Biomedical subjects

M Lanotte

Publications and source records attributed to M Lanotte.

At least 19 recordsLinked to original sources

PubMed2006

Chronic deep brain stimulation of the subthalamic nucleus for Parkinson's disease: effects on cognition, mood, anxiety and personality traits.

OBJECTIVE: To evaluate modifications occurring in cognitive functions and behavioural aspects in a group of 72 consecutive patients with Parkinson's disease (PD) 15 months after bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN). METHODS: 72 consecutive PD patients bilaterally implanted for DBS of the STN were evaluated before and after surgery with a mean follow-up of 15 months. A neuropsychological assessment was performed to evaluate reasoning (Raven Colour Matrices), memory (Bisyllabic Word Repetition Test, Corsi's Block-Tapping Test, Paired-Associate Learning) and frontal executive functions (Trail Making Test Part B, Nelson Modified Card Sorting Test, phonemic and category verbal fluency tasks). Mood and suicidal ideation were evaluated using the Beck Depression Inventory (BDI). Anxiety was measured by means of the State-Trait Anxiety Inventory and personality traits were evaluated with the Structured Clinical Interview for the DSM-III-R Axis II Disorders (SCID-II). Assessment of thought disorders and apathy was based on subitems of the Unified Parkinson's Disease Rating Scale. RESULTS: The comparisons between pre- and postoperative neuropsychological test scores showed a significant worsening only in phonemic and semantic verbal fluency tasks, while fewer errors were found in the Nelson Modified Card Sorting Test. Globally, behavioural assessment evidenced a small improvement in mood, as assessed by the BDI, in obsessive-compulsive and paranoid personality traits (SCID-II). Thought disorders worsened while suicidal ideation, anxiety and apathy showed no postoperative modifications. The analysis of individual outcomes (+/-1 SD criterion) evidenced a relevant postoperative cognitive decline in 3 patients out of 65 (4.5%). Moreover, following implantation, 1 patients exhibited psychosis (1.5%), 2 patients experienced a clinically relevant worsening of depressive symptoms (3%), 7 patients showed an increase in anxiety (12%) and 3 patients a worsening in depression and anxiety symptoms (3%). On the contrary, 12 patients (20%) showed a relevant improvement in mood and 14 patients (23%) a relevant reduction of anxiety symptoms after the surgery. CONCLUSIONS: The present study confirms that STN DBS is cognitively safe since the only relevant change observed was a mild decrease in verbal fluency tasks. Globally, a small postoperative improvement was found in the BDI, and in two SCID-II subscales concerning obsessive-compulsive and paranoid personality traits, even though postoperative behavioural disturbances can occur in individual patients.

Affect↗

PubMed2006

Impact of subthalamic nucleus stimulation on the initiation of gait in Parkinson's disease.

The effects of subthalamic nucleus (STN) stimulation on the anticipatory postural actions associated with the initiation of gait were studied in ten patients with idiopathic Parkinson's disease undergoing therapeutic deep brain stimulation. Kinematic, dynamic and electromyographic analysis was performed before and while subjects were starting gait in response to an external cue. Effects of STN stimulation on the standing posture preceding the go signal included significant improvement of the vertical alignment of the trunk and shank, decrease of the hip joint moment, backward shift of the center of pressure (CoP) and reduction of abnormal tonic and/or rhythmic activity in the thigh and leg muscles. Responses to bilateral STN stimulation were more consistent than those evoked by unilateral stimulation. Moreover, comparison between postural changes induced by STN stimulation applied prior to the gait initiation cue and during simple quiet standing revealed more significant responses in the former condition. Effects on the actual gait initiation process included shortening of the imbalance phase, larger backward/lateral displacement of CoP and more physiological expression of the underlying anticipatory muscular synergy. Additional changes were shortening of the unloading phase, shortening of the first-swing phase and increase in the length of the first step. Results demonstrate substantial influence of STN stimulation on functionally basic motor control mechanisms. In particular, the evidence of more significant responses upon attention-demanding conditions and the remarkable effects on postural programmes sub-serving feed-forward regulation of the onset of complex multijoint movements, suggests a consistent action on postural sub-systems relying on cognitive data processing and internal models of body mechanics.

Aged↗

PubMed2006

Telomerase targeting by retinoids in cells from patients with myeloid leukemias of various subtypes, not only APL.

Numerous strategies have been proposed to specifically inhibit telomerase (human telomerase reverse transcriptase (hTERT)) but to date only a few are clinically relevant in anticancer therapy. Recently, we have shown that long-term treatment with all-trans retinoic acid (ATRA), a compound clinically approved for differentiation therapy of acute promyelocytic leukemia (APL), represses hTERT in differentiation-resistant APL cell lines leading to telomere shortening and death. This signaling requires the co-activation of the retinoic acid receptor alpha (RARalpha) and the retinoic X receptor (RXR). In contrast to differentiation-therapy, which is only successful in this subtype of leukemia, the telomerase-targeted pathway could also be of use in non-APL. Here, we demonstrate that repression of hTERT occurs in fresh blasts cells from patients with myeloid leukemias of various subtypes exposed ex vivo to ATRA or synthetic retinoids. These results support the idea that, by hTERT targeting, retinoids can induce telomere shortening and cell death and their integration in therapy protocols for myeloid leukemias refractory to maturation should be considered.

Adult↗

PubMed2006

Telomeres and telomerase: Pharmacological targets for new anticancer strategies?

Telomeres are located at the ends of eukaryotic chromosomes. Human telomerase, a cellular reverse transcriptase, is a ribonucleoprotein enzyme that catalyzes the synthesis and extension of telomeric DNA. It is composed of at least, a template RNA component (hTR; human Telomerase RNA) and a catalytic subunit, the telomerase reverse transcriptase (hTERT). The absence of telomerase is associated with telomere shortening and aging of somatic cells, while high telomerase activity is observed in over 85% of human cancer cells, strongly indicating its key role during tumorigenesis. Several details regarding telomere structure and telomerase regulation have already been elucidated, providing new targets for therapeutic exploitation. Further support for anti-telomerase approaches comes from recent studies indicating that telomerase is endowed of additional functions in the control of growth and survival of tumor cells that do not depend only on the ability of this enzyme to maintain telomere length. This observation suggests that inhibiting telomerase or its synthesis may have additional anti-proliferative and apoptosis inducing effect, independently of the reduction of telomere length during cell divisions. This article reviews the basic information about the biology of telomeres and telomerase and attempts to present various approaches that are currently under investigation to inhibit its expression and its activity. We summarize herein distinct anti-telomerase approaches like antisense strategies, reverse transcriptase inhibitors, and G-quadruplex interacting agents, and also review molecules targeting hTERT expression, such as retinoids and evaluate them for their therapeutic potential. "They conceive a certain theory, and everything has to fit into that theory. If one little fact will not fit it, they throw it aside. But it is always the facts that will not fit in that are significant". "Death on the Nile". Agatha Christie.

Animals↗

PubMed2005

Retinoid/arsenic combination therapy of promyelocytic leukemia: induction of telomerase-dependent cell death.

Acute promyelocytic leukemia (APL) is efficiently treated with a cell differentiation inducer, all-trans retinoic acid (ATRA). However, a significant percentage of patients still develop resistance to this treatment. Recently, arsenic trioxide (As2O3), alone or in combination with ATRA, has been identified as an alternative therapy in patients with both ATRA-sensitive and ATRA-resistant APL. Previous investigations restricted the mechanism of this synergism to the modulation and/or degradation of PML-RARalpha oncoprotein through distinct pathways. In this study, using several ATRA maturation-resistant APL cell lines, we demonstrate in vitro that the success of ATRA/As2O3 treatment in APL pathology can be explained, at least in part, by a synergistic effect of these two drugs in triggering downregulation of telomerase efficient enough to cause telomere shortening and subsequent cell death. Such long-term low-dose combinatorial therapy strategies, developed also to avoid acute side effects, reinforce the notion that the antitelomerase strategy, based on a combination of active agents, should now be considered and evaluated not only in APL but also in other malignancies.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2004

Effects of bilateral subthalamic stimulation on gait kinematics and kinetics in Parkinson's disease.

Subthalamic nucleus (STN) stimulation, a recent surgical approach to Parkinson's disease (PD), has been shown to be effective in relieving motor symptoms. The present study carried out a full body gait analysis, during overground walking, on ten PD patients with bilaterally implanted STN stimulation devices. Walking performance was analyzed on the same day, in four conditions (Stim Off-Med Off, Stim On-Med Off, Stim Off-Med On, Stim On-Med On). The results showed that, on average, STN stimulation alone (S+M-) and L-dopa alone (S-M+), significantly increased gait speed, stride length and the lower limb joint Range of Motion (ROM) with respect to the basal condition (S-M-); also cadence was found to play a role in velocity increase, particularly when L-dopa was administered. Both treatments improved pelvis and trunk kinematics, and power production at the ankle and hip joints. The combination of the two treatments (S+M+) produced an additional effect on gait speed, stride length, ROM of knee and ankle joints, pelvis obliquity and trunk inclination. Given the additive and synergistic effects, it can be hypothesized that the two treatments have different mechanisms of action. Our results confirm the findings of earlier studies that employed treadmill walking.

Aged↗

PubMed2004

Rapid induction of cAMP/PKA pathway during retinoic acid-induced acute promyelocytic leukemia cell differentiation.

The second messenger cyclic adenosine monophosphate (cAMP) plays an important role in cell proliferation, differentiation and apoptosis. In the present work, we evaluated the cAMP signaling in acute promyelocytic leukemia (APL) cells in the context of differentiation induced by all-trans retinoic acid (ATRA). There was a marked increase in the intracellular cAMP level within a few minutes after treatment with ATRA in APL cell line NB4 and fresh APL cells, whereas no such phenomenon was observed in NB4-R1 cells that are resistant to ATRA-induced maturation. In addition, the basal level of intracellular cAMP was lower in NB4-R1 than in NB4 cells. Mechanistic study showed that this induction of cAMP was mediated through the activation of adenylate cyclase. Moreover, we found that cAMP-dependent protein kinase (PKA) activity was quickly upregulated in parallel in ATRA-treated NB4 cells, and the phosphorylation of RARalpha by PKA could increase its transactivation effect. Use of H-89, an inhibitor of PKA, could partially suppress the transcriptional expression of ATRA target genes and ATRA-induced differentiation of APL cells. Taken together, we suggested a crosstalk between ATRA-induced cytosolic pathway and nuclear pathway in APL cell differentiation.

Adenylyl Cyclases↗

PubMed2004

Sexual well being in parkinsonian patients after deep brain stimulation of the subthalamic nucleus.

OBJECTIVES: To evaluate changes in sexual well being in a group of patients with Parkinson's disease following deep brain stimulation (DBS) of the subthalamic nucleus (STN). METHODS: 31 consecutive patients with Parkinson's disease (21 men and 10 women), bilaterally implanted for DBS of STN, were evaluated one month before and 9-12 months after surgery. Sexual functioning was assessed using a reduced form of the Gollombok Rust inventory of sexual satisfaction (GRISS). Depression (Beck depression inventory) and anxiety (STAI-X1/X2) were also evaluated. Relations between sexual functioning and modifications in the severity of disease (Hoehn and Yahr stage), reduction in levodopa equivalent daily dosage (LEDD), age, and duration of disease were analysed. RESULTS: While no modifications were found in female patients, male patients reported slightly but significantly more satisfaction with their sexual life after DBS of STN. When only male patients under 60 years old were considered, a greater improvement in sexual functioning was found, though still small. Modifications in depressive symptoms and anxiety, as well as duration of the disease, reduction in LEDD, and improvement in the severity of disease, showed no relation with changes in sexual functioning after DBS of STN. CONCLUSIONS: DBS of STN appears to affect sexual functioning in a small but positive way. Male patients with Parkinson's disease, especially when under 60, appeared more satisfied with their sexual well being over a short term follow up period.

Aged↗

PubMed2002

High-frequency electrical stimulation of the subthalamic nucleus in Parkinson's disease: kinetic and kinematic gait analysis.

In the advanced phase of Parkinson's disease (PD), gait disturbances represent one of the main causes of disability. Several studies demonstrated that high-frequency electrical stimulation (HFS) of the subthalamic nucleus (STN) significantly improves the motor symptoms of PD. This study was finalised to quantitatively analyze the effect of STN HFS on gait of PD patients, through a three-dimensional gait analysis system. Ten PD patients were studied, with and without STN HFS. The results demonstrated that STN HFS significantly improves all the main gait parameters in PD patients.

Biomechanical Phenomena↗

PubMed2002

Deep brain stimulation of the subthalamic nucleus in Parkinson's disease: long-term follow-up.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been shown to be an effective therapy for the treatment of advanced Parkinson's disease (PD). Forty-seven patients were bilaterally implanted for STN DBS and clinically evaluated according to the Core Assessment Program for Intracerebral Transplantations before surgery and 3, 12 and 24 months after surgery. Electrical stimulation led to a significant improvement in motor symptoms and in the quality of life, allowing a significant reduction of dopaminergic drugs with a consequent improvement of drug-induced dyskinesias. Statistical differences were observed between UPDRS parts II, III and IV values and daily levodopa dosage in the pre- and postoperative periods, while no differences were evident between the 3 postoperative conditions.

Aged↗

PubMed2002

Quantitative analysis of gait in Parkinson's disease: a pilot study on the effects of bilateral sub-thalamic stimulation.

Four patients with Parkinson's disease who had a Subthalamic Nucleus (STN) stimulator implanted and four age-matched controls underwent gait analysis using a three-dimensional system. STN stimulation substantially improved most of the key variables in the patients, without producing inefficient compensatory movements of the trunk. A reduction of ankle power production during push off was the most persistent abnormality seen when the patients were stimulated. We also found a reduction of trunk lateral bending and torsion when the patients were not stimulated when compared with controls.

Biomechanical Phenomena↗

PubMed2002

All-trans retinoic acid down-regulates prion protein expression independently of granulocyte maturation.

The cellular prion protein (PrPc) is a sialoglycoprotein involved in the pathogenesis of prion diseases. It has been identified at the plasma membrane of several cell types. All-trans retinoic acid (ATRA) is known to induce differentiation of human leukemia cell lines in vitro. PrPc messenger ribonucleic acid (mRNA) and protein are down-regulated upon ATRA-induced differentiation of HL60 cells. In this report, we have investigated the regulation of PrPc mRNA and protein expression during ATRA-treatment of maturation-sensitive (NB4) and -resistant (NB4-R1 and NB4-R2) cell lines. In ATRA-induced maturation of NB4 cells, down-regulation of PrPc mRNA and protein were observed. We also show that down-regulation of PrPc mRNA is dependent on protein synthesis. Moreover, the same down-regulation of prion protein by ATRA was observed at the surface of maturation-resistant, ATRA-responsive NB4-R1 cells. In contrast, the maturation-resistant and ATRA-unresponsive NB4-R2 subline showed no variation in membrane prion protein expression. These results demonstrate a dissociation between the regulation of prion protein expression by ATRA and the process of granulocyte maturation. We propose that retinoids should be investigated further as a preventive strategy to slow down prion disease progression.

Cell Differentiation↗

PubMed2002

A novel mechanism of retinoic acid resistance in acute promyelocytic leukemia cells through a defective pathway in telomerase regulation.

Human telomerase, a cellular reverse transcriptase specifically activated in most malignant tumors and usually inactive in normal somatic cells, plays an important role in immortalization and tumorigenesis. Early reports have indicated that terminal differentiation of various cells is associated with a rapid inhibition of telomerase activity, preceded by a down-regulation of telomerase reverse transcriptase (hTERT) mRNA. Recently, we have shown that telomerase can be repressed by all-trans retinoic acid (ATRA) independently of terminal maturation during long-term ATRA treatment of the maturation-resistant promyelocytic leukemia cell line (NB4-R1), leading to shortening of telomeres and cell death, events overcome by ectopic hTERT expression. Here, we report the isolation of a variant of NB4-R1 cells (NB4-R1(SFD)), which bypasses this death step, because of a re-activated telomerase, despite the continuous presence of ATRA. While unresponsive to a long-term maturation independent regulation of telomerase by ATRA, these cells retain a functional pathway of telomerase down-regulation associated with retinoid-induced maturation. These findings reinforce the notion that two distinct pathways of telomerase regulation by retinoids co-exist in APL cells. Noteworthy, we show that the slow developing mechanism, that causes death of maturation-resistant cells, is subjected to a new type of retinoid-resistance as yet not understood.

Cell Differentiation↗

PubMed2001

Deep brain stimulation of the subthalamic nucleus in Parkinson's disease: comparison of pre- and postoperative neuropsychological evaluation.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for the motor symptoms of advanced Parkinson's disease (PD). The aim of this study was to assess the effect of the bilateral surgical procedure and STN DBS on the neuropsychological functions. Twenty Parkinson's disease patients underwent a neuropsychological assessment before and 6 months after surgery in four different conditions: medication on (with levodopa) and medication off (without levodopa) during the preoperative period, medication on/stimulation on (levodopa plus stimulators switched on) and medication off/stimulation on (stimulators switched on without levodopa) during the postoperative period. We did not find any significant difference in the four conditions for all the neuropsychological tests, confirming the lack of an overall cognitive decline after surgery. From a neuropsychological point of view, these results seem to indicate that bilateral STN DBS is a safe treatment for advanced PD.

Age Factors↗

PubMed2001

Orchestration of multiple arrays of signal cross-talk and combinatorial interactions for maturation and cell death: another vision of t(15;17) preleukemic blast and APL-cell maturation.

Despite intensive molecular biology investigations over the past 10 years, and an important breakthrough on how PML-RARalpha, the fusion protein resulting from t(15;17), can alter RARalpha and PML functions, no definitive views on how leukemia is generated and by what mechanism(s) the normal phenotype is restored, are yet available. 'Resistances' to pharmacological levels of all-trans-retinoic acid (ATRA) have been observed in experimental in vivo and in vitro models. In this review, we emphasize the key role played by signal cross-talk for both normal and neoplastic hemopoiesis. After an overview of reported experimental data on APL-cell maturation and apoptosis, we apply our current knowledge on signaling pathways to underline those which might generate signal cross-talks. The design of biological models suitable to decipher the integration of signal cross-talks at the transcriptional level should be our first priority today, to generate some realistic therapeutic approaches After 'Ten Years of Molecular APL', we still know very little about how the disease develops and how effective medicines work.

Apoptosis↗

PubMed2001

Maturation sensitive and resistant t(15;17) NB4 cell lines as tools for APL physiopathology: nomenclature of cells and repertory of their known genetic alterations and phenotypes.

Chromosomal translocations, leading to gene rearrangements that generate chimerical proteins, represent one of the initiating events of leukemia. Preleukemia cells eventually develop into overt leukemia by occurrence of secondary genetic alterations (tumor progression). The physiopathology of leukemia has made considerable progress during the last two decades, due to molecular biology investigations on the role played by the altered genes, during neoplasic hemopoiesis. In vitro studies have been facilitated by the establishment of stable leukemia cell lines bearing these gene rearrangements and secondary gene mutations. Investigations on acute promyelocytic leukemia (APL) have benefited from maturation sensitive and resistant cell lines (NB4 and UF-1) derived from APL patient's leukemia cells and bearing the t(15;17). The information concerning the NB4 cell line (responsiveness to retinoid/rexinoid, cAMP, arsenic, mutations causing resistance) is spread in an abundant literature. In this paper, we briefly recapitulate the cellular and molecular features of this cell line and its subclones with the aim of facilitating investigators in their choice of the most appropriate tool for their studies. As redundancy of several names given to NB4 sublines has sometimes created difficulties, we propose a nomenclature for the various NB4 sublines that most investigators certainly would be agreed with.

Apoptosis↗

PubMed2001

Lineage restriction of the RARalpha gene expression in myeloid differentiation.

To better understand the role of retinoids in myelopoiesis, expression of the retinoid receptor genes (retinoic acid receptors [RARs] and retinoid X receptors [RXRs]) were examined during differentiation of factor-dependent cell-Paterson (FDCP)-mixA4 murine progenitor cells. The major receptor expressed in undifferentiated A4 cells was RARalpha (primarily the RARalpha1 isoform). Following induction of myelomonocytic differentiation with granulocyte and granulocyte-macrophage colony-stimulating factors, a dramatic increase in RARalpha expression (particularly the RARalpha2 isoform) was seen. In contrast, expression of both RARalpha isoforms was rapidly extinguished upon induction of erythroid differentiation with erythropoeitin (EPO). A modest induction of RXRalpha expression was seen, particularly during differentiation in the myelomonocytic lineage. Low expression levels of RARgamma2 and RXRbeta remained unchanged, irrespective of differentiation pathway. Consistent with the gene expression patterns, RARalpha agonists and antagonists stimulated myelomonocytic and erythroid differentiation of FDCP-mixA4 cells, respectively. Taken together, these results suggest that erythropoiesis and granulopoiesis require diminished and enhanced RARalpha activities, respectively, which at physiological all-trans-retinoic acid (RA) concentrations may be accomplished by reciprocal effects of EPO and myelomonocytic growth factors on its expression. This hypothesis is corroborated by data showing that RA, which positively regulates RARalpha2 expression, can exert inhibitory effects on erythroid differentiation.

Bone Marrow↗

PubMed2001

Retinoids down-regulate telomerase and telomere length in a pathway distinct from leukemia cell differentiation.

Human telomerase, a cellular reverse transcriptase (hTERT), is a nuclear ribonucleoprotein enzyme complex that catalyzes the synthesis and extension of telomeric DNA. This enzyme is specifically activated in most malignant tumors but is usually inactive in normal somatic cells, suggesting that telomerase plays an important role in cellular immortalization and tumorigenesis. Terminal maturation of tumor cells has been associated with the repression of telomerase activity. Using maturation-sensitive and -resistant NB4 cell lines, we analyzed the pattern of telomerase expression during the therapeutic treatment of acute promyelocytic leukemia (APL) by retinoids. Two pathways leading to the down-regulation of hTERT and telomerase activity were identified. The first pathway results in a rapid down-regulation of telomerase that is associated with retinoic acid receptor (RAR)-dependent maturation of NB4 cells. Furthermore, during NB4 cell maturation, obtained independently of RAR by retinoic X receptor (RXR)-specific agonists (rexinoids), no change in telomerase activity was observed, suggesting that hTERT regulation requires a specific signaling and occurs autonomously. A second pathway of hTERT regulation, identified in the RAR-responsive, maturation-resistant NB4-R1 cell line, results in a down-regulation of telomerase that develops slowly during two weeks of all-trans retinoic acid (ATRA) treatment. This pathway leads to telomere shortening, growth arrest, and cell death, all events that are overcome by ectopic expression of hTERT. These findings demonstrate a clear and full dissociation between the process of tumor cell maturation and the regulation of hTERT mRNA expression and telomerase activity by retinoids. We propose telomerase expression as an efficient and selective target of retinoids in the therapy of tumors.

Cell Death↗