Level Of Central Nervous System Research Articles

Effects of intracerebroventricularly administered opioid peptide antagonists on tissue glycogen levels in rats after exercise

Background/aim Physical exercise is a state of physiological stress that requires adaptation of the organism to physical activity. Glycogen is an important and essential energy source for muscle contraction. Skeletal muscle and liver are two important glycogen stores, and the energy required to maintain exercise in rodents are provided by destruction of this glycogen depot. In this study, the effects of endogenous opioid peptide antagonism at the central nervous system level on tissue glycogen content after exhaustive exercise were investigated. Materials and methods Rats had intracerebroventricularly (icv) received nonspecific opioid peptide receptor antagonist, naloxone (50 μg/10 μL in saline) and δ-opioid receptor-selective antagonist naltrindole (50 μg/10 μL in saline) and then exercised till exhaustion. After exhaustion, skeletal muscle, heart, and liver were excised immediately. Results Both opioid peptide antagonists decreased glycogen levels in skeletal muscle. Although, in soleus muscle, this decrease was not statistically significant (p > 0.05), in gastrocnemius muscle, it was significant in the icv naloxone administered group compared with control (p < 0.05). Heart glycogen levels increased significantly in both naloxone and naltrindole groups compared to control and sham-operated groups (p < 0.05). Heart glycogen levels were higher in the naloxone group than naltrindole (p < 0.05). Liver glycogen levels were elevated significantly with icv naloxone administration compared with the control group (p < 0.05). Glycogen levels in the naloxone group was also significantly higher than the naltrindole group (p < 0.05). Conclusion Our findings indicate that icv administered opioid peptide antagonists may play a role in glycogen metabolism in peripheral tissues such as skeletal muscle, heart, and liver.

Role of the Melanocortin System in the Central Regulation of Cardiovascular Functions.

Increasing evidence indicates that the melanocortin system is not only a central player in energy homeostasis, food intake and glucose level regulation, but also in the modulation of cardiovascular functions, such as blood pressure and heart rate. The melanocortins, and in particular α- and γ-MSH, have been shown to exert their cardiovascular activity both at the central nervous system level and in the periphery (e.g., in the adrenal gland), binding their receptors MC3R and MC4R and influencing the activity of the sympathetic nervous system. In addition, some studies have shown that the activation of MC3R and MC4R by their endogenous ligands is able to improve the outcome of cardiovascular diseases, such as myocardial and cerebral ischemia. In this brief review, we will discuss the current knowledge of how the melanocortin system influences essential cardiovascular functions, such as blood pressure and heart rate, and its protective role in ischemic events, with a particular focus on the central regulation of such mechanisms.

Identification of the Ghrelin and Cannabinoid CB2 Receptor Heteromer Functionality and Marked Upregulation in Striatal Neurons from Offspring of Mice under a High-Fat Diet.

Cannabinoids have been reported as orexigenic, i.e., as promoting food intake that, among others, is controlled by the so-called “hunger” hormone, ghrelin. The aim of this paper was to look for functional and/or molecular interactions between ghrelin GHSR1a and cannabinoid CB2 receptors at the central nervous system (CNS) level. In a heterologous system we identified CB2-GHSR1a receptor complexes with a particular heteromer print consisting of impairment of CB2 receptor/Gi-mediated signaling. The blockade was due to allosteric interactions within the heteromeric complex as it was reverted by antagonists of the GHSR1a receptor. Cannabinoids acting on the CB2 receptor did not affect cytosolic increases of calcium ions induced by ghrelin acting on the GHSR1a receptor. In situ proximity ligation imaging assays confirmed the expression of CB2-GHSR1a receptor complexes in both heterologous cells and primary striatal neurons. We tested heteromer expression in neurons from offspring of high-fat-diet mouse mothers as they have more risk to be obese. Interestingly, there was a marked upregulation of those complexes in striatal neurons from siblings of pregnant female mice under a high-fat diet.

Chronic traumatic encephalopathy – current state of knowledge

Introduction and purpose. Chronic traumatic encephalopathy (CTE) is a tauopathy caused by repetitive, mild head injuries. It is characterized by perivascular accumulation of hyperphosphorylated tau protein in the neurons and astrocytes. CTE leads to changes in central nervous system, both on microscopic and macroscopic level. The aim of the study was to present the current knowledge on chronic traumatic encephalopathy among athletes, its predisposing factors, symptoms and consequences, as well as diagnostic methods and treatment.Description. CTE occurs among contact sport players, such as American football, ice hockey, soccer, baseball, box and MMA (mixed martial arts), as well as among soldiers and victims of domestic violence. Repetitive head injuries and long career duration increase the risk of CTE. Symptoms of chronic traumatic encephalopathy include a commonly occurring triad: cognitive disturbances, behavioral problems and mood disturbances. Other symptoms include memory loss, parkinsonism, headaches, speech and walking problems. Currently, the only diagnostic method of CTE is a posthumous detection of neuropathological markers. Methods such as detection of exosomal tau protein in plasma and imaging techniques give hope to diagnose CTE in alive patients. Treatment methods of CTE, such as LIPUS (low intensity pulsed ultrasound) therapy are currently being developed.Conclusions. Chronic traumatic encephalopathy among athletes is a serious problem that affects multiple people due to the popularity of contact sports. Thus, an emphasis should be put on prevention, raising awareness and appropriate protection of athletes through changes in regulations and improvement of protective equipment.

Does Dysbiosis Increase the Risk of Developing Schizophrenia? - A Comprehensive Narrative Review.

There is increasing evidence regarding the influence of the intestinal microbiota on the disease processes of various organs and systems. Dysbiosis, that is, alteration of the composition and function of the microbiota may constitute an important risk factor for the development of mental disorders, namely, schizophrenia. This works aims to review current evidence regarding the pathological mechanisms leading from dysbiosis to schizophrenia and in particular the deficit syndrome in schizophrenia. Scientific articles from PubMed, SCOPUS, EMBASE, and Web of Science Core Collection published between September 2017 and December 2020 were included in this review. The commensal intestinal flora plays an important role in neurodevelopment. In the presence of dysbiosis, this maturation gets disturbed, resulting in the modification of brain structures and inflammatory responses at the intestinal, systemic, and Central Nervous System (CNS) levels. These disturbances may be linked to the development of symptoms of the disease. The microbiota exerts its influence on the CNS through several pathways, however, in this paper we focused on the membrane hypothesis and the inflammatory hypothesis. We explored the evidence concerning the use of probiotics, prebiotics, and fecal transplants. Although there is no consensus regarding the alterations that could constitute a risk factor for schizophrenia, some of the species appear to be more frequently altered, and their relationship with the host is dysregulated in patients at risk and with established schizophrenia, particularly in deficit schizophrenia.

Role of Neuroimmune Crosstalk in Mediating the Anti-inflammatory and Analgesic Effects of Acupuncture on Inflammatory Pain.

Inflammatory pain is caused by peripheral tissue injury and inflammation. Inflammation leads to peripheral sensitization, which may further cause central sensitization, resulting in chronic pain and progressive functional disability. Neuroimmune crosstalk plays an essential role in the development and maintenance of inflammatory pain. Studies in recent years have shown that acupuncture can exert anti-inflammatory and analgesic effects by regulating peripheral (i.e., involving local acupoints and inflamed regions) and central neuroimmune interactions. At the local acupoints, acupuncture can activate the TRPV1 and TRPV2 channels of mast cells, thereby promoting degranulation and the release of histamine, adenosine, and other immune mediators, which interact with receptors on nerve endings and initiate neuroimmune regulation. At sites of inflammation, acupuncture enables the recruitment of immune cells, causing the release of opioid peptides, while also exerting direct analgesic effects via nerve endings. Furthermore, acupuncture promotes the balance of immune cells and regulates the release of inflammatory factors, thereby reducing the stimulation of nociceptive receptors in peripheral organs. Acupuncture also alleviates peripheral neurogenic inflammation by inhibiting the release of substance P (SP) and calcitonin gene-related peptide from the dorsal root ganglia. At the central nervous system level, acupuncture inhibits the crosstalk between glial cells and neurons by inhibiting the p38 MAPK, ERK, and JNK signaling pathways and regulating the release of inflammatory mediators. It also reduces the excitability of the pain pathway by reducing the release of excitatory neurotransmitters and promoting the release of inhibitory neurotransmitters from neurons and glial cells. In conclusion, the regulation of neuroimmune crosstalk at the peripheral and central levels mediates the anti-inflammatory and analgesic effects of acupuncture on inflammatory pain in an integrated manner. These findings provide novel insights enabling the clinical application of acupuncture in the treatment of inflammatory diseases.

Peripheral nerve adaptations to 10 days of horizontal bed rest in healthy young adult males.

Space analogs, such as bed rest, are used to reproduce microgravity-induced morphological and physiological changes and can be used as clinical models of prolonged inactivity. Nevertheless, nonuniform decreases in muscle mass and function have been frequently reported, and peripheral nerve adaptations have been poorly studied, although some of these mechanisms may be explained. Ten young healthy males (18-33 yr) underwent 10 days of horizontal bed rest. Peripheral neurophysiological assessments were performed bilaterally for the dominant (DL) and nondominant upper and lower limbs (N-DL) on the 1st and 10th day of bed rest, including ultrasound of the median, deep peroneal nerve (DPN), and common fibular nerve (CFN) , as well as a complete nerve conduction study (NCS) of the upper and lower limbs. Consistently, reduced F waves, suggesting peripheral nerve dysfunction, of both the peroneal (DL: P = 0.005, N-DL: P = 0.013) and tibial nerves (DL: P = 0.037, N-DL: P = 0.005) were found bilaterally, whereas no changes were observed in nerve ultrasound or other parameters of the NCS of both the upper and lower limbs. In these young healthy males, only the F waves, known to respond to postural changes, were significantly affected by short-term bed rest. These preliminary results suggest that during simulated microgravity, most changes occur at the muscle or central nervous system level. Since the assessment of F waves is common in clinical neurophysiological examinations, caution should be used when testing individuals after prolonged immobility.

Effect of Lipopolysaccharide and TNFα on Neuronal Ascorbic Acid Uptake.

Vitamin C (ascorbic acid: AA) uptake in neurons occurs via the sodium-dependent vitamin C transporter-2 (SVCT2), which is highly expressed in the central nervous system (CNS). During chronic neuroinflammation or infection, CNS levels of lipopolysaccharide (LPS) and LPS-induced tumor necrosis factor-α (TNFα) are increased. Elevated levels of LPS and TNFα have been associated with neurodegenerative diseases together with reduced levels of AA. However, little is known about the impacts of LPS and TNFα on neuronal AA uptake. The objective of this study was to examine the effect of LPS and TNFα on SVCT2 expression and function using in vitro and in vivo approaches. Treatment of SH-SY5Y cells with either LPS or TNFα inhibited AA uptake. This reduced uptake was associated with a significant decrease in SVCT2 protein and mRNA levels. In vivo exposure to LPS or TNFα also decreased SVCT2 protein and mRNA levels in mouse brains. Both LPS and TNFα decreased SLC23A2 promoter activity. Further, the inhibitory effect of LPS on a minimal SLC23A2 promoter was attenuated when either the binding site for the transcription factor Sp1 was mutated or cells were treated with the NF-κB inhibitor, celastrol. We conclude that inflammatory signals suppress AA uptake by impairing SLC23A2 transcription through opposing regulation of Sp1 and NF-κB factors.

Zizyphus spina christi Effect on Pentylenetetrazole-Induced Kindling

Background: Epilepsy is a common disorder of brain that is not well controlled via drugs available for it. Gephyrin, a well-known inhibitory synaptic regulator, has a role in epilepsy. Additionally, significant development of oxidative stresses tends to be involved in epileptic seizure pathophysiology that giving rise to neuronal cell death. Zizyphus spina christi is a vastly available Iraqi tree and its leaves have several beneficial effects on central nervous system level. Objective: To investigate the possible neuroprotective effect of crude Zizyphus spina christi extract in kindling model induced. Methods: The removed brains of forty albino male mice from four separate groups were exposed to immunohistochemical test for gephyrin, glutathione, and NeuN expressions. Results: The data found that pretreatment with Zizyphus spina christi crude extract shows highly significant difference (P value &lt;0.001) in immunohistochemical scores for all studied parameters as compared with those being of pentylenetetrazole-kindled group. Conclusion: These findings suggest that crude Zizyphus spina christi extract of leaves is effective in protection against kindling that induced via pentylenetetrazole when applied orally for male mice. Keywords: Gephyrin; glutathione; kindling; NeuN; pentylenetetrazole; Zizyphus spina christi Citation: Al-Humaidhi AM, Abd AH, Ghazi HF. Zizyphus spina christi effect on pentylenetetrazole-induced kindling. Iraqi JMS. 2021; 19(1): 49-55. doi: 10.22578/IJMS.19.1.7

Focused Ultrasound (FUS) for Chronic Pain Management: Approved and Potential Applications.

Chronic pain is one of the leading causes of disability and disease burden worldwide, accounting for a prevalence between 6.9% and 10% in the general population. Pharmacotherapy alone results ineffective in about 70-60% of patients in terms of a satisfactory degree of pain relief. Focused ultrasound is a promising tool for chronic pain management, being approved for thalamotomy in chronic neuropathic pain and for bone metastases-related pain treatment. FUS is a noninvasive technique for neuromodulation and for tissue ablation that can be applied to several tissues. Transcranial FUS (tFUS) can lead to opposite biological effects, depending on stimulation parameters: from reversible neural activity facilitation or suppression (low-intensity, low-frequency ultrasound, LILFUS) to irreversible tissue ablation (high-intensity focused ultrasounds, HIFU). HIFU is approved for thalamotomy in neuropathic pain at the central nervous system level and for the treatment of facet joint osteoarthritis at the peripheral level. Potential applications include HIFU at the spinal cord level for selected cases of refractory chronic neuropathic pain, knee osteoarthritis, sacroiliac joint disease, intervertebral disc nucleolysis, phantom limb, and ablation of peripheral nerves. FUS at nonablative dosage, LILFUS, has potential reversible and tissue-selective effects. FUS applications at nonablative doses currently are at a research stage. The main potential applications include targeted drug and gene delivery through the Blood-Brain Barrier, assessment of pain thresholds and study of pain, and reversible peripheral nerve conduction block. The aim of the present review is to describe the approved and potential applications of the focused ultrasound technology in the field of chronic pain management.

Central Nervous System Relapse in HIV Positive Patients Affected By Diffuse Large B Cell Lymphoma. Is the CNS-IPI Score Useful in This Population?

▪Background:Central nervous system (CNS) relapse is an important and most often fatal event in patients (pts) affected by Diffuse Large B cell lymphoma (DLBCL). Identifying high risk pts is critical to guide diagnostic and therapeutic approach.Recently, Schmitz et al. validated a risk score (CNS-IPI) that predicts the risk of CNS recurrence/progression in pts affected by DLBCL treated according to standard chemotherapy. It includes IPI score and kidney and/or adrenal glands involvement (scored 1 point if present or 0 if absent). Three levels of CNS recurrence/progression risk are defined: low (LR: 0-1 points), intermediate (IR: 2-3 points), high (HR: 4-6 points) showing significantly different rates of CNS disease at 2-years follow-up (0,6% for LR group, 3,4% for IR group, and 10.2% for HR group).This score has been validated in HIV negative population. Since DLBCL are more aggressive and at higher risk of CNS relapse/progression in HIV positive (HIV+) pts, studies of the validity of CNS-IPI score in this setting are particularly needed.The aim of our study was to evaluate the rate of CNS relapse in our HIV+ population as regard to CNS-IPI score. Furthermore, we evaluated if HIV-related parameters (such as CD4+ T cell count and HIV-RNA at lymphoma diagnosis) could influence the risk of CNS relapse.Methods: Observational, multicenter, cohort study involving 6 centres in Lombardy, Italy. HIV+ pts with DLBCL diagnosis observed from 2009 to 2015 were included in this analysis. The CNS relapse risk was estimated for all pts based on the CNS-IPI score (LR, IR, HR). Continuous variables were described by median values and first and third quartiles. Chi-square or Fisher's exact test and Kruskal-Wallis test were used for comparison of discrete and continuous variables, respectively.Results: Sixty-one HIV+ pts with DLBCL were included. General characteristics of population showed: 90% male; median age 49 years; median CD4+ T cell count at lymphoma diagnosis 224 cells/mm3; median HIV-RNA log10 4.2; 34% HCV Ab pos; 70.5% on antiretroviral treatment (ART) at the onset of DLBCL; 93.4% treated with R-CHOP like regimen and 6.6% pts with higher-intensity chemotherapeutic regimen; 54% with IPI ≥3 and 46% with IPI <3; 19.7% pts underwent intratechal (IT) prophylaxis. According to CNS-IPI score we defined 13 pts (21,3%) at HR of CNS relapse, 38 pts (62,3%) at IR and 10 pts (16,4%) at LR of CNS relapse. Pts belonging to HR group displayed significantly higher number of extranodal sites (84.6% showing 2-4 extranodal sites) as compared to IR and LR groups (20% and 0% showing 2-4 extranodal sites, respectively, p=0.03). In addition, pts with HR score showed a poor ECOG PS (61.5% showing >2) as compared to intermediate and low CNS relapse risk (20% and 20% showing ECOG PS >2, respectively, p=0.01).In our series, we didn't find any significant association among HIV-related characteristics at lymphoma diagnosis (CD4+ T cell count, nadir CD4+ T cell count, HIV-RNA log10, use of ART) and CNS-IPI risk score. After a median follow-up of 28 months (range 4-96), 6 pts (9.8%) displayed a CNS relapse. We found that CNS relapse was significantly more frequent in CNS-IPI HR pts (4/13, 30.8%) as compared to CNS-IPI IR or LR pts (2/30, 6.7% and 0/10, 0%, respectively, p=0.049). No association was found between HIV-related characteristics and CNS relapse. The risk of death was also significantly higher in CNS-IPI HR group (69.2%) as compared to IR and LR groups (33.3% and 0%, respectively, p<0.0001). As shown in Figure 1, all CNS relapses occurred in the first 12 months after diagnosis. No association was found between IT prophylaxis and CNS relapse, even if very few pts underwent this procedure.Discussion: In our study we found that CNS-IPI score could be considered as a valuable prognostic tool of CNS relapse/progression also in HIV+ pts. We found a higher rough proportion of DLBCL pts belonging to HR CNS-IPI group in our HIV+ cohort as compared to published data on general population, even if no relationship emerged between HIV-related parameters and CNS relapse risk. Further studies on larger HIV+ population are required to confirm the validity of this score; moreover, the integration of HIV-specific markers and histological characteristics of DLBCL could ameliorate the therapeutic approach and finally reduce the risk of CNS disease in HIV+ population. [Display omitted] DisclosuresGambacorti-Passerini:Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy.

Inflammation: A Mediator Between Hypertension and Neurodegenerative Diseases.

Hypertension is the most prevalent and modifiable risk factor for stroke, vascular cognitive impairment, and Alzheimer's disease. However, the mechanistic link between hypertension and neurodegenerative diseases remains to be understood. Recent evidence indicates that inflammation is a common pathophysiological trait for both hypertension and neurodegenerative diseases. Low-grade chronic inflammation at the systemic and central nervous system levels is now recognized to contribute to the physiopathology of hypertension. This review speculates that inflammation represents a mediator between hypertension and neurodegenerative diseases, either by a decrease in cerebral blood flow or a disruption of the blood-brain barrier which will, in turn, let inflammatory cells and neurotoxic molecules enter the brain parenchyma. This may impact brain functions including cognition and contribute to neurodegenerative diseases. This review will thus discuss the relationship between hypertension, systemic inflammation, cerebrovascular functions, neuroinflammation, and brain dysfunctions. The potential clinical future of immunotherapies against hypertension and associated cerebrovascular risks will also be presented.

THE INFLUENCE OF BOXING EXERCISES ON THE COGNITIVE PROCESSES AND SPEED OF SENSORIMOTOR REACTIONS OF 15-17 YEARS OLD BOYS

The article is dedicated to studying of the influence of boxing trainings on thinking processes of the process of physical education and speed of sensorimotor of 15-17 years old boys. The goal of the research is optimization process of the physical education and improvement of the cognitive processes of 15-17 years old boys. The methods of the research are methodological literature analysis, psychophysiological reaction testing, applying computer complex, pedagogical experiment and mathematical statistics methods. It was proved that boxers have better ability to fast reacting (t=2.513 with p0.05), higher indicators of functional level of central nervous system (t=3.165 with p0.05), stability of reaction (t=2.248 with p0.05), better indicators of average reaction time with sound and visual interferences (t=3.104 with p0.05), better indicators of attention capacity (t=2.317) with p0.05). Attention diversification (t=2.793 with p0.05), that prove positive impact of boxing exercises on the thinking processes. There was implemented author program, applying no-contact special boxing exercises. There were 30 students, 15-17 years old, in the experiment. The indicators of the average time of the reaction (Wilcoxon criteria T.emp.=144 with p0.05) and stability of reaction (Wilcoxon criteria T.emp.=133 with p0.05) become better after the experiment. Other indicators like indicators of average reaction time with sound and visual interferences (Wilcoxon criteriaT.emp.=112 with p0.05), indicators of attention capacity (Wilcoxon criteriaT.emp.=61.5 with p0.05) and indicators of attention diversification (Wilcoxon criteriaT.emp.=7 with p0.05) become better as well. The conclusions are: the results of the research prove the effectiveness of the experimental program.

"Conditions at the Central Nervous System Level Due to the Use of Psychopharm to Increase Academic Performance"

"Conditions at the Central Nervous System Level Due to the Use of Psychopharm to Increase Academic Performance"

Anandamide Influences Interleukin-1β Synthesis and IL-1 System Gene Expressions in the Ovine Hypothalamus during Endo-Toxin-Induced Inflammation.

Simple SummaryPro-inflammatory cytokines are considered to be one of the most important mediators affecting the function of central nervous system during an immune/inflammatory challenge. It was found that in acting on different hypothalamic nuclei, pro-inflammatory cytokines influence the centrally regulated processes including reproduction. Recently, it has been shown that the endocannabinoid system and endogenous cannabinoids may attenuate the inflammatory response. Therefore, in our study we examined the influence of anandamide, one of the earliest known endocannabinoids, on the synthesis of interleukin (IL)-1β and IL-1 system gene expressions in the hypothalamic structures involved in gonadotropin-releasing hormone (GnRH)-ergic activity, and thus the central control of reproduction, during immune stress induced by endotoxin injection. It was found that anandamide inhibited lipopolysaccharide (LPS)-stimulated synthesis of IL-1β in the hypothalamus, likely affecting posttranscriptional levels of this cytokine synthesis. Anti-inflammatory effect of anandamide at the level of central nervous system might also result from its stimulating action on IL-1 antagonist and IL-1 type II receptor gene expression. This study suggests the potential of endocannabinoids and/or their metabolites in the inhibition of inflammatory process at the level of the central nervous system, as well as their usefulness in the therapy of inflammation-induced neuroendocrine disorders, but further detailed research is required to investigate this issue.This study evaluated the effect of anandamide (AEA) on interleukin (IL)-1β synthesis and gene expression of IL-1β, its type I (IL-1R1) and II (IL-1R2) receptors, and IL-1 receptor antagonist (IL-1RN) in the hypothalamic structures, involved in the central control of reproduction, during inflammation. Animals were intravenously (i.v.) injected with bacterial endotoxin-lipopolysaccharide (LPS) (400 ng/kg) or saline, and two hours after LPS administration., a third group received i.v. injection of AEA (10 μg/kg). Ewes were euthanized one hour later. AEA injection (p < 0.05) suppressed LPS-induced expression of IL-1β protein in the hypothalamus. The gene expression of IL-1β, IL-1RN, and IL-1R2 in the hypothalamic structures was higher (p < 0.05) in animals treated with both LPS and AEA in comparison to other experimental groups. AEA administration did not influence LPS-stimulated IL-1R1 gene expression. Our study shows that AEA suppressed IL-1β synthesis in the hypothalamus, likely affecting posttranscriptional levels of this cytokine synthesis. However, anti-inflammatory effect of AEA might also result from its stimulating action on IL-1RN and IL-1R2 gene expression. These results indicate the potential of endocannabinoids and/or their metabolites in the inhibition of inflammatory process at the level of central nervous system, and therefore their usefulness in the therapy of inflammation-induced neuroendocrine disorders.

Wide distribution of prion infectivity in the peripheral tissues of vCJD and sCJD patients

Sporadic Creutzfeldt-Jakob disease (sCJD) is the commonest human prion disease, occurring most likely as the consequence of spontaneous formation of abnormal prion protein in the central nervous system (CNS). Variant Creutzfeldt–Jakob disease (vCJD) is an acquired prion disease that was first identified in 1996. In marked contrast to vCJD, previous investigations in sCJD revealed either inconsistent levels or an absence of PrPSc in peripheral tissues. These findings contributed to the consensus that risks of transmitting sCJD as a consequence of non-CNS invasive clinical procedures were low. In this study, we systematically measured prion infectivity levels in CNS and peripheral tissues collected from vCJD and sCJD patients. Unexpectedly, prion infectivity was detected in a wide variety of peripheral tissues in sCJD cases. Although the sCJD infectivity levels varied unpredictably in the tissues sampled and between patients, these findings could impact on our perception of the possible transmission risks associated with sCJD.

ESCCA/ISCCA protocol for the analysis of cerebrospinal fluid by multiparametric flow-cytometry in hematological malignancies.

Central nervous system (CNS) involvement is a serious but often underdiagnosed complication of hematological malignancies. Currently, the gold standard to detect CNS involvement is conventional cytology (CC) whose sensitivity though is lower than 50%. Multiparametric flow cytometry (MFC) demonstrated a superior sensitivity over CC, particularly when low levels of CNS infiltrating cells are present. Although prospective studies are few, a positive finding by MFC appears to anticipate an adverse outcome even if CC shows no infiltration. However, the use of MFC to diagnose CNS involvement presents some pitfalls, due to the typical hypocellularity of cerebrospinal fluids (CSF), and low cell vitality. Furthermore, the threshold to be used for defining the MFC positivity is not universally defined. In this paper, a working group of the European Society for Clinical Cell Analysis-ESCCA-and the Italian Society for Clinical Cell Analysis-ISCCA-will discuss the critical aspects of CSF processing, highlighting difficulties in storage and processing of samples, interpretation and reporting of data.

An integrative, hypothesis‐free, multi‐omics approach uncovers biological pathway alterations in Alzheimer’s disease

AbstractBackgroundIn recent years, different ‘omics approaches have identified multiple pathway alterations in Alzheimer’s disease (AD). However, the pathogenic mechanisms are still not fully understood. Here, we test an integrative approach combining multiple ‘omics results to identify and explore in depth central nervous system (CNS) pathway alterations in AD.MethodsMulti‐omics data were obtained from a well‐characterised cohort of community‐dwelling elder subjects including healthy volunteers with normal cognition and memory clinic patients with either mild cognitive impairment or mild AD dementia. Inflammatory biomarkers were quantified by sandwich immunoassays in cerebrospinal fluid (CSF) samples; metabonomics (covering amino acids, carboxylic acids, and central energy metabolism), ionomics, proteomics, and lipidomics were performed using nuclear magnetic resonance or mass spectrometry coupled to liquid, supercritical fluid or gas chromatography. Alterations associated with AD were identified using Elastic‐Net regression at single ‘omics level and Multi‐Omics Factor Analysis, a hypothesis‐free Bayesian approach, for multi‐omics integration. Pathway enrichment analysis was performed in the Reactome database for selected analytes.ResultsWe identified five major dimensions of heterogenicity (latent factors, LFs) within the cohort. We evaluated the performance of this model by separating participants in the cohort with low vs. high CSF expression levels of amyloid, tau and phosphorylated tau (P‐tau). Best performance was obtained for tau and P‐tau with 93 and 96% sensitivity, respectively. Using these LFs we could furthermore identify analytes associated with either amyloid pathology (21) or neurodegeneration (37). We also identified specific patterns of expression of these analytes across LFs, revealing interactions between multiple ‘omics modalities. Pathway enrichment analysis also revealed an over representation of the hemostasis, immune response and extracellular matrix signalling pathways.ConclusionsIn this proof‐of‐principle work, we demonstrate that integrating expression from multiple ‘omics levels allows for a more comprehensive exploration of alterations related to AD pathology at CNS level. We identify novel metabolic alterations at molecular and pathway levels, and describe their relationships with amyloid pathology, neuronal injury, and tau hyperphosphorylation.

Chemical Mediators’ Expression Associated with the Modulation of Pain in Rheumatoid Arthritis

The management of pain in patients with rheumatoid arthritis (RA) is a complex subject due to the autoimmune nature of the pathology. Studies have shown that chemical mediators play a fundamental role in the determination, susceptibility and modulation of pain at different levels of the central and peripheral nervous system, resulting in interesting novel molecular targets to mitigate pain in patients with RA. However, due to the complexity of pain physiology in RA cand the many chemical mediators, the results of several studies are controversial. The aim of this study was to identify the chemical mediators that are able to modulate pain in RA. In this review, a search was conducted on PubMed, ProQuest, EBSCO, and the Science Citation index for studies that evaluated the expression of chemical mediators on the modulation of pain in RA. Few studies have highlighted the importance of the expression of some chemical mediators that modulate pain in patients with rheumatoid arthritis. The expression of TRPV1, ASIC-3, and TDV8 encode ionic channels in RA and modulates pain, likewise, the transcription factors in RA, such as TNFα, TGF-β1, IL-6, IL-10, IFN-γ, IL-1b, mTOR, p21, caspase 3, EDNRB, CGRPCALCB, CGRP-CALCA, and TAC1 are also directly involved in pain perception. The expression of all chemical mediators is directly related to RA and the modulation of pain by a complex intra and extracellular signaling pathway, however, transcription factors are involved in modulating acute pain, while the ionic channels are involved in chronic pain in RA.

Aminopiridines in the treatment of multiple sclerosis and other neurological disorders.

Symptomatic treatment has a great relevance for the management of patients with neurologic diseases, since it reduces disease burden and improves quality of life. Aminopyridines (APs) are a group of potassium (K+) channel blocking agents that exert their activity both at central nervous system level and on neuromuscular junction. This review describes the use of APs for the symptomatic treatment of neurological conditions. We will describe trials leading to the approval of the extended-release 4-aminopyridine for MS and evidence in support of the use in other neurological diseases.