Improving toxicology testing protocols using computer simulations

Computer simulation can be used to integrate existing toxicity information within a biologically realistic framework. Simulation models calculate relevant measures of target tissue dose based on physiological, biochemical and physicochemical properties and readily support the dose, route, species and interchemical extrapolations necessary for human risk assessment. Because these models require very specific information, much of which can be obtained in vitro, they are much less dependent on extensive animal experiments than conventional risk assessment methods. With continuing development, simulation modeling will become an invaluable tool for improving experimental designs, for interpreting animal toxicity tests, and for estimating the importance of the animal toxicity observations for people.     

Campylobacter pyloridis in peptic ulcer disease. I. Gastric and duodenal infection caused by C. pyloridis: histopathologic and microbiologic findings

In this study 153 patients with dyspepsia were biopsied in the gastric antrum and duodenum. All specimens were investigated histopathologically and microbiologically for the presence of Campylobacter pyloridis, and the type of inflammation was recorded in accordance with Morson's criteria. C. pyloridis was found beneath the mucus close to the epithelial cells and mostly in connection with granulocytic infiltration (active gastritis). C. pyloridis was cultured from all of 10 patients with histologically active gastritis and active duodenitis, in 86% of 64 patients with active gastritis and morphologically normal duodenum, and in only 5% of 79 patients without morphologic gastric and duodenal changes. The close relation between active gastritis and C. pyloridis shows that C. pyloridis plays an important role in gastric inflammation, as it fulfils the criterion for a localized bacterial infection.     

Effects of cooling and heating of the tooth on pulpal blood flow in man

Abstract Laser Doppler flowmetry (LDF) was used to study the changes in pulpal blood flow (PBF) evoked by application of cold or heat to the palatinal surfaces of teeth 11 or 21 in nine young subjects. Switching from a thermode temperature of 33° to 5° G on average induced a slow decrease of PBF to about 80% of control, and also warming to 39°C evoked a small reduction in most subjects. Inter individual differences were large, however, and both cooling and warming sometimes triggered a rise in PBF. In contrast, skin blood flow, as recorded with LDF in the forearm, invariably rose during warming and fell during local cooling. The results suggested a more complex interaction between local and nervously mediated effects of moderate changes in temperature in the tooth pulp than skin, and that the previous held view of cold and heat decreasing and increasing PBF, respectively, is wrong.     

In vivo measurements show tensile axial strain in the proximal lateral aspect of the human femur

Two conflicting theories exist concerning the stress pattern for the proximal lateral aspect of the human femur. According to the classic theory of Pauwels, a bending moment on the femur leads to compression medially and to tension laterally. The alternative theory is that muscle forces contribute to a moment-free loading of the femur, with both the medial and lateral cortices subjected to compression. To examine these theories, we measured the strain at the external surface of the proximal lateral aspect of the femur of two female patients undergoing surgery for “snapping hip syndrome.” During the surgical procedure, a strain-gauge rosette was bonded to the lateral aspect of the femur and the cortical strains were monitored while the patient performed a series of activities. In both patients, principle tensile strain increased significantly during one-legged stance, walking, and stair climbing as compared with that during two-legged stance. During each loading situation, the principal tensile strain was aligned within 22° to the longitudinal femoral axis. Dynamic strain measurements consistently revealed tensile axial strain at the lateral aspect of the femur during each activity. The present studv supports the classic bending theory of Pauwels and demonstrates that the proximal lateral aspect of the femur is subjected to tension during the stance phase of gait.     

Epileptic seizures,arthrogryposis, and migrational brain disorders: a syndrome?

Introduction – Arthrogryposis multiplex congenita (AMC) may be associated with multiple developmental defects. In some severely affected newborns with AMC, autopsy studies have suggested a common mechanism of malmigration at the spinal and cerebral levels. To our knowledge, a constellation of arthrogryposis, epileptic seizures, and brain migrational anomalies in adult patients has not previously been described in a clinical material. Material and methods – Six consecutive adult patients with arthrogryposis multiplex congenita and epileptic seizures form the basis of the present study. Five patients had joint contractures and reduced muscle volume restricted to the lower extremities, whereas one patient had predominantly upper extremity affection. They were studied with magnetic resonance imaging (MRI), EEG, EMG, a neuropsychological test battery, and chromosome analysis. Results – Four of them had clear evidence of migrational brain disorders, demonstrated by MRI, in three of them roughly corresponding to the focal epileptiform EEG activity. Five of the patients had partial seizures, whereas one only had generalized tonic-clonic seizures. The MRI findings included polymicrogyria, pachygyria, and fused schizencephaly. Four had neurogenic EMG changes, one had myopathic EMG features, and one had an unremarkable EMG pattern in affected muscles. All patients witL demonstrable migrational disorders showed abnormal neuropsychological features. Three patients were mentally retarded. A chromosome abnormality in the form of a ring chromosome 18 was present in one patient. Conclusion – We suggest that AMC, epileptic seizures, and migrational brain disorders may form the integral parts of a hitherto undescribed syndrome in adults. A wide-spread defect in neuronal migration along the entire neural axis may be the underlying mechanism of the cerebral and the peripheral symptoms.     

The retention of [99mTc]-d,l-HM-PAO in the human brain after intracarotid bolus injection: a kinetic analysis

[99mTc]-d,l-HM-PAO (HM-PAO) was injected rapidly into the internal carotid artery and its retention in the brain was recorded by external scintillation cameras in eight human subjects. A model is described based on three compartments: the lipophilic tracer in the blood pool of the brain, the lipophilic tracer inside the brain, and the hydrophilic form retained in the brain. The retention curve initially drops abruptly, corresponding to the nonextracted fraction of the injectate leaving the brain; it then falls exponentially towards the asymptotic level of the fractional steady-state retention R. Cerebral blood flow (F) was measured using the xenon-133 intracarotid injection method. The first-pass extraction E of HM-PAO was calculated from F using an empiric regression equation. The residue curves for the whole brain after intracarotid HM-PAO injection were analyzed to yield a retention fraction (R') and the brain clearance backflux constant of lipophilic HM-PAO (k). From the kinetic model and the measured values of R', k, and F, the following parameter values could be calculated: the average retained fraction of all tracer supplied to the brain, R = 0.38 +/- 0.05 (mean +/- SD), the conversion rate constant (lipophilic to hydrophilic tracer) in the brain k3 = 0.80 +/- 0.12 min-1, the efflux rate constant (brain to blood) k2 = 0.69 +/- 0.11 min-1, the conversion/clearance ratio alpha = k3/k2 = 1.18 +/- 0.25, the influx (blood clearance) constant K1 = 0.45 +/- 0.11 ml/g/min, and the brain/blood partition ratio lambda = K1/k2 = 0.67 +/- 0.23 ml/g. Using the kinetic model and assuming constancy of alpha, an algorithm was developed that corrects for the blood flow dependent backflux of HM-PAO and results in a more linear relation between regional cerebral blood flow (rCBF) and HM-PAO distribution.     

Human spumaretrovirus antibody reactivity in multiple sclerosis

The role of human spumaretrovirus (HSRV) infections in the pathogenesis of multiple sclerosis (MS) was investigated with recombinant HSRV env-specific enzyme-linked immunosorbent assay. The presence of HSRV antibodies was determined in pairs of serum and cerebrospinal fluid (CSF) samples from 60 MS patients. In 7 of these patients serial serum and CSF samples were obtained in relation to the clinical activity of the disease during a period of 2 years. No increased antibody reactivity was demonstrable in the MS population compared with 14 aseptic meningitis patients, 50 blood donors and 16 healthy controls. Slightly elevated levels of antibodies were demonstrable in serum and/or CSF in 4 MS patients but also in 1 patient with aseptic meningitis, 1 blood donor and 1 child. No marked serum or CSF HSRV antibody fluctuation was observed in the MS patients followed longitudinally. Thus, this study does not support the involvement of HSRV in the pathogenesis of MS.     

Cancer incidence among creosote-exposed workers.

Cancer incidence was studied among 922 creosote-exposed impregnators at 13 plants in Sweden and Norway. The subjects had been impregnating wood (eg, railroad cross-ties and telegraph poles), but no data on individual exposures were available. The study population was restricted to men employed during the period 1950-1975, and their cancer morbidity was checked through the cancer registries. The total cancer incidence was somewhat lower than expected, 129 cases versus 137 expected [standardized incidence ratio (SIR) 0.94]. Increased risks in both countries combined were observed for lip cancer (SIR 2.50, 95% confidence interval (95% CI) 0.81-5.83), skin cancer (SIR 2.37, 95% CI 1.08-4.50), and malignant lymphoma (SIR 1.9, 95% CI 0.83-3.78). Exposure to sunlight may have contributed to the risk of lip and skin cancer. The small number of cancer cases does not permit valid conclusions. The findings indicate that impregnating wood with creosote in earlier decades increased the risk of skin cancer.