High prevalence of malignant melanoma in Israeli patients with Parkinson's disease.

The risk of melanoma is higher in patients with Parkinson's disease (PD) than in the general population. Whether the association is disease related or treatment related is unclear. The objective of this study was to assess melanoma prevalence in PD patients in Israel using active dermatologic screening. Consecutive patients with idiopathic PD were recruited by 12 Israeli centers. A movement disorder specialist assessed the severity of PD and obtained a medical, neurological, and medication history. Subsequently, a dermatologist assessed melanoma risk factors, recorded a dermatologic history, proactively performed a whole-body skin examination, and biopsied suspicious skin lesions. Of the enrolled patients (n = 1,395, mean age 69.5 ± 10.6 years, mean PD duration 7.3 ± 6.0 years), 95.3% were treated with dopaminergic agents. Biopsies revealed 8 patients with melanoma in situ and 1 with invasive malignant melanoma; 14 patients reported a melanoma prior to enrollment. The observed 5-year limited duration prevalence of melanoma in PD patients was 4.4 times greater (95% CI 2.6-7.6) than expected from melanoma prevalence in an age- and sex-matched cohort from the Israel National Cancer Registry. The increase was accounted for by an elevated prevalence of melanoma in situ [relative risk 12.5 (95% CI 6.7-23.2)]. Occurrence of melanoma did not correlate with levodopa therapy or time of onset of PD. Melanoma prevalence in PD patients was higher than expected in the general Israeli population. This was not related to levodopa treatment. PD patients should be actively screened for melanoma on a routine basis.

Regenerative effect of neural-induced human mesenchymal stromal cells in rat models of Parkinson's disease.

BACKGROUND: Human bone marrow multipotent mesenchymal stromal cells (hMSC), because of their capacity of multipotency, may provide an unlimited cell source for cell replacement therapy. The purpose of this study was to assess the developmental potential of hMSC to replace the midbrain dopamine neurons selectively lost in Parkinson's disease. METHODS: Cells were isolated and characterized, then induced to differentiate toward the neural lineage. In vitro analysis of neural differentiation was achieved using various methods to evaluate the expression of neural and dopaminergic genes and proteins. Neural-induced cells were then transplanted into the striata of hemi-Parkinsonian rats; animals were tested for rotational behavior and, after killing, immunohistochemistry was performed. RESULTS: Following differentiation, cells displayed neuronal morphology and were found to express neural genes and proteins. Furthermore, some of the cells exhibited gene and protein profiles typical of dopaminergic precursors. Finally, transplantation of neural-induced cells into the striatum of hemi-Parkinsonian rats resulted in improvement of their behavioral deficits, as determined by apomorphine-induced rotational behavior. The transplanted induced cells proved to be of superior benefit compared with the transplantation of naive hMSC. Immunohistochemical analysis of grafted brains revealed that abundant induced cells survived the grafts and some displayed dopaminergic traits. DISCUSSION: Our results demonstrate that induced neural hMSC may serve as a new cell source for the treatment of neurodegenerative diseases and have potential for broad application. These results encourage further developments of the possible use of hMSC in the treatment of Parkinson's disease.

Intravenous immunoglobulin treatment of experimental T cell-mediated autoimmune disease. Upregulation of T cell proliferation and downregulation of tumor necrosis factor alpha secretion.

It has been reported previously that intravenous administration of normal human immunoglobulins (IVIg) to human patients can suppress the clinical signs of certain autoimmune diseases. However, the mechanism(s) by which normal Ig interferes with the various disorders and the scheduling of treatment have been poorly delineated. To study these questions, we examined IVIg treatment of two experimentally induced T cell autoimmune diseases in rats: experimental autoimmune encephalomyelitis (EAE) and adjuvant arthritis (AA). We now report that IVIg treatment (0.4 g/kg) inhibited the active induction of both EAE and AA, and that this treatment did not affect the acquisition of resistance to reinduction of EAE. The importance of the site of administration and schedule of treatment were studied in the AA model. Ig was effective when given intravenously, but not when administrated subcutaneously or intraperitoneally. IVIg treatment was effective when given daily from immunization to outbreak of disease; but it was also effective when given once at the time of immunization or once 2 wk after induction of AA, just at the clinical outbreak of disease. Administration of IVIg between immunization and outbreak of AA was less effective. Prevention of disease by IVIg occurred despite the presence of T cell reactivity to the specific antigens in the disease. In fact, IVIg administrated to naive rats activated T cell reactivity to some self-antigens. Nevertheless, IVIg treatment led to decreased production of the inflammatory cytokine TNF alpha. Thus, IVIg treatment may exert its therapeutic power not by inhibiting T cell recognition of self-antigens, but by inhibiting the biological consequences of T cell recognition.

Intrastriatal transplantation of mouse bone marrow-derived stem cells improves motor behavior in a mouse model of Parkinson's disease.

Strategies of cell therapy for the treatment of Parkinson's disease (PD) are focused on replacing damaged neurons with cells to restore or improve function that is impaired due to cell population damage. In our studies, we used mesenchymal stromal cells (MSCs) from mouse bone marrow. Following our novel neuronal differentiation method, we found that the basic cellular phenotype changed to cells with neural morphology that express specific markers including those characteristic for dopaminergic neurons, such as tyrosine hydroxylase (TH). Intrastriatal transplantation of the differentiated MSCs in 6-hydroxydopamine-lesioned mice led to marked reduction in the amphetamine-induced rotations. Immunohistological analysis of the mice brains four months post transplantation, demonstrated that most of the transplanted cells survived in the striatum and expressed TH. Some of the TH positive cells migrated toward the substantia nigra. In conclusion, transplantation of bone marrow derived stem cells differentiated to dopaminergic-like cells, successfully improved behavior in an animal model of PD suggesting an accessible source of cells that may be used for autotransplantation in patient with PD.

Autotransplantation of bone marrow-derived stem cells as a therapy for neurodegenerative diseases.

Neurodegenerative diseases are characterized by a progressive degeneration of selective neural populations. This selective hallmark pathology and the lack of effective treatment modalities make these diseases appropriate candidates for cell therapy. Bone marrow-derived mesenchymal stem cells (MSCs) are self-renewing precursors that reside in the bone marrow and may further be exploited for autologous transplantation. Autologous transplantation of MSCs entirely circumvents the problem of immune rejection, does not cause the formation of teratomas, and raises very few ethical or political concerns. More than a few studies showed that transplantation of MSCs resulted in clinical improvement. However, the exact mechanisms responsible for the beneficial outcome have yet to be defined. Possible rationalizations include cell replacement, trophic factors delivery, and immunomodulation. Cell replacement theory is based on the idea that replacement of degenerated neural cells with alternative functioning cells induces long-lasting clinical improvement. It is reasoned that the transplanted cells survive, integrate into the endogenous neural network, and lead to functional improvement. Trophic factor delivery presents a more practical short-term approach. According to this approach, MSC effectiveness may be credited to the production of neurotrophic factors that support neuronal cell survival, induce endogenous cell proliferation, and promote nerve fiber regeneration at sites of injury. The third potential mechanism of action is supported by the recent reports claiming that neuroinflammatory mechanisms play an important role in the pathogenesis of neurodegenerative disorders. Thus, inhibiting chronic inflammatory stress might explain the beneficial effects induced by MSC transplantation. Here, we assemble evidence that supports each theory and review the latest studies that have placed MSC transplantation into the spotlight of biomedical research.

Recurrent hemorrhagic shoulder treated with hemiarthroplasty--a case report.

Recurrent hemorrhagic shoulder is a rare entity that is scarcely addressed in the literature. We describe a case of recurrent hemorrhagic shoulder and review treatment options for this unusual disorder.

Rasagiline as an adjunct to levodopa in patients with Parkinson's disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial.

BACKGROUND: Rasagiline mesylate is a novel drug for Parkinson's disease with selective, irreversible monoamine oxidase B (MAO-B) inhibitor activity, and is effective as monotherapy in early disease. This study investigated rasagiline efficacy and safety in levodopa-treated patients with Parkinson's disease and motor fluctuations. METHODS: In an 18-week, double-blind, multicentre (74 hospitals and academic centres in Israel, Argentina, and Europe) trial, 687 outpatients were randomly assigned to oral rasagiline (231 individuals; 1 mg once daily), entacapone (227; 200 mg with every levodopa dose), or placebo (229). Primary outcome was change in total daily off-time (intention-to-treat population). Other measures included the clinical global improvement (CGI) score and unified Parkinson's disease rating scale (UPDRS) scores. Analysis was by intention to treat. FINDINGS: 88 (13%) patients who were assigned treatment did not complete the study (23 rasagiline, 30 entacapone, 35 placebo), mainly because of withdrawal of consent (n=34) and adverse events (n=34). Both rasagiline and entacapone reduced mean daily off-time (-1.18 h rasagiline and -1.2 h entacapone vs placebo -0.4 h; p=0.0001, p<0.0001, respectively) and increased daily on-time without troublesome dyskinesia (0.85 h vs placebo 0.03 h; p=0.0005 for both). We recorded significant mean improvements in CGI scores (-0.86 rasagiline and -0.72 entacapone vs -0.37 placebo; p<0.0001, p=0.0002, respectively). Changes in UPDRS scores also significantly improved for activities of daily living during off-time (-1.71 and -1.38 vs placebo; p<0.0001, p=0.0006, respectively) and motor function during on-time (-2.94 and -2.73 vs placebo; both p<0.0001). Frequency of adverse events was similar for all treatments. INTERPRETATION: Once-daily rasagiline reduces mean daily off-time and improves symptoms of Parkinson's disease in levodopa-treated patients with motor fluctuations, an effect similar to that of entacapone.

Increased survival and migration of engrafted mesenchymal bone marrow stem cells in 6-hydroxydopamine-lesioned rodents.

Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra. Attempted replacement of these neurons by stem cells has proved inconclusive. Bone marrow mesenchymal stem cells (MSC) are multipotent, differentiating into a variety of cells, including neuron-like cells. We used the 6-hydroxydopamine (6-OHDA) animal model of Parkinson's disease to assess migration and differentiation of transplanted MSC. We found in rodents that transplanted MSC survive better in the 6-OHDA-induced damaged hemisphere compared to the unlesioned side. Moreover, contralaterally engrafted MSC migrated through the corpus callosum to populate the striatum, thalamic nuclei and substantia nigra of the 6-OHDA-lesioned hemisphere. In conclusion, we demonstrate that 6-OHDA-induced damage increases the viability of transplanted MSC and attracts these cells from the opposite hemisphere.

Amputation in patients with complex regional pain syndrome: a comparative study between amputees and non-amputees with intractable disease.

AIMS: Amputation in intractable cases of complex regional pain syndrome (CRPS) remains controversial. The likelihood of recurrent Complex Regional Pain Syndrome (CRPS), residual and phantom limb pain and persistent disability after amputation is poorly described in the literature. The aims of this study were to compare pain, function, depression and quality of life between patients with intractable CRPS who underwent amputation and those in whom amputation was considered but not performed. PATIENTS AND METHODS: There were 19 patients in each group, with comparable demographic details. The amputated group included 14 men and five women with a mean age of 31 years (sd 12) at the time of CRPS diagnosis. The non-amputated group consisted of 12 men and seven women and their mean age of 36.8 years (sd 8) at CRPS diagnosis. The mean time from CRPS diagnosis to (first) amputation was 5.2 years (sd 4.3) and the mean time from amputation to data collection was 6.6 years (sd 5.8). All participants completed the following questionnaires: Short-Form (SF) 36, Short Form McGill Pain questionnaire (SF-MPQ), Pain Disability Index (PDI), the Beck Depression Inventory (BDI) and a clinical demographic questionnaire. RESULTS: The amputation group showed consistently better results compared to the non-amputation group in the following parameters: median pain intensity (VAS): 80 (inter-quartile range (IQR) 13 to 92) vs 91 (IQR 85 to 100); p = 0.007; median SF-MPQ score 28 (IQR 9 to 35) vs 35 (IQR 31 to 38), p = 0.025; median PDI: 42 (IQR 11 to 64) vs 58 (IQR 50 to 62), p = 0.031; median BDI: 19 (IQR 5 to 28) vs 27 (IQR 21 to 32), p = 0.061 (borderline significant) and in six of the eight SF-36 domains. TAKE HOME MESSAGE: Amputation should be considered as a form of treatment for patients with intractable CRPS.

Dopamine-induced programmed cell death in mouse thymocytes.

Exposure of mouse thymocytes to dopamine caused apoptosis (programmed cell death). This was manifested by cellular condensation and membrane damage shown by flow cytometry measurements and scanning electron microscopic study. Dopamine also affected thymocytic nuclei and their genomic DNA integrity. Most of the DNA molecules accumulated in a subdiploid peak in flow cytometry analysis, indicating DNA fragmentation to small particles. DNA analysis showed the typical pattern of 'DNA ladder' caused by internucleosomal DNA cleavage. X-ray microanalysis of the cellular elements of dopamine-treated cells showed elevation of sodium (Na), chloride (Cl) and calcium (Ca) peaks, accompanied by reduction in phosphate (P) concentrations. Comparison of the potassium (K) and P concentrations showed significant differences between the two major death processes: necrosis (induced by exposure to sodium azide (NaN3)) and apoptosis (induced by dopamine). High concentrations of K indicated cell viability while reductions in P and elevations in Ca levels were found to be typical of apoptotic cell death. The antioxidant dithiothreitol (DTT) suppressed dopamine-induced apoptosis in thymocytes, suggesting that its toxicity may be mediated via generation of reactive oxygen radicals. Our study suggests that under certain circumstances, dopamine and/or its metabolites, may induce a process of apoptotic cell death of the dopamine-producing cells in the substantia nigra. Increased accessibility of dopamine to the nigral cell nucleus or inability to scavenge excess free radicals generated from dopamine oxidation triggering programmed cell death, may cause the progressive nigral degeneration in Parkinson's disease.

Integral therapeutic potential of bone marrow mesenchymal stem cells.

Bone marrow derived mesenchymal stem cells (MSC) are adult stem cells that reside within the bone marrow compartment. In the traditional developmental model, adult stem cells are able to differentiate only to the tissue in which they reside. Recent data have challenged the committed fate of the adult stem cells, presenting evidence for their multi-lineage differentiation potential. In addition, potential therapeutic benefits of MSC administration have been the main concern of much research, including clinical trials. These studies promote adult stem cell therapy by shedding some light on the therapeutic potential of MSC and their mechanism of action. Many doubts have found their way into MSC research. They question MSC potency and beneficial contribution. However, these obstacles should not arrest but set a challenge to MSC researchers to examine their achievements under a magnifying glass. Therapeutic benefits of MSC exogenous delivery do not run counter to its possible participation in endogenous repair. Several reports imply MSC involvement in physiological repair but no explicit data support this hypothesis. This review tries to put MSC research into perspective. Possible therapeutic applications of MSC therapy for damaged tissue replacement, tissue engineering and the underlying repair mechanisms will be discussed. In addition, reported data about MSC possible involvement in physiological multiple tissue repair, their homing to injury and site-specific differentiation will be presented.

The regional cerebral blood flow in patients under chronic hemodialytic treatment.

Regional cerebral blood flow (rCBF) was measured by the xenon-133 inhalation method in an unselected group of nine chronic hemodialysis patients before and after a single hemodialytic treatment. All patients underwent neurological, neuropsychological, and biochemical evaluations on the same occasions. Predialysis rCBF values did not differ from those obtained in age-matched normal controls. Following hemodialysis, there was a mild reduction in the rCBF by a mean of 7 +/- 2.6% (p = 0.02). The posthemodialysis rCBF reduction was not associated with any neurological or cognitive dysfunction. The causes of hemodialysis-induced rCBF decreases are unknown, but increased blood viscosity and biochemical changes, such as urea reduction and blood alkalinization, may play a role.

Effect of exercise on cerebral circulation.

The effect of supine physical exercise on cerebral blood flow (CBF) was measured in 30 normal subjects with the 133Xe inhalation technique. The CBF measurements were correlated to changes in PCO2, heart rate, and blood pressure, and to cardiac output and right atrial pressure in 10 of the subjects who underwent Swan-Ganz catheterization. No significant change was found in CBF during physical exercise, although a marked increase in cardiac output, blood pressure, and right atrial pressure and a mild decrease in PCO2 were found. Cerebrovascular resistance increased by 38%, in contrast to a decrease of 33% in the peripheral vascular resistance. The factors that affect the mechanism of cerebrovascular autoregulation during exercise are discussed.

Early-morning dystonia. A late side effect of long-term levodopa therapy in Parkinson's disease.

Four women with Parkinson's disease undergoing prolonged levodopa therapy had daily episodes of dystonic posturing, affecting one lower extremity, several years after initiation of treatment. The dystonia occurred only in the early morning, on awakening and before the first dose of levodopa, when the patients were in the akinetic-rigid state with no dyskinesias. It further interfered with gait, slowly subsided within one to two hours, and did not recur until next morning. This abnormal involuntary posture was unaffected by manipulations of daily levodopa dosage and schedule, completely disappeared after withdrawal of drug therapy, and recurred following its readministration. Additional adverse reactions including dyskinesias, "on-off" phenomena, and declining efficacy of levodopa were present in all patients. Early-morning dystonia may represent another late side effect secondary to long-term levodopa administration in parkinsonism.

Dementia and myoclonus in a case of cryptococcal encephalitis.

Dementia and generalized myoclonic jerks were the only neurologic features in a patient with cryptococcal encephalitis. Despite the presence of numerous budding yeasts identified as Cryptococcus neoformans in the CSF, there was no inflammatory reaction. Protein and glucose levels were normal, with no pleocytosis.

Paroxysmal dystonia as the initial manifestation of multiple sclerosis.

Paroxysmal dystonia was the initial manifestation of multiple sclerosis (MS) in eight patients. The disorder was generally characterized by dystonic posturing of unilateral extremities, averaging less than one minute in duration. Facial grimacing and dysarthria occurred in two of the eight patients. This paroxysmal phenomenon was frequently the cause of diagnostic confusion. The time elapsing before other neurological symptoms of MS developed was as long as ten years.

Regional cerebral blood flow in patients with Parkinson's disease.

Regional cerebral blood flow (rCBF) was measured by the xenon 133 inhalation method in 60 patients with Parkinson's disease and compared with flow data obtained in 51 age-matched normal control subjects. Mean brain rCBF was significantly reduced in patients with parkinsonism (9.5%, P less than .001). The most marked and significant rCBF decreases were observed in the older patients (18.8%, P less than .001). There was no correlation between degree of rCBF reduction and duration of parkinsonism. Decreases in hemispheric mean rCBF values were similar in both hemispheres even in patients with unilateral signs. The present study provides additional evidence for involvement of the cerebral cortex in Parkinson's disease. The rCBF decline may be associated in part with high prevalence of mental impairment and cortical atrophy and with diminished cerebral metabolic rate due to brain dopamine deficiency in patients with parkinsonism.

Open controlled therapeutic trial of intravenous immune globulin in relapsing-remitting multiple sclerosis.

Ten patients with relapsing-remitting multiple sclerosis were treated with intravenous immune globulin, 0.4 g/kg per day for 5 consecutive days, and then with additional booster doses of immune globulin of 0.4 g/kg, once every 2 months, for the next 12 months. Ten untreated patients with relapsing-remitting multiple sclerosis who were matched with the study patients for age, disease duration, and number of attacks per year served as controls. Immune globulin treatment was well tolerated, with no side effects. The exacerbation rate decreased from 3.7 +/- 1.2 exacerbations per year before treatment to 1.0 +/- 0.7 exacerbations per year during the treatment in the immune globulin-treated patients, while it remained unaltered in the controls. The posttreatment Kurtzke Expanded Disability Status Scale score decreased from a mean of 4.45 to 4.15, whereas in controls it increased from 3.55 to 3.75. The results suggest that immune globulin suppresses the ongoing pathologic process in multiple sclerosis and may be a promising treatment to prevent disease exacerbations.

Management of response fluctuations: practical guidelines.

More than 50% of patients with Parkinson's disease (PD) develop response fluctuations following prolonged treatment with levodopa. Some are due to central pharmacodynamic mechanisms such as reduced striatal synthesis and storage of dopamine from exogenous levodopa and subsensitization of post synaptic dopaminergic receptors. Other fluctuations, especially the "delayed on" (increased time latencies from dose intake to turning "on") and "no on" (complete failure of levodopa dose to induce an "on" response) are caused by peripheral pharmacokinetic mechanisms. Patients with PD, especially those with response fluctuations, have gastric atony. The reduced motility of the stomach, combined with the poor solubility of levodopa, is the cause for the delayed and incomplete absorption of levodopa. The best strategy to overcome central pharmacodynamic mechanisms and to increase daily "on" hours can be achieved by using dopamine agonists, controlled release preparations, MAO-B and COMT inhibitors. Therapeutic strategies that improve levodopa absorption are needed to overcome response fluctuations that are caused by peripheral mechanisms. This can be achieved by crushing levodopa and drinking it as a suspension. Administration of crushed levodopa or levodopa/carbidopa/ascorbic acid solutions orally or through gastroduodenal or gastrojejunostomy tubes may also be helpful. Prokinetic drugs, such as prepulsid, improve absorption of levodopa by enhancing gastric motility. Bypassing the stomach by subcutaneous dopamine agonists (apomorphine and lisuride pumps) or by the novel prodrug of levodopa, i.e., levodopa ethylester, may produce dramatic rescue from incapacitating "off" states.

Forms of dystonia in patients with Parkinson's disease.

We studied various forms of dystonia associated with Parkinson's disease (PD) in 207 patients who were on levodopa therapy for more than 1 year. Dystonia, sometimes more than one type, occurred in 63 (30%). In five patients, dystonia preceded initiation of treatment. Fifteen patients had peak-dose dystonia, 33 had early-morning dystonia, and 20 had "off-period" dystonia. The different clinical features of the dystonias are presented and compared. Findings indicate that dystonia is a frequent feature of levodopa-treated PD patients.