Occupational hydrocarbon exposure and chronic nephropathy

This review aims at discussing the questions raised by the hydrocarbon-related chronic nephropathy and its possible consequence, the hydrocarbon-related chronic renal failure. It has been attempted to adopt the point of view of the clinician. Therefore, the most important part of the review is devoted to a presentation and an analysis of the available data on humans. The main features of the available studies on human subjects are presented, their conclusions discussed in the light of the possible methodological flaws, and practical conclusions drawn. After a discussion of the main difficulties encountered for selecting the suitable exposure indicator, the studies are discussed in order of decreasing quality of the study design (cohort, case-control, cross-sectional studies, and the case reports). It is concluded that a great deal of controversies about chronic hydrocarbon-related nephropathy is explained by differences in the study design and that hydrocarbon-induced nephropathy is probably more than a mere hypothesis, although a causal relationship has not yet been proven. Finally, some practical consequences for dealing with a hydrocarbon-exposed patient diagnosed with a kidney disease and the need for further research are discussed.     

Ultrasensitive analysis of the intestinal absorption and compartmentalization of aluminium in uraemic rats: a 26Al tracer study employing accelerator mass spectrometry

BACKGROUND: Developments in accelerator mass spectrometry (AMS) now permit the determination of femtogram amounts of 26Al in blood and in various tissues with good precision and free of external contamination. METHODS: In the present study we used trace quantities of 26Al to investigate the intestinal absorption and compartmentalization of aluminium in rats with renal failure (Nx, 5/6 nephrectomy) and in pair- fed controls (C). Single oral doses of 20 ng 26Al were administered to six animals in each group and, subsequently, 24-h post-load 26Al was analysed in serum, urine, bone, liver, and spleen by means of AMS. RESULTS: Serum concentrations of 26Al were significantly lower in uraemic rats compared to controls, whereas urinary excretion was comparable (Nx, 7.11 +/- 5.78 pg/day vs C, 9.46 +/- 6.10 pg/day), suggesting a higher fraction of ultrafiltrable serum 26Al in uraemia. The target tissues of cellular transferrin-mediated 26Al uptake, liver and spleen, tended to show a larger degree of aluminium accumulation in controls (0.26 +/- 0.31 pg/g vs Nx, 0.14 +/- 0.10 pg/g and 0.37 +/- 0.27 pg/g vs Nx, 0.25 +/- 0.27 pg/g respectively). In contrast, in bone, a site of extracellular aluminium deposition, 26Al concentrations were more elevated in uraemia (1.22 +/- 0.59 pg/g vs C: 0.68 +/- 0.30 pg/g). Estimated total 26Al accumulation in all measured target tissues was significantly higher in uraemic rats (28.15 +/- 9.90 pg vs C: 17.03 +/- 7.03 pg) and total recovery of 26Al from tissue and urine was 26.58 +/- 6.74 pg in controls and 35.75 +/- 7.03 pg in uraemic animals, suggesting a fractional absorption of 0.133% and 0.175% respectively. CONCLUSIONS: Our data suggest that fractional absorption from a dietary level dose of 26Al is about 0.13%. Compartmentalization occurs in transferrin-dependent target tissues such as liver and spleen; however, in quantitative terms extracellular deposition in bone is more important. Uraemia has a significant effect on the intestinal absorption and compartmentalization of aluminium. It enhances fractional absorption and increases subsequent extracellular deposition of aluminium in bone. However, at the same time uraemia does not increase transferrin-dependent cellular accumulation of aluminium in liver and spleen.      

Pancreatic enzyme secretion in the conscious rat

1. A method for collecting duodenal juice and gastric content separately, in conscious rats, is described. Metal cannulas were implanted into the stomach fundus. For the main experiment a double lumen tube was inserted through the cannula via the pylorus into the duodenum. 2. The following secretion patterns were observed: a) In the resting state there was a constant flow rate of duodenal volume, bicarbonate, trypsin and amylase. b) Cholinergic stimuli were capable of increasing enzyme secretion as much as fourfold for a period of 30 to 40 min when administered as a single subcutaneous injection. This effect was annulled by atropine. c) Secretin and cholecystokinin-pancreozymin given together in a single injection s.c. or i.v., elicited a similarly strong response. d) Identical ranges of the secretion maxima were found with a tendency to decrease after the first hour, when the hormones were infused either s.c. or i.v. e) Doses from 0.5 to 25 U/100 g b.w. /hr showed identical responses. Doses below 0.2 U/100 g/hr were without effect. 3. Narcosis (pentobarbital) inhibited markedly the resting and stimulated enzyme secretion. 4. The method is suitable for examination of physiological and pharmacological effects on resting and stimulated enzyme secretion of the rat pancreas.     

Hydrocarbon exposure, pancreatitis, and bile acids.

The data on hydrocarbon induced pancreatitis are conflicting. This question was therefore studied in a non-selected population exposed to hydrocarbons and in "formerly" exposed workers. Neither the past clinical history nor the pancreatic tests provided any evidence for a causal relation between exposure and pancreatitis. No signs of hydrocarbon induced liver damage were seen either. As a healthy worker effect cannot be totally excluded, however, a case-control study in a group of patients suffering from non-alcohol induced pancreatitis could give useful indications for finally excluding the possibility of pancreatitis being induced by hydrocarbons.     

Presynaptic opioid receptors on dopaminergic nerves in the rabbit caudate nucleus: coupling to pertussis toxin-sensitive G-proteins and interaction with D2 autoreceptors?

Slices of the rabbit caudate nucleus, preincubated with [³H]dopamine and subjected to electrical field stimulation, were used (1) to investigate the involvement of G-proteins in the signal transduction of presynaptic D₂ (auto)receptors and -opioid receptors on dopaminergic axon terminals in this tissue and (2) to study a possible mutual interaction of these two presynaptic receptors. Pretreatment of the slices with either pertussis toxin (8 g/ml; 18 h), or N-ethylmaleimide (30 M, 30 min) significantly reduced the inhibitory effects of both the D₂ agonist quinpirole and the -opioid receptor agonist U-50488H on the [³H]overflow evoked by 36 pulses (2 ms, 24 mA, 0.3 Hz), suggesting the coupling of both receptors to G-proteins.Experiments designed to study possible interactions of these two presynaptic receptors were carried out under stimulation conditions (only 1 pulse), which strongly diminish interference of endogenous transmitters released in the tissue with modulatory effects of exogenous drugs. For instance, due to the presence of endogenous dopamine, quinpirole was much less potent during 36-pulse-than during 1-pulse field stimulation, whereas the D₂ antagonist domperidone was almost without effect in the latter case. Using the 1-pulse stimulation paradigm, the concentration/response curve of quinpirole was unaffected in the presence of the halfmaximal inhibitory concentration of U-50,488 H (0.1 M). On the other hand, also quinpirole at its halfmaximal inhibitory concentration (0.1 M), hardly affected the concentration/response curve of U-50,488 H: only high concentrations of U-50,488 H (above 1 M) seemed to be slightly less effective in the presence than in the absence of the D₂ agonist. U-50,488 H, at these high concentrations, was also less potent under 36-pulse than under 1-pulse stimulation conditions. From these findings, we conclude that there is only a limited interaction between presynaptic D₂ autoreceptors and -opioid receptors on dopaminergic axon terminals in the rabbit caudate nucleus, despite they are both coupled to PTX/NEM-sensitive G-proteins. Correspondence to: R. Jackisch at the above address     

Factors affecting and computation of myocardial perfusion reference images.

Many quantitative analysis methods for myocardial perfusion studies require as a central step a comparison with a 'normal' or average density distribution map or reference image. It has been recognized, however, that the normal distribution can be affected by patient attributes, including sex and weight or body habitus, and by acquisition attributes, including the choice of tracer and the position of the patient during imaging. Some authors have proposed separate reference images for the sexes and the tracer. This approach fails if a large number of binary attributes have to be considered, since one would need 2" reference images for each attribute. The problem is compounded when continuous attributes (e.g. age and weight) are included, especially if the approach is to average separate homogeneous groups for each attribute. We propose to create case-specific reference images for the interpretation of myocardial perfusion studies by creating a model based on the influence of each attribute. From a non-homogeneous population of normal cases, or cases presumed to be normal on the basis of the Diamond and Forrester stratification, the effect of patient and study attributes on the density distribution in the stress image and the density differences between rest and stress images were computed. The effects are computed by multi-linear regression, to account for cross-correlation. Significance is assigned on the basis of a partial Fisher test. The data are myocardial perfusion images matched in 3D to a template by an elastic transformation. Even though there was some cross-correlation in the data, we were able to show independent effects of sex, position (prone or supine), age, weight, tracer combination and stress method (exercise, persantine and adenosine). Taken as a whole, the multi-linear regression demonstrated a significant effect in 72% of the pixels within the myocardial volume. In addition, the distribution predicted by the model was equivalent to average images from homogeneous matched groups. In conclusion, our approach makes it possible to produce case-specific reference images without the need for multiple homogeneous large groups to produce averages for each possible patient or study attribute.     

Vivitrex, an injectable, extended-release formulation of naltrexone, provides pharmacokinetic and pharmacodynamic evidence of efficacy for 1 month in rats.

While oral naltrexone is effective in treating alcohol and opiate dependencies, poor patient adherence and widely fluctuating plasma levels limit its efficacy. To overcome these problems, an extended-release formulation of naltrexone (Vivitrex) was developed by encapsulating naltrexone into injectable, biodegradable polymer microspheres. Pharmacokinetic studies in rats demonstrated that this formulation produced stable, pharmacologically relevant plasma levels of naltrexone for approximately 1 month following either subcutaneous or intramuscular injections. While rats receiving placebo microspheres demonstrated a pronounced analgesic response to morphine in the hot-plate test, morphine analgesia was completely blocked in rats treated with extended-release naltrexone. This antagonism began on day 1 following administration and lasted for 28 days. Rats reinjected with extended-release naltrexone 34 days after the initial dose and tested for another 35 days showed consistent suppression of morphine analgesia for an additional 28 days. mu-Opioid receptor density, as measured by [(3)H]DAMGO autoradiography, increased up to two-fold following a single injection of extended-release naltrexone. Saturation binding assays using [(3)H]DAMGO showed changes in the midbrain and striatum at 1 week after extended-release naltrexone administration, and after 1 month in the neocortex. These receptor increases persisted for 2-4 weeks after dissipation of the morphine antagonist actions of naltrexone. These data suggest that therapeutically relevant plasma levels of naltrexone can be maintained using monthly injections of an extended-release microsphere formulation, and that changes in mu-opioid receptor density do not impact its efficacy in suppressing morphine-induced analgesia in the rat. Clinical trials of extended release naltrexone for treating alcohol and opiate dependency are currently ongoing.