary and biliary excretion.

Previous iv studies from our laboratories have shown that the disappearance half-life of blood aluminum increased with dose. Experiments were initiated to determine if saturation of biliary and/or urinary excretion could be responsible for this dose-dependent behavior. Biliary aluminum excretion (0-12 h) accounted for less than 1% of the injected amount at 0.1- and 1.0-mg/kg doses. During the same interval, urinary excretion accounted for 16.7 +/- 2.66 and 8.85 +/- 2.2% of administered dose at the low and high doses, respectively (p less than 0.05); corresponding long term (0 to 13 or 22 days) urinary recoveries were 37.6 +/- 3.67 and 28.4 +/- 1.88% of the injected dose (p less than 0.05), with most (66-70%) of the excretion occurring in the first 24 h. This is consistent with many previous reports showing that urinary excretion is one major elimination pathway for aluminum. Both biliary and urinary clearances decreased with increasing blood aluminum concentration; the biliary and urinary clearance values at low concentrations (500-900 ng/mL) were approximately four- and threefold higher than the corresponding values at higher concentrations (10,000-12,000 ng/mL), respectively. It appears that this apparent saturability of biliary clearance may be due to concentration-dependent of transfer from blood to liver, rather than from liver to bile. In vitro ultrafiltration studies support the hypothesis that decreases in urinary clearance were due to decreased filterability of aluminum at the glomerulus as its blood concentration was increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Kinetics of aluminum in rats I: Dose-dependent elimination from blood after intravenous administration.

Aluminum (Al) kinetics after intravenous bolus administration were studied in the rat. The animals received either 0.1 or 1.0 mg/kg (n = 6 at each dose) of elemental Al as the sulfate salt. The Al content of serial blood samples was determined by flameless atomic absorption spectrophotometry. Blood and plasma Al-time profiles after both doses were monoexponential in most cases. Increasing the administered dose increased the elimination half-life (mean +/- SD) from 1.20 +/- 0.25 to 2.41 +/- 0.26 h. A corresponding decrease in systemic clearance was observed (49.6 +/- 11.0 to 18.4 +/- 4.6 mL/kg.h). Both changes were significant (p less than 0.05). Significant differences were also observed in the volume of distribution, the values of which were 78.3 +/- 17.2 and 58.9 +/- 8.5 mL/kg at the low and high doses, respectively. At both doses, blood:plasma ratios ranged from 0.8 to 1.0, indicating considerable uptake/binding of the element by blood cells.