Charting the future of patient care: A strategic leadership guide to harnessing the potential of artificial intelligence.

Artificial Intelligence (AI) applications have the potential to revolutionize conventional healthcare practices, creating a more efficient and patient-centred approach with improved outcomes. This guide discuses eighteen AI-based applications in clinical decision-making, precision medicine, operational efficiency, and predictive analytics, including a real-world example of AI's role in public health during the early stages of the COVID-19 pandemic. Additionally, we address ethical questions, transparency, data privacy, bias, consent, accountability, and liability, and the strategic measures that must be taken to align AI with ethical principles, legal frameworks, legacy information technology systems, and employee skills and knowledge. We emphasize the importance of informed and strategic approaches to harness AI's potential and manage its challenges. Moreover, this guide underscores the importance of evaluating and integrating new skills and competencies to navigate and use AI-based technologies in healthcare management, such as technological literacy, long-term strategic vision, change management skills, ethical decision-making, and alignment with patient needs.

Dynamic measures of skeletal muscle dialysate and plasma amino acid concentration in response to exercise and nutrient ingestion in healthy adult males.

Nutrient stimulation of muscle protein synthesis (MPS) is regulated by the change in extracellular essential amino acid (EAA) concentration. In vivo microdialysis (MD) is a minimally invasive sampling technique, capable of sampling solute in the interstitial space of a target tissue. In a contralateral limb design (REST vs. EX), this study utilised in vivo MD to examine the change in skeletal muscle dialysate amino acid concentration following ingestion of whey protein isolate (WPI) and flavoured water (CON). Four male subjects undertook unilateral, concentric lower limb knee extensor resistance exercise (RE) on two occasions. After RE, an MD catheter (CMA 63) was inserted into m. vastus lateralis of the exercise and resting leg and sampled serially over 7 h. Following a 2.5 h equilibration period subjects consumed either 0.55 g/kg WPI or CON. Peak plasma EAA (2656 ± 152 µM) preceded the peak in dialysate EAA (2345 ± 164 µM) by 30 min in response to WPI ingestion; however, the post-prandial elevation in dialysate EAA extended beyond that of the plasma. This resulted in no difference in the dialysate EAA area under the curve (ΔAUC270) relative to plasma in response to WPI ingestion [220 ± 29 vs. 206 ± 7.9 mmol min/L (p = 0.700)]. A bout of unilateral lower limb RE had no effect of the subsequent dialysate amino acid concentration in response to either WPI or CON ingestion. These data represent a novel report describing the time course and magnitude of change in skeletal muscle dialysate concentration of key nutrient regulators of MPS sampled by in vivo MD, in response to nutrient ingestion with and without RE.

An in vivo microdialysis characterization of the transient changes in the interstitial dialysate concentration of metabolites and cytokines in human skeletal muscle in response to insertion of a microdialysis probe.

Skeletal muscle has recently been described as an endocrine organ, capable of releasing cytokines and regulators of metabolism. Microdialysis of the interstitial space of skeletal muscle enables analysis of the release of such cytokines. The purpose of this study was to determine the transient changes in concentration of metabolites and cytokines in human skeletal muscle in a 7h period following the insertion of a microdialysis probe. In total, sixteen microdialysis catheters were inserted into the vastus lateralis of male participants (age 26.2±1.35y, height 180.8±3.89cm, mass 83.9±3.86kg, BMI 25.7±0.87kgm(-2), body fat 26.1±3.0%). Serial samples were analyzed by micro-enzymatic and multiplexed immunoassay. Muscle interstitial glucose and lactate levels remained stable throughout, amino acid concentrations stabilized after 2.5h, however, insertion of a microdialysis catheter induced a 29-fold increase in peak IL-6 (p<0.001) and 35-fold increase in peak IL-8 concentrations (p<0.001) above basal levels 6h post insertion. In contrast to stable amino acid, glucose and lactate concentrations after 2h, commonly reported markers of tissue homeostasis in in vivo microdialysis, the multi-fold increase in IL-6 and IL-8 following insertion of a microdialysis catheter is indicative of a sustained disturbance of tissue homeostasis.

Whole-brain traumatic controlled cortical impact to the left frontal lobe: Magnetic resonance image-based texture analysis.

This research assesses the capability of texture analysis (TA) derived from high-resolution (HR) T2-weighted magnetic resonance imaging to identify primary sequelae following 1-5 hours of controlled cortical impact mild or severe traumatic brain injury (TBI) to the left frontal cortex (focal impact) and secondary (diffuse) sequelae in the right frontal cortex, bilateral corpus callosum, and hippocampus in rats. The TA technique comprised first-order (histogram-based) and second-order statistics (including gray-level co-occurrence matrix, gray-level run length matrix, and neighborhood gray-level difference matrix). Edema in the left frontal impact region developed within 1 hour and continued throughout the 5-hour assessments. The TA features from HR images confirmed the focal injury. There was no significant difference among radiomics features between the left and right corpus callosum or hippocampus from 1 to 5 hours following a mild or severe impact. The adjacent corpus callosum region and the distal hippocampus region (s), showed no diffuse injury 1-5 hours after mild or severe TBI. These results suggest that combining HR images with TA may enhance detection of early primary and secondary sequelae following TBI.

Striatal NTS1 , dopamine D2 and NMDA receptor regulation of pallidal GABA and glutamate release--a dual-probe microdialysis study in the intranigral 6-hydroxydopamine unilaterally lesioned rat.

The current microdialysis study elucidates a functional interaction between the striatal neurotensin NTS(1) receptor and the striatal dopamine D(2) and N-methyl-d-aspartic acid (NMDA) receptors in the regulation of striatopallidal gamma-aminobutyric acid (GABA) and glutamate levels after an ipsilateral intranigral 6-hydroxydopamine-induced lesion of the ascending dopamine pathways to the striatum. Lateral globus pallidus GABA levels were higher in the lesioned group while no change was observed in striatal GABA and glutamate levels. The 6-hydroxydopamine-induced lesion did not alter the ability of intrastriatal NT (10 nm) to counteract the decrease in pallidal GABA and glutamate levels induced by the dopamine D(2) -like receptor agonist quinpirole (10 µm). A more pronounced increase in the intrastriatal NMDA- (10 µm) induced increase in pallidal GABA levels was observed in the lesioned group while it attenuated the increase in striatal glutamate levels and amplified the increase in pallidal glutamate levels compared with that observed in the controls. NT enhanced the NMDA-induced increase in pallidal GABA and glutamate and striatal glutamate levels; these effects were counteracted by the NTS(1) antagonist SR48692 (100 nm) in both groups. These findings demonstrate an inhibitory striatal dopamine D(2) and an excitatory striatal NMDA receptor regulation of striatopallidal GABA transmission in both groups. These actions are modulated by NT via antagonistic NTS(1) /D(2) and facilitatory NTS(1) /NMDA receptor-receptor interactions, leading to enhanced glutamate drive of the striatopallidal GABA neurons associated with motor inhibition, effects which all are counteracted by SR48692. Thus, NTS(1) antagonists in combination with conventional treatments may provide a novel therapeutic strategy in Parkinson's disease.

Protocol for a systematic review of the validity of animal models of polydipsia with a basis in schizophrenia aetiology.

Objective: Primary polydipsia most commonly affects those with schizophrenia. The pathophysiology of this occurrence is not established. The aim of this systematic review is to critically assess the internal and external validity of the preclinical animal models available. Search strategy: PubMed and Embase will be searched systematically to identify all relevant animal studies that describe polydipsia induction with a basis in schizophrenia aetiology. The SYRCLE (SYstematic Review Center for Laboratory animal Experimentation) search filters to identify all animal studies in both databases will be used. All studies published up to the date of the search will be considered. Screening and annotation: Two independent reviewers will screen the retrieved studies for eligibility based on (1) title and abstract and (2) full text. Disagreements between researchers will be resolved by discussion and referral back to the predefined eligibility criteria with involvement of a third researcher if required.

Community aquatic therapy for Parkinson's disease: an international qualitative study.

PURPOSE: To explore the opinions of people living with Parkinson's disease about access to and participation in community aquatic therapy. METHODS: Focus groups and individual interviews were conducted with people living with Parkinson's disease in Ireland (n = 24) and Australia (n = 10). All discussions were audio-recorded, transcribed verbatim, and thematically analysed. RESULTS: Four main themes were identified. Primarily, participants were optimistic about their reasons for choosing aquatic therapy and found it beneficial to their health and well-being. Optimal components of aquatic therapy identified were access to individually tailored aquatic programs, completed as a minimum once a week, at a moderate to high-intensity level, and guided by a credentialed instructor. Fear was a significant barrier for a small proportion of participants and was linked to water competence, past experiences, and fall risk associated with the aquatic environment. Participants identified a strong need for education and increased awareness about aquatic therapy benefits to promote greater engagement. CONCLUSION: Aquatic therapy is a popular exercise choice for people with Parkinson's disease, especially in the early to middle disease stages. Considering the views of people living with Parkinson's disease can aid the design and implementation of interventions and future aquatic research internationally.Implications for RehabilitationAquatic therapy is emerging as an effective physiotherapy approach for managing motor and non-motor symptoms in Parkinson's disease.Little is known regarding community-based aquatic therapy programs from the perspectives of people living with Parkinson's disease internationally.People with Parkinson's disease may benefit from timely information about the unique benefits, prerequisites, and local aquatic therapy facilities to promote greater uptake of aquatic programs.Tailored aquatic therapy interventions delivered within a group setting by a credentialed healthcare professional may increase long-term adherence.

Evidence-Based Aquatic Therapy Guidelines for Parkinson's Disease: An International Consensus Study.

BACKGROUND: Aquatic therapy is one therapy option for people living with Parkinson's disease (PD). However, the optimal prescription, dosage, and delivery remain unclear. OBJECTIVE: i) To generate consensus statements, ii) to establish evidence-based clinical practice aquatic therapy guidelines for PD. METHODS: Seventy-three international experts were invited to participate in a 3-step modified Delphi study. Gaps in the aquatic therapy evidence, patient preferences, and stakeholder engagement were considered when developing the initial list of 43-statements identified by the research development group. Practice experts rated each statement on an 11-point Likert scale. Consensus for inclusion was set at a priori of ≥70% of respondents scoring an item ≥7. Two rounds of Delphi questionnaires were completed online, and the expert comments were analyzed using content analysis. An online consensus meeting with an expert subgroup (n = 10) then advised on the guideline's acceptability and debated items until consensus for inclusion was reached. RESULTS: Fifty experts participated in the Delphi round one (83% response rate) and 45 in round two (90% response rate), representing 15 countries. In round one, 35 statements met the criteria for consensus. Content analysis informed the revised statements in round two, where 12 of the remaining 16 statements met consensus. The final agreed aquatic therapy guidelines include key information about dosage, content, safety, contraindications, and the optimal aquatic therapy delivery throughout the disease course. CONCLUSION: Stakeholders, including international practice experts, informed a rigorous evidence-based approach to integrate the best available evidence, patient preferences, and practice expertise to inform these guidelines.

AAV-mediated chronic over-expression of SNAP-25 in adult rat dorsal hippocampus impairs memory-associated synaptic plasticity.

Long-term memory is formed by alterations in glutamate-dependent excitatory synaptic transmission, which is in turn regulated by synaptosomal protein of 25 kDa (SNAP-25), a key component of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex essential for exocytosis of neurotransmitter-filled synaptic vesicles. Both reduced and excessive SNAP-25 activity has been implicated in various disease states that involve cognitive dysfunctions such as attention deficit hyperactivity disorder, schizophrenia and Alzheimer's disease. Here, we over-express SNAP-25 in the adult rat dorsal hippocampus by infusion of a recombinant adeno-associated virus vector, to evaluate the consequence of late adolescent-adult dysfunction of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein in the absence of developmental disruption. We report a specific and significant increase in the levels of extracellular glutamate detectable by microdialysis and a reduction in paired-pulse facilitation in the hippocampus. In addition, SNAP-25 over-expression produced cognitive deficits, delaying acquisition of a spatial map in the water maze and impairing contextual fear conditioning, both tasks known to be dorsal hippocampal dependent. The high background transmission state and pre-synaptic dysfunction likely result in interference with requisite synapse selection during spatial and fear memory consolidation. Together these studies provide the first evidence that excess SNAP-25 activity, restricted to the adult period, is sufficient to mediate significant deficits in the memory formation process.

Temporal dysregulation of cortical gene expression in the isolation reared Wistar rat.

The critical sequence of molecular, neurotransmission and synaptic disruptions that underpin the emergence of psychiatric disorders like schizophrenia remain to be established with progress only likely using animal models that capture key features of such disorders. We have related the emergence of behavioural, neurochemical and synapse ultrastructure deficits to transcriptional dysregulation in the medial prefrontal cortex of Wistar rats reared in isolation. Isolation reared animals developed sensorimotor deficits at postnatal day 60 which persisted into adulthood. Analysis of gene expression prior to the emergence of the sensorimotor deficits revealed a significant disruption in transcriptional control, notably of immediate early and interferon-associated genes. At postnatal day 60 many gene transcripts relating particularly to GABA transmission and synapse structure, for example Gabra4, Nsf, Syn2 and Dlgh1, transiently increased expression. A subsequent decrease in genes such as Gria2 and Dlgh2 at postnatal day 80 suggested deficits in glutamatergic transmission and synapse integrity, respectively. Microdialysis studies revealed decreased extracellular glutamate suggesting a state of hypofrontality while ultrastructural analysis showed total and perforated synapse complement in layer III to be significantly reduced in the prefrontal cortex of postnatal day 80 isolated animals. These studies provide a molecular framework to understand the developmental emergence of the structural and behavioural characteristics that may in part define psychiatric illness.

Capillary and microchip electrophoresis in microdialysis: recent applications.

The theme of this review is to highlight the importance of microscale electrophoretic-based separation systems in microdialysis (microD). The ability of CE and MCE to yield very rapid and highly efficient separations using just nanolitre volumes of microdialysate samples will also be discussed. Recent advances in this area will be highlighted, by illustration of some exciting new applications while the need for further innovation will be covered. The first section briefly introduces the concept of microD sampling coupled with electrophoresis-based separation and the inherent advantages of this approach. The following section highlights some specific applications of CE separations in the detection of important biomarkers such as low-molecular-weight neurotransmitters, amino acids, and other molecules that are frequently encountered in microD. Various detection modes in CE are outlined and some of the advantages and drawbacks thereof are discussed. The last section introduces the concepts of micro-total analysis systems and the coupling of MCE and microD. Some of the latest innovations will be illustrated. The concluding section reflects on the future of this important chemical alliance between microD and CE/MCE.

Is Aquatic Therapy Optimally Prescribed for Parkinson's Disease? A Systematic Review and Meta-Analysis.

BACKGROUND: Aquatic therapy offers an alternative physiotherapy approach to managing the motor and non-motor symptoms associated with Parkinson's disease (PD). OBJECTIVE: This review examined exercise prescription for aquatic therapy in PD and evaluated if aquatic therapy is as effective as land-based physiotherapy for improving movement, disability and wellbeing in people living with PD. METHODS: A systematic search of eight databases was conducted to identify suitable randomized controlled trials from inception until August 2019. Aquatic therapy prescription data and outcomes of interest included gait, balance, motor disability, mobility, falls, mood, cognitive function and health related quality of life data was extracted and synthesised. A meta-analysis was performed where appropriate. RESULTS: Fourteen studies involving 472 participants (Hoehn & Yahr scale I-IV) met the inclusion criteria. Eight were of modest quality, scoring 70-80% on the PEDro scale. Seven studies were included in the meta-analysis. Exercise prescription was highly variable and often insufficiently dosed. Similar gains were shown for aquatic therapy and land exercises for balance, motor disability or quality of life. A statistically significant difference was found for mobility as measured using the TUG (-1.5 s, 95 % CI -2.68 to -0.32; p = 0.01, I2 = 13%), in favor of aquatic therapy. CONCLUSION: Aquatic therapy had positive outcomes for gait, balance and mobility that were comparable to land-based physiotherapy in the early stages of PD. The optimal dosage, content and duration of aquatic interventions for PD could not be confirmed in this meta-analysis. Many trials appeared to be under-dosed and therapy duration was low, ranging from 3-11 weeks.

Current separation and detection methods in microdialysis the drive towards sensitivity and speed.

This review outlines some of the analytical challenges associated with the analysis of microdialysis (MD) samples, in particular, the minute complex sample volumes that are often encountered. In MD sampling many different low-molecular-weight molecules can be collected, but the research findings are often limited by the sensitivity, specificity, and reliability of the analytical technique that is coupled to the dialysis probe. Therefore it is critical that a lot of consideration is given in selecting the most suitable analytical method including the most appropriate detector. This review aims to highlight the strengths and weaknesses of a range of commonly used analytical methods employed in MD. In Section 1, a brief overview of the MD technique is described, followed by a discussion on some of the advantages and drawbacks of this sampling technique. Sections 2 and 3 examine analytical and other technical considerations regarding analysis, with special emphasis on the factors that specifically influence analytical detection. Section 4 outlines the most commonly employed analytical techniques used in MD, including HPLC coupled with various detectors. Detail is given regarding the LOD and LOQ for many applications using each detector. As MS is of such high importance in MD, a special sub-section has been devoted to it. The importance of CE is also highlighted, with specific applications described. In addition, analytical techniques that do not appear to have found routine use in MD are discussed. Section 5 is concerned with recent innovations in chemical separation techniques, in particular MCE and ultra-performance liquid chromatography. Specific applications of the coupling of these techniques with MD are highlighted, along with technical challenges associated with miniaturization. In the Section 6, the future outlook of MD is discussed. Techniques other than electrophoretic- and chromatographic based separation methods are outside the scope of this review.

Increased intestinal permeability in rats subjected to traumatic frontal lobe percussion brain injury.

BACKGROUND: Dysfunction of the gastrointestinal tract is a common occurrence after traumatic brain injury (TBI). We hypothesized that increased intestinal permeability may result from a precisely controlled percussion injury to the exposed brains of anesthetized rats and that such an effect could be assessed in vitro using excised intestinal mucosae mounted in Ussing chambers. METHODS: After craniotomy over the left medial prefrontal cortex on anesthetized rats, neurotrauma was produced using a pneumatically driven impactor on the exposed brain. Control rats were subjected to identical procedures but did not receive an impact. Muscle-stripped rat intestinal ileal and colonic segments were mounted in Ussing chambers within 30 minutes of death. Transepithelial electrical resistance (TEER) and the apparent permeability coefficient (Papp) of [C]-mannitol were recorded from intestinal tissue for 120 minutes. Histopathologic analysis was also performed to determine any gross morphologic changes in the intestine. RESULTS: Ileal and colonic mucosae showed no differences in TEER in ileum or colon of TBI rats compared with controls. The Papp of mannitol was significantly increased in ilea from rats previously exposed to TBI compared with controls. Histologic analysis showed gross changes to 50% of the ileal but not the colonic sections from TBI rats. CONCLUSION: TBI results in significantly reduced ileal barrier function, most likely mediated by open tight junctions. For patients with acute head injury, this may have implications for subsequent oral absorption of nutrients. Systemic delivery of luminal endotoxins may contribute to multiple organ failure.

Intracerebroventricular Administration of Amyloid ß-protein Oligomers Selectively Increases Dorsal Hippocampal Dialysate Glutamate Levels in the Awake Rat.

Extensive evidence supports an important role for soluble oligomers of the amyloid ß-protein (Aß) in Alzheimer's Disease pathogenesis. In the present study we combined intracerebroventricular (icv) injections with brain microdialysis technology in the fully conscious rat to assess the effects of icv administered SDS-stable low-n Aß oligomers (principally dimers and trimers) on excitatory and inhibitory amino acid transmission in the ipsilateral dorsal hippocampus. Microdialysis was employed to assess the effect of icv administration of Aß monomers and Aß oligomers on dialysate glutamate, aspartate and GABA levels in the dorsal hippocampus. Administration of Aß oligomers was associated with a +183% increase (p.

Ambient lighting: effect of illumination on soft-copy viewing of radiographs of the wrist.

OBJECTIVE: The aim of the work was to establish optimum ambient light conditions for viewing radiologic images of the wrist on liquid crystal display monitors. MATERIALS AND METHODS: Five ambient light levels were investigated: 480, 100, 40, 25, and 7 lux. Seventy-nine experienced radiologists were asked to examine 30 posteroanterior wrist images and decide whether a fracture was present. All images were displayed on liquid crystal display monitors. Receiver operating characteristic analysis was performed, and the numbers of false-positive and false-negative findings were recorded. RESULTS: For all the radiologists, greater area under the receiver operating characteristic curve and lower numbers of false-positive and false-negative findings were recorded at 40 and 25 lux compared with 480 and 100 lux. At 7 lux, the results were generally similar to those at 480 and 100 lux. The experience and knowledge of radiologists specializing in imaging of musculoskeletal trauma appeared to compensate in part for inappropriate lighting levels. CONCLUSION: Typical office lighting and current recommendations on ambient lighting can reduce diagnostic efficacy compared with lower levels of ambient lighting. If, however, no light other than that of the monitor is used, results are similar to those with excessive levels of lighting. Careful control of ambient lighting is therefore required to ensure that diagnostic accuracy is maximized, particularly for clinicians not expert in interpreting posteroanterior wrist images.

Impaired formalin-evoked changes of spinal amino acid levels in diabetic rats.

To investigate mechanisms by which diabetes alters sensory processing, we measured levels of amino acid neurotransmitters in spinal dialysates from awake, unrestrained control and diabetic rats under resting conditions and following hind paw formalin injection. Under resting conditions, glutamate concentrations in spinal dialysates were significantly (P<0.05) decreased in diabetic rats compared to those of control rats whereas aspartate, taurine, glycine and citrulline remained unchanged and GABA was significantly (P<0.05) increased. Noxious stimulation of the hind paw by subcutaneous injection of 0.5% formalin into the dorsum caused a defined flinching behavior in the afflicted paw, and the amount of flinching was significantly (P<0.05) greater in diabetic rats than in controls. Paw formalin injection significantly (P<0.05) increased dialysate levels of glutamate, aspartate, taurine, glycine and citrulline by 3- to 4-fold above basal in both control and diabetic rats. The concentration of glutamate in dialysate samples collected immediately after paw formalin injection remained significantly (P<0.05) lower in diabetic rats compared to those in controls. Formalin injection did not alter dialysate GABA concentrations in control rats, whereas in diabetic rats there was an increase of 151+/-15% above basal levels. These findings indicate that the selective depression of basal and stimulus-evoked glutamate levels in the spinal cord of diabetic rats occurs in parallel with elevated spinal GABA levels. Because increased pain-associated behavior is accompanied by an attenuated spinal glutamate spike following paw formalin injection, hyperalgesia in diabetic rats does not appear to be secondary to enhanced glutamatergic input to the spinal cord.

Microdialysis of the lateral and medial temporal lobe during temporal lobe epilepsy surgery.

BACKGROUND: This study was undertaken to establish whether, in temporal lobe epilepsy (TLE), there are relative differences between the lateral and ipsilateral medial temporal lobe in the extracellular levels of 3 of the human brain's major neuroactive amino acids. METHODS: Seven generally anesthetized patients with TLE undergoing anatomically standardized resective surgery had at operation microdialysis catheters inserted within the middle temporal gyrus (ie, lateral temporal lobe) and anterior hippocampus (ie, medial temporal lobe). Surface electrocorticography (ECoG) recordings were also obtained. Samples of 10-minute dialysate were quantified for glutamate, aspartate, and gamma-aminobutyric acid (GABA) using high-performance liquid chromatography; corresponding ECoG data were assessed for epileptiform activity. Where available, resection tissue was subjected to histopathological analysis. RESULTS: The ratio of mean "sample 3" dialysate levels of glutamate, aspartate, and GABA was approximately 20:2:1, respectively, in both the minimally epileptiform lateral (n = 7) and medial (n = 5) temporal lobe; between the 2 sets of samples, these levels were not significantly different (P > 0.05 for each amino acid studied). From the vigorously epileptiform medial temporal lobe of 2 patients, sample 3 dialysate levels of the excitatory amino acids glutamate and aspartate were found in considerably greater concentrations (between 15- and 37-fold) with correspondingly less dramatic increases of the inhibitory amino acid GABA (more than 11- and 13-fold). Laterally resected tissue (obtained in 3 cases) did not demonstrate significant cortical or subcortical abnormalities; medial resection tissue from all patients demonstrated, in varying degrees, hippocampal sclerosis. CONCLUSIONS: In the absence of significant tissue hyperexcitability, despite known differences in local cellular and/or histopathological architecture, the extracellular relationship among glutamate, aspartate, and GABA is not dissimilar in both the lateral and ipsilateral medial temporal lobe of TLE patients. Considerable disparity in dialysate levels recovered (eg, from the vigorously epileptiform medial temporal lobe) may be related to the functional (ie, hyperexcitable) status of the sampled tissue.

Clozapine and GABA transmission in schizophrenia disease models: establishing principles to guide treatments.

Schizophrenia disease models are necessary to elucidate underlying changes and to establish new therapeutic strategies towards a stage where drug efficacy in schizophrenia (against all classes of symptoms) can be predicted. Here we summarise the evidence for a GABA dysfunction in schizophrenia and review the functional neuroanatomy of five pathways implicated in schizophrenia, namely the mesocortical, mesolimbic, ventral striopallidal, dorsal striopallidal and perforant pathways including the role of local GABA transmission and we describe the effect of clozapine on local neurotransmitter release. This review also evaluates psychotropic drug-induced, neurodevelopmental and environmental disease models including their compatibility with brain microdialysis. The validity of disease models including face, construct, etiological and predictive validity and how these models constitute theories about this illness is also addressed. A disease model based on the effect of the abrupt withdrawal of clozapine on GABA release is also described. The review concludes that while no single animal model is entirely successful in reproducing schizophreniform symptomatology, a disease model based on an ability to prevent and/or reverse the abrupt clozapine discontinuation-induced changes in GABA release in brain regions implicated in schizophrenia may be useful for hypothesis testing and for in vivo screening of novel ligands not limited to a single pharmacological class.

Changes in purine levels and adenosine receptors in kindled seizures in the rat.

Adenosine is an inhibitory modulator of neuronal activity and its possible involvement in seizures is of interest. We have examined changes in adenosine, its metabolites and receptors in brains of hippocampus-kindled rats, a model of partial epilepsy. Purine levels were measured by in vivo microdialysis and showed a small increase in adenosine and a dramatic increase in its metabolites after kindled seizures. Adenosine A1 receptor binding using [H]DPCPX was unaltered after seizures, whereas A1 agonist stimulated binding of GTP[gamma-S] and A1 mRNA expression increased in the CA3 and other regions. Striatal adenosine A2A mRNA and receptor binding with [H]SCH-58261 decreased. These findings indicate that kindled seizures increase adenosine release and metabolism and induces adaptive changes in adenosine receptors.