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Three experiments were conducted to contrast the hypothesis that hippocampal N-methyl- d-aspartate ( NMDA) receptors participate directly in the mechanisms of hippocampus-dependent learning with an alternative view that apparent impairments of learning induced by NMDA receptor antagonists arise because of drug-induced neuropathological and/or sensorimotor disturbances. In Experiment 1, rats given a chronic i.c.v. infusion of d- AP5 (30 m m) at 0.5 μL/h were selectively impaired, relative to a CSF-infused animals, in place but not cued navigation learning when they were trained during the 14-day drug infusion period, but were unimpaired on both tasks if trained 11 days after the minipumps were exhausted. d- AP5 caused sensorimotor disturbances in the spatial task, but these gradually worsened as the animals failed to learn. Histological assessment of potential neuropathological changes revealed no abnormalities in d-AP5-treated rats whether killed during or after chronic drug infusion. In Experiment 2, a deficit in spatial learning was also apparent in d- AP5-treated rats trained on a spatial reference memory task involving two identical but visible platforms, a task chosen and shown to minimise sensorimotor disturbances. HPLC was used to identify the presence of d- AP5 in selected brain areas. In Experiment 3, rats treated with d- AP5 showed a delay-dependent deficit in spatial memory in the delayed matching-to-place protocol for the water maze. These data are discussed with respect to the learning mechanism and sensorimotor accounts of the impact of NMDA receptor antagonists on brain function. We argue that NMDA receptor mechanisms participate directly in spatial learning. [ABSTRACT FROM AUTHOR]

Neuregulin 1 ( NRG1) has been identified as one of the leading candidate genes for schizophrenia. However, its functional mechanisms and its effects on neurocognition remain unclear. In this study, we used two well-established oculomotor endophenotypes, the antisaccade (AS) and smooth pursuit eye movement (SPEM) tasks, to investigate the functional mechanisms of a single nucleotide polymorphism (SNP) in NRG1 (rs3924999) at the neurocognitive level in a healthy volunteer sample. A total of 114 healthy Caucasian volunteers completed genotyping for NRG1 rs3924999 and infrared oculographic assessment of AS and SPEM (at target velocities of 12°, 24° and 36° per second). Additionally, self-report questionnaires of schizotypy, neuroticism, attention deficit hyperactivity and obsessive-compulsive traits were included. A significant effect of rs3924999 genotype, with gender as a covariate, was found for AS amplitude gain ( P < 0.01), with an increasing number of A alleles being associated with increasingly hypermetric performance. No statistically significant associations were found for other AS and SPEM variables or questionnaire scores. These findings indicate that NRG1 rs3924999 affects spatial accuracy on the AS task, suggesting an influence of the gene on the neural mechanisms underlying visuospatial sensorimotor transformations, a mechanism that has been previously found to be impaired in patients with schizophrenia and their relatives. [ABSTRACT FROM AUTHOR]

Background: Digoxin remains a commonly prescribed medication for the treatment of congestive cardiac failure or atrial tachyarrhythmias. Its utility is offset by its narrow therapeutic index requiring regular blood concentration monitoring. Recent evidence suggests that a lower therapeutic range (0.5–0.8 µg/L, or 0.6–1.0 nmol/L) is associated with reduced mortality in patients with congestive cardiac failure. Therapeutic drug monitoring for digoxin is carried out by immunoassays that are well established in routine clinical practice. Laboratories using different immunoassays may be involved in monitoring individual patients throughout the protracted course of therapy. These results should be concordant to ensure consistent dose individualization and optimum clinical management. We have investigated the discordance in digoxin measurements involving five different laboratories across the Adelaide metropolitan area. Methods: Aliquots from routine digoxin samples ( n= 261) were analysed by accredited laboratories using commercially available immunoassays. Results: The results showed that 119 (46%) of 261 samples were so varied that a different clinical outcome was indicated when reviewed by the treating physician. The differences between the highest and lowest readings from any one sample were also substantial, with 45% of the measurements exceeding 0.3 µg/L. Conclusions: Our study shows the considerable variation in the routine monitoring of digoxin. This makes therapeutic drug monitoring difficult to interpret and complicates clinical management when treating physicians are endeavouring to avoid toxicity and optimize dosing. These results raise a significant concern for the quality of therapeutic drug monitoring of digoxin and have direct repercussions on patient care. [ABSTRACT FROM AUTHOR]

Alterations in emotional and social functioning such as impaired ability to recognize emotions in others, a lack of empathy and poor insight have commonly been reported following prefrontal cortex damage. This study sought to investigate the subtleties of such difficulties in 34 individuals with discrete unilateral and bilateral neurosurgical lesions encroaching on the orbitofrontal, medial, and dorsolateral regions of the prefrontal cortex. A specifically devised self- and informant report measure, the social- emotional questionnaire was used to examine five factors of functioning: emotion recognition; empathy; social conformity; antisocial behaviour; and sociability. There were some specific significant differences between the clinical and control groups' informant-ratings in certain domains of social and emotional functioning. Individuals with damage involving the orbitofrontal region were reported to display elevated levels of antisocial behaviour. Individuals with bilateral orbitofrontal lesions were rated as showing significantly reduced social and emotional functioning in comparison with individuals with unilateral lesions and controls. In addition, individuals with bilateral lesions had significantly less insight overall regarding their social-emotional abilities. The right unilateral lesion group showed significantly less insight into their abilities to recognize emotion in others in comparison with the left unilateral group. In conclusion, these results suggest that specific social-emotional and insight deficits may form separate constellations of impairment. The findings also indicate that marked changes in social and emotional functioning are more likely following bilateral damage, and unilateral lesions do not inevitably lead to impairments. [ABSTRACT FROM AUTHOR]

The 2004 EJN Lecture was an attempt to lay out further aspects of a developing neurobiological theory of hippocampal function [Morris, R.G.M., Moser, E.I., Riedel, G., Martin, S.J., Sandin, J., Day, M. & O'Carroll, C. (2003) Phil. Trans. R. Soc. Lond. B Biol. Sci., 358, 773–786.] These are that (i) activity-dependent synaptic plasticity plays a key role in the automatic encoding and initial storage of attended experience; (ii) the persistence of hippocampal synaptic potentiation over time can be influenced by other independent neural events happening closely in time, an idea with behavioural implications for memory; and (iii) that systems-level consolidation of memory traces within neocortex is guided both by hippocampal traces that have been subject to cellular consolidation and by the presence of organized schema in neocortex into which relevant newly encoded information might be stored. Hippocampal memory is associative and, to study it more effectively than with previous paradigms, a new learning task is described which is unusual in requiring the incidental encoding of flavour–place paired associates, with the readout of successful storage being successful recall of a place given the flavour with which it was paired. NMDA receptor-dependent synaptic plasticity is shown to be critical for the encoding and intermediate storage of memory traces in this task, while AMPA receptor-mediated fast synaptic transmission is necessary for memory retrieval. Typically, these rapidly encoded traces decay quite rapidly over time. Synaptic potentiation also decays rapidly, but can be rendered more persistent by a process of cellular consolidation in which synaptic tagging and capture play a key part in determining whether or not it will be persistent. Synaptic tags set at the time of an event, even many trivial events, can capture the products of the synthesis of plasticity proteins set in train by events before, during or even after an event to be remembered. Tag–protein interactions stabilize synaptic potentiation and, by implication, memory. The behavioural implications of tagging are explored. Finally, using a different protocol for flavour–place paired associate learning, it is shown that rats can develop a spatial schema which represents the relative locations of several different flavours of food hidden at places within a familiar space. This schema is learned gradually but, once acquired, enables new paired associates to be encoded and stored in one trial. Their incorporation into the schema prevents rapid forgetting and suggests that schema play a key and hitherto unappreciated role in systems-level memory consolidation. The elements of what may eventually mature into a more formal neurobiological theory of hippocampal memory are laid out as specific propositions with detailed conceptual discussion and reference to recent data. [ABSTRACT FROM AUTHOR]

Aim To explore relationships between sirolimus dosing, concentration and clinical outcomes. Methods Data were collected from 25 kidney transplant recipients (14 M/11 F), median 278 days after transplantation. Outcomes of interest were white blood cell (WBC) count, platelet (PLT) count, and haematocrit (HCT). A naive pooled data analysis was performed with outcomes dichotomized (Mann–Whitney U-tests). Results Several patients experienced at least one episode when WBC ( n = 9), PLT ( n = 12), or HCT ( n = 21) fell below the lower limits of the normal range. WBC and HCT were significantly lower ( P < 0.05) when sirolimus dose was greater than 10 mg day−1, and sirolimus concentration greater than 12 µg l−1. No relationship was shown for PLT and dichotomized sirolimus dose or concentration. Conclusions Given this relationship between sirolimus concentration and effect, linked population pharmacokinetic–pharmacodynamic modelling using data from more renal transplant recipients should now be used to quantify the time course of these relationships to optimize dosing and minimize risk of these adverse outcomes. [ABSTRACT FROM AUTHOR]

As a model for the recognition of effete cells by their viable neighbors, BALB/c mouse thymocytes were coincubated with isologous peritoneal macrophages. The macrophages bound preferentially to thymocytes undergoing apoptosis, a mode of death induced in these cells by treatment with the glucocorticoid hormone methyl-prednisolone. Binding occurred in the absence of serum and was inhibited by N,N'-diacetyl chitobiose, N-acetyl glucosamine and, to a lesser extent, by N-acetyl galactosamine and n-galactose. L-fucose, 0-mannose and N-acetyl neuraminic acid had no effect. The results suggest the presence of lectin-like molecules on the surface of the macrophage that recognize changes in the cell-surface carbohydrate of the apoptotic cell. The pattern of inhibition of binding by monosaccharides differs from that of previously described endogenous mammalian lectins. [ABSTRACT FROM AUTHOR]

Vasopressin (AVP) increases both water permeability (Pf) and the cell height of isolated perfused renal collecting ducts. The mechanism of AVP-induced cell swelling remains unclear. We aimed to determine whether NKCCl is necessary for the AVP-induced cell swelling. The presence of NKCC1 mRNA and protein in rat inner medullary collecting ducts (IMCD) were confirmed by RT-PCR and immunoblotting. For functional studies, IMCDs were microdissected and perfused in vitro. Cell height was measured using differential interference contrast microscopy. Pf was measured under an imposed 200 mOsm bath-to-lumen osmolality gradient (addition of NaCl) using fluorescein sulfonate as a volume marker. AVP increased cell height by 23% of the control condition, which can be inhibited by 100 µM bumetanide in the peritubular bath. This is consistent with the presence of bumetanide-sensitive transporter in the basolateral membrane of the IMCD cell. When IMCD was perfused under a 200 mOsm osmolality gradient by mannitol addition, AVP did not increase cell height, even though Pf increased from 74+12 to 371+33 [am/s, suggesting that AVP-induced cell swelling is dependent on a favorable NaCl gradient, and is not a necessary concomitant of increased lumen-to-bath osmotic water flux. Isolated perfused IMCDs dissected from NKCCl null mice revealed that AVP did not increase the cell height. These results show that NKCCl plays a key role in AVP-induced cell swelling in IMCD cell. [ABSTRACT FROM AUTHOR]

Aims: To review (retrospectively) the relationships between lamotrigine (LTG) dosage and plasma concentrations based on data generated in a routine therapeutic drug monitoring laboratory from a heterogeneous sample of patients with epilepsy. To distinguish patients taking concomitant anti-epileptic therapy which induced or inhibited drug metabolising enzymes, or a combination of both, together with LTG. To survey medical staff who use a routine LTG assay service with a view to establishing the utility of higher plasma LTG concentrations than those used in early clinical trials., Methods: All patient assays for LTG received over a 12 month period (339 requests from 149 patients) were reviewed and relationships between dosage and concentration calculated and grouped according to concomitant antiepileptic drug therapy. The doctors requesting the tests were surveyed by questionnaire (n=40 of 67 responded). They were asked for details about the patient's seizure control, rationale used for LTG dosage adjustment and their acceptance of the proposed 'therapeutic range' adopted by the laboratory of 3-14 mg(-1)., Results: Linear relationships were demonstrated between LTG dosage and concentration for the 3 treatment groups (LTG plus valproic acid (VPA), LTG plus enzyme inducing antiepileptic drugs, and LTG plus VPA and inducers), however, there were significant differences between groups (P<0.001) with a 4.4 fold difference in dosage: concentration ratios between the LTG plus VPA group and the LTG plus inducers group. The questionnaire showed that the therapeutic range was well accepted by 88% of responders, none of whom considered this higher range to be wrong., Conclusions: Metabolic inhibition by VPA was shown to have a marked effect on LTG kinetics, suggesting either a significant LTG dosage reduction is required if plasma LTG concentrations are elevated, or alternatively, higher plasma LTG concentrations could be attained from lower dosages. The higher therapeutic range adopted by the laboratory (3-14 mg(-1)) was widely accepted and increasingly applied in clinical practice in the management of patients with epilepsy.

Aims: To study the dose-response relationship of the pharmacokinetic interaction between diltiazem and cyclosporin in kidney transplant recipients., Methods: Eight stable kidney transplant recipients maintained on cyclosporin but not taking diltiazem, were given increasing doses of diltiazem to a maximum dose of 180 mg day(-1). Following a 2 week period on each dose of diltiazem, thirteen blood samples were taken over a 24 h period to allow morning and evening AUCs to be determined for cyclosporin, diltiazem and three metabolites of diltiazem., Results: Mean cyclosporin AUC(0, 24 h) increased sharply following the lowest dose of diltiazem used (10 mg day(-1)), the rate of increase slowed after 30-60 mg day(-1) but continued to increase up to the maximum dose tested. The effect of a single morning dose of DTZ was evident over both morning (0-12 h) and evening (12-24 h) cyclosporin AUCs. There was considerable interpatient variation in response to DTZ., Conclusions: The dose of diltiazem required to increase cyclosporin AUC (and hence allow significant reduction in cyclosporin dose) is less than that currently used for many patients. Lower doses of diltiazem should result in fewer adverse effects and may allow its use in situations where it was hitherto contraindicated. Because of the significant interpatient variation in response, we recommend individual patient blood cyclosporin concentration monitoring both before and after the introduction of diltiazem.

The pharmacokinetic interaction between the calcium channel blocking drug, diltiazem (DTZ), the antifungal agent itraconazole (ICZ) and the immunosuppressive drug cyclosporin (CsA) was studied in a patient with a single lung transplant. The CsA area under curve estimations demonstrated a significant increase when ICZ was co-prescribed (5836 micrograms l-1 h vs 8159 micrograms l-1 h) but no increase when DTZ was co-prescribed with CsA (5836 micrograms l-1 h vs 5069 micrograms l-1 h). Despite widespread use as a CsA-sparing agent, DTZ does not always increase CsA concentrations.

The ability to make any meaningful interpretation of a drug assay result is very dependent upon a knowledge of the limitations of the method(s) used (sensitivity, specificity etc.), and the concentration that may be measured in plasma and its relationship to CNS effects. We need more information about 'critical' concentrations for each drug and sedation in the setting of the brain-injured patient before meaningful interpretation can be applied to such data. While the above discussion is critical of screen-type assays, the alternative specific assays are not easily provided for, as obviously the resourcing of laboratories to be able to deliver such specialized services for a range of therapeutic drugs, in addition to 'social' drugs or other toxins (e.g. glues, pesticides, solvents, environmental substances etc), becomes an increasingly complex issue in the current economic climate. Hence, the analytical laboratory can offer valuable support to the clinical team however, the interpretation of such results must be assessed in the light of many limitations of such assay methods and not seen as the 'gold standard' for assessment of brain function.

The study tested the ability of the Warrington Recognition Memory Test (1984) to discriminate between patients with left and right temporal lobe lesions. Forty-seven patients who had undergone unilateral temporal lobectomy (TL) (23 right- and 24 left-sided operations) were tested on the two components of the test, recognition memory for words (RMW) and recognition memory for faces (RMF). The results show that the right TL group were significantly worse than the left TL group on RMF. Conversely, the left TL group were significantly worse on the RMW test, confirming earlier results relating to material-specific deficits in long-term memory following TL. The RMF test was relatively sensitive and specific in detecting significant impairments associated with right TL, but the RMW proved much less sensitive to the effects of left TL. RMW and RMF discrepancy scores were found not to discriminate well between the two groups of patients.

This study explored the effects of concurrent articulation on memory-span performance, comparing patients with early Alzheimer-type dementia (AD) and matched controls. Reduction in memory span due to concurrent articulation was the same in AD patients as controls, supporting the notion that the contribution of articulatory rehearsal to memory-span performance is undiminished in early AD.