Gene-Age Interactions in Blood Pressure Regulation: A Large-Scale Investigation with the CHARGE, Global BPgen, and ICBP Consortia.

Although age-dependent effects on blood pressure (BP) have been reported, they have not been systematically investigated in large-scale genome-wide association studies (GWASs). We leveraged the infrastructure of three well-established consortia (CHARGE, GBPgen, and ICBP) and a nonstandard approach (age stratification and metaregression) to conduct a genome-wide search of common variants with age-dependent effects on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure. In a two-staged design using 99,241 individuals of European ancestry, we identified 20 genome-wide significant (p ≤ 5 × 10(-8)) loci by using joint tests of the SNP main effect and SNP-age interaction. Nine of the significant loci demonstrated nominal evidence of age-dependent effects on BP by tests of the interactions alone. Index SNPs in the EHBP1L1 (DBP and MAP), CASZ1 (SBP and MAP), and GOSR2 (PP) loci exhibited the largest age interactions, with opposite directions of effect in the young versus the old. The changes in the genetic effects over time were small but nonnegligible (up to 1.58 mm Hg over 60 years). The EHBP1L1 locus was discovered through gene-age interactions only in whites but had DBP main effects replicated (p = 8.3 × 10(-4)) in 8,682 Asians from Singapore, indicating potential interethnic heterogeneity. A secondary analysis revealed 22 loci with evidence of age-specific effects (e.g., only in 20 to 29-year-olds). Age can be used to select samples with larger genetic effect sizes and more homogenous phenotypes, which may increase statistical power. Age-dependent effects identified through novel statistical approaches can provide insight into the biology and temporal regulation underlying BP associations.

Ultrasound assessment of ocular vascular effects of repeated intravitreal injections of ranibizumab for wet age-related macular degeneration.

PURPOSE: Determine the effect of repeated intravitreal injections of ranibizumab (0.5 mg; 0.05 ml) on retrobulbar blood flow velocities (BFVs) using ultrasound imaging quantification in twenty patients with exudative age-related macular degeneration treated for 6 months. METHODS: Visual acuity (ETDRS), central macular thickness (OCT), peak-systolic, end-diastolic and mean-BFVs in central retinal (CRA), temporal posterior ciliary (TPCA) and ophthalmic (OA) arteries were measured before, 2 days, 3 weeks and 6 months after the first injection. Patients were examined monthly and received 1-5 additional injections depending on ophthalmologic examination results. RESULTS: Six months after the first injection, a significant increase in visual acuity 50.9 ± 25.9 versus 44.4 ± 21.7 (p < 0.01) and decrease in mean central macular thickness 267 ± 74 versus 377 ± 115 μm (p < 0.001) were observed compared to baseline. Although mean-BFVs decreased by 16%±3% in CRA and 20%±5% in TPCA (p < 0.001) 2 days after the first injection, no significant change was seen thereafter. Mean-BFVs in OA decreased by 19%±5% at week 3 (p < 0.001). However, the smallest number of injections (two injections) was associated with the longest time interval between the last injection and month 6 (20 weeks) and with the best return to baseline levels for mean-BFVs in CRA, suggesting that ranibizumab had reversible effects on native retinal vascular supply after its discontinuation. Moreover, a significant correlation between the number of injections and percentage of changes in mean-BFVs in CRA was observed at month 6 (R = 0.74, p < 0.001) unlike TPCA or OA. CONCLUSION: Ranibizumab could impair the native choroidal and retinal vascular networks, but its effect seems reversible after its discontinuation.

Mutilations génitales féminines: l'adolescente en quête de réponses [Female genital mutilation: need for answers at the age of adolescence]

En Suisse, le nombre de filles et de femmes migrantes excisées au cours de leur enfance dans leur pays d'origine ou menacées de mutilations génitales rituelles est estimé à 6-7000. Les professionnels de la santé en tant qu'interlocuteurs privilégiés doivent donc être en mesure de répondre aux questions y relatives, non seulement durant l'adolescence, mais aussi dans toutes les phases de la vie. L'absence d'information ou de transmission par des aînées aussi bien avant l'excision qu'au moment de la maturité sexuelle en fait souvent un événement biographique traumatisant. Arrivées en Suisse, le décalage entre les attentes socioculturelles et familiales et le vécu individuel, influencé par le pays d'accueil, peut s'avérer particulièrement difficile à vivre pour les jeunes filles concernées. In Switzerland, the estimated number of survivors after traditional female genital mutilation in the country of origin or girls and adult women at risk is 6-7000. Health professionals must be able to respond adequately to their questions not only during adolescence but through out the different periods of life. The lack of information or transmission by the seniors as well before the excision as at the time of sexual maturity contributes in a large measure to the frequent biographic trauma. It can be very difficult for the girls to deal with the gap between socio cultural and family expectations and their individual life experience in Switzerland.

Prospective study evaluating the predictability of need for retreatment with intravitreal ranibizumab for age-related macular degeneration.

PURPOSE: To investigate the rhythm and predictability of the need for retreatment with intravitreal injections of ranibizumab for neovascular age-related macular degeneration (nAMD). METHODS: This prospective study enrolled 39 patients with treatment-naïve nAMD. After three loading doses of intravitreal ranibizumab, patients underwent an intensified follow-up for 12 months (initially weekly, then with stepwise increases to every 2 weeks and to monthly after each injection). Patients were retreated on an as-needed basis if any fluid or increased central retinal thickness (CRT) (>50 μm) was found on spectral domain optical coherence tomography (OCT). Statistical analysis included patients who received at least two retreatments (five injections). RESULTS: A mean of 7.5 injections (range 0-12) were given between months 3 and 15. The mean visual acuity increased by 13.1 and 12.6 ETDRS letters at months 12 and 15 respectively. Two or more injection-retreatment intervals were found in 31 patients. The variability of their intra-individual intervals up to 14 weeks was small (SD 0-2.13 weeks), revealing a high regularity of the retreatment rhythm. The SD was correlated with the mean interval duration (r = 0.89, p < 0.001). The first interval was a good predictor of the following intervals (regression coefficient =0.81). One retreatment criterion was stable in 97 % of patients (cysts or subretinal fluid). CONCLUSION: The results of this study demonstrate a high intra-individual predictability of retreatment need with ranibizumab injections for nAMD. These findings may be helpful for developing individualized treatment plans for maintained suppression of disease activity with a minimum of injections and visits.

Visualitzador de molècules d'ADN per laboratori virtual

RESUM Com a continuació del treball de final de carrera “Desenvolupament d’un laboratori virtual per a les pràctiques de Biologia Molecular” de Jordi Romero, s’ha realitzat una eina complementaria per a la visualització de molècules integrada en el propi laboratori virtual. Es tracta d’una eina per a la visualització gràfica de gens, ORF, marques i seqüències de restricció de molècules reals o fictícies. El fet de poder treballar amb molècules fictícies és la gran avantatge respecte a les solucions com GENBANK que només permet treballar amb molècules pròpies. Treballar amb molècules fictícies fa que sigui una solució ideal per a l’ensenyament, ja que dóna la possibilitat als professors de realitzar exercicis o demostracions amb molècules reals o dissenyades expressament per a l’exercici a demostrar. A més, permet mostrar de forma visual les diferents parts simultàniament o per separat, de manera que ofereix una primera aproximació interpretació dels resultats. Per altra banda, permet marcar gens, crear marques, localitzar seqüències de restricció i generar els ORF de la molècula que nosaltres creem o modificar una ja existent. Per l’implementació, s’ha continuat amb l’idea de separar la part de codi i la part de disseny en les aplicacions Flash. Per fer-ho, s’ha utilitzat la plataforma de codi lliure Ariware ARPv2.02 que proposa un marc de desenvolupament d’aplicacions Flash orientades a objectes amb el codi (classes ActionScript 2.0) separats del movieclip. Per al processament de dades s’ha fet servir Perl per ser altament utilitzat en Bioinformàtica i per velocitat de càlcul. Les dades generades es guarden en una Base de Dades en MYSQL (de lliure distribució), de la que s’extreuen les dades per generar fitxers XML, fent servir tant PHP com la plataforma AMFPHP com a enllaç entre Flash i la resta de parts.

Creació d'una botiga virtual i automatització dels albarans, factures i cobraments

L’augment de la utilització de les noves tecnologies a la nostra societat permet a les empreses arribar al client d’una forma més rapida i facilitant la informació de manera àgil i ordenada. Amb aquest objectiu s’ha creat una botiga virtual que serà la part visible als usuaris i clients de l’empresa PRINTONER S.L , dedicada al sector dels consumibles, especialment els reciclats. Per l’empresa un dels objectius principals és oferir al client la possibilitat de comprar els seus productes de manera còmode a través d’Internet, ja que accedint amb un nom d’usuari i una contrasenya podrà obtenir totes les referències de les que es disposa, podrà tramitar les comandes i controlar-ne l’estat fins el moment de l’entrega. A part de les seccions destinades a usuaris i clients s’ha creat una zona d’administració, on els responsables de l’empresa podran gestionar tots els productes, modificar i visualitzar les comandes. A més aprofitant que aquestes quedaran guardades a una base de dades juntament amb els productes venuts, s’integrarà el sistema de facturació de l’empresa, cosa que fins el moment es feia de manera manual i maldestre. També es programarà una part on els responsables podran insertar reparacions i vendes informàtiques que s’hagin de facturar o per fer-ne un us estadístic en un futur. Tot això ens portarà a implementar un sistema d’usuaris registrats amb diferents permisos i diferents nivells d’accés a l’aplicació, fins a un total de 5. S’ha intentat fer de l’aplicació, un sistema a mida i que compleixi tots els requisits que l’empresa ens ha demanat, amb la previsió que més endavant s’hi pugui implementar un sistema de gestió d’estocs i altres millores per oferir als seus clients un servei inigualable. Per tal de portar a terme tot aquest treball s’ha utilitzat una tecnologia de lliure distribució com és el llenguatge PHP i la base de dades MySQL, aquesta opció a part d’una filosofia es produeix per intentar minimitzar els costos de l’aplicatiu. La finalitat de l’empresa amb aquest projecte és oferir millor imatge i servei, efectivitat i rapidesa en tot el procés de vendes, així com reduir costos de facturació i també de publicitat, ja que es podrà potenciar molt més la pàgina web via internet.

Teclat virtual amb predicció del llenguatge

L'objectiu de la realització d'aquest treball és la creació d'un teclat virtual destinat a ajudar a persones amb mobilitat reduïda, que no poden utilitzar el teclat físic de l'ordinador, a escriure intentant aconseguir una velocitat d'escriptura raonable per a textos de qualsevol mida. Per aconseguir aquesta velocitat d'escriptura raonable s'ha implementat un sistema de predicció del llenguatge que té dos aspectes. D'una banda es prediuen paraules segons la seva freqüència d'ús en un determinat diccionari i, d'altra banda, es prediuen paraules seguint les regles d'escriptura de la gramàtica catalana. Un altre aspecte important era que el programa creat es pogués utilitzar en diferents sistemes operatius ja que només hi havia versions específiques per a cada un d'ells. El programa creat es pot executar en els sistemes operatius Windows XP, Mac OS i Ubuntu Linux. El programa creat pretén ser una base per a posteriors millores i ampliacions en diferents parts del seu conjunt. No obstant això, com a resultat s'ha obtingut un programa que permet escriure raonablement ràpid i permet a l'usuari gestionar diccionaris i els dos tipus de predicció que s'han implementat.

Ranibizumab versus Bevacizumab for Neovascular Age-related Macular Degeneration: Results from the GEFAL Noninferiority Randomized Trial.

OBJECTIVE: To evaluate the relative efficacy and safety profile of bevacizumab versus ranibizumab intravitreal injections for the treatment of neovascular age-related macular degeneration (AMD). DESIGN: Multicenter, prospective, noninferiority, double-masked, randomized clinical trial performed in 38 French ophthalmology centers. The noninferiority limit was 5 letters. PARTICIPANTS: Patients aged ≥50 years were eligible if they presented with subfoveal neovascular AMD, with best-corrected visual acuity (BVCA) in the study eye of between 20/32 and 20/320 measured on the Early Treatment of Diabetic Retinopathy Study chart and a lesion area of less than 12 optic disc areas (DA). METHODS: Patients were randomly assigned to intravitreal administration of bevacizumab (1.25 mg) or ranibizumab (0.50 mg). Hospital pharmacies were responsible for preparing, blinding, and dispensing treatments. Patients were followed for 1 year, with a loading dose of 3 monthly intravitreal injections, followed by an as-needed regimen (1 injection in case of active disease) for the remaining 9 months with monthly follow-up. MAIN OUTCOME MEASURES: Mean change in visual acuity at 1 year. RESULTS: Between June 2009 and November 2011, 501 patients were randomized. In the per protocol analysis, bevacizumab was noninferior to ranibizumab (bevacizumab minus ranibizumab +1.89 letters; 95% confidence interval [CI], -1.16 to +4.93, P < 0.0001). The intention-to-treat analysis was concordant. The mean number of injections was 6.8 in the bevacizumab group and 6.5 in the ranibizumab group (P = 0.39). Both drugs reduced the central subfield macular thickness, with a mean decrease of 95 μm for bevacizumab and 107 μm for ranibizumab (P = 0.27). There were no significant differences in the presence of subretinal or intraretinal fluid at final evaluation, dye leakage on angiogram, or change in choroidal neovascular area. The proportion of patients with serious adverse events was 12.6% in the bevacizumab group and 12.1% in the ranibizumab group (P = 0.88). The proportion of patients with serious systemic or ocular adverse events was similar in both groups. CONCLUSIONS: Bevacizumab was noninferior to ranibizumab for visual acuity at 1 year with similar safety profiles. Ranibizumab tended to have a better anatomic outcome. The results are similar to those of previous head-to-head studies. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Adiposity in children born small for gestational age.

Epidemiological studies indicate that children born small for gestational age (SGA) have an increased risk of metabolic and cardiovascular disorders as adults. This suggests that foetal undernutrition leads to permanent metabolic alterations, which predispose to metabolic abnormalities upon exposure to environmental factors such as low physical activity and/or high-energy intake in later life (thrifty phenotype hypothesis). However, this relationship is not restricted to foetal undernutrition or intrauterine growth retardation, but is also found for children born premature, or for high birth weight children. Furthermore, early post-natal nutrition, and more specifically catch-up growth, appear to modulate cardiovascular risk as well. Intrauterine growth retardation can be induced in animal models by energy/protein restriction, or ligation of uterine arteries. In such models, altered glucose homeostasis, including low beta-cell mass, low insulin secretion and insulin resistance is observed after a few weeks of age. In humans, several studies have confirmed that children born SGA have insulin resistance as adolescents and young adults. Alterations of glucose homeostasis and increased lipid oxidation can indeed be observed already in non-diabetic children born SGA at early pubertal stages. These children also have alterations of stature and changes in body composition (increased fat mass), which may contribute to the pathogenesis of insulin resistance. Permanent metabolic changes induced by foetal/early neonatal nutrition (metabolic inprinting) may involve modulation of gene expression through DNA methylation, or alterations of organ structure. It is also possible that events occurring during foetal/neonatal development lead to long-lasting alterations of the hypothalamo-pituitary-adrenal axis or the hypothalamo-pituitary-insulin-like growth factor-1 axis.

Microvascular burden and Alzheimer-type lesions across the age spectrum.

The occurrence of microvascular and small macrovascular lesions and Alzheimer's disease (AD)-related pathology in the aging human brain is a well-described phenomenon. Although there is a wide consensus about the relationship between macroscopic vascular lesions and incident dementia, the cognitive consequences of the progressive accumulation of these small vascular lesions in the human brain are still a matter of debate. Among the vast group of small vessel-related forms of ischemic brain injuries, the present review discusses the cognitive impact of cortical microinfarcts, subcortical gray matter and deep white matter lacunes, periventricular and diffuse white matter demyelinations, and focal or diffuse gliosis in old age. A special focus will be on the sub-types of microvascular lesions not detected by currently available neuroimaging studies in routine clinical settings. After providing a critical overview of in vivo data on white matter demyelinations and lacunes, we summarize the clinicopathological studies performed by our center in large cohorts of individuals with microvascular lesions and concomitant AD-related pathology across two age ranges (the younger old, 65-85 years old, versus the oldest old, nonagenarians and centenarians). In conjunction with other autopsy datasets, these observations fully support the idea that cortical microinfarcts are the only consistent determinant of cognitive decline across the entire spectrum from pure vascular cases to cases with combined vascular and AD lesion burden.

Mort des voyageurs: risques réels, risques virtuels [True and virtual risks of travellers].

Evidence-based information on travel associated mortality is scarce. Perception, intuition and the availability of interventions such as vaccinations and chemoprophylaxis often guide pre-travel advice. Important risks including accidents and cardiovascular events are not routinely included in pre-travel consultations although they cause more fatalities and costs than infectious diseases. The increased risk of sustaining a road accident in poor economy countries should always be mentioned. The general practitioner is further best placed to discuss possible problems of travellers with chronic diseases before travel.