Objective: To investigate the efficacy of caring for patient’s with Parkinson’s disease (PD) in a rural home-based setting and to have movement disorders fellows coordinate and manage all health care delivery. Background: The University of Florida Center for Movement Disorders and Neurorestoration established operation “housecall” to serve patients with PD who could not otherwise afford to travel to an expert center or to pay for medical care. PD is known to lead to significant disability, frequent hospitalizations, early nursing home placement and morbidity. Methods: Movement disorders fellows travelled to the home(s) of underserved PD patients and coordinated the care of eight patients. The diagnosis of Parkinson’s disease was confirmed using standardized criteria, and a Unified Parkinson’s Disease Rating Scale was performed and best treatment practices delivered. Results: All eight patients have been followed longitudinally every 3 to 6 months in the home setting, and they remain functional and independent. None have been hospitalized for PD related complications. Each patient has a new updatable electronic medical record. All operation housecall cases are presented during video rounds, for the interdisciplinary PD team can make recommendations for care (neurology, neurosurgery, neuropsychology, psychiatry, physical therapy, occupational therapy, speech therapy, and social work). Two operation housecall patients have successfully received deep brain stimulation (DBS). Financial support for medical supplies and transportation remains privately funded. Conclusion: This program provides a proof of concept for PD housecalls. Operation housecall provides underserved PD patients’ with quality medical care, allows them to remain in their home setting, and may prevent hospitalizations. Advanced medical care such as evaluation for DBS is possible. This program could provide a proof of concept for the construction of a larger visiting physician or nurse program. Acknowledgements: This program is supported by the Smallwood Foundation and the National Parkinson Foundation Center of Excellence located at the University of Florida. Disclosure: Dr. Hack has nothing to disclose. Dr. Akbar has nothing to disclose. Dr. Eilers has nothing to disclose. Dr. Rundle-Gonzalez has nothing to disclose. Dr. Martinez-Ramirez has nothing to disclose. Dr. Morita has nothing to disclose. Dr. Malaty has received personal compensation for activities with Prime-CME as a speaker. Dr. Malaty has received research support from the National Parkinson Foundation, Michael J. Fox Foundation, Tourette Syndrome Association for Parkinson, National Institutes of Health, and Abbott. Dr. Okun has received royalty payments from Demos, Humana, Amazon and Cambridge. Dr. Okun has received research support from the Michael J. Fox Foundation, the National Parkinson Foundation, the Parkinson Alliance, the Smallwood Foundation, the Tourette Syndrome Association, the Bachmann-Strauss Foundation, and the National Institutes of Health.

Introduction Weight loss is common in Parkinson's Disease (PD) and sometimes may precede the diagnosis. Weight loss is associated with multiple factors but its impact on health-related quality of life (HRQL) in PD remains unknown. We sought to investigate the factors associated with weight change and to quantify its effect on HRQL. Methods The National Parkinson Foundation Quality Improvement Initiative (NPF-QII) data was used to analyze PD patients longitudinally between two visits, separated by 12±6 months. Multiple linear regression analyses were used to assess the associations between baseline covariates and body weight change per month, and to evaluate whether, and to what degree, Parkinson's Disease Questionnaire (PDQ-39) scores were affected. Results A higher Hoehn & Yahr stage, higher number of comorbidities, older age, lower MOCA estimate, and higher rate of levodopa usage were observed in patients who lost weight. Multivariate regression analysis indicated that age and levodopa usage were significantly associated with weight loss. Furthermore, monthly body weight loss was significantly associated with HRQL decline in PD patients. Loss of 1 lb (0.45 kg) per month was associated with a decline in QOL: an increase of 0.5% in PDQ-39 Summary Index score (p=0.004), and 1.1% and 1.5% increases in the mobility and ADL dimensions, respectively. Conclusion Weight loss in PD is common and seems to correlate with worsened HRQL. Awareness of factors associated with weight loss and its relation to HRQL may help practitioners improve patient management and expectations.

Hippocampal specimens resected to cure medically intractable temporal lobe epilepsy (TLE) provide a unique possibility to study functional consequences of morphological alterations. One intriguing alteration predominantly observed in cases of hippocampal sclerosis is an uncommon network of granule cells monosynaptically interconnected via aberrant supragranular mossy fibers. We investigated whether granule cell populations in slices from sclerotic and nonsclerotic hippocampi would develop ictaform activity when challenged by low-frequency hilar stimulation in the presence of elevated extracellular potassium concentration (10 and 12 mm) and whether the experimental activity differs according to the presence of aberrant mossy fibers. We found that ictaform activity could be evoked in slices from sclerotic and nonsclerotic hippocampi (27 of 40 slices, 14 of 20 patients; and 11 of 22 slices, 6 of 12 patients, respectively). However, the two patient groups differed with respect to the pattern of ictaform discharges and the potassium concentration mandatory for its induction. Seizure-like events were already induced with 10 mm K+. They exclusively occurred in slices from sclerotic hippocampi, of which 80% displayed stimulus-induced oscillatory population responses (250-300 Hz). In slices from nonsclerotic hippocampi, atypical negative field potential shifts were predominantly evoked with 12 mm K+. In both groups, the ictaform activity was sensitive to ionotropic glutamate receptor antagonists and lowering of [Ca2+]o. Our results show that, in granule cell populations of hippocampal slices from TLE patients, high K+-induced seizure-like activity and ictal spiking coincide with basic electrophysiological abnormalities, hippocampal sclerosis, and mossy fiber sprouting, suggesting that network reorganization could play a crucial role in determining type and threshold of such activity.

Einleitung: Die pharmakoresistente mesiale Temporallappenepilepsie (mTLE) geht häufig mit einer Ammonshornsklerose (AHS) einher. Die AHS ist durch Verlust an Nervenzellen und strukturelle Veränderungen der Astrozyten (Gliose) charakterisiert. Wir vermuteten, dass diese Astrozyten ihre Fähigkeit verloren haben, Kaliumionen mittels bariumsensitiver K+-Kanäle aufzunehmen und umzuverteilen. Deshalb untersuchten wir die Wirkung von Barium auf evozierte Anstiege der extrazellulären Kaliumkonzentration (K+)o im Hippokampusgewebe von Epilepsiepatienten, epileptischen Ratten und nichtepileptischen Kontrollratten. Methodik: Die Veränderungen evozierter K+-Signale durch Barium wurden mit Hilfe zweikanaliger K+-selektiver Referenz Mikroelektroden in der CA1-Region akuter Hirnschnitte aus Hippokampusresektaten mit und ohne AHS und aus dem Hippokampus von Ratten (mit chronischer Epilepsie [Pilokarpin-Modell], mit Kindling-Epilepsie und ohne Epilepsie) gemessen. Die Auslösung der Signale erfolgte durch repetitive elektrische Reizung des Alveus oder durch K+-Iontophorese. Ergebnisse: Barium verursachte eine Vergrößerung iontophoretisch evozierter K+-Signale in der CA1 von Kontrolltieren und von Hippokampusresektaten ohne AHS. Barium vergrößerte auch die durch antidrome Reizung ausgelösten K+-Signale in der nichtsklerotischen CA1 von Epilepsiepatienten, Ratten mit Kindling-Epilepsie und Kontrollratten. Im Gegensatz dazu war in der CA1 von Resektaten mit AHS und im Gewebe chronisch epileptischer Ratten der Bariumeffekt nicht nachweisbar bzw. stark verringert. Schlussfolgerungen: Der Bariumeffekt auf die evozierten K+-Signale reflektiert die gliale Pufferkapazität für die während neuronaler Aktivität freigesetzten Kaliumionen. Das Fehlen des Bariumeffektes bei humaner TLE mit AHS lässt auf eine Verminderung der glialen Pufferkapazität und damit auf eine mögliche Störung der K+-Regulation schließen.

Introduction: Pharmacoresistant mesial temporal lobe epilepsy (mTLE) is frequently accompanied by Ammon's horn sclerosis (AHS), characterised by nerve cell loss and structural alteration of astrocytes ("gliosis"). We supposed that such astrocytes may have lost their capability to take up and to redistribute potassium ions by barium-sensitive K+-channels, and hence we investigated the effects of barium on evoked rises of (K+)(o) in hippocampal tissue of epilepsy patients, epileptic rats and control rats. Methods: Changes of evoked K+ signals by barium were measured using double-barrelled K+ selective reference microelectrodes placed into the CA1-region of brain slices from hippocampal specimens with and without AHS, from hippocampi of chronic epileptic rats (Pilocarpine-model), rats with Kindling epilepsy, or control rats. The K+ signals were elicited by repetitive electrical simulation of the alveus or by K+ ionophoresis. Results: Barium caused an augmentation of ionophoretically evoked K+ signals in the CA1 pyramidal cell layer from control rats and from hippocampal specimens without AHS but not from those with AHS. Barium also augmented K+ signals elicited by antidromic stimulation in the non-sclerotic CA1 of epilepsy-patients, of rats with Kindling epilepsy, and control rats. In contrast, the barium effect was strongly reduced in the CA1 of hippocampal specimens with AHS and of hippocampal tissue of pilocarpine treated chronic epileptic rats. Conclusions: The effect of barium on evoked K+ signals reflects the glial K+ buffer capacity for potassium ions released during neuronal activity. The very small effect of barium on K+ signals in human TLE with AHS indicates a loss of buffer capacity and, thereby, a possible alteration of the K+ regulation.

c-Jun N-terminal kinases (JNKs) regulate gene expression by phosphorylating transcription factors, such as c-Jun. Studies with JNK: knockout mice suggest that JNK activity may be required for excitotoxin-induced apoptosis in the adult hippocampus and for apoptosis in the developing embryonic neural tube. Here we investigate the role of JNKs in classical neurotrophin-regulated developmental neuronal death by using nerve growth factor (NGF)-dependent sympathetic neurones. In this system, NGF withdrawal leads to an increase in JNK activity, an increase in c-Jun protein levels and c-Jun N-terminal phosphorylation before the cell death commitment point, and c-Jun activity is required for cell death. To inhibit JNK activity in sympathetic neurones we have used two different JNK inhibitors that act by distinct mechanisms: the compound SB 203580 and the JNK binding domain (JBD) of JNK interacting protein 1 (JIP-1). We demonstrate that JNK activity is required for c-Jun phosphorylation, c-jun promoter activation and NGF withdrawal-induced apoptosis. We also show that ATF-2, a c-Jun dimerization partner that can regulate c-jun gene expression, is activated following NGF deprivation. Finally, by co-expressing the JBD and a regulatable c-Jun dominant negative mutant we demonstrate that JNK and AP-1 function in the same pro-apoptotic signalling pathway after NGF withdrawal.

Neuronal fibres of the hippocampal formation of normal and chronic epileptic rats were investigated by fluorescent tracing methods using the pilocarpine model of limbic epilepsy. Two months after onset of spontaneous limbic seizures, hippocampal slices were prepared and maintained in vitro for 10 h. Small crystals of fluorescent dye [fluorescein (fluoro-emerald (R)) and tetramethylrhodamine (fluoro-ruby (R))] were applied to different hippocampal regions. The main findings were: (i) in control rats there was no supragranular labelling when the mossy fibre tract was stained in stratum radiatum of area CA3. However, in epileptic rats a fibre network in the inner molecular layer of the dentate gyrus was retrogradely labelled; (ii) a retrograde innervation of area CA3 by CA1 pyramidal cells was disclosed by labelling remote CA1 neurons after dye injection into the stratum radiatum of area CA3 in chronic epileptic rats; (iii) labelling of CA1 neurons apart from the injection site within area CA1 was observed in epileptic rats but not in control animals; and (iv), a subicular-hippocampal projection was present in pilocarpine-treated rats when the tracer was injected just below the stratum pyramidale of area CA1. The findings show that fibre rearrangement in distinct regions of the epileptic hippocampal formation can occur as an aftermath of pilocarpine-induced status epilepticus.

Summary: Purpose: Comparison of extracellular K+ regulation in sclerotic and nonsclerotic epileptic hippocampus. Methods: Measurements of K+ signals with double‐barreled K+‐selective reference microelectrodes in area CA1 of slices from human and rat hippocampus, induction of increases in extracellular potassium concentration by repetitive alvear stimulation or iontophoresis, and block of inward‐rectifying and background K+ channels in astrocytes by barium. Results: In the CA1 pyramidal layer from normal rat hippocampus, barium augmented extracellular K+ accumulation induced by iontophoresis or antidromic stimulation in a dose‐dependent manner. Similarly, barium augmented stimulusinduced K+ signals from nonsclerotic hippocampi (human mesial temporal lobe epilepsy). In contrast, barium failed to do so in sclerotic hippocampi (human mesial temporal lobe epilepsy, rat pilocarpine model). Conclusions: Our findings suggest that in areas of reduced neuronal density (hippocampal sclerosis), glial cells adapt to permit rather large increases in extracellular potassium accumulation. Such increases might be involved in the transmission of activity through the sclerotic area.

In the hippocampus of patients with therapy‐refractory temporal lobe epilepsy, glial cells of area CA1 might be less able to take up potassium ions via barium‐sensitive inwardly rectifying and voltage‐independent potassium channels. Using ion‐selective microelectrodes we investigated the effects of barium on rises in [K+]o induced by repetitive alvear stimulation in slices from surgically removed hippocampi with and without Ammon's horn sclerosis (AHS and non‐AHS). In non‐AHS tissue, barium augmented rises in [K+]o by 147% and prolonged the half time of recovery by 90%. The barium effect was reversible, concentration dependent, and persisted in the presence of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionate (AMPA), N‐methyl‐d‐aspartate (NMDA) and γ‐aminobutyric acid [GABA(A)] receptor antagonists. In AHS tissue, barium caused a decrease in the baseline level of [K+]o. In contrast to non‐AHS slices, in AHS slices with intact synaptic transmission, barium had no effect on the stimulus‐induced rises of [K+]o, and the half time of recovery from the rise was less prolonged (by 57%). Under conditions of blocked synaptic transmission, barium augmented stimulus‐induced rises in [K+]o, but only by 40%. In both tissues, barium significantly reduced negative slow‐field potentials following repetitive stimulation but did not alter the mean population spike amplitude. The findings suggest a significant contribution of glial barium‐sensitive K+‐channels to K+‐buffering in non‐AHS tissue and an impairment of glial barium‐sensitive K+‐uptake in AHS tissue.

There has been considerable interest in the molecular mechanisms of apoptosis in mammalian neurons because this form of neuronal cell death is important for the normal development of the nervous system and because inappropriate neuronal apoptosis may contribute to the pathology of human neurodegenerative diseases. The aim of recent research has been to identify the key components of the cell death machinery in neurons and understand how the cell death programme is regulated by intracellular signalling pathways activated by the binding of neurotrophins or death factors to specific cell surface receptors. The aim of this commentary was to review research that has investigated the role of the Jun N-terminal kinase (JNK)/c-Jun signalling pathway in neuronal apoptosis, focusing in particular on work carried out with developing sympathetic neurons. Experiments with sympathetic neurons cultured in vitro, as well as with cerebellar granule neurons and differentiated PC12 cells, have demonstrated that JNK/c-Jun signalling can promote apoptosis following survival factor withdrawal. In addition, experiments with Jnk(-/-) knockout mice have provided evidence that Jnk3 may be required for apoptosis in the hippocampus in vivo following injection of kainic acid, an excitotoxin, and that Jnk1 and Jnk2 are required for apoptosis in the developing embryonic neural tube. However, in the embryonic forebrain, Jnk1 and Jnk2 have the opposite function and are necessary for the survival of developing cortical neurons. These results suggest that JNKs and c-Jun are important regulators of the cell death programme in the mammalian nervous system, but that their biological effects depend on the neuronal type and stage of development.

Summary: Purpose: Neuronal network reorganization might be involved in epileptogenesis in human and rat limbic epilepsy. Apart from aberrant mossy fiber sprouting, a more wide‐spread fiber rearrangement in the hippocampal formation might occur. Therefore, we studied sprouting in area CA1 because this region is most affected in human temporal lobe epilepsy. Methods: In slices from hippocampi of patients operated on for temporal lobe epilepsy (n = 134), from pilocarpine‐treated rats (n = 74), and from control rats (n = 15), viable neurons were labeled with fluorescent dextran amines. Results: In human hippocampi as well as in pilocarpine‐treated rats, the degree of nerve cell loss varied. In 67 of 134 slices from human specimens with distinct Ammon's horn sclerosis and in 23 of 74 slices from pilocarpine‐treated rats, a severe shrunken area CA1 presented with a similar picture: few damaged neurons were labeled, and aberrant fiber connections were not visible. This was in contrast to human resected hippocampi and hippocampi from pilocarpine‐treated rats with no or moderate loss of neurons. In these cases, pyramidal cells remote from the injection site were labeled (human tissue, n = 59 of 134; pilocarpine‐treated rats, n = 39 of 74). In human resected hippocampi without obvious pathology and in control animals, no pyramidal neurons were labeled apart from the injection site. Conclusions: Axon collaterals of CA1 pyramidal cells are increased in human temporal lobe epilepsy and in pilocarpine‐treated rats. Adjacent CA1 pyramidal cells project via aberrant collaterals to the stratum pyramidale and the stratum radiatum of area CA1. This network reorganization can contribute to hyperexcitability via increased backward excitation.

Conference Abstract| October 01 1999 c-Jun and Bax: regulators of programmed cell death in developing neurons A. Eilers; A. Eilers 1Eisai London Research Laboratories, University College London, Gower Street, London WC1E 6BT Search for other works by this author on: This Site PubMed Google Scholar J. Whitfield; J. Whitfield 1Eisai London Research Laboratories, University College London, Gower Street, London WC1E 6BT Search for other works by this author on: This Site PubMed Google Scholar K. Vekrellis; K. Vekrellis 1Eisai London Research Laboratories, University College London, Gower Street, London WC1E 6BT Search for other works by this author on: This Site PubMed Google Scholar S. J. Neame; S. J. Neame 1Eisai London Research Laboratories, University College London, Gower Street, London WC1E 6BT Search for other works by this author on: This Site PubMed Google Scholar B. Shah; B. Shah 1Eisai London Research Laboratories, University College London, Gower Street, London WC1E 6BT Search for other works by this author on: This Site PubMed Google Scholar J. Ham J. Ham 1Eisai London Research Laboratories, University College London, Gower Street, London WC1E 6BT Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (1999) 27 (5): A135. https://doi.org/10.1042/bst027a135c Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Cite Icon Cite Get Permissions Citation A. Eilers, J. Whitfield, K. Vekrellis, S. J. Neame, B. Shah, J. Ham; c-Jun and Bax: regulators of programmed cell death in developing neurons. Biochem Soc Trans 1 October 1999; 27 (5): A135. doi: https://doi.org/10.1042/bst027a135c Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search This content is only available as a PDF. © 1999 Biochemical Society1999 Article PDF first page preview Close Modal You do not currently have access to this content.

Immature glia may not be able to buffer K+ ions released during neuronal activity. Therefore, we investigated entorhinal-hippocampal slices of juvenile rats (ages P15-18 and P22-26) using a perfusion medium containing 2 mM BaCl2 in order to block glial inward rectifying and leak potassium channels. In contrast to adult animals, rises in [K+]o in slices from juvenile animals elicited by repetitive alvear stimulation were not augmented by Ba2+. Ba2+ effects on fast field potentials, slow field potentials and the applied current sink source distribution were roughly similar as in adult rats. We conclude that the capacity to buffer large quantities of K+ ions by mechanisms involving Ba2+-sensitive K+ channels has not yet developed in juveniles.