losartan-potassium and Parkinson-Disease

Cognitive dysfunction is a core feature in a range of neuropsychiatric disorders which reduces patients' workforce capacity - the largest socio-economic cost of these disorders. Nevertheless, there is no clinically available medical treatment with robust and enduring efficacy on cognitive deficits in most neuropsychiatric conditions. Recent research has shown that erythropoietin may have beneficial effects on cognitive dysfunction across neuropsychiatric disorders, including bipolar and unipolar disorders, schizophrenia, Parkinson's disease and multiple sclerosis.

Topics: Bipolar Disorder; Cognition; Cognitive Dysfunction; Erythropoietin; Humans; Mood Disorders; Multiple Sclerosis; Parkinson Disease; Schizophrenia

Two hematopoietic cytokines are currently gaining increasing attention within neurological research. Erythropoietin (EPO) and granulocyte-colony stimulating factor (G-CSF) have long been known for their ability to induce the proliferation of certain populations of hematopoietic lineage cells. However, it has recently been found that EPO, G-CSF, and their respective receptors are also expressed in the human central nervous system (CNS) and may be an important part of the brain's endogenous system of protection. Both hematopoietic cytokines have been shown to have neuroprotective potential in a variety of animal disease models both in vitro and in vivo, through the inhibition of apoptosis, induction of angiogenesis, exertion of anti-inflammatory and neurotrophic effects, as well as by the enhancement of neurogenesis. EPO and G-CSF have been extensively studied in the context of hematological disorders and have recently been successfully applied in the first clinical trials in stroke patients. Intravenous high-dose EPO therapy was associated with an improvement in the clinical outcome and preclinical studies with intravenous high-dose G-CSF therapy have clearly shown that it has considerable neuroprotective potential in the acute, as well as in the chronic phase of stroke. In this review, the current knowledge of the neuroprotective mechanisms of EPO and G-CSF is summarized with regard to in vitro and in vivo data. Focus is placed on the role of EPO in neurological disease models with an emphasis on its influence on functional outcome. New experimental results are assessed in detail and correlated with the findings of recent clinical studies.

Topics: Animals; Apoptosis; Brain; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; In Vitro Techniques; Inflammation; Models, Neurological; Neovascularization, Physiologic; Nervous System Diseases; Neurology; Neuroprotective Agents; Parkinson Disease; Research Design; Signal Transduction; Stroke

No neuroprotective treatment has been able to successfully halt the progression of Parkinson disease or prevent development of associated complications. Recombinant erythropoetin (EPO), an erythropoiesis-stimulating agent originally indicated in anemia, produced and manufactured in Cuba (iorEPOCIM, CIMAB S.A, Havana, Cuba) has neuroprotective properties. NeuroEPO is a new nasal formulation of recombinant EPO with a low content of sialic acid and without hematopoietic effects. It has neuroprotective effects in animal models.. Evaluate short-term tolerance of intranasal NeuroEPO in patients with Parkinson disease.. As part of a monocentric randomized placebo-controlled double-blind study (registered at www.clinicaltrials.gov number NCT04110678), 26 patients with Parkinson disease (stages 1 and 2 on Hoehn & Yahr Scale), were randomly divided into two groups: NeuroEPO (n = 15) and placebo (n = 11), both treated intranasally either with the drug (1 mL, at a concentration of 1 mg/mL of NeuroEPO) or placebo once a week for 5 weeks. At each application, we recorded any adverse events and blood pressure. To assess potential hematopoietic effects of the drug, hematological and biochemical variables were evaluated one week before and one week after the intervention.. There were no significant differences (p = 0.22) between the two groups in terms of frequency of adverse events (20.0% in NeuroEPO and 9.1% in placebo groups). Three patients in NeuroEPO presented nausea, and one vomited (possibly due to the patient's positioning during drug application). One patient in placebo group reported polyuria and nasal irritation. In both groups, the adverse events were mild, brief, required no treatment and did not present sequelae.. Nasally administered NeuroEPO for five weeks in patients with Parkinson disease stages 1 and 2 on Hoehn & Yahr Scale is well tolerated.

Topics: Administration, Intranasal; Adult; Aged; Cuba; Double-Blind Method; Erythropoietin; Humans; Middle Aged; Neuroprotective Agents; Parkinson Disease; Recombinant Proteins

Parkinson's disease is characterized by motor dysfunctions including bradykinesia. In a recent study, eight weeks of daily transcranial stimulation with bipolar pulsed electromagnetic fields improved functional rate of force development and decreased inter-hand tremor coherence in patients with mild Parkinson's disease.. To investigate the effect of long-term treatment with transcranial bipolar pulsed electromagnetic fields on motor performance in terms of movement speed and on neurotrophic and angiogenic factors.. Patients diagnosed with idiopathic Parkinson's disease had either daily 30-min treatment with bipolar (±50 V) transcranial pulsed electromagnetic stimulation (squared pulses, 3ms duration) for three eight-week periods separated by one-week pauses (T-PEMF group) (n = 16) or were included in a PD-control group (n = 8). Movement speed was assessed in a six-cycle sit-to-stand task performed on a force plate. Cerebrospinal fluid and venous blood were collected and analyzed for erythropoietin and vascular endothelial growth factor.. Major significant improvement of movement speed compared to the natural development of the disease was found (p = 0.001). Thus, task completion time decreased gradually during the treatment period from 10.10s to 8.23s (p<0.001). The untreated PD-control group did not change (p = 0.458). The treated group did not differ statistically from that of a healthy age matched reference group at completion of treatment. Erythropoietin concentration in the cerebrospinal fluid also increased significantly in the treated group (p = 0.012).. Long-term treatment with transcranial bipolar pulsed electromagnetic fields increased movement speed markedly and elevated erythropoietin levels. We hypothesize that treatment with transcranial bipolar pulsed electromagnetic fields improved functional performance by increasing dopamine levels in the brain, possibly through erythropoietin induced neural repair and/or protection of dopaminergic neurons.

Topics: Aged; Electromagnetic Fields; Erythropoietin; Female; Humans; Magnetic Field Therapy; Male; Middle Aged; Movement; Parkinson Disease; Prospective Studies

Numerous animal studies and clinical trials have demonstrated that erythropoietin (EPO) has therapeutic effects in ischemic and degenerative diseases. However, few clinical trials have investigated the effect of EPO in Parkinson's disease (PD) patients. This study was an exploratory pilot study to investigate the effects of recombinant human EPO (rhEPO) on motor and non-motor symptoms (NMS) in PD patients.. A total of 26 PD patients at the Hanyang University Hospital were enrolled in the study. The participants were randomly assigned to rhEPO and placebo groups. The rhEPO group was infused intravenously (40,000 IU each) twice a week for 5 weeks. Clinical improvement was estimated using the Unified Parkinson's Disease Rating Scale-III (UPDRS-III), the NMS Scale (NMSS) and the 39-Item Parkinson's Disease Questionnaire (PDQ-39). [(18)F] N-(3-fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) nortropane (FP-CIT) photon emission tomography (PET) scanning was performed on each participant at baseline and again after 12 months.. The rhEPO administration significantly improved the NMSS and PDQ-39 scores at 12 months. The UPDRS-III, which reflects motor function, did not change significantly after the rhEPO treatment. With the NMSS, the domains of cardiovascular autonomic function, sleep/fatigue, mood/cognition and attention/memory showed significant changes. None of the participants experienced any serious adverse effects.. We found that rhEPO had beneficial effects on NMS but not on motor function. Dopaminergic refractory NMS, such as cardiovascular autonomic dysfunction and cognition, showed improvement after the administration of rhEPO. Our results suggest that rhEPO might be a good candidate for the treatment of NMS in PD patients.

Topics: Aged; Aged, 80 and over; Brain; Cognition Disorders; Erythropoietin; Female; Humans; Male; Mental Disorders; Middle Aged; Parkinson Disease; Positron-Emission Tomography; Prospective Studies; Single-Blind Method; Sleep Wake Disorders; Surveys and Questionnaires; Time Factors; Tomography, X-Ray Computed; Tropanes; Vascular Diseases

Recombinant human erythropoietin is used primarily to treat anemia. There is evidence of its neuroprotective capacity from preclinical studies in Parkinson's disease and other neurodegenerative diseases. Recombinant human erythropoietin produced in Cuba (ior-EPOCIM) is registered and approved for use in humans in Cuba and in a number of other countries.. Assess safety and possible neuroprotective effect of ior-EPOCIM in a group of Parkinson's disease patients.. A three-phase exploratory study (proof of concept) was conducted from August 2008 to April 2009: preliminary assessment, treatment (weeks 1-5), and post-treatment (weeks 6-35). Participants were 10 Parkinson's disease patients (8 men, 2 women) from the outpatient clinic at the International Neurological Restoration Center, all at least one year post onset, aged 47-65 years. The ior-EPOCIM was administered subcutaneously in a once-weekly dose (60 IU/kg body weight) for five weeks. Therapy with patients' antiparkinsonian drugs was maintained throughout the study, except during motor examination, conducted following a 12-hour withdrawal (OFF condition). Safety was evaluated primarily by recording adverse events (by intensity and causality) from start of treatment until the study's completion. Hematological parameters and blood pressure were also measured because of their direct relationship to the medication's action. To evaluate possible neuroprotective activity, variables were included related to patients' motor function and cognitive and affective status, measured using internationally recognized scales. All variables were evaluated before, during and after treatment. Data were processed using a fixed-effects linear model, with a repeated-measures design (significance level p ≤ 0.05).. Three patients experienced mild adverse events (precordial discomfort and hypertension in one; leg fatigue in another; renal colic in a third), with a possible causal relationship in the first two that was neither life threatening nor required hospitalization. Hemoglobin was the only hematological parameter that showed a growing and significant increase (p < 0.001), but without reaching pathological levels. The other variables presented clinically positive and statistically significant changes compared to pretreatment assessment: motor function (p < 0.001), cognitive status (p < 0.001) and mood (p = 0.013). CONCLUSIONS At the dosage used, ior-EPOCIM was safe and well tolerated in these Parkinson's disease patients. Further studies are needed to corroborate these results and evaluate the medication's possible neuroprotective effect. KEYWORDS Parkinson disease, erythropoietin, recombinant proteins, neuroprotective agents, clinical trial, safety, ior-EPOCIM, Cuba.

Topics: Aged; Blood Pressure; Cuba; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Neuroprotective Agents; Neuropsychological Tests; Parkinson Disease; Recombinant Proteins; Severity of Illness Index; Treatment Outcome

Among the properties of lactoferrin (LF) are bactericidal, antianemic, immunomodulatory, antitumour, antiphlogistic effects. Previously we demonstrated its capacity to stabilize in vivo HIF-1-alpha and HIF-2-alpha, which are redox-sensitive multiaimed transcription factors. Various tissues of animals receiving recombinant human LF (rhLF) responded by expressing the HIF-1-alpha target genes, hence such proteins as erythropoietin (EPO), ceruloplasmin, etc. were synthesized in noticeable amounts. Among organs in which EPO synthesis occurred were brain, heart, spleen, liver, kidneys and lungs. Other researchers showed that EPO can act as a protectant against severe brain injury and status epilepticus in rats. Therefore, we tried rhLF as a protector against the severe neurologic disorders developed in rats, such as the rotenone-induced model of Parkinson's disease and experimental autoimmune encephalomyelitis as a model of multiple sclerosis, and observed its capacity to mitigate the grave symptoms. Moreover, an intraperitoneal injection of rhLF into mice 1 h after occlusion of the medial cerebral artery significantly diminished the necrosis area measured on the third day in the ischaemic brain. During this period EPO was synthesized in various murine tissues. It was known that EPO induces nuclear translocation of Nrf2, which, like HIF-1-alpha, is a transcription factor. In view that under conditions of hypoxia both factors demonstrate a synergistic protective effect, we suggested that LF activates the Keap1/Nrf2 signaling pathway, an important link in proliferation and differentiation of normal and malignant cells. J774 macrophages were cultured for 3 days without or in the presence of ferric and ferrous ions (RPMI-1640 and DMEM/F12, respectively). Then cells were incubated with rhLF or Deferiprone. Confocal microscopy revealed nuclear translocation of Nrf2 (the key event in Keap1/Nrf2 signaling) induced by apo-rhLF (iron-free, RPMI-1640). The reference compound Deferiprone (iron chelator) had the similar effect. Upon iron binding (in DMEM/F12) rhLF did not activate the Keap1/Nrf2 pathway. Added to J774, apo-rhLF enhanced transcription of Nrf2-dependent genes coding for glutathione S-transferase P and heme oxygenase-1. Western blotting revealed presence of Nrf2 in mice brain after 6 days of oral administration of apo-rhLF, but not Fe-rhLF or equivalent amount of PBS. Hence, apo-LF, but not holo-LF, induces the translocation of Nrf2 from cytoplasm to the nucle

Topics: Animals; Brain Ischemia; Encephalomyelitis, Autoimmune, Experimental; Erythropoietin; Female; Humans; Lactoferrin; Male; Mice; Mice, Inbred BALB C; Multiple Sclerosis; Neuroprotection; Neuroprotective Agents; NF-E2-Related Factor 2; Parkinson Disease; Rats; Rats, Wistar; Recombinant Proteins

Erythropoietin (EPO) may become a potential therapeutic candidate for the treatment of the neurodegenerative disorder -- Parkinson's disease (PD), since EPO has been found to prevent neuron apoptosis through the activation of cell survival signalling. However, the underlying mechanisms of how EPO exerts its neuroprotective effect are not fully elucidated. Here we investigated the mechanism by which EPO suppressed 6-hydroxydopamine (6-OHDA)-induced neuron death in in vitro and in vivo models of PD. EPO knockdown conferred 6-OHDA-induced cytotoxicity. This effect was reversed by EPO administration. Treatment of PC12 cells with EPO greatly diminished the toxicity induced by 6-OHDA in a dose- and time-dependent manner. EPO effectively reduced apoptosis of striatal neurons and induced a significant improvement on the neurological function score in the rat models of PD. Furthermore, EPO increased the expression of phosphorylated Akt and phosphorylated FoxO3a, and abrogated the 6-OHDA-induced dysregulation of Bcl-2, Bax and Caspase-3 in PC12 cells and in striatal neurons. Meanwhile, the EPO-dependent neuroprotection was notably reversed by pretreatment with LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K). Our data suggest that PI3K/Akt/FoxO3a signalling pathway may be a possible mechanism involved in the neuroprotective effect of EPO in PD.

Topics: Animals; Apoptosis; Chromones; Erythropoietin; Forkhead Box Protein O3; Forkhead Transcription Factors; Locomotion; Male; Morpholines; Neurons; Neuroprotective Agents; Oxidopamine; Parkinson Disease; PC12 Cells; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Signal Transduction

The purpose of this study was to determine the effectiveness of the systemic administration of high dose erythropoietin (EPO) in a 6‑hydroxydopamine (6‑OHDA)‑ induced rat model. Rats were divided into 7 groups. Groups 1‑4 were administered daily EPO doses of 0; 2,500; 5,000 and 10,000 U/kg via intraperitoneal injection (i.p.) for 5 days. The EPO concentration in cerebrospinal fluid (CSF) was determined by enzyme‑linked immunosorbent assay (ELISA) and western blot analysis. The dose of 10,000 U/kg was then selected for subsequent experiments. In group 5, rats received saline via medial forebrain bundle (MFB). In group 6, rats received 6‑OHDA via MFB. In group 7, an EPO concentration of 10,000 U/kg was constantly administered i.p. for 5 days to rats prior to 6‑OHDA injection via MFB. Behavioral analysis was performed for groups 5‑7 by rat rotation tests. The number of tyrosine hydroxylase (TH)‑immunopositive cells in the substantia nigra (SN) was measured by immuno-cyto-chemistry. The activation of c‑Jun N‑terminal kinase (JNK), extracellular signal‑regulated kinase (ERK), p38 mitogen‑activated protein kinases (MAPKs) and caspase‑3 signaling in rats were analyzed using western blotting. The results showed that there was a significant increase in EPO levels in the CSF in 10,000 U/kg group compared with the 2,500 and 5,000 U/kg groups (P<0.01). Significantly fewer rotational counts were obtained in rats that were pretreated with EPO compared with saline‑pretreated 6‑OHDA‑lesioned rats (P<0.001). The dopaminergic neurons in the 6‑OHDA‑lesioned SN were also increased in the EPO‑pretreated rats when compared with control rats (P<0.01). Western blot analysis revealed that EPO inhibited the 6‑OHDA‑induced activation of JNK, ERK, p38 MAPK and caspase‑3 signaling in the rat model. In conclusion, systemic administration of a high dose of EPO exerted neuroprotective effects in reversing behavioral deficits associated with Parkinson's disease and prevented loss of the dopaminergic neurons through the MAPK pathway.

Topics: Animals; Disease Models, Animal; Dopaminergic Neurons; Erythropoietin; Humans; Hydroxydopamines; Mitogen-Activated Protein Kinase Kinases; Neuroprotective Agents; Parkinson Disease; Rats; Tyrosine 3-Monooxygenase

Parkinson's disease is characterized by progressive degeneration of dopaminergic neurons. Thus the development of therapeutic neuroprotection and neurorescue strategies to mitigate disease progression is important. In this study we evaluated the neuroprotective/rescue effects of erythropoietin Fc fusion protein (EPO-Fc) and carbamylated erythropoietin Fc fusion protein (CEPO-Fc) in a rat model of Parkinson's disease. Adult female Sprague-Dawley rats received intraperitoneal injection of EPO-Fc, CEPO-Fc or PBS. Behavioral evaluations consisted of rota-rod, cylinder and amphetamine-induced rotation tests. In the neuroprotection experiment, the CEPO-Fc group demonstrated significant improvement compared with the EPO-Fc group on the amphetamine-induced rotation test throughout the four-week follow-up period. Histologically, significantly more tyrosine hydroxylase (TH)-positive neurons were recognized in the substantia nigra (SN) pars compacta in the CEPO-Fc group than in the PBS and EPO-Fc groups. In the neurorescue experiment, rats receiving CEPO-Fc showed significantly better behavioural scores than those receiving PBS. The histological data concerning striatum also showed that the CEPO-Fc group had significantly better preservation of TH-positive fibers compared to the PBS and EPO-Fc groups. Importantly, there were no increases in hematocrit or hemoglobin levels in the CEPO-Fc group in either the neuroprotection or the neurorescue experiments. In conclusion, the newly developed CEPO-Fc might confer neuroprotective and neurorescue benefits in a rat model of Parkinson's disease without the side effects associated with polycythemia. CEPO-Fc might be a therapeutic tool for patients with Parkinson's disease.

Topics: Adrenergic Agents; Amphetamine; Analysis of Variance; Animals; Corpus Striatum; Disease Models, Animal; Drug Administration Schedule; Erythropoietin; Female; Hematocrit; Hemoglobins; Neuroprotective Agents; Oxidopamine; Parkinson Disease; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Rotarod Performance Test; Stereotyped Behavior; Substantia Nigra; Time Factors; Tyrosine 3-Monooxygenase

We have recently shown that intrastriatal injection of recombinant human erythropoietin (EPO) protects dopaminergic (DA) neurons in the substantia nigra (SN) from 6-hydroxydopamine (6-OHDA) toxicity in a rat model of Parkinson's disease. However, systemic administration of EPO did not protect nigral DA neurons, suggesting that the blood-brain barrier limits the passage of EPO protein into the brain. In the present study, we used an adeno-associated viral (AAV) serotype 9 (AAV9) vector to deliver the human EPO gene into the brain of 6-OHDA-lesioned rats. We observed that expression of the human EPO gene was robust and stable in the striatum and the SN for up to 10 weeks. EPO-immunoreactive (IR) cells were widespread throughout the injected striatum, and EPO-IR neurons and fibers were also found in the ipsilateral SN. Enzyme-linked immunosorbent assay and western blot analyses exhibited dramatic levels of EPO protein in the injected striatum. As a result, nigral DA neurons were protected against 6-OHDA-induced toxicity. Amphetamine-induced rotational asymmetry and spontaneous forelimb use asymmetry were both attenuated. Interestingly, we also observed that intrastriatal injection of AAV9-EPO vectors led to increased numbers of red blood cells in peripheral blood. This highlights the importance of using an inducible gene delivery system for EPO gene delivery.

Topics: Animals; Dependovirus; Erythrocyte Count; Erythropoietin; Female; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Hydroxydopamines; Parkinson Disease; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Substantia Nigra

Parkinson's disease (PD) is a neurodegenerative disorder with motor symptoms caused by the loss of dopaminergic (DA) cells and consequently dopamine release in the nigrostriatal system. In vivo and in vitro 6-hydroxydopamine (6-OHDA) PD models are widely used to study the effect of striatal dopamine depletion as well as novel neuroprotective or restorative therapeutic strategies for PD. In the present study, we investigated in vitro the toxicity of 6-OHDA on DA neurons derived from E14 rat ventral mesencephalon (VM) and the neuroprotective efficiency of erythropoietin (Epo) on VM-derived cell cultures against 6-OHDA toxicity. Using E14 VM-derived DA-rich primary cultures, we could demonstrate that 6-OHDA toxicity works in a time-and concentration-dependent way, and leads to cell death not only in DA cells but also in non-DA cells in direct relation to concentration and incubation times. In addition, we found that 6-OHDA toxicity induces caspase-3 activation and an increment of intracellular reactive oxygen species (ROS) in VM-derived cultures. When 6-OHDA-treated VMs were cultured in the presence of the anti-apoptotic protein erythropoietin (Epo), the total neuronal population, including the DA neurons, was protected. However, untreated VM cultures exposed to Epo showed an increase in the total neuronal population, but not an additional increase in DA neuron cell number. These findings suggest that 6-OHDA toxicity is time and concentration-dependent and does not exclusively affect DA neurons. In high concentration and long incubation times, 6-OHDA influences the survival of other neuronal and non-neuronal cell populations derived from the VM cultures. 6-OHDA toxicity induces caspase-3 activation, indicating cell death via the apoptotic pathway which could be restricted or even prevented by pre-exposure to Epo, known to interact via the apoptotic pathway. Our results support and expand on previous findings showing that Epo is an interesting candidate molecule to mediate neuroprotective effects on DA neurons in PD. Furthermore, it could be used in promoting the survival of DA neurons after transplantation in clinical trials.

Topics: Adrenergic Agents; Animals; Caspase 3; Cells, Cultured; Dopamine; Dose-Response Relationship, Drug; Embryo, Mammalian; Erythropoietin; Mesencephalon; Neurons; Neuroprotective Agents; Oxidopamine; Parkinson Disease; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Tubulin; Tyrosine 3-Monooxygenase

Topics: Endothelium, Vascular; Erythropoietin; Humans; Neuroprotective Agents; NF-E2-Related Factor 2; Parkinson Disease

Epidemiological studies report that a third of the cases of anaemia in older persons is unexplained. We compared erythropoietin (EPO), inflammatory markers and major comorbidities between older subjects with normal haemoglobin levels and those with different aetiologic forms of anaemia, including unexplained anaemia. Participants were a representative sample of 964 persons aged > or =65 years, with no evidence of bleeding, complete blood tests, and a complete blood count within 6 h of phlebotomy. Anaemia was defined as haemoglobin <130 g/l in men and 120 g/l in women, and classified as a result of chronic kidney disease, iron deficiency, chronic disease and B12/folate deficiency anaemia, or unexplained anaemia based on standard criteria. Of the 124 anaemic participants, 42 (36.8%) had unexplained anaemia. Participants with anaemia of chronic diseases had significantly higher interleukin-6 (IL-6) and C-reactive protein (CRP) levels, while those with unexplained anaemia had significantly lower CRP than non-anaemic controls. Iron deficiency anaemia was characterised by significantly higher EPO levels compared with other types of anaemia and normal haemoglobin, B12 and/or folate deficiency. Unexplained anaemia was characterised by unexpectedly low EPO and low lymphocyte count. Unexplained anaemia is associated with reduced kidney EPO response, low levels of pro-inflammatory markers and low lymphocyte counts.

Topics: Aged; Aging; Anemia; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Case-Control Studies; Diabetes Mellitus; Erythropoietin; Female; Health Surveys; Humans; Inflammation Mediators; Interleukin-6; Italy; Kidney Diseases; Lymphocyte Count; Male; Osteoarthritis; Parkinson Disease; Stroke; Tumor Necrosis Factor-alpha