Pyrethroids and enhanced inhibition in the hippocampus of the rat

The pyrethroid insecticides have been divided into two classes on the basis of their biochemical actions and behavioral indices of toxicity. Both types of pyrethroids have effects on sodium conductance, and Type II pyrethroids have been reported to antagonize gamma-aminobutyric acid (GABA) by interacting with the t-butyl-bicyclophosphorothionate (TBPS)/picrotoxinin binding site. The dentate gyrus of the hippocampus is equipped with GABAergic recurrent inhibitory circuits. The present experiment was designed to demonstrate dissociation in the biochemistry of pyrethroids by activating the perforant path with pairs of stimulus pulses and monitoring the recurrent inhibition in this circuit. Antagonism of GABA leads to a reduction in inhibition, measured as an increase in the size of the population spike in response to the second pulse of the pair. The GABAergic properties of the pyrethroids were assessed by examining paired pulse inhibition before and after oral treatment with 20 mg/kg of cismethrin (Type I), 20 mg/kg of fenvalerate, or 10 mg/kg of deltamethrin (Type IIs). Input/output (I/O) functions revealed a reduction in excitatory postsynaptic potential (EPSP) following cismethrin and deltamethrin. Population spike height was unaffected. Fenvalerate had no effect on I/O functions. In contrast to the prediction of reduced inhibition following treatment with Type II pyrethroids, deltamethrin and fenvalerate increased inhibition up to 500 and 150 ms interpulse intervals, respectively. Cismethrin was without effect on paired pulse inhibition. These findings fail to provide evidence of GABA antagonistic properties of Type II pyrethroids and may be best explained by a differential effect of these three pyrethroids on sodium channel kinetics.     

Stereoselective disposition of (+/-)-sotalol at steady-state conditions.

The objective of this study was to assess, under steady-state conditions, the stereoselective disposition of (+/-)-sotalol in man. In all patients studied (n = 7) values of oral clearance (137 +/- 51 ml min-1), renal clearance (96 +/- 42 ml min-1) and nonrenal clearance (41 +/- 25 ml min-1) of (-)-sotalol were greater than those for (+)-sotalol (123 +/- 45 ml min-1, 89 +/- 39 ml min-1 and 34 +/- 23 ml min-1, respectively; P < 0.05, Student's paired t-test). Binding to plasma proteins was greater for (+)-sotalol (38 +/- 9% vs 35 +/- 9% for the (-)-enantiomer; P < 0.05) such that unbound oral clearance (+)/(-) ratio (0.95 +/- 0.06) and unbound renal clearance (+)/(-) ratio (0.97 +/- 0.06) were not stereoselective. In contrast, estimated unbound nonrenal clearance, which represents approximately 25% of the total unbound clearance of the drug, was greater for the (-)-enantiomer (64 +/- 42 ml min-1) compared with (+)-sotalol (57 +/- 42 ml min-1; P < 0.05). The difference in the pharmacokinetics of sotalol enantiomers is mainly related to stereoselectivity in plasma protein binding.     

The Development and Teaching of the Ethical Principles and Guidelines for Family Scientists*

This article describes the development of the Ethical Principles and Guidelines for Family Scientists that the National Council on Family Relations Board of Directors unanimously approved. Furthermore, it discusses the importance of ethics education for family professionals and provides suggestions for educators. Finally, the ethical principles and guidelines are delineated. We argue that the development of a scholarship on ethics education is important for current and future family scientists.     

Trial of an intervention to reduce chronic benzodiazepine use among residents of aged-care accommodation

Abstract Background: Many residents of aged-care accommodation are chronic users of benzodiazepines. This pattern of use contradicts current guidelines and may adversely affect residents. It was hypothesised that a lasting reduction in benzodiazepine use could be achieved through a programme which involved prescribers, residents and caregivers in the change process. Aim: To demonstrate that an intervention which involved education and relaxation training for patients, and education of prescribers and caregivers, could reduce levels of chronic benzodiazepine use among residents of an aged-care facility. Methods: Two aged-care facilities from metropolitan Adelaide were chosen; one received the intervention, the other was a no-intervention comparison. Pre-test, post-test and follow-up interviews were conducted with 60 residents: 27 from the intervention setting and 33 from the comparison setting. Residents at the intervention setting were provided with relaxation skills training, and their medical practitioners and caregivers were provided with information about alternative strategies for managing sleep disturbance. Outcome measures were: the proportion of residents using benzodiazepines, total medication use, cognitive performance, emotional responsiveness, subjective health and sleep ratings and an index of well-being. Results: The proportion of participants in the intervention condition who used benzodiazepines declined significantly (from 70% to 35%); the reduction was maintained over the subsequent three months. No adverse consequences were associated with cessation of benzodiazepine use; there was improvement in emotional responsiveness among those who ceased benzodiazepine use. This structured intervention strategy is a useful approach for reducing levels of chronic benzodiazepine use among residents of aged-care accommodation.     

Introns and gene evolution

In one scenario of gene evolution, exon shuffling has a fundamental role in increasing gene diversity. As DNA sequences accumulate in the databases, the picture of the intron/exon structures of genes becomes more and more clear. We discuss in this review some features of this picture that suggest that introns have been present since the early stages of evolution, and that exon shuffling was a fundamental process in the construction of ancient as well as modern genes.     

Linitis Plastica of the Esophagus

A 62-yr-old woman was evaluated for a 2-wk history of regurgitation and weight loss. Radiologic studies demonstrated a stenotic region in the distal third of the esophagus. Multiple endoscopic biopsies were nondiagnostic. Esophagectomy and esophagogastrostomy revealed a diffusely infiltrating adenocarcinoma ("linitis plastica") of the distal esophagus, sparing the gastroesophageal junction and stomach. Despite the absence of metastatic disease at laparotomy, the patient developed metastases unresponsive to chemotherapy. The pathologic, radiographic, and endoscopic findings are consistent with primary linitis plastica of the esophagus.     

Preventing percutaneous absorption of industrial chemicals: the "skin" denotation

Percutaneous absorption has received comparatively little attention in occupational health, although this route of entry has repeatedly caused occupation-related intoxications. In practice, the evaluation of skin penetration rates is far from simple. Much evidence has been obtained from studies of chemicals used for cosmetics and topical therapeutics, but the information available on compounds encountered in occupational health is limited. The data obtained from experimental studies have confirmed that the concentration, type of vehicle, skin area, skin condition, and extent of occlusion are important factors in determining the degree of percutaneous absorption, but no general model has been developed. Also, too little is known about the basic chemical properties governing the rate of penetration. Thus, prediction is difficult and bound to be rather inaccurate. Current preventive practice follows the procedure used by ACGIH and is mainly based on a "skin" denotation in official listings of chemicals to which exposure limits have been allocated. The number of substances and groups of chemicals which have received skin denotation in 17 selected countries varies between 24 and 179 and a total of 275 are listed as a skin hazard in one or more countries; ACGIH lists 143. Thus, the denotation practice varies. As an unfortunate result of these discrepancies and the dichotomy of skin denotation, the absence of skin denotation may erroneously indicate that efforts to protect the skin are unnecessary. Thus, an evaluation of skin penetration potentials should be incorporated in occupational health practice as a supplement to the official denotations.     

Local circuits and ocular dominance columns in monkey striate cortex

The relationships between ocular dominance columns and intrinsic cortical circuitry were examined in brain slices prepared from the striate cortex of macaques. Ocular dominance columns in layer 4C beta were visualized in vitro following anterograde transport of rhodamine injected into the lateral geniculate nucleus in vivo. The axonal and dendritic arborizations of individual layer 4C beta cells were revealed by intracellular fluorescent dye injections. Both qualitative observations and quantitative analysis showed that the dendrites of cells close to borders remained preferentially, although not absolutely, in the "home" column (the column containing the cell body). Thus, the segregated pattern of afferent input appears to have considerable influence on the pattern of dendritic arbors. Similarly, while axon collaterals within layer 4C beta could cross into the adjacent column, their limited lateral spread produced arbors that remained primarily within the home column. The terminal arbors of collaterals that travelled from layer 4C beta to layer 3 had a larger lateral spread, and the termination pattern appeared to be independent of column borders. Thus, our observations indicate that, while the course of many layer 4C beta dendrites appears to be guided by columnar boundaries as defined by geniculate afferents, there exist morphological substrates for intercolumnar interactions even between 4C beta cells. Intercolumnar interactions are seen more commonly in layer 3, however, where larger, denser axon arbors originating from 4C beta cells can freely cross ocular dominance column boundaries.     

The Role of Horizontal Connections in Generating Long Receptive Fields in the Cat Visual Cortex

The cells in the primary visual cortex possess numerous functional properties that are more complex and varied than those seen in the cortical input. These properties result from the network of intrinsic cortical connections running across the cortical layers and between cortical columns. In the current study we relate the long receptive fields that are characteristic of layer 6 cells to the input that these cells receive from layer 5. The axons of layer 5 pyramidal cells project over long distances within layer 6, enabling layer 6 cells to collect input from regions of cortex representing large parts of the visual field. When layer 5 was locally inactivated by injection of the inhibitory transmitter GABA, layer 6 cells lost sensitivity over the portion of their receptive fields corresponding to the inactivated region of layer 5. This suggests that the extensive convergence in the projection from layer 5 to layer 6 is responsible for generating the long receptive fields characteristic of the layer 6 cells.