Induction of light hydrocarbon nephropathy by p-dichlorobenzene

In order to clarify the etiology of a dose-related increase in the incidence of tubular cell adenocarcinomas of the kidney in male rats, the nephrotoxicity of p-dichlorobenzene (p-DCB) was investigated in a subchronic study. Groups of ten male and ten female Fischer 344 rats were dosed by gavage with 0 (controls), 75, 150, 300 or 600 mg p-DCB/kg/day in corn oil. Half of the animals were sacrificed after 4 weeks and the remainder after 13 weeks. Increased urinary LDH and epithelial cell excretion and exacerbation of hyaline droplet accumulation in the cytoplasm of renal cortical cells were observed in male rats over the entire dose range investigated. Tubular single cell necrosis, dilated tubules with granular cast formation in the outer zone of the medulla, were evident in male rats after 4 and 13 weeks of treatment with doses of 150–600 mg/kg/day. In female rats there was no indication of a nephrotoxic action of p-DCB. The effects on the kidney, both in their morphological characteristics and the fact that they occur exclusively in male animals, correspond to the light hydrocarbon nephropathy observed as a result of short-term treatment with a number of aliphatic and cyclic hydrocarbons. The development of cortical renal tumors seems to be associated with this kind of kidney damage which is unique to male rats. The literature on this subject generally regards these renal effects as not predictive for man.     

Thiol Reduction of 3′-Azidothymidine to 3′-Aminothymidine: Kinetics and Biomedical Implications

The ability of thiols to reduce 3-azidothymidine (AZT) to 3-aminothymidine has been investigated. Incubation with glutathione, dithiothreitol (DTT), or mercaptoethanol at pH 7.2 and 37°C leads to quantitative reduction of the azido moiety to an amine. The reaction is first order in AZT and first order in reducing agent (mono- or dithiol). The second-order rate constants are 2.77 × 10^–3, 6.55 × 10^–5, and 6.35 × 10^–6 M ^–l sec^–1 for the dithiothreitol, glutathione, and mercaptoethanol reductions, respectively. The thiol reduction of alkyl azide to amine under mild conditions is a synthetic method particularly suitable for water-soluble azido compounds that are sensitive to catalytic hydrogenation. The potential for the mono- or dithiol-mediated reduction of alkyl azides under biological conditions must be considered when conducting studies of azido drugs.     

Histochemical study of pituitary adenomas with Ki-67 and anti-DNA polymerase α monoclonal antibodies,bromodeoxyuridine labeling,and nucleolar organizer region counts

Summary The growth potential of 65 pituitary adenomas was determined by histochemical analysis with Ki-67 and anti-DNA polymerase monoclonal antibodies, bromodeoxyuridine (BrdUdR) labeling, and counts of argyrophilic nucleolar organizer regions (Ag-NORs). The mean proliferating cell indices (PCIs) determined by Ki-67 and anti-DNA polymerase and the BrdUdR labeling index (LI) were generally very low [1.0±0.2%, 1.1±0.2%, and 0.5±0.1% (±SE), respectively]. Apart from adrenocorticotropic hormone-positive adenomas, which had significantly higher indices, there were no statistically significant differences in the indices among the other subtypes of pituitary adenomas. Recurrent tumors had higher Ki-67 and DNA polymerase PCIs and BrdUdR LIs (3.6%, 4.2%, 1.4%) than primary tumors (0.8%, 0.8%, 0.3%; P<0.005). The number of Ag-NORs did not correlated significantly with any of the three indices. The mean number of Ag-NORs was higher in nonfunctioning adenomas than in functioning adenomas (2.04 vs 1.66, P<0.005); among prolactin-positive adenomas, those treated preoperatively with bromocriptine had more Ag-NORs than untreated tumors (1.75 vs 1.57, P<0.005). These results suggest that the Ki-67 and DNA polymerase PCIs and the BrdUdR LI predict the growth potential of individual pituitary adenomas, whereas the number of Ag-NORs appears to correlate with hormone production rather than with the proliferative potential.Supported by grants CA-13525 and CA-50210 from the National Cancer Institute, by a grant from the Phi Beta Psi Sorority, and by Grant-in-Aid A 63771083 from the Ministry of Education, Science, and Culture of Japan     

Regional brain kinetics of 6-fluoro-(β-11C)-L-dopa and (β-11C)-L-dopa following COMT inhibition. A study in vivo using positron emission tomography

Summary The regional brain kinetics of (-11C)-L-dopa and 6-fluoro-(-11C)-L-dopa was measured in six Rhesus monkeys using positron emission tomography (PET). Radioactivity accumulated specifically in the striatal region and the increase in L-dopa-derived radioactivity utilization with time was calculated using surrounding brain as a reference area, this being devoid of dopaminergic activity. The rate constant for selective striatal utilization i.e. grossly decarboxylation was 0.0110 ± 0.0007 (S.D) and 0.0057 ± 0.0006 min1 for (-11C)-L-dopa and 6-fluoro-(-11C)-L-dopa, respectively. After pre-treatment of the monkeys with the peripherally and centrally active catecholamine-O-methyl transferase (COMT) inhibitor Ro 40-7592 10 mg/kg, the decarboxylation rate remained unchanged (0.0112 ± 0.0015 min-1) for (11C)-L-dopa, whereas an increase in rate was measured for 6-fluoro-(-11C)L-dopa (0.0092 ± 0.0015 min–1). Differences in the distribution of radiolabelled metabolites i.e. the corresponding O-methyl-L-dopa in the reference area is most probably the reason for the difference in calculated decarboxylation rate seen between the radiotracers. The higher decarboxylation rate measured for 6-fluoro-(-11C)-L-dopa after blockade of COMT shows that the radiolabelled metabolites i.e. 6-fluoro-O-methyl-(-11C)-L-dopa significantly contributes to background radioactivity.     

Spectrum of morphological appearance of amyloid deposits in Alzheimer's disease

Summary Immunocytochemical staining with monoclonal antibodies to the -protein on tissue sections which have been pretreated with formic acid is not only a very specific but also a highly sensitive method for the detection of amyloid deposits in the brains of Alzheimer's disease victims. We report here a spectrum of morphological appearance of the brain amyloid deposits which are one of the main histopathological correlates of this disorder. Deposits of the -protein are not only found in the well-known lesions [congophilic angiopathy and senile (neuritic) plaques] but are also seen under various morphological forms for which the word plaques does not appear an appropriate term: amyloid fibrils are found as large areas of diffuse infiltration of the neuropil, as ribbon-like infiltration in the subpial layer of the cerebral cortex, as granular deposits in the white matter, as diffuse deposits in the molecular layer of the cerebellum and the basal ganglia and as star-shaped deposits in the cerebellar Purkinje cell layer. The morphology of these deposits seems to depend on the cyto-and fibroarchitectonics of the brain region in which they are found, on the amount of amyloid deposited, and also on the type of staining technique used. It is only under specific circumstances that the deposition of amyloid in the neuropil is accompanied by the formation of paired helical filaments in nerve cell processes and their parent perikarya. In conclusion, our studies suggest that the extent of brain amyloidosis in Alzheimer's disease is much wider than so far appreciated.Supported in part by grants 5-AGO-4220-05 and 5-HD-22634-02 from the National Institutes of Heath     

Diffuse type of senile plaques in the cerebellum of Alzheimer-type dementia demonstrated byβ protein immunostain

Summary We studied senile plaques (SP) in the cerebella of six autopsied subjects with Alzheimer-type dementia (ATD) and ten non-ATD autopsied subjects between the ages of 78 and 90. Neither SP nor amyloid angiopathy (AA) was observed in any of the non-ATD subjects. In the four of the six ATD subjects, diffuse plaques in the molecular layer were seen as ill-defined areas of fine fibrillar materials by protein immunostaining with formic acid pretreatment, the modified Bielschowsky stain, and periodic acid-methenamine silver (PAM) stain. The plaques were not visible with Bodian, Congo red, or periodic acid-Schiff stains. Compact plaques in the Purkinje cell or in the granular cell layers were found in three of the six subjects. Their amyloid core was often surrounded by areolar amyloid deposits. AA was observed in three of the six subjects. The argyrophilia of the diffuse and compact plaques, demonstrated by the modified Bielschowsky and PAM stains, became undetectable when the sections were first treated with formic acid. Such treatment made the plaques immunoreactive with protein antiserum. The findings suggested that cerebellar diffuse plaques and compact plaques consist mainly of an amyloid component, and are characteristic of ATD.     

“Occult” hydrocephalus in children

The authors describe 32 children between 2 and 15 years of age who had hydrocephalus that was only clinically manifest late in life. The clinical picture of these children did not suggest an obvious increase in intracranial pressure; instead, the presenting signs were rather nonspecific and included macrocrania, mild psychomotor retardation, unsteady gait, increased muscle tone and deep tendon reflexes in the lower limbs, impaired ocular movement, epilepsy, and endocrine dysfunction. Their histories suggest the possible causes of the ventricular dilation in about one third of the cases were: perinatal hemorrhage, leptomeningitis, neurofibromatosis, and untreated aneurysm of the great vein of Galen. In 20 patients, however, no positive anamnestic findings were reported. CT scan revealed triventricular dilation in more than half of the cases; tetraventricular dilation was present in 6 patients, and biventricular dilation in the remaining subjects. All children underwent CSF shunting, which resulted in complete recovery in all but 2 cases. The most frequently recorded surgical complication was postoperative subdural effusion (7 subjects), which required surgical treatment in only 2 cases.Presented at the 15th Annual Scientific Meeting of the International Society for Pediatric Neurosurgery, New York, 1987     

Neuropeptides: Animal behaviour and human psychopathology

Summary Animal studies have demonstrated that neuropeptides modulate nervous system functions. It has been postulated that disturbances in neuropeptide systems may be aetiological factors in psychiatric and neurological disorders. Neuropeptides related to ACTH/MSH, including ORG 2766, increase motivation and attention and facilitate recovery processes after nerve damage. These peptides may be effective during the early stage of dementia. Vasopressin and related peptides improve memory processes in animals and humans. In addition, these peptides influence social behaviour, mood and addictive behaviour. The non-opioid -type endorphins have neurolepticlike activities in animals and antipsychotic effects in a category of schizophrenic patients. Peptides related to CCK have also been found to be effective in these patients. Some neuropeptides, e.g. TRH and PLG, have been reported to exert antidepressant effects. Further research may eventually produce neuropeptides with therapeutic action in psychiatric and neurological diseases.Parts of this article were presented on the occasion of the inauguration ceremony of the Department of Psychiatry of the University of Mainz on April 2 and 3, 1987     

β-Methyl-15-p-iodophenylpentadecanoic acid metabolism and kinetics in the isolated rat heart

The use of 15-p-iodophenyl--methyl-pentadecanoic acid (Me-IPPA) as an indicator of long chain fatty acid (LCFA) utilization in nuclear medicine studies was evaluated in the isolated, perfused, working rat heart. Time courses of radioctivity (residue curves) were obtained following bolus injections of both Me-IPPA and its straight chain counterpart 15-p-iodophenyl-pentadecanoic acid (IPPA). IPPA kinetics clearly indicated flow independent impairment of fatty acid oxidation caused by the carnitine palmitoyltransferase I inhibitor 2[5(4-chlorophenyl)pentyl]oxirane-2-carboxylate (POCA). In contrast, Me-IPPA kinetics were insenstive to changes in fatty acid oxidation rate and net utilization of long chain fatty acid. Analysis of radiolabeled species in coronary effluent and heart homogenates showed the methylated fatty acid to be readily incorporated into complex lipids but a poor substrate for oxidation. POCA did not significatly alter metabolism of the tracer, suggesting that the tracer is poorly metabolized beyond Me-IPPA-CoA in the oxidative pathway.     

The reduction of water intake in rats caused by a low dose of apomorphine is unaltered by α-methyl-p-tyrosine: are autoreceptors not involved?

Summary Low doses of the dopamine (DA) agonist apomorphine (APO) induces a behavioural syndrome characterized by reduced spontaneous activity, reduced food and water intake and induction of yawning and penile erections. Traditionally these effects of APO have been considered to be caused by a preferential stimulation of DA autoreceptors, causing a decreased amount of transmitter at the postsynaptic receptors. If this is so, it could be hypothesized that 1) the same behavioural effects should be obtained if DA transmission is decreased by some other means, for example by synthesis inhibition, and that 2) the response to APO should be altered if DA transmission is already lowered.It was found that high doses of -methyl-p-tyrosine (-MPT; 50–200 mg/ kg) did not reduce water intake in thirsty rats, which low doses of APO do. It was further found that pretreatment with -MPT did not alter the response to APO. These results are difficult to reconcile with the DA autoreceptor hypothesis claiming that behavioural effects of low doses of APO are caused by a decreased release of DA. An alternative interpretation is that low doses of APO stimulates a certain population of sensitive postsynaptic D-2 receptors.