Permanent Neurological Disorders Research Articles

A Foodborne Disease “Campylobacteriosis”: Global Epidemiology, Pathogenicity, Diagnosis and Treatment

Abstract: Campylobacteriosis is a foodborne disease caused by Campylobacter, which is one of the leading causative agents of bacterial gastrointestinal diseases in developed and developing countries. According to WHO, Campylobacter species infects a hundred million people yearly. The bacterium is thermotolerant, cytochrome oxidase-positive, spiral-shaped, gram-negative, and microaerophilic, by exhibiting corkscrew motility it passes through the intestines of animals and birds. It is generally transmitted through the consumption of contaminated food associated with animal and their products. The main infectious species include C. coli, C. jejuni, C. fetus and C. upsaliensis. Infection symptoms can be mild to serious depending upon the patient's age and in some cases can lead to permanent neurological disorders. Detection of Campylobacter in food, clinical and environmental samples is accomplished with the help of combinatorial usage of selective enrichment and culture methods. Currently, there is no sole viable approach for infection management because of resistance emergence. In this review article, we discuss Campylobacter epidemiology, pathogenicity, various diagnostic methods and treatment of Campylobacteriosis.

Seizure outcomes and safety profiles of surgical options for epilepsy associated to hypothalamic hamartomas: a systematic review and meta-analysis

PurposeSeveral surgical options are available for treating hypothalamic hamartoma-related epilepsy but their respective efficacy and safety profiles are poorly defined. MethodsA literature search identified English-language articles reporting series of patients (minimum 3 patients with a follow-up ≥12 months) operated on by either microsurgery, endoscopic surgery, radiosurgery, radiofrequency thermocoagulation or laser interstitial thermal therapy for hypothalamic hamartoma-related epilepsy. The unit of analysis was each selected study. Pooled rates of seizure freedom and of neurological and endocrinological complications were analyzed using meta-analysis to calculate both fixed and random effects. The results of meta-analyses were compared. ResultsThirty-nine studies were included. There were 568 and 514 participants for seizure outcome and complication analyses, respectively. The pairwise comparison showed that: i) the proportion of seizure-free cases was significantly lower for radiosurgery as compared to microsurgery, radiofrequency thermocoagulation and laser ablation, and significantly lower for endoscopic surgery as compared to radiofrequency thermocoagulation; ii) the proportion of permanent hypothalamic dysfunction was significantly higher for microsurgery as compared to all other techniques, and significantly lower for endoscopic surgery as compared to radiofrequency thermocoagulation and laser ablation; iii) the incidence of permanent neurological disorders was significantly higher for microsurgery as compared to endoscopic surgery, radiosurgery and radiofrequency thermocoagulation, and significantly lower for radiosurgery as compared to laser ablation. ConclusionsMinimally invasive surgical techniques, including endoscopic surgery, radiofrequency thermocoagulation and laser ablation, represent an acceptable compromise between efficacy and safety in the treatment of hypothalamic hamartoma-related epilepsy. Microsurgery and radiosurgery should be considered in carefully selected cases.

Crocin alleviates neurotoxicity induced by bupivacaine in SH-SY5Y cells with inhibition of PI3K/AKT signaling.

Bupivacaine, a common local anesthetic, can cause neurotoxicity and permanent neurological disorders. Crocin has been widely reported as a potential neuroprotective agent in neural injury models. The aim of this study was to investigate the role and regulatory mechanism of crocin underlying bupivacaine-induced neurotoxicity. Human neuroblastoma SH-SY5Y cells were treated with bupivacaine and/or crocin for 24h, followed by detecting cell viability using 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay. The effect of crocin or bupivacaine on SH-SY5Y cell proliferation was measured by Ki67 immunofluorescence assay. The levels of apoptosis-related proteins and the markers in the PI3K/Akt signaling pathway were examined using western blot analysis. The activities of caspase 3, catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione peroxidase (GSH-Px) were tested using respective commercial assay kits. Flow cytometry analysis was executed for detecting SH-SY5Y cell apoptosis. Crocin attenuated bupivacaine-induced neurotoxicity in SH-SY5Y cells. Meanwhile, crocin inhibited SH-SY5Y cell apoptosis induced by bupivacaine via repressing the activity of caspase-3, reducing Bax expression, and elevating Bcl-2 expression. Moreover, crocin mitigated oxidative stress in SH-SY5Y cells by increasing the content of CAT, SOD, GSH-Px and reducing the content of MDA. Additionally, crocin protected against bupivacaine-induced dephosphorylation of Akt and GSK-3β. The protective effects of crocin against bupivacaine-induced neurotoxicity in SH-SY5Y cells were counteracted by the Akt inhibitor. These results suggested that crocin may exert a neuroprotective function by promoting cell proliferation and suppressing apoptosis and oxidative stress in SH-SY5Y cells. Thus, crocin might become a promising drug for the treatment of bupivacaine-induced neurotoxicity.

Rehabilitation of Gait and Balance in Cerebral Palsy: A Scoping Review on the Use of Robotics with Biomechanical Implications.

Cerebral palsy (CP) is a congenital and permanent neurological disorder due to non-progressive brain damage that affects gross motor functions, such as balance, trunk control and gait. CP gross motor impairments yield more challenging right foot placement during gait phases, as well as the correct direction of the whole-body center of mass with a stability reduction and an increase in falling and tripping. For these reasons, robotic devices, thanks to their biomechanical features, can adapt easily to CP children, allowing better motor recovery and enjoyment. In fact, physiotherapists should consider each pathological gait feature to provide the patient with the best possible rehabilitation strategy and reduce extra energy efforts and the risk of falling in children affected by CP.

Molecular Mechanism and Role of Japanese Encephalitis Virus Infection in Central Nervous System-Mediated Diseases.

The Japanese encephalitis virus (JEV) is the most common cause of neurodegenerative disease in Southeast Asia and the Western Pacific region; approximately 1.15 billion people are at risk, and thousands suffer from permanent neurological disorders across Asian countries, with 10-15 thousand people dying each year. JEV crosses the blood-brain barrier (BBB) and forms a complex with receptors on the surface of neurons. GRP78, Src, TLR7, caveolin-1, and dopamine receptor D2 are involved in JEV binding and entry into the neurons, and these receptors also play a role in carcinogenic activity in cells. JEV binds to GRP78, a member of the HSP70 overexpressed on malignant cells to enter neurons, indicating a higher chance of JEV infection in cancer patients. However, JEV enters human brain microvascular endothelial cells via an endocytic pathway mediated by caveolae and the ezrin protein and also targets dopamine-rich areas for infection of the midbrain via altering dopamine levels. In addition, JEV complexed with CLEC5A receptor of macrophage cells is involved in the breakdown of the BBB and central nervous system (CNS) inflammation. CLEC5A-mediated infection is also responsible for the influx of cytokines into the CNS. In this review, we discuss the neuronal and macrophage surface receptors involved in neuronal death.

Engineering the Single Domain Antibodies Targeting Receptor Binding Motifs Within the Domain III of West Nile Virus Envelope Glycoprotein.

West Nile virus (WNV) is a mosquito-borne neurotrophic flavivirus causing mild febrile illness to severe encephalitis and acute flaccid paralysis with long-term or permanent neurological disorders. Due to the absence of targeted therapy or vaccines, there is a growing need to develop effective anti-WNV therapy. In this study, single-domain antibodies (sdAbs) were developed against the domain III (DIII) of WNV’s envelope glycoprotein to interrupt the interaction between DIII and the human brain microvascular endothelial cells (hBMEC). The peripheral blood mononuclear cells of the llama immunized with recombinant DIIIL297–S403 (rDIII) were used to generate a variable heavy chain only (VHH)-Escherichia coli library, and phage display was performed using the M13K07ΔpIII Hyperphages system. Phages displaying sdAbs against rDIII were panned with the synthetic analogs of the DIII receptor binding motifs, DIII-1G299–K307 and DIII-2V371–R388, and the VHH gene from the eluted phages was subcloned into E. coli SHuffle. Soluble sdAbs purified from 96 E. coli SHuffle clones were screened to identify 20 candidates strongly binding to the synthetic analogs of DIII-1G299–K307 and DIII-2V371–R388 on a dot blot assay. Among them, sdAbA1, sdAbA6, sdAbA9, and sdAbA10 blocked the interaction between rDIII and human brain microvascular endothelial cells (hBMECs) on Western blot and cell ELISA. However, optimum stability during the overexpression was noticed only for sdAbA10 and it also neutralized the WNV–like particles (WNV-VLP) in the Luciferase assay with an half maximal effective concentration (EC50) of 1.48 nm. Furthermore, the hemocompatibility and cytotoxicity of sdAbA10 were assessed by a hemolytic assay and XTT-based hBMEC proliferation assay resulting in 0.1% of hemolytic activity and 82% hBMEC viability, respectively. Therefore, the sdAbA10 targeting DIII-2V371–R388 of the WNV envelope glycoprotein is observed to be suitable for in vivo trials as a specific therapy for WNV–induced neuropathogenesis.

Progressive spinal cord compression technique in experimental rabbit animal model for cervical spondylotic myelopathy

IntroductionCervical spondylotic myelopathy (CSM) presently estimated at 54% population, commonly cause of myelopathy due to chronic compression of the spinal cord in older people. Physiological injuries caused by static and dynamic forces including compressed, pinched, and pulled out inducing secondary injuries at the molecular level. MethodsWe examined the rabbit model approach with the clinical case of spondylotic myelopathy, in which the disk and facet maintained the cervical spine mobility, and compression was given 0.5 mm per week three times in this model. In this study, a group of 14 days was made (early into the chronic phase) and the 21 day group had a chronic process for 1 week, that period can be categorized as a chronic process and CSM is a chronic process. By examining motor scores, histological examination and immunohistochemistry of the spinal cord, this model efficiently produces myelopathy. The distribution of microglia expressing GFAP, S100-β, and Neurofilaments were observed by immunohistochemical techniques. ResultsThere was a significant difference in the number of cells expressing GFAP between the control group and the 21-day compression group (p = 0.001). There is a decrease in S100-β expression of spinal cord tissue after receiving compression exposure. There was a significant difference in the number of cells expressing NF between the control group, the 14-day compression group (p = 0.04) and 21-day compression group (p = 0.04). DiscussionNeurons have the intrinsic ability to regenerate after injury, although not spontaneously. Cervical spondylotic myelopathy causes permanent neurological disorders, partly due to glial scar formation consisting of astrocytes and microglia. The difference between our study and previous research methods is that we perform compression of the spinal cord in stages (0.5 mm, 1.0 mm & 1.5 mm) so that it is more like the natural occurrence of chronic spinal cord compression. ConclusionAn increasing of GFAP value in this study indicates the presence of astrocyte activity which can be associated with chronic spinal cord injury. There is a decrease in S100-β expression of spinal cord tissue neuron cells after receiving compression exposure. The expression of NF decreased indicating degenerative axons.

INFLUENCE OF SELECTED AEROBIC EXERCISES on serum vitamin D level IN PATIENTS WITH MULTIPLE SCLEROSIS

Background: Multiple sclerosis is the most common permanent neurological disorder affecting young adult causing strength deficits. Aim of the study: This study was conducted to investigate influence of selected aerobic exercises on serum Vitamin D level in patients with multiple sclerosis. Subject and methods: 30 patients (20 female and 10 male) with relapsing remitting multiple sclerosis recently diagnosed by Expanded Disability Status Scale score less than 5, vitamin D insufficiency less than 20- 30 ng/mL, age from 20 to 40 years old with body mass index less than 25 kg/m² were recruited, assessed for and assigned into 2 groups. They received treatment program as follows: control group (A) received conventional medical treatment (Corticosteroids, Interferon beta medications, Dimethyl fumarate, muscle relaxants, medications to reduce fatigue)in addition to vitamin D supplementation only, while experimental group (B) received conventional medical treatment(Corticosteroids, Interferon beta medications, Dimethyl fumarate, muscle relaxants, medications to reduce fatigue), vitamin D supplementation in addition to selected aerobic exercises. the outcome measures included serum vitamin D level by lab test ,timed 25 walk test by measure timing of performance of lower limb gait in multiple sclerosis. Results: both groups showed significant difference in the outcome measures in the post treatment assessment, but the selected aerobic exercises (B) showed a more significant improvement over the control group at p-value >0. 001. Conclusion: selected aerobic exercises is an effective physical therapy modality when added to the conventional medical treatment (Corticosteroids, Interferon beta medications, Dimethyl fumarate, muscle relaxants, medications to reduce fatigue) so it may provide better outcomes for a patient with multiple sclerosis.

Unilateral or bilateral cerebral perfusion in hemiarch replacement: A prospective randomized study.

We designed a prospective randomized clinical study to compare unilateral and bilateral antegrade cerebral perfusion (ACP) under moderate hypethermia in open distal aortic hemiarch replacement in ascending aortic aneurysm. Forty-two patients were prospectively randomized into two groups; unilateral ACP to Group 1 and bilateral ACP to Group 2. Inclusion criteria were pathological aortic aneurysm in the ascending aorta and/or aortic arch, elective operation, normal preoperative carotid Doppler ultrasonography, and nonexistence of preoperative neurological event. Patients were evaluated with preoperative and postoperative biochemical blood analysis, magnetic resonance imaging (MRI), and neurological disorders. The primary endpoints were permanent neurological disorder and death. There were 21 patients in each group. Mean age was 56.57 ± 10.06 years in Group 1 and 50.95 ± 15.64 years in Group 2 (p = .170). No significant difference was found according to demographic data. ACP times were significantly higher in bilateral ACP (Group 1: 12.62 ± 5.04 min, Group 2: 18.23 ± 9.04 min, p = .018) whereas cross-clamp time and cardiopulmonary bypass times were not (p = .693 and p = .584 sequentially). Transient neurological disorder was found in seven patients in Group 1 and in 4 patients in Group 2 (p = .484). Postoperative MRI revealed new milimetric ischemic zones in three patients in Group 1 but none in Group 2. No permanent neurological disorder or mortality was seen. The present randomized clinical prospective study could not prove the superiority of one of the technique in cerebral protection probably because, our overall ACP time was too short.

Tick-Borne Encephalitis Virus: A Quest for Better Vaccines against a Virus on the Rise.

Tick-borne encephalitis virus (TBEV), a member of the family Flaviviridae, is one of the most important tick-transmitted viruses in Europe and Asia. Being a neurotropic virus, TBEV causes infection of the central nervous system, leading to various (permanent) neurological disorders summarized as tick-borne encephalitis (TBE). The incidence of TBE cases has increased due to the expansion of TBEV and its vectors. Since antiviral treatment is lacking, vaccination against TBEV is the most important protective measure. However, vaccination coverage is relatively low and immunogenicity of the currently available vaccines is limited, which may account for the vaccine failures that are observed. Understanding the TBEV-specific correlates of protection is of pivotal importance for developing novel and improved TBEV vaccines. For affording robust protection against infection and development of TBE, vaccines should induce both humoral and cellular immunity. In this review, the adaptive immunity induced upon TBEV infection and vaccination as well as novel approaches to produce improved TBEV vaccines are discussed.

Impaired Cardiovascular Responses To Acute Exercise In Adults With Cerebral Palsy

Cerebral palsy (CP) is a non-progressive and permanent neurological disorder leading to musculoskeletal dysfunction and immobility. A major clinical problem with CP is early development of cardiovascular diseases with increased rates of mortality. Due to the inevitability of motor dysfunction adults with CP can develop health risk factors, such as obesity and hypertension, at a higher rate compared to the general population. To date, the physiological basis for CP has not been established; how cardiovascular dynamics, such as heart rate (HR), blood pressure (BP), and blood flow (BF), are controlled in individuals with CP has never been identified. PURPOSE: To determine differential cardiovascular responses to acute dynamic exercise in adults with CP. METHODS: Total of ten adults with and without CP participated in the study. HR from ECG, beat-to-beat arterial BP from Finapres and brachial BP, and respiration via pneumobelt were continuously measured before, during and after 2 minutes of dynamic handgrip exercise at 35% and 50% of maximal voluntary contraction. In addition, diameter, blood velocity, and flow of the brachial artery were measured using Doppler ultrasound on the contracting arm throughout the experiment. RESULTS: HR was significantly increased to exercise from rest in both groups with no group differences (∆9.8±1.2 control vs. ∆10.1±8.4 CP, bpm). Both control and CP groups had increases in BF during exercise compared to at rest (∆132±22 control vs. ∆75±32 CP, ml/min). Mean BP was significantly increased to exercise from rest in control; however, there were only minor changes in BP to exercise from rest in CP group (∆7.2±1.6 control, ∆2.2±0.1 CP, mmHg). CONCLUSION: While HR and BF increased to exercise from rest in similar fashion, BP did not change to exercise in adults with CP. Our preliminary data speculate that other mechanisms, possibly vascular contribution from non-contracting limbs, may contribute to impaired BP response during exercise in CP. Supported by CASA RSCA Infusion, Central RSCA, and Undergraduate Research Grant, SJSU

Graphene transistor arrays functionalized with genetically engineered antibody fragments for Lyme disease diagnosis

Lyme disease is an infectious disease caused by the Borrelia burgdorferi bacterium. Early diagnosis of Lyme disease could prevent patients from developing serious side effects such as chronic arthritis and permanent neurological disorders. Lyme disease diagnosis is currently held back by a lack of reliable tools that are sufficiently sensitive and specific to allow early stage detection. Here, we demonstrate all electronic nano-biosensors for multiplexed detection of antigens of B. burgdorferi at concentrations as low as 2 pg ml−1. The sensors are based on graphene field-effect transistors (GFETs) coupled with genetically engineered antibody fragments. Single-chain variable fragment (scFv) antibodies are used to obtain a closer proximity of the target-binding event to the graphene sensor surface and for higher immobilization density. When compared to GFET nano-biosensors that use the parental immunoglobulin G (IgG) antibodies, scFv GFET nano-biosensors achieve approximately a 4000 × improvement to the limit of detection. We also demonstrate multiplexed detection of B. burgdorferi antigens through site-specific immobilization of scFvs on GFET arrays, which can potentially reduce the false-positive diagnosis ratio of Lyme disease. This work offers a pathway towards point-of-care detection of Lyme disease at an early stage.

Differential Effect of Obesity on Muscular Strength in Adults with Cerebral Palsy

Cerebral palsy (CP) is a non-progressive and permanent neurological disorder that is characterized by muscular deterioration and atrophy. The major clinical problem with CP is early development of cardiovascular disease with increased rates of mortality. Due to the inevitability of motor dysfunction adults with CP can develop health risk factors such as obesity at a higher rate compared to the general population. Limited information is available to identify levels of obesity and its relation to muscular function in adults with CP. PURPOSE: To determine whether severity of obesity may affect muscular function and strength in adults with CP. METHODS: We studied total of sixteen adults with and without CP. Muscular strength (i.e., torque, work, and power) during knee extension and flexion was measured at 90, 150, and 210 °/sec in the lower extremity using Humac Norm Isokinetic Dynamometer. Maximal isometric forearm muscular strength was measured using a handgrip dynamometer. Body mass index (BMI), waist to hip ratio, and whole-body scan from Dual Energy X-Ray Absorptiometry were used to identify the levels of obesity. RESULTS: Compared to control, individuals with CP had similar BMI (26.8±3.0 CP vs. 22.9±1.0 control kg/m2; P>0.05), % body fat (35.2±4.5 CP vs. 28.4±3.7 control %; P>0.05), and % leg fat (40.7±4.3 CP vs. 30.5±4.1 control %; P>0.05). However, waist to hip ratio was significantly greater in CP (0.90±0.02 CP vs. 0.80±0.02 control; P<0.05); muscular strength was significantly lower in CP compared to control (e.g., knee extensor peak torque at 90°/sec; 25.9±8.1 CP vs. 72.5±12.2 control ft-lb; P<0.05). There was no relationship between BMI and extensor/flexor peak torque in both groups; however, there was a linear relationship between waist to hip ratio and extensor/flexor peak torque only in CP group (R2=0.34). A strong inverse relationship between % leg fat and extensor/flexor peak torque was observed in both groups (R2=0.79). CONCLUSION: These findings suggest that central obesity rather than BMI appeared to influence muscular strength in CP adults. In addition, less fat in the legs rather than the total body may contribute for higher leg muscular strength in adults with CP. Supported by Central RSCA and Undergraduate Research Grant, SJSU

Interleukin-1β Disturbs the Proliferation and Differentiation of Neural Precursor Cells in the Hippocampus via Activation of Notch Signaling in Postnatal Rats Exposed to Lipopolysaccharide.

Infectious exposure during the perinatal period may predispose to permanent neurological disorders in later life. Here we investigated whether changes in interleukin-1β (IL-1β) are associated with cognitive dysfunction in later life of septic neonatal rats through suppression of neurogenesis in the hippocampus. Sprague-Dawley rats (1-day old) administered lipopolysaccharide (LPS) showed upregulated expression of IL-1β and IL-1 receptors in the hippocampus. At 28 days of age, rats showed longer escape latencies and decreased numbers of crossings after LPS administration. This was coupled with increased numbers of glial fibrillary acidic protein positive (GFAP+) astrocytes and decreased numbers of neuronal nuclei positive (NeuN+) cells. The numbers of sex-determining region Y-box 2 positive (SOX2+) and doublecortin positive (DCX+) cells were decreased at 1 and 3 days but was increased at 7 and 14 days. The proliferation of SOX2+ cells was inhibited at 1 and 3 days but increased at 7 and 14 days. In vitro IL-1β administration suppressed the proliferation of neural progenitor cells (NPCs) in neurospheres derived from the hippocampus. GFAP expression was upregulated in differentiated NPCs treated with IL-1β for 4 days, but expression of DCX and microtubule associated protein-2 (MAP2) was decreased. Remarkably, the Notch signaling pathway involved in antineurogenic and progliogenic differentiation of NPCs was activated after IL-1β administration. The results show that following LPS injection in neonatal rats, microglia were activated and generated excess amounts of IL-1β in the hippocampus. It is suggested that this might have contributed to inhibiting neurogenesis but promoting gliogenesis of NPCs via activation of the Notch signaling pathway and maybe one of the causes for cognitive dysfunction in septic neonatal rats in later life.

Assessment of Dietary Intake of Manganese in Relation to Tolerable Upper Intake Level

The Norwegian Scientific Committee for Food and Environment (Vitenskapskomiteen for mat og miljø, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), evaluated the intake of manganese from the diet and 1, 5 or 10 mg manganese per day in food supplements. The former maximum limit for manganese in food supplements was 5 mg per daily dose. &#x0D; Manganese (Mn) is an essential dietary mineral for mammals, and is a component of metalloenzymes such as superoxide dismutase, arginase and pyruvate carboxylase. Manganese is involved in amino acid-, lipid- and carbohydrate metabolism and in proteoglycan synthesis in bone formation. In 2013, the European Food Safety Authority (EFSA) suggested 3 mg/day to represent an adequate intake (AI) of manganese because data was considered insufficient to set an average requirement (AR).&#x0D; Reports of adverse effects resulting from manganese exposure in humans are associated primarily with inhalation in occupational settings. Excess oral exposure to manganese, especially from contaminated water sources, has been shown to cause permanent neurological disorder known as “manganism” which can be irreversible. The amount of manganese absorbed is inversely related to the concentration of manganese in the diet. This regulation seems to be part of the adaptive changes to the amount of dietary manganese intake, which allow the maintenance of manganese homeostasis over a wide range of intakes. Manganese is mainly absorbed as Mn(II), and absorption is reported to be below 10% of ingested manganese.&#x0D; The main route of elimination of manganese from the body is via bile to the small intestine, while very little is excreted in the urine. Half-life for manganese can vary from 13 to 37 days, with a longer half-life in women than in men, but large inter-individual variation exists. &#x0D; In Norway, manganese content in drinking water is low, and does not contribute to any magnitude of manganese intake. Daily dietary intake of manganese in Norway is not known, but it is proposed that manganese intake is adequate in the Scandinavian countries (NNR Project Group, 2012). Results from the Swedish Market Basket study, 2015, indicate an average daily manganese intake of 4.2 mg per person and day. Calculations based on data from Denmark, 2013 and 2015, evaluate mean dietary intake of manganese to 3.9 mg/day for adults and up to 6.9 mg/day in the higher intake groups. EFSA report on an observed mean intake in EU around 3 mg/day for adults. Main contributor to dietary manganese intake is cereals (57%) followed by fruit, vegetables, nuts and coffee/tea. &#x0D; Irreversible neurotoxic adverse effects from intakes of manganese close to adequate intakes have been reported in humans (SCF, 2000). The Scientific Committee on Food (SCF) could not set a no observed adverse effect level (NOAEL), because no relevant dose-response animal studies were found. Consequently SCF did not set a tolerable upper intake level (UL) for manganese. &#x0D; VKM considers that any dose of manganese as an ingredient in food supplements may be associated with increased risk of negative health effects. &#x0D; VKM emphasises that the current assessment of maximum limits for manganese in food supplements is merely based on published reports concerning upper levels from the IOM (2001, USA), SCF (2003, EU), EVM (2003, UK) and NNR (2012, Nordic countries). VKM has not conducted any systematic review of the literature for the current opinion, as this was outside the scope of the terms of reference from NFSA.

Paeoniflorin attenuated bupivacaine-induced neurotoxicity in SH-SY5Y cells via suppression of the p38 MAPK pathway.

Bupivacain, a common local anesthetic, can cause neurotoxicity and permanent neurological disorders. Paeoniflorin has been widely reported as a potential neuroprotective agent in neural injury models. However, the roles and molecular basis of paeoniflorin in bupivacaine-induced neurotoxicity are still undefined. In the current study, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed to detect cell viability. Apoptotic rate was measured through double-staining of Annexin V-FITC and propidium iodide on a flow cytometer. Western blot assay was carried out to examine the protein levels of p38 mitogen-activated protein kinase (p38 MAPK), phosphorylated-p38 MAPK (p-p38 MAPK), Bcl-2, and Bax. caspase-3 activity was determined using a caspase-3 activity assay kit. We found that paeoniflorin dose-dependently attenuated bupivacaine-induced viability inhibition and apoptosis in SH-SY5Y cells. Moreover, paeoniflorin inhibited bupivacaine-induced activation of p38 MAPK pathway in SH-SY5Y cells. Paeoniflorin alone showed no significant effect on cell viability, apoptosis and p38 MAPK signaling in SH-SY5Y cells. Inhibition of p38 MAPK signaling by SB203580 or small interfering RNA targeting p38 (si-p38) abated bupivacaine-induced viability inhibition and apoptosis in SH-SY5Y cells. In conclusion, paeoniflorin alleviated bupivacaine-induced neurotoxicity in SH-SY5Y cells via suppression of the p38 MAPK pathway, highlighting the potential values of paeoniflorin in relieving bupivacaine-induced neurotoxicity.

Investigation of the histological changes in spinal nerve roots post intrathecal ketamine administration

Background: Ketamine is a general anesthetic agent, administered intramuscularly or intravenously. It is generally used for induction and less frequently for the continuation of surgical anesthesia. Although ketamine was initially thought to be used as an intrathecal agent, psychomimetic side effects were observed. Objectives: In this study, the differences in the spinal nerve roots postintrathecal ketamine injection have been examined in the light and electron microscope. Materials and Methods: 30 min, 1 h, and 24-h postintrathecal ketamine (0.5 mg/kg) injection; the rabbits were sacrificed. The tissue samples taken from the injection area fixed with 1st 2% glutaraldehyde and later 1% OsO4. Following dehydration tissue samples embedded in Araldite and sections were taken and examined in the light and electron microscope. Results: There were severe degenerations in the myelinated nerve fibers postintrathecal injection of ketamine. Fading on the myelin lamellae, shrinking and vacuolization of the axoplasm, endoneurial edema, organelle loss, and cystic parts were observed. The vacuolization and lack of organelles in the Schwann cell cytoplasm were clear. The degeneration of the large myelinated nerve fibers was observed more than unmyelinated fibers. Conclusion: The general and local anesthetics used have significant side effects such as respiratory depression or permanent neurological disorders. Therefore, new options are searched, and the effects of the drugs used in different fields of anesthesia were investigated.

Combination therapy for the focal form of mixed tick-borne encephalitis-Borrelia infection

The focal form of mixed tick-borne encephalitis-Borrelia infection (MTBEBI) is characterized by a nervous system lesion with the development of permanent neurological disorders and a possible fatal outcome. Uniform approaches to treating MTBEBI have not been currently elaborated. Obviously, adequate treatment of the mixed infection requires a comprehensive approach and simultaneous action on tick-borne encephalitis and tick-borne borreliosis. Its promising treatment is immunocorrection with normal human immunoglobulin that contains a wide spectrum of antibodies and exerts an immunomodulatory effect. Objective: to evaluate the efficiency of combination (etiotropic and pathogenetic) therapy with normal human immunoglobulin for the focal form of MTBEBI. Patients and methods. The results of the treatment were analyzed in 57 patients with MTBEBI with a nervous system lesion, who had been notified in the Kemerovo Region in 2000 to 2014. Results and discussion. It was shown that the use of normal human immunoglobulin in a treatment regimen for the focal form of MTBEBI could considerably reduce the incidence of residual neurological deficit. The administration of normal human immunoglobulin was assumed to improve the efficiency of treatment for the focal form of MTBEBI. The paper also describes a clinical case of a patient with MTBEBI, which demonstrates the efficiency of combination therapy for this disease.

Severe hypoglycaemia in elderly patients with type 2 diabetes and coexistence of cardiovascular history.

Hypoglycaemia is a condition that occurs when blood glucose levels fall below 3.9 mmol/L (70 mg/dL), while hypoglycaemic coma is usually associated with glycaemia around 1.1 mmol/L (20 mg/dL). Recurrent severe hypoglycaemia may result in permanent neurological disorders and also has a negative impact on the cardiovascular system. To evaluate the causes of severe hypoglycaemia in elderly patients with type 2 diabetes and coexistence of cardiovascular history. We analysed retrospectively the history of 33 elderly patients with type 2 diabetes and coexistence of cardiovascular history, who were admitted to our clinic due to severe hypoglycaemia with loss of consciousness. The mean age of the patients was 76.0 ± 11.1 years, and the mean duration of diabetes was 12.0 ± 9.8 years. Glycated haemoglobin (HbA1c) was measured and the prevalence of cardiovascular diseases and therapeutic procedures were evaluated. In the group of patients with severe hypoglycaemia, the mean value of HbA1c was 6.3 ± 1.2% (44 ± 13.1 mmol/mol), which indicates a mean glucose value below 7.8 mmol/L (140 mg/dL). Ischaemic heart disease was diagnosed in 18 patients (eight had a history of myocardial infarction), and 22 patients had arterial hypertension. Severe hypoglycaemia requiring hospitalisation in elderly patients with type 2 diabetes and coexistence of cardiovascular history was related to insulin or sulfonylurea therapy. A low HbA1c level indicates inappropriate intensification of therapy and was associated with high risk of severe hypoglycaemic episodes in older people. The majority of severe hypoglycaemic episodes were observed in sulphonylurea or insulin-treated type 2 diabetic patients.

Improved Epilepsy and Speech Outcomes with Human Embryonic Stem Cell Therapy in Children with Cerebral Palsy

Title: Improved Epilepsy and Speech Outcomes with Human Embryonic Stem Cell Therapy in Children with Cerebral Palsy Introduction: CP is a group of permanent neurological disorders which is prevalent in children of neonatal age and is often associated with epilepsy and speech disorders. The various conventional treatments and therapies available so far are unable to treat these comorbidities. In this study, we aimed to evaluate 101 patients with CP having speech disorders and epilepsy. The patients were treated using hESC therapy and assessed by Gross Motor Function Classification System - Expanded and Revised (GMFCS – E & R) score. Materials and Methods: Patients were given hESCs via different routes of administration for duration of 8 weeks and evaluated before and after the treatment on the basis of their le