Materials and Methods: This study compared two tests, STRATIFY JCV™ DxSelect™, and IMMUNOWELL ™ JCV antibody tests, for assessing the risk of PML in patients diagnosed with relapsing- remitting multiple sclerosis (RRMS) who had received disease-modifying therapy (DMT) with branded natalizumab (Tysabri®). The main objective was to determine the comparability of these tests in classifying PML risk. Eligible patients were selected from a database, and all specimens for the STRATIFY JCV™ DxSelect™ and IMMUNOWELL™ JCV antibody tests were collected on the same day. Patients were classified into three risk categories (low, intermediate, or high) based on threshold values for each test.

Results: The analysis showed 85.5% agreement between the two tests for risk classification. Ten discordant cases were identified, mainly between intermediate- and high-risk categories. Compared to STRATIFY JCV™ DxSelect™, IMMUNOWELL™ JCV antibody test tended to categorize more patients as higher risk. No significant association was found between discordance and prior use of immunosuppressant drugs and >24 doses of natalizumab. The agreement between tests, assessed with the weighted Cohen’s Kappa coefficient, was substantial (κ=0.6222).

Conclusions: Compared to the STRATIFY JCV™ DxSelect™, the IMMUNOWELL™ JCV test tends to place more patients in higher risk categories. Further, longitudinal studies are needed to evaluate the clinical impact of these differences in PML risk assessment.

Conclusion: The first patient has the clinical symptoms associated to the MEGD(H)EL syndrome, and the biochemical and genetic confirmation of the diagnosis, without reservations. However, in the second patient, the progressive paraparesis and cognitive impairment did not appear to be caused by multiple sclerosis nor subcortical vascular leukoencephalopathy (without vascular risk factors). The abnormal biochemical profile is suggestive of SERAC1 Deficiency, even without genetic con-firmation. In what should we believe?]]> https://www.benthamscience.comarticle/131605 https://www.benthamscience.comarticle/130488 https://www.benthamscience.comarticle/125016Background: An increased risk of manic episodes has been reported in patients with neurodegenerative disorders, but the clinical features of bipolar disorder (BD) in different subtypes of dementia have not been thoroughly investigated.

Objectives: The main aim of this study is to systematically review clinical and therapeutic evidence about manic syndromes in patients with Alzheimer’s disease (AD), vascular dementia (VaD), and frontotemporal dementia (FTD). Since manic-mixed episodes have been associated to negative outcomes in patients with dementia and often require medical intervention, we also critically summarized selected studies with relevance for the treatment of mania in patients with cognitive decline.

Methods: A systematic review of the literature was conducted according to PRISMA guidelines. PubMed, Scopus, and Web of Science databases were searched up to February 2022. Sixty-one articles on patients with AD, VaD, or FTD and BD or (hypo) mania have been included.

Results: Manic symptoms seem to be associated to disease progression in AD, have a greatly variable temporal relationship with cognitive decline in VaD, and frequently coincide with or precede cognitive impairment in FTD. Overall, mood stabilizers, and electroconvulsive therapy may be the most effective treatments, while the benefits of short-term treatment with antipsychotic agents must be balanced with the associated risks. Importantly, low-dose lithium salts may exert neuroprotective activity in patients with AD.

Conclusion: Prevalence, course, and characteristics of manic syndromes in patients with dementia may be differentially affected by the nature of the underlying neurodegenerative conditions.

Objective: This study aimed to know the level of cognitive deficiency, in particular, the verbal and semantic fluency of people living with HIV and AIDS.

Methods: In this study, a comparative analysis was carried out. The Stewart test was used to compare the average independent samples. For clarity, the average values, the test statistics, and the estimated significance levels are presented in the tables. Additionally, a statistical mechanism of factor selection was used by the forward stepwise method. The Wilks' Lambda statistic reported values between 0 and 1, with values close to zero indicating good discrimination of the model.

Results: According to this research, the HIV positives participants generated fewer verbs than the ones from the control group. The data were partially confirmed by the present study. There were differences in terms of both adjectives and nouns among people living with HIV and AIDS.

Conclusion: The study data proves that language deficits are detectable in neurocognitive testing of HIV. The overall hypothesis of the study has been confirmed. The language impairments are primarily qualitative and can be used as a marker for the initial and subsequent therapy assessment.

Methods: Our study was registered in the Prospective Register of Systematic Reviews (PROSPERO) under the protocol CDR42021265443. Based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we selected 51 studies for whole-manuscript analysis.

Results: Magnetic resonance imaging (MRI) was the most common imaging method. The pattern, sites of lesion, signs, and symptoms of neurologic injury varied. Such manifestations possibly resulted from a direct viral infection or, most likely, from indirect mechanisms including coagulation disturbances, hypoxemia, and immunological responses.

Conclusion: The heterogeneity of the studies precludes any generalization of the findings. Brain MRI is the most informative imaging exam. Population studies, including the entire spectrum of COVID-19 are missing. There is still a need for future population studies evaluating neurologic manifestations of all COVID-19 severities acutely and chronically.

Objective: This review summarizes the available safety data for all the Disease-Modifying Therapies for Multiple Sclerosis and presents the monitoring plan before and during the treatment.

Methods: A literature search was conducted using PUBMED and COCHRANE databases. Key journals and abstracts from major annual meetings of Neurology, references of relevant reviews, and relative articles were also manually searched. We prioritized systematic reviews, large randomized controlled trials (RCTs), prospective cohort studies, and other observational studies. Special attention was paid to guidelines and papers focusing on the safety and monitoring of DMTs.

Conclusion: Data for oral (Sphingosine 1-phosphate (S1P) receptor modulators, Fumarates, Teriflunomide, Cladribine), injectables (Interferons, Glatiramer acetate, Ofatumumab), and infusion therapies (Natalizumab, Ocrelizumab, Alemtuzumab) are presented.

Objective: The objective of this study is to expand the clinical manifestations of H-ABC due to UFM1 mutation and suggest clues for clinical diagnosis.

Methodology: Retrospective analysis of all 9 cases with H-ABC due to c.-273_-271delTCA mutation in UFM1 treated during 2013-2020 in a Neuropediatric Ward in Plovdiv, Bulgaria.

Results: Presentation is no later than 2 months with inspiratory stridor, impaired sucking, swallowing, vision and hearing, and reduced active movements. By the age of 10 months, a monomorphic disease was observed: microcephaly (6/9), malnutrition (5/9), muscle hypertonia (9/9) and axial hypotonia (4/9), progressing to opisthotonus (6/9), dystonic posturing (5/9), nystagmoid ocular movements (6/9), epileptic seizures (4/9), non-epileptic spells (3/9). Dysphagia (7/9), inspiratory stridor (9/9), dyspnea (5/9), bradypnea (5/9), apnea (2/9) were major signs. Vision and hearing were never achieved or lost by 4-8 mo. Neurodevelopment was absent or minimal with subsequent regression after 2-5 mo. Brain imaging revealed cortical atrophy (7/9), atrophic ventricular dilatation (4/9), macrocisterna magna (5/9), reduced myelination (6/6), corpus callosum atrophy (3/6) and abnormal putamen and caput nuclei caudati. The age at death was between 8 and 18 mo.

Conclusion: Roma patients with severe encephalopathy in early infancy with stridor, opisthotonus, bradypnea, severe hearing and visual impairment should be tested for the Roma founder mutation of H-ABC in UFM1.

Objective: The aim of the study was to evaluate changes in the JCV index during treatment with several DMTs.

Methods: This longitudinal study evaluated the JCV index before starting DMT (T0) and during treatment with DMT (T1).

Results: A total of 260 participants (65.4 % females, mean age 43 ± 11.3 ) were enrolled: 68 (26.2 %) treated with fingolimod (FTY), 65 (25 %) rituximab or ocrelizumab (RTX/OCR), 37 (14.2 %) dimethyl-fumarate (DMF), 29 (11.2 %) cladribine (CLD), 23 (8.8 %) teriflunomide (TFM), 20 (7.7 %) interferon or glatiramer acetate (IFN/GA), and 18 (6.9 %) alemtuzumab (ALM). At T1, the percentage of patients with JCV index <0.90 was found to be significantly increased in the ALM group (16.7 % versus 66.7 %, p = 0.05), while the percentage of patients with JCV index >1.51 was found to be significantly reduced in the RTX/OCR group (51.6 % versus 37.5 %, p = 0.04). In the FTY group, a significant reduction in the percentage of patients with JCV index <0.90 was also found (23.5 % versus 1.4 %, p = 0.0006). The mean JCV index was reduced in the RTX/OCR and ALM groups, while a significant increase was observed in the FTY group.

Conclusion: DMTs with a T and/or B depleting mechanism of action induced a significant reduction in the JCV index. These results may suggest new possible sequencing strategies potentially maximizing disease control while reducing the PML risk.

Background: Levamisole, an anthelmintic drug with immunomodulatory effects, has long been used worldwide till the early 2000s, when its association with demyelinating leukoencephalopathy was established. However, in the developing countries, it is still widely used for the prevention and treatment of helminthic invasion in humans. The actual prevalence of levamisole-induced multiple inflammatory leukoencephalopathy (LEV-induced MIL) in Russia remains unknown, and therefore, the study of its frequency and characteristics is indisputably important.

Objectives: The objective of this study is to determine the clinical features and MRI findings of levamisole- induced MIL in the Russian population, and to analyse the frequency of diagnostic errors at the initial assessment.

Methods: A single-center retrospective analysis of total 30 patients who were diagnosed with LEV- induced MIL and attended the Research Center of Neurology was conducted. Inclusion criteria were 1) clinically: acute or subacute polysymptomatic onset of neurological disturbances, 2) MRI: multifocal demyelinating lesion with no evidence of dissemination in time, 3) anamnestic data: levamisole exposure from 2 to 8 weeks before symptoms onset as well as monophasic disease course (absence of relapses according to follow up assessments up to 3 years).

Results: Clinically, presentation with constitutional symptoms including headache, fever, fatigue and myalgia, focal motor disturbances and dysarthria prevailed in our cohort. On the brain MRI, multiple foci of demyelination with simultaneous gadolinium enhancement were observed. The link between neurological symptoms and levamisole intake has often been detected only during follow- up assessments. Patients were most often misdiagnosed with acute disseminated encephalomyelitis, stroke and multiple sclerosis. In most cases, LEV-induced MIL was successfully treated with intravenous corticosteroids and/or plasma exchange (PLEX), however, residual neurologic symptoms were preserved in some patients. Additionally, two detailed clinical cases of patients being initially misdiagnosed are presented in the article.

Conclusion: The differential diagnosis remains difficult for suspected cases of LEV-induced MIL that could lead to delayed therapy initiation, and consequently incomplete recovery. Growing evidence suggests that a single administration of levamisole even in low doses might potentially lead to severe neurological deficit or death. Therefore, changes in medication management policies are required in order to prevent the uncontrolled use of levamisole.

Methods: This study enrolled a total of 130 pregnant women, including 90 PE patients (51 mild PE and 39 severe PE) and 40 healthy controls. miR-27b-3p expression in the serum of PE patients and healthy controls was detected using RT-qPCR. The correlation among miR-27b-3p expression and 24-h urine protein, systolic blood pressure (SBP), diastolic blood pressure (DBP), serum creatinine, and fetal birth weight was analyzed using Pearson's correlation coefficient. The targeting relationship between miR-27b-3p and PPARG was verified. PPARG protein level in PE patients was detected using ELISA kits. The predictive efficiency of miR-27b-3p and PPARG in PE was analyzed using the receiver operating characteristic (ROC) curve.

Results: Compared to normal pregnant women, PE pregnant women, especially severe PE patients, had higher miR-27b-3p expression. miR-27b-3p was positively correlated with 24-h urine protein, SBP, DBP, and serum creatinine but negatively correlated with fetal birth weight. PPARG was poorly expressed in PE patients and negatively correlated with miR-27b-3p. ROC curve showed that both miR-27b-3p and PPARG had good predictive efficacy on PE.

Conclusion: miR-27b-3p expression in serum of pregnant women with PE was positively correlated with the severity of PE symptoms, suggesting the involvement of miR-27b-3p in PE occurrence.

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

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

Conclusion: Natalizumab proves to be effective, has an adequate safety profile and can be administered with good tolerability for a rather extended period of time, provided that the patients are closely monitored.]]> https://www.benthamscience.comarticle/115901 https://www.benthamscience.comarticle/113140 https://www.benthamscience.comarticle/110092 https://www.benthamscience.comarticle/115294 https://www.benthamscience.comarticle/114309 https://www.benthamscience.comarticle/113553Introduction: Endovascular therapy (EVT) for intracranial arterial aneurysms is depicted with several complications. Very recently, delayed non-ischemic cerebral enhanced (NICE) lesions have been identified as a rare complication associated with EVT. This complication always stands a higher chance of being missed in asymptomatic patients. We report a case of multiple NICE lesions in a known chronic hepatitis B infection and chronic gastritis patient with left internal carotid aneurysm (ICA) treated with detachable coils.

Case Presentation: A 52 years old female with left ICA was treated with detachable coils via the endovascular route. Three weeks after the operation, she presented with numbness of her right limbs which was persistent and waked her up from sleep each night. She admitted skin allergies after wearing metals except for gold and silver since childhood. MRI revealed multiple abnormal lesions in the left temporal lobe, hippocampus, insula, and parietal lobe and some perifocal edema which were consistent with the diagnosis of delayed NICE lesions.

Conclusion: It is very important to report the occurrences of these lesions in literature because of their allergic origin. We advocate that allergy to metals especially those used in coating endovascular equipment should be evaluated before every EVT for intracranial aneurysms.

Objective: The study set sights on virtual screening (molecular docking and PreADMET study), MD simulation, and metabolism study of compounds from Crucifereae family along with the intensive structure-activity relationship studies in search of potent lead targeting HSP90.

Methods: All the chemical structures were drawn using ChemDraw and converted into suitable 3D-structures. The target protein, HSP90 was retrieved from RCSB PDB. All the compounds of Crucifereae family and analogs were subjected to Lipinski’s rule of five and ADMET prediction using Molinspiration and PreADMET software respectively. The screened compounds were further exposed to MD simulation and metabolism studies.

Conclusion: The docking results showed the promising inhibitory potential of Ana51 against Hsp90 with the binding energy of -11.32 kcal/mol as compared to its parent compound ‘spirobrassinin’ and a known inhibitor ‘Ganetespib’ exhibiting binding energy of -7.57 kcal/mol and -9.83 kcal/mol respectively. Optimization, flexibility prediction, and ascertaining the stability of Hsp90 in complex with the ligands were done by means of Molecular Dynamics (MD) simulations for 50 ns. The Hsp90-Ana51 complex exhibited stability with an RMSD value of 0.15 nm and Rg value to be 1.62 nm. The investigation further extends towards the SOM analysis of Ana51 to forecast the probable toxic and non-toxic in vivo metabolites via in silico tools (SMARTCyp, Xenosite Web, and PASS online server).

Results: Ana 51 came out to be metabolically stable withstanding phase I metabolism and producing non-toxic metabolites compared to the parent compound and the standard drug. Obtained results propose Ana51 as a novel anti-Hsp90 lead compound with exceptional antiangiogenic capability.

Objective: The study aims to bring to the attention of public health officials, addiction medicine specialists, treatment officials, therapists, and the general public the alarming increase of dangerous toxic adulterants being added to street drugs and their potentially lethal synergistic effects. Also, it aims to provide insights into how these new formulations can have serious pathophysiological effects on individuals with Substance Abuse Disorders (SUDs) during the COVID-19 pandemic.

Methods: The literature on street drug cutting agents, toxic adulterants, NPS, manufacturing byproducts, and other industrial compounds will be reviewed. Also, a review of the literature of pathophysiological effects, especially on SUD patients, in light of the COVID-19 pandemic will be presented. This is combined with international and USA studies that were carried out by the Colombo Plan that identified these new combinations of toxic adulterants in street drugs, using state-of-the-art field and forensic laboratory detection technologies.

Results: The majority of street drugs, in some cases more than ninety-five percent, now have multiple toxic adulterants. It is rare that a street purchase of cocaine or heroin does not contain multiple toxic adulterants, cutting agents, NPS, manufacturing byproducts, or industrial chemicals.

Conclusion: This dangerous new composition in world street drug supply is unprecedented and may be the undetected cause of many psychostimulant and opioid overdose deaths, as many toxic adulterants are not routinely tested in post-mortem or street drug seizure cases. In addition, several of these toxic adulterants create a catastrophic drop in white blood cells, causing neutropenia and making the substance users susceptible to a wide range of opportunistic infections, including COVID-19. This profound change in the world street drug supply has catastrophic implications for individuals with SUDs and our health care system, especially in the era of the COVID-19 pandemic.

Objective: To review the diagnostic performance of published articles for TREC and TREC/ KREC based NBS for PID and its different types.

Methods: Different research resources were used to get an approach for the published data of TREС and KREC based NBS for PID like PubMed, Scopus, Google Scholar, Research gate EMBASE. We extracted TREC and KREC screening Publisher with years of publication, content and cut-off values, and a number of retests, repeat DBS, and referrals from the different published pilot, pilot cohort, Case series, and cohort studies.

Results: We included the results of TREC, combined TREC/KREC system based NBS screening from different research articles, and divided these results between the Pilot studies, case series, and cohort. For each of these studies, different parameter data are excluded from different articles. Thirteen studies were included, re-confirming 89 known SCID cases in case series and reporting 53 new SCID cases in 3.15 million newborns. Individual TREC contents in all SCID patients were <25 TRECs/μl (except in those evaluated with the New York State assay).

Conclusion: TREC and KREC sensitivity for typical SCID and other types of PID was 100 %. It shows its importance and anticipating the significance of implementation in different undeveloped and developed countries in the NBS program in upcoming years. Data adapting the screening algorithm for pre-term/ill infants reduce the amount of false-positive test results.

Objective: This report presents data regarding the case of a single family, from the city of Djerba, with five individuals affected with hereditary spastic paraplegia, the largest number of spastic paraplegia type 5 mutated family members so far reported in current literature.

Methods: To emphasize the importance of genetic testing, we retrospectively reviewed a familial confirmed case of hereditary spastic paraplegia. Clinical features of family members were described.

Results: The family presents a large phenotypic variation that, in part, differs from the known phenotypic presentations. Age of onset and clinical manifestation showed interfamilial variations. The alteration found in CYP7B1 (c.1081C>T; p.R361*) may help emphasize the importance of genetic testing and the much-needed treatment options already in use in current neurological practice.

Conclusion: The understanding of the molecular pathways of hereditary spastic paraplegia, together with the establishment of disease biomarkers, will hopefully lead to better and more personalized treatment.

Materials and Methods: Current antiretroviral therapy can prevent viral replication but cannot cure the disease completely. HAART-Highly active antiretroviral therapy is used for the treatment of HIV infection. Challenges in neuro-AIDS therapy are as shown in the graphical abstract. One of the challenges is latent viral reservoirs like the brain; which act as a sanctuary site for viruses. Nearly ~50% of HIV patients show neuropathological signs. Nervous system related disorders, including AIDS dementia, sensory neuropathy, and myelopathy have a 25% of prevalence in patients having access to a highly active combination of antiretroviral therapy.

Results and Conclusions: Brain is one of the viral sanctuary sites for HIV. The current need of neuro-AIDS therapy is to target the brain as a viral reservoir. Drugs should cross or bypass the blood-brain barrier to reach the brain with effective concentrations. Current research on novel drug delivery approaches may prove helpful in treating neuro-AIDS and related disorders effectively.

Multiple Sclerosis (MS), as one of the prevalent autoimmune diseases, is characterized by abnormal regulation of the immune system that periodically attacks parts of the nervous system; brain and spinal cord. Symptoms and impairments include weakness, numbness, visual problems, tingling pain that are quietly variable among patients.

Amyotrophic Lateral Sclerosis (ALS) is another neurodegenerative disease that is characterized by the degeneration of motor neurons in the brain and spinal cord. Unlike MS, symptoms begin with muscle weakness and progress to affect speech, swallowing and finally breathing. Despite the major differences between MS and ALS, misdiagnosis is still influencing disease prognosis and patient’s quality of life.

Diagnosis depends on obtaining a careful history and neurological examination as well as the use of Magnetic Resonance Imaging (MRI), which are considered challenging and depend on the current disease status in individuals.

Fortunately, a myriad of treatments is available now for MS. Most of the cases are steroid responsive. Disease modifying therapy is amongst the most important set of treatments.

In ALS, few medications that slow down disease progression are present. The aim of this paper is to summarize what has been globally known and practiced about MS and ALS, as they are currently classified as important growing key players among autoimmune diseases. In terms of treatments, it is concluded that special efforts and input should be directed towards repurposing of older drugs and on stem cells trials. As for ALS, it is highlighted that supportive measurements and supplementary treatments remain essentially needed for ALS patients and their families. On the other hand, it is noteworthy to clarify that the patient-doctor communication is relatively a cornerstone in selecting the best treatment for each MS patient.

Objective: This assessment highlights the overview of the recent patents of Bortezomib. This review includes patents grouped in sections like product patents, process patent, composition related patents as well as the treatment methodology. The objective of this article is to facilitate researchers with all existing patents at a single place.

Methods: Data were searched from various online databases. In which, paid databases include SciFinder® and Orbit®. Free databases include Patentscope® (WIPO), Worldwide Espacenet® (EPO), Google Patents and InPASS (Indian patent database).

Results: Several new processes and composition related patents of Bortezomib have been recently patented as its orange-book listed patents are going to soon expire during July 2022. Further, due to the problem of oxidation during development and long-term storage of Bortezomib formulation, a number of excipients are tried in these patents to stabilize the same. However, there is still a need for further development of an improved formulation of Bortezomib with better characteristics.

Conclusion: Extensive research has been carried out on various processes for preparing Bortezomib and the composition thereof. This type of dynamic research will clear the path for many generic players in the United States, which lead to the reduction of the price of the composition and thereby enhancing global health care at cheaper prices.

Objective: We performed comparative transcriptional profiling microarray and proteomic analyses on post-mortem frontal lobe specimen from 2 CADASIL patients and 5 non neurologically diseased controls in order to identify dysregulated pathways potentially involved in the development of tissue damage in CADASIL.

Methods: Transcriptional microarray analysis of material extracted from frontal grey and white matter (WM) identified subsets of up- or down-regulated genes enriched into biological pathways mostly in WM areas. Proteomic analysis of these regions also highlighted cellular processes identified by dysregulated proteins.

Results: Discrepancies between proteomic and transcriptomic data were observed, but a number of pathways were commonly associated with genes and corresponding proteins, such as: “ribosome” identified by upregulated genes and proteins in frontal cortex or “spliceosome” associated with down-regulated genes and proteins in frontal WM.

Conclusion: This latter finding suggests that defective expression of spliceosomal components may alter widespread splicing profile, potentially inducing expression abnormalities that could contribute to cerebral WM damage in CADASIL.

Objectives: This review summarizes the role of targeted therapy with MKIs in the management of RRDTC and advanced/metastatic MTC patients, focusing on side-effect profiles of these drugs, with a presentation of several recent patents published in this field.

Methods: We review the scientific literature on advanced thyroid cancer and analyze the International Pharmacovigilance database (FAERS, Eudravigilance, and WHO Vigibase) for adverse drug reactions.

Results: This systematic analysis highlights the difference in the safety profile of the recent drugs used in the treatment of advanced thyroid cancer and the recent discoveries for diagnosis or treatment of the thyroid cancer.

Conclusion: It is essential to investigate the safety profile of recent anticancer drugs for advanced thyroid cancer to allow health professionals to make the best choice for each patient by conducting risk/benefit assessment.

Methods: We undertook a structured search of bibliographic databases for peer-reviewed research literature using a focused review question.

Results: This review has intended to summarize the current knowledge concerning the clinical impact of polymorphisms in enzymes and transporters involved in MTX disposition and mechanism of action on paediatric patients with ALL.

Conclusion: In this work, we describe why, in spite of the significant research efforts, pharmacogenetics findings in this setting have not yet found their way into routine clinical practice.

Methods: We undertake a systemic English-language search of Medline, EMBASE, Cochrane Library electronic databases to identify all potential studies with PK, PD or PG properties of NAT (up to October 2017).

Results: Five papers contain detailed pharmacokinetic parameters are included in this review. Body weight is the most important factor associated with NAT concentration. Greater PK similarity and PD comparability is observed following Subcutaneous (SC) administration than Intramuscular (IM) administration. Initial difference in PK measures was observed between SC and Intravenous (IV) administration. However, trough NAT serum concentrations are similar between SC and IV administration after repeated dosing. Antibodies against NAT result in a low serum NAT concentration and cause a loss of efficacy of NAT. Gln-152, Lys-201, and Lys-256 are the three important point mutation on the α4 residues that NAT binds to. Syndecan-1 gene is a potential candidate gene for personalized approach for NAT use in MS.

Conclusion: As MS is a disease that affects young women most and NAT can pass placental barrier before delivery and into breast milk, a proper risk-benefit analysis of NAT therapy in lactating women are still needed. The relationship between Single Nucleotide Polymorphisms (SNPs) and NAT treatment are still not clear.]]> https://www.benthamscience.comarticle/91660 https://www.benthamscience.comarticle/88791

Objective: This review summarizes the mechanisms of action, clinical benefits, and safety profiles of current multiple sclerosis disease-modifying therapies, including highly efficacious monoclonal antibodies or convenient oral therapies, and with a special focus on the pegylated interferon beta 1a formulation.

Methods: We reviewed the recent literature and human clinical trials on multiple sclerosis therapies by bibliographic search in PubMed and clinicaltrials.gov.

Results and Conclusion: Although the first-line interferon beta exhibits a favorable benefit-torisk profile, treatment compliance is compromised potentially due to its known adverse events and frequent injectable administration. Less frequent dosing and improved pharmacological properties have been achieved by reaction of interferon beta with chemically activated polyethylene glycol. Provided that none of the available therapies show better effectiveness for all outcomes and their safety in clinical practice is of a fundamental concern, the pegylated form of interferon beta seems to keep its place as a competitive therapeutic option.]]> https://www.benthamscience.comarticle/83198

Aims: This review aims to summarize the imaging features of a number of acquired metabolic and toxic encephalopathies.

Discussion: These conditions are not diagnosed easily. Imaging is very important in terms of diagnosis, assessment of treatment response and prediction of prognosis. Therefore, it is important for radiologists to know the imaging features of relatively frequent acquired metabolic and toxic encephalopathies.

Conclusion: Integration of clinical information with the MRI findings can help physicians in diagnosis and treatment of the underlying disease.]]> https://www.benthamscience.comarticle/87635

Materials and Methods: The study was designed to induce dementia by inhalation of toluene vapours (0.7% in air for 15 min.) for a period of 14 days in rats and then divided among different groups, i.e. Treatment group, negative control and two groups of sinapic acid, (at a dose of 20 and 40mg/kg, p.o.). These groups were treated and observed until the 28th day of experimental trial. The avoidance/escape behaviour was measured via Pole Climbing Apparatus; spatial memory was measured via Morris Water Maze, and locomotion was measured via photoactometer (beam breaks). The behavioral, Neuronal and biochemical parameters were determined. The estimation of Monoamine Oxidase (MAO-A, MAO-B), TNF-α, Acetylcholine esterase Enzyme and various antioxidant enzymes (GSH, TBARS, Nitrite, Catalase) was done by methods available in literature. Histological changes in the brain were also observed.

Result: Rats receiving 40 mg/kg of sinapic acid showed a significant therapeutic activity against toluene induced dementia of LEP type in rats.

Conclusion: From the present experimental findings, it has been concluded that a dose of 40 mg/kg, (p.o.) of sinapic acid provides better neuromodulation in neurons against toluene induced dementia of LEP type in rats with a better choice of drug.]]> https://www.benthamscience.comarticle/85160

Objective: The present paper is a review of the recent knowledge regarding present and new drugs that have been recently added to the therapeutic arsenal for MS as well as those which seem to be beneficial for patients with NMOSD.

Methods: A step-by-step description of the evolving drug arsenal is presented for both MS and Neuro-Myelitis Optica Spectrum Disorder (NMOSD).

Results: Modern drug therapy for MS started with the introduction of ACTH (Adrenocorticotropic hormone) and somewhat later was followed by high dose corticosteroids for treatment of the neurological deficits during an acute relapse. This mode of treatment, which became popular during the years 1970-1980 failed to reduce the number of relapses or to affect the outcome of the disease. Only during the last two decades, the field of MS drug therapy underwent a remarkable change from simple amelioration of symptoms of an acute attack to the development of numerous Disease Modifying Treatments (DMTs). The formulation of DMTs evolved from the older inconvenient subcutaneous or intramuscular route of administration to oral preparations or periodic intravenous infusions of biological drugs. A new treatment was approved in 2017 for reducing disease progression rate for the first time in primary progressive MS.

Besides MS, progress was made in delineating the pathophysiology of NMOSD, a devastating demyelinating disorder that is still frequently confused with MS.

Although beneficial, the new treatment modalities carry with them adverse effects that may be serious and even life threatening. With the increase in the usage of those drugs, the spectrum of the reported adverse effects is expanding and calls for additional research in regard to the safest way of their utilization.

Conclusion: Targeting the immune system in general in RRMS and NMOSD and even PPMS has proven successful, with efficacy varying based on the specific treatment. There are still unmet needs for medications that will address safety and efficacy altogether and prevent disability even more.

Areas Covered: The mode of action and main characteristics and side effects of current DMTs for both MS and NMOSD and their place in the therapeutic algorithm of both diseases based on updated evidence from clinical trials.]]> https://www.benthamscience.comarticle/88037 https://www.benthamscience.comarticle/85590

Objectives: The purpose of the present review paper is to outline the antibody engineering technologies, the immunologic and pharmacologic concepts of mbs and the current status of treatment in MS with emphasis on clinical efficacy and safety.

Method: We conducted a through review of the scientific literature published until 31 December 2014 (print and electronic publications) concerning the production, applications and side effects of the use of Mabs. Sixty five articles were used in total (both original research and review papers).

Conclusion: With the introduction of mAbs the treatment of MS has entered a new era, both with respect to efficacy and target specificity. However, administration of mAbs carries the risk of immune reactions such as acute anaphylaxis, serum sickness, infection and other autoimmune diseases. In addition, unexpected consequences arise from our incomplete knowledge of the immune system. For example, natalizumab, a monoclonal antibody targeting α4-integrin on leukocytes increases the risk of developing progressive multifocal leukoencephalopathy, without causing notable immunosuppression. Further study on the use of mabs is required, both in vitro and in the clinical field, in order to increase our knowledge upon these new revolutionary therapeutic agents.]]> https://www.benthamscience.comarticle/84514

Objective: Beside the most commonly described nephro- and hepatotoxicity, cisplatin therapy is also accompanied with gastrointestinal, reproductive, hematological, cardiovascular and neurological side effects. Since it has been reported that cisplatin induce oxidative damage in various tissues, it seems reasonable to investigate an antioxidant supplementation as potential therapeutical approach for attenuation of cisplatin toxicities.

Methods: We performed a structured search of bibliographic databases for research literature using a focused review question and inclusion/exclusion criteria. The quality of retrieved papers (101 in total) was appraised using standard tools.

Results: Numerous antioxidants (such as thiol compounds, polyphenols, vitamins, etc.) had been reported for their beneficial effects on cisplatin-induced cardiotoxicity. The effects of various antioxidants, including sulfur-containing amino acids, have also been explored for mitigation of cisplatin neurotoxicity. However, the results for antioxidant supplementation in reduction of cisplatin-induced toxicities are still to be applied in clinical trials.

Conclusion: Considering the facts that sulfur-containing amino acids: (a) do not interfere with chemotherapeutics antitumor action; (b) do not exhibit any toxic effect (unless applied in dose several times above the recommended); and (c) produce significant protective effects on some cisplatin-induced toxicities connected to augmentation of oxidative damage - it seems that their administration can be harmless and protective supplementation against numerous adverse effects of certain antineoplastic agents.]]> https://www.benthamscience.comarticle/85148

Material and Methods: We prospectively assessed the serum levels of 15 cytokines from the Th17 Cytokine Panel using Bio-plex Pro Human in a group of 29 RRMS patients treated with NAT and 29 healthy subjects (HS) at inclusion and after 8 months of NAT treatment. For each patient, demographic data, number of relapses and Expanded Disability Status Scale (EDSS) were collected and compared with the initial and final values of each cytokine. Moreover, the Th17/Treg shift was assessed using the interleukine (IL)-17F/IL-10 ratio and the cytokine signature (the sum of all the cytokines). Advanced statistical analysis was used.

Results: RRMS patients had significantly lower serum levels of IL-23, IL-17F, IL-1β and IL-31 compared to HS. Serum sCD40L, IL-17F, IL-31 and cytokine signature levels significantly decreased after 8 months of NAT treatment. Positively correlations were found between the relapse number and IL- 17F, IL-1β, IL-31 serum levels and between EDSS and tumor necrotic factor-α, IL-1β and IL-17/IL-10 serum levels. IL-10 serum levels correlated negatively with the EDSS score.

Conclusion: In evaluating the mode of action of NAT, it is important to determine the value of each cytokine, the Th17/Treg shift and the cytokine signature. NAT significantly decreased peripheral serum levels of some pro-inflammatory cytokines as a novel mechanism of action. IL-17F, sCD40L and IL-31 were the best biomarkers to assess the effectiveness of NAT.]]> https://www.benthamscience.comarticle/84107

Objective: GVHD is an immune-mediated process characterized by an inflammatory immune response in acute GVHD and mixed inflammatory and fibrotic states in chronic GVHD. The clinical presentations of cutaneous GVHD are heterogeneous. Method: Acute cutaneous GVHD classically presents as an erythematous morbilliform eruption appearing within a few weeks after transplantation. Chronic cutaneous GVHD may manifest as poikiloderma, lichenoid lesions, or sclerodermatous changes. The sclerodermatous form of cutaneous GVHD is associated with substantial long-term morbidity, including joint contractures, myalgias, and mobility restriction.

Results: First-line pharmacologic treatment options typically include corticosteroids and in some cases, calcineurin inhibitors. Biologics and immunotherapies are an active area of investigation for GVHD that is refractory to corticosteroid treatment. Non-pharmacologic treatment options that have shown benefit for cutaneous GVHD include extracorporeal photopheresis and phototherapy.

Conclusion: Accurate diagnosis and treatment of cutaneous GVHD is essential to preventing and alleviating the long-term sequelae and morbidity associated with this condition.]]> https://www.benthamscience.comarticle/86821

Objective: To examine, from the morphohistopathological point of view, the main toxic effects induced by fluoropyrimidines.

Methods: Pertinent articles were retrieved through PubMed search.

Results: Unlike dermatologic toxicity, with evident histopathological observations because of the easy approach to skin examination, cardio- and neurotoxicity are scarcely documented, with most imaging and functional data poorly altered. Animal models are useful to corroborate data obtained in humans. Fluoropyrimidines can associate with specific cutaneous side effects, including the hand-foot syndrome (HFS), with symmetrical erythema, dysaesthesia, dryness, rash, swelling and desquamation on palms and soles. Cardiotoxicity includes angina pectoris, arrhythmias, palpitation, hypotension, hypertension, malaise and dyspnea, until life-threatening damages, with myocardial infarction and sudden death. Neurotoxicity is an uncommon but potentially severe side effect, consisting of rare cases of cerebellar alterations with ataxia, as well as multifocal cerebral leukoencephalopathy, with or without seizures, announcing with dizziness, memory deficits, trismus, headache, vertigo, gait disturbances and confusion, until coma. These adverse events are likely due to direct chemotoxic effects of fluoropyrimidine metabolites and most of them can be regarded as allergic reactions triggered by the hapten-like properties of these molecules.

Conclusion: Fluoropyrimidines are able to induce specific morphohistopathological changes in tissues.]]> https://www.benthamscience.comarticle/84773

Method: A detailed, extensive and critic literature search has been made in Web of Science™.

Results: Great efforts are applying to optimize the function of chlorophyll-based photosensitizers, to understand the molecular mechanisms of the antioxidant and antigenotoxic properties of chlorophyll derivatives and, lastly, to investigate new biological actions of them. However, the fundamental physiological functions of the chlorophylls are their physicochemical properties.

Conclusion: This review aims to reflect the chemical grounds of the healthy and/or medical features of chlorophylls, including the consequences, advantages or even new actions that modifications over the chlorophyll structure introduce. Finally, new perspectives in the functionality of chlorophylls at molecular level are discussed.]]> https://www.benthamscience.comarticle/82825

Conclusion: Lifestyle changes are the cornerstone of antihypertensive treatment. No clear recommendations for a specific antihypertensive agent can be made. In most cases antihypertensive management needs to be individualized to each patient. Calcium channel blockers (CCBs) are considered as first line option, while renin-angiotensin-aldosterone system (RAAS) blockers should be the agents of choice in patients with proteinuria. Centrally acting antihypertensive agents and diuretics can also be used. Careful monitoring is critical during therapy and BP should be assessed every week and before any new cycle or infusion of anti-VEGF therapy. If BP remains uncontrolled anti-VEGF treatment discontinuation should be considered. Withdrawal of anti-VEGF therapy needs also a re-evaluation of antihypertensive therapy since BP will return to the prior baseline levels.]]> https://www.benthamscience.comarticle/85133

Methods: Literatures were searched by using key words psoriasis, topical treatment, systemic treatment, biologics and phototherapies, on Embase, Medline, Jstor, Cochrane and Merck Index databases.

Results: Life-style choices such as smoking, alcohol consumption, obesity and stress are recognised as risk factors and triggers associated with psoriasis. Psoriasis poses psycho-social and economic burden on affected patients that sometimes leads to depression, reduced social interaction and suicidal tendencies in patients. Depending on the type, severity and extent of the disease, comorbidities, patient preference, efficacy and safety profile, numerous treatment modalities and therapeutic agents are available such as topical, systemic, biologic and phototherapeutic treatments. However, it was found that among all the current available treatments for psoriasis, biologic agents and phototherapeutic modalities are the most commonly employed treatment modalities for moderate to severe psoriasis.

Conclusion: Evaluation of present-day available treatment alternatives will surely help physician to select a suitable module for each patient while keeping in mind the financial status of the patient. Future research should aim to develop therapies which are efficient, safe and cost-effective.]]> https://www.benthamscience.comarticle/78063

Methods: Here, we report a rare pathogenic mutation on exon 14 of the NOTCH3 gene in a Chinese family affected by CADASIL with phenotypic peculiarities. We performed genetic testing, clinical and neuropsychological examination, brain magnetic resonance images (MRI), and electron microscopy (EM) in skin biopsies.

Results: NOTCH3 gene analysis revealed a c.2182C>T substitution on exon 14, which is the first example of this mutation in a Chinese individual from the Han ancestry. Granular osmiophilic material (GOM) was found in the proband, and all patients had migraine, subcortical ischemic events, and mood disturbances, without progressive cognitive impairment. Cranial MRI further showed white matter hyperintensity, involving bilateral basal ganglia and multiple microbleeds (MBs), in the thalamus and brain stem.

Conclusions: This study suggests that different missense mutations in NOTCH3 might contribute to atypical clinical features of CADASIL. This report also indicates that for individuals with a positive family history having clinical and neuroradiological findings suggestive of CADASIL, genetic testing and GOM detection should be performed.]]> https://www.benthamscience.comarticle/77764

The receptor proteins that are targeted by currently used anticancer drugs comprise the epithelial growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor(VEGFR). Target anticancer drugs may affect extracellular receptor domains (antibodies) or intracellular receptor domains (tyrosine kinase inhibitors).

The blocking of the mRNA thread containing information about the structure of oncogenes (signal transduction proteins) is another molecular target of anticancer drugs. That type of treatment, referred to as antisense therapy, is in clinical trials.

When the synthesis of genetic material is disturbed, in most cases the passage to the next cycle phase is blocked. The key proteins responsible for the blockage are cyclines and cycline- dependent kinases (CDK). Clinical trials are focused on natural and synthetic substances capable of blocking various CDKs.

The paper discusses the molecular targets and chemical structure of target anticancer drugs that have been approved for and currently applied in antineoplastic therapy together with indications and contraindications for their application.]]> https://www.benthamscience.comarticle/73780 https://www.benthamscience.comarticle/72843 https://www.benthamscience.comarticle/70785 https://www.benthamscience.comarticle/78442 https://www.benthamscience.comarticle/77765 https://www.benthamscience.comarticle/77265

Om triambkum yajamahe, sughandhim puushtivardhanam, urvarukmev vandhanaat, mrityu mokshay mamritaat!!!!

Hawan is a scientific experiment in which special herbs (Hawan Samagri) are offered in the fire of medicinal woods ignited in a specially designed fire pit called agni-kuñda. Aromatherapy was also employed in ancient times for a number of mental disorders. The hypothesis is based on action of Hawan components on Alzheimer Disease through integration of modern and ancient concepts. Hawan seems to be designed by the ancient scholars to fight with the diseases of the brain. Our review demonstrates that the components of Hawan are having a number of volatile oils that are specifically useful for AD through one or the other mechanism of action. Due to high temperature of fire the vapors of these oils enter into the central nervous system through nasal route. The routine of performing Hawan might keep the threshold value of the therapeutic components in the body and help in preventing AD. In the present manuscript authors have tried to highlight and integrate the modern and ancient concepts for treatment and prevention of AD.]]> https://www.benthamscience.comarticle/74796

Method: As the 2011 report of drug-induced TCM, case reports of drug-induced TCM were identified by a comprehensive search in Medline/PubMed database. From December 2010 to March 2015 search terms were Takotsubo cardiomyopathy, Takotsubo cardiomyopathy, stress cardiomyopathy, transient-left-ventricular ballooning syndrome, ampulla cardiomyopathy, apical ballooning syndrome, OR broken heart syndrome; together with “iatrogenic”, “drug-induced”, OR “induced by”. Publications limited to English, Spanish, and French, in humans, and with full texts were retrieved. Articles that recognized any drug as a possible trigger of TCM were selected.

Results: Overall, 405 different references were retrieved and 67 were selected (62 case reports and 5 case series) involving 78 patient cases with TCM possibly associated to drugs were reviewed. At total of 44 drugs were recognized as possible drug-induced TCM, mainly with sympathetic effect, and 37 (84.1%) were different to those 20 identified in the 2011 review; therefore, a list of 57 drugs associated to TCM was obtained.

Conclusion: There are new case reports that linked drug-use with the development of TCM. The list of 57 drugs obtained is principally integrated by drugs that generate sympathetic overstimulation. Consequently, the recommendation “drug-induced TCM would be considered in patients with TCM, particularly those in which no clear emotional or stress trigger could be identified” is endorsed.

]]> https://www.benthamscience.comarticle/75386

Objectives: Our observational study evaluated the presence of these HIV CIDs prior to HIV diagnosis among a population of late presenters and assessed its correlation to disease progression.

Method: A retrospective cohort study was conducted in HIV late presenters diagnosed from 2007 to 2013 at University Hospital of Ferrara (Italy). Hazard Ratios (H.R.s) for disease progression (new AIDS-events and death) were estimated by Cox proportional hazard model.

Results: We analysed 77 patients and we found that those with CIDs prior to HIV diagnosis (22%) had a 2.8 fold higher rate of disease progression compared to those without HIV CIDs (H.R. 2.82; 95% CI 1.21-6.53; P 0.02). Other factors associated with disease progression were AIDS presentation, HCV coinfection and Haemoglobin levels, with H.R.s of 3.14 (95%CI 1.23-7.99), 2.95 (95% CI 1.14-7.61) and 0.74 (95% CI 0.60-0.91), respectively.

Conclusion: HIV CIDs confer a higher risk for disease progression even after adjustment for these confounding factors. Evaluation of previous HIV CIDs at HIV diagnosis could be an additional tool to identify and better manage HIV late presenters with higher risks of disease progression.

]]> https://www.benthamscience.comarticle/73144

Methods and Results: We analysed the distribution of SNPs in chemokines (CCL3, CCL4, CCL5, CXCL12) and chemokine receptor (CXCR6) genes, in 268 HIV-1 infected patients (HIV-1+) and 221 healthy controls from Northeast Brazil, and their possible connection with susceptibility to HIV-1 infection. The genotyping were performed through allele specific fluorogenic probes using real time PCR. We observed that the T alleles and AT genotype of rs1719153 CCL4 SNP were more frequent in healthy controls (19.8% and 35.0%, respectively) than in HIV-1+ patients (T allele: 14.1%; OR=0.67; 95%CI=0.47-0.95; p-value=0.020; and AT genotype: 24.4%; OR=0.61; 95%CI=0.40- 0.93; p-value=0.021) after correcting for age and sex. The rs1719134 (CCL3) and rs1719153 (CCL4) SNPs presented linkage disequilibrium (D’=0.83). The AT haplotype frequency was increased in healthy controls (17.3%) in relation to HIV-1+ patients (11.0%; OR=0.62; 95%CI=0.42-0.93; p-value=0.020).

Conclusion: Since our results revealed an increased frequency of alleles and genotypes of CCL3/CCL4 SNPs and haplotype (CCL3-CCL4) among healthy controls, we suggest that these variations might have a potential protective role against HIV-1 infection.

]]> https://www.benthamscience.comarticle/73873 https://www.benthamscience.comarticle/72517 https://www.benthamscience.comarticle/73281 https://www.benthamscience.comarticle/73603 https://www.benthamscience.comarticle/73510 https://www.benthamscience.comarticle/73929 https://www.benthamscience.comarticle/71067

Biologics, reducing TNFα bioavailability or inhibiting proximal regulators of inflammatory cascade, represent an established therapeutic strategy of inflammatory autoimmune diseases, with remarkable efficacy and a safety profile that is extensively examined and monitored.

The biology and the immunological effects of TNFα, IL-12, IL-23 and related signalling pathways are accurately summarized. The dosing regimens, methods of administration, pharmacodynamics profiles, and side effects of the currently licensed TNFα antagonists and IL12/IL23 inhibitor are discussed in detail.]]> https://www.benthamscience.comarticle/72230 https://www.benthamscience.comarticle/72575 https://www.benthamscience.comarticle/697654β₇, are currently in development, with some of these reaching clinical trials. Gut-trophic molecules and their receptors are critical to the development of both tolerant and inflammatory immune responses in the gut. However, we know little regarding the function of homing molecules as it relates to IBD. Data have suggested both pathological and protective roles for gut homing molecules in IBD development and maintenance. In addition, recent research findings have suggested that chemokines can influence T cell differentiation and function. Given the current clinical relevance, it is essential to obtain a better understanding of the role of gut homing molecules in the regulation of IBD.]]> https://www.benthamscience.comarticle/71839 https://www.benthamscience.comarticle/69652 https://www.benthamscience.comarticle/71525

Objectives: We hypothesize that HIV-1/PML initiation may involve reactivation of JCV by cytokine disturbances in the brain such as occur in HIV-1/AIDS. In this study, the objective was to evaluate HIV-1/PML clinical samples for expression of TNF-α and its receptors and subcellular localization of NF-κB p65 and NFAT4 compared to non-PML controls.

Methods: We evaluated HIV-1/PML clinical samples and non-PML controls for expression of TNF-α and its receptors and subcellular localization of NF-κB p65 and NFAT4 using Western blot and immunohistochemistry.

Results: Consistent with our hypothesis, compared to non-PML controls, HIV-1/PML tissue has high levels of TNF-α and TNFR1 expression and NF-κB and NFAT4 were preferentially localized to the nucleus.

Conclusion: The involvement of TNF-α/NF-κB/NFAT4 signaling in JCV regulation that we reported from experiments in cultured human glial cells may be clinically relevant in PML.]]> https://www.benthamscience.comarticle/69145

Methods: A systematic literature search in MEDLINE and Cochrane Central Register for Controlled Trials (CENTRAL) in a 10-year period, from 2005 to 2014, was conducted, to identify studies designed to detect drug safety signals through the use of disproportionality measures applied to spontaneous reporting databases of adverse drug reactions.

Results: Seventy three studies were included. The number of publications has been rising over the study time period. Forty nine studies focus on drug-event combinations. Large international and smaller national or regional databases were identified. The disproportionality measures applied included frequentist and Bayesian methods and some studies used more than one method. SDRs were identified in more than ninety percent of the studies. Ten studies were found to be confirmatory of previous regulatory decision.

Conclusion: It was not found any safety signal issued by drug regulatory agencies exclusively generated by DA. More research devoted to this issue is needed, since the value of these methods on drug safety signaling and their impact on drug regulation actions remains to be established.]]> https://www.benthamscience.comarticle/66691