Experiences of patients enrolled and staff involved in the prehabilitation of elective patients undergoing cardiac surgery trial: a nested qualitative study.

The purpose of this study was to understand the views and experiences of patients enrolled and staff involved in the prehabilitation of elective patients undergoing cardiac surgery trial. This sub-study was informed by normalisation process theory, a framework for evaluating complex interventions, and used consecutive sampling to recruit patients assigned to both the intervention and control groups. Patients and all staff involved in delivering the trial were invited to participate in focus groups, which were recorded, transcribed verbatim and subjected to reflexive thematic analysis. Five focus groups were held comprising 24 participants in total (nine patients assigned to the prehabilitation; seven assigned to control; and eight staff). Five themes were identified. First, preparedness for surgery reduced fear, where participants described that knowing what to expect from surgery and preparing the body physically increased feelings of control and subsequently reduced apprehension regarding surgery. Second, staff were concerned but trusted in a safe environment, describing how, despite staff's concerns regarding the risks of exercise in this population, the patients felt safe in their care whilst participating in an exercise programme in hospital. Third, rushing for recovery and the curious carer, where patients from both groups wanted to mobilise quickly postoperatively whilst staff visited patients on the ward to observe their recovery progress. Fourth, to survive and thrive postoperatively, reflecting staff and patients' expectations from the trial and what motivated them to participate. Fifth, benefits are diluted by lengthy waiting periods, reflecting the frustration felt by patients waiting for their surgery after completing the intervention and the fear about continuing exercise at home before they had been 'fixed'. To conclude, functional exercise capacity may not have improved following prehabilitation in people before elective cardiac surgery due to concerns regarding the safety of exercise that may have hindered delivery and receipt of the intervention. Instead, numerous non-physical benefits were elicited. The information from this qualitative study offers valuable recommendations regarding refining a prehabilitation intervention and conducting a subsequent trial.

A randomised controlled trial of prehabilitation in patients undergoing elective cardiac surgery.

The feasibility, safety and efficacy of prehabilitation in adult patients awaiting elective cardiac surgery are unknown. A total of 180 participants undergoing elective cardiac surgery were allocated randomly to receive either standard pre-operative care or prehabilitation, consisting of pre-operative exercise and inspiratory muscle training. The primary outcome was change in six-minute walk test distance from baseline to pre-operative assessment. Secondary outcomes included change in inspiratory muscle strength (maximal inspiratory pressure); sarcopenia (handgrip strength); quality of life and compliance. Safety outcomes were pre-specified surgical and pulmonary complications and adverse events. All outcomes were assessed at baseline; at pre-operative assessment; and 6 and 12 weeks following surgery. Mean (SD) age was 64.7 (10.2) years; 33/180 (18%) were women. In total, 65/91 (71.4%) participants who were allocated to prehabilitation attended at least four of eight supervised in-hospital exercise classes; participants aged > 50 years were more likely than younger participants to attend (odds ratio (95%CI) of 4.6 (1.0-25.1)). Six-minute walk test was not significantly different between groups (mean difference (95%CI) -7.8 m (-30.6-15.0), p = 0.503) in the intention-to-treat analysis. Subgroup analyses based on tests for interaction indicated improvements in six-minute walk test distance were larger amongst sarcopenic patients in the prehabilitation group (p = 0.004). Change in maximal inspiratory pressure from baseline to all time-points was significantly greater in the prehabilitation group, with the greatest mean difference (95%CI) observed 12 weeks after surgery (10.6 cmH2 O (4.6-16.6) cmH2 O, p < 0.001). There were no differences in handgrip strength or quality of life up to 12 weeks after surgery. There was no significant difference in postoperative mortality (one death in each group), surgical or pulmonary complications. Of 71 pre-operative adverse events, six (8.5%) were related to prehabilitation. The combination of exercise and inspiratory muscle training in a prehabilitation intervention before cardiac surgery was not superior to standard care in improving functional exercise capacity measured by six-minute walk test distance pre-operatively. Future trials should target patients living with sarcopenia and include inspiratory muscle strength training.

Cemented Exeter total hip arthroplasty with a 32 mm head on highly crosslinked polyethylene: Does age influence functional outcome, satisfaction, activity, stem migration, and periprosthetic bone mineral density?

OBJECTIVES: Our primary aim was to describe migration of the Exeter stem with a 32 mm head on highly crosslinked polyethylene and whether this is influenced by age. Our secondary aims were to assess functional outcome, satisfaction, activity, and bone mineral density (BMD) according to age. PATIENTS AND METHODS: A prospective cohort study was conducted. Patients were recruited into three age groups: less than 65 years (n = 65), 65 to 74 years (n = 68), and 75 years and older (n = 67). There were 200 patients enrolled in the study, of whom 115 were female and 85 were male, with a mean age of 69.9 years (sd 9.5, 42 to 92). They were assessed preoperatively, and at three, 12 and, 24 months postoperatively. Stem migration was assessed using Einzel-Bild-Röntgen-Analyse (EBRA). Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Harris Hip Score (HHS), Hip Disability and Osteoarthritis Outcome Score (HOOS), EuroQol-5 domains questionnaire (EQ-5D), short form-36 questionnaire (SF-36,) and patient satisfaction were used to assess outcome. The Lower Extremity Activity Scale (LEAS), Timed Up and Go (TUG) test, and activPAL monitor (energy expelled, time lying/standing/walking and step count) were used to assess activity. The BMD was assessed in Gruen and Charnley zones. RESULTS: Mean varus/valgus tilt was -0.77° and axial subsidence was -1.20 mm. No significant difference was observed between age groups (p ⩾ 0.07). There was no difference according to age group for postoperative WOMAC (p ⩾ 0.11), HHS (p ⩾ 0.06), HOOS (p ⩾ 0.46), EQ-5D (p ⩾ 0.38), patient satisfaction (p ⩾ 0.05), or activPAL (p ⩾ 0.06). Patients 75 years and older had a worse SF-36 physical function (p = 0.01) and physical role (p = 0.03), LEAS score (p < 0.001), a shorter TUG (p = 0.01), and a lower BMD in Charnley zone 1 (p = 0.02). CONCLUSION: Exeter stem migration is within normal limits and is not influenced by age group. Functional outcome, patient satisfaction, activity level, and periprosthetic BMD are similar across all age groups.Cite this article: N. D. Clement, M. Bardgett, K. Merrie, S. Furtado, R. Bowman, D. J. Langton, D. J. Deehan, J. Holland. Cemented Exeter total hip arthroplasty with a 32 mm head on highly crosslinked polyethylene: Does age influence functional outcome, satisfaction, activity, stem migration, and periprosthetic bone mineral density? Bone Joint Res 2019;8:275-287. DOI: 10.1302/2046-3758.86.BJR-2018-0300.R1.

Increased symptoms of stiffness 1 year after total knee arthroplasty are associated with a worse functional outcome and lower rate of patient satisfaction.

PURPOSE: Symptoms of stiffness after total knee arthroplasty (TKA) cause significant morbidity, but there is limited data to facilitate identification of those most at risk after surgery. Stratifying risk can aid earlier directed treatment options. METHODS: A retrospective cohort consisting of 2589 patients undergoing a primary TKA was identified from an established arthroplasty database. Patient demographics, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and short form (SF) 12 scores were collected pre-operatively and 1 year post-operatively. In addition, patient satisfaction was assessed for 1 year. Patients with a worse WOMAC stiffness score in 1 year were defined as the "increased" stiffness group and the other cohort as the non-stiffness group. RESULTS: At 1 year after surgery 129 (5%) patients had a significant increase in their stiffness symptoms (20%, 95% confidence interval (CI) 17.9-22.0, p < 0.001), and had significantly (all p < 0.001) less of an improvement in their pain, function and total WOMAC scores, and SF-12 scores compared to the non-stiffness group (n = 2460). Patient satisfaction was significantly lower (odds ratio (OR) 0.178, CI 0.121 to 0.262, p < 0.001) for the increased stiffness group. Logistic regression analysis identified male gender (OR 1.66, p = 0.02), lung disease (OR 2.06, p = 0.002), diabetes (OR 1.82, p = 0.02), back pain (OR 1.81, p = 0.005), and a pre-operative stiffness score of 44 or more (OR 5.79, p < 0.001) were significantly predictive of increased stiffness. CONCLUSION: Patients with increased symptoms of stiffness after TKA have a worse functional outcome and a lower rate of patient satisfaction, and patients at risk of being in this group should be informed pre-operatively. LEVEL OF EVIDENCE: Retrospective prognostic study, Level III.

Which patients are satisfied with their overall outcome but dissatisfied with their return to recreational activities after total knee arthroplasty?

BACKGROUND: The primary aim of this study was to assess whether patients dissatisfied with both recreational activities and overall outcome were different to those dissatisfied with recreational activities but satisfied with their overall outcome one year after total knee arthroplasty (TKA). METHODS: A retrospective cohort consisting of 3324 primary TKA were identified from an established arthroplasty database. Patient demographics, comorbidities, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Short Form (SF) 12 scores were collected pre-operatively and one year post-operatively. Overall patient satisfaction and satisfaction with recreational activities were assessed at one year. RESULTS: The rate of patient satisfaction with recreational activities (n = 2672, 80.4%) was significantly (odds ratio (OR) 0.47, 95% confidence intervals (CI) 0.41 to 0.54, p < 0.001) lower than satisfaction with the overall outcome (n = 2982, 89.7%). When adjusting for confounding variables older age (OR 1.03, p = 0.008), increasing BMI (OR 1.05, p = 0.01) and absence of hypertension (OR 0.66, p = 0.02) were independent predictors of being dissatisfied with recreational activities in isolation. The one-year components and total WOMAC scores were significant (p < 0.001) predictors of satisfaction with recreational activities and were reliable with an area under the curve of ≥0.82 CONCLUSION: Patients of older age, higher BMI and without hypertension are more likely to be dissatisfied with recreational activities despite being satisfied with their overall outcome.

Patient age of less than 55 years is not an independent predictor of functional improvement or satisfaction after total knee arthroplasty.

INTRODUCTION: Management of the young patient with end-stage osteoarthritis of the knee is difficult, with surgical options of osteotomy, partial or total knee arthroplasty (TKA). The primary aim of this study was to assess whether age of less than 55 years was an independent predictor of functional outcome and satisfaction after total knee arthroplasty (TKA). The secondary aims were to identify pre-operative differences in patient demographics, comorbidity and function between patients less than 55 years old compared to those 55 years old and over. MATERIALS AND METHODS: A retrospective cohort consisting of 2589 patients undergoing a primary TKA was identified from an established arthroplasty database. Patient demographics, comorbidity, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Short Form (SF) 12 scores were collected pre-operatively and 1 year post-operatively. In addition, patient satisfaction was assessed at 1 year. Regression analysis was used to identify independent pre-operative predictors of change in the WOMAC and SF-12 scores, and patient satisfaction. RESULTS: Patients less than 55 years old were significantly less likely to be satisfied with the overall outcome of their TKA (OR 0.4, p = 0.001). After adjusting for confounding variables age group was not an independent predictor of overall satisfaction with overall outcome (OR 0.71, p = 0.16). Independent predictors of an increased risk of dissatisfaction with the overall outcome at 1 year were depression (OR 0.58, p = 0.008) and worse pre-operative SF-12 MCS (p = 0.04). CONCLUSION: Age of less than 55 years is not an independent predictor of functional outcome or rate of patient satisfaction after TKA. However, depression and poor mental health are significantly more prevalent in patients less than 55 years old and were independently associated with a lower satisfaction rate.

The rate and predictors of patient satisfaction after total knee arthroplasty are influenced by the focus of the question: a standard satisfaction question is required.

Aims: The primary aim of this study was to assess the rate of patient satisfaction one year after total knee arthroplasty (TKA) according to the focus of the question asked. The secondary aims were to identify independent predictors of patient satisfaction according to the focus of the question. Patients and Methods: A retrospective cohort of 2521 patients undergoing a primary unilateral TKA were identified from an established regional arthroplasty database. Patient demographics, comorbidities, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and 12-Item Short-Form Health Survey (SF-12) scores were collected preoperatively and one year postoperatively. Patient satisfaction was assessed using four questions, which focused on overall outcome, activity, work, and pain. Logistic regression analysis was used to identify independent preoperative predictors of increased stiffness when adjusting for confounding variables. Results: Using patient satisfaction with the overall outcome (n = 2265, 89.8%) as the standard, there was no difference in the rate of satisfaction for pain relief (n = 2277, odds ratio (OR) 0.95, 95% confident intervals (CI) 0.79 to 1.14, p = 0.60), but patients were more likely to be dissatisfied with activities (79.3%, n = 2000/2521, OR 2.22, 95% CI 1.96 to 2.70, p < 0.001) and work (85.8%, n = 2163/2521, OR 1.47, 95% CI 1.23 to 1.75, p < 0.001). Logistic regression analysis identified different predictors of satisfaction for each of the focused satisfaction questions. Overall satisfaction was influenced by diabetes (p = 0.03), depression (p = 0.004), back pain (p < 0.001), and SF-12 physical (p = 0.008) and mental (p = 0.01) components. Satisfaction with activities was influenced by depression (p = 0.001), back pain (p < 0.001), WOMAC stiffness score (p = 0.03), and SF-12 physical (p < 0.001) and mental (p < 0.001) components. Satisfaction with work was influenced by depression (p = 0.007), back pain (p < 0.001), WOMAC function (p = 0.04) and stiffness (p = 0.05) scores, and SF-12 physical (p < 0.001) and mental (p < 0.001) components. Satisfaction with pain relief was influenced by diabetes (p < 0.001), back pain (p < 0.001), and SF-12 mental component (p = 0.04). Conclusion: The focus of the satisfaction question significantly influences the rate and the predictors of patient satisfaction after TKA. Cite this article: Bone Joint J 2018;100-B:740-8.

Three groups of dissatisfied patients exist after total knee arthroplasty: early, persistent, and late.

AIMS: The primary aim of this study was to assess whether patient satisfaction one year after total knee arthroplasty (TKA) changed with longer follow-up. The secondary aims were to identify predictors of satisfaction at one year, persistence of patient dissatisfaction, and late onset dissatisfaction in patients that were originally satisfied at one year. PATIENTS AND METHODS: A retrospective cohort consisting of 1369 patients undergoing a primary TKA for osteoarthritis that had not undergone revision were identified from an established arthroplasty database. Patient demographics, comorbidities, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, and Short Form 12 (SF-12) questionnaire scores were collected preoperatively, and one and five years postoperatively. In addition, patient satisfaction was assessed at one and five years postoperatively. Logistic regression analysis was used to identify independent predictors of satisfaction at one and five years. RESULTS: The overall rate of satisfaction did not change from one (91.7%, n = 1255) to five (90.1%, n = 1234) years (p = 0.16). Approximately half (n = 53/114) of the patients who were dissatisfied at one year became satisfied with their TKA at five years, whereas 6% (n = 74/1255) of those who were satisfied at one year became dissatisfied at five years. At one year, patients with lung disease (p = 0.04), with depression (p = 0.001), with back pain (p < 0.001), undergoing unilateral TKA (p = 0.001), or with a worse preoperative WOMAC pain score (p = 0.04) were more likely to be dissatisfied. Patients with gastric ulceration (p = 0.04) and a worse WOMAC stiffness score (p = 0.047) were at increased risk of persistent dissatisfaction at five years. In contrast, a worse WOMAC pain score (p = 0.01) at one year was a predictor of dissatisfaction in previously satisfied patients at five years. CONCLUSION: Three groups of dissatisfied patients exist after TKA: 'early' dissatisfaction at one year, 'persistent' dissatisfaction with longer follow-up, and 'late' dissatisfaction developing in previously satisfied patients at one year. All three groups have different independent predictors of satisfaction, and potentially addressing risk factors specific to these groups may improve patient outcome and their satisfaction. Cite this article: Bone Joint J 2018;100-B:161-9.

Patient-reported factors influencing return to work after joint replacement.

BACKGROUND: An increasing number of patients in the working population are undergoing total hip and knee replacement for osteoarthritis and the timing and success of return to work (RTW) is becoming increasingly important as a measure of success for these patients. There is limited understanding of the patient variables that determine the ability to RTW. AIMS: To explore the factors influencing RTW following hip and knee replacement from the patient's perspective. METHODS: A cross-sectional population-based postal survey carried out with patients of working age after hip and knee replacement surgery in a UK teaching hospital. Free text comments were collected regarding the experiences of patients returning to work following hip and knee replacement. Qualitative thematic analysis was undertaken to identify the factors influencing RTW from the patient's perspective. RESULTS: From the patients' perspective three key factors were identified that influenced RTW. Patients reported an improved physical and psychological performance at work after surgery in comparison to pre-operative functioning, although there was a lack of informed advice regarding RTW after surgery. Workplace support and adaptation of the job role enhanced the experience of RTW. CONCLUSIONS: Return to work is influenced by a combination of patient, clinician and occupational factors. The relationship between each of these needs to be explored in greater depth through further qualitative work to gain a wider understanding of the variables influencing patients' RTW following hip and knee replacement.

Understanding the patient-reported factors determining time taken to return to work after hip and knee arthroplasty.

PURPOSE: The key factors underscoring safe and early return to work after hip (THA) or knee (TKA) arthroplasty are poorly defined. The aim of this study was to evaluate the effect of patient-reported variables upon time taken to return to work after THA or TKA in a working population. METHODS: Questionnaires asking about employment history, education, general health and experiences of returning to work after THA and TKA were administered by post and at outpatients' clinic. RESULTS: One hundred and two from 272 eligible patients, of whom 52 had undergone THA and 50 TKA, were recruited sequentially. In total, 83 patients were employed pre-operatively and 80 returned to work at median 12 (2-64) weeks. Those in more manual occupations (p = 0.001) without pre-operative sick leave due to their hip or knee arthritis (p = 0.016) and a higher level of qualification (p = 0.041) returned to employment significantly quicker than the rest of the cohort. THA patients report a greater improvement in terms of performance at work (63 vs 44 %, p = 0.007) and job prospects (50 vs 36 %, p = 0.046) as compared with patients after TKA. CONCLUSIONS: Patients with pre-operative sick leave, basic or no qualifications and more physically demanding occupations take longer to return to work. Operating patients before their arthritis forces them to become unemployed would improve their chances to return to work. Hip arthroplasty patients have a greater perceived benefit in terms of performance at work and job prospect. A more tailored return to work time predictions to allow a faster return to work and avoid frustration. LEVEL OF EVIDENCE: IV.

Deletion of the N-terminus of murine map2 by gene targeting disrupts hippocampal ca1 neuron architecture and alters contextual memory.

Microtubule-associated protein-2 (MAP2) is a brain specific A-kinase anchoring protein that targets the cyclic AMP-dependent protein kinase holoenzyme (PKA) to microtubules. Phosphorylation of MAP2 by different protein kinases is crucial for neuronal growth. The N-terminus of MAP2 contains the binding site for regulatory subunit II of cAMP-dependent protein kinase (PKA-RIIbeta). Using homologous recombination, we created a mutant line of mice (delta1-158) that express truncated MAP2 lacking the N-terminal peptide and the PKA binding site. Deletion of the PKA binding site from the MAP2 gene resulted in decreased efficiency of MAP2 phosphorylation. Biochemical and immunohistochemical studies demonstrate major changes in the morphology of hippocampal neurons in delta1-158 mice. Behavioral tests indicate that delta1-158 mice were impaired (exhibited less conditioned freezing) relative to Wild-Type (WT) controls during a test of contextual, but not during auditory cue, fear conditioning when tested at 8 weeks or 8 months of age. The delta1-158 mice displayed a heightened sensitivity to shock at 8 weeks, but not at 8 months of age. We conclude that PKA binding to MAP2 and MAP2 phosphorylation is essential for the selective development of contextual memory.

Methods for inducing neuronal loss in preweanling rats using intracerebroventricular infusion of kainic acid.

Excitotoxins, such as kainic acid (KA), have been shown to produce neuronal degeneration in the adult rat brain. While preweanling rats have been shown to be relatively resistant to the neurotoxicity of lower doses of KA, the presence of neuronal loss at higher doses (of KA) has only begun to be investigated in such animals. A reliable method of producing neuronal loss in preweanling rats is to administer nmol concentrations of KA via intracerebroventricular (i.c.v.) injections on postnatal day 7 (P7). Using a three-dimensional, non-biased cell counting technique, we have shown that neuronal loss is observed in the CA3 subfield of the hippocampal formation at P45 and P75. Further, immunohistochemical studies of markers for cell death may be useful to examine the types of cellular processes associated with such neuronal loss. Data from our own experiments suggest the activation of immediate-early genes in the neuronal loss produced by KA administration at P7. This developmental animal model of neuronal loss may be useful in studying neurodevelopmental disorders where the onset of symptoms or cognitive deficits is thought to follow an early developmental insult.

Maturation of locomotor and Fos responses to the NMDA antagonists, PCP and MK-801.

Antagonists at the N-methyl-D-aspartate (NMDA)-type glutamate receptor, such as phencyclidine (PCP) and dizocilpine (MK-801), are well-known to evoke increases in locomotor activity in adult rats and mice. However, little is known about the effects of NMDA antagonists on locomotor activity as a function of development. The present study examined locomotor responses to PCP or MK-801 in male rats of varying ages and found that prepubertal rats were more sensitive to the locomotor-elevating effects of PCP (1.5 mg/kg and 3. 0 mg/kg, s.c.) than were adults. Locomotor responses to MK-801 (0.1 and 0.2 mg/kg, s.c.) were not dependent on age. The age-dependent response to PCP may be related to developmental events in the motor cortex, since more Fos-immunoreactive neurons were observed in the motor cortex of prepubertal animals after PCP administration relative to adult animals. An opposite pattern of age-dependent Fos responses was observed in the posterior retrosplenial cortex. The results suggest that locomotor responses to NMDA antagonists can be influenced in an age- and drug-dependent manner and that maturational events in the motor cortex may modify responses to PCP.

Locomotor activity and accumbens Fos expression driven by ventral hippocampal stimulation require D1 and D2 receptors.

Numerous studies have suggested that excitatory projections from the ventral hippocampus to the nucleus accumbens modulate locomotor activity in rats. Furthermore, the ability of ventral hippocampal neurons to alter locomotor activity may involve the dense dopaminergic innervation found in the nucleus accumbens. The purpose of this study was to: (i) more fully characterize the locomotor effects of acute alterations in ventral hippocampal activity; (ii) ascertain the influence of dopamine agonists and antagonists on locomotor changes produced by altered ventral hippocampal activity; and (iii) use immediate early gene induction to determine whether dopamine antagonists alter the response of nucleus accumbens neurons to ventral hippocampal stimulation. By comparing a variety of excitatory amino acid agonists, it was found that ventral hippocampal infusion of N-methyl-D-aspartate elevated locomotor activity in a subconvulsive manner, while other excitatory amino acid receptor agonists did not. Inactivation of the ventral hippocampus achieved by lidocaine infusion did not suppress ongoing locomotor activity, nor did it affect amphetamine-induced increases in locomotor activity. Increases in locomotor activity induced by ventral hippocampal N-methyl-D-aspartate infusion were blocked by systemic administration of haloperidol (a D2 receptor antagonist), SCH-23390 (a D1 receptor antagonist) or reserpine. Cellular expression of the protein product of the immediate early gene, c-fos, was dramatically increased in the nucleus accumbens shell after ventral hippocampal N-methyl-D-aspartate infusion, and haloperidol, SCH-23390 and reserpine attenuated this effect. These results suggest that the increases, but not decreases, in ventral hippocampal activity have a measurable effect on ongoing rates of locomotion, and that this effect requires both D1 and D2 receptors. Moreover, the studies of Fos expression suggest that dopamine receptor antagonists attenuate neuronal responses to ventral hippocampal stimulation within the nucleus accumbens, a brain region important in the generation and maintenance of locomotor activity.

Neuroleptic influences on a lateralized behavioral bias in unoperated rats.

RATIONALE: Abnormalities of the ascending dopaminergic system have been associated with hemineglect, and evidence suggests that neuroleptic treatments normalize the right hemispatial attentional impairment that is sometimes observed in acutely psychotic schizophrenic patients. OBJECTIVE: A research program was initiated to develop an animal model of hemineglect-drug interactions. METHODS: Female rats were tested repeatedly on removing a "nuisance stimulus" - strips of surgical tape applied loosely to the forelimbs. Subjects were assigned to groups dependent upon showing a behavioral orientation preference (BOP) during pre-drug baseline tests. Animals representing left-BOP, right-BOP and no preference continued to be tested during chronic exposure either to a dopamine antagonist (0.05 mg haloperidol/kg) or agonist (1.0 mg d-amphetamine/kg) or vehicle only. RESULTS: Three weeks of haloperidol treatments to rats only with an initial right BOP gradually eliminated the response bias, as revealed by declines in choosing the right forepaw and the latencies between attending to the two forepaws. CONCLUSION: The results recommend right BOP female rats as a simple, non-invasive behavioral animal model for evaluating and comparing neuroleptic medications.

Gene targeting reveals a critical role for neurturin in the development and maintenance of enteric, sensory, and parasympathetic neurons.

Neurturin (NTN) is a neuronal survival factor that activates the Ret tyrosine kinase in the presence of a GPI-linked coreceptor (either GFR alpha1 or GFR alpha2). Neurturin-deficient (NTN-/-) mice generated by homologous recombination are viable and fertile but have defects in the enteric nervous system, including reduced myenteric plexus innervation density and reduced gastrointestinal motility. Parasympathetic innervation of the lacrimal and submandibular salivary gland is dramatically reduced in NTN-/- mice, indicating that Neurturin is a neurotrophic factor for parasympathetic neurons. GFR alpha2-expressing cells in the trigeminal and dorsal root ganglia are also depleted in NTN-/- mice. The loss of GFR alpha2-expressing neurons, in conjunction with earlier studies, provides strong support for GFR alpha2/Ret receptor complexes as the critical mediators of NTN function in vivo.

Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance-associated protein contribute to the blood-cerebrospinal-fluid drug-permeability barrier.

The blood-brain barrier and a blood-cerebrospinal-fluid (CSF) barrier function together to isolate the brain from circulating drugs, toxins, and xenobiotics. The blood-CSF drug-permeability barrier is localized to the epithelium of the choroid plexus (CP). However, the molecular mechanisms regulating drug permeability across the CP epithelium are defined poorly. Herein, we describe a drug-permeability barrier in human and rodent CP mediated by epithelial-specific expression of the MDR1 (multidrug resistance) P glycoprotein (Pgp) and the multidrug resistance-associated protein (MRP). Noninvasive single-photon-emission computed tomography with 99mTc-sestamibi, a membrane-permeant radiopharmaceutical whose transport is mediated by both Pgp and MRP, shows a large blood-to-CSF concentration gradient across intact CP epithelium in humans in vivo. In rats, pharmacokinetic analysis with 99mTc-sestamibi determined the concentration gradient to be greater than 100-fold. In membrane fractions of isolated native CP from rat, mouse, and human, the 170-kDa Pgp and 190-kDa MRP are identified readily. Furthermore, the murine proteins are absent in CP isolated from their respective mdr1a/1b(-/-) and mrp(-/-) gene knockout littermates. As determined by immunohistochemical and drug-transport analysis of native CP and polarized epithelial cell cultures derived from neonatal rat CP, Pgp localizes subapically, conferring an apical-to-basal transepithelial permeation barrier to radiolabeled drugs. Conversely, MRP localizes basolaterally, conferring an opposing basal-to-apical drug-permeation barrier. Together, these transporters may coordinate secretion and reabsorption of natural product substrates and therapeutic drugs, including chemotherapeutic agents, antipsychotics, and HIV protease inhibitors, into and out of the central nervous system.

Delayed neuronal loss after administration of intracerebroventricular kainic acid to preweanling rats.

Excitotoxins, such as kainic acid (KA), have been shown to produce both immediate and delayed neuronal degeneration in adult rat brain. While preweanling rats have been shown to be resistant to the immediate neurotoxicity of KA, the presence of delayed neuronal loss has not been investigated in such animals. To determine whether intracerebroventricular (i.c.v.) administration of KA would produce delayed neuronal loss, preweanling rats were administered 5 nmol or 10 nmol KA i.c.v. on postnatal day 7 (P7) and then examined at P14, P45, and P75. Using three-dimensional, non-biased cell counting, neuronal loss was observed in the CA3 subfield of the hippocampal formation at P45 and P75 in animals administered 10 nmol KA, as compared to animals administered 5 nmol KA or artificial cerebrospinal fluid. Further, the amount of immunoreactivity to jun, the protein product of the immediate early gene, c-jun, adjusted for the number of remaining neurons was increased in the same brain areas. Antibody labeling of inducible heat shock protein and glial fibrillary acidic protein was not similarly increased in animals administered i.c.v. KA. The data suggest that while i.c.v. KA does not produce immediate neuronal loss in preweanling rats, the hippocampus is altered so that neuronal loss occurs after a delay, perhaps through apoptosis. These findings may be relevant to the pathogenesis of neuropsychiatric disorders, such as schizophrenia, that are characterized by early limbic-cortical deficits but onset of illness in young adulthood.

Cerebrospinal fluid glutamate inversely correlates with positive symptom severity in unmedicated male schizophrenic/schizoaffective patients.

BACKGROUND: Recent hypotheses have suggested that diminished brain glutamate may be of importance in the neurochemical basis of schizophrenia. METHODS: We assayed cerebrospinal fluid for glutamate and obtained clinical symptom ratings in 19 medication-free (except p.r.n. chloral hydrate) schizophrenic or schizoaffective (typically with significant schizophrenic qualities) male inpatients. RESULTS: Ratings of positive symptoms were significantly inversely correlated (rs = -.457, p < .05, one-tailed test) with glutamate concentrations. Hallucinatory behavior was strongly correlated (rs = -.621, p < .01, one-tailed test) with glutamate. A subset of 11 patients consented to a second lumbar puncture (LP) after treatment with haloperidol (typically 15 or 20 mg/day) for 2-4 weeks. Haloperidol treatment did not alter glutamate concentrations. No correlations were noted between glutamate and symptoms in the medicated subsample. Though approximately half the patients received chloral hydrate during the 72 hours prior to the unmedicated LP, the correlations between positive symptoms and glutamate in the patients who received no chloral hydrate prior to the LP were quite similar to those found in the overall sample. CONCLUSIONS: The results provide further support for the potential importance of glutamate in the neurochemical basis of schizophrenia.

Progressive neurodegeneration after intracerebroventricular kainic acid administration in rats: implications for schizophrenia?

BACKGROUND: Intracerebroventricular (ICV) administration of kainic acid to rats produces limbic-cortical neuronal damage that has been compared to the neuropathology of schizophrenia. METHODS: Groups of adult rats were administered ICV kainic acid and then assessed for neuronal loss and the expression of proteins relevant to mechanisms of neuronal damage after one and fourteen days. Neuronal loss was assessed by two-dimensional cell counting and protein expression was assessed by immunohistochemistry. RESULTS: ICV kainic acid administration was associated with both immediate (day 1) and delayed (day 14) neuronal loss in the dorsal hippocampus. The immediate injury was largely limited to the CA3 hippocampal subfield, while the delayed injury included the CA1 subfield. Multiple mechanisms of cell death appeared to be involved in the delayed neuronal loss, as evidenced by changes in the expression of glutamate receptor subunits, heat shock protein and jun protein. CONCLUSIONS: ICV kainic acid administration to adult rats produces progressive damage to limbic-cortical neurons, involving both fast and slow mechanisms of cell death. Given the evidence for clinical deterioration, cognitive deficits and hippocampal neuropathy in some cases of schizophrenia, this animal model may be relevant for hypotheses regarding mechanisms of neurodegeneration in that disorder.