Publications by authors named "Dafin Fior Muresanu"

38 Publications

Community-acquired systemic infection complicated with rhombencephalitis.

Clin Case Rep 2021 Aug 13;9(8). Epub 2021 Aug 13.

Iuliu Hațieganu University of Medicine and Pharmacy Cluj-Napoca Cluj-Napoca Romania.

Rhombencephalitis is a rapidly progressing disease that should be taken into consideration in a patient with abrupt onset of cerebellar ataxia with rapid neurologic deterioration (tetraparesis, coma) after vascular etiology has been ruled out.
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http://dx.doi.org/10.1002/ccr3.3666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385686PMC
August 2021

Real-World Data Regarding Long-Term Administration of Natalizumab from a Neurology Department along Literature Review.

CNS Neurol Disord Drug Targets 2021 Aug 26. Epub 2021 Aug 26.

Department of Clinical Neurosciences, "Carol Davila" University of Medicine and Pharmacy, Bucharest. Romania.

Background: Natalizumab is a humanized monoclonal antibody with high efficacy and an acceptable safety profile used in the treatment of patients with multiple sclerosis (MS).

Objectives: Our aim was to report data regarding long-term administration of Natalizumab in patients with relapsing-remitting multiple sclerosis (RRMS) from our clinic.

Methods: A retrospective observational study was performed including RRMS patients who underwent treatment with ≥ 24 Natalizumab infusions. We analyzed the EDSS values, the relapse rate and the rate and type of adverse events related to Natalizumab administration.

Results: 51 subjects were included with a predominance of women (62.74%), an average age of 40.43±1.49 years, a mean disease duration of 9.86±0.7 years and mean number of Natalizumab infusions of 45.58±2.74. An increased number of patients (80.39%) were relapse-free and there was observed a mild reduction of the mean EDSS value following Natalizumab initiation in patients who had not been treated with other disease modifying therapies anteriorly. Among the encountered adverse events we registered: increased liver transaminases (13.72%), local infections (7.84%) and dysmenorrhea in one patient. The rate of severe adverse events was 3.92 and there were registered no cases of Progressive Multifocal Leukoencephalopathy (PML).

Conclusions: Natalizumab proves to be effective, has an adequate safety profile and can be administered with good tolerability for a rather extended period of time, provided that the patients are closely monitored.
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http://dx.doi.org/10.2174/1871527320666210827113733DOI Listing
August 2021

Coffee and Tea Consumption Impact on Amyotrophic Lateral Sclerosis Progression: A Multicenter Cross-Sectional Study.

Front Neurol 2021 28;12:637939. Epub 2021 Jul 28.

Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.

Amyotrophic lateral sclerosis (ALS) is a devastating and still untreatable motor neuron disease. The causes of ALS are unknown, but nutritional factors may impact the rate of disease progression. We aimed to ascertain the influence of coffee and tea consumption on ALS progression rate. In this multicenter cross-sectional study, we recruited 241 patients, 96 females, and 145 males; the mean age at onset was 59.9 ± 11.8 years. According to El Escorial criteria, 74 were definite ALS, 77 probable, 55 possible, and 35 suspected; 187 patients had spinal onset and 54 bulbar. Patients were categorized into three groups, according to their ΔFS (derived from ALS Functional Rating Scale-Revised score and disease duration from onset): slow (81), intermediate (80), and fast progressors (80). Current coffee consumers were 179 (74.3%), 34 (14.1%) were non-consumers, and 22 (9.1%) were former consumers, whereas six (2.5%) consumed decaffeinated coffee only. The log-ΔFS was weakly correlated with the duration of coffee consumption ( = 0.034), but not with the number of cup-years, or the intensity of coffee consumption (cups/day). Current tea consumers were 101 (41.9%), 6 (2.5%) were former consumers, and 134 (55.6%) were non-consumers. Among current and former consumers, 27 (25.2%) consumed only green tea, 51 (47.7%) only black tea, and 29 (27.1%) both. The log-ΔFS was weakly correlated only with the consumption duration of black tea ( = 0.028) but not with the number of cup-years. Our study does not support the hypothesis that coffee or tea consumption is associated with the ALS progression rate.
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http://dx.doi.org/10.3389/fneur.2021.637939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356721PMC
July 2021

Prognostic Factors in COVID-19 Patients With New Neurological Manifestations: A Retrospective Cohort Study in a Romanian Neurology Department.

Front Aging Neurosci 2021 17;13:645611. Epub 2021 Jun 17.

Neurology Department, Colentina Clinical Hospital, Bucharest, Romania.

The emerging Coronavirus Disease (COVID-19) pandemic caused by Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a serious public health issue due to its rapid spreading, high mortality rate and lack of specific treatment. Given its unpredictable clinical course, risk assessment, and stratification for severity of COVID-19 are required. Apart from serving as admission criteria, prognostic factors might guide future therapeutic strategies. We aimed to compare clinical features and biological parameters between elderly (age ≥ 65 years) and non-elderly (age <65 years) patients with COVID-19 and new neurological symptoms/conditions. We also aimed to determine factors independently associated with all-cause in-hospital mortality. All consecutive patients with COVID-19 and new neurological symptoms/conditions admitted in our Neurology Department between April 1 and August 23, 2020 were enrolled in this observational retrospective cohort study. Patient characteristics such as demographic data, comorbidities, biological parameters, imaging findings and clinical course were recorded. All-cause in-hospital mortality was the main outcome, whereas COVID-19 severity, hospitalization duration and the levels of supplemental oxygen were the secondary outcomes. One hundred forty-eight patients were included, out of which 54.1% were women. The average age was 59.84 ± 19.06 years and 47.3% were elderly, the majority having cardiovascular and metabolic comorbidities. In the elderly group, the most frequent neurological symptoms/manifestations responsible for hospitalization were stroke symptoms followed by confusion, whereas in the non-elderly, headache prevailed. The final neurological diagnosis significantly varied between the two groups, with acute cerebrovascular events and acute confusional state in dementia most commonly encountered in the elderly (65.71 and 14.28%, respectively) and secondary headache attributed to SARS-CoV-2 infection often experienced by the non-elderly (38.46%). The elderly had statistically significant higher median values of white blood cell (8,060 vs. 6,090/μL) and neutrophil count (6,060 vs. 4,125/μL), C-reactive protein (29.2 vs. 5.72 mg/L), ferritin (482 vs. 187 mg/dL), fibrinogen (477 vs. 374 mg/dL), D-dimer (1.16 vs. 0.42), prothrombin time (151.15 vs. 13.8/s), aspartate transaminase (26.8 vs. 20.8 U/l), creatinine (0.96 vs. 0.77 mg/dL), and blood urea nitrogen level (51.1 vs. 27.65 mg/dL), as well as lower median value of hemoglobin (13.05 vs. 13.9 g/dL) and lymphocyte count (1,245 vs. 1,670/μL). Moreover, advanced age was significantly associated with more extensive lung involvement (25 vs. 10%) and higher fatality rate (40 vs. 9%). Overall, the mortality rate was 23.6%. Age as well as neutrophil count, C-reactive protein, fibrinogen, and activated partial thromboplastin time levels were independently associated with mortality. Older age, higher neutrophil count, C-reactive protein, fibrinogen, and activated partial thromboplastin time levels are independent predictors of mortality in COVID-19 patients with new neurological manifestations/conditions at admission.
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http://dx.doi.org/10.3389/fnagi.2021.645611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245846PMC
June 2021

The Impact of Lifetime Alcohol and Cigarette Smoking Loads on Amyotrophic Lateral Sclerosis Progression: A Cross-Sectional Study.

Life (Basel) 2021 Apr 17;11(4). Epub 2021 Apr 17.

Neurology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy.

Background-Amyotrophic lateral sclerosis (ALS) is a devastating and untreatable motor neuron disease; smoking and alcohol drinking may impact its progression rate. Objective-To ascertain the influence of smoking and alcohol consumption on ALS progression rates. Methods-Cross-sectional multicenter study, including 241 consecutive patients (145 males); mean age at onset was 59.9 ± 11.8 years. Cigarette smoking and alcohol consumption data were collected at recruitment through a validated questionnaire. Patients were categorized into three groups according to ΔFS (derived from the ALS Functional Rating Scale-Revised and disease duration from onset): slow ( = 81), intermediate (80), and fast progressors (80). Results-Current smokers accounted for 44 (18.3%) of the participants, former smokers accounted for 10 (4.1%), and non-smokers accounted for 187 (77.6%). The age of ALS onset was lower in current smokers than non-smokers, and the ΔFS was slightly, although not significantly, higher for smokers of >14 cigarettes/day. Current alcohol drinkers accounted for 147 (61.0%) of the participants, former drinkers accounted for 5 (2.1%), and non-drinkers accounted for 89 (36.9%). The log(ΔFS) was weakly correlated only with the duration of alcohol consumption ( = 0.028), but not with the mean number of drinks/day or the drink-years. Conclusions: This cross-sectional multicenter study suggested a possible minor role for smoking in worsening disease progression. A possible interaction with alcohol drinking was suggested.
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http://dx.doi.org/10.3390/life11040352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072690PMC
April 2021

Severe cervical compressive polydiscopathic myelopathy with features of motor neuron disease: A case report.

Clin Case Rep 2021 Mar 9;9(3):1266-1272. Epub 2021 Jan 9.

Department of Clinical Neurosciences "Iuliu Hațieganu" University of Medicine and Pharmacy Cluj-Napoca Romania.

Cervical myelopathy is part of ALS mimic syndrome and should be considered in patients with clinical signs of motor neuron disease.
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http://dx.doi.org/10.1002/ccr3.3740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981701PMC
March 2021

Binswanger's disease: Case presentation and differential diagnosis.

Clin Case Rep 2020 Dec 27;8(12):3450-3457. Epub 2020 Oct 27.

Iuliu Haţieganu University of Medicine and Pharmacy Cluj-Napoca Cluj-Napoca Romania.

Establishing a diagnosis of Binswanger's disease requires a multimodal approach. As new pathophysiological mechanisms are revealed, tests that should yield greater specificity will become available in the years to come.
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http://dx.doi.org/10.1002/ccr3.3459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752439PMC
December 2020

Paraneoplastic Stiff Person Syndrome in Early-Stage Breast Cancer with Positive Anti-Amphiphysin Antibodies.

Case Rep Neurol 2020 Sep-Dec;12(3):339-347. Epub 2020 Oct 2.

Department of Neuroscience, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.

Stiff person syndrome (SPS) is a rare neurologic disorder, characterized by muscle rigidity and spasms. Anti-glutamic acid decarboxylase (anti-GAD) antibodies are associated with the classic form of SPS, while antibodies against amphiphysin are associated with the paraneoplastic form of the disease. We present the case of a patient with paraneoplastic SPS, presenting with muscle cramps of lower extremities that progressed to severe muscle rigidity and spasms, associated with a right breast tumor and positive anti-amphiphysin antibodies. Paraneoplastic SPS is a rare neurological disorder, challenging for the physicians both to diagnose and treat.
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http://dx.doi.org/10.1159/000508942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588701PMC
October 2020

Diagnosis Accuracy of Carpal Tunnel Syndrome in Diabetic Neuropathy.

Medicina (Kaunas) 2020 Jun 5;56(6). Epub 2020 Jun 5.

Centre for Neurological Research and Diagnostic, RoNeuro Institute, 400364 Cluj-Napoca, Romania.

Carpal tunnel syndrome (CTS) is a common pathology, but sometimes the diagnosis is delayed in patients with diabetic neuropathy (DN). The aim of the study is twofold: first, to compare the accuracy of ultrasound (US) with that of electroneurography (ENG) in the diagnosis of CTS associated with DN, using the clinical diagnosis as a reference standard, and second, to investigate the correlation between morphological US parameters and electrodiagnosis (EDX) measurements in patients with CTS and DN. This study included patients with DN. They were divided into two groups: Control (patients without CTS) and Cases (patients with CTS). We performed US and ENG in both hands, totaling 56 wrists, with 28 wrists in each group. We found that the difference in the sensory distal latencies between the median and the ulnar nerves (ring finger) exhibited the highest diagnostic accuracy of all the US and ENG parameters, areas under the receiver operating characteristic (AUC) = 0.99 (95% CI 0.97-1), and it was significantly different from the best US diagnostic method. The wrist cross-sectional area (CSA) had the most accurate US diagnosis, while the wrist-to-forearm ratio had the worst AUC. Moreover, in the group of CTS and DN patients, the wrist CSA enlargement was statistically directly proportional to the median compound muscle action potential (CMAP) distal latency and inversely proportional to the antidromic median nerve conduction study (NCS) and the orthodromic median palm-wrist NCS. Both examinations can be used with confidence in the diagnosis of CTS overlapping with DN, but the EDX examination seems to be more accurate. Furthermore, we found a positive correlation between the US and EDX parameters.
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http://dx.doi.org/10.3390/medicina56060279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353862PMC
June 2020

Assessment of Cortical Auditory Function Using Electrophysiological and Neuropsychological Measurements in Children with Bone-Anchored Hearing Aids.

J Med Life 2020 Jan-Mar;13(1):102-106

Department of Neurosciences, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.

Children suffering from conductive or mixed hearing loss may benefit from a bone-anchored hearing aid system (BAHA Attract implantable prosthesis). After audiological rehabilitation, different aspects of development are improving. The objective of this case report is to propose a comprehensive framework for monitoring cortical auditory function after implantation of a bone-anchored hearing aid system by using electrophysiological and neuropsychological measurements. We present the case of a seven-year-old boy with a congenital hearing loss due to a plurimalformative syndrome, including outer and middle ear malformation. After the diagnosis of hearing loss and the audiological rehabilitation with a BAHA Attract implantable prosthesis, the cortical auditory evoked potentials were recorded. We performed a neuropsychological evaluation using the Wechsler Intelligence Scale for Children - Fourth Edition, which was applied according to a standard procedure. The P1 latency was delayed according to the age (an objective biomarker for quantifying cortical auditory function). The neuropsychological evaluation revealed that the child's working memory and verbal reasoning abilities were in the borderline range comparing with his nonverbal reasoning abilities and processing abilities, which were in the average and below-average range, respectively. Cortical auditory evoked potentials, along with neuropsychological evaluation, could be an essential tool for monitoring cortical auditory function in children with hearing loss after a bone-anchored hearing aid implantation.
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http://dx.doi.org/10.25122/jml-2019-0097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175444PMC
June 2020

The Potential Use of P1 CAEP as a Biomarker for Assessing Central Auditory Pathway Maturation in Hearing loss and Associated Disabilities: a case report.

J Med Life 2019 Oct-Dec;12(4):457-460

Department of Neurosciences, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.

We report a case in which we quantified the maturation of the central auditory pathway in children with hearing loss and associated disabilities; the audiological intervention was performed using the BAHA softband. The hearing aid was applied according to the international clinical protocols. The presented case reveals the importance of using the P1 CAEP biomarker in clinical practice along with a neuropsychological evaluation to assess the maturation of the central auditory pathways and to objectively quantify the results of auditory rehabilitation in children with hearing loss and associated disabilities.
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http://dx.doi.org/10.25122/jml-2019-0096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993302PMC
April 2020

Exacerbation of blood-brain barrier breakdown, edema formation, nitric oxide synthase upregulation and brain pathology after heat stroke in diabetic and hypertensive rats. Potential neuroprotection with cerebrolysin treatment.

Int Rev Neurobiol 2019 18;146:83-102. Epub 2019 Jul 18.

International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden. Electronic address:

There is a growing trend of hypertension among military and civilian populations due to lifetime stressful situations. If hypertension is uncontrolled it leads to development of diabetes and serious neurological complications. Most of the World populations live in temperate zone across the World. Thus, a possibility exists that these hypertensive and diabetic people may have external heat as potential risk factors for brain damage. We have seen brain edema and brain damage following exposure to heat stress at 38°C for 4h. A possibility exists that heat exposure in diabetic-hypertensive (DBHY) cases exacerbates exacerbation of brain pathology and edema formation. This hypothesis is examined in a rat model. The role of nitric oxide (NO) in exacerbation of HS-induced brain pathology was also evaluated using nitric oxide synthase (NOS) immunoreactivity. Hypertensive rats (produced by two-kidney one clip (2K1C) method) were made diabetic with streptozotocine (50mg/kg, i.p./day for 3days) treatment. After 6weeks, DBHY rats show 20-30mM/L Blood Glucose and hypertension (180-200mmHg). Subjection of these rats to 4h HS resulted in six- to eightfold higher BBB breakdown, brain edema formation and brain pathology. At this time, neuronal or inducible NOS expression was four- to sixfold higher in DBHY rats compared to controls. Interestingly, iNOS expression was higher than nNOS in DBHY rats. Cerebrolysin in high doses (10-mL/kg, i.v. instead of 5-mL/kg) induced significant neuroprotection and downregulation of nNOS and iNOS in DBHY animals whereas normal animals need only 5-mL/kg doses for this purpose. Our observations demonstrate that co-morbidly factors exacerbate brain damage in HS through NOS expression and require double dose of cerebrolysin for neuroprotection as compared to normal rats, not reported earlier.
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http://dx.doi.org/10.1016/bs.irn.2019.06.007DOI Listing
February 2020

Anesthetics influence concussive head injury induced blood-brain barrier breakdown, brain edema formation, cerebral blood flow, serotonin levels, brain pathology and functional outcome.

Int Rev Neurobiol 2019 8;146:45-81. Epub 2019 Jul 8.

International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden.

Several lines of evidences show that anesthetics influence neurotoxicity and neuroprotection. The possibility that different anesthetic agents potentially influence the pathophysiological and functional outcome following neurotrauma was examined in a rat model of concussive head injury (CHI). The CHI was produced by an impact of 0.224N on the right parietal bone by dropping a weight of 114.6g from a 20cm height under different anesthetic agents, e.g., inhaled ether anesthesia or intraperitoneally administered ketamine, pentobarbital, equithesin or urethane anesthesia. Five hour CHI resulted in profound volume swelling and brain edema formation in both hemispheres showing disruption of the blood-brain barrier (BBB) to Evans blue and radioiodine. A marked decrease in the cortical CBF and a profound increase in plasma or brain serotonin levels were seen at this time. Neuronal damages were present in several parts of the brain. These pathological changes were most marked in CHI under ether anesthesia followed by ketamine (35mg/kg, i.p.), pentobarbital (50mg/kg, i.p.), equithesin (3mL/kg, i.p.) and urethane (1g/kg, i.p.). The functional outcome on Rota Rod performances or grid walking tests was also most adversely affected after CHI under ether anesthesia followed by pentobarbital, equithesin and ketamine. Interestingly, the plasma and brain serotonin levels strongly correlated with the development of brain edema in head injured animals in relation to different anesthetic agents used. These observations suggest that anesthetic agents are detrimental to functional and pathological outcomes in CHI probably through influencing the circulating plasma and brain serotonin levels, not reported earlier. Whether anesthetics could also affect the efficacy of different neuroprotective agents in CNS injuries is a new subject that is currently being examined in our laboratory.
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http://dx.doi.org/10.1016/bs.irn.2019.06.006DOI Listing
February 2020

Potentiation of spinal cord conduction and neuroprotection following nanodelivery of DL-3-n-butylphthalide in titanium implanted nanomaterial in a focal spinal cord injury induced functional outcome, blood-spinal cord barrier breakdown and edema formation.

Int Rev Neurobiol 2019 8;146:153-188. Epub 2019 Jul 8.

International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden. Electronic address:

Spinal cord injury (SCI) is a devastating disease inflicting lifetime disability to the victims. Military personnel are quite often victims of SCI for which no suitable therapeutic strategies have been developed so far. The main reason for SCI induced disability is loss of neural connections below and above the lesion site causing motor paralysis and somatosensory disturbances Loss of neuronal connections thwart spinal cord conduction resulting in motor function disability. To enhance spinal cord conduction grafting of peripheral nerves, implant of hydrogels filled with neuroprotective drugs is used but so far, no satisfactory results re achieved. In this regards implants of microelectrode for enhancing tissue connectivity is suggested that is still under experimental state. We have used titanium implant with or without TiO nanowires in a focal spinal cord injury and studies spinal cord pathology and motor function. In addition, we also combined with nanowired delivery of a potential neuroprotective drug DL-3-n-butylphthalide (DL-NBP) to the spinal cord in a rat model. Our observations show that a combination of titanium implant with nanowired delivery of DL-NBP induces superior neuroprotection and enhance motor functions after SCI. This treatment also restored blood-spinal cord barrier (BSCB) function and reduces edema formation and cell injury after SCI, not reports earlier.
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http://dx.doi.org/10.1016/bs.irn.2019.06.009DOI Listing
February 2020

Neuroprotective effects of a potent bradykinin B2 receptor antagonist HOE-140 on microvascular permeability, blood flow disturbances, edema formation, cell injury and nitric oxide synthase upregulation following trauma to the spinal cord.

Int Rev Neurobiol 2019 9;146:103-152. Epub 2019 Jul 9.

International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden.

Bradykinin is a mediator of vasogenic brain edema formation. Recent reports suggest that bradykinin interacts with nitric oxide synthase (NOS) system in the central nervous system (CNS). However, role of bradykinin in spinal cord injury (SCI) induced alterations in the blood-spinal cord barrier (BSCB), spinal cord blood flow (SCBF), edema formation and cell changes are still not well known. Our previous reports showed that SCI induces marked upregulation of neuronal NOS (nNOS) in the cord associated with BSCB disruption, edema formation and cell injury. Thus, a possibility exists that bradykinin participates in SCI induced nNOS upregulation and cord pathology. To explore this idea a potent bradykinin B2 receptor antagonist HOE-140 was used in our rat model of SCI and cord pathology. SCI was inflicted in Equithesin anesthetized rats by making a longitudinal incision (2mm deep and 5mm long) into the right dorsal horn of the T10-11 segment. The animals were allowed to survive 5h after injury. A focal SCI significantly disrupted BSCB to Evans blue and I-sodium in the traumatized and adjacent segments. Interestingly, far remote spinal cord segments C4 and T5 segments also affected within 5h. These spinal cord segments also exhibited pronounced reductions in the SCBF (mean-30%), increased edematous swelling and profound neuronal damages. Upregulation of nNOS expression is seen in both the dorsal and ventral horns of the spinal cord exhibiting cord pathology. At the ultrastructural level, exudation of lanthanum is seen within the endothelial cell cytoplasm and occasionally in the basal lamina. Pretreatment with low doses of HOE-140 (0. 1mg to 1mg/kg, i.v.) 30min prior to SCI significantly enhanced the SCBF and reduced the BSCB disruption, edema formation, nNOS upregulation and cell injury. However, HOE-140 in doses ranging from 2mg to 5mg/kg, i.v. did not induce significant neuroprotection. These observations are the first to suggest that bradykinin B2 receptors play an important role in BSCB permeability, SCBF, edema formation, nNOS upregulation and cell injury following acute SCI, not reported earlier.
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http://dx.doi.org/10.1016/bs.irn.2019.06.008DOI Listing
February 2020

5-Hydroxytryptophan: A precursor of serotonin influences regional blood-brain barrier breakdown, cerebral blood flow, brain edema formation, and neuropathology.

Int Rev Neurobiol 2019 18;146:1-44. Epub 2019 Jul 18.

International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden. Electronic address:

5-Hydroxytryptophan (5-HTP), a precursor of serotonin, is therapeutically used for several psychiatric disorders such as anxiety and depression in the clinic. However, severe side effects, including abnormal mental functions, behavioral disturbances and intolerance are associated with this treatment. 5-HTP-induced elevation of plasma and brain serotonin levels may affect blood-brain barrier (BBB) breakdown, edema formation and regional cerebral blood flow (CBF) disturbances. Breakdown of BBB to serum proteins leads to vasogenic brain edema formation and cellular injuries. However, 5-HTP-neurotoxicity is still not well known. In this investigations 5-HTP induced elevation of endogenous plasma and brain serotonin levels and its effect on BBB breakdown, edema formation neuronal injuries was examined in a rat model. Furthermore, potential role of oxidative stress and nitric oxide (NO) was evaluated. In addition, several neurochemical agents such as p-CPA (5-HT synthesis inhibitor) indomethacin (prostaglandin synthase inhibitor), diazepam (ant stress drug), cyproheptadine, ketanserin (5-HT2 receptor antagonists) and vinblastine (inhibitor of microtubule function) were examined on 5-HT neurotoxicity. Our observations suggest that 4h after 5-HTP administrations, the endogenous serotonin levels increased by fourfold (150mg/kg) in the plasma and brain associated with profound hyperthermia (+3.86±0.24°C, oxidative stress and NO upregulation. Breakdown of the BBB to Evans blue albumin (EBA) in 8 brain regions and to Iodine in 14 brain regions was observed. The CBF exhibited marked reduction in all the brain regions examined. Brain edema and cellular injuries are present in the areas associated with BBB disruption. Drug treatments reduced the BBB breakdown, edema formation NO production and brain pathology. These observations are the first to point out that 5-HTP-neurotoxicity caused by BBB breakdown, edema formation and NO production is instrumental in causing adverse mental and behavioral abnormalities, not reported earlier.
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http://dx.doi.org/10.1016/bs.irn.2019.06.005DOI Listing
February 2020

Cerebrolysin increases motor recovery and decreases inflammation in a mouse model of autoimmune encephalitis.

Rom J Morphol Embryol 2018 ;59(3):755-762

Department of Research Methodology, University of Medicine and Pharmacy of Craiova, Romania;

Multiple sclerosis (MS) is a complex chronic neurodegenerative disease that involves an abnormal autoimmune response directed against the brain, nerves and spinal cord; it is considered the most frequent cause of neurological disability, because MS-associated inflammatory lesions can affect a wide range of systems to a varying degree and may cause a plethora of neurological comorbidities and symptoms. The symptoms are quite variable from patient to patient and depend on the spatial distribution of the central nervous system (CNS) lesions, but usually involve sensory disturbances, cognitive deficits, unilateral vision loss, bladder dysfunction, ataxia, fatigue, double vision, weakness of the limbs and intestinal disorders. Experimental autoimmune encephalitis (EAE) mouse model reproduces the pathological features of the human disease, and is a widely used model used for studying the pathology and different treatment options in the preclinical stage. In this study, we aimed to evaluate the motor function, as well as the degree of demyelination and inflammatory changes in the brains of mice immunized for the myelin oligodendrocyte glycoprotein (MOG)35-55, and treated with Cerebrolysin. Animals were randomly assigned to one of the three groups: (i) EAE untreated group (n=10), (ii) EAE treated group (n=10), and (iii) control group (n=5), and their motor dysfunction was followed until the clinical pathology begun to improve. We also analyzed histologically and immunohistochemically the lesions in the optical nerves, cervical spinal cord and medulla. Our results showed higher deficit scores for untreated animals compared to treated animals. After harvesting the tissue, we have first evaluated the density of myelin in the optical nerves, cervical spinal cord and medulla and we found significant differences between treated and untreated groups of animals. We continued to investigate the structure of the CNS parenchyma by evaluating the intensity and morphology of the neuronal cytoskeleton and microglia by immunohistochemical stainings. Although larger animal groups are necessary, this is the first pilot study to investigate the use of a neurotrophic factor as a putative treatment option for a MS model.
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December 2018

Cerebrolysin and Aquaporin 4 Inhibition Improve Pathological and Motor Recovery after Ischemic Stroke.

CNS Neurol Disord Drug Targets 2018 ;17(4):299-308

Department of Clinical Neurosciences, University of Medicine and Pharmacy "Iuliu Hatieganu" and "RoNeuro" Institute for Neurological Research and Diagnostic, Cluj-Napoca, Romania.

Background: Edema represents one of the earliest negative markers of survival and consecutive neurological deficit following stroke. The mixture of cellular and vasogenic edema makes treating this condition complicated, and to date, there is no pathogenically oriented drug treatment for edema, which leaves parenteral administration of a hypertonic solution as the only non-surgical alternative.

Objective: New insights into water metabolism in the brain have opened the way for molecular targeted treatment, with aquaporin 4 channels (AQP4) taking center stage. We aimed here to assess the effect of inhibiting AQP4 together with the administration of a neurotropic factor (Cerebrolysin) in ischemic stroke.

Methods: Using a permanent medial cerebral artery occlusion rat model, we administrated a single dose of the AQP4 inhibitor TGN-020 (100 mg/kg) at 15 minutes after ischemia followed by daily Cerebrolysin dosing (5ml/kg) for seven days. Rotarod motor testing and neuropathology examinations were next performed.

Results: We showed first that the combination treatment animals have a better motor function preservation at seven days after permanent ischemia. We have also identified distinct cellular contributions that represent the bases of behavior testing, such as less astrocyte scarring and a larger neuronalsurvival phenotype rate in animals treated with both compounds than in animals treated with Cerebrolysin alone or untreated animals.

Conclusion: Our data show that water diffusion inhibition and Cerebrolysin administration after focal ischemic stroke reduces infarct size, leading to a higher neuronal survival in the peri-core glial scar region.
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http://dx.doi.org/10.2174/1871527317666180425124340DOI Listing
August 2019

Inhibition of Aquaporin-4 Improves the Outcome of Ischaemic Stroke and Modulates Brain Paravascular Drainage Pathways.

Int J Mol Sci 2017 Dec 23;19(1). Epub 2017 Dec 23.

Department of Clinical Neurosciences, University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca 400000, Romania.

Aquaporin-4 (AQP4) is the most abundant water channel in the brain, and its inhibition before inducing focal ischemia, using the AQP4 inhibitor TGN-020, has been showed to reduce oedema in imaging studies. Here, we aimed to evaluate, for the first time, the histopathological effects of a single dose of TGN-020 administered after the occlusion of the medial cerebral artery (MCAO). On a rat model of non-reperfusion ischemia, we have assessed vascular densities, albumin extravasation, gliosis, and apoptosis at 3 and 7 days after MCAO. TGN-020 significantly reduced oedema, glial scar, albumin effusion, and apoptosis, at both 3 and 7 days after MCAO. The area of GFAP-positive gliotic rim decreased, and 3D fractal analysis of astrocytic processes revealed a less complex architecture, possibly indicating water accumulating in the cytoplasm. Evaluation of the blood vessels revealed thicker basement membranes colocalizing with exudated albumin in the treated animals, suggesting that inhibition of AQP4 blocks fluid flow towards the parenchyma in the paravascular drainage pathways of the interstitial fluid. These findings suggest that a single dose of an AQP4 inhibitor can reduce brain oedema, even if administered after the onset of ischemia, and AQP4 agonists/antagonists might be effective modulators of the paravascular drainage flow.
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http://dx.doi.org/10.3390/ijms19010046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5795996PMC
December 2017

TiO-Nanowired Delivery of DL-3-n-butylphthalide (DL-NBP) Attenuates Blood-Brain Barrier Disruption, Brain Edema Formation, and Neuronal Damages Following Concussive Head Injury.

Mol Neurobiol 2018 01;55(1):350-358

Cerebrovascular Research Laboratory, Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, SE-751 85, Uppsala, Sweden.

DL-3-n-butylphthalide (DL-NBP) is one of the constituents of Chinese celery extract that is used to treat stroke, dementia, and ischemic diseases. However, its role in traumatic brain injury is less well known. In this investigation, neuroprotective effects of DL-NBP in concussive head injury (CHI) on brain pathology were explored in a rat model. CHI was inflicted in anesthetized rats by dropping a weight of 114.6 g from a height of 20 cm through a guide tube on the exposed right parietal bone inducing an impact of 0.224 N and allowed them to survive 4 to 24 h after the primary insult. DL-NBP was administered (40 or 60 mg/kg, i.p.) 2 and 4 h after injury in 8-h survival group and 8 and 12 h after trauma in 24-h survival group. In addition, TiO-nanowired delivery of DL-NBP (20 or 40 mg/kg, i.p.) in 8 and 24 h CHI rats was also examined. Untreated CHI showed a progressive increase in blood-brain barrier (BBB) breakdown to Evans blue albumin (EBA) and radioiodine (I), edema formation, and neuronal injuries. The magnitude and intensity of these pathological changes were most marked in the left hemisphere. Treatment with DL-NBP significantly reduced brain pathology in CHI following 8 to 12 h at 40-mg dose. However, 60-mg dose is needed to thwart brain pathology at 24 h following CHI. On the other hand, TiO-DL-NBP was effective in reducing brain damage up to 8 or 12 h using a 20-mg dose and only 40-mg dose was needed for neuroprotection in CHI at 24 h. These observations are the first to suggest that (i) DL-NBP is quite effective in reducing brain pathology and (ii) nanodelivery of DL-NBP has far more superior effects in CHI, not reported earlier.
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http://dx.doi.org/10.1007/s12035-017-0746-5DOI Listing
January 2018

Co-Administration of TiO2 Nanowired Mesenchymal Stem Cells with Cerebrolysin Potentiates Neprilysin Level and Reduces Brain Pathology in Alzheimer's Disease.

Mol Neurobiol 2018 01;55(1):300-311

Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, SE-75185, Uppsala, Sweden.

Neprilysin (NPL), the rate-limiting enzyme for amyloid beta peptide (AβP), appears to play a crucial role in the pathogenesis of Alzheimer's disease (AD). Since mesenchymal stem cells (MSCs) and/or cerebrolysin (CBL, a combination of neurotrophic factors and active peptide fragments) have neuroprotective effects in various CNS disorders, we examined nanowired delivery of MSCs and CBL on NPL content and brain pathology in AD using a rat model. AD-like symptoms were produced by intraventricular (i.c.v.) administration of AβP (1-40) in the left lateral ventricle (250 ng/10 μl, once daily) for 4 weeks. After 30 days, the rats were examined for NPL and AβP concentrations in the brain and related pathology. Co-administration of TiO2-nanowired MSCs (10 cells) with 2.5 ml/kg CBL (i.v.) once daily for 1 week after 2 weeks of AβP infusion significantly increased the NPL in the hippocampus (400 pg/g) from the untreated control group (120 pg/g; control 420 ± 8 pg/g brain) along with a significant decrease in the AβP deposition (45 pg/g from untreated control 75 pg/g; saline control 40 ± 4 pg/g). Interestingly, these changes were much less evident when the MSCs or CBL treatment was given alone. Neuronal damages, gliosis, and myelin vesiculation were also markedly reduced by the combined treatment of TiO2, MSCs, and CBL in AD. These observations are the first to show that co-administration of TiO2-nanowired CBL and MSCs has superior neuroprotective effects in AD probably due to increasing the brain NPL level effectively, not reported earlier.
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http://dx.doi.org/10.1007/s12035-017-0742-9DOI Listing
January 2018

GFAP and antibodies against NMDA receptor subunit NR2 as biomarkers for acute cerebrovascular diseases.

J Cell Mol Med 2015 Sep 17;19(9):2253-61. Epub 2015 Jun 17.

Department of Microbiology and Epidemiology, University of Medicine and Pharmacy "Carol Davila", Bucharest, Romania.

We studied whether the serum levels of glial fibrillary acidic protein (GFAP) and of antibodies against the N-methyl-d-aspartate receptor subunit NR2 (NR2 RNMDA ) can discriminate between intracerebral haemorrhage (ICH) and ischaemic stroke (IS) in stroke patients. We prospectively recruited patients with suspected stroke (72 confirmed) and 52 healthy controls. The type of brain lesion (ICH or IS) was established using brain imaging. The levels of GFAP and of antibodies against NR2 RNMDA were measured in blood samples obtained within 12 hrs after stroke onset and 24, 48 and 72 hrs and 1 and 2 weeks later using ELISA immunoassay. Improvement in diagnostic performance was assessed in logistic regression models designed to predict the diagnosis and the type of stroke. GFAP peaks early during haemorrhagic brain lesions (at significantly higher levels), and late in ischaemic events, whereas antibodies against NR2 RNMDA have significantly higher levels during IS at all time-points. Neither of the two biomarkers used on its own could sufficiently discriminate patients, but when they are used in combination they can differentiate at 12 hrs after stroke, between ischaemic and haemorrhagic stroke with a sensitivity and specificity of 94% and 91%, respectively.
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http://dx.doi.org/10.1111/jcmm.12614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568929PMC
September 2015

Effects and tolerability of betahistine in patients with vestibular vertigo: results from the Romanian contingent of the OSVaLD study.

Int J Gen Med 2014 4;7:531-8. Epub 2014 Dec 4.

"RoNeuro" Institute for Neurological Research and Diagnostic Cluj-Napoca, University of Medicine and Pharmacy "Iuliu Haţieganu", Department of Clinical Neurosciences, Cluj-Napoca, Romania.

Background And Methods: An efficacy population of 245 patients with vertigo of peripheral vestibular origin was recruited in Romania as part of a 3-month multinational, post-marketing surveillance study of open-label betahistine 48 mg/day (OSVaLD). Endpoints were changes in the Dizziness Handicap Index (primary endpoint), Medical Outcome Study Short-Form 36 (SF-36v2(®)), and the Hospital Anxiety and Depression Scale.

Results: During treatment, the total Dizziness Handicap Index score improved by 41 points (on a 100-point scale). Statistically significant improvements of 12-14 points were recorded in all three domains of the Dizziness Handicap Index scale (P<0.0001). Betahistine therapy was also accompanied by progressive improvements in mean Hospital Anxiety and Depression anxiety and depression scores (P<0.0001) and significant improvements in both the physical and mental component summary of the SF-36v2 (P<0.0001). Betahistine was well tolerated, with only one suspected adverse drug reaction recorded in the Romanian safety population (n=259).

Conclusion: Betahistine 48 mg/day was associated with improvements in multiple measures of health-related quality of life and had a good tolerability profile in these Romanian patients with recurrent peripheral vestibular vertigo.
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http://dx.doi.org/10.2147/IJGM.S71015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260659PMC
December 2014

The role of functionalized magnetic iron oxide nanoparticles in the central nervous system injury and repair: new potentials for neuroprotection with Cerebrolysin therapy.

J Nanosci Nanotechnol 2014 Jan;14(1):577-95

Functionalized Magnetic Iron Oxide Nanoparticles (FMIONPs) are being explored for the development of various biomedical applications, e.g., cancer chemotherapy and/or several other radiological or diagnostic purposes. However, the effects of these NPs per se on the central nervous system (CNS) injury or repair are not well known. This review deals with different aspects of FMIONPs in relation to brain function based on the current literature as well as our own investigation in animal models of CNS injuries. It appears that FMIONPs are innocuous when administered intravenously within the CNS under normal conditions. However, abnormal reactions to FMIONPs in the brain or spinal cord could be seen if they are combined with CNS injuries e.g., hyperthermia or traumatic insults to the brain or spinal cord. Thus, administration of FMIONPs in vivo following whole body hyperthermia (WBH) or a focal spinal cord injury (SCI) exacerbates cellular damage. Since FMIONPs could help in diagnostic purposes or enhance the biological effects of radiotherapy/chemotherapy it is likely that these NPs may have some adverse reaction as well under disease condition. Thus, under such situation, adjuvant therapy e.g., Cerebrolysin (Ever NeuroPharma, Austria), a suitable combination of several neurotrophic factors and active peptide fragments are the need of the hour to contain such cellular damages caused by the FMIONPs in vivo. Our observations show that co-administration of Cerebrolysin prevents the FMIONPs induced pathologies associated with CNS injuries. These observations support the idea that FMIONPs are safe for the CNS in disease conditions when co-administered with cerebrolysin. This indicates that cerebrolysin could be used as an adjunct therapy to prevent cellular damages in disease conditions where the use of FMIONPs is required for better efficacy e.g., cancer treatment.
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http://dx.doi.org/10.1166/jnn.2014.9213DOI Listing
January 2014

The vascular component of Alzheimer's disease.

Curr Neurovasc Res 2014 May;11(2):168-76

Departmenr of Psychiatry, University of Medicine Rostock, Germany.

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 central to protection and recovery and represent the background of endogenous defense activity (EDA). The historical concept of neuroprotection being the suppression of pathophysiological processes by a single mechanism or molecule may have been effective in clinical practice, but is now obsolete and indicates a failure of the reductionist approach to neuroprotection in the clinical setting. Pharmacological intervention should address modulation not suppression. The more pathophysiological processes are modulated, the better the chances are for therapeutic success in brain protection and recovery. Therefore, drugs with pleiotropic neuroprotective mechanisms of action are the best candidates for acute neuroprotection.
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http://dx.doi.org/10.2174/1567202611666140408105333DOI Listing
May 2014

Disease activity and disability evolution under glatiramer acetate: a clinical approach.

Neuropsychopharmacol Hung 2014 Mar;16(1):11-8

Dept. of Neurosciences, University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca, Romania.

Introduction: By analyzing literature data regarding glatiramer acetate in the treatment of relapsing-remitting multiple sclerosis one might find controversial data but the majority of authors state that the clinical evolution under the treatment showed a positive course.

Materials And Methods: Our goal was to analyze groups of patients, both non-treated and treated with the drug, for relapse rate, Kurtzke's Expanded Disability Status Scale (EDSS) score, Multiple Sclerosis Functional Composite (MSFC) score - upper limb disability, lower limb disability and cognition, and for cognitive dysfunction, using the Montreal Cognitive Assessment (MoCA) test, in order to objectively quantify the clinical impact of the drug.

Results/conclusions: Our results are in accordance with the literature for most of the investigated measures - relapse rate, EDSS, MSFC -, and furthermore suggest the possibility to use more extensively the MoCA test for evaluation of MS patients from the point of view of cognitive functions, after a much wider comparative assessment.
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March 2014

Two novel HTRA1 mutations in a European CARASIL patient.

Neurology 2014 Mar 5;82(10):898-900. Epub 2014 Feb 5.

From the Department of Medical, Surgical and Neurological Sciences (S.B., C.D.P., G.N.G., I.T., A.P, F.R., A.R., M.T.D., A.F.), University of Siena, Siena, Italy; Department of Neurology (D.F.M.), University of Medicine and Pharmacy "Iuliu Hatieganu," Cluj-Napoca, Romania; and Neuroimaging and Neurointervention Unit (A.C.), Azienda Ospedaliera Universitaria Senese, Policlinico "Santa Maria alle Scotte," Siena, Italy.

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http://dx.doi.org/10.1212/WNL.0000000000000202DOI Listing
March 2014

Characterization of CD4+ and CD8+ Tregs in a Hodgkin's lymphoma patient presenting with myasthenia-like symptoms.

Ideggyogy Sz 2013 Sep;66(9-10):343-8

Department of Clinical and Experimental Medicine, University of Perugia, Italy.

The co-occurrence of Hodgkin's lymphoma (HL) and myasthenia gravis (MG) is a rare phenomenon that is sometimes considered a paraneoplastic manifestation. There are a few documented cases in which myasthenia symptoms manifested only after the surgical removal of the tumor. However, the biological basis of this association is unknown. One hypothesis is that it derives from the infiltration of the residual thymic tissue by the developing tumor. In our case, the myasthenic symptoms led to the HL diagnosis. Our objective was to investigate the T cell phenotype in a HL patient presenting myasthenia-like symptoms. In patients with autoimmune disease, Tregs are usually decreased, but in some diseases, they appear to be increased. It has been speculated that this phenomenon may occur due to a homeostatic attempt by the immune system to control the expansion of auto-reactive effector cells. In the described patient the proportion of lymphoma infiltrating Tregs was high (more than 10% of CD4+ and 1.34% of CD8+ cells), suggesting that Tregs are increased in patients suffering from HL and eventually of myasthenia gravis. Treg involvement in HL is controversial and is currently under investigation. In this context, our data may contribute to a better understanding of the underlying mechanism of the link between HL and autoimmune phenomena.
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September 2013

Cerebrovascular profile assessment in Parkinson's disease patients.

CNS Neurol Disord Drug Targets 2014 ;13(4):712-7

Department of Clinical Neurosciences, University of Medicine and Pharmacy "Iuliu Hatieganu", Victor Babes Street No. 8, 400012 Cluj-Napoca, Romania.

Introduction: Parkinson's disease (PD) is one of the most common neurodegenerative diseases, and PD patients can present a variety of comorbidities that increase with age. Among them, cardiovascular and cerebrovascular diseases are the most prominent.

Aim: To assess the cardiovascular and cerebrovascular profiles of PD patients.

Patients And Methods: The cardiovascular risk factors of 126 PD patients were assessed according to laboratory tests (fasting blood sugar, serum cholesterol, triglycerides, and total lipids), Doppler ultrasound examinations and personal histories of cerebrovascular disease (ischemic/hemorrhagic), cardiovascular disease (myocardial infarct or angina confirmed by electrocardiogram), hypertension and diabetes. All patients underwent cerebral structural imaging procedures: computed tomography or magnetic resonance imaging.

Results: 58.73% of the patients presented with hypertension, with a slight predominance of female patients (65.38% vs 47.92%, P = 0.05). Carotid or vertebral atheromatosis was present in 39 (30.95%) and 28 (22.22%) of patients, respectively, and was statistically correlated with the presence of ischemic lesions on cerebral imaging. Regarding the computed tomography findings, 33 patients (28.21%) presented with cortical atrophy that was not correlated with any of the investigated cardiovascular factors.

Conclusions: Our findings indicate that risk factors for cardiovascular and cerebrovascular diseases are common in PD patients, possibly due to their older age. The presence of atherosclerosis and its complications can be detected in cerebral imaging studies.
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http://dx.doi.org/10.2174/1871527313666140618110409DOI Listing
February 2015

Pleiotropic neuroprotective and metabolic effects of Actovegin's mode of action.

J Neurol Sci 2012 Nov 19;322(1-2):222-7. Epub 2012 Aug 19.

Molecular Genetics and Diagnosis, Department of Internal Medicine IV, Otfried Müller Str. 10, University Hospital, D-72076 Tübingen, Germany.

This article reviews the mechanisms of action of Actovegin in the context of its preclinical effects and new concepts in the pharmacological treatment of neurological disorders. Actovegin is an ultrafiltrate of calf blood, composed of more than 200 biological substances. The drug is used for a broad spectrum of diseases, including disturbances of peripheral and cerebral blood circulation, burns, impaired wound healing, radiation-induced damage and diabetic polyneuropathy. Actovegin is composed of small molecules present under normal physiological conditions, therefore pharmacokinetic and pharmacodynamic studies to determine its active substance are not feasible. Preclinical data have revealed that it improves metabolic balance by increasing glucose uptake and improving oxygen uptake under conditions of ischemia. Actovegin also resists the effects of gamma-irradiation and stimulates wound healing. More recent preclinical studies have suggested that anti-oxidative and anti-apoptotic mechanisms of action specifically underlie the neuroprotective properties of Actovegin. The drug has been found to exert these beneficial effects experimentally, in primary rat hippocampal neurons and in an STZ-rat model of diabetic polyneuropathy, while also providing evidence that it positively affects the functional recovery of neurons. Latest data suggest that Actovegin also has a positive influence on the NF-κB pathway, but many molecular and cellular pathways remain unexplored. In particular, Actovegin's influence on neuroplasticity, neurogenesis and neurotrophicity are questions that ideally should be answered by future research. Nevertheless, it is clear that the multifactorial and complex nature of Actovegin underlies its pleiotropic neuroprotective mechanisms of action and positive effect on clinical outcomes.
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http://dx.doi.org/10.1016/j.jns.2012.07.069DOI Listing
November 2012
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