Miracle-dz/UniFAR-FTUs huggingface dataset:
T2 relaxation rate of basal ganglia and cortex in patients with β-thalassaemia major

In thalassaemic patients, neurophysiological disturbances have been associated with high serum ferritin levels and desferrioxamine therapy. In the presence of a magnetic field, ferritin, the main iron storage protein, induces a preferential decrease of the T2 relaxation time. The purpose of this study was to evaluate thalassaemic patients for brain iron deposition by assessing the T2 relaxation rate (1/T2) of the grey matter. 41 thalassaemic patients (age range 8.5–44 years, mean 24 years) and 58 age- and sex-matched controls were included in the study. Current serum ferritin levels were obtained. The 1/T2 values of the cortex (motor and temporal) (mean 0.0122 ms−1, SD 0.0004), putamen (mean 0.0137 ms−1, SD 0.0004) and caudate nucleus (mean 0.0132 ms−1, SD 0.0003) were higher in patients compared with the controls (mean 0.0110 ms−1, SD 0.0004; mean 0.0120 ms−1, SD 0.0005; mean 0.0117 ms−1, SD 0.0003, respectively) (p<0.001 for all parameters). No statistically significant differences were found in the glo.
Antibody effector mechanisms in myasthenia gravis—Pathogenesis at the neuromuscular junction

Myasthenia gravis (MG) is an autoimmune disorder caused by autoantibodies that are either directed to the muscle nicotinic acetylcholine receptor (AChR) or to the muscle-specific tyrosine kinase (MuSK). These autoantibodies define two distinct subforms of the disease—AChR-MG and MuSK-MG. Both AChR and MuSK are expressed on the postsynaptic membrane of the neuromuscular junction (NMJ), which is a highly specialized region of the muscle dedicated to receive and process signals from the motor nerve. Autoantibody binding to proteins of the postsynaptic membrane leads to impaired neuromuscular transmission and muscle weakness. Pro-inflammatory antibodies of the human IgG1 and IgG3 subclass modulate the AChR, cause complement activation, and attract lymphocytes; together acting to decrease levels of the AChR and AChR-associated proteins and to reduce postsynaptic folding. In patients with anti-MuSK antibodies, there is no evidence of loss of junctional folds and no apparent loss of AChR density. Anti-MuSK antibodies are predominantly of the IgG4 isotype, which functionally differs from other IgG subclasses in its anti-inflammatory activity. Moreover, IgG4 undergoes a posttranslational modification termed Fab arm exchange that prevents cross-linking of antigens. These findings suggest that MuSK-MG may be different in etiological and pathological mechanisms from AChR-MG. The effector functions of IgG subclasses on synapse structure and function are discussed in this review.
Effect of Methyl Testosterone Treatment on Muscular Performance and the Central Nervous System of Older Men

IN AN EARLIER investigation (1) improvement of endurance in dynamic and static work, of finger ergograph performance, of the fusion frequency of flicker and, to a lesser extent, of muscular strength in four male subjects with diminished sexual hormone production (two eunuchoids, two castrates) were reported after four weeks' oral administration of methyl testosterone. An adequate level of male-sex hormone might be important for the maintenance of working capacity. If this is so, then the reduction and final cessation of the sex-hormone production with age might influence the reduction of working capacity with age. In other words, the reduction of working capacity with age might proceed differently if the sex-hormone concentration could be artificially maintained at a higher level. A very large amount of material would be necessary to prove or disprove this hypothesis. In the present paper we are reporting an investigation to determine whether exaggerated fatigue in older men might be partially due to redu.
Increased T regulatory cells lead to development of Th2 immune response in male SJL mice

SJL mice represent a mouse model in which young adult females are susceptible to autoimmune disease, while age-matched males are relatively resistant. T cells primed in female SJL mice secrete cytokines associated with a Th1 phenotype. By contrast, T cells primed in males secrete cytokines associated with a Th2 phenotype. Activation of Th2-type T cells in males vs. Th1 cells in females correlates with increased CD4+CD25+ T regulatory cells (Treg) in males. T cells primed in males depleted of CD4+CD25+ T cells preferentially secrete IFN-γ and decreased IL-4 and IL-10 compared to CD4+CD25+ T-cell-sufficient males, suggesting that Treg influence subsequent antigen-specific cytokine secretion. Treg from males and females exhibit equivalent in vitro T-cell suppression. Treg from males express increased CTLA-4 and CD62L and preferentially secrete IL-10. These data suggest that an increased frequency of IL-10 secreting Treg in male SJL mice may contribute resistance to autoimmune disease by favoring the development of Th2 immune responses.
Study of polymorphisms in 4q27, 10p15, and 22q13 regions in autoantibodies stratified type 1 diabetes patients

Type 1 diabetes (T1D) is a multifactorial disease mainly associated with the human leukocyte antigen region. Previous studies suggested the association of interleukin-2 (IL2) gene polymorphisms and its alpha- and beta-chain receptor (IL2RA and IL2RB) variants with different autoimmune diseases such as T1D, celiac disease, multiple sclerosis, and rheumatoid arthritis. All T1D studies were conducted in diabetic patients younger than 17 years at diagnosis. The aim of our study was to replicate these associations not only in pediatric patients, but also in individuals with late onset. We performed a genetic association study of chromosomal regions 4q27, 10p15, and 22q13 containing the IL2, IL2RA, and IL2RB genes in 445 T1D subjects and 828 healthy controls. Seven single nucleotide polymorphisms (SNPs) were selected, previously described as genetic factors related to several autoimmune diseases, and were analyzed by TaqMan assays. The reported association with T1D patients of the IL2RA-rs41295061 located in the 10p15 region was replicated and our data suggest a trend of association of the polymorphisms IL2-rs17388568 and IL2-rs6822844 in 4q27. The effect of these markers was independent of the age at disease onset. Furthermore, the polymorphisms studied in 4q27 were not dependent on the presence of autoantibodies; however, the effect of the associated SNP in 10p15 (IL2RA-rs41295061) was specific of patients sera positive for diabetes antibodies. In conclusion, our results seem to indicate that late-onset and young T1D patients share most genetic factors located in the studied regions, but some markers could correlate with the presence of T1D specific autoantibodies.
Epidemiology of Type 1 Diabetes Complications in African-Americans

Unlike type 2 diabetes, where prevention is possible, type 1 diabetes is a lifelong incurable metabolic disorder. The annual incidence of type 1 diabetes continues to rise annually. Despite increased access to treatment and improved disease management, type 1 diabetes is associated with excess morbidity and early mortality. African-Americans with type 1 diabetes are at increased risk of premature mortality compared to Caucasians. This disparity is likely fueled by differences in the prevalence of complications; however, there is limited information available on the racial differences in type 1 diabetes complications in individuals of African descent (i.e. African-American, Afro-Caribbean). Using the data from the U.S. Virgin Islands Childhood Diabetes Registry, this dissertation provides contemporary insights on the incidence of childhood diabetes in African-American youth and for the first time evaluates type 1 diabetes mortality in African-Americans, in the U.S. Virgin Islands. In addition, this dissertation assesses racial differences in the prevalence of type 1 diabetes complications and risk factors using a national sample from the National Health and Nutrition Examination Survey. The incidence of type 1 and type 2 diabetes in youth in the U.S. Virgin Islands is rapidly increasing. The well-established pubertal increase in type 1 diabetes incidence appears to be missing in African-American boys. Individuals diagnosed at later ages (>14), have significantly higher risk of mortality compared to those diagnosed at earlier ages. Despite advances in diabetes care, there were no temporal improvements observed in mortality in the U.S. Virgin Islands. African-Americans in the U.S. Virgin Islands had a similar type 1 diabetes mortality experience as African-Americans in Allegheny County, PA. African-Americans in the national sample had significantly higher rates of nephropathy and retinopathy. Race was associated with both complications, even after adjusting for clinical and demographic factors. The public health implications of this dissertation are considerable, as it provides insight on the burden of type 1 diabetes in the U.S. Virgin Islands and African-Americans in the U.S. These findings provide evidence to support additional services and potentially intensive diabetes management strategies for African-Americans with type 1 diabetes.
Formulation development and optimization of polyox based quick dissolving film of quetiapine

Quick dissolving film prepared by various grades of polyox like Polyox N10, N80, N750 and N205. Polyox having excellent film forming capacity with rapid hydration power which leads to rapid disintegration of film upon contact with saliva. Film is optimized for concentration of polymer and plasticizer using CCD design. The tensile Strength, folding Endurance, % drug released at 10 min (Y10) and disintegration time were selected as dependent variables. The data revealed that 2% of polyox N 750 and 15% of PEG 400 showed excellent film forming property with rapid drug release profile.
The role of somatic hypermutation in the generation of pathogenic antibodies in SLE

The formation of antibodies against double-stranded (ds)DNA is considered to be the serologic hallmark of systemic lupus erythematosus (SLE) and anti-dsDNA antibodies play an important role in the pathogenesis of the disease. Anti-dsDNA antibodies from lupus mice and SLE patients arise by somatic mutation. Importantly, autoantibodies in which somatic mutations have been reverted to germ-line V regions did not show any measurable autoreactivity, suggesting that anti-dsDNA autoantibodies develop from non-autoreactive B-cells by somatic hypermutation, presumably during the germinal center reaction. As the random nature of somatic hypermutation will inevitably create autoreactive B cells, self-tolerance checkpoints at the postmutational stage of B cell differentiation have to exist that normally prevent the induction of pathogenic anti-dsDNA specificities. This review summarizes the proposed mechanisms for the generation of anti-dsDNA in murine lupus and in SLE patients.
Somatic mutagenesis in autoimmunity

Our laboratory investigates systemic autoimmune disease in the context of mouse models of systemic lupus erythematosus (SLE). SLE is associated with high titers of serum autoantibodies of the IgG class that are predominantly directed against nuclear antigens, with pathological manifestations that are considered by many to be characteristic of an immune-complex mediated disease. In this review, we focus on the known and potential roles of somatic mutagenesis in SLE. We will argue that anti-nuclear antibodies (ANA) arise predominantly from nonautoreactive B cells that are transformed into autoreactive cells by the process of somatic hypermutation (SHM), which is normally associated with affinity maturation during the germinal center reaction. We will also discuss the role of SHM in creating antigenic peptides in the V region of the B cell receptor (BCR) and its potential to open an avenue of unregulated T cell help to autoreactive B cells. Finally, we will end this review with new experimental evidence suggesting that spontaneous somatic mutagenesis of genes that regulate B cell survival and activation is a rate-limiting causative factor in the development of ANA.
Pharmacologic therapy for Peyronie’s disease: what should we prescribe?

Introduction: Peyronie’s disease (PD) is a wound healing disorder of the penis with a myriad of proposed treatment options reported in the literature. Evaluating the available data and therapeutic management of PD can be challenging and confusing, even for the most experienced treating physician. This review provides a comprehensive overview of pharmacologic treatment options for PD, focusing on the best available evidence. Areas covered: A comprehensive literature search for published articles evaluating oral, topical, and injectable pharmacologic agents for PD was completed. Prospective, controlled trials were given precedence for inclusion. Expert opinion: Although a multitude of oral agents have been proposed and evaluated in PD patients, results vary widely and a reproducible objective benefit has not yet been strongly established for any single oral agent. Well-designed, large-scale, randomized controlled trials evaluating oral agents in PD patients are lacking. Consistent objective benefit from injectable agents has been supported for years by various non-controlled trials. Recently, injectable collagenase Clostridium histolyticum became the first pharmacologic agent to obtain FDA approval for use in PD patients, supported by data from a large-scale, Phase III randomized controlled trial. Further elucidation of the genetic and mechanistic pathways involved in the development and progression of PD will help define future therapeutic targets.
Efficacy of indacaterol as a single therapy versus salmeterol/fluticasone therapy in patients with milder chronic obstructive pulmonary disease

Introduction: In non-exacerbation chronic obstructive pulmonary disease (COPD) with mild lung function impairment, single bronchodilator therapy might be as effective as combined inhaled corticosteroid/bronchodilator therapy, whereas the risk of pneumonia associated with the latter would be practically absent. Areas covered: We performed an analysis of a recent study evaluating the efficacy and safety of inhaled indacaterol versus inhaled salmeterol/fluticasone in COPD patients. Expert opinion: Both therapies were found to exert comparable effects on lung function, symptom severity and health status.
Cluster headache management and beyond

The therapeutic management of cluster headache is based on a very stable triad of drugs. Acute treatment has, in subcutaneous sumatriptan, its gold standard if compared to pure oxygen or indomethacin. Preventative treatment is based on verapamil at high doses (≥ 360 mg) and is a gold standard if compared to lithium carbonate or topiramate. Transitional treatments, based on the short-term use of corticosteroids with either systemic or local administration (GON), can be useful for the suppression of most resistant cluster periods, but with a well-known carry-over phenomenon related to the length of the cluster period itself. The role of invasive or noninvasive neuromodulation approaches must still be determined on a large scale; therefore, its use is not recommended as of yet. Lifestyle changes, including alcohol avoidance during the active phase of the disease, sleep hygiene and use of vasodilation drugs, should be carefully considered and the patients should be fully informed.
Prevalence of fatigue in patients with multiple sclerosis and its effect on the quality of life

Objective: This prospective study was carried out to observe the prevalence of fatigue in patients with multiple sclerosis (MS) and its effect on quality-of-life (QoL). Study Design and Setting: Prospective observational study in a University Tertiary Research Hospital in India. Patients and Methods: A total of 31 patients (25 females) with definite MS according to McDonald's criteria presented in out-patient/admitted in the Department of Neurology (between February 2010 and December 2011) were included in the study. Disease severity was evaluated using the Kurtzke's expanded disability status scale (EDSS). Fatigue was assessed using Krupp's fatigue severity scale (FSS). QoL was assessed by the World Health Organization QoL-BREF questionnaire. Results: The mean age of patients was 30.1 ± 9.1 years. The mean age at first symptom was 25.23 ± 6.4 years. The mean number of relapses was 4.7 ± 3.6 in the patients. The mean duration of illness was 4.9 ± 4.4 years. The mean EDSS score was 3.5 ± 2.2. Mean fatigue score was 38.7 ± 18.5 (cut-off value 36 in FSS). The prevalence of fatigue in patients with MS was 58.1% (18/31). MS patients with fatigue were significantly more impaired (P < 0.05) on all QoL domains (i.e., physical, psychosocial, social, and environment) than MS patients without fatigue. Conclusion: Prevalence of fatigue was found to be high in the MS patients in the study. All four domains of QoL were significantly more impaired in the group with fatigue than in those without fatigue.
Immunosuppressive effect of ethanol extract of Artemisia annua on specific antibody and cellular responses of mice against ovalbumin

Artemisia annua has been widely used to treat autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis in traditional Chinese medicine. In this study, the ethanol extract of A. annua (EEAA) was evaluated for the immunosuppressive potentials on mice splenocyte proliferation in vitro, and the specific antibody and cellular immune responses in the ovalbumin (OVA)-immunized mice. EEAA significantly suppressed concanavalin A (Con A)- and lipopolysaccharide (LPS)-stimulated splenocyte proliferation in vitro in a concentration-dependent manner. EEAA also significantly suppressed Con A-, LPS- and OVA-induced splenocyte proliferation in the OVA-immunized mice in a dose-dependent manner. Meanwhile, the OVA-specific serum IgG, IgG1 and IgG2b antibody levels in the OVA-immunized mice were markedly reduced by EEAA. The results suggest that EEAA could suppress the cellular and humoral response in mice. This study provided evidence to understand the therapeutic effects of A. annua for treatment of some autoimmune diseases and an immunosuppressive natural products to further researches to be developed as immunosuppressant.
The natural history of Dandy-Walker syndrome in the United States: A population-based analysis

Background: Dandy-Walker syndrome (DWS) is a congenital disorder typically manifesting with hydrocephalus. The classic anatomic hallmarks of DWS are hypoplasia of the cerebellar vermis, anterior-posterior enlargement of the posterior fossa, upward displacement of the torcula and transverse sinuses, and cystic dilatation of the fourth ventricle. Aims: Although optimal treatment of DWS typically requires neurosurgical intervention to prevent intracranial pressure increases incompatible with life, the natural history of this disorder has yet to be evaluated on a nationwide level. Settings and Design/Materials and Methods: The Kids’ Inpatient Database covering 1997-2003 was used for analysis. Children younger than age 18 admitted for DWS (ICD-9-CM = 742.3) were analyzed with a matched control group. The primary procedure codes for operative CSF drainage were coded into the analysis. The incidence of DWS was 0.136%; 14,599 DWS patients were included. Statistical Analysis Used: Multiple logistic regression models were used. Odds ratios (OR) were reported with 95% confidence intervals. Results and Conclusions: Mortality (OR = 10.02; P < 0.0001) and adverse discharge disposition (OR = 4.59; P < 0.0001) were significantly greater in DWS patients compared with controls. 20.4% of DWS patients received operative cerebrospinal fluid (CSF) drainage, 81-times more than controls (P < 0.0001). CSF drainage reduced mortality by 44% among DWS patients (P < 0.0001). Although DWS is associated with a 10-fold increase in mortality, operative CSF drainage nearly halves the mortality rate. Based on these findings (Class IIB evidence), it is likely that the increased mortality associated with DWS is directly attributable to the nearly 80% of DWS patients who did not receive operative CSF drainage for hydrocephalus. Consequently, increased access to neurosurgical intervention could reduce the mortality rate of DWS towards that of the general population.
Rifaximin and eluxadoline — newly approved treatments for diarrhea-predominant irritable bowel syndrome: what is their role in clinical practice alongside alosetron?

ABSTRACT Introduction: Diarrhea-predominant irritable bowel syndrome (IBS-D) is a common functional gastrointestinal condition in which patients experience abdominal pain, diarrhea, bloating, cramps, flatulence, fecal urgency, and incontinence. Areas Covered: We review two recently approved therapies that focus on treating underlying pathogenic mechanisms of IBS-D: (1) the non-absorbable antibiotic rifaximin, and (2) the opioid receptor agonist/antagonist eluxadoline. We compare the safety and efficacy data emerging from rifaximin and eluxadoline registration trials with safety and efficacy data from the alosetron clinical development program. Expert Opinion: The rifaximin and eluxadoline clinical development programs for IBS-D have demonstrated significant improvement in IBS-D endpoints compared to placebo. Direct comparison of primary endpoint results from the alosetron, rifaximin, and eluxadoline pivotal trials is not possible; however, general estimates of efficacy can be made, and these demonstrate similar and significantly greater responses to ‘adequate relief’ and a composite endpoint of abdominal pain/stool form for each agent compared to placebo. With the recent approval in the United States of rifaximin and eluxadoline for IBS-D, how should clinicians employ these agents? We suggest that they be utilized sequentially, taking into consideration patient symptoms and severity, prior medical history, mode of action, cost, availability, managed care coverage, and adverse event profiles.
Pharmacologic treatment of status epilepticus

ABSTRACT Introduction: Status epilepticus (SE) requires rapid identification of its cause and urgent pharmacological treatment. Despite an estimated incidence of up to 61 per 100,000 per year, evidence from high-class clinical trials is only available for the early stages of SE. Areas covered: Following a four-stage approach of SE (early, established, refractory and super-refractory), we present pharmacological treatment options and their clinical utility. Expert opinion: Intravenous lorazepam and intramuscular midazolam appear as most effective treatments for early SE. In children, buccal midazolam has emerged as first-line non-intravenous drug with similar efficacy and safety to other intravenous or rectal benzodiazepines. In established SE intravenous antiepileptic drugs are in use. There are no double-blind, but six randomized open studies with valproate and two with levetiracetam. A meta-analysis found higher rates of seizure cessation with valproate 75.7% (95% CI 63.7–84.8) and phenobarbital 73.6%, (95% CI 58.3–84.8) than with levetiracetam (68.5%, 95% CI 56.2–78.7) or phenytoin (50.2%, 95% CI 34.2–66.1). Based on the favourable tolerability profile of levetiracetam and valproate, the authors prefer these drugs in established SE over phenytoin. Treatment options in refractory SE are intravenous anaesthetics. In super-refractory SE ketamine, magnesium, steroids and other drugs have been used with variable outcomes. At this stage therapeutic decisions are based on doctors’ preferences, patient factors such as age and comorbidity, and cause of SE, if identified.