Killing of rat adenocarcinoma 13762 in situ by adoptive transfer of CD4+ anti-tumor T cells requires tumor expression of cell surface MHC class II molecules

Cerebrovascular disease exemplifies the poor regenerative capacity of the CNS. While there are methods to prevent cerebral infarction, there is no effective therapy available to ameliorate the anatomical, neurochemical and behavioral deficits which follow cerebral ischemia. Focal and transient occlusion of the middle cerebral artery (MCA) in rodents has been reported to result in neuropathology similar to that seen in clinical cerebral ischemia. Using specific techniques, this MCA occlusion can result in a well-localized infarct of the striatum. This review article will provide data accumulated from animal studies using the MCA occlusion technique in rodents to examine whether neural transplantation can ameliorate behavioral and morphological deficits associated with cerebral infarction. Recent advances in neural transplantation as a treatment modality for neurodegenerative disorders such as Parkinson's disease, have revealed that fetal tissue transplantation may produce neurobehavioral recovery. Accordingly, fetal tissue transplantation may provide a potential therapy for cerebral infarction. Preliminary findings in rodents subjected to unilateral MCA occlusion, and subsequently transplanted with fetal striatal tissue into the infarcted striatum have produced encouraging results. Transplanted fetal tissue, assessed immunohistochemically, has been demonstrated to survive and integrate with the host tissue, and, more importantly, ameliorate the ischemia-related behavioral deficits, at least in the short term. Although, this review will focus primarily on cerebral ischemia, characterized by a localized CNS lesion within the striatum, it is envisioned that this baseline data may be extrapolated and applied to cerebral infarction in other brain areas.     

Sertoli cell transplants: their use in the treatment of neurodegenerative disease

The efficacy of treating neurodegenerative diseases with the transplantation of fetal tissue has been demonstrated in animal models of Parkinson's disease, Huntington's disease and stroke. In the clinical setting, neural transplantation as a treatment for patients with Parkinson's disease has shown promising results. However, for this treatment method to be effective neuronal survival needs to be improved through either trophic support or localized immunoprotection. Co-transplanting Sertoli cells, which express many nutritive, regulatory, trophic and immunosuppressive factors, with fetal neural cells could provide both of these requirements. Such a strategy could enhance the recovery benefits associated with transplantation and decrease the need for, and the risks associated with, long-term systemic immunosuppression.     

Effects of combined BDNF and GDNF treatment on cultured dopaminergic midbrain neurons

Neural transplantation is an experimental therapy for Parkinson's disease. Pretreatment of fetal donor tissue with neurotrophic factors may improve survival of grafted dopaminergic neurons. Free-floating roller tube cultures of fetal rat ventral mesencephalon were treated with brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), or a combination of both. Dopamine content of the culture medium, the number of tyrosine hydroxylase-immunoreactive neurons, and culture volumes were moderately increased in the BDNF- and GDNF-treated cultures but significantly increased by 6.8-, 3.2- and 2.4-fold, respectively after treatment with the combination of both factors. We conclude that pretreatment of dopaminergic tissue in culture with a combination of BDNF and GDNF may be an effective means to improve the quality of tissue prior to grafting.     

Testis-derived Sertoli cells survive and provide localized immunoprotection for xenografts in rat brain

Transplantation of neural tissue into the mammalian central nervous system has become an alternative treatment for neurodegenerative disorders such as Parkinson's disease. Logistical and ethical problems in the clinical use of human fetal neural grafts as a source of dopamine for Parkinson's disease patients has hastened a search for successful ways to use animal dopaminergic cells for human transplantation. The present study demonstrates that transplanted testis-derived Sertoli cells into adult rat brains survive. Furthermore, when cotransplanted with bovine adrenal chromaffin cells (xenograft), Sertoli cells produce localized immunoprotection, suppress microglial response and allow the bovine cells to survive in the rat brain without continuous systemic immunosuppressive drugs. These novel features support Sertoli cells as a viable graft source for facilitating the use of xenotransplantation for Parkinson's disease and suggest their use as facilitators, (i.e., localized immunosuppression) for cell transplantation in general.     

Growth/differentiation factor 5 and glial cell line-derived neurotrophic factor enhance survival and function of dopaminergic grafts in a rat model of Parkinson's disease

Growth/differentiation factor 5 is a member of the transforming growth factor beta superfamily, which has neurotrophic and neuroprotective effects on dopaminergic neurons both in vitro and in vivo. Here we investigate the effects of growth/differentiation factor 5 on foetal mesencephalic grafts transplanted into a rat model of Parkinson's disease, and compare them with those of glial cell line-derived neurotrophic factor. Mesencephalic tissue was suspended in solutions containing either growth/differentiation factor 5 or glial cell line-derived neurotrophic factor prior to transplantation into the left striatum of rats with 6-hydroxydopamine lesions of the left medial forebrain bundle. Both proteins enhanced graft-induced compensation of amphetamine-stimulated rotations. Positron emission tomography studies showed that both neurotrophins increased graft-induced recovery of striatal binding of [11C]RTI-121, a marker for dopaminergic nerve terminals. Post mortem analysis at 8 weeks after transplantation showed that both neurotrophins significantly increased the survival of grafted dopaminergic neurons. This study shows that growth/differentiation factor 5 is at least as effective as glial cell line-derived neurotrophic factor in enhancing the survival and functional activity of mesencephalic grafts, and thus is an important candidate for use in the treatment of Parkinson's disease.     

Review of Geriatric rehabilitation.

Reviews the book, Geriatric Rehabilitation, edited by Bryan Kemp, Kenneth Brummel-Smith, and Joseph W. Ramsdell (1989). There is an increasing need for rehabilitation services for older adults and, consequently, a growing need for texts about geriatric rehabilitation. Compiling a single volume that effectively covers this diverse area is a challenge. Rehabilitation is not so much a specialized field of knowledge as it is an approach to health care focusing on the restoration of function. A text on geriatric rehabilitation therefore needs to include information on common disabling conditions of the elderly, therapeutic strategies used by a variety of disciplines including medicine, psychology, and physical and occupational therapy, and a conceptual framework for integrating misinformation. Geriatric Rehabilitation was created to provide such a text and, in general, has done so successfully. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Introduction of integrated care pathways for patients with multiple sclerosis in an inpatient neurorehabilitation setting

Rehabilitation of progressive neurological disorders such as multiple sclerosis poses particular problems, and clear setting of goals and clinical audit are essential for effective management. Integrated care pathways (ICPs) offer a unique opportunity to document and audit the rehabilitation process. This preliminary study has shown that ICPs are useful in both assessing process and auditing goals. Their introduction has led to the identification of the key worker role within the neurorehabilitation unit (NRU), and has provided an opportunity to increase the participation of patients and carers in the rehabilitation process. Continuing refinement of the pathway is necessary, and its application to other neurological disorders such as cerebrovascular accident may be appropriate.     

A scientific rationale for protective therapy in Parkinson's disease

The desire to introduce neuroprotective therapy for Parkinson's disease has begun to focus attention on pathogenetic mechanisms responsible for cell death. Considerable theory and some evidence have now accumulated to suggest that factors related to oxidative stress, mitochondrial bioenergetic defects, excitatory neurotoxicity, calcium cytotoxicity, and trophic factor deficiencies acting either singularly or in combination may contribute to the development of cell death in Parkinson's disease. A better understanding of the specific pathogenetic mechanism involved in cell degeneration might provide a scientific basis for testing a putative neuroprotective therapy. This chapter reviews the theory and evidence in support of these different mechanisms and possible strategies that might provide neuroprotection and interfere with the natural progression of Parkinson's disease.     

Simultaneous transplantation of fetal mesencephalic cells to the striatum and globus pallidus of rats with lesions induced by 6-hydroxydopamine

INTRODUCTION: Studies of neural transplants in experimental models of Parkinson's disease have concentrated their attention on ectopic transplants of foetal mesencephalic cells to denervated striatum. However, the external globus pallidus has recently been shown to play an important part in the physiopathology of this disease. OBJECTIVE: Bearing in mind the importance of loss of extra-striatal dopamine in the genesis of the clinical signs found in parkinsonism, the objective of this study was to evaluate the effect of foetal mesencephalic transplantation to the globus pallidus of hemiparkinsonian rats. MATERIAL AND METHODS: Following conventional transplantation methodolgy, suspensions of cells from the ventral mesencephalum of rat embryos (E-14) were implanted. The tissue was grafted into the striatum, pallidum-striatum and pallidum areas of rats with unilateral lesions of the striatonigral bundle. One, two, three and six months after transplantation, the rotatory activity induced by D-amphetamine was evaluated. The rotatory behaviour induced by apomorphine was evaluated at three months. Motor ability of the front legs was evaluated in all experimental groups three months after transplantation using the 'ladder test'. RESULTS: In the experimental groups in which a transplant was made to the globus pallidus there was a significant reduction (p < 0.01) in rotatory activity induced by D-amphetamine and by apomorphine as compared with the non-transplanted groups. CONCLUSIONS: Transplants of foetal dopaminergic cells survive in the globus pallidus of hemiparkinsonian rats and can improve the rotational activity induced by dopaminergic agonists.     

Identification of disease genes and somatic gene therapy: an overview and prospects for the aged

Positional cloning strategies for identification of disease genes include genetic linkage analysis in disease families and identification of individuals in whom the disease is associated with a specific chromosomal anomaly. Once a genomic region likely to contain the disease gene has been identified, overlapping genomic clones are isolated and the candidate gene sought. Somatic gene therapy entails introduction of the cloned gene into somatic cells to either replace genetically defective functions or alter pathological disease processes. Transfer of the gene may be accomplished by either DNA- or viral-mediated methods into a variety of tissue targets. Once the success and reliability of ongoing gene therapy trials for various human diseases is established, it may then be considered in the prevention and treatment of chronic, disabling diseases such as Alzheimer's disease, Parkinson's disease, arthritis, and diabetes as well as intervention of immunosenescence, when the relevant genes have been cloned. Ethical considerations for gene therapy for aging are similar to those for gene therapy in general. In addition, the ethics of gene therapy for treating diseases versus intervention of the normal aging process must be considered.     

Lung transplantation for pulmonary sarcoidosis

Patients with end-stage sarcoidosis have now undergone lung transplantation successfully with good short-term and intermediate-term results. Lung transplantation for sarcoidosis requires several considerations unique to this disease. Selection of pulmonary sarcoidosis patients for transplantation requires that medical therapy has been exhausted. This may involve the use of corticosteriods and alternative medications. Causes of pulmonary dysfunction other than pulmonary sarcoidosis, such as bronchiectasis and myocardial sarcoidosis, must be excluded before candidates are considered for transplantation. The extent and severity of extrapulmonary disease must also be assessed and may preclude lung transplantation. The presence of mycetomas is considered a relative contra-indication by some transplant centres and an absolute contra-indication by others. Relatively few patients with pulmonary sarcoidosis have undergone transplantation and, therefore, there are few data on outcome. Sarcoidosis frequently recurs in the allograft, but rarely causes symptoms or pulmonary dysfunction. More severe acute rejection episodes may occur in sarcoidosis transplant recipients, although at present there is no evidence of an increased risk of obliterative bronchiolitis or increased mortality.     

Physiologic studies of spinal inhibitory circuits in patients with stiff-person syndrome

Human protoporphyria results from mutations in the ferrochelatase gene. Heritable deficiency of ferrochelatase causes overproduction of protoporphyrin IX, principally in the erythron. Photosensitivity is a universal feature of protoporphyria but hepatic clearance of the hydrophobic protoporphyrin molecule with excretion in bile may lead to precipitation within biliary pathways. Thus cholestatic injury and protoporphyrin gallstones occur. Minor hepatic abnormalities are frequent, but at least 30 patients have been reported with a progressive liver disease that requires transplantation. Fulminant hepatic disease appears to be recessively inherited in some pedigrees. Hazards of liver transplantation include tissue photolysis, hemolysis, and an unexplained neurological syndrome, but most of the 15 patients reported after transplantation have survived for several months to > 6 years. Aspects of protoporphyria, its pathogenesis and contemporary therapeutic strategies are considered, with emphasis on hepatic sequelae.     

Treatment and outcome of patients with acute myocardial infarction and prior cerebrovascular events in the thrombolytic era: the Israeli Thrombolytic National Survey

Changes in sleep after fetal preoptic (POA) tissue transplantation were studied in rats which had been made insomniac by a medial preoptic area (mPOA) lesion. Two days after the N-methyl D-aspartic acid (NMDA) lesion of the mPOA, fetal POA tissues (obtained from 14- to 17-day-old fetuses) were transplanted into the lesioned mPOA. Insomnia was less marked in these animals, as compared to nontransplanted lesioned rats, even on the 4th day after transplantation. The quantum of sleep nearly attained the prelesion level by the 20th day. Body weight also showed recovery after transplantation. Rectal temperature, which was increased by the lesion of the mPOA, remained unaltered even after the transplantation. These results suggest that the recovery of sleep and rectal temperature may follow different time courses. Surviving transplanted neurons were seen at the site of lesion on postmortem examination. Humoral interaction between the host and the transplant may be responsible for the early recovery of sleep, though the establishment of neural connections between the host and transplant might have contributed to the later recovery. This is the first study to show the recovery of sleep function in insomniac animals after fetal preoptic tissue transplantation. However, the specificity of the POA fetal tissue, in comparison with other neural tissues to promote sleep recovery, remains to be established.     

Neurosurgical interventions in the treatment of idiopathic Parkinson disease: neurostimulation and neural implantation

With the exception of thalamotomy for drug-refractory tremor, surgical therapy for Parkinson's disease has been almost abandoned as treatment for Parkinsonian symptoms between 1965 and 1985. Reasons for this development relate to inconsistent postoperative results, complications associated with stereotactic surgical techniques and, most importantly, the advent of levodopa, which is still considered to be the gold standard in pharmacotherapy for Parkinson's disease. However, both, the long-term experience with L-DOPA therapy on the one hand and the progress of advanced stereotactic techniques and fetal graft research on the other hand have lead to reconsideration of surgical therapy in Parkinson's disease for patients, who can not be treated satisfactorily with medication. Both lesions (via thermocoagulation) and/or neurostimulation (via chronic intracerebral implantation of electrodes) in thalamic nuclei (nucleus ventralis oralis posterior/intermedialis thalami; VOP/VIM) may alleviate rest tremor in PD patients. In principle neurostimulation has the significant advantage of reversibility with regard to side effects in comparison to lesion surgery. Furthermore ventro-posterior pallidotomy or chronic stimulation in this structures may ameliorate bradykinesia and levodopa-induced dyskinesias. Additionally, "switching-off" the subthalamic nucleus by neurostimulation has been reported to reduce rigidity, bradykinesia and levodopa-induced ON-OFF-fluctuations. On the other hand, neuronal transplantation of fetal nigral dopamine precursor cells aims at restoring the striatal dopamine deficit. Both animal and clinical experiments have shown that fetal grafts survive intrastriatal transplantation and may ensue moderate to satisfactory improvements, especially in regard to bradykinesia and ON-OFF-fluctuations. Further progress in the field of neuronal transplantation will largely depend on the development of alternative cell resources.     

Cancer metastasis: a search for therapeutic inhibition

Parkinson's disease (PD) has no cure and is a progressive neurological disorder with treatment aimed at the maintenance of function and limitation of the symptoms. No extensive studies of the disease's impact on health-related quality of life (HRQoL) have been conducted. The purpose of this study was to assess the potential usefulness of the Medical Outcomes Study Short Form (SF-36) and the Functional Status Questionnaire (FSQ) in Parkinson's disease research. This cross-sectional study of 193 PD patients who visited two hospital-based neurology clinics used self-administered in-clinic and take-home questionnaires to ascertain the demographic and environmental characteristics of the subjects and to gain health profile measures from the SF-36 and the FSQ. The two health profiles provide important HRQoL information supplementary to the traditional signs and symptoms evaluated by the Unified Parkinson's Disease Rating Scale (UPDRS). Many of the HRQoL measures discriminate progressive stages of disease in this study group and distinguish those with complications of therapy from subjects without complications.     

Developmental subtypes of juvenile bipolar disorder

The incidence of hip fractures has increased over the past decades, and for patients with hip fractures, medical and social conditions have deteriorated during the same time. In this study the results of orthopaedic rehabilitation of patients with Parkinson's disease and a hip fracture are compared with those in all other hip fracture patients. A total of 74 patients with Parkinson's disease and hip fracture were compared with 1,361 patients without the disease. Prior to fracture, patients with Parkinson's disease were less likely to be living an independent life in their own homes. Postoperatively women with Parkinson's disease were hospitalized for a significantly longer period. Postoperative rehabilitation was significantly slower and less successful than among patients without the disease. Patients with Parkinson's disease comprise a subgroup of hip fracture patients who need more rehabilitation resources than can easily be provided at an ordinary orthopaedic ward. A team-work between an orthopaedic surgeon, a neurologist and a rehabilitation unit seems to be mandatory in order to achieve shorter hospitalization and earlier return to the pre-fracture environment.     

Effects of Parkinsonism on motor control

Parkinson's disease, which pathology results predominantly from nigros triatal pathway damage, has been associated with motor dysfunction due to basal ganglia impairment. It is argued that the variability seen within and between individual patients through the course of this neurological disorder may result from abnormal non-uniform neurotransmitter levels as well as functional segregation of neural populations in the basal ganglia. We review evidence that the wide spectrum of motor impairments observed in Parkinsonism may be due to a reduced capability of neurochemical modulation of pallido-thalamocortical activities that impairs movement implementation and execution.     

Impact of metyrapone on MK-801-induced alterations in the rat dopamine D1 receptors

The control of cytomegalovirus infection and disease continues to be a major problem in transplantation and different strategies have been developed to reduce its incidence. Early diagnosis of infection soon after transplantation, using molecular tools such as the polymerase chain reaction, have resulted in successful clinical trials using the strategy of pre-emptive therapy. Adoptive transfer of immune cells, which are predominantly the cytomegalovirus-specific cytotoxic T lymphocytes, into transplant recipients has been shown to restore effective immunity. A vaccine preparation has been in development aimed at preventing primary infections in allograft recipients though effective protection has yet to be shown. The mechanisms of viral pathogenesis in chronic graft rejection remain unclear; however, recent contributions from the field of cell biology have increased our understanding of possible processes which have the potential for application in the field of gene therapy for the treatment of disease.     

Indications and relative indications for stem cell transplantation in non-Hodgkin's lymphoma

High dose chemotherapy with or without total body irradiation and autologous stem cell rescue has proven to be effective treatment to cure patients with relapsed intermediate grade and high grade non-Hodgkin's lymphoma. Important factors for selection of candidates most likely to do well with these approaches include patients whose disease is responsive to conventional therapy and those who have minimal disease volume at the time of transplant. The treatment-related mortality of autologous stem cell transplantation has diminished from 20% to less than 5% with improved supportive care and selection of patients with less advanced disease. Although the treatment-related mortality of allogeneic stem cell transplantation may be as high as 20-40%, a graft versus lymphoma effect may decrease relapse with the result that overall survival is not substantially different between autologous and allogeneic transplantation. The definitive indications for stem cell transplantation include patients who have relapsed with intermediate or high grade NHL. Relative indications include intermediate/high grade non-Hodgkin's lymphoma patients, "high risk" first complete remission (CR), resistant relapse; low grade non-Hodgkin's lymphoma in sensitive or resistant relapse, advanced disease (sensitive or resistant relapse, transformation), first CR (younger patients). Relative contraindications include specific patient profiles such as bulky high grade lymphoma which progresses on appropriate conventional therapy, poor performance status, active serious infection, serious cardiac, renal, pulmonary or liver dysfunction, active, central nervous system (CNS) disease unresponsive to cranial irradiation/intrathecal therapy. For patients with previous marrow involvement or active marrow involvement at the time of harvest or transplant, "purged" autografts, peripheral blood stem cell transplantation and allografts have been used successfully.     

Myelodysplastic syndrome as a late complication following autologous bone marrow transplantation for non-Hodgkin's lymphoma

PURPOSE: To determine the incidence, natural history, and risk factors associated with myelodysplastic syndrome (MDS) occurring as a late complication following autologous bone marrow transplantation for patients with non-Hodgkin's lymphoma. METHODS: We retrospectively reviewed the charts of all 262 patients who underwent autologous bone marrow transplantation for non-Hodgkin's lymphoma at the Dana-Farber Cancer Institute from 1982 through 1991. Although patients received a variety of treatments before they were eligible for transplant, identical myeloablative therapy (cyclophosphamide 60 mg/kg/d for 2 days plus total-body irradiation twice daily for 3 days) was administered in each case. By collecting data on pretransplant and early posttransplant variables, we attempted to identify risk factors for the development of MDS. RESULTS: The crude overall incidence of posttransplant MDS or acute myeloid leukemia (AML) was 7.6%. The actuarial risk at 6 years was 18% +/- 9%. The median time of onset was 31 months (range, 10 to 101) after transplant or 69 months (range, 27 to 141) after initial treatment for lymphoma. Pretreatment variables predictive for the development of MDS (univariate analysis) included prolonged interval between initial treatment and the transplant procedure (P = .003), increased duration of exposure to chemotherapy (P = .019) or to alkylating agents (P = .045), and use of radiation therapy (P = .032) or pelvic radiation (P = .003) before transplant. CONCLUSION: MDS is a potential complication of autologous bone marrow transplantation for non-Hodgkin's lymphoma; bone marrow stem-cell damage sustained before the transplant may be the most important risk factor.