Fingolimod: therapeutic mechanisms and ocular adverse effects.

Fingolimod is an oral immunomodulating drug used in the management of relapsing-remitting multiple sclerosis (RRMS). We aim to review the published literature on ocular manifestations of fingolimod therapy and their possible underlying mechanisms. The therapeutic effects of fingolimod are mediated via sphingosine receptors, which are found ubiquitously in various organs, including lymphoid cells, central nervous system, cardiac myocytes, and smooth muscle cells. Fingolimod-associated macular oedema (FAME) is the most common ocular side effect but retinal haemorrhages and retinal vein occlusion can occur. The visual consequences appear to be mild and, in cases of FAME, resolution is often attained with discontinuation of therapy. However, in cases of retinal vein occlusion, discontinuation of fingolimod alone may not be sufficient and intra-vitreal therapy may be required. We also propose a pragmatic service pathway for monitoring patients on fingolimod therapy, which includes stratifying them by risk and visual acuity

Macrocytosis may be associated with mortality in chronic hemodialysis patients: a prospective study

<p>Abstract</p> <p>Background</p> <p>Macrocytosis occurs in chronic hemodialysis (CHD) patients; however, its significance is unknown. The purpose of this study was to establish the prevalence and distribution of macrocytosis, to identify its clinical associations and to determine if macrocytosis is associated with mortality in stable, chronic hemodialysis patients.</p> <p>Methods</p> <p>We conducted a single-centre prospective cohort study of 150 stable, adult CHD patients followed for nine months. Macrocytosis was defined as a mean corpuscular volume (MCV) > 97 fl. We analyzed MCV as a continuous variable, in tertiles and using a cutoff point of 102 fl.</p> <p>Results</p> <p>The mean MCV was 99.1 ± 6.4 fl, (range 66-120 fl). MCV was normally distributed. 92 (61%) of patients had an MCV > 97 fl and 45 (30%) > 102 fl. Patients were not B12 or folate deficient in those with available data and three patients with an MCV > 102 fl had hypothyroidism. In a logistic regression analysis, an MCV > 102 fl was associated with a higher Charlson-Age Comorbidity Index (CACI) and higher ratios of darbepoetin alfa to hemoglobin (Hb), [(weekly darbepoetin alfa dose in micrograms per kg body weight / Hb in g/L)*1000]. There were 23 deaths at nine months in this study. Unadjusted MCV > 102 fl was associated with mortality (HR 3.24, 95% CI 1.42-7.39, P = 0.005). Adjusting for the CACI, an MCV > 102 fl was still associated with mortality (HR 2.47, 95% CI 1.07-5.71, P = 0.035).</p> <p>Conclusions</p> <p>Macrocytosis may be associated with mortality in stable, chronic hemodialysis patients. Future studies will need to be conducted to confirm this finding.</p

Aldose Reductase Inhibition Prevents Metaplasia of Airway Epithelial Cells

BACKGROUND: Goblet cell metaplasia that causes mucus hypersecretion and obstruction in the airway lumen could be life threatening in asthma and chronic obstructive pulmonary disease patients. Inflammatory cytokines such as IL-13 mediate the transformation of airway ciliary epithelial cells to mucin-secreting goblet cells in acute as well as chronic airway inflammatory diseases. However, no effective and specific pharmacologic treatment is currently available. Here, we investigated the mechanisms by which aldose reductase (AR) regulates the mucus cell metaplasia in vitro and in vivo. METHODOLOGY/FINDINGS: Metaplasia in primary human small airway epithelial cells (SAEC) was induced by a Th2 cytokine, IL-13, without or with AR inhibitor, fidarestat. After 48 h of incubation with IL-13 a large number of SAEC were transformed into goblet cells as determined by periodic acid-schiff (PAS)-staining and immunohistochemistry using antibodies against Mucin5AC. Further, IL-13 significantly increased the expression of Mucin5AC at mRNA and protein levels. These changes were significantly prevented by treatment of the SAEC with AR inhibitor. AR inhibition also decreased IL-13-induced expression of Muc5AC, Muc5B, and SPDEF, and phosphorylation of JAK-1, ERK1/2 and STAT-6. In a mouse model of ragweed pollen extract (RWE)-induced allergic asthma treatment with fidarestat prevented the expression of IL-13, phosphorylation of STAT-6 and transformation of epithelial cells to goblet cells in the lung. Additionally, while the AR-null mice were resistant, wild-type mice showed goblet cell metaplasia after challenge with RWE. CONCLUSIONS: The results show that exposure of SAEC to IL-13 caused goblet cell metaplasia, which was significantly prevented by AR inhibition. Administration of fidarestat to mice prevented RWE-induced goblet cell metaplasia and AR null mice were largely resistant to allergen induced changes in the lung. Thus our results indicate that AR inhibitors such as fidarestat could be developed as therapeutic agents to prevent goblet cell metaplasia in asthma and related pathologies

Informational entropy : a failure tolerance and reliability surrogate for water distribution networks

Evolutionary algorithms are used widely in optimization studies on water distribution networks. The optimization algorithms use simulation models that analyse the networks under various operating conditions. The solution process typically involves cost minimization along with reliability constraints that ensure reasonably satisfactory performance under abnormal operating conditions also. Flow entropy has been employed previously as a surrogate reliability measure. While a body of work exists for a single operating condition under steady state conditions, the effectiveness of flow entropy for systems with multiple operating conditions has received very little attention. This paper describes a multi-objective genetic algorithm that maximizes the flow entropy under multiple operating conditions for any given network. The new methodology proposed is consistent with the maximum entropy formalism that requires active consideration of all the relevant information. Furthermore, an alternative but equivalent flow entropy model that emphasizes the relative uniformity of the nodal demands is described. The flow entropy of water distribution networks under multiple operating conditions is discussed with reference to the joint entropy of multiple probability spaces, which provides the theoretical foundation for the optimization methodology proposed. Besides the rationale, results are included that show that the most robust or failure-tolerant solutions are achieved by maximizing the sum of the entropies

Evolution and Phylogenetic Analysis of Full-Length VP3 Genes of Eastern Mediterranean Bluetongue Virus Isolates

Bluetongue virus (BTV) is the ‘type’ species of the genus Orbivirus within the family Reoviridae. The BTV genome is composed of ten linear segments of double-stranded RNA (dsRNA), each of which codes for one of ten distinct viral proteins. Previous phylogenetic comparisons have evaluated variations in genome segment 3 (Seg-3) nucleotide sequence as way to identify the geographical origin (different topotypes) of BTV isolates. The full-length nucleotide sequence of genome Seg-3 was determined for thirty BTV isolates recovered in the eastern Mediterranean region, the Balkans and other geographic areas (Spain, India, Malaysia and Africa). These data were compared, based on molecular variability, positive-selection-analysis and maximum-likelihood phylogenetic reconstructions (using appropriate substitution models) to 24 previously published sequences, revealing their evolutionary relationships. These analyses indicate that negative selection is a major force in the evolution of BTV, restricting nucleotide variability, reducing the evolutionary rate of Seg-3 and potentially of other regions of the BTV genome. Phylogenetic analysis of the BTV-4 strains isolated over a relatively long time interval (1979–2000), in a single geographic area (Greece), showed a low level of nucleotide diversity, indicating that the virus can circulate almost unchanged for many years. These analyses also show that the recent incursions into south-eastern Europe were caused by BTV strains belonging to two different major-lineages: representing an ‘eastern’ (BTV-9, -16 and -1) and a ‘western’ (BTV-4) group/topotype. Epidemiological and phylogenetic analyses indicate that these viruses originated from a geographic area to the east and southeast of Greece (including Cyprus and the Middle East), which appears to represent an important ecological niche for the virus that is likely to represent a continuing source of future BTV incursions into Europe

Social Algorithms

This article concerns the review of a special class of swarm intelligence based algorithms for solving optimization problems and these algorithms can be referred to as social algorithms. Social algorithms use multiple agents and the social interactions to design rules for algorithms so as to mimic certain successful characteristics of the social/biological systems such as ants, bees, bats, birds and animals.Comment: Encyclopedia of Complexity and Systems Science, 201

Investigating Tissue Optical Properties and Texture Descriptors of the Retina in Patients with Multiple Sclerosis

PURPOSE: To assess the differences in texture descriptors and optical properties of retinal tissue layers in patients with multiple sclerosis (MS) and to evaluate their usefulness in the detection of neurodegenerative changes using optical coherence tomography (OCT) image segmentation. PATIENTS AND METHODS: 38 patients with MS were examined using Stratus OCT. The raw macular OCT data were exported and processed using OCTRIMA software. The enrolled eyes were divided into two groups, based on the presence of optic neuritis (ON) in the history (MSON+ group, n = 36 and MSON- group, n = 31). Data of 29 eyes of 24 healthy subjects (H) were used as controls. A total of seven intraretinal layers were segmented and thickness as well as optical parameters such as contrast, fractal dimension, layer index and total reflectance were measured. Mixed-model ANOVA analysis was used for statistical comparisons. RESULTS: Significant thinning of the retinal nerve fiber layer (RNFL), ganglion cell/inner plexiform layer complex (GCL+IPL) and ganglion cell complex (GCC, RNFL+GCL+IPL) was observed between study groups in all comparisons. Significant difference was found in contrast in the RNFL, GCL+IPL, GCC, inner nuclear layer (INL) and outer plexiform layer when comparing MSON+ to the other groups. Higher fractal dimension values were observed in GCL+IPL and INL layers when comparing H vs. MSON+ groups. A significant difference was found in layer index in the RNFL, GCL+IPL and GCC layers in all comparisons. A significant difference was observed in total reflectance in the RNFL, GCL+IPL and GCC layers between the three examination groups. CONCLUSION: Texture and optical properties of the retinal tissue undergo pronounced changes in MS even without optic neuritis. Our results may help to further improve the diagnostic efficacy of OCT in MS and neurodegeneration

The impact of multimorbidity on adult physical and mental health in low- and middle-income countries: what does the study on global ageing and adult health (SAGE) reveal?

BACKGROUND: Chronic diseases contribute a large share of disease burden in low- and middle-income countries (LMICs). Chronic diseases have a tendency to occur simultaneously and where there are two or more such conditions, this is termed as 'multimorbidity'. Multimorbidity is associated with adverse health outcomes, but limited research has been undertaken in LMICs. Therefore, this study examines the prevalence and correlates of multimorbidity as well as the associations between multimorbidity and self-rated health, activities of daily living (ADLs), quality of life, and depression across six LMICs. METHODS: Data was obtained from the WHO's Study on global AGEing and adult health (SAGE) Wave-1 (2007/10). This was a cross-sectional population based survey performed in LMICs, namely China, Ghana, India, Mexico, Russia, and South Africa, including 42,236 adults aged 18 years and older. Multimorbidity was measured as the simultaneous presence of two or more of eight chronic conditions including angina pectoris, arthritis, asthma, chronic lung disease, diabetes mellitus, hypertension, stroke, and vision impairment. Associations with four health outcomes were examined, namely ADL limitation, self-rated health, depression, and a quality of life index. Random-intercept multilevel regression models were used on pooled data from the six countries. RESULTS: The prevalence of morbidity and multimorbidity was 54.2 % and 21.9 %, respectively, in the pooled sample of six countries. Russia had the highest prevalence of multimorbidity (34.7 %) whereas China had the lowest (20.3 %). The likelihood of multimorbidity was higher in older age groups and was lower in those with higher socioeconomic status. In the pooled sample, the prevalence of 1+ ADL limitation was 14 %, depression 5.7 %, self-rated poor health 11.6 %, and mean quality of life score was 54.4. Substantial cross-country variations were seen in the four health outcome measures. The prevalence of 1+ ADL limitation, poor self-rated health, and depression increased whereas quality of life declined markedly with an increase in number of diseases. CONCLUSIONS: Findings highlight the challenge of multimorbidity in LMICs, particularly among the lower socioeconomic groups, and the pressing need for reorientation of health care resources considering the distribution of multimorbidity and its adverse effect on health outcomes