Comparison of therapeutic effects and mortality data of levodopa and levodopa combined with selegiline in patients with early,mild Parkinson's disease. Parkinson's Disease Research Group of the United Kingdom.

OBJECTIVE: To compare effectiveness of levodopa and levodopa combined with selegiline in treating early, mild Parkinson''s disease. DESIGN: Open, long term, prospective randomised trial. SETTING: 93 hospitals throughout United Kingdom. SUBJECTS: 520 patients with early Parkinson''s disease who were not receiving dopaminergic treatment. INTERVENTIONS: Treatment with levodopa and dopa decarboxylase inhibitor (arm 1) or levodopa and decarboxylase inhibitor in combination with selegiline (arm 2). MAIN OUTCOME MEASURES: Assessments of serial disability, frequency and severity of adverse events, and deaths from all causes. RESULTS: After average of 5-6 years'' follow up, mortality ratio in arm 2 compared with arm 1 was 1.57 (95% confidence interval 1.09 to 2.30), and difference in survival between the two arms was significant (log rank test, P = 0.015). Hazard ratio adjusted for age and sex was 1.49 (1.02 to 2.16), and after adjustment for other baseline factors it increased to 1.57 (1.07 to 2.31). Patients in arm 1 had slightly worse disability scores than those in arm 2, but differences were not significant. Functionally disabling peak dose dyskinesias and on/off fluctuations were more frequent in arm 2 than arm 1. During the trial the dose of levodopa required to produce optimum motor control steadily increased in arm 1 (median daily dose 375 mg at 1 year and 625 mg at 4 years), but median dose in arm 2 did not change (375 mg). CONCLUSIONS: Levodopa in combination with selegiline seemed to confer no clinical benefit over levodopa alone in treating early, mild Parkinson''s disease. Moreover mortality was significantly higher with combination treatment, casting doubts on its chronic use in Parkinson''s disease.     

The effects of levodopa therapy in patients with Parkinson's disease I. Clinical response

Eighty-eight patients with Parkinson''s disease were treated with levodopa. A group of elderly patients 65 years and older was compared with a second group under the age of 65, and it was found that generally the younger patients could be treated with greater success than the older ones. Most of the elderly could not tolerate the large doses required to produce optimal physical recovery. Severity of complications forced discontinuance of treatment in a larger percentage of elderly patients. The rate of complications was about equal in the two groups, except the incidence of confusion, which was significantly higher in the elderly. Of the two deaths that occurred, both were in the older group. Results of treatment were better in patients whose families gave positive support.     

Circulating endothelial progenitor cells in kidney transplant patients

Background

Kidney transplantation (RTx) leads to amelioration of endothelial function in patients with advanced renal failure. Endothelial progenitor cells (EPCs) may play a key role in this repair process. The aim of this study was to determine the impact of RTx and immunosuppressive therapy on the number of circulating EPCs.

Methods

We analyzed 52 RTx patients (58±13 years; 33 males, mean ± SD) and 16 age- and gender-matched subjects with normal kidney function (57±17; 10 males). RTx patients received a calcineurin inhibitor (CNI)-based (65%) or a CNI-free therapy (35%) and steroids. EPC number was determined by double positive staining for CD133/VEGFR2 and CD34/VEGFR2 by flow cytometry. Stromal cell-derived factor 1 alpha (SDF-1) levels were assessed by ELISA. Experimentally, to dissociate the impact of RTx from the impact of immunosuppressants, we used the 5/6 nephrectomy model. The animals were treated with a CNI-based or a CNI-free therapy, and EPCs (Sca+cKit+) and CD26+ cells were determined by flow cytometry.

Results

Compared to controls, circulating number of CD34+/VEGFR2+ and CD133+/VEGFR2+ EPCs increased in RTx patients. There were no correlations between EPC levels and statin, erythropoietin or use of renin angiotensin system blockers in our study. Indeed, multivariate analysis showed that SDF-1 – a cytokine responsible for EPC mobilization – is independently associated with the EPC number. 5/6 rats presented decreased EPC counts in comparison to control animals. Immunosuppressive therapy was able to restore normal EPC values in 5/6 rats. These effects on EPC number were associated with reduced number of CD26+ cells, which might be related to consequent accumulation of SDF-1.

Conclusions

We conclude that kidney transplantation and its associated use of immunosuppressive drugs increases the number of circulating EPCs via the manipulation of the CD26/SDF-1 axis. Increased EPC count may be associated to endothelial repair and function in these patients.     

Detection of cytokines in supernatant from hematopoietic stem/progenitor cells co-cultured with mesenchymal stem cells and endothelial progenitor cells

This study aimed to investigate the significance of cytokine expression in supernatant from hematopoietic stem/progenitor cells (HSCs/HPCs) co-cultured with mesenchymal stem cells (MSCs) or endothelial progenitor cells (EPCs). Mononuclear cells (MNCs) were isolated from normal human umbilical cord blood and then cultured solely or co-cultured with MSCs or EPCs. Changes in the number of MNCs and HSCs/HPCs were observed, and MNC proliferation was tested by carboxyfluorescein diacetate succinimidyl ester. The cultured supernatants of the treated MSCs and EPCs were collected at 24 h after co-culture and used to determine the concentrations of IL-3, IL-6, stem cell factor (SCF), TPO, Flt3l, and VEGF. The total number and proliferation of MNCs increased significantly when co-cultured with MSCs or EPCs than when cultured alone, particularly when MNCs were co-cultured with EPCs. The differences in IL-3 and Flt3l concentrations between groups were not significant. However, IL-6 in the MSC group was significantly higher than that in the two other groups. The SCF and TPO concentrations were highly expressed in the EPC group. The VEGF concentrations in the MSC group and the EPC group were higher than those in the control group. These results indicated that MSCs and EPCs possibly favor the proliferation of MNCs and HSCs/HPCs. IL-6 and VEGF may be related to hematopoietic reconstitution and homing ability of HSCs/HPCs. TPO may have a specific relationship with the promotion of HSCs/HPCs differentiation.     

Modulation of habit formation by levodopa in Parkinson's disease

Dopamine promotes the execution of positively reinforced actions, but its role for the formation of behaviour when feedback is unavailable remains open. To study this issue, the performance of treated/untreated patients with Parkinson's disease and controls was analysed in an implicit learning task, hypothesising dopamine-dependent adherence to hidden task rules. Sixteen patients on/off levodopa and fourteen healthy subjects engaged in a Go/NoGo paradigm comprising four equiprobable stimuli. One of the stimuli was defined as target which was first consistently preceded by one of the three non-target stimuli (conditioning), whereas this coupling was dissolved thereafter (deconditioning). Two task versions were presented: in a 'Go version', only the target cue required the execution of a button press, whereas non-target stimuli were not instructive of a response; in a 'NoGo version', only the target cue demanded the inhibition of the button press which was demanded upon any non-target stimulus. Levodopa influenced in which task version errors grew from conditioning to deconditioning: in unmedicated patients just as controls errors only rose in the NoGo version with an increase of incorrect responses to target cues. Contrarily, in medicated patients errors went up only in the Go version with an increase of response omissions to target cues. The error increases during deconditioning can be understood as a perpetuation of reaction tendencies acquired during conditioning. The levodopa-mediated modulation of this carry-over effect suggests that dopamine supports habit conditioning under the task demand of response execution, but dampens it when inhibition is required. However, other than in reinforcement learning, supporting dopaminergic actions referred to the most frequent, i. e., non-target behaviour. Since this is passive whenever selective actions are executed against an inactive background, dopaminergic treatment could in according scenarios contribute to passive behaviour in patients with Parkinson's disease.     

Long-term therapy of Parkinson's disease with amantadine,alone and combined with levodopa

A dual study was conducted to assess (1) the long-term antiparkinsonian action of amantadine without levodopa and (2) the advantage of combined amantadine and levodopa over single-drug therapy, including changes in symptom severity when placebo replaces amantadine but levodopa is maintained.Good to excellent results were obtained in 25% of the total pool of 77 patients on amantadine. No decline in therapeutic effect took place during a mean follow-up of 21 months.Thirty-seven patients with considerable residual deficit after single-drug therapy derived improvement from the second drug (levodopa or amantadine). Gains in neurological signs and activities of daily living (ADL) ranged between 50 and 60% and for timed skills close to 25%. Depending on the individual indices, between 64 and 100% of patients improved with the second drug.Placebo instead of amantadine produced deterioration. There was 75% loss in ADL, 45% loss in timed skills and losses in neurological signs exceeded gains produced by two-drug therapy.     

Role of integrin-linked kinase for functional capacity of endothelial progenitor cells in patients with stable coronary artery disease

Number and function of endothelial progenitor cells (EPCs) are down-regulated in patients with coronary artery disease (CAD). Integrin-linked kinase (ILK) is a signal and adaptor protein that regulates survival of mature endothelial cells and vascular development.Here we show that EPC dysfunction in patients with CAD is paralleled by down-regulation of ILK while restoration of ILK expression rescues the migratory defect of CAD-EPCs. Human EPCs transduced with dominant-negative ILK (DN-ILK) display significantly reduced expression of CD34⁺/VEGFR-2⁺, DiI-Ac-LDL uptake, and Ulex europaeus lectin binding. Mechanistically, DN-ILK-transfected EPCs are characterized by decreased proliferation, while proliferation is increased in wild-type ILK-transfected EPCs. These effects are paralleled by changes in cyclin D1 expression, colony forming units, and cytoskeletal rearrangement. Functionally, ILK is necessary and sufficient for SDF-1-triggered migration and adhesion in EPCs.These data extend current knowledge about the role of ILK in EPC biology and implicate ILK as a therapeutic target in CAD.     

Improved angiogenic activity of endothelial progenitor cell in diabetic patients treated with insulin plus metformin

Type 2 diabetes (T2DM) is associated with an increased vascular disease. Moreover, endothelial progenitor cell (EPC) function is impaired in diabetic patients. Decreased EPC number plays a critical role in reduced endothelial repair and development of the vascular disorder. To determine the effect of metformin and insulin plus metformin on functional activity of EPCs, 130 participants were divided into three groups (group 1: healthy control; group 2: metformin; group 3: insulin plus metformin). The concentration of EPCs in the circulation was first quantified. Thereafter, circulating EPCs (cEPCs) were harvested and the biological features of these cells including proliferative, clonogenicity, tubulogenic, and migratory properties were analyzed after expansion. The serum protein levels of some proangiogenic factors were also measured. Our results showed greater numbers of cEPCs in control and in diabetic patients treated with insulin plus metformin than in metformin-treated patients. Insulin plus metformin therapy was associated with augmented proliferative, clonogenicity, migratory, and tubulogenic activity of cEPCs in patients with T2DM. Increased serum concentrations of angiogenic factors were also observed in patients treated with insulin plus metformin. Western blot analysis showed increased protein levels of pTie-2/Tie2 and Pakt/AKT in cEPCs harvested from T2DM, treated with insulin metformin plus. This study showed that treatment with insulin plus metformin in diabetic patients is associated with increased mobilization of EPCs into the circulation, with potential beneficial effect in vascular protection in diabetic patients.     

Enhanced angiogenic potency of monocytic endothelial progenitor cells in patients with systemic sclerosis

Introduction  

Microvasculopathy is one of the characteristic features in patients with systemic sclerosis (SSc), but underlying mechanisms still remain uncertain. In this study, we evaluated the potential involvement of monocytic endothelial progenitor cells (EPCs) in pathogenic processes of SSc vasculopathy, by determining their number and contribution to blood vessel formation through angiogenesis and vasculogenesis.     

Idiopathic orthostatic hypotension treated with levodopa and MAO inhibitor: a preliminary report

The clinical and pathophysiological features of a case of idiopathic orthostatic hypotension (Shy-Drager syndrome) are presented. Recent reports on the pathological findings in this condition indicate that there may be a defect in catecholamine synthesis in the pigmented brain stem nuclei and sympathetic ganglia similar to that in idiopathic parkinsonism. On this basis a new form of therapy using levodopa combined with MAO inhibition is derived. The results of a trial of this therapy, which produced improvements in both the hypotension and in the extrapyramidal features of the disease, are reported.     

Effect of levodopa on interleukin-15 and RANTES circulating levels in patients affected by Parkinson's disease

Parkinson's disease (PD) is an extra-pyramidal neurodegenerative disorder, in which alterations of the immune system are involved. Interleukin (IL)-15 stimulates cellular immune response and induces growth and differentiation of various immune cells. RANTES, promoting leukocyte infiltration to sites of inflammation, mediates the trafficking and homing of immune cells. To clarify the potential effect of levodopa on the immunological network of PD, we analyzed IL-15 and RANTES serum levels in PD patients, treated or not with levodopa, and in healthy donors. Levodopa-treated patients showed significantly higher IL-15 and RANTES circulating levels with respect to healthy controls and higher, although not significantly, levels with respect to untreated patients. So, we hypothesize that the immunological alterations found in PD may be linked, at least in part, to levodopa therapy.     

Decreased circulating endothelial progenitor cell levels and function in patients with nonalcoholic fatty liver disease

Objectives

Nonalcoholic fatty liver disease (NAFLD) is associated with advanced atherosclerosis and a higher risk of cardiovascular disease. Increasing evidence suggests that injured endothelial monolayer is regenerated by circulating bone marrow derived-endothelial progenitor cells (EPCs), and levels of circulating EPCs reflect vascular repair capacity. However, the relation between NAFLD and EPC remains unclear. Here, we tested the hypothesis that patients with nonalcoholic fatty liver disease (NAFLD) might have decreased endothelial progenitor cell (EPC) levels and attenuated EPC function.

Methods and Results

A total of 312 consecutive patients undergoing elective coronary angiography because of suspected coronary artery disease were screened and received examinations of abdominal ultrasonography between July 2009 and November 2010. Finally, 34 patients with an ultrasonographic diagnosis of NAFLD, and 68 age- and sex-matched controls without NAFLD were enrolled. Flow cytometry with quantification of EPC markers (defined as CD34⁺, CD34⁺KDR⁺, and CD34⁺KDR⁺CD133⁺) in peripheral blood samples was used to assess circulating EPC numbers. The adhesive function, and migration, and tube formation capacities of EPCs were also determined in NAFLD patients and controls. Patients with NAFLD had a significantly higher incidence of metabolic syndrome, previous myocardial infarction, hyperuricemia, and higher waist circumference, body mass index, fasting glucose and triglyceride levels. In addition, patients with NAFLD had significantly decreased circulating EPC levels (all P<0.05), attenuated EPC functions, and enhanced systemic inflammation compared to controls. Multivariate logistic regression analysis showed that circulating EPC level (CD34⁺KDR⁺ [cells/10⁵ events]) was an independent reverse predictor of NAFLD (Odds ratio: 0.78; 95% confidence interval: 0.69–0.89, P<0.001).

Conclusions

NAFLD patients have decreased circulating EPC numbers and functions than those without NAFLD, which may be one of the mechanisms to explain atherosclerotic disease progression and enhanced cardiovascular risk in patients with NAFLD.     

高同型半胱氨酸血症与内皮祖细胞凋亡

内皮祖细胞在内皮损伤后的修复中起重要作用.高同型半胱氨酸血症作为动脉粥样硬化的一个独立危险因素,可影响外周血内皮祖细胞的数量和功能,导致内皮功能障碍.在其引起内皮祖细胞损伤的机制中,凋亡扮演了重要角色.本文就高同型半胱氨酸血症对内皮祖细胞凋亡的影响及机制的研究进展进行了综述.     

Homocysteine-induced caspase-3 activation by endoplasmic reticulum stress in endothelial progenitor cells from patients with coronary heart disease and healthy donors

Previous studies have suggested an association of hyperhomocysteinemia-induced vascular pathology with enhanced apoptotic potential of endothelial progenitor cells in patients with coronary heart disease. Our results indicate that 500 μmol/L homocysteine induced endothelial progenitor cell apoptosis and activation of caspase-3, both of which were abolished by 100 μmol/L and 200 μmol/L salubrinal, an agent that prevents endoplasmic reticulum stress-induced apoptosis. The addition of 500 μmol/L homocysteine caused a release of Ca(2+) from intracellular stores, and enhanced phosphor-eukaryotic initiation factor 2α phosphorylation at Ser51 and the expression of a glucose-regulated protein of 78 kDa and a C/EBP homologous protein independently of extracellular Ca(2+). These effects of homocysteine on endothelial progenitor cells were significantly greater in patients with coronary heart disease than in healthy donors. These findings suggest that homocysteine induces endoplasmic reticulum stress-mediated activation of caspase-3 in endothelial progenitor cells, an event that is enhanced in patients with coronary heart disease. Furthermore, enhanced endoplasmic reticulum stress-mediated activation of caspase-3 in endothelial progenitor cells might be involved in hyperhomocysteinemia-associated vascular pathology.     

Tissue engineering of angiogenesis with autologous endothelial progenitor cells

Adult bone marrow and peripheral blood contain small subsets of mononuclear cells that can be differentiated into endothelial-like cells in vitro. Experimental and clinical transplantation of such cell isolates--often referred to as endothelial stem/progenitor cells--into ischaemic or infarcted areas shows their incorporation into sites of new vessel growth along with improvement of regional blood flow. Emerging evidence suggests that these beneficial effects on vascular growth can be attributed to the paracrine activation of resident endothelial cells, rather than their integration into new endothelium. Autologous endothelial progenitor cells can also substitute for native vessel-derived endothelial cells in tissue-engineered vascular autografts.     

Comparisons of therapeutic effects of levodopa,levodopa and selegiline,and bromocriptine in patients with early,mild Parkinson's disease: three year interim report. Parkinson's Disease Research Group in the United Kingdom.

OBJECTIVE--To determine the optimum treatment for early Parkinson''s disease. DESIGN--An open, long term, prospective randomised trial conducted by the Parkinson''s Disease Research Group of the United Kingdom. SETTING--93 hospitals throughout the United Kingdom. SUBJECTS--782 patients with early Parkinson''s disease who were not receiving dopaminergic treatment. INTERVENTIONS--Patients allocated to treatment with levodopa/dopa decarboxylase inhibitor alone (arm 1), levodopa/decarboxylase inhibitor/selegiline in combination (arm 2), or bromocriptine (arm 3). MAIN OUTCOME MEASURES--Disability assessment as judged by improvement on Hoehn and Yahr, modified Webster, and North Western University disability scales. Adverse event profile and mortality ratios. RESULTS--Interim results indicate that all three treatment regimens led to improvement in baseline disabilities after 12 months'' treatment and that deterioration in control was apparent by three years. No significant differences were found between the results of treatment in arm 1 and arm 2, but both were significantly more effective than bromocriptine (arm 3) and had fewer early adverse reactions. The adjusted difference (95% confidence interval) in Webster rating for arm 3 v 1 was 0.93 points (0.27 to 1.50; p = 0.0058) and for arm 3 v 2 was 1.25 points (0.61 to 1.89; p = 0.0002). The incidence of dyskinesias and motor oscillations, however, was significantly lower in arm 3 (2% and 5%, respectively) than in arm 1 (27% and 33%, respectively) and arm 2 (34% and 35%, respectively). CONCLUSIONS--As there were no marked differences in functional improvement between the three groups the choice of treatment in the early stages of Parkinson''s disease may not be critical.