Genotyping of presenilin-1 polymorphism in amyotrophic lateral sclerosis

The mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis are not fully understood. Recent studies suggest that apoptosis is involved in the abnormal neural death that occurs in this devastating disease. Presenilin-1, a transmembrane protein, seems to be implicated in apoptosis. To determine whether presenilin-1 intron 8 polymorphism has an influence in the course of amyotrophic lateral sclerosis, we examined this polymorphism genotypes in a large group of patients (n=72) with amyotrophic lateral sclerosis and in a random sample of 213 healthy individuals. The results showed a significant difference in genotype (P < 0.04) and allele (P < 0.03) distribution between patients and controls. These results suggest a possible intervention of presenilin-1 in the pathogenesis of amyotrophic lateral sclerosis. Received: 14 February 2000 / Received in revised form: 20 April 2000 / Accepted: 4 June 2000     

Breast cancer stem cells: Multiple capacities in tumor metastasis

Breast cancer is the leading cause of cancer death among women worldwide. Accumulating evidence indicates that the local recurrent and/or distant metastatic tumors, the major causes of lethality in the clinic, are related to the aggressive phenotype of a small fraction of cancer cells loosely termed as cancer stem cells (CSCs), tumor initiating cells (TICs), or cancer metastasis-initiating cells (CMICs). Breast cancer stem cells (BCSCs) are shown to exhibit unique growth abilities including self-renewal, differentiation potential, and resistance to most anti-cancer agents including chemo- and/or radiotherapy, all of which are believed to contribute to the development and overall aggressiveness of the recurrent or metastatic lesions. It is in the urgent need not only to further define the nature of heterogeneity in each tumor but also to characterize the precise mechanisms governing tumor–host cross-talk which is assumed to be initiated by BCSCs. In this review, we will focus on recently identified key factors, including the BCSCs among circulating tumor cells, interaction of BCSCs with the host, epithelial mesenchymal transition (EMT), tumor microenvironment, the intrinsic resistance due to HER2 expression, potential biomarkers of BCSCs and cancer cell immune signaling. We believe that new evidence coming from both bench and clinical research will help to develop more effective approaches to control or significantly reduce the aggressiveness of metastatic tumors.     

Cuprizone [Bis(Cyclohexylidenehydrazide)] is Selectively Toxic for Mature Oligodendrocytes

Cuprizone [bis(cyclohexylidenehydrazide)]-induced toxic demyelination is an experimental animal model commonly used to study de- and remyelination in the central nervous system. In this model, mice are fed with the copper chelator cuprizone which leads to oligodendrocyte death with subsequent demyelination. The underlying mechanisms of cuprizone-induced oligodendrocyte death are still unknown, and appropriate in vitro investigations to study these mechanisms are not available. Thus, we studied cuprizone effects on rat primary glial cell cultures and on the neuroblastoma cell line SH-SY5Y. Treatment of cells with different concentrations of cuprizone failed to show effects on the proliferation and survival of SH-SY5Y cells, microglia, astrocytes, and oligodendrocyte precursor cells (OPC). In contrast, differentiated mature oligodendrocytes (OL) were found to be significantly affected by cuprizone treatment. This was accompanied by a reduced mitochondrial potential in cuprizone-treated OL. These results demonstrate that the main toxic target for cuprizone is mature OL, whilst other glial cells including OPC are not or only marginally affected. This explains the selective demyelination induced by cuprizone in vivo.     

Preserved Axin expression is associated with an aggressive phenotype in invasive breast carcinomas

Reduced Axin expression has been associated with an aggressive behavior in lung and esophageal squamous cell carcinomas. Its role in breast cancer has not been defined. The aim of our study was to investigate the expression pattern of Axin protein in invasive breast carcinomas, in relation to the behavior and prognosis of the disease. Immunohistochemistry was performed for the detection of Axin expression in 232 breast cancer tissues. Univariate and multivariate statistical analyses were used to assess the relation of Axin expression with classic clinicopathological parameters, patients' survival and various biologic markers Human Epidermal Factor‐2 (HER‐2), Ki‐67, topoIIα, glycogen synthase kinase‐3β (GSK‐3β)]. Preserved cytoplasmic Axin expression was positively correlated to lymph node invasion, HER‐2 and GSK‐3β and inversely to Ki‐67 and topoIIα. Nuclear Axin was positively associated with tumor size. Stromal Axin showed a parallel association with lymph node status and HER‐2. In the subgroup of lobular breast carcinomas, preserved Axin was found to exert an unfavorable impact on patients' overall survival. Our findings indicate, for the first time, that in invasive breast cancer preserved Axin expression is associated with a more aggressive phenotype and that in the discrete subtype of lobular breast carcinomas Axin negatively influences patients' overall survival.     

Effect of octreotide administration on serum interleukin-6 (IL-6) levels of patients with acute edematous pancreatitis

BACKGROUND/AIMS: Based on former studies in experimental animals on the effect of octreotide on serum and ascitic levels of tumor necrosis factor-alpha and interleukin-6 in the field of necrotizing pancreatitis, the present study was designed to investigate the effect of octreotide on serum interleukin-6 of patients with acute edematous pancreatitis. METHODOLOGY: A total of 36 patients with acute edematous pancreatitis and initiation of symptoms 12 hours before their admission were enrolled in the study; 20 were treated with octreotide 200 microg tid and 16 with octreotide 500 microg tid for five days. Blood was sampled at regular time intervals. Interleukin-6 was determined by an enzyme-immunoassay and C-reactive protein by nephelometry. RESULTS: Mean concentrations of interleukin-6 of patients treated with octreotide 200 microg tid were 59.52 pg/mL before and 94.08, 46.25, 49.94, 58.16 and 26.08 pg/mL at 3, 6, 24, 48 and 72 hours after the start of therapy respectively. Respective values of patients treated with octreotide 500 microg tid were 57.19, 53.07, 57.83, 36.06, 54.29 and 65.49 pg/mL. Mean C-reactive protein of patients treated with octreotide 200 microg tid were 67.37 mg/L before and 48.51, 106.08 and 95.58 mg/L at 24, 48 and 72 hours after the start of therapy respectively. Respective values of patients treated with octreotide 500 microg tid were 65.51, 60.56, 90.68 and 64.22 mg/L. CONCLUSIONS: A transient, but not statistically significant, decrease of serum interleukin-6 levels was documented after administration of octreotide in the field of acute edematous pancreatitis. That decrease was earlier after the application of the 500 microg tid dose than the 200 microg tid dose. Studies with a greater number of patients are mandatory to fully clarify the effect of octreotide, if any, on acute pancreatitis.     

Coronary endothelial vasomotor function and vascular remodeling in heart transplant recipients randomized for tacrolimus or cyclosporine immunosuppression.

OBJECTIVES: This study aimed to compare changes in coronary endothelial function, systemic endothelin-1 (ET-1) levels, and vascular remodeling in heart transplant recipients randomized to cyclosporin A (CyA) or tacrolimus (Tac) immunosuppression. BACKGROUND: Functional endothelial abnormalities and intimal thickening are sensitive measures of early cardiac allograft vasculopathy (CAV). METHODS: The randomized, prospective study was performed in two groups of 22 patients, maintained on Tac or CyA and mycophenolate mofetil immunosuppression, 1 and 12 months after heart transplantation. We investigated epicardial luminal diameter, coronary blood flow velocity, and ET-1 plasma levels at 1 and 12 months after transplantation. Structural coronary alterations were determined using intravascular ultrasound. RESULTS: Epicardial vasomotor function at baseline and during follow-up was comparable between the groups. Deterioration of microvascular endothelial function during follow-up was significantly enhanced in the CyA versus Tac group (p < 0.05). Circulating ET-1 concentration increased in the CyA group but significantly decreased over time in the Tac group (CyA +17% vs. Tac -25%; p < 0.05). The time-dependent increase in mean intimal area was significantly enhanced in the CyA versus Tac group, whereas the vessel area significantly increased during follow-up in the Tac compared with the CyA group. CONCLUSIONS: Epicardial endothelial function is comparable between CyA- and Tac-treated patients. Microvascular endothelial function deteriorates more in CyA-treated patients, a finding that correlates with enhanced ET-1 concentration and an increased intimal area during follow-up. The mean vessel area in the Tac group increased over time, indicating positive vascular remodeling. Tac is superior to CyA with respect to microvascular endothelial function, intimal thickening, and vascular remodeling.     

Effect of early application of social distancing interventions on COVID-19 mortality over the first pandemic wave: An analysis of longitudinal data from 37 countries

ObjectivesTo estimate the effect of early application of social distancing interventions on Covid-19 cumulative mortality during the first pandemic wave.MethodsEcological longitudinal study using multivariable negative binomial regression for panel data. Daily numbers of Covid-19 cases and deaths, and data on social distancing interventions, for the 37 member countries of the Organization for Economic Cooperation and Development (OECD) were analysed.ResultsCovid-19 cumulative mortality over the first pandemic wave varied widely across countries (range, 4.16 to 855 deaths per million population). On average, one-day delay in application of mass gatherings ban was associated with an adjusted increase in Covid-19 cumulative mortality by 6.97% (95% CI, 3.45 to 10.5), whilst a one-day delay in school closures was associated with an increase of 4.37% (95% CI, 1.58 to 7.17) over the study period. We estimated that if each country had enacted both interventions one week earlier, Covid-19 cumulative mortality could have been reduced by an average of 44.1% (95% CI, 20.2 to 67.9).ConclusionsEarly application of mass gatherings ban and school closures in outbreak epicentres was associated with an important reduction in Covid-19 cumulative mortality during the first pandemic wave. These findings may support policy decision making.     

ABP 501 for the treatment of rheumatoid arthritis

Introduction: Rheumatoid arthritis (RA) is an autoimmune disease, which has a negative impact on the ability to perform activities daily. Tumour necrosis factor α (TNF) is a cytokine with diverse cellular effects, and a key regulator of the inflammatory response. ABP 501 is a biosimilar to adalimumab, a TNF inhibitor.

Areas covered: In this review, we examined ABP 501, as a biosimilar candidate to adalimumab in the treatment of RA focusing on the available data. Current data indicate that ABP 501 is a highly similar alternative to adalimumab in terms of safety, efficacy, tolerability and immunogenicity. ABP 501 has already been approved by health authorities in Europe and the United States of America, as a subcutaneous (s.c.) therapy option for the treatment of patients with RA, but also for the full spectrum approved for its bio-originator adalimumab.

Expert opinion: Current body of evidence suggests that all biologic activities have been demonstrated to be equivalent between ABP 501 and the originator, including binding rates and affinity to TNF, and also the effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC). Therefore, it is fully expected to have same efficacy and safety in all indications.     

Pleural effusion in psoriatic arthritis patients: a case series and review of the literature

Clinical Rheumatology - Psoriatic arthritis (PsA) is a chronic inflammatory disease associated with psoriasis. Pulmonary involvement is a rare extra-articular manifestation of the disease...