Nonlinear protein binding and enzyme heterogeneity: effects on hepatic drug removal

The kinetics of substrate removal by the liver and the resulting nonlinear changes in unbound fraction along the flow path at varying input drug concentrations were examined by a model simulation study. Specifically, we varied the binding association constant, KA, and the Michaelis-Menten constants (Km and Vmax) to examine the steady state drug removal (expressed as hepatic extraction ratio E) and changes in drug binding for (i) unienzyme systems and (ii) simple, parallel metabolic pathways; zonal metabolic heterogeneity was also added as a variable. At low KA, E declined with increasing input drug concentration, due primarily to saturation of enzymes; only small differences in binding were present across the liver. At high KA, a parabolic profile for E with concentration was observed; changes in unbound fraction between the inlet and the outlet of the liver followed in parallel fashion. Protein binding was the rate-determining step at low input drug concentrations, whereas enzyme saturation was the rate-controlling factor at high input drug concentration. Heterogeneous enzymic distribution modulated changes in unbound fraction within the liver and at the outlet. Despite marked changes in unbound fraction occurring within the liver for different enzymic distributions, the overall transhepatic differences were relatively small. We then investigated the logarithmic average unbound concentration and the length averaged concentration as estimates of substrate concentration in liver in the presence of nonlinear drug binding. Fitting of simulated data, with and without assigned random error (10%), to the Michaelis-Menten equation was performed; fitting was repeated for simulated data obtained with presence of a specific inhibitor of the high-affinity, anteriorly distributed pathway. Results were similar for both concentration terms: accurate estimates were obtained for anterior, high affinity pathways; an overestimation of parameters was observed for the lower affinity posteriorly distributed pathways. Improved estimations were found for posteriorly distributed pathways upon inhibition with specific inhibitors; with added random error, however, the improvement was much decreased. We applied the method for fitting of several sets of metabolic data obtained from rat liver perfusion studies performed with salicylamide (SAM) (i) without and (ii) with the presence of 2,6-dichloro-4-nitrophenol (DCNP), a SAM sulfation inhibitor. The fitted results showed that SAM sulfation was a high-affinity high-capacity pathway; SAM glucuronidation was of lower affinity but comparable capacity as the sulfation pathway, whereas SAM hydroxylation was of lower affinity and lower capacity.     

Morphological changes induced by colchicine in the chick optic cup in early stages of development. A stereological study

In this study chick embryo optic cups at HH stage 13 of development were analyzed under normal conditions and after inoculation with colchicine for 1, 2, 4, and 8 h. Several changes were seen after these periods of treatment: 1) modifications of the structure, with thicker regions in the cup and a general decrease in the total volume according to the duration of exposure to the drug (about 4 times less than normal, 5,035 x 10(3) microns 3 vs 1,334 x 10(3) microns 3 after 8 h of treatment); 2) enlargement of the ventricular cavity and its closure, due to failure of approximation of retinal and pigmentary layers; 3) failure of lens development, with delay and impairment of pit formation and deformation of all structures; lens volume was less than normal (about 4 times less, 2,148 x 10(3) microns 3 vs 658 x 10(3) microns 3 after 8 h of treatment); 4) a general segregation of the cells making up the structure, principally in the more active proliferating zones. The local alterations found are described.     

Clinical risk factors determining recurrence in Crohn''s disease

Absorbable and nonabsorbable buried sutures were studied in primary cleft lip repair. Group 1 (N = 56) consisted of patients repaired with buried nonabsorbable material (monofilament nylon). Group 2 (N = 47) consisted of patients repaired with absorbable materials (polyglyconate, polydioxanone). All patients were monitored for 12 months. There were stitch abscesses in Group 1 (14%). There were no abscesses in Group 2. This difference was significant (p = 0.007). Abscesses were located in the suture line with no identifiable distribution. There was no significant difference in the cosmetic appearance of the scars in Groups 1 and 2. These results support the view that absorbable sutures are preferable to nonabsorbable sutures for primary cleft lip repair.     

Shear horizontal wave propagation in periodically layeredcomposites

The transverse resonance approach to guided wave analysis is applied to shear horizontal (SH) wave propagation in periodically layered composites. It is found for SH waves that at high values of the guided wavevector β, the wave energy is trapped in the slower of the two media and propagates accordingly at the slower wavespeed. At low values of β, however, the modes demonstrate a clustering behavior, indicative of the underlying Floquet wave structure. The number of modes in a cluster is observed to correlate with the number of unit cells in the layered plate. New physical insights into the behavior of these systems are obtained by analyzing the partial waves of the guided SH modes in terms of Floquet waves. We show that the fast and slow shear waves in the periodically layered composite play an analogous role to the longitudinal and shear partial waves comprising Lamb waves in a homogeneous plate     

Decision by the Principle Board of the Polish Allergy Society

A review of isolates of Neisseria meningitidis and other laboratory evidence of meningococcal infection was carried out for the period 1990-1995. Thirty-three patients with evidence of meningococcal disease were identified over the six year period. Group B organisms were the most commonly identified, but an increase in Group C has occurred and is almost equal in number. Data from clinical, laboratory and public health sources should be centralized in a National Surveillance Centre.     

Mean residence time of gas in mechanically agitated gas–liquid contactors

In the present study of gas–liquid contactors, mean residence/contact time was calculated from knowledge of superficial velocity and the gas phase hold-up, for various gas rates and impeller geometry and speeds, and compared with values obtained from RTD measurements. A new correlation, involving Flow Number, Froude Number, system geometry and the physical properties, is proposed. This uses the authors data and those available in literature.     

Low birth weight as an additional indication for chromosomal analysis

INTRODUCTION: Even though there are few epidemiological studies evaluating the birth weights of different groups of malformed babies with chromosomal abnormalities, it is widely known that infants with trisomy 18, and to a lesser degree those with trisomy 13 and other chromosomal alterations, have low birth weights. PATIENTS AND METHODS: In this study we present the analysis of the birth weights and gestational ages of a large sample of babies (23,155 malformed and a similar number of nonmalformed babies), separating the different groups of chromosomal anomalies and comparing the weight in the clinical groups of malformed infants. RESULTS: Most of the groups with chromosomal abnormalities present lower birth weights in comparison to the other groups. CONCLUSIONS: The results of our study support the conclusion that the relationship between chromosomal alterations and low birth weight is sufficiently important that such a low birth weight in children with minor or major anomalies should be considered as one more indication to perform chromosomal analysis.     

Magnetic resonance of the encephalon in 17 patients with ocular Beh?et''s disease

OBJECTIVE: To evaluate the relationships between patient and physician pretreatment expectations of pain relief and subsequent pain relief reported by chronic pain patients immediately after treatment. DESIGN: Prospective study of consecutive patients undergoing a procedure in a pain clinic for treatment of chronic pain. Patients rated their current pain level and their expectation of pain relief immediately prior to undergoing a procedure (e.g., intravenous drug infusion, nerve block) for the treatment of chronic pain. Simultaneously and independently, the treating physician completed a similar questionnaire. At completion of the procedure, patients rated their current pain level and degree of pain relief. SETTING: University of Washington Multidisciplinary Pain Center procedure suite. PATIENTS: Forty-six consecutive chronic pain patients. INTERVENTION: Intravenous drug infusions and nerve blocks. OUTCOME MEASURES: Current pain and pain relief ratings. RESULTS: Patients' pain relief expectation ratings were not correlated significantly with their postprocedure pain relief ratings or pre-post procedure changes in pain ratings. However, a statistically significant correlation was found between physician expectations of pain relief and patient pain relief ratings and patient pre-post procedure changes in pain. CONCLUSIONS: The results of this study suggest that physicians are better predictors than are patients of patients responses to these procedures and/or that physicians may somehow subtly communicate their expectations to patients during the procedure, and these expectations then influence patient response. Patient pretreatment expectations may not always play a significant role in nonspecific treatment effects.     

Ventricular arrhythmias in myocardial hypertrophy of various origins

BACKGROUND: Elevated serum sialic acids are associated with increased cardiovascular mortality, but sialic acid levels have not been studied in cardiac tissue. METHODS: Myocardial samples were obtained at the time of transplantation from 23 patients (age 54 +/- 12 years) with heart failure secondary to ischemic heart disease and 16 patients (age 51 +/- 7 years) with idiopathic dilated cardiomyopathy (DCM). A control group comprised postmortem samples obtained from 14 patients (age 70 +/- 5 years) who died of non-cardiovascular causes. Ventricular sialylation was quantitated using the sialic acid-specific lectins Maackia amurensis agglutinin (MAA) and Sambucus nigra agglutinin (SNA) using a chemiluminescence assay. Results are expressed as the percentage (+/-standard error of the mean) of the binding of lectin to a standardized control sample of human myocardium. RESULTS: Ventricular sialylation recognized by MAA was 55 +/- 7% in patients with heart failure secondary to ischemic heart disease compared with 26 +/- 7% for DCM (p = 0.006) and 32 +/- 8% for controls (p = 0.04), and that recognized by SNA was 69 +/- 7% in patients with heart failure secondary to ischemic heart disease compared with 42 +/- 6% for DCM (p = 0.006) and 38 +/- 7% for controls (p = 0.006). No significant difference in ventricular sialylation was observed between patients with DCM and controls. CONCLUSION: Myocardial levels of sialic acids are significantly increased in patients with heart failure secondary to ischemic heart disease compared with patients with idiopathic dilated cardiomyopathy and controls. Our findings are important in view of recent reports of an association between serum sialic acid concentration and cardiovascular mortality and require further investigation.