On the origin of strain hardening in glassy polymers

The influence of network density on the strain hardening behaviour of amorphous polymers is studied. The network density of polystyrene is altered by blending with poly(2,6-dimethyl-1,4-phenylene-oxide) and by cross-linking during polymerisation. The network density is derived from the rubber-plateau modulus determined by dynamic mechanical thermal analysis. Subsequently uniaxial compression tests are performed to obtain the intrinsic deformation behaviour and, in particular, the strain hardening modulus. At room temperature, the strain hardening modulus proves to be proportional to the network density, irrespective of the nature of the network, i.e. physical entanglements or chemical cross-links. With increasing temperature, the strain hardening modulus is observed to decrease. This decrease appears to be related to the influence of thermal mobility of the chains, determined by the distance to the glass-transition temperature (T−T_g).     

Prediction of brittle-to-ductile transitions in polystyrene

In this study it is attempted to predict brittle-to-ductile transitions (BDTs) in polystyrene blends, induced either by an increase in temperature or by a decrease in inter-particle distance. A representative, two-dimensional volume element (RVE) of a polystyrene matrix with 20% circular voids, is deformed in tension. During deformation a hydrostatic-stress based craze-nucleation criterion [1] is evaluated. The simulations demonstrate that crazes initiate at low temperatures while a transition from crazing to shear yielding (BDT) is found around 75 °C. The numerical results correlate well with tensile tests on similar heterogeneous polystyrene. The presence of an absolute length, as experimentally found, is more difficult to explain. Near a free surface a T_g-depression is measured for polystyrene and also the resistance to indentation in polystyrene is lower than expected from bulk properties. Both observations are rationalised by an enhanced segmental mobility of chains near a free surface. As a consequence of these findings, an absolute length-scale could be incorporated in the numerical simulations. For simplicity, the length-scale is modelled by taking a temperature gradient over a thin layer near the internal free surfaces of the RVE. Deformation of the RVE with different absolute length-scales shows that indeed also the experimentally found brittle-to-ductile transition can be predicted if the ligament thickness between the inclusions (‘voids’) in polystyrene is below a critical value of ca. 15 nm.     

An extended pharmacokinetic/pharmacodynamic model describing quantitatively the influence of plasma protein binding, tissue binding, and receptor binding on the potency and time course of action of drugs

An extended pharmacokinetic/pharmacodynamic (PK/PD) model is presented, in which the effect of binding of the drug to plasma proteins and to tissue binding sites in a peripheral compartment, and nonspecific and receptor binding in the effect compartment are taken into account. It represents an extension of the classical Sheiner model, and the model proposed by Donati and Meistelman. The present model is characterized by the following parameters: Kue (exit rate constant of unbound drug from the effect compartment), Pue (ratio of the unbound clearances to and from the effect compartment), fue (fraction of drug in effect compartment that is not bound to nonspecific binding sites), Kd (equilibrium dissociation constant of drug-receptor binding), and Rtot (concentration of receptor binding sites in effect compartment). The rate of association and dissociation of the drug-receptor complex can be incorporated in the model. The influence of the pharmacokinetic parameters (V1, V2, fu, fu2, CLu10, CLu20, CLu12, CLu21) and the PK/PD model parameters (kue, Pue, fue, Kd, Rtot) on various dynamic parameters is analyzed. These include potency (single dose needed to produce 90% effect, ED90), constant infusion dosing rate needed to maintain a constant effect of 90%, time to maximum effect (onset time), and duration to 90% recovery. The neuromuscular blocking agent vecuronium is used as an example. It is shown that both potency and time course of action are strongly dependent on the ratio V1/fu, CLu10, kue, Pue (at equipotent doses the time course is not affected by Pue), fue, Kd, and Rtot (only if Rtot is high), whereas they are less affected by the ratio V2/fu2, CLu20, CLu12, and CLu21. In general, the model parameters affect the ED90 and the time course of action in the same direction, e.g., an increase of V1 results in an increase of ED90 and an increase of onset time and duration. However, the unbound clearance CLu10, the intercompartmental unbound clearance CLu12 and the receptor affinity Kd have an opposite effect on ED90 and the time course parameters, e.g., an increase of CLu10 results in an increase of ED90 and a decrease of onset time and duration. This effect may be responsible for the inverse relationship between onset time and potency of neuromuscular blocking drugs observed in animal experiments and clinical studies. We demonstrate that PK/PD analysis using the traditional effect compartment model (Sheiner model) results in an apparent value of keo, which is a function of kue, fue, Kd, Rtot, as well as the unbound drug concentration in the effect compartment Cue. On the other hand, the model proposed by Donati and Meistelman gives correct values of keo (equal to the product fue.kue), but the receptor affinity Kd and the receptor density Rtot obtained by this method are apparent values, which depend on fu, fue, and Pue.     

Effect of thapsigargin on calcium homeostasis in Trypanosoma cruzi trypomastigotes and epimastigotes

By using the fluorescent calcium indicator fura-2, it was found that the concentration of free Ca2+ in the cytoplasm of Trypanosoma cruzi trypomastigotes incubated in the presence or absence of external calcium was maintained at very low levels (10-20 nM). When trypomastigotes were incubated in the presence of succinate and ATP and permeabilized with digitonin, they lowered the medium calcium concentration to a submicromolar level. In the presence of 1 microM FCCP the initial rate of Ca2+ sequestration by these permeabilized cells was very slow. When succinate alone was present, the initial rate of Ca2+ accumulation was slower than with ATP plus succinate, and the calcium set point was about 0.6 microM. The succinate dependence and FCCP sensitivity of the later Ca2+ uptake indicate that it may be exerted by the mitochondria. High concentrations of the tumor promoter thapsigargin slightly increased cytosolic Ca2+ in the presence of extracellular Ca2+ but had no effect on the FCCP- and oligomycin/antimycin A-insensitive Ca2+ pool. In addition, when used at those concentrations (4-20 microM), thapsigargin was shown to release Ca2+ from the mitochondria and to decrease the inner mitochondrial membrane potential of trypomastigotes and epimastigotes as measured using safranine O. Despite the presence of inositol phosphates as determined by [3H]inositol incorporation, no IP3-sensitive Ca2+ release could be detected in trypomastigotes.     

Diagnosis of systemic causes of uveitis; a matter of ophthalmologist and internist

OBJECTIVE: To assess how often the aetiology is established in patients with uveitis, what systemic disease are found and what is the contribution of the internist to the diagnostic process. DESIGN: Retrospective study. SETTING: University Hospital Leiden, the Netherlands. METHOD: From January 1987 to April 1992, 342 patients presented with uveitis. All patients underwent a standard ophthalmological examination. Referral to an internist and individualised laboratory screening followed in patients with recurrent, chronic, bilateral or panuveitis. Recorded were: ophthalmological data, results of laboratory screening, results of analysis by the internist, final diagnosis and presence of systemic disease. RESULTS: 149 (44%) patients were examined by the internist, 18 (5.2%) were seen by another specialist. In 169 (49%) patients a specific diagnosis was made. 74 (22%) had a systemic disease, 74 a primary ocular disease. In 28 (8%) a systemic disease was presumed (5% were HLA-B27 positive, 3% had abnormal laboratory results); 5 (1%) patients had endophthalmitis as a complication of a septic process. CONCLUSION: In approximately 1/3 of the patients with uveitis a systemic disease was found. Examination by the internist tailored to the individual patient is essential in the evaluation of uveitis patients.     

Is electrogastrography a substitute for manometric studies in children with functional gastrointestinal disorders?

We performed simultaneous fasting and fed antroduodenal manometry and EGG in 25 children with functional bowel disorders. Three patients (12%) had an uninterpretable EGG. The manometric studies showed severe neuropathy in six patients; milder neuropathic changes in five patients; postprandial hypomotility in one patient; myopathy in four patients, and normal motility in the remaining six patients. The percentage of tachygastria time (frequency > 3.5 cycles/min) was higher in the patiens with mild (44.1 +/- 15.8%) and severe (48 +/- 19.1%) neuropathy than in the patients with myopathy (20 +/- 16.2%, P < 0.05) or with normal motility (23 +/- 13.3%, P < 0.05). There was a considerable overlap in the percentage of tachygastria and total arrhythmia time among the different study groups. The ratio of post- to preprandial power was significantly higher (2.5 +/- 0.07) in children with normal motility than in the other patients groups. Every child with total arrhythmia time < 35% and a ratio of post- to preprandial power > 2.4 had normal manometry. In summary, EGG differentiated groups of children with normal manometry from others with neuropathic or myopathic changes, but in a minority of patients the study was not interpretable and there was overlap in EGG results between children with normal and abnormal manometry.     

Changes in the orientation of the smooth-muscle cells of the tunica media from major arteries under constant lengthwise stretching in situ

It has been shown that changes in the orientation of arterial smooth muscle cells during a constant longitudinal stretching of the artery in vivo are not similar in different sections of the stretching zone. Cells in the proximal and distal sections keep their orientation but this orientation differs from that of smooth muscle cells in the control arteries. Cells in the central part of the stretching region lose their definite orientation to settle randomly.