- Örebro, Orebro Lan, Sweden
- Prof. Nikolaos Venizelos−Medicine Doctor's degree (Ph.D. in medicine) at Karolinska Institute, Sweden.−Docent and Pro... moreProf. Nikolaos Venizelos−Medicine Doctor's degree (Ph.D. in medicine) at Karolinska Institute, Sweden.−Docent and Professor in biomedicine, School of Medical Sciences, Örebro University, Sweden. −Research focus in Experimental Neuropsychiatry and Longevity.edit
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ABSTRACT. We investigated whether some in vitro polymorphonuclear (PMN) granulocyte functions were impaired in patients with hypothyroidism, since this disease has previously been associated with an increased susceptibility to infectious... more
ABSTRACT. We investigated whether some in vitro polymorphonuclear (PMN) granulocyte functions were impaired in patients with hypothyroidism, since this disease has previously been associated with an increased susceptibility to infectious agents and decreased leukocyte heat production. PMNs from 9 of 17 hypothyroid patients exhibited a decreased ability to kill Staph. aureus in vitro compared with euthyroid controls (p<0.02). This was normalized in all patients tested after therapy with levothyroxine. In 3 patients, studied repeatedly during the initial phase of therapy, PMN bactericidal capacity was gradually normalized. In addition, PMN adherence to nylon fibers showed a transient decrease approximately 6 weeks after initiation of therapy. PMN chemiluminescence during phagocytosis of Staph. aureus and stimulated and spontaneous migration under agarose were normal and did not change during therapy. Thus, the decreased bactericidal capacity found in half of these hypothyroid patients might confer an increased susceptibility to certain infectious agents.
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In acute myelogenous leukemia the remission time may be prolonged by adding immunotherapy to maintenance chemotherapy. The mechanisms for this action are nuclear. We have studied polymorphonuclear neutrophil (PMN) functions in 18 patients... more
In acute myelogenous leukemia the remission time may be prolonged by adding immunotherapy to maintenance chemotherapy. The mechanisms for this action are nuclear. We have studied polymorphonuclear neutrophil (PMN) functions in 18 patients with acute myelogenous leukemia in remission treated either with chemotherapy (CT; n = 7) or the combination of chemotherapy and immunotherapy (CT + IT; n = 11); in addition comparisons were made with healthy controls. PMN migration under agarose stimulated by a bacterial factor from Escherichia coli was significantly lower in both patient groups compared with healthy controls. When migration was stimulated with serum, it was low only in the CT + IT group. The capacity of PMNs to kill Staphylococcus aureus was reduced in the CT + IT group but normal in the CT group. The adherence to nylon fibers was higher in the CT + IT group compared to the controls and the CT group. There was no difference in chemiluminescence during phagocytosis between the two groups. Thus, there was no indication that monthly maintenance CT essentially impaired the PMN functions investigated. However, IT was associated with impairments of migratory and bactericidal functions and enhanced adherence of neutrophils. The mechanisms and clinical significance of this remain nuclear.
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This study has shown that the agarose technique is well suited for determination of whether impaired PMN migration is due to defective direction finding of deficient locomotive ability. By assessments of the degree of orientation of... more
This study has shown that the agarose technique is well suited for determination of whether impaired PMN migration is due to defective direction finding of deficient locomotive ability. By assessments of the degree of orientation of neutrophils together with measures of migration distances, we demonstrated that vinblastine treated normal neutrophils and PMNs from patients with the immotile cilia syndrome mainly move in a chemokinetic manner, whereas cytochalasin B hampers locomotive ability, but leaves direction finding intact. Hence, information whether chemotaxis or chemokinesis predominates is easily obtained in one single assay system.
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Tyrosine transport was examined in cultured skin fibroblasts from patients with schizophrenia (DSM-III-R) and normal subjects. The transport capacity (Vmax) was lower in the patients. The results confirm previous findings of decreased... more
Tyrosine transport was examined in cultured skin fibroblasts from patients with schizophrenia (DSM-III-R) and normal subjects. The transport capacity (Vmax) was lower in the patients. The results confirm previous findings of decreased tyrosine transport in schizophrenia. In cells incubated with psychotropic drugs at different concentrations, tyrosine transport was not differentially influenced across patients and normal subjects. Dopaminergic and beta-adrenergic receptor mechanisms did not seem to influence tyrosine uptake. There seems to be a primary disturbance of tyrosine transport in schizophrenia which indicates a generalized cell membrane dysfunction.
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Research Interests: Endocrinology, Genetics, Gastroenterology, Liver diseases, Humans, and 15 moreInternal Medicine, Female, Male, Hypoglycemia, Infant, Clinical Sciences, Brain atrophy, Enzyme activity, Cardiomyopathies, Liver Disease, Clinical Presentation, creatine kinase activity, Lactic acidosis, Hypotonia, and Fatal outcome
Interleukin-1beta inhibits tyrosine transport in fibroblasts from ptients with schizophrenia and healthy controls
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Altered tryptophan and alanine transport in fibroblasts from boys with attention-deficit/ hyperactivity disorder (ADHD): an in vitro study
Schizophrenia is a complex disorder and the view that schizophrenia is caused by hyperdopaminergic activity is an oversimplification. In fact, there are clinical evidence in accordance with a hypodopaminergic condition. Thus, untreated... more
Schizophrenia is a complex disorder and the view that schizophrenia is caused by hyperdopaminergic activity is an oversimplification. In fact, there are clinical evidence in accordance with a hypodopaminergic condition. Thus, untreated patients show motor disturbances in line with a decreased dopamine activity in the extrapyramidal system, likewise cognitive deficits and negative symptoms. In our research we have explored the evidence of schizophrenia as a hyper- or hypodopaminergic condition. With Positron Emission Tomography (PET) we have not seen any evidence of increased D2-dopamine receptors in the brain of never medicated patients. The major dopamine metabolite homovanillic acid (HVA) was lowered in CSF in line with a decreased dopamine turnover in the brain. Tyrosine is precursor to the synthesis of dopamine and for that aim we have made transport studies in an in vitro model with fibroblasts to determine tyrosine kinetics. The results demonstrated that tyrosine transport is lower in patients with schizophrenia in comparison to healthy controls. Tyrosine kinetics measured with PET demonstrated dysregulation of tyrosine transport into the brain. We have found evidence of schizophrenia as a hypodopaminergic condition. This fact is a problem realizing that our antipsychotics are D2-dopamine antagonists, thus decreasing dopamine activity even further. The concept of schizophrenia as both a hypo- and hyperdopaminergic condition may explain why clozapine, a week D2-antagonist, works more efficiently than other antipsychotic compounds. It should be recognized that positive symptoms are, at least partly, related to changes in dopamine activity and therefore respond very efficiently to D2-dopamine antagonists.
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An alteration of dopaminergic transmission in the brain has been proposed for schizophrenia. To explore this, the rate constant for the intransport of L-tyrosine across the blood-brain barrier in healthy controls and in patients with... more
An alteration of dopaminergic transmission in the brain has been proposed for schizophrenia. To explore this, the rate constant for the intransport of L-tyrosine across the blood-brain barrier in healthy controls and in patients with schizophrenia (DSM-III-R) was determined with PET and L-[1-11C] tyrosine as the tracer. Kinetics for tyrosine transport were determined according to a two-compartment model using radioactivity data of arterial blood and brain tissue sampled between 1 and 3.5 min after a bolus injection of L-[1-11C] tyrosine. Radioactivity was measured every second in the blood and in 10-sec intervals in the brain tissue. In the normal controls the brain intransport rate constant for tyrosine was 0.052 ml/g/min with an influx rate of 2.97 nmol/g/min. The patients had a similar intransport rate constant (0.045 ml/g/min) but a lower influx rate of tyrosine 1.95 nmol/g/min (p less than 0.05). The patients' tyrosine concentrations in the blood were lower. For data sample...
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Amino acid transport was studied in vitro in cultured fibroblasts from schizophrenic patients and controls. An isolated decrease in the transport capacity (Vmax) for tyrosine was observed in cells from the patients. The Km for tyrosine... more
Amino acid transport was studied in vitro in cultured fibroblasts from schizophrenic patients and controls. An isolated decrease in the transport capacity (Vmax) for tyrosine was observed in cells from the patients. The Km for tyrosine transport was unaffected. The kinetic parameters for phenylalanine, tryptophan, leucine and glycine transport did not differ between patients and controls. Competitive inhibition among the amino acids transported by the L-system and its exchange properties were normal in cells from the patients. No differences in intracellular levels of amino acids between patients and controls were observed. The decreased tyrosine transport in the cells from schizophrenic patients appears not to be related to any known amino acid transport system and may reflect a more general defect in plasma membrane function in schizophrenia.
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Purpose: To apply experimentally and further develop a new image interpretation model based on repeated imaging and aimed at improving assessments of technical efficacy and diagnostic accuracy in the detection of small lesions. Material... more
Purpose: To apply experimentally and further develop a new image interpretation model based on repeated imaging and aimed at improving assessments of technical efficacy and diagnostic accuracy in the detection of small lesions. Material and Methods: VX2 carcinoma was implanted in the liver of 14 rabbits as two 1.1–1.7 mm3 cores. Magnetic resonance imaging was performed before and 4 days after implantation and then every second day up to the 14th to 20th day. One T2‐weighted sequence (TSE T2) and three T1‐weighted sequences (SE T1, GE T1, and TFL T1) were used. Interpretation was performed stepwise: three readers independently interpreted image sequences chronologically (step 1). Tumors were included at the last examination (step 2). By concurrent interpretation of repeated examinations, the earliest day at which tumors became visible and tumor size were recorded (step 3). Records were corrected (step 4) and autopsy was performed (step 5). Two procedures for use in calculating repeat...
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s of Award-Winning Posters, 16th International Forum on Mood and Anxiety Disorders, Rome, December 8–10, 2016
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receptors in fibroblasts from boys with attention-deficit/ hyperactivity disorder (ADHD)
Bipolar disorder is a complex and highly heritable psychiatric disorder characterized by severe mood alterations. The precise geneticunderpinnings of the disease have not been identified so far, de ...
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Tyrosine transport through LAT1 transport system in fibroblasts of schizophrenic patients and healthy controls
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ABSTRACTS OF THE 3rd SWEDISH-HELLENIC LIFE SCIENCES RESEARCH CONFERENCE Athens, March 25-27, 2010 Preface
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Research Interests: Genetics, Biomedicine, Kinetics, Humans, Female, and 15 moreMale, Genetic determinism, Aged, Family Health, Adult, Cognitive Function, Human Fibroblasts, Genetic Susceptibility, Binding Site, Cognition disorders, Cell Membrane, fibroblasts, Endophenotype, Cognitive dysfunction, and Maternal Inheritance
Background The catecholaminergic and serotonergic neurotransmitter systems are implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). The amino acid tyrosine is the precursor for synthesis of the... more
Background The catecholaminergic and serotonergic neurotransmitter systems are implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). The amino acid tyrosine is the precursor for synthesis of the catecholamines dopamine and norepinephrine, while tryptophan is the precursor of serotonin. A disturbed transport of tyrosine, as well as other amino acids, has been found in a number of other psychiatric disorders, such as schizophrenia, bipolar disorder and autism, when using the fibroblast cell model. Hence, the aim of this study was to explore whether children with ADHD may have disturbed amino acid transport. Methods Fibroblast cells were cultured from skin biopsies obtained from 14 boys diagnosed with ADHD and from 13 matching boys without a diagnosis of a developmental disorder. Transport of the amino acids tyrosine, tryptophan and alanine across the cell membrane was measured by the cluster tray method. The kinetic parameters, maximal transport capacit...
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Research Interests: Genetics, Family, Biology, Medicine, Humans, and 15 moreEffect size, Female, Male, Middle Aged, Adult, American Medical Association, Amino Acid Profile, Human Fibroblasts, Archives General Psychiatry, Plasma Membrane, Binding Site, Age of Onset, Cell Membrane, fibroblasts, and Medical and Health Sciences
Research Interests: Immunology, Rheumatoid Arthritis, Medicine, Humans, Internal Medicine, and 13 moreFasting, Escherichia coli, Weight Loss, Female, Clinical Sciences, Middle Aged, Neutrophils, Adult, Public health systems and services research, Body Weight, Joints, Erythrocyte Sedimentation Rate, and Clinical Trials as Topic
Schizophrenia involves neural catecholaminergic dysregulation. Tyrosine is the precursor of catecholamines, and its major transporter, according to studies on fibroblasts, in the brain is the L-type amino acid transporter 1 (LAT1). The... more
Schizophrenia involves neural catecholaminergic dysregulation. Tyrosine is the precursor of catecholamines, and its major transporter, according to studies on fibroblasts, in the brain is the L-type amino acid transporter 1 (LAT1). The present study assessed haplotype tag single-nucleotide polymorphisms (SNPs) of the <i>SLC7A5</i>/<i>LAT1</i> gene in 315 patients with psychosis within the schizophrenia spectrum and 233 healthy controls to investigate genetic vulnerability to the disorder as well as genetic relationships to homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), the major catecholamine metabolites in the cerebrospinal fluid (CSF). Moreover, the involvement of the different isoforms of the system L in tyrosine uptake and LAT1 tyrosine kinetics were studied in fibroblast cell lines of 10 patients with schizophrenia and 10 healthy controls. The results provide suggestive evidence of individual vulnerability to schizophrenia related to the <i>LAT1 </i>SNP rs9936204 genotype. A number of SNPs were nominally associated with CSF HVA and MHPG concentrations but did not survive correction for multiple testing. The LAT1 isoform was confirmed as the major tyrosine transporter in patients with schizophrenia. However, the kinetic parameters (maximal transport capacity, affinity of the binding sites, and diffusion constant of tyrosine transport through the LAT1 isoform) did not differ between patients with schizophrenia and controls. The present genetic findings call for independent replication in larger samples, while the functional study seems to exclude a role of LAT1 in the aberrant transport of tyrosine in fibroblasts of patients with schizophrenia.
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The large use of perfluorinated compounds (PFCs) to produce fluoropolymers in consumer and industrial applications, including insecticides, plastics, non-stick surfaces and fire fighting foams has ...
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The large neutral amino acids tyrosine and tryptophan are precursors of the neurotransmitters dopamine and serotonin and their availability in the brain may influence neurotransmission. Disturbed n ...
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Decreased density of muscarinic acetylcholine receptors in fibroblasts from children with Attention Deficit/Hyperactivity Disorder (ADHD)
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Background: It is believed that the neurotransmitters, dopamine and norepinephrine are involved in the pathophysiology of the neurobehavioral disorder Attention Deficit/Hyperactivity Disorder (ADHD ...
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Tyrosine and tryptophan are precursors to dopamine and serotonin and are involved in partial regulation of dopamine and serotonin synthesis. Changes in tyrosine and or tryptophan availability may i ...
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Interleukin-1beta inhibits tyrosine transport in fibroblasts from ptients with schizophrenia and healthy controls
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It has been demonstrated, that long-term chronic tryptophan deficiency, results in decreased serotonin synthesis, which may lead to low bone mass and low bone formation. Findings from studies in male patients with idiopathic osteoporosis... more
It has been demonstrated, that long-term chronic tryptophan deficiency, results in decreased serotonin synthesis, which may lead to low bone mass and low bone formation. Findings from studies in male patients with idiopathic osteoporosis suggested a decreased transport of tryptophan in erythrocytes of osteoporotic patients, indicating that serotonin system defects may be involved in the etiology of low bone mass. Tryptophan is the precursor of serotonin, and a disturbed transport of tryptophan is implicated in altered serotonin synthesis. However, no study has investigated the tryptophan transport kinetics in MIO patients. The aim of this study is to investigate the kinetic parameters of tryptophan transport in fibroblasts derived from MIO patients compared to age and sex matched controls.Fibroblast cells were cultured from skin biopsies obtained from 14 patients diagnosed with Male Idiopathic Osteoporosis and from 13 healthy age-sex matched controls, without a diagnosis of osteoporosis. Transport of the amino acid tryptophan across the cell membrane was measured by the cluster tray method. The kinetic parameters, maximal transport capacity (Vmax) and affinity constant (Km) were determined by using the Lineweaver-Burke plot equation.The results of this study have shown a significantly lower mean value for Vmax (p = 0.0138) and lower Km mean value (p = 0.0009) of tryptophan transport in fibroblasts of MIO patients compared to the control group. A lower Vmax implied a decreased tryptophan transport availability in MIO patients.In conclusion, reduced cellular tryptophan availability in MIO patients might result in reduced brain serotonin synthesis and its endogenous levels in peripheral tissues, and this may contribute to low bone mass/formation. The findings of the present study could contribute to the etiology of idiopathic osteoporosis and for the development of novel approaches for diagnosis, treatment and management strategies of MIO.
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Background: Proinflammatory cytokines and oxidative stress responses have been extensively implicated in the pathophysiology of neuropsychiatric disorders over the past 2 decades. Moreover, disturbed transport of the dopamine precursor... more
Background: Proinflammatory cytokines and oxidative stress responses have been extensively implicated in the pathophysiology of neuropsychiatric disorders over the past 2 decades. Moreover, disturbed transport of the dopamine precursor (i.e., the amino acid tyrosine) has been demonstrated, in different studies, across fibroblast cell membranes obtained from neuropsychiatric patients. However, the role and influences of proinflammatory cytokines and oxidative stress, and the reasons for disturbed tyrosine transport in neuropsychiatric disorders, are still not evaluated. Aims: The present study aimed to assess the role of proinflammatory cytokines and oxidative stress, indicated in many neuropsychiatric disorders, in tyrosine transportation, by using human skin-derived fibroblasts. Methods: Fibroblasts obtained from a healthy control were used in this study. Fibroblasts were treated with proinflammatory cytokines (IL-1β, IFN-γ, IL-6, TNF-α), their combinations, and oxidative stress, optimized for concentrations and incubation time, to analyze the uptake of 14C-tyrosine compared to untreated controls. Results and Conclusion: This study demonstrates that proinflammatory cytokines and oxidative stress decrease the transport of tyrosine (47% and 33%, respectively), which can alter dopamine synthesis. The functionality of the tyrosine transporter could be a new potential biomarker to target for discovering new drugs to counteract the effects of proinflammatory cytokines and oxidative stress in the pathophysiology of neuropsychiatric disorders.
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Schizophrenia (SZ) is a serious psychiatric disease, with a complex genetic basis that affects around 1% of the population worldwide. The symptoms of the disease are divided into positive, negative and cognitive symptoms. Positive... more
Schizophrenia (SZ) is a serious psychiatric disease, with a complex genetic basis that affects around 1% of the population worldwide. The symptoms of the disease are divided into positive, negative and cognitive symptoms. Positive symptoms include hallucinations, delusions as well as disorganised speech and behaviour. Negative symptoms include anhedonia, social withdrawal, and lack of motivation and energy. Finally, cognitive symptoms involve cognitive dysfunctions of patients suffering from SZ. Pharmacological treatment of the disease mostly deals with the positive, psychotic symptoms of the disease, but does not improve cognitive and social dysfunction. Moreover, the etiology of SZ predicates upon a combination of genetic and environmental factors, probably in early life, that affect neurogenesis and neuronal plasticity [1]. DNA microarray technologies enabling genome-wide gene expression profiling have been intensely exploited in the last decade, in order to promote the elucidation of the underlying biological mechanisms of SZ [2-5]. These studies, through the high dimensional data that they yield, can prove to be very useful for the generation of diagnostic biomarker signatures in the management of SZ. The usefulness of these data is based on the fact that they may reveal several genes that act synergistically. Probably, the genes that present these synergistic effects with other genes cannot be associated with SZ on their own. The importance of the development of classification models in SZ is great as, at the moment, the diagnosis of the disease is based exclusively on the evaluation of the clinical symptoms after they have manifested. Despite much research effort, some of the most crucial questions regarding SZ have not been answered. The heterogeneity and the multi-factorial background of SZ suggest the study of this disease through statistical methods for the identification of patterns in the data. Differentially expressed genes occurring from microarray experiments can be utilized as classifying biomarkers gain and can reveal underlying genetic factors in relation to important psychiatric diseases, such as SZ [6].
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Introduction: Butyrate is a short-chain fatty acid metabolite produced by microbiota in the colon. With its antioxidant properties, butyrate has also been shown to alter the neurological functions in affective disorder models, suggesting... more
Introduction: Butyrate is a short-chain fatty acid metabolite produced by microbiota in the colon. With its antioxidant properties, butyrate has also been shown to alter the neurological functions in affective disorder models, suggesting it as a key mediator in gut-brain interactions. Objective: Here, we evaluated the negative effect of oxidative stress on the transport of the serotonin precursor tryptophan as present in affective disorders. Butyrate was hypothesized to be able to rescue these deficits due to its antioxidative capacities and its effect on transmembrane transport of tryptophan. Human skin-derived fibroblasts were used as cellular models to address these objectives. Methods: Human fibroblasts were treated with hydrogen peroxide to induce oxidative stress. Stressed as well as control cells were treated with different concentrations of butyrate. Tryptophan (3H) was used as a tracer to measure the transport of tryptophan across the cell membranes (n = 6). Furthermore, ge...
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The experience and knowledge I have concerning, Sisay Ambaye MSc, is based on my position, as a course director/examine of the Master Degree Projects in Medicine at. Our department is an educational and research department provide... more
The experience and knowledge I have concerning, Sisay Ambaye MSc, is based on my position, as a course director/examine of the Master Degree Projects in Medicine at. Our department is an educational and research department provide educational programs in Medical/Biomedical Sciences including BSc-, MSc-and PhD-levels. Sisay Ambaye has been completed our Master program (Biomedicine and Methods in Medical Diagnostics, profile Experimental Medicine 120 credits), and he was performed well both the theoretical and practical courses. He has completed a 45 ECTS Master Degree Project thesis at the department of Laboratory Medicine, University Hospital Örebro, with a project entitled "Method development and advancement of Human papilloma virus (HPV) detection and genotyping". He carried out his thesis project and passed it very well. Sisay Ambaye is an ambitious student, he showed a great interest in participating in our seminars and research activities, and had a very good social competence and a genuine interest on the research field conducted his Master Thesis. He is an open communicative person and was always followed the instruction's/research's plans etc.. I believe that he has all the qualification and the capacity to complete the Healthcare Leadership and Commissioning course. I warmly recommend him. Sincerely yours, _____________________________________ Nikolaos Venizelos, Professor Senior/Researcher