Decreased medial entorhinal cortical thickness in olanzapine exposed female rats is not ameliorated by exercise.

Aerobic exercise has been associated with hippocampal plasticity, both in healthy adults and in psychosis patients, but its impact on cortical regions remains unclear. The entorhinal cortex serves as a critical gateway for the hippocampus, and recent studies suggest that this region may also be impacted following an exercise regime. In order to investigate the effects of antipsychotic medications and exercise on the entorhinal cortex, female rats were chronically administered either olanzapine or vehicle and were either sedentary or had access to a running wheel for 9 weeks. Olanzapine-treated rats had decreased medial entorhinal cortical thickness compared to vehicle-treated rats. A statistically significant interaction was observed for layer II of the entorhinal cortex, with exercising rats having significantly greater thickness compared to sedentary rats in the vehicle group, but not the olanzapine group. Greater total entorhinal and lateral entorhinal cortical thickness was associated with greater average activity. In exercising rats, decreasing glucose intolerance was associated with larger total entorhinal and layer II cortical thickness. Lower fasting insulin levels were associated with greater total entorhinal, lateral entorhinal, and layer II cortical thickness. The relationship between increased activity and greater entorhinal cortical thickness was mediated by reduced fasting insulin, indicating that regulation of metabolic risk factors may contribute to impact of aerobic exercise on the entorhinal cortex. Aerobic exercise may be helpful in counteracting metabolic side effects of antipsychotic medications and managing these side effects may be key to promoting entorhinal cortical plasticity in patients treated with second-generation antipsychotic drugs.

Exercise prevents downregulation of hippocampal presynaptic proteins following olanzapine-elicited metabolic dysregulation in rats: Distinct roles of inhibitory and excitatory terminals.

Schizophrenia patients treated with olanzapine, or other second-generation antipsychotics, frequently develop metabolic side-effects, such as glucose intolerance and increased adiposity. We previously observed that modeling these adverse effects in rodents also resulted in hippocampal shrinkage. Here, we investigated the impact of olanzapine treatment, and the beneficial influence of routine exercise, on the neurosecretion machinery of the hippocampus. Immunodensities and interactions of three soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins (syntaxin-1, synaptosome-associated protein of 25kDa (SNAP-25) and vesicle-associated membrane protein (VAMP)), synaptotagmin and complexins-1/2 were quantified in the hippocampus of sedentary and exercising rats exposed over 9weeks to vehicle (n=28) or olanzapine (10mg/kg/day, n=28). In addition, brain sections from subgroups of sedentary animals (n=8) were co-immunolabeled with antibodies against vesicular GABA (VGAT) and glutamate (VGLUT1) transporters, along with syntaxin-1, and examined by confocal microscopy to detect selective olanzapine effects within inhibitory or excitatory terminals. Following olanzapine treatment, sedentary, but not exercising rats showed downregulated (33-50%) hippocampal densities of SNARE proteins and synaptotagmin, without altering complexin levels. Strikingly, these effects had no consequences on the amount of SNARE protein-protein interactions. Lower immunodensity of presynaptic proteins was associated with reduced CA1 volume and glucose intolerance. Syntaxin-1 depletion appeared more prominent in VGAT-positive terminals within the dentate gyrus, and in non-VGAT/VGLUT1-overlapping areas of CA3. The present findings suggest that chronic exposure to olanzapine may alter hippocampal connectivity, especially in inhibitory terminals within the dentate gyrus, and along the mossy fibers of CA3. Together with previous studies, we propose that exercise-based therapies might be beneficial for patients being treated with olanzapine.

Effects of chronic exercise and treatment with the antipsychotic drug olanzapine on hippocampal volume in adult female rats.

Numerous studies have reported that the hippocampus in schizophrenia patients is reduced in volume compared to the normal population. Antipsychotic medications have had mixed benefits in maintaining hippocampal volume or reversing volume loss. Recent evidence indicates that routine aerobic exercise represents a promising intervention for reversing hippocampal loss and cognitive deficits. In the present study, we measured the effects of chronic treatment with olanzapine and daily exercise on the hippocampal volumes of rats. Adult female rats were treated during the week with either olanzapine (10mg/kg) or vehicle for 9 consecutive weeks. Subgroups of animals were provided access to exercise running wheels for 1 or 3h per day during the same period, or were sedentary. Metabolic indices, including glucose tolerance, were measured on a weekly basis. At the conclusion of the study, brains were perfused and hippocampal sections were Nissl stained. Total hippocampal volume was measured using the Cavalieri estimator. Treatment with olanzapine caused a significant decrease in hippocampal volume in sedentary rats. However, exercise was able to reverse most of this volume loss. The hippocampal sub-regions of the dentate gyrus and CA1 were most strongly affected by olanzapine and exercise. Of interest, there was a strong and highly significant negative correlation between glucose intolerance and hippocampal volume, whereby greater glucose intolerance was associated with a smaller hippocampal volume. These findings indicate that exercise may have beneficial effects on the hippocampus when antipsychotic medication can contribute to changes in volume.

Decreased mRNA expression of uncoupling protein 2, a mitochondrial proton transporter, in post-mortem prefrontal cortex from patients with bipolar disorder and schizophrenia.

Although the neurobiological basis of bipolar disorder (BD) remains unknown, mitochondrial dysfunction, oxidative stress and oxidative cell damage have been identified in this disease. Uncoupling proteins (UCP) are proton carriers located in the inner membrane of the mitochondria involved in controlling the production of mitochondrial reactive oxygen species (ROS). Therefore, in this study we wished to investigate the involvement of UCP in BD. We analyzed the RNA and protein levels of UCP2 in the dorsolateral prefrontal cortex (DLPFC) of subjects with BD and schizophrenia (SCZ) and assessed the potential relationship between the antioxidant superoxide dismutase (SOD1 and SOD2) and UCP2 in the same region. Our results showed a downregulation of UCP2 mRNA levels in the DLPFC of subjects with BD and SCZ. There were no differences in UCP2 protein, SOD1 and SOD2 levels between patients and controls. Although more studies are necessary, our results suggest that UCP2 is not been used as a compensatory mechanism to oppose the higher levels of oxidative stress found in BD and SCZ.

Prominent synaptic and metabolic abnormalities revealed by proteomic analysis of the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder.

There is evidence for both similarity and distinction in the presentation and molecular characterization of schizophrenia and bipolar disorder. In this study, we characterized protein abnormalities in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder using two-dimensional gel electrophoresis. Tissue samples were obtained from 35 individuals with schizophrenia, 35 with bipolar disorder and 35 controls. Eleven protein spots in schizophrenia and 48 in bipolar disorder were found to be differentially expressed (P<0.01) in comparison to controls, with 7 additional spots found to be altered in both diseases. Using mass spectrometry, 15 schizophrenia-associated proteins and 51 bipolar disorder-associated proteins were identified. The functional groups most affected included synaptic proteins (7 of the 15) in schizophrenia and metabolic or mitochondrial-associated proteins (25 of the 51) in bipolar disorder. Six of seven synaptic-associated proteins abnormally expressed in bipolar disorder were isoforms of the septin family, while two septin protein spots were also significantly differentially expressed in schizophrenia. This finding represented the largest number of abnormalities from one protein family. All septin protein spots were upregulated in disease in comparison to controls. This study provides further characterization of the synaptic pathology present in schizophrenia and of the metabolic dysfunction observed in bipolar disorder. In addition, our study has provided strong evidence implicating the septin protein family of proteins in psychiatric disorders for the first time.

Understanding the neurotransmitter pathology of schizophrenia: selective deficits of subtypes of cortical GABAergic neurons.

Research aimed at understanding the neurotransmitter pathology of schizophrenia has been underway for half a century, with much emphasis on the dopamine system. Although this approach has advanced our understanding of treatment mechanisms, identification of primary dopaminergic abnormalities in the disease has been elusive. The increasing emphasis on a neuronal pathology of schizophrenia has led to the identification of abnormalities in GABAergic and glutamatergic systems; and we have identified selective deficits in GABAergic interneurons containing the calcium binding proteins parvalbumin and calbindin. Here we report further evidence for a loss of parvalbumin-immunoreactive neurons in both dorsolateral prefrontal and medial temporal cortex, indicating that these deficits are consistent with a subtle neurodevelopmental pathogenesis and hypothesizing that they may contribute to a further degenerative process in schizophrenia.

Density and distribution of white matter neurons in schizophrenia, bipolar disorder and major depressive disorder: no evidence for abnormalities of neuronal migration.

The neurodevelopmental hypothesis of schizophrenia suggests that this disorder may result from a disruption of normal brain development. While widely cited, neuropathological evidence for this is far from conclusive. Alterations in the density and position of white matter neurons have been previously described in the frontal and temporal lobes and have led to suggestions that abnormal neuronal migration may play a role in the aetiology of schizophrenia. However, these findings have not been replicated. Furthermore, developmental abnormalities may not be specific to schizophrenia. The aim of this study was to examine the density and spatial pattern distribution of white matter neurons in psychiatric and control subjects using sophisticated computerised image analysis techniques. White matter neurons immunoreactive for microtubule associated protein-2 were quantified in the frontal lobe in schizophrenia, bipolar disorder, major depressive disorder and matched controls (each group n = 15). Analysis showed that the density and spatial distribution of white matter neurons did not differ significantly between the control and psychiatric groups. This study cannot replicate the earlier findings of white matter abnormalities in schizophrenia and finds no evidence for abnormal brain development in any of the disorders studied.

Neurochemical correlates of cortical GABAergic deficits in schizophrenia: selective losses of calcium binding protein immunoreactivity.

Deficits in a variety of different neurochemical species are consistent with a loss of cortical gamma-aminobutyric acid (GABA)ergic interneurons in schizophrenia. As well as neurochemical markers that indicate all neurons using GABA as a transmitter, and which include GABA uptake sites and glutamate decarboxylase, deficits of certain neuropeptides and calcium binding proteins coexisting with GABA have been reported. These abnormalities are indicative of losses specific to certain subtypes of GABAergic neurons. The calcium binding proteins in particular demonstrate selective deficits; we find losses of parvalbumin- and calbindin-, but not calretinin-immunoreactive cells in the prefrontal cortex in schizophrenia. These selective reductions in the density of parvalbumin- and calbindin-containing neurons could reflect functional loss of expression in intact cells or alternatively a deficit in the density of certain GABAergic neuronal subtypes. The latter interpretation is consistent with a neurodevelopmental pathogenesis involving neuronal damage at a time prior to the expression of these protective calcium-binding proteins. In this review we discuss the evidence for altered GABAergic transmission in schizophrenia.

GABAergic neuronal subtypes in the human frontal cortex--development and deficits in schizophrenia.

Recent studies have provided evidence for a deficit of GABA-containing interneurons in the frontal cortex in schizophrenia. That this deficit might be brought about during early foetal or neonatal life is a hypothesis consistent with the substantial indications for a neurodevelopmental aetiology of the disease. GABAergic neurons can be defined by the presence of one of three types of calcium binding proteins, which are thought to have neuroprotective properties. We have undertaken an investigation into the postnatal ontology of these neuronal subtypes and find that calretinin expression is relatively constant and present from before birth, calbindin expression is also present early but redistributes in the cortex over the first months of life, while parvalbumin-immunoreactivity is not observed until between 3 and 6 months of age. Investigation of frontal cortical tissue taken post mortem from a series of schizophrenic patients and matched control subjects revealed that parvalbumin-, but not calretinin-immunoreactive cells are significantly diminished in schizophrenia. These observations support the hypothesis that GABAergic deficits in schizophrenia may stem from toxic events occurring during cortical development which selectively target immature neurons before protection by parvalbumin is conferred.

A method for estimating solid organ donor potential by organ procurement region.

OBJECTIVES: This study sought to develop a methodology for estimating potential solid organ donors and measuring donation performance in a geographic region based on readily available data on the hospitals in that region. METHODS: Medical records were reviewed in a stratified random sample of 89 hospitals from 3 regions to attain a baseline of donor potential. Data on a range of hospital characteristics were collected and tested as predictors of donor potential through the use of hierarchical Poisson regression modeling. RESULTS: Five hospital characteristics predicted donor potential: hospital deaths, hospital Medicare case-mix index, total hospital staffed beds, medical school affiliation, and trauma center certification. Regional estimates were attained by aggregating individual hospital estimates. Confidence intervals for these regional estimates indicated that actual donations represented from 28% to 44% of the potential in the regions studied. CONCLUSIONS: This methodology accurately estimates organ donor potential within 3 geographic regions and lays the foundation for evaluating organ donation effectiveness nationwide. Additional research is needed to test the validity of the model in other geographic regions and to further explore organ donor potential in hospitals with fewer than 50 beds.

Readiness of critical care physicians and nurses to handle requests for organ donation.

BACKGROUND: Critical care nurses and physicians usually care for those patients whose condition progresses to brain death and are also often responsible for requesting organ donation from the family of a brain-dead patient. We hypothesized that staff support, knowledge, and training levels would be significantly associated with organ donation rates. OBJECTIVE: To assess the readiness of critical care staff to successfully handle requests for organ donation. METHODS: A total of 1061 critical care staff from 28 hospitals in four separate regions of the United States completed a questionnaire that assessed (1) factual knowledge about organ donation, (2) understanding of brain death, (3) previous training in procedures for requesting donations, and (4) comfort levels with the donation process. RESULTS: Staff training in effective procedures for requesting organ donations was significantly correlated with hospitals' donation rates. Less than a third of respondents, however, had received training in explaining brain death to and requesting organ donation from a grieving family. In hospitals with high rates of organ donation, 52.9% of staff had received training; in hospitals with low rates of organ donation, 23.5% of staff had received training. Levels of factual knowledge about organ donation and brain death were unexpectedly low but were not significantly related to hospitals' rates of organ donation. CONCLUSIONS: Training of critical care nurses and physicians in effective procedures for requesting organ donation is significantly associated with higher rates of organ donation, yet two thirds of critical care staff report no relevant training. Consequently, critical care staff cannot be considered ready to effectively handle requests for organ donation.

Improving the request process to increase family consent for organ donation.

The greatest impediment to organ donation is refusal of family consent. This study examined the impact of 3 modifiable elements of the donation request on family consent rates: (1) decoupling (i.e., the family understands and accepts brain death before discussion of organ donation is begun); (2) the procurement coordinator participates in the request for consent; and (3) donation is requested in a quiet, private place. Data on the request process were collected prospectively for 707 medically suitable potential donors who had been referred to 3 organ procurement organizations. The average rate of consent for donation was 62.2%. Higher consent rates were independently associated with the 3 characteristics studied. These components were summarized in the Request Process Scale. Multivariate regression analyses indicated that consent rates can be as high as 74% when all 3 process elements are present. Hospitals and organ procurement organizations should incorporate these elements into their standard of practice when requesting organ donation.

Living kidney donation: a survey of professional attitudes and practices.

Living donation is an option for meeting the needs of patients with end-stage renal disease. We surveyed kidney transplant professionals to understand their attitudes, opinions, and practices regarding living donation and to generate a rough estimate of the national potential for living related kidney donation. Although this sample of health practitioners expressed strong support for living donation, their actual professional practice does not necessarily reflect such support. Given the disparity between support and practice, we recommend that leaders in the kidney transplant community focus on several concrete objectives to optimize living donation: estimate the underlying potential for living donation; identify and implement best demonstrated practices for making the living donation request; explore and respond to the ethical issues that surround living donation; and address the needs of both donors and recipients.

Medical record review as a measure of the effectiveness of organ procurement practices in the hospital.

Organ procurement efforts are central to the transplant sector of the health care system, yet procurement effectiveness is not routinely assessed. MRRs provide a solid foundation for identifying gaps in organ procurement performance, implementing and tracking the success of QI initiatives, and monitoring ongoing performance.

Parvalbumin-immunoreactive neurons are reduced in the prefrontal cortex of schizophrenics.

Recent studies have provided evidence for a functional impairment of gamma-aminobutyric acid (GABA)-containing interneurons in the prefrontal cortex of schizophrenics. This evidence includes reported deficits of basket and chandelier cells, which are known to contain the calcium-binding protein parvalbumin. Using a monoclonal antibody against parvalbumin we investigated possible changes in this subpopulation of neurons in the prefrontal cortex of schizophrenic cases and controls. Significantly reduced numbers of parvalbumin-immunoreactive neurons were observed in laminae III and IV, while no difference was detected in cortical width. Our findings are consistent with damage following a toxic insult, occurring during a developmental 'window of vulnerability' and specifically affecting this subpopulation of GABAergic neurons.

The impact of a comprehensive, hospital-focused intervention to increase organ donation.

In this article the results of a 2-year intervention designed to increase rates of organ donation while improving services to bereaved families of potential donors are described. The project focused on improving key elements of the organ donation process. The intervention was implemented in 50 hospitals within the service areas of three organ procurement organizations. Results show an increase in identification, referral, and asking rates. The overall donation rate increased significantly, from 33% to 43%. However, consent rates remained unchanged. Future efforts should focus on improving the request process by systematically incorporating practices that are associated with higher consent rates. This should enable hospital and organ procurement organization staff to appropriately and effectively offer families the option of organ donation; further increases in organ donation should follow.

Organ donor potential and performance: size and nature of the organ donor shortfall.

OBJECTIVES: To estimate the potential for solid organ donation; to identify modifiable reasons for nondonation. DESIGN: Retrospective medical records review. SETTING: Sixty-nine acute care hospitals in four geographic areas of the United States in 1990, and a stratified random sample of 89 hospitals in three of the same areas and 33 of the same hospitals in 1993. PATIENTS: PATIENTS < or = 70 yrs of age who were brain dead and medically suitable for donation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Standard forms were used to record patient demographic and hospital information. Reasons for nondonation were coded as "not identified," "family not asked," "consent denied," or "other." The main outcome measures were rate of donation and rates of nonidentification, not asking, and nonconsent. Organ donation occurred among 33% (299/916) of medically suitable cases identified in 1990 (95% confidence interval 30% to 36%). Ninety-four potential donors were not identified, 156 were not asked, 326 families denied consent, and 41 potential donors were categorized as "other," including patients who had suffered a cardiac arrest, and medical examiner prohibition of donation. In the 1993 study, organ donation occurred in an estimated 33% of suitable cases. In 1990, rates of donation were highest among patients <50 yrs of age, patients who died of traumatic causes, and non-Hispanic white patients. Logistic regression showed lower odds of donation for African American patients (odds ratio 0.38, 95% confidence interval 0.23 to 0.63) independent of potentially confounding hospital and patient variables (p=.0001). Donation rates did not vary by hospital size or type. CONCLUSIONS: Despite legal and policy initiatives, only one third of potential donors became donors in 1990, with similar results in 1993. Extrapolating the 1990 findings to the United States suggests a pool of 13,700 medically suitable donors per year. Prospective identification and requesting donation in all suitable potential donor cases could lead to 1,800 additional donors per year.