Baetid abundances are a rapid indicator of thermal stress and riparian zone intactness.

Riparian zone vegetation plays an integral role in freshwater ecology, notably by buffering water temperatures, and in providing habitat for the adult stages of many aquatic species. We measured the contribution that riparian vegetation makes to temperature buffering, and how this affects the freshwater fauna, specifically using changes in abundances of baetid may flies for the Luvuvhu River catchment in South Africa. Water temperatures were compared for shaded versus un-shaded sites, and thermal stress between seasons was estimated using a cumulative probability model for the most widespread mayfly species, Dabulamanzia media. It is concluded that thermal stress due to losses in riparian shading could be detected using mayfly abundances in a regular monitoring programme.

Wide variation and systematic bias in expert clinicians' perceptions of prognosis following brain injury.

BACKGROUND: The heterogeneous nature of traumatic brain injury (TBI) makes outcome prediction difficult. Although a considerable evidence base exists in the form of well-validated predictive models, these models are not widely used. We hypothesised that this prognostic gap, between the availability and use of prognostic data, leads to inaccurate perceptions of patient outcome. We investigated whether outcome predictions in TBI made by expert clinicians were consistent and accurate when compared to a well-validated prognostic model (IMPACT). METHODS: Neurosurgeons and neurointensivists were asked to predict probability of death at 6 months for 12 case vignettes describing patients with isolated TBI. Predictions were compared to IMPACT prognosis for each vignette. To interrogate potential sources of bias in clinical predictions, respondents were given one of two sets of vignettes (A or B) identical apart from one critical factor known to make a large difference to outcome. RESULTS: 27 of 33 questionnaires were returned. Clinicians were consistently more pessimistic about outcomes than the IMPACT model, predicting a significantly greater probability of death (mean difference + 16.3%, 95% CI 13.3-19.4, p < 0.001). There was wide variation between clinicians predicting outcomes for any given vignette (mean range 68.3%), and within the predictions made by each individual: 30% of clinicians were both the most pessimistic respondent, and the most optimistic, for at least one vignette. Clinicians modified their predictions appropriately for most of the factors altered between corresponding vignettes. However when the reported blood glucose was changed, clinicians' predictions deviated widely from IMPACT predictions, indicating that clinicians systematically overlooked the prognostic relevance of this information. CONCLUSION: Clinical experts' predictions of outcome in TBI are widely variable and systematically pessimistic compared to IMPACT. Clinicians overlook important factors in formulating these predictions. Use of well-validated outcome models may add value and consistency to prognostication.

Evaluation of larvicides in developing management guidelines for long-term control of pest blackflies (Diptera: Simuliidae) along the Orange River, South Africa.

In 2000 and 2001 Orange River levels were higher than normal: associated serious outbreaks of blackfly had a substantial detrimental impact on the local economy. The poor control was attributed to the suspected development of larval resistance to temephos. A long-term solution to blackfly control, through the identification of a suitable replacement to temephos for use during high flow conditions, was proposed. This study, however, failed to identify or register a suitable larvicide for use during high flow conditions. Although permethrin was highly effective against blackfly larvae, it was rejected because of its detrimental impacts on non-target fauna. Various formulations of locally produced dry Bacillus thuringiensis var. israelensis (B.t.i.) were tested, but these were ineffective against blackflies. The study also confirmed that resistance to temephos has developed among Simulium chutteri in the middle and lower Orange River. The feasibility of "reversing" the resistance to temephos through the use of the synergist piperonyl butoxide (PBO) was investigated, but the results were not favourable. Furthermore, PBO was highly toxic to blackflies and non-target organisms, and was not recommended for further testing. This means that B.t.i. currently remains the only symptomatic measure of treatment currently applied. Although resistance to B.t.i. has not been reported for blackflies elsewhere in South Africa, there is a need to remain vigilant and to implement an operational strategy that minimizes the risks of resistance developing.

Adaptive management and water temperature variability within a South African river system: what are the management options?

Water temperatures, and in particular daily maximum water temperatures, are a critical water quality parameter. An understanding of associated resource management issues, including links between water temperature variability and aquatic diversity values, should be part of any management programme that considers river systems. Simple rule-based models have been shown to be appropriate tools within an adaptive management approach, both because of their heuristic value and in their application for scenario generation. Such a model was developed to simulate changes in the condition factor of Chiloglanis anoterus [Crass, R.S., 1960. Notes on the freshwater fishes of Natal with descriptions of 4 new species. Annals of the Natal Museum 14, 405-458] (Pisces: Mochokidae) in response to annual frequency of exceedance of a threshold temperature under three broad environmental scenarios for part of the Sabie River falling within South Africa's Kruger National Park. This model has potential for application within the adaptive management programme being implemented by the Kruger National Park. Results show that under broad scenarios of a 10% reduction in mean daily flow rates, or a 2 degrees C increase in mean daily air temperatures, system variability is likely to increase relative to reference conditions . It is suggested that so-called "thresholds of probable concern" (TPCs), which are based on current levels of "natural" system variability, are useful as management targets for achieving a "desired future state" for the river system. The model, recognised as a preliminary hypothesis, highlights a lack of knowledge regarding the nature of system variability, and the correspondingly wide confidence limits of the proposed TPC restricts its utility in a short-term management context. Thus, it is now recognised that its value lies more in its use as a long-term modelling tool to reflect water temperature responses to flow variability. This highlights the fact that research outcomes may not always be those intended at the beginning of a project and that opportunities to implement these may be lost as lags in understanding relative to project lifetimes often exist.

The altered structure of renal papillary outflow tracts in obesity.

Weight gain is associated with an expanded renal medullary interstitium in humans and in animal models of obesity. In this study, the consequence of obesity and this expanded matrix on renal papillary structure was examined in 15 obese rabbits fed a high fat diet for 8-12 weeks compared to 21 rabbits fed a standard diet. When examined under a dissecting microscope, the tips of the renal papillae from formalin-fixed, methylene blue-stained kidneys showed patent ducts of Bellini in 5 of 5 instances from 2 lean rabbits, but in only 2 out of 12 ducts from 3 obese rabbits. The ostia of the remaining ducts were significantly distended (205 +/- 42 microns versus 56 +/- 8 microns) and occupied by lightly staining granular material. When examined with scanning electron microscopy, all ducts were patent in lean rabbits (6 ducts in 4 rabbits, averaging 104 +/- 12 microns across), whereas only 6 of 11 ducts were patent in papillae from 4 obese rabbits. Renal medullary parenchymal tissue appeared at the openings of the remaining 5 ducts of Bellini in the 4 rabbits. Not only were these 5 ducts significantly distended by the interstitial material (with openings averaging 248 +/- 56 microns across), but the associated collecting ducts were dilated relative to control (100 +/- 15 microns versus 75 +/- 7 microns). Since the ducts of Bellini are the only renal openings that are not corsetted by a fibrous capsule, the authors speculate that the expanded medullary interstitium and increased renal sinus lipid partially obstruct renal outflow and elevate renal interstitial hydrostatic pressure in obesity, causing a prolapse of parenchymal contents, further obstructing urine outflow and leading to distention of the collecting ducts and ducts of Bellini.

Nitric oxide delivery to the lung: a model.

Dedicated nitric oxide equipped ventilators are now available commercially but are not yet common in clinical practice. With other ventilators, there is no standardized procedure for the administration or monitoring of nitric oxide. We describe the use of nitric oxide in conjunction with a simple time-cycled, pressure regulated, flow generating ventilator attached to a model infant-sized lung. The measured nitric oxide concentrations were always less than calculated. Infusion site, minute ventilation and sampling port all affected nitric oxide concentration (P < 0.05). Increasing minute ventilation lowered measured nitric oxide concentration exponentially. Mixing of gases improved when nitric oxide was infused closer to the ventilator. Acid contamination was found in water samples from humidifier, water trap and ventilator gas outlet. Acidification was reduced, without change in measured nitric oxide delivery, when infused prehumidifier. We recommend, when used as therapy, nitric oxide levels in inspired gases should always be measured.

Olanzapine: preclinical pharmacology and recent findings.

Olanzapine possesses a broad pharmacological profile, interacting with a range of different neurotransmitter receptors. Although its affinity for muscarinic receptors is relatively greater than for dopamine receptors, on schedule-controlled behaviour olanzapine displays a profile resembling a dopamine antagonist. Likewise, in a test of cognitive function, olanzapine does not produce anticholinergic-like deficits. In drug discrimination assays, olanzapine substitutes for clozapine in clozapine-trained animals and clozapine generalises to olanzapine in olanzapine-trained animals. Olanzapine also reverses the behavioural deficits produced by inhibiting N-methyl-D-aspartate receptor glutamatergic transmission. This profile suggests that olanzapine will be effective against both positive and negative symptoms of schizophrenia while producing minimal extrapyramidal side-effects.

Olanzapine: a basic science update.

Olanzapine, an atypical antipsychotic, has a broad receptor binding profile, which may account for its pharmacological effects in schizophrenia. In vitro receptor binding studies showed a high affinity for dopamine D2, D3, and D4 receptors; all 5-HT2 receptor subtypes and the 5-HT6 receptor; muscarinic receptors, especially the M1 subtype: and alpha 1-adrenergic receptors. In vivo studies showed that olanzapine had potent activity at D2 and 5-HT2A receptors, but much less activity at D1 and muscarinic receptors, and that it inhibited dopaminergic neurons in the A10 but not the A9 tract, suggesting that this agent will not cause extrapyramidal side-effects (EPS). Microdialysis studies showed that olanzapine increased the extracellular levels of norepinephrine and dopamine, but not 5-HT, in the prefrontal cortex, and increased extracellular dopamine levels in the neostriatum and nucleus accumbens, areas of the brain associated with schizophrenia. Studies of gene expression showed that olanzapine 10 mg/kg also increased Fos expression in the prefrontal cortex, the dorsolateral striatum, and the nucleus accumbens. These findings are consistent with the effectiveness of olanzapine on both negative and positive symptoms and suggest that, with careful dosing, olanzapine should not cause EPS.

Behavioural pharmacology of the new generation of antipsychotic agents.

In conclusion, the newer agents all have behavioural profiles which can be clearly differentiated from those of the older, classical agents. Behavioural data indicate that to a greater or lesser extent, all the newer antipsychotics will produce fewer acute EPS than the older agents. However, the new 'atypical' agents all have distinct profiles. Olanzapine has a profile similar to that of clozapine, albeit somewhat more potent. Olanzapine, like clozapine, displays a wide margin between the doses predictive of efficacy and those which induce EPS. The compound also substitutes for clozapine in drug discrimination assays and increases punished responding in a conflict paradigm. Quetiapine also has a clozapine-like profile, although it lacks the cholinergic receptor affinity and is relatively weak in most behavioural assays. Quetiapine, like olanzapine, also reverses PCP-induced deficits, and substitutes for clozapine in drug discrimination assays. However, no data are currently available regarding quetiapine's action in anxiolytic tests. Risperidone, sertindole and ziprasidone have profiles of activity different from those of older agents, predominantly due to their 5-HT2a affinity. All these agents possess some properties similar to those of clozapine, but there are some differences: for example, risperidone and sertindole fail to substitute for clozapine in drug discrimination assays and are inactive in classical conflict models of anxiety. It is more difficult to make an accurate assessment of the behavioural profile of ziprasidone, due to a lack of published data. Given the behavioural differences exhibited by animals receiving the new antipsychotic agents, one would predict that these drugs will have distinct clinical profiles. All the agents display activity indicative of agents with a reduced propensity to induce EPS. However, significant differences may be observed in their efficacy against negative and cognitive symptoms. It will be important to assess the clinical profiles of these agents carefully if the predictive value of the pre-clinical 'models' is to be improved.

Effects of the group II metabotropic glutamate receptor agonist, LY354740 on schedule-controlled behaviour in rats.

The present study examined the effect of the novel, systemically active Group II metabotropic glutamate (mGlu) receptor agonist, LY354740, on schedule-controlled behaviour in rats. Responding for food reward was maintained by three different operant procedures; the first, a three-component conflict schedule; the second, a multiple fixed-interval 60 s/fixed-ratio 10 (FI60/FR10) schedule and the third, a differential reinforcement of low rates of responding 10 s (DRL10) schedule. In the first procedure, rats were trained to respond for food on a schedule comprising of variable-interval 30 s (food, VI30) and fixed-ratio 10 (food + shock, FR10) components separated by time-out (TO). LY354740 (1.25-5 mg/kg, i.p.) produced a dose-related reduction in responding during the VI component and increased responding during the TO component, while having no effect on responding during the punished FR10 phase. In the FI60/FR10 schedule, LY354740 produced a dose-related reduction in the high rates of responding observed during the FR10 component of the schedule. Although LY354740 (0.6-10 mg/kg, i.p.) had no effect on the overall response rates produced by the FI60 component, there was a shift in the temporal distribution of responding as measured by the quarter-life. LY354740 (10 mg/kg, i.p.) increased the low rates towards the start of the interval, while decreasing the rates of responding towards the end of the FI60 period. In the DRL10 s schedule, LY354740 (5-20 mg/kg, i.p.) had no effect on the total number of responses but produced a significant reduction in the total number of rewards, suggesting that the temporal control of responding had been disrupted. The changes in operant responding occurred at doses that decreased exploratory behaviour. In summary, LY354740 modified responding maintained by all three operant schedules at doses which suppressed spontaneous activity. These data demonstrate that stimulation of Group II mGlu receptors can produce changes in responding which are dependent on the base-line rate of responding, suggesting that mGlu 2/3 receptors may be involved in the stimulus and temporal control of behaviour.

In vitro and in vivo biochemistry of olanzapine: a novel, atypical antipsychotic drug.

BACKGROUND: Classical (typical) antipsychotic drugs are in wide use clinically, but some patients do not respond at all to treatment, while in others, negative symptoms and cognitive deficits fail to respond. Also, these drugs often cause serious motor disturbances. Clozapine, an atypical antipsychotic, appears to correct many of these deficiencies, but has a significant incidence of potentially fatal agranulocytosis. Accordingly, we attempted to develop a prototype of a new generation of antipsychotics that is both more efficacious and safe. Our strategy was to create a compound that is not only active in behavioral tests that predict antipsychotic action but also shares the rich, multifaceted receptor pharmacology of clozapine without its side effects. To this end, Eli Lilly and Co. developed olanzapine. In this article we characterize the in vitro and in vivo receptor pharmacology of olanzapine. METHOD: We evaluated olanzapine interactions with neuronal receptors using standard assays of radioreceptor binding in vitro and well-established in vivo (functional) assays. RESULTS: Binding studies showed that olanzapine interacts with key receptors of interest in schizophrenia, having a nanomolar affinity for dopaminergic, serotonergic, alpha 1-adrenergic, and muscarinic receptors. In vivo olanzapine is a potent antagonist at DA receptors (DOPAC levels; pergolide-stimulated increases in plasma corticosterone) and 5-HT receptors (quipazine-stimulated increases in corticosterone), but is weaker at alpha-adrenergic and muscarinic receptors. Olanzapine has little or no effect at other receptors, enzymes, or key proteins in neuronal function. Olanzapine has a receptor profile that is similar to that of clozapine: it is relatively nonselective at dopamine receptor subtypes and it shows selectivity for mesolimbic and mesocortical over striatal dopamine tracts (electrophysiology; Fos). CONCLUSION: The binding and functional profile of olanzapine (1) is similar to that of clozapine, (2) indicates that olanzapine is an atypical antipsychotic drug, and (3) is consistent with clinical efficacy. If olanzapine also proves to be safe, then it will have high potential to become a more ideal antipsychotic drug.

Behavioral pharmacology of olanzapine: a novel antipsychotic drug.

BACKGROUND: In this paper, we review the behavioral pharmacology of olanzapine and compare it to its in vitro profile and to clozapine and a number of other antipsychotic agents, and we estimate the likelihood that olanzapine will be an effective and safe antipsychotic with fewer side effects. METHOD: Since there is no model of schizophrenia, per se, a battery of behavioral assays was used. RESULTS: Behavioral assays confirmed the in vitro results that olanzapine interacts with dopamine, serotonin, and muscarinic receptor subtypes. Moreover, olanzapine appears to have a clozapine-like atypical profile based on (1) mesolimbic selectivity, (2) blocking 5-HT receptors at a lower dose than dopamine receptors, and (3) inhibiting the conditioned avoidance response (indicative of antipsychotic efficacy) at doses that are lower than those required to induce catalepsy (indicative of extrapyramidal side effects). No only is this profile similar to that of clozapine, but olanzapine has other similarities: olanzapine substitutes for clozapine in a drug discrimination assay; like clozapine and unlike "typical" antipsychotics, olanzapine increases responding in a conflict procedure; and olanzapine, like clozapine, reverses changes induced by antagonists of the NMDA receptor. CONCLUSION: On the basis of these findings, we predict that olanzapine will be an efficacious antipsychotic, active against both positive and negative symptoms, while producing fewer extrapyramidal symptoms than existing treatments.

Acute Cerebral Artery Constriction in the Spontaneously Hypertensive Rat following Blood and Plasma Administration into the Subarachnoid Space.

The purpose of the present study was to demonstrate, using a vascular casting technique, acute vasoconstrictive changes in the cerebral vasculature 1 h following whole-blood or plasma infusion into the subarachnoid space of conscious spontaneously hypertensive rats. Vascular casts from animals infused (over 20 min) with 0.45 ml of heparinized autologous arterial blood or plasma exhibited incomplete filling, while casts from saline-infused controls exhibited virtually no filling defects. Significant elevations in intracranial pressure were noted in blood, but not in plasma- or saline-infused rats. Two characteristic forms of constriction occurred, depending upon the vessel lumen diameter. Vessels with lumen diameters >100 &mgr;m were flattened longitudinally with deep endothelial nuclear imprints, while smaller vessels had focal circular constrictions resembling beads. Arterial cast filling terminated in vessels with lumen diameters from 70 to 120 &mgr;m with focal signs of constriction at or near the point of cast termination. The results indicate that the presence of both blood and plasma in the subarachnoid space produces acute small-artery constriction. This phenomenon is due to a noncellular blood component and does not correlate with increases in intracranial pressure. Copyright 1996 S. Karger AG, Basel

Radioreceptor binding profile of the atypical antipsychotic olanzapine.

The affinities of olanzapine, clozapine, haloperidol, and four potential antipsychotics were compared on binding to the neuronal receptors of a number of neurotransmitters. In both rat tissues and cell lines transfected with human receptors olanzapine had high affinity for dopamine D1, D2, D4, serotonin (5HT)2A, 5HT2C, 5HT3, alpha 1-adrenergic, histamine H1, and five muscarinic receptor subtypes. Olanzapine had lower affinity for alpha 2-adrenergic receptors and relatively low affinity for 5HT1 subtypes, GABAA, beta-adrenergic receptors, and benzodiazepine binding sites. The receptor binding affinities for olanzapine was quite similar in tissues from rat and human brain. The binding profile of olanzapine was comparable to the atypical antipsychotic clozapine, while the binding profiles for haloperidol, resperidone, remoxipride, Org 5222, and seroquel were substantially different from that of clozapine. The receptor binding profile of olanzapine is consistent with the antidopaminergic, antiserotonergic, and antimuscarinic activity observed in animal models and predicts atypical antipsychotic activity in man.

Light and electron microscopic observations of epithelial shedding in stored canine small intestine.

Simple cold storage of canine small intestine is accompanied by ischemic damage to the intestinal mucosa. Progression of damage observed during cold storage is unique and has not been observed with other organs. The mucosal damage begins within 15 min after the onset of the storage, with progressive involvement of the gut as the storage period lengthens. Cytoplasmic blebs develop from the base of the epithelial cells and detach the epithelium from the basal lamina. While the process begins uniformly along the length of the villus, separation of the epithelium occurs first at the villus tip. The epithelium, which is shed into the intestinal lumen, is otherwise undamaged. Blebbing occurs in enteroendocrine and goblet cells and is not restricted to enterocytes. Early blebs occur in proximity to mucosal mast cells and subepithelial nerves. Tissue damage in cold is possibly related to enzymes that are still active at storage temperatures.

Effects of olanzapine and other antipsychotic agents on responding maintained by a conflict schedule.

The effects of the "atypical" antipsychotic olanzapine and several other antipsychotics were examined using a conflict schedule. Rats were trained to respond for food on a three-component schedule, comprising variable-interval 30s (food, VI30) and fixed-ratio 10s (food + shock, FR10) components separated by time-out (TO). Olanzapine (0.3125-1.25mg/kg), clozapine (1.25-5mg/kg) and chlordiazepoxide (2.5-5mg/kg) decreased or had no effect on VI30 responding, whereas responding in the FR10 component increased. Chlordiazepoxide (5mg/kg) also increased TO responding. The antipsychotic agents haloperidol (0.125 and 0.25mg/kg), trifluoperazine (0.0625-0.25mg/kg), remoxipride (1.25-5mg/kg) and risperidone (0.0625-0.5mg/kg) decreased V130 responding and either had no effect, or decreased TO and FR10 rates. The anticholinergic agent scopolamine (0.03125-0.25mg/kg) decreased VI30 responding. The 5-HT(2) antagonist ritanserin (2.5 and 5mg/kg) and the anticholinergic agent trihexyphenidyl (2.5 and 5mg/kg) had no effect on responding. Flumezanil (10mg/kg) reduced the anticonflict effect of chlordiazepoxide but not olanzapine. These results further emphasize the unusual profile of olanzapine.

5-HT1A-mediated lower lip retraction: effects of 5-HT1A agonists and antagonists.

This study investigated the production of lower lip retraction (LLR) in the rat by the 5-hydroxytryptamine1A (5-HT1A) agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and the effect of the putative 5-HT1A antagonists pindolol and (1-(2-methoxy-phenyl)-4-[4-(2-phthalimido)-butyl]-piperazine (NAN190). 8-OH-DPAT (0.125-1.0 mg/kg, IP) caused a dose-related increase in LLR. Pindolol (10-40 mg/kg, IP) and NAN190 (2.5-10 mg/kg, IP) produced a dose-related block of 8-OH-DPAT-induced LLR. Pindolol (10-40 mg/kg, IP) when administered alone was also found to cause LLR, suggesting that pindolol behaves as a partial agonist in this model. This was not the case with NAN190 (2.5-10 mg/kg, IP), which failed to produce LLR; however, NAN190 (2.5-10 mg/kg, IP) produced a dose-related block of the pindolol-induced LLR. These results clearly demonstrate that the LLR model can be used to detect 5-HT1A agonists, partial agonists, and antagonists.

Effect of L-type calcium channel modulators on stimulant-induced hyperactivity.

The present study investigated the effect of L-type calcium channel modulators on stimulant-induced locomotor activity. The L-channel activator, (+/-)BayK8644, produced a marked, long-lasting enhancement of cocaine-induced activity, while having no effect on amphetamine hyperactivity. Nicardipine reduced cocaine hyperactivity but had no effect on the amphetamine response.