Efficacy and safety of a three-times-weekly dosing regimen of glatiramer acetate in relapsing–remitting multiple sclerosis patients: 3-year results of the Glatiramer Acetate Low-Frequency Administration open-label extension study

Background: The 1-year placebo-controlled (PC) phase of the Glatiramer Acetate Low-Frequency Administration (GALA) study showed that glatiramer acetate 40 mg/mL three times weekly (GA40) significantly reduced annualized relapse rate (ARR) and magnetic resonance imaging (MRI) activity in patients with relapsing–remitting multiple sclerosis. Patients completing the PC phase were invited to an open-label (OL) extension. Objective: To evaluate the effects of early start (ES) and delayed start (DS) of GA40 over 3 years. Methods: A total of 97.2% of patients completing the PC phase received GA40 in the OL extension. ES (n = 943) patients received GA40 throughout; DS (n = 461) patients received placebo during the PC phase and GA40 during the OL phase. Relapse, MRI, disease progression, and safety were evaluated. Results: A total of 1041 patients completed 3 years of follow-up. During the OL phase, ES and DS patients showed comparable ARRs (0.20–0.22) and similar numbers of gadolinium-enhancing T1 (p = 0.49) and new or enlarging T2 lesions (p = 0.51) at Year 3. ES patients showed significantly smaller changes in gray matter volume than DS patients from Months 12 to 36 (mean difference, 0.371%; p = 0.015), with similar trend in whole-brain volume (p = 0.080). Adverse events were mild, consistent with the well-established glatiramer acetate (GA) safety profile. Conclusion: GA40 conferred treatment benefit over 3 years: sustained low ARR and lesion activity and favorable safety

Autonomic neuropathy in Fabry disease: a prospective study using the Autonomic Symptom Profile and cardiovascular autonomic function tests

<p>Abstract</p> <p>Background</p> <p>Fabry patients have symptoms and signs compatible with autonomic dysfunction. These symptoms and signs are considered to be due to impairment of the peripheral nervous system, but findings indicative of autonomic neuropathy in other diseases, such as orthostatic intolerance and male sexual dysfunction, are infrequently reported in Fabry disease. The aim of our study was to investigate autonomic symptoms and cardiovascular autonomic function in a large cohort of male and female Fabry patients.</p> <p>Methods</p> <p>Forty-eight Fabry patients (15 male, 30 treated with enzyme replacement therapy) and 48 sex- and age-matched controls completed a questionnaire on autonomic symptoms (the Autonomic Symptom Profile). Thirty-six Fabry patients underwent cardiovascular function tests.</p> <p>Results</p> <p>The Autonomic Symptom Profile revealed a significantly higher sum score in Fabry patients than in healthy control subjects (22 versus 12), but a relatively low score compared to patients with proven autonomic neuropathy. Fabry patients scored worse than healthy controls in the orthostatic intolerance domain. Scores in the male sexual dysfunction domain were comparable between healthy controls and male Fabry patients. The cardiovascular autonomic function tests revealed only mild abnormalities in seven patients. None of these seven patients showed more than one abnormal test result. Enzyme replacement therapy was not associated with less severe disease, lower ASP scores or less frequent abnormal cardiovascular function test results.</p> <p>Conclusions</p> <p>Male sexual function and autonomic control of the cardiovascular system are nearly normal in Fabry patients, which cast doubt on the general accepted assumption that autonomic neuropathy is the main cause of symptoms and signs compatible with autonomic dysfunction in Fabry disease. Possibly, end-organ damage plays a key role in the development of symptoms and signs in Fabry patients. An exceptional kind of autonomic neuropathy is another but less likely explanation.</p

Cannabinoid pharmacology in cancer research: A new hope for cancer patients?

Cannabinoids have been used for many centuries to ease pain and in the past decade, the endocannabinoid system has been implicated in a number of pathophysiological conditions, such as mood and anxiety disorders, movement disorders such as Parkinson's and Huntington's disease, neuropathic pain, multiple sclerosis, spinal cord injury, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity, and osteoporosis. Several studies have demonstrated that cannabinoids also have anti-cancer activity and as cannabinoids are usually well tolerated and do not produce the typical toxic effects of conventional chemotherapies, there is considerable merit in the development of cannabinoids as potential anticancer therapies. Whilst the presence of psychoactive effects of cannabinoids could prevent any progress in this field, recent studies have shown the value of the non-psychoactive components of cannabinoids in activating apoptotic pathways, inducing anti-proliferative and anti-angiogenic effects. The aforementioned effects are suggested to be through pathways such as ERK, Akt, mitogen-activated protein kinase (MAPK) pathways, phosphoinositide 3-kinase (PI3K) pathways and hypoxia inducible factor 1 (HIF1), all of which are important contributors to the hallmarks of cancer. Many important questions still remain unanswered or are poorly addressed thus necessitating further research at basic pre-clinical and clinical levels. In this review, we address these issues with a view to identifying the key challenges that future research needs to address

Robust sequence alignment using evolutionary rates coupled with an amino acid substitution matrix

BACKGROUND: Selective pressures at the DNA level shape genes into profiles consisting of patterns of rapidly evolving sites and sites withstanding change. These profiles remain detectable even when protein sequences become extensively diverged. A common task in molecular biology is to infer functional, structural or evolutionary relationships by querying a database using an algorithm. However, problems arise when sequence similarity is low. This study presents an algorithm that uses the evolutionary rate at codon sites, the dN/dS (ω) parameter, coupled to a substitution matrix as an alignment metric for detecting distantly related proteins. The algorithm, called BLOSUM-FIRE couples a newer and improved version of the original FIRE (Functional Inference using Rates of Evolution) algorithm with an amino acid substitution matrix in a dynamic scoring function. The enigmatic hepatitis B virus X protein was used as a test case for BLOSUM-FIRE and its associated database EvoDB. RESULTS: The evolutionary rate based approach was coupled with a conventional BLOSUM substitution matrix. The two approaches are combined in a dynamic scoring function, which uses the selective pressure to score aligned residues. The dynamic scoring function is based on a coupled additive approach that scores aligned sites based on the level of conservation inferred from the ω values. Evaluation of the accuracy of this new implementation, BLOSUM-FIRE, using MAFFT alignment as reference alignments has shown that it is more accurate than its predecessor FIRE. Comparison of the alignment quality with widely used algorithms (MUSCLE, T-COFFEE, and CLUSTAL Omega) revealed that the BLOSUM-FIRE algorithm performs as well as conventional algorithms. Its main strength lies in that it provides greater potential for aligning divergent sequences and addresses the problem of low specificity inherent in the original FIRE algorithm. The utility of this algorithm is demonstrated using the Hepatitis B virus X (HBx) protein, a protein of unknown function, as a test case. CONCLUSION: This study describes the utility of an evolutionary rate based approach coupled to the BLOSUM62 amino acid substitution matrix in inferring protein domain function. We demonstrate that such an approach is robust and performs as well as an array of conventional algorithms.This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at [email protected]

Peptide hormones and lipopeptides: from self-assembly to therapeutic applications

This review describes the properties and activities of lipopeptides and peptide hormones and how the lipidation of peptide hormones could potentially produce therapeutic agents combating some of the most prevalent diseases and conditions. The self-assembly of these types of molecules is outlined, and how this can impact on bioactivity. Peptide hormones specific to the uptake of food and produced in the gastrointestinal tract are discussed in detail. The advantages of lipidated peptide hormones over natural peptide hormones are summarised, in terms of stability and renal clearance, with potential application as therapeutic agent

Acute inflammatory myelopathies

Inflammatory injury to the spinal cord causes a well-recognized clinical syndrome. Patients typically develop bilateral weakness, usually involving the legs, although the arms may also become affected, in association with a pattern of sensory changes that suggests a spinal cord dermatomal level. Bowel and bladder impairment is also common in many patients. Recognition of the clinical pattern of spinal cord injury should lead clinicians to perform imaging studies to evaluate for compressive etiologies. MRI of the spine is particularly useful in helping visualize intraparenchymal lesions and when these lesions enhance following contrast administration a diagnosis of myelitis is made. Cerebrospinal fluid analysis can also confirm a diagnosis of myelitis when a leukocytosis is present. There are many causes of non-compressive spinal cord injury including infectious, parainfectious, toxic, nutritional, vascular, systemic as well as idiopathic inflammatory etiologies. This review focuses on inflammatory spinal cord injury and its relationships with multiple sclerosis, neuromyelitis optica, acute disseminated encephalomyelitis and systemic collagen vascular and paraneoplastic diseases

Linking cortical surface area to computational properties in human visual perception

Summary: Cortical structure and function are closely linked, shaping the neural basis of human behavior. This study explores how cortical surface area (SA), a structural feature, influences computational properties in human visual perception. Using a combination of psychophysical, neuroimaging, and computational modeling approaches, we find that variations in SA across the parietal and frontal cortices are linked to distinct behavioral patterns in a motion perception task. These differences in behavior correspond to specific parameters within a divisive normalization model, indicating a unique contribution of SA to the spatial organization of cortical circuitry. This work highlights the importance of cortical architecture in modifying computational processes that underlie perception, enhancing our understanding of how structural differences can influence neural function and behavior

Utilization and Treatment Patterns of Disease-Modifying Therapy in Pediatric Patients with Multiple Sclerosis in the United States.

BackgroundThe current landscape and treatment patterns of disease-modifying therapy (DMT) use in pediatric patients with multiple sclerosis (MS) are not yet well understood. This study examined DMT utilization and treatment patterns in pediatric patients newly diagnosed as having MS.MethodsPediatric patients (&lt;18 years old) with two MS diagnosis claims from January 1, 2010, to December 31, 2016, were identified from the MarketScan Commercial Database. The index date was defined as the date of first MS diagnosis, and patients were followed up for 1 year post-index date. Outcomes evaluated included percentage of patients who initiated treatment after MS diagnosis, different DMTs initiated, treatment discontinuation, and switching treatment during follow-up.ResultsOf 182,057 patients newly diagnosed as having MS, 288 pediatric patients (mean age, 14 years; 61% female) were identified. Within the first year of diagnosis, 188 patients (65.3%) did not receive any DMT. The most common first-initiated treatments were interferons and glatiramer acetate (83%), but 28% of patients switched or discontinued from first-initiated treatment within 6 months of treatment initiation.ConclusionsThis study suggests that a considerable proportion of pediatric patients with MS remain untreated within 1 year of diagnosis. Patients most commonly initiated injectables as their first DMT. Overall, therapy failed early in approximately one in three patients. Thus, the study warrants urgency in treating these patients with currently approved treatment options