Wilcoxon-Mann-Whitney odds ratio: A statistical measure for ordinal outcomes such as EDSS.

BACKGROUND: In many clinical situations, ordinal scales afford the primary method of semi-quantifying patient outcomes. In the field of multiple sclerosis, the primary ordinal scale is the Expanded Disability Status Scale. Predominant methods of ordinal scale statistical analysis provide a p-value without effect size or rely heavily on the assumption of proportionality of odds, subjecting them to lack of power and error. The Wilcoxon-Manny-Whitney Odds is a statistical method which provides significant information such as p-value, effect size, number needed to treat, confidence intervals, and is largely assumption-free. However, its utility has not been demonstrated in the field of multiple sclerosis. METHODS: Three clinical studies in the field of multiple sclerosis were selected which utilized ordinal scale outcomes at group or individual levels. Data from these studies was extracted using WebPlotDigitizer, and a custom Wilxocon-Mann-Whitney Odds software was applied to each dataset to re-analyze the main outcomes of the studies. RESULTS: Re-analysis of the manuscript by Muraro et al., 2017 demonstrated that autologous stem cell transplantation for relapsing remitting multiple sclerosis resulted in a 65% chance of improving from any Expanded Disability Status Scale category, although not significant. Re-analysis of the manuscript by Songthammawat et al., 2019 demonstrated chance of improvement with intravenous methylprednisolone and concurrent plasma exchange was 185% versus 32% in intravenous methylprednisolone with add-on plasma exchange, although not significant. Re-analysis of Kister et al., 2012 demonstrated the chances of mobility or cognition scores generally favored decline at every 5-year increment of study, and although statistically significant, these were smaller effect sizes ranging from an 11% chance of improvement to a 66% chance of decline over a 5-year interval. DISCUSSION: The Wilcoxon-Mann-Whitney Odds simplifies ordinal data analysis with its robust largely assumption-free nature. In the place of numerous statistical tests, this single test provides effect size estimate, number needed to treat, p-values, and confidence intervals. Importantly, the Wilcoxon-Mann-Whitney Odds effect size calculation is intuitively applicable to both individual and population-levels. Further, the Wilcoxon-Mann-Whitney Odds allows intuitive description of the progression of large cohorts over time, and we were able to clearly convey the odds of mobility and cognitive decline over 30 years in a large multiple sclerosis cohort. Overall, the Wilcoxon-Mann-Whitney Odds is a powerful and robust statistical test with significant promise within the field of multiple sclerosis.

Efficacy of ginger-based treatments against infection with Gyrodactylus turnbulli in the guppy (Poecilia reticulata (Peters)).

Monogenean infections of commercially farmed fishes are responsible for significant economic losses and existing chemical therapeutants, often stressful to the fish, pose associated risks. As part of a recent trend to move towards the use of alternative, plant-based remedies for commonly occurring aquaculture-related diseases, the efficiency of ginger (Zingiber officinale) was investigated against the monogenean parasite Gyrodactylus turnbulli in the guppy. In vitro trials revealed the clear anti-parasitic effects of ginger. Ethanolic and aqueous extracts, prepared from freeze dried ginger, were tested. An increase in extract concentration was associated with reduced time to parasite immobilisation, with ethanolic extract being more efficient; at 75 and 200ppt aqueous ginger extract parasites died at 65.6±2.8 and 1.8±0.2min, respectively, whereas at 5 and 40ppt ethanolic extract parasites died at 26.1±0.7 and 4.9±0.3min, respectively. Bathing G. turnbulli-infected fish in ethanolic ginger extract (i.e. 5 and 7.5ppt for 90 and 30min, respectively) significantly reduced infection prevalence and intensity when compared to the water and ethanol controls. The higher concentration (i.e. 7.5ppt) proved as equally effective as Praziquantel, the conventionally used chemical treatment for gyrodactylosis, with the fish appearing to be completely cleared of the infection in both cases. Oral treatments of G. turnbulli-infected guppies with diets supplemented with 10 and 20% ginger powder proved to be ineffective in decreasing parasite load. These findings demonstrate that immersion in ginger extract offers an effective, alternative treatment against monogenean infection in fish.

Efficacy of garlic based treatments against monogenean parasites infecting the guppy (Poecilia reticulata (Peters)).

Monogenean infections of commercially farmed fishes are responsible for significant economic losses. Garlic (Allium sativum) is a well-known spice which also possesses anti-microbial and anti-parasitical properties. The current work aimed to test the efficacy of garlic-based treatments against infection with monogenean sp. in the guppy (Poecilia reticulata). Clipped sections of tail fins of guppies heavily infected with Gyrodactylus turnbulli were exposed to aqueous garlic extract (7.5 to 30 mL L(-1)) and visually observed under a dissecting microscope. Results revealed that exposure to garlic caused detachment of parasite and cessation of movement indicating death. A positive correlation was seen between garlic concentration and time to detachment and death of parasites, which, at the highest concentration of 30 mL L(-1), occurred at 4.1 and 8.6 min, respectively. Bathing in aqueous garlic extract (7.5 and 12.5 mL L(-1)) was tested in guppies infected with G. turnbulli. Prior acute toxicity tests revealed the maximum tolerance levels of guppies to garlic extract to be 12.5 mL L(-1) for 1h. Bathing of infected fish in garlic extract (7.5 and 12.5 mL L(-1)) significantly (p<0.05) reduced infection prevalence and intensity as compared to the control. Oral treatments using dry garlic powder-supplemented diet were tested on guppies infected with G. turnbulli and Dactylogyrus sp. Fish were fed with food containing 10% and 20% dry garlic powder for 14 days. Groups fed with garlic supplemented diets showed significantly reduced (p<0.05) mean prevalence and mean intensity of parasites as compared to the control. Dietary application of garlic did not appear to affect palatability. Fresh crushed garlic was added at a level of 1 gL(-1) and applied as an indefinite bath for 14 days. This treatment was seen to significantly reduce (p<0.05) parasite prevalence and mean intensity as compared to the control. Histopathology revealed elevated muscular dystrophy in the 20% garlic-fed group, as compared to control. These findings demonstrate the potential of garlic as a natural alternative to currently used chemical treatments for monogenean sp. infection in the guppy.

Structural differentiation of apical openings in active mitochondria-rich cells during early life stages of Nile tilapia (Oreochromis niloticus L.) as a response to osmotic challenge.

This study examines the structural differentiation of the apical crypts of mitochondria-rich cells (MRCs) in Nile tilapia as a response to osmotic challenge. Larvae were transferred from freshwater at 3 days post-hatch to 12.5 and 20 ppt and were sampled at 24- and 48-h post-transfer. Scanning electron microscopy allowed quantification of MRCs, based on apical crypt appearance and surface area, resulting in a morphological classification of 'sub-types', that is, Type I or absorptive (surface area range 5.2-19.6 µm(2)), Type II or active absorptive form (surface area range 1.1-15.7 µm(2)), Type III or weakly functioning form (surface area range 0.08-4.6 µm(2)) and Type IV or active secreting form (surface area range 4.1-11.7 µm(2)). Mucus cell crypts were discriminated from those of MRCs based on the presence of globular extensions and quantified. Density and frequency of MRCs and mucus cells varied significantly according to the experimental salinity and time post-transfer; in freshwater-adapted larvae, all types were present except Type IV but, following transfer to elevated salinities, Type I and Type II disappeared and appeared to be replaced by Type IV crypts. Type III crypt density remained constant following transfer. Transmission electron microscopy with immunogold labelling, using a novel pre-fixation technique with anti-Na(+)/K(+)-ATPase, allowed complementary ultrastructural visualisation of specific localisation of the antibodies on active MRCs, permitting a review of MRC apical morphology and related Na(+)/K(+)-ATPase binding sites.

Ontogenetic changes in location and morphology of chloride cells during early life stages of the Nile tilapia Oreochromis niloticus adapted to fresh and brackish water.

Ontogenetic changes in the location, size, density and morphology of chloride cells in the Nile tilapia Oreochromis niloticus adapted to fresh and brackish water are described using Na(+) /K(+) -ATPase immunohistochemistry, light microscopy (LM), scanning electron microscopy (SEM) and confocal scanning laser microscopy (CSLM). The pattern of chloride cell distribution changed during development under both treatments, with chloride cell density decreasing significantly from hatch to 7 days post-hatch, but appearing on the inner opercular area at 3 days post-hatch and increasing significantly thereafter (P < 0·05). Chloride cells were always denser in fresh- than in brackish-water larvae. In both treatments, chloride cells located on the outer operculum and tail showed a marked increase in size with age, but cells located on the abdominal epithelium of the yolk sac and the inner operculum showed a significant decrease in size (P < 0·05). Chloride cells from brackish-water adapted larvae from 1 day post-hatch onwards were always significantly larger (P < 0·05) than those from freshwater-adapted larvae. SEM revealed structural differences in chloride cell apical morphology according to environmental conditions. There appears to be clearly defined temporal staging of the appearance of adaptive mechanisms that confer an ability to cope with varying environmental conditions during early development.

Efectos del bromacepam sobre la variación negativa contingente y el tiempo de reacción en una tarea visuomotora / The effects of bromazepam on contingent negative variation and reaction time in a visuomotor task

Introducción. El bromacepam es el segundo benzodiacepínicomás utilizado en Brasil. La investigación psicofisiológicasobre esta sustancia es aún incipiente. Objetivo. Contrastar la neurotoxicidaddel bromacepam a través de los tiempos de reacción(TR) y de las variaciones negativas contingentes (VNC). Sujetos ymétodos. Utilizando un videojuego elaborado en nuestro laboratoriopara la investigación psicofisiológica (Car Acquisition), 14 voluntariossanos –9 hombres–, entre 23 y 42 años, conducían un vehículopor una carretera llena de curvas (distractor) mientras tenían queresponder a los estímulos imperativos (comandos para apretar elbotón del joystick) precedidos por estímulos de alerta (paradigmaS1-S2-RM con distractor). Comparamos los TR, las amplitudes y laslatencias de las VNC, en cada uno de los tres electrodos de la líneamedia (Fz, Cz y Pz), una hora después del placebo (P), de 3 mg debromacepam (B3) o 6 mg de bromacepam (B6) –aleatorio, doble ciego,cruzado y en días diferentes–. Estadística: ANOVA one-way yPost Hoc Scheffé. Resultados. Los TR no diferirán de manera significativa.En Pz, las amplitudes de las VNC diferirán significativamentepara P, B3 y B6 (p = 0,006), y también para B3 y B6 (p =0,018), con B6 > B3 = P. En Fz, una tendencia no significativa (p =0,074) sugería una diferencia entre las latencias, menor en B6 queen B3 (p = 0,098), ambas equivalentes al placebo. Las amplitudesoscilaban de media entre 2,4 y 5,9 μV. Conclusiones. La neurotoxicidad,comportamental y neurofisiológica, fue insignificante una horadespués de la administración de una dosis única de 3 o 6 mg de bromacepamen adultos jóvenes y sanos. Las amplitudes menores erancompatibles con la interferencia de los distractores, y no se observaroncomo efecto aislado

Introduction. Bromazepam is the second most commonly used benzodiazepine in Brazil. Psychophysiologicalresearch on this substance is still in its early stages. Aim. To determine the neurotoxicity of bromazepam by examiningreaction times (RT) and contingent negative variations (CNV). Subjects and methods. Using a videogame produced in ourlaboratory for psychophysiological research purposes (Car Acquisition), 14 healthy volunteers (9 males) aged between 23and 42 drove a vehicle along a road full of curves (i.e. distractors) while they had to respond to imperative stimuli (i.e. ordersto press the button on the joystick) that were preceded by warnings (S1-S2-RM paradigm with distractor). We compared RT,amplitudes and latencies of the CNV at each of the three electrodes on the median line (Fz, Cz and Pz) one hour after random,double-blind and crossed administration of placebo (P), 3 mg of bromazepam (B3) or 6 mg of bromazepam (B6) on differentdays. Statistics: one-way ANOVA and Post Hoc Scheffé. Results. No significant differences were observed in the RT. At Pz, theCNV amplitudes displayed significant differences for P, B3 and B6 (p = 0.006), and also for B3 and B6 (p = 0.018), with B6> B3 = P. At Fz, a non-significant tendency (p = 0.074) suggested a difference between the latencies, shorter in B6 than in B3(p = 0.098), both equivalent to placebo. The mean amplitudes ranged between 2.4 and 5.9 μV. Conclusions. Behavioural andneurophysiological neurotoxicity was insignificant one hour after administration of a single 3 or 6 mg dose of bromazepam inhealthy young adults. Low mean amplitudes were compatible with the interference from distractors and did not result in flooreffect

[The effects of bromazepam on contingent negative variation and reaction time in a visuomotor task]. / Efectos del bromacepam sobre la variación negativa contingente y el tiempo de reacción en una tarea visuomotora.

INTRODUCTION: Bromazepam is the second most commonly used benzodiazepine in Brazil. Psychophysiological research on this substance is still in its early stages. AIM: To determine the neurotoxicity of bromazepam by examining reaction times (RT) and contingent negative variations (CNV). SUBJECTS AND METHODS: Using a videogame produced in our laboratory for psychophysiological research purposes (Car Acquisition), 14 healthy volunteers (9 males) aged between 23 and 42 drove a vehicle along a road full of curves (i.e. distractors) while they had to respond to imperative stimuli (i.e. orders to press the button on the joystick) that were preceded by warnings (S1-S2-RM paradigm with distractor). We compared RT, amplitudes and latencies of the CNV at each of the three electrodes on the median line (Fz, Cz and Pz) one hour after random, double-blind and crossed administration of placebo (P), 3 mg of bromazepam (B3) or 6 mg of bromazepam (B6) on different days. STATISTICS: one-way ANOVA and Post Hoc Scheffé. RESULTS: No significant differences were observed in the RT. At Pz, the CNV amplitudes displayed significant differences for P, B3 and B6 (p = 0.006), and also for B3 and B6 (p = 0.018), with B6 > B3 = P. At Fz, a non-significant tendency (p = 0.074) suggested a difference between the latencies, shorter in B6 than in B3 (p = 0.098), both equivalent to placebo. The mean amplitudes ranged between 2.4 and 5.9 microV. CONCLUSIONS: Behavioural and neurophysiological neurotoxicity was insignificant one hour after administration of a single 3 or 6 mg dose of bromazepam in healthy young adults. Low mean amplitudes were compatible with the interference from distractors and did not result in floor effect.

Nuevo uso de un medio de preservación de eritrocitos para la prueba inversa / New use of preservation medium for erythrocytes to perfom inverse test

Fundamento: los medios actuales de preservación de eritrocitos humanos (MPE) artesanales son eficaces por cortos períodos. Objetivo: obtener un MPE útil por un período prolongado, para efectuar la prueba inversa del grupo sanguíneo ABO en donantes de sangre y receptores transfusionales. Material y método: la técnica se basó en utilizar el MPE de la OMS para controles de calidad de contadores hematológicos (glutaraldehído 0,37 por ciento, formaldehído 2,7 por ciento, citrato trisódico 26 por ciento, y antibióticos). Se prepararon distintos lotes al 3 y 5 por ciento de glóbulos preservados a partir de sangre de bolsa de donantes con serología no reactiva. Se ensayaron 1.080 muestras. Se evaluaron reacciones en platina y en tubo. Se comparó la reactividad de los glóbulos en MPE y en solución salina. Se evaluó el grado de discrepancia con respecto a la prueba directa ABO dentro de los 40 días de preparados los reactivos. Resultados: los resultados obtenidos en platina dentro de las 2 semanas mostraron una discrepancia total del 2,3 por ciento, siendo en todos los casos, aglutinación débil. Las discrepancias fueron resueltas al pasar a soporte tubo. De las 1030 muestras evaluadas en soporte tubo con MPE se obtuvo una discrepancia del 0,7 por ciento dentro de los 40 días de preparación. El grado de discrepancia en función del tiempo de preparación reactivo se incrementó del 0,2 al 0,7 por ciento entre la tercera y la cuarta semanas. Estos porcentajes no difieren con los descriptos en la bibliografía con otros reactivos. Fijando el límite de discrepancia en 0,2 por ciento y en soporte tubo, el reactivo es estable hasta los 21 días. Conclusiones: el presente trabajo se considera un aporte a la sección de inmunohematología para evitar la preparación diaria de suspensiones y economizar en la compra de reactivo comercial. A futuro también podría utilizarse como MPE en los paneles para anticuerpos irregulares. (AU)

Nuevo uso de un medio de preservación de eritrocitos para la prueba inversa / New use of preservation medium for erythrocytes to perfom inverse test

Fundamento: los medios actuales de preservación de eritrocitos humanos (MPE) artesanales son eficaces por cortos períodos. Objetivo: obtener un MPE útil por un período prolongado, para efectuar la prueba inversa del grupo sanguíneo ABO en donantes de sangre y receptores transfusionales. Material y método: la técnica se basó en utilizar el MPE de la OMS para controles de calidad de contadores hematológicos (glutaraldehído 0,37 por ciento, formaldehído 2,7 por ciento, citrato trisódico 26 por ciento, y antibióticos). Se prepararon distintos lotes al 3 y 5 por ciento de glóbulos preservados a partir de sangre de bolsa de donantes con serología no reactiva. Se ensayaron 1.080 muestras. Se evaluaron reacciones en platina y en tubo. Se comparó la reactividad de los glóbulos en MPE y en solución salina. Se evaluó el grado de discrepancia con respecto a la prueba directa ABO dentro de los 40 días de preparados los reactivos. Resultados: los resultados obtenidos en platina dentro de las 2 semanas mostraron una discrepancia total del 2,3 por ciento, siendo en todos los casos, aglutinación débil. Las discrepancias fueron resueltas al pasar a soporte tubo. De las 1030 muestras evaluadas en soporte tubo con MPE se obtuvo una discrepancia del 0,7 por ciento dentro de los 40 días de preparación. El grado de discrepancia en función del tiempo de preparación reactivo se incrementó del 0,2 al 0,7 por ciento entre la tercera y la cuarta semanas. Estos porcentajes no difieren con los descriptos en la bibliografía con otros reactivos. Fijando el límite de discrepancia en 0,2 por ciento y en soporte tubo, el reactivo es estable hasta los 21 días. Conclusiones: el presente trabajo se considera un aporte a la sección de inmunohematología para evitar la preparación diaria de suspensiones y economizar en la compra de reactivo comercial. A futuro también podría utilizarse como MPE en los paneles para anticuerpos irregulares.

[Synthesis and immunomodulating activity of new diglycopeptides of of glycyrrhizinic acid and it's 30-methyl ester]. / Sintez i immunomoduliruiushchaia aktivnost' novykh diglikopeptidov glitsirrizinovoi kisloty i ee 30-metilovogo éfira.

New amino acid derivatives of glycyrrhizic acid and its methyl ester were selectively synthesized using active N-succinimide esters. The compounds with residues of glycine ethyl ester and alanine methyl and butyl esters increased the level of agglutinins and hemolysins in blood serum of mice two- to threefold in comparison with the control upon parenteral administration at a dose of 2 mg/kg for 14 days. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 2; see also http://www.maik.ru.

[Synthesis and immunostimulating activity of cysteine-containing glycopeptide derivatives of glycyrrhizic acid]. / Sintez i immunostimuliruiushchaia aktivnost' tsisteinsoderzhashchikh glikopeptidnykh proizvodnykh glitsirrizinovoi kisloty.

New cysteine-containing derivatives of glycyrrhizic acid were synthesized by its coupling with Cys(Bzl) esters or the Cys(Bzl)-Val-OBu(t) dipeptide by the active ester method (DCC/HOSu) or by Woodward's reagent K. The derivatives with Cys(Bzl) and Cys(Bzl)-Val residues attached to the carbohydrate part of the molecule stimulated the primary immune response and the reaction of delayed-type hypersensitivity in mice at a dose of 2 mg/kg. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 1; see also http://www.maik.ru.

Molecular mechanisms of beta-catenin recognition by adenomatous polyposis coli revealed by the structure of an APC-beta-catenin complex.

The adenomatous polyposis coli (APC) tumor suppressor protein plays a critical role in regulating cellular levels of the oncogene product beta-catenin. APC binds to beta-catenin through a series of homologous 15 and 20 amino acid repeats. We have determined the crystal structure of a 15 amino acid beta-catenin binding repeat from APC bound to the armadillo repeat region of beta-catenin. Although it lacks significant sequence homology, the N-terminal half of the repeat binds in a manner similar to portions of E-cadherin and XTcf3, but the remaining interactions are unique to APC. We discuss the implications of this new structure for the design of therapeutics, and present evidence from structural, biochemical and sequence data, which suggest that the 20 amino acid repeats can adopt two modes of binding to beta-catenin.

[The immunotropic activity of erakond]. / Immunotropnaia aktivnost' érakonda.

The effect of eracond on some parameters of immunity and allergic reactions was studied in experiments on mice and guinea pigs. The drug was found to possess an immunomodulating effect.

Characterization of desamino-5-[125I]iodo-3-methoxy-zacopride ([125I]MIZAC) binding to 5-HT3 receptors in the rat brain.

1. Antagonists at 5-HT3 receptors have shown activity in animal models of mental illness, however, few radiolabeled 5-HT3 ligands are available for preclinical studies. MIZAC, an analogue of the selective 5-HT3 antagonist, zacopride, binds with high affinity (1.3-1.5 nM) to CNS 5-HT3 sites. The authors report here the selectivity of MIZAC for these sites in rat brain homogenates. 2. Ninety-seven percent of total specific binding of [125I]MIZAC (0.1 nM) of was displaced by bemesetron (3 microM), a selective 5-HT3 antagonist. Competition studies using ligands with known affinities for 5-HT3 sites give a high correlation with reported pKi values (r2 0.98). Bemesetron displaceable binding has a regional distribution consistent with that of the 5-HT3 receptor, i.e. highest in cortex and hippocampus, and lowest in striatum and cerebellum. 3. Potent antagonists present at concentrations sufficient to occupy 95% of other 5-HT receptor populations (1A, 1B, 1D, 2A, 2B, 2C, 5A, 5B, 6, and 7) showed minimal ability to displace [125I]MIZAC binding (3 nM). Specificity studies using radioligand binding assays selective for 5-HT4, 5-HT6, and 5-HT7 receptors, and for binding sites of other neurotransmitters indicate a high degree of selectivity of [125I]MIZAC for the 5-HT3 receptor. 4. [125I]MIZAC binds to an apparent low affinity (benzac) site having a unique pharmacology. Low affinity binding was displaceable by benztropine, but not by other muscarinic agents nor inhibitors of dopamine uptake. The regional distribution of the low affinity site differed markedly from that of the high affinity site. The apparent affinity of [125I]MIZAC for the benzac site is two orders of magnitude lower than for the 5-HT3 receptor. Given its high selectivity for 5-HT3 binding sites, [125I]MIZAC appears to be a promising ligand for labeling 5-HT3 receptors in vitro and in vivo.

Ammonia uptake by plants.

The paper considers the methodology and results of experimental determination of dry deposition and ammonia uptake by isolated plant leaves. Analytical expressions are proposed which allow a transition from rates obtained in an isolated chamber to dry ammonia deposition by standing crops leaves.

[Effect of antiadrenergic and myotropic hypotensive agents on the blood kallikrein-kinin system in experimental hypertension]. / Vliianie antiadrenergicheskikh i miotropnykh gipotenzivnykh sredstv na kallikrein-kininovuiu sistemu krovi pri éksperimental'noi gipertenzii.

In the period of vasorenal hypertension formation in rats phase changes in the kallikrein-kinin system of the blood are observed: one month after kidney-skin anastomosis a significant increase of the levels of prekallikrein, kininogen and kallikrein inhibitor is noted and by the end of the second month a drastic decrease of the levels of these components occurs due to the "unregulated" activation of the kallikrein-kinin system of the blood. Antiadrenergic agents (reserpine, tropaphen) prescribed for treatment of hypertension prevent the development of the "unregulated" activation of the kallikrein-kinin system and reduce consumption of its components. These drugs are advisable to use under threat of the kallikrein-kinin system exhaustion. beta-adrenoblocking agent obsidan and myotropic drugs produce a significant enhancement of kallikreino- and kininogenesis, but the degree of activation of the processes is less pronounced than in untreated hypertensive rats.