Levodopa-Carbidopa-Entacapone Intestinal Gel in Advanced Parkinson Disease: A Multicenter Real-Life Experience.

BACKGROUND: For Parkinson disease (PD) patients who have been diagnosed with advanced disease that can no longer be effectively controlled with optimized oral or transdermal medications, a range of device-aided therapies (DAT) are available, comprising either deep brain stimulation or infusion therapies providing continuous dopaminergic stimulation. Levodopa-entacapone-carbidopa intestinal gel (LECIG) infusion is the latest DAT for advanced PD (APD) that was approved in Romania in 2021. STUDY QUESTION: What is the experience to date in real-world clinical practice in Romania regarding the efficacy and tolerability of LECIG in APD? STUDY DESIGN: A retrospective evaluation of 74 APD patients treated with LECIG at 12 specialized APD centers in Romania. MEASURES AND OUTCOMES: Demographic data and various clinical parameters were recorded, including Mini Mental State Evaluation score or Montreal Cognitive Assessment Test score. Levodopa-equivalent daily dose and the administered doses of levodopa and other PD medications were evaluated at baseline and after starting LECIG treatment. The efficacy of LECIG in reducing daily hours of off time, motor fluctuations, and dyskinesias were assessed. Any percutaneous endoscopic gastrojejunostomy system or device complications after starting LECIG treatment were noted. RESULTS: At baseline, patients were taking oral levodopa for a mean of 5.3 times per day, with a high proportion also taking concomitant add-on therapies (dopamine agonists, 86%, monoamine oxidase type-B inhibitors, 53%; catechol-O-methyltransferase inhibitors, 64%). LECIG treatment significantly reduced daily off time versus baseline from 5.7 h/d to 1.7 hours per day ( P < 0.01). Duration and severity of dyskinesias was also significantly reduced versus baseline, and improvements were observed in Hoehn and Yahr Scale scores. LECIG treatment also allowed a significant reduction in the use of concomitant oral medications. CONCLUSIONS: These findings suggest that LECIG treatment is an effective DAT option in APD that can simplify the treatment regimen.

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

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.

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

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.

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

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.

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

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.

The impact of the COVID-19 pandemic on the mental health of patients diagnosed with inflammatory bowel diseases.

Understanding the profound impact of a viral pandemic on the mental health of patients with autoimmune diseases undergoing biological treatment is crucial for future insights. This cross-sectional case-control study aimed to assess the mental health implications of the COVID-19 pandemic on individuals with inflammatory bowel disease (IBD) in Romania, spanning from November 2022 to March 2023. A specialized self-report questionnaire in the Romanian language was developed to measure the multifaceted effects of COVID-19 on the mental well-being of these patients. The findings revealed a significant decline in the mental health of patients with IBD during the pandemic compared to the control group. Patients with IBD exhibited elevated levels of anxiety and concern regarding the virus. Intriguingly, despite the challenges, the vaccination rate was notably higher among patients with IBD, indicating a proactive approach to safeguarding their health. The study also shed light on various coping mechanisms employed by patients with IBD to navigate the pandemic-related restrictions. Engaging in activities such as social media and computer games emerged as effective strategies for managing heightened stress and limitations. In conclusion, the emergence of a novel viral pathogen represents a significant distress factor for patients with autoimmune diseases. Recognizing and comprehending these consequences enhances our understanding of the intricate interplay between physical and mental health and equips authorities with valuable insights to better manage future epidemics or viral outbreaks. This study underscores the importance of tailored support systems and strategies for patients with autoimmune diseases during global health crises.

Association among VKORC1 rs9923231, CYP4F2 rs2108622, GGCX rs11676382 polymorphisms and acute ischemic stroke.

Acute ischemic stroke is a major cause of morbidity and mortality worldwide, and genetic factors play a role in the risk of stroke. Single nucleotide polymorphisms (SNPs) in the VKORC1, CYP4F2, and GGCX genes have been linked to clinical outcomes, such as bleeding and cardiovascular diseases. This study aimed to investigate the association between specific polymorphisms in these genes and the risk of developing the first episode of acute ischemic stroke in patients without a known embolic source. This retrospective, cross-sectional, observational, analytical, case-control study included adult patients diagnosed with acute ischemic stroke. The SNPs in VKORC1 rs9923231, CYP4F2 rs2108622, GGCX rs11676382 genes were genotyped and analyzed together with the demographic and clinical factors of the 2 groups of patients. The presence of SNPs in VKORC1 or CYP4F2 genes significantly increased the risk of ischemic stroke in the context of smoking, arterial hypertension, and carotid plaque burden. The multivariate logistic model revealed that smoking (odds ratio [OR] = 3.920; P < .001), the presence of carotid plaques (OR = 2.661; P < .001) and low-density lipoprotein cholesterol values >77 mg/dL (OR = 2.574; P < .001) were independently associated with stroke. Polymorphisms in the VKORC1 and CYP4F2 genes may increase the risk of ischemic stroke in patients without a determined embolic source. Smoking, the presence of carotid plaques, and high low-density lipoprotein cholesterol levels were reconfirmed as important factors associated with ischemic stroke.

Nanowired Delivery of Curcumin Attenuates Methamphetamine Neurotoxicity and Elevates Levels of Dopamine and Brain-Derived Neurotrophic Factor.

Curcumin is a well-known antioxidant used as traditional medicine in China and India since ages to treat variety of inflammatory ailments as a food supplement. Curcumin has antitumor properties with neuroprotective effects in Alzheimer's disease. Curcumin elevates brain-derived neurotrophic factor (BDNF) and dopamine (DA) levels in the brain indicating its role in substance abuse. Methamphetamine (METH) is one of the most abused substances in the world that induces profound neurotoxicity by inducing breakdown of the blood-brain barrier (BBB), vasogenic edema and cellular injuries. However, influence of curcumin on METH-induced neurotoxicity is still not well investigated. In this investigation, METH neurotoxicity and neuroprotective effects of curcumin nanodelivery were examined in a rat model. METH (20 mg/kg, i.p.) neurotoxicity is evident 4 h after its administration exhibiting breakdown of BBB to Evans blue albumin in the cerebral cortex, hippocampus, cerebellum, thalamus and hypothalamus associated with vasogenic brain edema as seen measured using water content in all these regions. Nissl attaining exhibited profound neuronal injuries in the regions of BBB damage. Normal curcumin (50 mg/kg, i.v.) 30 min after METH administration was able to reduce BBB breakdown and brain edema partially in some of the above brain regions. However, TiO2 nanowired delivery of curcumin (25 mg/kg, i.v.) significantly attenuated brain edema, neuronal injuries and the BBB leakage in all the brain areas. BDNF level showed a significant higher level in METH-treated rats as compared to saline-treated METH group. Significantly enhanced DA levels in METH-treated rats were also observed with nanowired delivery of curcumin. Normal curcumin was able to slightly elevate DA and BDNF levels in the selected brain regions. Taken together, our observations are the first to show that nanodelivery of curcumin induces superior neuroprotection in METH neurotoxicity probable by enhancing BDNF and DA levels in the brain, not reported earlier.

Repetitive transcranial magnetic stimulation (rTMS) as a therapeutic option in paraneoplastic cerebellar ataxia - a case report.

Paraneoplastic cerebellar ataxia is a paraneoplastic neurological syndrome (PNS) that can be the first clinical manifestation of underlying cancer. It is usually associated with onco-neuronal antibodies and has no other specific paraclinical feature. After the surgical and oncologic treatment of the primary cancer, the remaining neurological symptoms have limited therapeutic options. We describe a case of severe ataxia as the primary manifestation of ovarian cancer, with a significant clinical and paraclinical improvement of the neurological symptoms after 20 sessions of rTMS intervention.

Neutrophils-to-Lymphocyte Ratio Is Associated with Progression and Overall Survival in Amyotrophic Lateral Sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating and untreatable motor neuron disease, with a 3-5-year survival from diagnosis. Possible prognostic serum biomarkers include albumin, C-reactive protein, ferritin, creatinine, uric acid, hemoglobin, potassium, sodium, calcium, glucose, and the neutrophil-to-lymphocyte ratio (NLR), a marker of subclinical inflammation. OBJECTIVE: To ascertain the influence of NLR on ALS progression rate and survival. METHODS: Cross-sectional multicenter study including 146 consecutive incident and prevalent patients (88 males), aged >18 years, diagnosed according to the El Escorial criteria. The exclusion criteria were: (1) patients with tracheostomy or receiving mechanical ventilation; (2) patients with percutaneous endoscopic gastrostomy; and (3) patients who did not sign the informed consent. The rate of disease progression (ΔFS score) represents the monthly decline of the ALSFRS-R score, and was computed as (48 - total ALSFRS-R at recruitment)/symptom duration in months. Patients were followed up to tracheotomy, death, or the end of the follow-up, whichever occurred first. To validate our findings, we used data retrieved from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) Database. RESULTS: The median disease duration was 15 (range = 2-30) months. The mean ALSFRS-R score at recruitment was 35.8 ± 8.0 (range: 10-48), and the median ΔFS was 0.66 (range: 0-5.33). Age at onset, at diagnosis, and at recruitment were significantly lower in the lowest NLR tertile. NLR values positively correlated with ΔFS values (r = 0.28): the regression slope of NLR (log-values) was 0.60 (p < 0.001) before and 0.49 (p = 0.006) after adjustment for age at recruitment. The ΔFS score progressively increased from the lowest to the highest NLR tertile: 0.35 (IQR: 0.18-0.93), 0.62 (IQR: 0.25-1.09), and 0.86 (IQR: 0.53-1.92). Patients were followed for a median of 2 years. The mortality rate passed from 15.9 events per 100 person-years in patients belonging to the lowest NLR tertile to 52.8 in those in the highest tertile. The optimal cut-off value which best classified patients with the lowest and the highest mortality rate was set at the NLR value of 2.315. Indeed, the mortality rate of patients with an NLR value above such cut-off was twice the mortality rate of patients with a value below the cut-off (age adjusted hazard ratio (HR): 2.16, 95% confidence interval (CI): 1.32-3.53). In the PRO-ACT validation sample, patients with an NLR value above the cut-off consistently had a higher mortality rate than those with a value below the cut-off (age adjusted HR: 1.17, 95%CI: 1.01-1.35). CONCLUSIONS: NLR could be a candidate easy, fast, and low-cost marker of disease progression and survival in ALS. It may be associated with low-grade inflammation either as a direct mirror of the pathological process of disease progression, or as a consequence of neuronal death (reverse causation). However, prospective studies are needed to understand whether NLR changes during the course of the disease, before using it to monitor disease progression in ALS.

Superior neuroprotective effects of cerebrolysin in heat stroke following chronic intoxication of Cu or Ag engineered nanoparticles. A comparative study with other neuroprotective agents using biochemical and morphological approaches in the rat.

The possibility that cerebrolysin, a mixture of several active fragments of neurotrophic factors and peptides induces neuroprotection following nanoparticles induced exacerbation of brain damage in heat stroke was examined in a rat model. For this purpose, the therapeutic efficacy of Cerebrolysin (2.5 or 5 ml/kg) recommended for stroke treatment was used in comparison with other drugs in standard doses recommended for such therapy in clinical situations e.g., levetiracetam (44 mg/kg), pregabalin (200 mg/kg), topiramate (40 mg/kg,i.p.) and valproate (400 mg/kg). Rats subjected to 4 h heat stress in a biological oxygen demand (BOD) incubator at 38 degrees C (Rel Humid 45-47%; Wind vel 22.4 to 25.6 cm/sec) developed profound behavioral symptoms of heat stroke e.g., hyperthermia, profuse salivation, prostration and gastric ulcerations in the stomach. These rats also exhibited marked brain pathology at this time. Thus, breakdown of the blood-brain barrier (BBB) to proteins associated with brain edema formation could be seen in these heat stressed rats as compared to control groups. The edematous brain areas showed profound neuronal damage and/or distortion in large areas of the neuropil. These pathological symptoms were further exacerbated in Cu or Ag nanoparticles treated group (50-60 nm particle size, 50 mg/kg, i.p./day for 7 days) after identical heat stress on the 8th day. Pretreatment with cerebrolysin (2.5 ml/kg, i.v.) daily for 3 days in normal rats before heat stress significantly reduced the behavioral stress symptoms and the breakdown of the BBB function, edema formation and neuronal injuries. However, the magnitude and intensity of these neuroprotective effects were much less intense in all other drug treated rats after similar heat stress. On the other hand, almost double dose of cerebrolysin (5 ml/kg) was needed to achieve comparable neuroprotection in nanoparticles treated animals after heat stress. Whereas, double dose of all other compounds was much less effective in inducing neuroprotection in nanoparticles treated heat-exposed animals. These observations are the first to show that cerebrolysin exerts the most superior neuroprotective effects in heat stress as compared to other neuroprotective agents on brain pathology in normal and in nanoparticles treated group. Furthermore, cerebrolysin in double dose was the most effective in inducing neuroprotection in nanoparticles treated heat exposed rats on brain pathology as compared to double doses of other drugs. Taken together, our results show that cerebrolysin has the most superior neuroprotective effects on brain pathology in heat stroke in both normal and nanoparticles treated rats as compared to other contemporary neuroprotective agents, not reported earlier.

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

Background/objectives: 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. Subjects/methods: 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). Results: 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 (p = 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 (p = 0.028) but not with the number of cup-years. Conclusions: Our study does not support the hypothesis that coffee or tea consumption is associated with the ALS progression rate.

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

Introduction: 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. Aim: 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. Methods: 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. Results: 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. Conclusions: 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.

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

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 (n = 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 (p = 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.

Chronic hypertension aggravates heat stress-induced brain damage: possible neuroprotection by cerebrolysin.

Whole body hyperthermia (WBH) aggravates brain edema formation and cell damage in chronic hypertensive rats compared with normotensive animals. In this investigation, we examined the influence of cerebrolysin on WBH-induced edema formation and brain pathology in hypertensive and normotensive rats. Rats subjected to 4 h WBH at 38 degrees C in a biological oxygen demand (BOD) incubator showed breakdown of the blood-brain barrier (BBB), reduced cerebral blood flow (CBF), edema formation and cell injuries in several parts of the brain. These effects were further aggravated in chronic hypertensive rats (two-kidney one clip model (2K1C), for 4 weeks) subjected to WBH. Pretreatment with cerebrolysin (5 mL/kg, 24 h and 30 min before heat stress) markedly attenuated the BBB dysfunction and brain pathology in normal animals. However, in hypertensive animals, a high dose of cerebrolysin (10 mL/kg, 24 h and 30 min before heat stress) was needed to attenuate WBH-induced BBB dysfunction and brain pathology. These observations indicate that heat stress could affect differently in normal and hypertensive conditions. Furthermore, our results suggest that patients suffering from various chronic cardiovascular diseases may respond differently to hyperthermia and to neuroprotective drugs, e.g., cerebrolysin not reported earlier.

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

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.

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

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.

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.

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 [131]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.

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

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.

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

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 [131]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.