Dear and Glorious Physician, who are we in COVID-19?

We are on the brink of a public health crisis. Science is changing, medicine is evolving, politics are adapting as we are attempting to retain our "normal lives". The origin of COVID-19 is not exclusively a medical or scientific one. Rather, it lingers more towards damaged public policies with a global pandemic surfacing as merely a consequence of failed economic and health strategies. In this paper we provide a narrative review of the evolution of COVID-19 with emphasis on the its origin and the place of physicians in an ethical perspective.

Nous sommes à l'aube d'une crise de santé publique. La science change, la médecine évolue, la politique s'adapte alors que nous tentons de retrouver une "vie normale". L'origine de COVID-19 n'est pas exclusivement médicale ou scientifique. Il s'agit plutôt d'une politique publique endommagée, avec une pandémie mondiale qui fait surface comme simple conséquence de l'échec des stratégies économiques et sanitaires. Dans cet article, nous présentons un examen narratif de l'évolution de COVID-19 en mettant l'accent sur son origine et la place des médecins dans une perspective éthique.

Lingual Focal Hyperplastic Lesion in a Pediatric Patient: Report of an Unusual Case / Lesión hiperplásica focal lingual en un paciente pediátrico: Informe de un caso inusual

Abstract: Focal fibrous hyperplasia (FFH) is an oral mucosal localized non-neoplastic enlargement representing a reaction to chronic local irritations or injuries. The purpose of this report is to describe the management of an asymptomatic fibrotic lesion located in the tongue, in a preschooler boy. A 7-year-6-month old boy attended our clinic for the evaluation of an exophytic pedunculated tumor-like round mass located in the dorsal surface of the tongue. Based on the initial examination and the natural history of the lesion, the presumptive clinical diagnosis determined an irritation FFH. The lesion was surgically excised with a diode laser device, and the postoperative period evolution occurred without any complication. The appropriate treatment of FFH in children initially consists of the removal of local irritant factors. Excellent oral hygiene maintenance and close follow-up care are strongly suggested. Surgical excision is the most frequent modality for persistent lesions. Early diagnosis and proper management of FFH can reduce the risk of future recurrences or complications.

Resumen: La hiperplasia fibrosa focal (HFF) es un agrandamiento no neoplásico localizado en la mucosa oral que representa una reacción a irritaciones o lesiones locales crónicas. El propósito de este informe es describir el tratamiento de una lesión fibrótica asintomática ubicada en la lengua, en un niño en edad preescolar. Un niño de 7 años y 6 meses de edad asistió a nuestra clínica para la evaluación de una masa redonda exofítica y pedunculada con forma de tumor ubicada en la superficie dorsal de la lengua. Basado en el examen inicial y la historia natural de la lesión, el diagnóstico clínico presuntivo determinó una irritación HFF. La lesión se extirpó quirúrgicamente con un láser de diodo, y la evolución en el período postoperatorio se produjo sin ninguna complicación. El tratamiento apropiado de HFF en niños inicialmente consiste en la eliminación de factores irritantes locales. Se recomienda un excelente mantenimiento de la higiene bucal y una estrecha atención de seguimiento. La escisión quirúrgica es la modalidad más frecuente para lesiones persistentes. El diagnóstico temprano y el manejo adecuado de la HFF pueden reducir el riesgo de futuras recurrencias o complicaciones.

Low Serum Tryptophan Levels as an Indicator of Global Cognitive Performance in Nondemented Women over 50 Years of Age.

Aging is a physiological decline process. The number of older adults is growing around the world; therefore, the incidence of cognitive impairment, dementia, and other diseases related to aging increases. The main cellular factors that converge in the aging process are mitochondrial dysfunction, antioxidant impairment, inflammation, and immune response decline, among others. In this context, these cellular changes have an influence on the kynurenine pathway (KP), the main route of tryptophan (Trp) catabolism. KP metabolites have been involved in the aging process and neurodegenerative diseases. Although there are changes in the metabolite levels with age, at this time, there is no study that has evaluated cognitive decline as a consequence of Trp catabolism fluctuation in aging. The aim of this study was to evaluate the relation between the changes in Trp catabolism and cognitive impairment associated with age through KP metabolites level alterations in women over 50 years of age. Seventy-seven nondemented women over 50 years old were examined with a standardized cognitive screening evaluation in Spanish language (Neuropsi), Beck anxiety inventory (BAI), and the geriatric depression scale (GDS). Also, serum levels of Trp, kynurenine (Kyn), kynurenic acid (KYNA), and 3-hydroykynurenine (3-HK) and the glutathione ratio (GSH/GSSG) were measured. Results showed a negative correlation between age and Trp levels and a positive correlation between age and KYNA/Trp and 3-HK/Trp ratios. The level of cognitive impairment showed a significant positive association with age and with kynurenine pathway activation and a significant negative correlation with Trp levels. The GSH/GSSG ratio correlated positively with Trp levels and negatively with Kyn/Trp and 3-HK/Trp ratios. The depression score correlated negatively with Trp and positively with the 3-HK/Trp ratio. We concluded that KP activation increases with age and it is strongly associated with the level of cognition performance in nondemented women over 50 years of age.

Actividad antioxidante y marcha fitoquímica de los capítulos de Tagetes filifolia Lag. "pacha anís" / Antioxidant activity and phytochemical screening of capitula of Tagetes filifolia Lag. or "pacha anís"

Objetivo: Estudiar la actividad antioxidante y marcha fitoquímica de los capítulos de Tagetes filifolia Lag. "pacha anís".Materiales y métodos: Estudio de tipo experimental en el cual se empleó 5 kg de los capítulos de la planta medicinal Tagetes filifolia lag., provenientes de Junín. Se usó el método de cribado fitoquímico de Olga Lock para la marcha fitoquímica y el método DPPH para la determinación de la actividad antioxidante. Se dividió la muestra en 3 grupos: etéreo, alcohol etílico y agua destilada a concentraciones de 100, 50 y 5 µg/ml.Resultados: Se encontró fenoles en cantidades abundantes tanto en el extracto en agua destilada como en el extracto en alcohol etílico, además este último tuvo cantidades moderadas de quinonas. Por otro lado, el extracto en alcohol etílico fue el que presentó el mayor porcentaje de captación de radicales libres (91.26%) a una concentración de 100 µg/ml, similares resultados se encontró con el extracto etéreo (88.94%) y el extracto en agua destilada (75.58%).Conclusiones: Los principales componentes químicos fueron fenoles y quinonas. El mayor efecto antioxidante se obtuvo del extracto etanólico de la planta Tagetes filifolia a una concentración de 100 µg/ml.

Genomewide Association Study of Tacrolimus Concentrations in African American Kidney Transplant Recipients Identifies Multiple CYP3A5 Alleles.

We previously reported that tacrolimus (TAC) trough blood concentrations for African American (AA) kidney allograft recipients were lower than those observed in white patients. Subtherapeutic TAC troughs may be associated with acute rejection (AR) and AR-associated allograft failure. This variation in TAC troughs is due, in part, to differences in the frequency of the cytochrome P450 CYP3A5*3 allele (rs776746, expresses nonfunctional enzyme) between white and AA recipients; however, even after accounting for this variant, variability in AA-associated troughs is significant. We conducted a genomewide association study of TAC troughs in AA kidney allograft recipients to search for additional genetic variation. We identified two additional CYP3A5 variants in AA recipients independently associated with TAC troughs: CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343). All three variants and clinical factors account for 53.9% of the observed variance in troughs, with 19.8% of the variance coming from demographic and clinical factors including recipient age, glomerular filtration rate, anticytomegalovirus drug use, simultaneous pancreas-kidney transplant and antibody induction. There was no evidence of common genetic variants in AA recipients significantly influencing TAC troughs aside from the CYP3A gene. These results reveal that additional and possibly rare functional variants exist that account for the additional variation.

Mantenedor telescópico anterior en pérdida dental prematura en dentición decidua: caso clíncio / Anterior telescopic maintainer in premature loss of teeth in deciduous dentition: case report

Los dientes deciduos son los responsables de conservar el espacio para alinear los dientes permanentes. Sin embargo, aunque en el sector anterior no haya perdida de espacio, si un paciente presenta una perdida prematura de un incisivo superior deciduo y las piezas definitivas presentan una escasa calcificación de su raíz, es conveniente la mantención del espacio, de lo contrario realizar el control. Si sólo se ha perdido un incisivo, se puede indicar el uso de un mantenedor telescópico. Se presenta el caso de un niño de 5 años de edad, que acudió al Servicio de Operatoria Dental del Instituto Nacional de Salud del Niño (INSN), par fractura de corona de incisivo superior anteriormente tratada. El tratamiento consistió en la confección de un mantenedor telescópico anterior para suplir la carencia de este...

The deciduos teeth are responsible for preserving the space to align the permanent teeth. However, while in the anterior region is no loss of space, if a patient has a premature loss of a maxillary incisor deciduos and permanent teeth have poor root calcification, is appropriate space maintenance, otherwise make a control. If only it is lost one incisor, may be indicate the use of a telescopic maintainer. We present a case of a 5 year old boy, who attended the Operative Dental Service of the National Institute of Child Health, because he had a crown fracture previously treated in maxillary incisor. The treatment consisted in making an anterior telescopic maintainer to supply this deficiency...

Uréter retrocavo no obstructivo junto con megauréter terminal. Aporte de un caso / Retrocaval non-obstructive ureter and terminal megaureter. Case report

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HGF/c-Met signaling promotes liver progenitor cell migration and invasion by an epithelial-mesenchymal transition-independent, phosphatidyl inositol-3 kinase-dependent pathway in an in vitro model.

Oval cells constitute an interesting hepatic cell population. They contribute to sustain liver regeneration during chronic liver damage, but in doing this they can be target of malignant conversion and become tumor-initiating cells and drive hepatocarcinogenesis. The molecular mechanisms beneath either their pro-regenerative or pro-tumorigenic potential are still poorly understood. In this study, we have investigated the role of the HGF/c-Met pathway in regulation of oval cell migratory and invasive properties. Our results show that HGF induces c-Met-dependent oval cell migration both in normal culture conditions and after in vitro wounding. HGF-triggered migration involves F-actin cytoskeleton reorganization, which is also evidenced by activation of Rac1. Furthermore, HGF causes ZO-1 translocation from cell-cell contact sites to cytoplasm and its concomitant activation by phosphorylation. However, no loss of expression of cell-cell adhesion proteins, including E-cadherin, ZO-1 and Occludin-1, is observed. Additionally, migration does not lead to cell dispersal but to a characteristic organized pattern in rows, in turn associated with Golgi compaction, providing strong evidence of a morphogenic collective migration. Besides migration, HGF increases oval cell invasion through extracellular matrix, a process that requires PI3K activation and is at least partly mediated by expression and activation of metalloproteases. Altogether, our findings provide novel insights into the cellular and molecular mechanisms mediating the essential role of HGF/c-Met signaling during oval cell-mediated mouse liver regeneration.

Neotropical Bats from Costa Rica harbour Diverse Coronaviruses.

Bats are hosts of diverse coronaviruses (CoVs) known to potentially cross the host-species barrier. For analysing coronavirus diversity in a bat species-rich country, a total of 421 anal swabs/faecal samples from Costa Rican bats were screened for CoV RNA-dependent RNA polymerase (RdRp) gene sequences by a pancoronavirus PCR. Six families, 24 genera and 41 species of bats were analysed. The detection rate for CoV was 1%. Individuals (n = 4) from four different species of frugivorous (Artibeus jamaicensis, Carollia perspicillata and Carollia castanea) and nectivorous (Glossophaga soricina) bats were positive for coronavirus-derived nucleic acids. Analysis of 440 nt. RdRp sequences allocated all Costa Rican bat CoVs to the α-CoV group. Several CoVs sequences clustered near previously described CoVs from the same species of bat, but were phylogenetically distant from the human CoV sequences identified to date, suggesting no recent spillover events. The Glossophaga soricina CoV sequence is sufficiently dissimilar (26% homology to the closest known bat CoVs) to represent a unique coronavirus not clustering near other CoVs found in the same bat species so far, implying an even higher CoV diversity than previously suspected.

Myosin isoform expression in the prehensile tails of didelphid marsupials: functional differences between arboreal and terrestrial opossums.

Prehensile tails are defined as having the ability to grasp objects and are commonly used as a fifth appendage during arboreal locomotion. Despite the independent evolution of tail prehensility in numerous mammalian genera, data relating muscle structure, physiology, and function of prehensile tails are largely incomplete. Didelphid marsupials make an excellent model to relate myosin heavy chain (MHC) isoform fiber type with structure/function of caudal muscles, as all opossums have a prehensile tail and tail use varies between arboreal and terrestrial forms. Expanding on our previous work in the Virginia opossum, this study tests the hypothesis that arboreal and terrestrial opossums differentially express faster versus slower MHC isoforms, respectively. MHC isoform expression and percent fiber type distribution were determined in the flexor caudae longus (FCL) muscle of Caluromys derbianus (arboreal) and Monodelphis domestica (terrestrial), using a combination of gel electrophoresis and immunohistochemistry analyses. C. derbianus expresses three MHC isoforms (1, 2A, 2X) that are distributed (mean percentage) as 8.2% MHC-1, 2.6% 1/2A, and 89.2% 2A/X hybrid fibers. M. domestica also expresses MHC-1, 2A, and 2X, in addition to the 2B isoform, distributed as 17.0% MHC-1, 1.3% 1/2A, 9.0% 2A, 75.2% 2A/X, and 0.3% 2X/B hybrid fibers. The distribution of similar isoform fiber types differed significantly between species (P < 0.001). Although not statistically significant, C. derbianus was observed to have larger cross-sectional area (CSA) for each corresponding fiber type along with a greater amount of extra-cellular matrix. An overall faster fiber type composition (and larger fibers) in the tail of an arboreal specialist supports our hypothesis, and correlates with higher muscle force required for tail hanging and arboreal maneuvering on terminal substrates. Conversely, a broader distribution of highly oxidative fibers in the caudal musculature is well suited for tail nest building/remodeling behaviors of terrestrial opossums.

Efecto antinociceptivo del extracto etanólico de las hojas de Maytenus macrocarpa (Ruiz & Pav.) Briq. ôchuchuhuasiõ mediante la prueba de contorsiones abdominales en ratones / Antinociceptive effect of the ethanol extract of the leaves of Maytenus macrocarpa (Ruiz & Pav.) Briq. ôchuchuhuasiõ Through the Writhing Test in mice

Objetivo: Determinar el efecto y actividad antinociceptiva de las hojas de Maytenus macrocarpa (Ruiz & Pav) Briq. ôchuchuhuasiõ mediante la prueba de contorsiones abdominales en roedor. Material y Métodos: Se utilizaron 40 ratones albinos machos, con pesos medios de 25g, se empleó la prueba de contorsiones abdominales para determinar la actividad antinociceptiva. El grupo Control, no recibió ninguna sustancia. Se administró extracto etanólico de las hojas de M. macrocarpa (Ruiz & Pav.) Briq. 2000 mg/kg, Tramadol 10 mg/kg y Diclofenaco sódico 10 mg/kg. Las sustancias fueron administradas por la vía oral una hora antes de la inducción de dolor. Para la validación estadística se usó la prueba de Shapiro-Wilk, ANOVA de una cola, Tukey, y Newman-Keuls. Resultados: El número de contorsiones abdominales fue 41+/- 3.04, 27+/- 3.55, 9 +/- 4.14, y 18 +/- 2.65 respectivamente. El porcentaje de inhibición de la conducta nociceptiva fue: 0%, 34%, 77%, y 55%. La prueba de ANOVA de una vía, demostró diferencias estadísticas (p<0.05, IC 95%), y la prueba de Tukey y Newman-Keuls, demostraron diferencias significativas entre los grupos, frente al control. Conclusiones: Se comprobó el efecto antinociceptivo de las hojas de Maytenus macrocarpa (Ruiz & Pav.) Briq. ôchuchuhuasiõ, en dosis de 2000 mg/kg.

Objetives: To determine the effect and antinociceptive activity of the leaves of Maytenus macrocarpa (Ruiz & Pav ) Briq . ôChuchuhuasi ô by the writhing test in rodents. Material and Methods: 40 male albino mice were used, with average weights of 25g, the writhing test was used to determine the antinociceptive activity. The experimental groups were: Control; received no substance, ethanol extract of the leaves of M. macrocarpa Briq (Ruiz & Pav.) 2000 mg/kg, Tramadol 10 mg/kg and 10mg Sodium Diclofenac /kg. The substances were administered orally one hour before the induction of pain. For statistical validation the Shapiro -Wilk test, one-tailed ANOVA, Tukey, and Newman -Keuls was used. Results: Writhing number was 41 +/- 3.04, 27 +/- 3.55, 9 +/- 4.14, and 18 +/- 2.65 respectively. The inhibition percentage of the nociceptive behavior was: 0%, 34%, 77% and 55%. The test of one-way ANOVA showed statistical differences (p < 0.05, 95% CI), and the Tukey and Newman-Keuls test showed significant differences between groups versus control. Conclusions: Antinociceptive effect of the leaves of Maytenus macrocarpa (Ruiz & Pav.) Briq ôChuchuhuasiô was found at doses of 2000 mg/kg.

Testosterone regulates bone response to inflammation.

This study evaluated the alveolar bone response to testosterone and the impact of Resolvin D2 (RvD2) on testosterone-induced osteoblast function. For the in vivo characterization, 60 male adult rats were used. Treatments established sub-physiologic (L), normal (N), or supra-physiologic (H) concentrations of testosterone. Forty rats were subjected to orchiectomy; 20 rats received periodical testosterone injections while 20 rats received testicular sham-operation. Four weeks after the surgeries, 10 rats in each group received a subgingival ligature around the lower first molars to induce experimental periodontal inflammation and bone loss. In parallel, osteoblasts were differentiated from neonatal mice calvariae and treated with various doses of testosterone for 48 h. Cell lysates and conditioned media were used for the determination of alkaline phosphatase, osteocalcin, RANKL, and osteoprotegerin. Micro-computed tomography linear analysis demonstrated that bone loss was significantly increased for both L and H groups compared to animals with normal levels of testosterone. Gingival IL-1ß expression was increased in the L group (p<0.05). Ten nM testosterone significantly decreased osteocalcin, RANKL, and OPG levels in osteoblasts; 100 nM significantly increased the RANKL:OPG ratio. RvD2 partially reversed the impact of 10 nM testosterone on osteocalcin, RANKL, and OPG. These findings suggest that both L and H testosterone levels increase inflammatory bone loss in male rats. While low testosterone predominantly increases the inflammatory response, high testosterone promotes a higher osteoblast-derived RANKL:OPG ratio. The proresolving mediator RvD2 ameliorates testosterone-derived downregulation of osteocalcin, RANKL, and OPG in primary murine osteoblasts suggesting a direct role of inflammation in osteoblast function.

Interacciones farmacológicas de las hojas de Maytenus macrocarpa o ôchuchuhuasiõ con fármacos inhibitorios y estimuladores de la motilidad intestinal / Pharmacological interactions from the leaves of Maytenus macrocarpa \"chuchuhuasi\" with inhibitory and stimulating bowel motility drugs

Objetivo: Determinar las posibles interacciones farmacológicas de las hojas de Maytenus macrocarpa, con fármacos estimulantes e inhibitorios de la motilidad intestinal. Métodos: Se utilizaron 110 ratones albinos machos, con pesos medios de 25 g, se empleó el método de Arbos y col, se administró carbón activado al 5

vía oral, dosis de 0.1ml/10g, como marcador intestinal. Los grupos experimentales fueron: control (agua destilada 0,3ml), hojas de chuchuhuasi 1 (500mg/kg), hojas de chuchuhuasi 2 (3000mg/kg), atropina (1,5mg/kg), loperamida (5mg/kg), neostigmina (0,4mg/kg), metoclopramida (10mg/kg), hojas de chuchuhuasi 1 con metoclopramida, hojas de chuchuhuasi 1 con loperamida, hojas de chuchuhuasi 2 con metoclopramida y hojas de chuchuhuasi 2 con loperamida. Para la validación estadística se usó la prueba de Wilconxon, ANOVA y Tukey. Resultados: El porcentaje de recorrido intestinal de carbón activado fue de 27,04, 34,15, 31,66, 25,57, 15,89, 43,30, 33,99, 32,40, 27,90, 49,34 y 25,36 respectivamente, el test de ANOVA de dos colas revelo una p=0,0007. El test de Tukey indico p<0.05 versus el control para neostigmina, loperamida y la interacción chuchuhuasi 3000 mg/kg con metoclopramida, en este último, el test de Wilconxon presento un valor p<0,05. Conclusiones: Se observó interacciones farmacológicas de antagonismo sobre la motilidad intestinal, entre chuchuhuasi y Loperamida y sinergismo entre chuchuhuasi y metoclopramida.

Objectives: To determine the possible pharmacological interactions from the leaves of Maytenus macrocarpa with inhibitory and stimulating bowel motility drugs. Methods: We used 110 male albino mice with average weight of 25g, Arbos and others method was applied. Activated charcoal was administered at 5

at dose of 0.1ml/10g, as an intestinal marker. The experimental groups included 0.1 ml/10 g of distilled water, leave extract of M. macrocarpa 1 (500mg/kg), leave extract of M. macrocarpa 2 (3000 mg/kg), 1,5mg/kg of atropine, 5mg/kg of loperamide, 0.4mg/kg of neostigmine, 10mg/kg of metoclopramide, leave extract of M. macrocarpa 1 with metoclopramide, leave extract of M. macrocarpa 1 with loperamide, leave extract of M. macrocarpa 2 with metoclopramide and leave extract of M. macrocarpa 2 with loperamide. The statistical validation was based on Wilconxon, ANOVA and Tukey test. Results: The intestinal charcoal run percentage was 27.04, 34.15, 31.66, 25.57, 15.89, 43.30, 33.99, 32.40, 27.9, 49.34 and 25.36 respectively. The ANOVA test result in p= 0.0007. The Tukey test indicated p <0.05 versus the control group for neostigmine, loperamide, and the interaction between leave extract of M. macrocarpa 2 with metoclopramide, for the last the Wilcoxon test result in p <0.05. Conclusions: It was observed antagonism drug interactions on gastrointestinal motility between leaves extract of M. macrocarpa with loperamide and synergism interactions with metoclopramide.

Efficacy of malic acid against Listeria monocytogenes attached to poultry skin during refrigerated storage.

This work evaluated the effect of malic acid washing on the growth of Listeria monocytogenes on poultry legs stored at 4°C for 8 d. Fresh inoculated chicken legs were dipped into a 1 or 2% malic acid solution (vol/vol) for 5 min or distilled water (control). Surface pH values, sensorial characteristics (odor, color, texture, and overall appearance) and L. monocytogenes, mesophile, psychrotroph, and Enterobacteriaceae counts were evaluated after treatment (d 0) and after 1, 3, 6, and 8 d of storage at 4°C. Legs washed with 2% malic acid showed a significant (P < 0.05) inhibitory effect on L. monocytogenes compared with control legs, with a decrease of about 1.66 log units after treatment. Sensory quality was not adversely affected by malic acid. Treatments with malic acid reduced bacterial growth and preserved reasonable sensorial quality after storage at 4°C for 6 d. This study demonstrates that, although malic acid did reduce populations of L. monocytogenes on poultry, it did not completely inactivate the pathogen. The application of malic acid may be used as an additional hurdle contributing to extend the shelf life of raw poultry.

EGFR is dispensable for c-Met-mediated proliferation and survival activities in mouse adult liver oval cells.

Liver progenitor cells rise as potential critical players in hepatic regeneration but also carcinogenesis. It is therefore mandatory to define the signals controlling their activation and expansion. Recently, by using a novel in vitro model of oval cell lines expressing a mutant tyrosine kinase-inactive form of c-Met we demonstrated that autocrine c-Met signalling plays an essential role in promoting oval cell survival. Here, we investigated the significance of the epidermal growth factor receptor (EGFR) signalling in oval cell proliferation and survival, as well as a potential functional crosstalk between the c-Met and the EGFR pathways. We found an autocrine activation of the EGFR-triggered pathway in Met(flx/flx) and Met(-/-) oval cells as judged by constitutive expression of the EGFR ligands, transforming growth factor-alpha (TGF-α) and heparin-binding EGF like growth factor (HB-EGF), and activation of EGFR. On the other hand, treatment with AG1478, a specific inhibitor of EGFR, effectively blocked endogenous and EGF-induced proliferation, while increased serum withdrawal and transforming growth factor-beta (TGF-ß)-induced apoptosis. These results suggest that constitutively activated EGFR might promote oval cell proliferation and survival. We found that hepatocyte growth factor (HGF) does not transactivate EGFR nor EGF transactivates c-Met. Furthermore, treatment with AG1478 or EGFR gene silencing did not interfere with HGF-mediated activation of target signals, such as protein kinase B (AKT/PKB), and extracellular signal-regulated kinases 1/2 (ERK 1/2), nor did it have any effect on HGF-induced proliferative and antiapoptotic activities in Met(flx/flx) cells, showing that HGF does not require EGFR activation to mediate such responses. EGF induced proliferation and survival equally in Met(flx/flx) and Met(-/-) oval cells, proving that EGFR signalling does not depend on c-Met tyrosine kinase activity. Together, our results provide strong evidence that in normal, untransformed oval cells, c-Met and EGFR represent critical molecular players to control proliferation and survival that function independent of one another.

Association of UV radiation with multiple sclerosis prevalence and sex ratio in France.

BACKGROUND: French farmers and their families constitute an informative population to study multiple sclerosis (MS) prevalence and related epidemiology. We carried out an ecological study to evaluate the association of MS prevalence and ultraviolet (UV) radiation, a candidate climatologic risk factor. METHODS: Mean annual and winter (December-March) UVB irradiation values were systematically compared to MS prevalence rates in corresponding regions of France. UVB data were obtained from the solar radiation database (SoDa) service and prevalence rates from previously published data on 2,667 MS cases registered with the national farmer health insurance system, Mutualité Sociale Agricole (MSA). Pearson correlation was used to examine the relationship of annual and winter UVB values with MS prevalence. Male and female prevalence were also analyzed separately. Linear regression was used to test for interaction of annual and winter UVB with sex in predicting MS prevalence. RESULTS: There was a strong association between MS prevalence and annual mean UVB irradiation (r = -0.80, p < 0.001) and average winter UVB (r = -0.87, p < 0.001). Both female (r = -0.76, p < 0.001) and male (r = -0.46, p = 0.032) prevalence rates were correlated with annual UVB. Regression modeling showed that the effect of UVB on prevalence rates differed by sex; the interaction effect was significant for both annual UVB (p = 0.003) and winter UVB (p = 0.002). CONCLUSIONS: The findings suggest that regional UVB radiation is predictive of corresponding MS prevalence rates and supports the hypothesis that sunlight exposure influences MS risk. The evidence also supports a potential role for gender-specific effects of UVB exposure.

MHC transmission: insights into gender bias in MS susceptibility.

OBJECTIVE: Major histocompatibility complex (MHC) genes dominate genetic susceptibility factors in multiple sclerosis (MS). Given the general consensus that incidence and prevalence of MS has been rising and specifically in women, we evaluated MHC-gender interactions. METHODS: In a large family-based cohort consisting of 7,093 individuals (2,127 affected individuals) from 1,055 MS families, we examined MHC transmission by family structure and gender stratified by genetic distance of affected relatives from the MS proband. RESULTS: We found that affected individuals with HLA-DRB1*15-positive genotypes have higher female-to-male ratios as compared with affected individuals with HLA-DRB1*15-negative genotypes (χ(2) = 9.97, p = 0.0015) with the exception of multiplex families with 3 or more affected across 2 generations. Transmission disequilibrium test results show that HLA-DRB1*15 transmission was more distorted in collateral families vs nuclear families (χ(2) = 8.030, p = 0.0046), exclusively in affected female-female pairs (χ(2) = 7.81, p = 0.0051), but not in mixed gender pairs (χ(2) = 1.58, p = 0.21) or matched male pairs (Fisher p = 0.21). CONCLUSIONS: These observations implicate the MHC as the site of interactions and modifications mediating the female-to-male gender ratio in MS and its progressive increase. They further suggest this occurs via gene-environment interactions and epigenetic modifications in this region. The difference between collateral and nuclear families provides some insight into the inheritance, decay, and gender specificity of putative epigenetic marks.

A role for coding functional variants in HNF4A in type 2 diabetes susceptibility.

AIMS/HYPOTHESIS: Rare mutations in the gene HNF4A, encoding the transcription factor hepatocyte nuclear factor 4α (HNF-4A), account for ~5% of cases of MODY and more frequent variants in this gene may be involved in multifactorial forms of diabetes. Two low-frequency, non-synonymous variants in HNF4A (V255M, minor allele frequency [MAF] ~0.1%; T130I, MAF ~3.0%)-known to influence downstream HNF-4A target gene expression-are of interest, but previous type 2 diabetes association reports were inconclusive. We aimed to evaluate the contribution of these variants to type 2 diabetes susceptibility through large-scale association analysis. METHODS: We genotyped both variants in at least 5,745 cases and 14,756 population controls from the UK and Denmark. We also undertook an expanded association analysis that included previously reported and novel genotype data obtained in Danish, Finnish, Canadian and Swedish samples. A meta-analysis incorporating all published association studies of the T130I variant was subsequently carried out in a maximum sample size of 14,279 cases and 26,835 controls. RESULTS: We found no association between V255M and type 2 diabetes in either the initial (p = 0.28) or the expanded analysis (p = 0.44). However, T130I demonstrated a modest association with type 2 diabetes in the UK and Danish samples (additive per allele OR 1.17 [95% CI 1.08-1.28]; p = 1.5 × 10⁻4), which was strengthened in the meta-analysis (OR 1.20 [95% CI 1.10-1.30]; p = 2.1 × 10⁻5). CONCLUSIONS/INTERPRETATION: Our data are consistent with T130I as a low-frequency variant influencing type 2 diabetes risk, but are not conclusive when judged against stringent standards for genome-wide significance. This study exemplifies the difficulties encountered in association testing of low-frequency variants.

Global microRNA expression profiles in insulin target tissues in a spontaneous rat model of type 2 diabetes.

AIMS/HYPOTHESIS: MicroRNAs regulate a broad range of biological mechanisms. To investigate the relationship between microRNA expression and type 2 diabetes, we compared global microRNA expression in insulin target tissues from three inbred rat strains that differ in diabetes susceptibility. METHODS: Using microarrays, we measured the expression of 283 microRNAs in adipose, liver and muscle tissue from hyperglycaemic (Goto-Kakizaki), intermediate glycaemic (Wistar Kyoto) and normoglycaemic (Brown Norway) rats (n = 5 for each strain). Expression was compared across strains and validated using quantitative RT-PCR. Furthermore, microRNA expression variation in adipose tissue was investigated in 3T3-L1 adipocytes exposed to hyperglycaemic conditions. RESULTS: We found 29 significantly differentiated microRNAs (p(adjusted) < 0.05): nine in adipose tissue, 18 in liver and two in muscle. Of these, five microRNAs had expression patterns that correlated with the strain-specific glycaemic phenotype. MiR-222 (p(adjusted) = 0.0005) and miR-27a (p(adjusted) = 0.006) were upregulated in adipose tissue; miR-195 (p(adjusted) = 0.006) and miR-103 (p(adjusted) = 0.04) were upregulated in liver; and miR-10b (p(adjusted) = 0.004) was downregulated in muscle. Exposure of 3T3-L1 adipocytes to increased glucose concentration upregulated the expression of miR-222 (p = 0.008), miR-27a (p = 0.02) and the previously reported miR-29a (p = 0.02). Predicted target genes of these differentially expressed microRNAs are involved in pathways relevant to type 2 diabetes. CONCLUSION: The expression patterns of miR-222, miR-27a, miR-195, miR-103 and miR-10b varied with hyperglycaemia, suggesting a role for these microRNAs in the pathophysiology of type 2 diabetes, as modelled by the Gyoto-Kakizaki rat. We observed similar patterns of expression of miR-222, miR-27a and miR-29a in adipocytes as a response to increased glucose levels, which supports our hypothesis that altered expression of microRNAs accompanies primary events related to the pathogenesis of type 2 diabetes.

Performance of a flameless combustion furnace using biogas and natural gas.

Flameless combustion technology has proved to be flexible regarding the utilization of conventional fuels. This flexibility is associated with the main characteristic of the combustion regime, which is the mixing of the reactants above the autoignition temperature of the fuel. Flameless combustion advantages when using conventional fuels are a proven fact. However, it is necessary to assess thermal equipments performance when utilizing bio-fuels, which usually are obtained from biomass gasification and the excreta of animals in bio-digesters. The effect of using biogas on the performance of an experimental furnace equipped with a self-regenerative Flameless burner is reported in this paper. All the results were compared to the performance of the system fueled with natural gas. Results showed that temperature field and uniformity are similar for both fuels; although biogas temperatures were slightly lower due to the larger amount of inert gases (CO(2)) in its composition that cool down the reactions. Species patterns and pollutant emissions showed similar trends and values for both fuels, and the energy balance for biogas showed a minor reduction of the efficiency of the furnace; this confirms that Flameless combustion is highly flexible to burn conventional and diluted fuels. Important modifications on the burner were not necessary to run the system using biogas. Additionally, in order to highlight the advantages of the Flameless combustion regime, some comparisons of the burner performance working in Flameless mode and working in conventional mode are presented.