Hyperglycemia and inflammation are involved in the progression of spontaneous intracerebral hemor... more Hyperglycemia and inflammation are involved in the progression of spontaneous intracerebral hemorrhage (sICH)-induced brain injury, but their role in predicting clinical outcome is not clear. We sought to determine whether elevation of white blood cell count (WBC), C-reactive protein (CRP), and blood glucose (BG) concentration at presentation prognosticate poor outcome in sICH patients. Between November 1, 2005 and October 31, 2009, 210 patients admitted to 2 intensive care units were prospectively consecutively evaluated after exclusion of patients with underlying inflammatory conditions. WBC, CRP, and BG were measured and ICH scores were calculated on first evaluation. Primary outcome was 30-day mortality. Secondary outcome was 30-day functional outcome using the Glasgow Outcome scale. The median CRP concentration was 7.85 mg/L (interquartile range, 4.0-12.0 mg/L), median WBC count was 8.05×10(9)/L (interquartile range, 6.45-9.9×10(9)/L) and median glucose concentration was 7.66 mmol/L (interquartile range, 6.11-10.83 mmol/L). At 30 days, 63 patients (30%) were dead and 101 (48.1%) had poor outcome (Glasgow Outcome scale score, 1-3). Higher WBC (P<0.001), CRP (P<0.05), and BG (P<0.001) were associated with mortality on univariate analyses, but only CRP remained associated with mortality (P<0.005) after adjustment for multiple confounders. CRP improved mortality prediction when added to the ICH score. None of the markers tested had significant associations with functional outcome. Higher WBC, CRP, and BG are associated with increased mortality in sICH patients. Only CRP elevation portends higher risk of death independently of other indicators of sICH severity.
Cognitive abilities depend primarily on cerebrovascular health and aging. In this work, we examin... more Cognitive abilities depend primarily on cerebrovascular health and aging. In this work, we examine the pathogenic mechanisms of brain dysfunction linked to vascular risk factors, insulin signaling and cerebrovascular damage and explore how these mechanisms interfere with neurodegeneration. Although Abeta hypothesis prevails in the ethiology of Alzheimer's Disease(AD), it has become increasingly evident that disturbances in cerebral glucose metabolism is an invariant pathophysiological feature of AD and may provide an ubiquituos mechanism underlying the pathogenesis of AD. Currently, it is difficult to identify efficient therapeutic approach for brain protection and recovery, especially because we do not fully understand the underlying neurobiological processes, the nature of the pathophysiological mechanisms and the links between these two categories. Endogenous neurobiological processes, such as "brain reserves", neurotrophicity, neuroplasticity and neurogenesis, are ...
The circadian clock coordinates the internal physiology to increase the homeostatic capacity ther... more The circadian clock coordinates the internal physiology to increase the homeostatic capacity thereby providing both a survival advantage to the system and an optimization of energy budgeting. Multiple-oscillator circadian mechanisms are likely to play a role in regulating human health and may contribute to the aging process. Our aim is to give an overview of how the central clock in the hypothalamus and peripheral clocks relate to aging and metabolic disorders, including hyperlipidemia and hyperglycemia. In particular, we unravel novel putative mechanisms to link circadian clocks to healthy aging. This review may lead to the design of large-scale interventions to help people stay healthy as they age by adjusting daily activities, such as feeding behavior, and or adaptation to age-related changes in individual circadian rhythms.
Major depressive disorder (MDD) is a severe psychiatric illness that is associated with significa... more Major depressive disorder (MDD) is a severe psychiatric illness that is associated with significant morbidity and mortality. Despite advances in the treatment of major depression, one-third of depressed patients fail to respond to conventional antidepressant medication. One pathophysiologic mechanism hypothesized to contribute to treatment resistance in depression is inflammation. Inflammation has been linked to depression by a number of putative mechanisms involving perfusion deficits that can trigger microglial activation and subsequent neuroinflammation in the elderly. However, the pathophysiological mechanisms remain to be further elucidated. This review focusses on recent studies addressing the complex relationships between depression, aging, inflammation and perfusion deficits in the elderly. We expect that a better understanding of neuroinflammatory mechanisms associated with age-related diseases may lead to the discovery of new biomarkers of MDD and development of new therap...
Ageing is associated with changes in the function of various organ systems. Changes in the cardio... more Ageing is associated with changes in the function of various organ systems. Changes in the cardiovascular system affect both directly and indirectly the function in a variety of organs, including the brain, with consequent neurological (motor and sensory performance) and cognitive impairments, as well as leading to the development of various psychiatric diseases. Post-stroke depression (PSD) is among the most frequent neuropsychiatric consequences of cerebral ischemia. This review discusses several animal models used for the study of PSD and summarizes recent findings in the genomic profile of the ageing brain, which are associated with age-related disorders in the elderly. Since stroke and depression are diseases with increased incidence in the elderly, great clinical benefit may especially accrue from deciphering and targeting basic mechanisms underlying PSD. Finally, we discuss the relationship between ageing, circadian rhythmicity and PSD.
To a great extent, cognitive health depends on cerebrovascular health and a deeper understanding ... more To a great extent, cognitive health depends on cerebrovascular health and a deeper understanding of the subtle interactions between cerebrovascular function and cognition is needed to protect humans from one of the most devastating affliction, dementia. However, the underlying biological mechanisms are still not completely clear. Many studies demonstrated that the neurovascular unit is compromised in cerebrovascular diseases and also in other types of dementia. The hemodynamic neurovascular coupling ensures a strong increase of the cerebral blood flow (CBF) and an acute increase in neuronal glucose uptake upon increased neural activity. Dysfunction of cerebral autoregulation with increasing age along with age-related structural and functional alterations in cerebral blood vessels including accumulation of amyloid-beta (Aβ) in the media of cortical arterioles, neurovascular uncoupling due to astrocyte endfeet retraction, impairs the CBF and increases the neuronal degeneration and sus...
Stroke has limited treatment options, demanding a vigorous search for new therapeutic strategies.... more Stroke has limited treatment options, demanding a vigorous search for new therapeutic strategies. Initial enthusiasm to stimulate restorative processes in the ischemic brain by means of cell-based therapies has meanwhile converted into a more balanced view recognizing impediments related to unfavorable environments that are in part related to aging processes. Since stroke afflicts mostly the elderly, it is highly desirable and clinically important to test the efficacy of cell therapies in aged brain microenvironments. Although widely believed to be refractory to regeneration, recent studies using both neural precursor cells and bone marrow-derived mesenchymal stem cells for stroke therapy suggest that the aged rat brain is not refractory to cell-based therapy, and that it also supports plasticity and remodeling. Yet, important differences exist in the aged compared with young brain, i.e., the accelerated progression of ischemic injury to brain infarction, the reduced rate of endogen...
Irritable bowel syndrome (IBS) is a functional syndrome characterized by chronic abdominal pain a... more Irritable bowel syndrome (IBS) is a functional syndrome characterized by chronic abdominal pain accompanied by altered bowel habits. Although generally considered a functional disorder, there is now substantial evidence that IBS is associated with a poor quality of life and significant negative impact on work and social domains. Neuroimaging studies documented changes in the prefrontal cortex, ventro-lateral and posterior parietal cortex and thalami, and implicate alteration of brain circuits involved in attention, emotion and pain modulation. Emerging data reveals the interaction between psychiatric disorders including generalized anxiety disorder, panic disorder, major depressive disorder, bipolar disorder, and schizophrenia and IBS, which suggests that this association should not be ignored when developing strategies for screening and treatment. Psychological, social and genetic factors appear to be important in the development of IBS symptomatology through several mechanisms: al...
Restorative strategies after stroke are focused on the remodeling of cerebral endothelial cells a... more Restorative strategies after stroke are focused on the remodeling of cerebral endothelial cells and brain parenchymal cells. The latter, i.e., neurons, neural precursor cells and glial cells, synergistically interact with endothelial cells in the ischemic brain, providing a neurovascular unit whose components can be used as target for stroke therapies. Following focal cerebral ischemia, brain capillary cells are enabled to sprout. Neural precursor cells proliferate and migrate along cerebral microvessels to the ischemic lesion. Glial cells promote the restoration of functional microvessels and at the same time control the buildup of the extracellular matrix, creating a favorable environment to neuronal plasticity both in the ischemic and contralesional brain hemiphere. Until now, a large majority of studies have been performed in young, otherwise healthy animals. Recent behavioral, histochemical and molecular biological studies have shown that restorative brain responses differ betw...
C-reactive protein (CRP) is a blood marker of inflammation and a hallmark of the acute-phase resp... more C-reactive protein (CRP) is a blood marker of inflammation and a hallmark of the acute-phase response. Its elevation bears negative prognostic implications for many conditions and it has also been shown to be a nonspecific predictor of long-term risk of cerebrovascular disease (CVD) in several populations, while elevations of CRP associated with the major acute-phase response following ischemic or hemorrhagic stroke are associated with death and vascular complications. High-sensitivity assays that accurately measure levels of CRP have been proposed for use in risk assessment for CVD and as a prognostic marker after an acute event, although the pathogenic and clinical significance of these associations is controversial. In this article, we critically review the literature in narrative format and describe major epidemiological studies, novel experiments and possible future developments that may inform the debate. In our discussion, we will distinguish the different pathophysiological ...
The neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophic factor 3 (NT3) could ... more The neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophic factor 3 (NT3) could play a role in addictive behavior. Interactions between BDNF and dopamine transmission influence the alcohol intake. It has been hypothesized that extensive alcohol consumption leads to diminished circulating BDNF levels and impaired BDNF-mediated protective mechanisms. What is more, alcohol dependency causes changes in lipid metabolism which in turn may influence the neurotrophin system. In this study, we tested the hypothesis that alcohol withdrawal increases the serum levels of BDNF in alcoholic patients and investigated correlations between serum BDNF and NT3 and alcohol in breath as well as with the body-mass-index (BMI), lipoprotein profiles and lifestyle factors in 110 male in-patients diagnosed with alcohol addiction on the first day after admission and at discharge. The intoxication level (alcohol in breath at admission) was significantly correlated with liver enzymes and BDNF c...
In aged humans, stroke is a major cause of disability for which no neuroprotective measures are a... more In aged humans, stroke is a major cause of disability for which no neuroprotective measures are available. Granulocyte-colony stimulating factor (G-CSF), a member of the cytokine family of growth factors, promotes brain neurogenesis and improves functional outcome after stroke in young animals. We tested the hypothesis that G-CSF provides a restorative therapeutic benefit in aged animals. Focal cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery in 19- to 20-month-old male Sprague-Dawley rats. One hour after reperfusion, the aged rats were treated daily with 15 microg/kg G-CSF and for 15 days total. Rats were behaviorally tested and the brains removed for analysis at 28 days poststroke. G-CSF treatment after stroke exerted a robust and sustained beneficial effect on survival rate and running function. Transient improvement after G-CSF treatment could be observed for coordinative motor function on the inclined plane test and for working memory i...
Induced pluripotent stem cells (iPSCs) improve behavior and form neurons after implantation into ... more Induced pluripotent stem cells (iPSCs) improve behavior and form neurons after implantation into the stroke-injured adult rodent brain. How the aged brain responds to grafted iPSCs is unknown. We determined survival and differentiation of grafted human fibroblast-derived iPSCs and their ability to improve recovery in aged rats after stroke. Twenty-four months old rats were subjected to 30 min distal middle cerebral artery occlusion causing neocortical damage. After 48 h, animals were transplanted intracortically with human iPSC-derived long-term neuroepithelial-like stem (hiPSC-lt-NES) cells. Controls were subjected to stroke and were vehicle-injected. Cell-grafted animals performed better than vehicle-injected recipients in cylinder test at 4 and 7 weeks. At 8 weeks, cell proliferation was low (0.7 %) and number of hiPSC-lt-NES cells corresponded to 49.2% of that of implanted cells. Transplanted cells expressed markers of neuroblasts and mature and GABAergic neurons. Cell-grafted r...
Chronic lymphocytic leukemia (CLL) is characterized by a predominant humoral immune deficiency pr... more Chronic lymphocytic leukemia (CLL) is characterized by a predominant humoral immune deficiency predisposing the patients to infections. Oxidative stress leads to an increased immunoglobulin k light chain production in B cells and contributes to the antibodies' deficiency and hypogammaglobulinemia. Aim of the Study. To evaluate the global oxidative status in patients with CLL and to determine whether the administration of antioxidants decreases complications due to infections. Patients and Method. We studied 84 patients with CLL stratified by Binet staging. Free oxygen radicals and antioxidant status were determined by the FORT and FORD test, respectively, at diagnosis and in the presence of infections. The patients were distributed in two groups: group A, treated only with antileukemic treatment, and group B, treated with antileukemic treatment and antioxidants. Results. By FORD and FORT assay, all patients had at diagnosis a low antioxidant capacity, and high levels of hydroperoxides. Infectious complications were more frequent in group A (B/C stages of disease) than in group B. Administrations of antioxidants stimulated the immune response and decreased infectious complications in CLL. Conclusions. Administrations of antioxidants and a healthy life style may improve the quality of life of patients with CLL and reduce the risk of infectious complications.
Stroke has limited treatment options, demanding a vigorous search for new therapeutic strategies.... more Stroke has limited treatment options, demanding a vigorous search for new therapeutic strategies. Initial enthusiasm to stimulate restorative processes in the ischemic brain by means of cell-based therapies has meanwhile converted into a more balanced view recognizing impediments related to unfavorable environments that are in part related to aging processes. Since stroke afflicts mostly the elderly, it is highly desirable and clinically important to test the efficacy of cell therapies in aged brain microenvironments. Although widely believed to be refractory to regeneration, recent studies using both neural precursor cells and bone marrow-derived mesenchymal stem cells for stroke therapy suggest that the aged rat brain is not refractory to cell-based therapy, and that it also supports plasticity and remodeling. Yet, important differences exist in the aged compared with young brain, i.e., the accelerated progression of ischemic injury to brain infarction, the reduced rate of endogenous neurogenesis and the delayed initiation of neurological recovery. Pitfalls in the development of cell-based therapies may also be related to age-associated comorbidities, e.g., diabetes or hyperlipidemia, which may result in maladaptive or compromised brain remodeling, respectively. These age-related aspects should be carefully considered in the clinical translation of restorative therapies.
Hyperglycemia and inflammation are involved in the progression of spontaneous intracerebral hemor... more Hyperglycemia and inflammation are involved in the progression of spontaneous intracerebral hemorrhage (sICH)-induced brain injury, but their role in predicting clinical outcome is not clear. We sought to determine whether elevation of white blood cell count (WBC), C-reactive protein (CRP), and blood glucose (BG) concentration at presentation prognosticate poor outcome in sICH patients. Between November 1, 2005 and October 31, 2009, 210 patients admitted to 2 intensive care units were prospectively consecutively evaluated after exclusion of patients with underlying inflammatory conditions. WBC, CRP, and BG were measured and ICH scores were calculated on first evaluation. Primary outcome was 30-day mortality. Secondary outcome was 30-day functional outcome using the Glasgow Outcome scale. The median CRP concentration was 7.85 mg/L (interquartile range, 4.0-12.0 mg/L), median WBC count was 8.05×10(9)/L (interquartile range, 6.45-9.9×10(9)/L) and median glucose concentration was 7.66 mmol/L (interquartile range, 6.11-10.83 mmol/L). At 30 days, 63 patients (30%) were dead and 101 (48.1%) had poor outcome (Glasgow Outcome scale score, 1-3). Higher WBC (P<0.001), CRP (P<0.05), and BG (P<0.001) were associated with mortality on univariate analyses, but only CRP remained associated with mortality (P<0.005) after adjustment for multiple confounders. CRP improved mortality prediction when added to the ICH score. None of the markers tested had significant associations with functional outcome. Higher WBC, CRP, and BG are associated with increased mortality in sICH patients. Only CRP elevation portends higher risk of death independently of other indicators of sICH severity.
Cognitive abilities depend primarily on cerebrovascular health and aging. In this work, we examin... more Cognitive abilities depend primarily on cerebrovascular health and aging. In this work, we examine the pathogenic mechanisms of brain dysfunction linked to vascular risk factors, insulin signaling and cerebrovascular damage and explore how these mechanisms interfere with neurodegeneration. Although Abeta hypothesis prevails in the ethiology of Alzheimer's Disease(AD), it has become increasingly evident that disturbances in cerebral glucose metabolism is an invariant pathophysiological feature of AD and may provide an ubiquituos mechanism underlying the pathogenesis of AD. Currently, it is difficult to identify efficient therapeutic approach for brain protection and recovery, especially because we do not fully understand the underlying neurobiological processes, the nature of the pathophysiological mechanisms and the links between these two categories. Endogenous neurobiological processes, such as "brain reserves", neurotrophicity, neuroplasticity and neurogenesis, are ...
The circadian clock coordinates the internal physiology to increase the homeostatic capacity ther... more The circadian clock coordinates the internal physiology to increase the homeostatic capacity thereby providing both a survival advantage to the system and an optimization of energy budgeting. Multiple-oscillator circadian mechanisms are likely to play a role in regulating human health and may contribute to the aging process. Our aim is to give an overview of how the central clock in the hypothalamus and peripheral clocks relate to aging and metabolic disorders, including hyperlipidemia and hyperglycemia. In particular, we unravel novel putative mechanisms to link circadian clocks to healthy aging. This review may lead to the design of large-scale interventions to help people stay healthy as they age by adjusting daily activities, such as feeding behavior, and or adaptation to age-related changes in individual circadian rhythms.
Major depressive disorder (MDD) is a severe psychiatric illness that is associated with significa... more Major depressive disorder (MDD) is a severe psychiatric illness that is associated with significant morbidity and mortality. Despite advances in the treatment of major depression, one-third of depressed patients fail to respond to conventional antidepressant medication. One pathophysiologic mechanism hypothesized to contribute to treatment resistance in depression is inflammation. Inflammation has been linked to depression by a number of putative mechanisms involving perfusion deficits that can trigger microglial activation and subsequent neuroinflammation in the elderly. However, the pathophysiological mechanisms remain to be further elucidated. This review focusses on recent studies addressing the complex relationships between depression, aging, inflammation and perfusion deficits in the elderly. We expect that a better understanding of neuroinflammatory mechanisms associated with age-related diseases may lead to the discovery of new biomarkers of MDD and development of new therap...
Ageing is associated with changes in the function of various organ systems. Changes in the cardio... more Ageing is associated with changes in the function of various organ systems. Changes in the cardiovascular system affect both directly and indirectly the function in a variety of organs, including the brain, with consequent neurological (motor and sensory performance) and cognitive impairments, as well as leading to the development of various psychiatric diseases. Post-stroke depression (PSD) is among the most frequent neuropsychiatric consequences of cerebral ischemia. This review discusses several animal models used for the study of PSD and summarizes recent findings in the genomic profile of the ageing brain, which are associated with age-related disorders in the elderly. Since stroke and depression are diseases with increased incidence in the elderly, great clinical benefit may especially accrue from deciphering and targeting basic mechanisms underlying PSD. Finally, we discuss the relationship between ageing, circadian rhythmicity and PSD.
To a great extent, cognitive health depends on cerebrovascular health and a deeper understanding ... more To a great extent, cognitive health depends on cerebrovascular health and a deeper understanding of the subtle interactions between cerebrovascular function and cognition is needed to protect humans from one of the most devastating affliction, dementia. However, the underlying biological mechanisms are still not completely clear. Many studies demonstrated that the neurovascular unit is compromised in cerebrovascular diseases and also in other types of dementia. The hemodynamic neurovascular coupling ensures a strong increase of the cerebral blood flow (CBF) and an acute increase in neuronal glucose uptake upon increased neural activity. Dysfunction of cerebral autoregulation with increasing age along with age-related structural and functional alterations in cerebral blood vessels including accumulation of amyloid-beta (Aβ) in the media of cortical arterioles, neurovascular uncoupling due to astrocyte endfeet retraction, impairs the CBF and increases the neuronal degeneration and sus...
Stroke has limited treatment options, demanding a vigorous search for new therapeutic strategies.... more Stroke has limited treatment options, demanding a vigorous search for new therapeutic strategies. Initial enthusiasm to stimulate restorative processes in the ischemic brain by means of cell-based therapies has meanwhile converted into a more balanced view recognizing impediments related to unfavorable environments that are in part related to aging processes. Since stroke afflicts mostly the elderly, it is highly desirable and clinically important to test the efficacy of cell therapies in aged brain microenvironments. Although widely believed to be refractory to regeneration, recent studies using both neural precursor cells and bone marrow-derived mesenchymal stem cells for stroke therapy suggest that the aged rat brain is not refractory to cell-based therapy, and that it also supports plasticity and remodeling. Yet, important differences exist in the aged compared with young brain, i.e., the accelerated progression of ischemic injury to brain infarction, the reduced rate of endogen...
Irritable bowel syndrome (IBS) is a functional syndrome characterized by chronic abdominal pain a... more Irritable bowel syndrome (IBS) is a functional syndrome characterized by chronic abdominal pain accompanied by altered bowel habits. Although generally considered a functional disorder, there is now substantial evidence that IBS is associated with a poor quality of life and significant negative impact on work and social domains. Neuroimaging studies documented changes in the prefrontal cortex, ventro-lateral and posterior parietal cortex and thalami, and implicate alteration of brain circuits involved in attention, emotion and pain modulation. Emerging data reveals the interaction between psychiatric disorders including generalized anxiety disorder, panic disorder, major depressive disorder, bipolar disorder, and schizophrenia and IBS, which suggests that this association should not be ignored when developing strategies for screening and treatment. Psychological, social and genetic factors appear to be important in the development of IBS symptomatology through several mechanisms: al...
Restorative strategies after stroke are focused on the remodeling of cerebral endothelial cells a... more Restorative strategies after stroke are focused on the remodeling of cerebral endothelial cells and brain parenchymal cells. The latter, i.e., neurons, neural precursor cells and glial cells, synergistically interact with endothelial cells in the ischemic brain, providing a neurovascular unit whose components can be used as target for stroke therapies. Following focal cerebral ischemia, brain capillary cells are enabled to sprout. Neural precursor cells proliferate and migrate along cerebral microvessels to the ischemic lesion. Glial cells promote the restoration of functional microvessels and at the same time control the buildup of the extracellular matrix, creating a favorable environment to neuronal plasticity both in the ischemic and contralesional brain hemiphere. Until now, a large majority of studies have been performed in young, otherwise healthy animals. Recent behavioral, histochemical and molecular biological studies have shown that restorative brain responses differ betw...
C-reactive protein (CRP) is a blood marker of inflammation and a hallmark of the acute-phase resp... more C-reactive protein (CRP) is a blood marker of inflammation and a hallmark of the acute-phase response. Its elevation bears negative prognostic implications for many conditions and it has also been shown to be a nonspecific predictor of long-term risk of cerebrovascular disease (CVD) in several populations, while elevations of CRP associated with the major acute-phase response following ischemic or hemorrhagic stroke are associated with death and vascular complications. High-sensitivity assays that accurately measure levels of CRP have been proposed for use in risk assessment for CVD and as a prognostic marker after an acute event, although the pathogenic and clinical significance of these associations is controversial. In this article, we critically review the literature in narrative format and describe major epidemiological studies, novel experiments and possible future developments that may inform the debate. In our discussion, we will distinguish the different pathophysiological ...
The neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophic factor 3 (NT3) could ... more The neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophic factor 3 (NT3) could play a role in addictive behavior. Interactions between BDNF and dopamine transmission influence the alcohol intake. It has been hypothesized that extensive alcohol consumption leads to diminished circulating BDNF levels and impaired BDNF-mediated protective mechanisms. What is more, alcohol dependency causes changes in lipid metabolism which in turn may influence the neurotrophin system. In this study, we tested the hypothesis that alcohol withdrawal increases the serum levels of BDNF in alcoholic patients and investigated correlations between serum BDNF and NT3 and alcohol in breath as well as with the body-mass-index (BMI), lipoprotein profiles and lifestyle factors in 110 male in-patients diagnosed with alcohol addiction on the first day after admission and at discharge. The intoxication level (alcohol in breath at admission) was significantly correlated with liver enzymes and BDNF c...
In aged humans, stroke is a major cause of disability for which no neuroprotective measures are a... more In aged humans, stroke is a major cause of disability for which no neuroprotective measures are available. Granulocyte-colony stimulating factor (G-CSF), a member of the cytokine family of growth factors, promotes brain neurogenesis and improves functional outcome after stroke in young animals. We tested the hypothesis that G-CSF provides a restorative therapeutic benefit in aged animals. Focal cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery in 19- to 20-month-old male Sprague-Dawley rats. One hour after reperfusion, the aged rats were treated daily with 15 microg/kg G-CSF and for 15 days total. Rats were behaviorally tested and the brains removed for analysis at 28 days poststroke. G-CSF treatment after stroke exerted a robust and sustained beneficial effect on survival rate and running function. Transient improvement after G-CSF treatment could be observed for coordinative motor function on the inclined plane test and for working memory i...
Induced pluripotent stem cells (iPSCs) improve behavior and form neurons after implantation into ... more Induced pluripotent stem cells (iPSCs) improve behavior and form neurons after implantation into the stroke-injured adult rodent brain. How the aged brain responds to grafted iPSCs is unknown. We determined survival and differentiation of grafted human fibroblast-derived iPSCs and their ability to improve recovery in aged rats after stroke. Twenty-four months old rats were subjected to 30 min distal middle cerebral artery occlusion causing neocortical damage. After 48 h, animals were transplanted intracortically with human iPSC-derived long-term neuroepithelial-like stem (hiPSC-lt-NES) cells. Controls were subjected to stroke and were vehicle-injected. Cell-grafted animals performed better than vehicle-injected recipients in cylinder test at 4 and 7 weeks. At 8 weeks, cell proliferation was low (0.7 %) and number of hiPSC-lt-NES cells corresponded to 49.2% of that of implanted cells. Transplanted cells expressed markers of neuroblasts and mature and GABAergic neurons. Cell-grafted r...
Chronic lymphocytic leukemia (CLL) is characterized by a predominant humoral immune deficiency pr... more Chronic lymphocytic leukemia (CLL) is characterized by a predominant humoral immune deficiency predisposing the patients to infections. Oxidative stress leads to an increased immunoglobulin k light chain production in B cells and contributes to the antibodies' deficiency and hypogammaglobulinemia. Aim of the Study. To evaluate the global oxidative status in patients with CLL and to determine whether the administration of antioxidants decreases complications due to infections. Patients and Method. We studied 84 patients with CLL stratified by Binet staging. Free oxygen radicals and antioxidant status were determined by the FORT and FORD test, respectively, at diagnosis and in the presence of infections. The patients were distributed in two groups: group A, treated only with antileukemic treatment, and group B, treated with antileukemic treatment and antioxidants. Results. By FORD and FORT assay, all patients had at diagnosis a low antioxidant capacity, and high levels of hydroperoxides. Infectious complications were more frequent in group A (B/C stages of disease) than in group B. Administrations of antioxidants stimulated the immune response and decreased infectious complications in CLL. Conclusions. Administrations of antioxidants and a healthy life style may improve the quality of life of patients with CLL and reduce the risk of infectious complications.
Stroke has limited treatment options, demanding a vigorous search for new therapeutic strategies.... more Stroke has limited treatment options, demanding a vigorous search for new therapeutic strategies. Initial enthusiasm to stimulate restorative processes in the ischemic brain by means of cell-based therapies has meanwhile converted into a more balanced view recognizing impediments related to unfavorable environments that are in part related to aging processes. Since stroke afflicts mostly the elderly, it is highly desirable and clinically important to test the efficacy of cell therapies in aged brain microenvironments. Although widely believed to be refractory to regeneration, recent studies using both neural precursor cells and bone marrow-derived mesenchymal stem cells for stroke therapy suggest that the aged rat brain is not refractory to cell-based therapy, and that it also supports plasticity and remodeling. Yet, important differences exist in the aged compared with young brain, i.e., the accelerated progression of ischemic injury to brain infarction, the reduced rate of endogenous neurogenesis and the delayed initiation of neurological recovery. Pitfalls in the development of cell-based therapies may also be related to age-associated comorbidities, e.g., diabetes or hyperlipidemia, which may result in maladaptive or compromised brain remodeling, respectively. These age-related aspects should be carefully considered in the clinical translation of restorative therapies.
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