The history of sclerosing foams.

BACKGROUND: The use of foamed sclerosants in phlebology is undergoing a renaissance. The use of foam sclerotherapy was relaunched only a few years ago. Despite this, the early developments, pioneer findings, and improvements, especially in foaming techniques, are not widely recognized. OBJECTIVE: The objective of this study was to give an overview from the very beginnings of foam sclerotherapy until the most recent and progressive techniques, as described by Tessari or the double syringe system technique. RESULTS: The publications found after a thorough research for literature about foam sclerotherapy allow us to examine what has been invented between Orbach's work in 1944 and now and--surprisingly--even before 1944. The contributions of greatly reputed and also of unknown colleagues, such as Orbach, Sigg, Mayer, or Flückiger, are presented, giving a historical overview from the very beginnings of foam sclerotherapy until the most recent techniques. Basically, the literature shows that remarkable work was carried out in the field of noncommercial foam sclerotherapy and that sclerosing foams have been used by numerous doctors continuously for the past six decades, especially for the treatment of varicose veins of the lower limbs. CONCLUSION: The use of foamed sclerosing agents in therapy of large or small varicose veins is not new. It started as early as 1939 and has continuously been improved in the past decades.

Acute and subchronic neurotoxicological evaluation of tetrahydrofuran by inhalation in rats.

Groups of adult male and female rats received exposure to tetrahydrofuran (THF) vapor by inhalation in acute or subchronic exposure scenarios. Acute exposure concentrations were 0, 500, 2500, or 5000 ppm for 6 hr. Evaluations conducted immediately after exposure included clinical observations, motor activity assessments (MA), and a battery of functional tests (FOB) designed to reveal nervous system dysfunction. During exposure to 2500 and 5000 ppm, rats had a diminished or absent startle response to a punctate auditory alerting stimulus. Following exposure to 5000 ppm, male and female rats were lethargic, exhibited abnormal gait or mobility, and splayed rear feet. Lethargy and splayed rear feet were also observed in females exposed to 2500 ppm. During the subsequent FOB, males exposed to 5000 ppm had a lower incidence of palpebral closure, higher incidences of slow or absent righting reflex, and a biphasic pattern of reduced motor activity followed by increased motor activity. Females exposed to 5000 ppm had increased incidences of palpebral closure in the open field, increased incidences of slow or absent righting reflex, and decreased motor activity. During the 14-week subchronic exposure series, daily THF exposure concentrations were 0, 500, 1500, or 3000 ppm, and neurobehavioral evaluations occurred on non-exposure days at approximately monthly intervals. Diminished startle responses to an auditory alerting stimulus were observed during exposure to 1500 or 3000 ppm; however, repeated exposures did not cause additional neurobehavioral or pathological effects. This pattern of effects is suggestive of transient sedation. Despite daily reinstatement of acute sedative effects during repeated exposure with up to 3000 ppm, THF did not produce any persistent or cumulative effects on nervous system structure or function. The demonstrated no-observed-effect level of THF for both acute and subchronic exposure was 500 ppm.

Acute inhalation exposure to cyclohexane and schedule-controlled operant performance in rats: comparison to d-amphetamine and chlorpromazine.

Adult male rats pressed a lever on a multiple fixed ratio-fixed interval (FR20-FI120 sec) schedule of food presentation, and after attaining a stable baseline subjects received an acute inhalation exposure to cyclohexane vapor (0 ppm, 500 ppm, 2000 ppm, or 7000 ppm) for 6 hr. During the operant session that began 30 min after termination of exposure, FR running rate for the 7000 ppm group decreased 11% relative to performance on the previous day. FR post-reinforcement pause duration and the rate and pattern of FT performance were unaffected. Cyclohexane exposures of 500 or 2000 ppm had no detectable effects. No enduring effects of cyclohexane occurred up to 2 weeks after exposure. An independent set of rats, trained under nominally identical conditions, received various doses (i.p.) of d-amphetamine (AMPH) or chlorpromazine (CPZ) at 1-2 week intervals. Effective doses of AMPH decreased FR running rate, decreased FR post-reinforcement pause duration and increased FI rate of response. AMPH also decreased the FI index of curvature, indicating a change from an accelerating rate during the FI to a more constant rate. Effective doses of CPZ decreased FR rate, increased FR pause duration, decreased FI rate, and decreased FI index of curvature. Thus, schedule-controlled operant procedures that were sensitive to the effects of psychoactive drugs were able to identify only a minor and transient effect of the highest concentration (7000 ppm) of cyclohexane vapor on operant performance.

Assessing the risks of exposures to multiple chemicals with a common mechanism of toxicity: how to cumulate?

The Food Quality Protection Act (FQPA) of 1996 requires the U.S. EPA to consider the "cumulative effects" of pesticides and other substances that have a "common mechanism of toxicity." Several different methods for combining the exposures to estimate the risk of groups of common mechanism chemicals with different potencies and exposure characteristics are critically evaluated. These are the hazard index (HI), toxicity equivalence factor (TEF), and combined margin of exposure (MOE(T)) procedures as well as the point of departure index (PODI) and cumulative risk index (CRI) methods that are the reciprocals of the HI and MOE(T) approaches, respectively. Each of these methods ideally requires, at a minimum, the availability of in vivo toxicology data for the same toxicological endpoint in the same animal species. Furthermore, all assume that the effects of the individual components in the mixture are independent in nature (i.e., are additive rather than synergistic or antagonistic) and that the dose-response functions for all compounds have a similar slope. The point of departure (POD), preferably the dose corresponding to a given effect level (e.g., the ED(10)), can be used as a measure of the relative potency of the different chemicals in the group. If appropriate exposure and toxicology data are available, and the chemicals in the group have a common uncertainty factor (UF), all the procedures yield a numerically identical result. The fact that different chemicals in the group often have different UFs raises issues for all summation procedures and, in the case of the TEF approach, the UF of the index chemical selected dictates the final result of the assessment. A major distinction between the different methods for addition is the point in the process at which uncertainty is considered. The HI and CRI approaches are problematic because they require application of policy-driven UFs (in the form of RfDs) at that stage of the process where exposure should be expressed in terms of potency. In contrast, the PODI and MOE(T) approaches require application of a single group UF(G) at the end of the risk assessment process although they will also accommodate the application of data-based adjustments earlier in the analysis. Importantly, both the PODI and the MOE(T) approaches allow policy- and data-driven UFs to be separated and thus make the process more transparent; these should be considered the methods of choice for cumulative risk assessment. Assignment of a single group UF is somewhat different from developing an UF for a single chemical and the total weight of evidence available in the group database can be used to advantage to reduce the UFs that need to be applied to the group. This larger database can also be used to refine the PODs for individual members of the group. It is important to emphasize that there remains a great deal of scientific uncertainty about how to proceed with cumulative risk assessment as described in the FQPA. The serious difficulties associated with defining "common mechanism of toxicity" and "concurrent exposure" combined with the current paucity of data and methodology required to conduct cumulative risk assessment suggest that the procedure is not yet ready for use in pesticide regulation.

Evaluation of a method used to test for potential toxicity of carpet emissions.

After a private testing laboratory had reported mortality, neurotoxicity, and respiratory irritation in mice exposed to emissions from heated carpet in a modified application of the sensory irritation test (ASTM E981-84), the studies reported in this paper were conducted to evaluate the method used in testing for carpet toxicity and to see if the reported findings were reproducible. Mice were exposed head-only to offgasses generated by heating carpet (AT #3) to temperatures that ranged from 37 to 70 degrees C. Control mice were simultaneously exposed to heated air. The animals were evaluated for mortality, clinical signs and respiratory irritation. Neurotoxicity was evaluated using functional observational battery and motor activity monitoring. Pathological evaluations of organs and tissues, including the nervous system, were also conducted. The carpet samples heated to higher temperatures produced greater concentrations of total volatile organic compounds than those heated to 37 degrees C. Both carpet-exposed and control mice displayed some effects, such as body weight loss, mortality and pathological lesions, that were due to the exposure system. There was no mortality or neurotoxicity, nor were there clinical signs or pathological lesions as a result of carpet exposures. Mice exposed to carpet heated to 70 degrees C had slightly decreased respiratory rates and an increased incidence of breathing patterns indicative of sensory irritation. Therefore, none of the results reported by the private testing laboratory could be reproduced when this carpet was heated to temperatures below 70 degrees C, and slight sensory irritation was the only effect observed at the 70 degrees C test conditions. Effects from the exposure system itself made interpretation of results difficult, and concurrent controls were considered essential for interpretation of data.

In vitro electrophysiology of neurons in the lateral dorsal tegmental nucleus.

The lateral dorsal tegmental nucleus (LDT) provides ascending cholinergic projections to forebrain structures such as prefrontal cortex, septum, habenula, and thalamus, but relatively little is known of the physiology of LDT neurons. Intracellular recordings from LDT neurons in guinea pig brain slices found that most neurons fired action potentials either tonically or in bursts. The voltage dependent characteristics of the neurons suggest that a prolonged afterhyperpolarization due to an outward potassium current and a low-threshold calcium conductance contributed to these two modes of firing. Intracellular injections of Lucifer Yellow and subsequent staining for NADPH-diaphorase activity permitted positive identification of cholinergic neurons.

Electrophysiological properties of neurons in the lateral habenula nucleus: an in vitro study.

1. The electroresponsive characteristics of neurons in the lateral habenula were studied with intracellular recordings in a brain slice preparation of guinea pig diencephalon maintained in vitro. One hundred and two neurons met the criteria for recording stability, and of these, 18 were analyzed in detail. For these 18 neurons, the mean resting membrane potential was -61.9 mV, the mean input resistance was 124 M omega, and the mean spike amplitude of fast action potentials was 60.3 mV. 2. Lateral habenula neurons were found to have distinct patterns of activity dependent on membrane potential. At membrane potentials more positive than -65 mV, depolarization elicited trains of sodium-dependent fast action potentials. At membrane potentials more negative than -65 mV, slight depolarization elicited a tetrodotoxin-insensitive wave of depolarization, called a low-threshold spike (LTS), from which a burst of fast action potentials were triggered. The principal conductance underlying the LTS is a low-threshold calcium conductance, which is inactivated at membrane potential more positive than -65 mV and deinactivated when the membrane is hyperpolarized to potentials more negative than -65 V. 3. Upon termination of injected hyperpolarizing current, many neurons displayed oscillation in membrane potential at a frequency of 3-10 Hz, thereby generating repetitive bursts of fast spikes. 4. The pattern of neuronal activity in lateral habenula neurons was highly sensitive to slight alterations in membrane potential. The ability of these neurons to fire action potentials in two modes, tonically and in bursts, and the propensity of these neurons to dramatically alter their output in response to transient hyperpolarizing input, indicate that transmission through this relay in the dorsal diencephalic conduction system may be greatly augmented by relatively small hyperpolarizing influences on the individual neurons.

Reduction of dopamine receptor activity differentially alters striatal neuropeptide mRNA levels.

We have investigated the effect of dopamine receptor blockade on striatal proenkephalin mRNA and protachykinin mRNA by Northern gel analysis and by in situ hybridization histochemistry. Chronic haloperidol treatment resulted in a 3.5 fold increase in striatal proenkephalin mRNA and a 30% decrease in protachykinin mRNA (no apparent change in alpha-tubulin mRNA was observed). The changes in mRNA levels for protachykinin and proenkephalin were uniform throughout the caudate-putamen of the rat as determined by in situ hybridization histochemistry. The results imply that altering receptor-mediated neurotransmitter functions can lead to profound, specific, and long-lasting alterations in neuronal gene expression.

Stimulation of the lateral habenula inhibits dopamine-containing neurons in the substantia nigra and ventral tegmental area of the rat.

Neurons in the lateral habenula (LHb) of rats have efferent projections that terminate in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA), where cell bodies of dopamine-containing neurons are located. In order to study the influence of the habenula on dopaminergic activity, single-cell electrophysiological techniques were used to record unit discharge of dopamine-containing neurons in the SNC and VTA during electrical stimulation of the LHb or adjacent structures. Dopamine-containing neurons in the SNC and VTA were identified by their characteristic spike duration (greater than 2 msec), discharge rate (2-8 spikes/sec), and irregular firing pattern. Analysis of peristimulus time histograms showed that 85% of SNC cells and 91% of VTA neurons were inhibited after single pulse stimulation (0.25 mA, 0.1 msec) of the LHb. The mean time between stimulation and onset of inhibition was 11 msec (range, 2-22 msec) and mean duration of maximal suppression was 76 msec (range, 20-250 msec). Stimulation of structures adjacent to the LHb (hippocampus, lateral thalamus, medial dorsal thalamus, medial habenula) had little or no effect. Destruction of the fasciculus retroflexus, the fiber pathway that contains most habenular efferents, blocked the stimulation effects on dopamine-containing neurons. Destruction of the stria medullaris, which contains most habenular afferents, did not alter the inhibitory effect of habenular stimulation. Injection of a cytotoxin, kainic acid, in the LHb 1 week before recording sessions blocked the inhibitory consequences of habenular stimulation. These experiments show that activation of neuronal perikarya in the LHb causes orthodromic inhibition of dopamine-containing neurons in SNC and VTA via the fasciculus retroflexus.

Kainate and electrolytic lesions of the lateral habenula: effect on avoidance responses.

Male Sprague Dawley rats (n = 24), which received either bilateral electrolytic lesions, kainic acid lesions or sham treatments in the lateral habenula, were tested for acquisition of a one-way, conditioned avoidance response. Animals with electrolytic lesions failed to learn the avoidance task within 15 trials. In contrast, rats with kainic acid lesions performed as well as the control group. The results indicate that the disruption of the septal-medial habenula-interpenduncular nucleus pathway may be responsible for the observed avoidance deficit in electrolytically lesioned animals.