Anti-D in a D-positive renal transplant patient

PURPOSE: We report a case of postoperative reparalysis in the recovery room, following nebulized epinephrine. The patient was pharmacologically reversed with edrophonium after paralysis with rocuronium. CLINICAL FINDINGS: A 12-yr-old girl developed postoperative reparalysis following the intraoperative administration of rocuronium. A total of 0.92 mg.kg-1 rocuronium was administered. After surgery, pharmacological reversal was achieved with 20 mg edrophonium with 0.15 mg atropine sulfate iv 35 min after the last administration of rocuronium. Muscular relaxation was monitored using an ulnar peripheral nerve stimulator (PNS). After reversal, a full train-of-four and sustained tetanus at 50 Hz were present. In the recovery room, following nebulized epinephrine, the patient became apneic. The patient was paralyzed and an ulnar PNS demonstrated only one faint twitch. The paralysis was reversed with 1.5 mg neostigmine with 0.3 mg glycopyrrolate. CONCLUSION: Postoperative reparalysis following rocuronium may be a cause of postoperative respiratory distress. The definitive diagnosis is made using PNS and observing the response to pharmacological reversal. Nebulized epinephrine may have a previously undescribed role in the development of postoperative reparalysis.     

The pharmacokinetics and pharmacodynamics of the oral iron chelator deferiprone (L1) in relation to hemoglobin levels

Recently, we demonstrated that administration of the orally active iron chelating agent deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one (L1)) at 6-hour intervals results in significantly greater urinary iron excretion than that induced during administration of the drug at 12-hour intervals. That study was conducted in thalassemia patients, all of whom had received a packed red cell transfusion of 15 cc/kg. 72 hours prior to evaluation of urinary iron excretion, at a time when endogenous erythropoiesis would be expected to be at its lowest. In clinical practice however, thalassemia patients, suppression of endogenous erythropoiesis is not sustained between transfusions. We set out to determine the influence that administration of deferiprone has on urinary iron excretion at lower hemoglobin concentrations, immediately prior to transfusion. We hypothesized that hemoglobin levels will affect the ability of deferiprone to chelate iron. Ten regularly transfused patients with homozygous beta-thalassemia (HBT) aged mean +/- SD, 20.9 +/- 4.7, range 13 - 27 years, receiving long-term therapy with deferiprone, were treated with deferiprone 75 mg/kg/day, administered every 6 hours (or every 12 hours) for 72 hours immediately prior to a blood transfusion in the first month. One month later each patient received the other of the 2 dosing regimens for 72 hours immediately prior to transfusion. The deferiprone-induced 24-hour urinary iron excretion was similar during both dosing regimens; 0.56 +/- 0.45 mg/kg when L1 was given every 6 hours and 0.48 +/- 0.52 mg/kg when L1 was administered every 12 hours (p = 0.79). However, the calculated 24-hour area under the plasma concentration-time curve (AUC0-24) of deferiprone was significantly lower when deferiprone was administered at 6-hour intervals (6,762.8 +/- 1,601.6 mg*min/l), than that observed when deferiprone was administered every 12 hours (8,250.1 +/- 1,235.7 mg*min/l) (p = 0.04). The pharmacokinetics of deferiprone when administered immediately prior to transfusions are different from those following transfusions. More studies assessing total body iron excretion are needed to determine the contribution of the fecal route in iron excretion.     

Preface

Multibody System Dynamics -     

The effect of growth hormone replacement on cortisol metabolism and glucocorticoid sensitivity in hypopituitary adults

OBJECTIVE: Growth hormone (GH) replacement therapy in hypopituitary adults is associated with sodium and water retention. The underlying mechanisms are incompletely understood and a possible contribution of altered cortisol metabolism or action has not been evaluated. We have investigated the effect of GH replacement therapy on cortisol metabolism, cortisol binding globulin and in-vitro glucocorticoid sensitivity in a group of adult hypopituitary patients. DESIGN AND PATIENTS: We studied 19 adult hypopituitary patients (18 adult onset, M:F, 6:13), who were receiving conventional hydrocortisone (16 patients), thyroxine (14 patients), triiodothyronine (1 patient), sex steroid (9 patients), human chorionic gonadotrophin (1 patient) or desmopressin (6 patients) replacement during a 6-month, double blind controlled trial of GH therapy (active:placebo, 8:11) followed by a 6-month open phase of GH (mean dose: 0.2 IU/kg/week, range 0.051-0.27) and after a 6-week washout phase following discontinuation of GH therapy. MEASUREMENTS: Twenty-four-hour urine free cortisol, cortisol metabolites (CoM), ratio 11-hydroxy/11-oxo CoM (F/E) and ratio 5 alpha/beta tetrahydrocortisol were measured at 6 months, 12 months and after the 6 week washout phase. Serum cortisol binding globulin was measured basally, at 6 months, 12 months and after washout. Glucocorticoid sensitivity was determined in lymphocyte preparations from 8 patients, during GH therapy and after washout, using an in-vitro technique dependent on dexamethasone suppression of phytohaemagglutinin-stimulated thymidine incorporation into DNA. Plasma renin activity and aldosterone were measured after 6-12 months GH therapy and after washout. RESULTS: After 6 months of GH, in patients on hydrocortisone (n = 9), there were significant decreases in CoM (mean decrement 21%, P < 0.01), F/E (mean decreased from 1.27 to 1.0, P = 0.04; reference range 0.33-1.29) and 5 alpha/5 beta tetrahydrocortisol (mean decreased from 0.67 to 0.48, P = 0.01) and a subsequent increase after washout. Patients not on hydrocortisone (n = 2) demonstrated a normal basal F/E falling by 25% on GH therapy but no change in CoM. During 12 months of GH therapy, patients on hydrocortisone (n = 7) demonstrated a further trend to decrement in CoM (P = 0.09) which reversed after washout (P = 0.04). Urine free cortisol tended to fall during GH therapy and increased significantly following washout after 12 months treatment (P < 0.02). Serum cortisol binding globulin decreased by 20% (P < 0.05) during 12 months GH treatment but remained within the reference range. In-vitro studies demonstrated a trend to reduced glucocorticoid sensitivity on GH therapy; the maximum inhibition of phytohaemagglutinin by dexamethasone tended to be less on GH therapy (P = 0.052) and was also lower than in 29 normal volunteers (P < 0.05). There were no significant changes in plasma renin but there was a small increment in aldosterone in recumbent patients (P = 0.04) during the open phase of GH therapy in the placebo arm. CONCLUSIONS: GH therapy in hypopituitary adults is associated with an apparent reduction in availability of administered hydrocortisone as measured by urine cortisol metabolites and urine free cortisol. This effect is unlikely to be clinically significant except possibly in ACTH deficient subjects on suboptimal hydrocortisone replacement. The changes in F/E suggest that GH may directly or indirectly modulate the activity of 11 beta-hydroxysteroid dehydrogenase. The apparent decrease in glucocorticoid sensitivity during GH therapy, demonstrated in vitro, merits further investigation.     

On the Gröbner basis triangularization of constraint equations in natural coordinates

Efficient dynamic simulation code is essential in many situations (including hardware-in-the-loop and model-predictive control applications), and highly beneficial in others (such as design optimization, sensitivity analysis, parameter identification, and controller tuning tasks). When the number of modeling coordinates n exceeds the degrees-of-freedom of the system f, as is often the case when closed kinematic chains are present, the governing dynamic equations consist of n second-order ordinary differential equations (ODEs) coupled with m=n?f algebraic constraint equations. This set of n+m index-3 differential-algebraic equations can be difficult to solve in an efficient yet accurate manner. Embedding (or generalized coordinate partitioning) can be used to obtain f ODEs (one for each independent acceleration), which are generally more amenable to numerical integration; however, the dependent positions are typically computed from the independent positions at each time step. Newton–Raphson iteration is often used for solving the position-level kinematics, but only provides solutions to within a specified tolerance, and can require several iterations to converge. In this work, Gröbner bases are used to obtain recursively solvable symbolic solutions for the dependent positions, which can then be evaluated to within machine precision using a fixed number of arithmetic operations. Natural coordinates are particularly attractive in this context, since the resulting constraint equations are maximally quadratic polynomials and are, therefore, easily triangularized. The proposed approach is suitable for use in an automated formulation procedure and, as demonstrated by three examples, is capable of generating highly efficient simulation code with minimal additional effort required at the formulation stage.     

Anisotropy of radiance in tissue phantoms and Dunning R3327 rat tumors: radiance measurements with flat cleaved fiber probes

OBJECTIVE: To compare the prevalence of conduct problems (CP) according to level of urbanization and to determine which factors account for the potential difference in prevalence rates. METHOD: Study 1 used a questionnaire survey of a nationally representative sample of 10,462 Norwegian adolescents. Study 2 used a questionnaire survey of a representative sample of 1,346 adolescents living in Oslo. Self-reported CP included most DSM-III-R criteria for conduct disorder. RESULTS: CP rates were similar in all levels of urbanization, except for the only semimetropolitan city in the country, the capital Oslo, which had CP rates twice those of the rest of the country. This increase rate could not be explained by a series of commonly advocated explanations: family structure and parental practices, social network, socioeconomic status, integration in community activities, religious involvement, and race. However, involvement in "soft" drugs and associating with antisocial peers could explain the statistically differential rates. Furthermore, in the Oslo study, adolescents' CP did not vary according to density of population or region within the city. CONCLUSIONS: The results support previous studies showing increased rates of CP in urban areas. However, urbanization must pass a certain threshold before it has this effect. Moreover, the lack of support for commonly advocated explanations for the difference between urban and nonurban areas suggests that investigations specifically addressing potential explanations for this difference should be conducted. The results indicate that the increased rates of substance use in highly urbanized areas may account for the difference in CP rates by prolonging and aggravating CP.     

Parameter identification in dynamic systems using the homotopy optimization approach

Identifying the parameters in a mathematical model governed by a system of ordinary differential equations is considered in this work. It is assumed that only partial state measurement is available from experiments, and that the parameters appear nonlinearly in the system equations. The problem of parameter identification is often posed as an optimization problem, and when deterministic methods are used for optimization, one often converges to a local minimum rather than the global minimum. To mitigate the problem of converging to local minima, a new approach is proposed for applying the homotopy technique to the problem of parameter identification. Several examples are used to demonstrate the effectiveness of the homotopy method for obtaining global minima, thereby successfully identifying the system parameters.