Overview of risk factors for age-related macular degeneration (AMD)

Age related macular degeneration (AMD) is the leading cause of blindness in individuals older than 65 years of age. It is a multifactorial disorder and identification of risk factors enables individuals to make life style choices that may reduce the risk of disease. This review discusses the role of genetics, sunlight, diet, cardiovascular factors, smoking, and alcohol as possible risk factors for AMD. Genetics plays a more significant role in AMD than previously thought, especially in younger patients, histocompatibility locus antigen (HLA) and complement system genes being the most significant. Whether the risk of AMD is increased by exposure to sunlight, cardiovascular risk factors, and diet is more controversial. Smoking is the risk factor most consistently associated with AMD. Current smokers are exposed to a two to three times higher risk of AMD than non-smokers and the risk increases with intensity of smoking. Moderate alcohol consumption is unlikely to increase the risk of AMD. Optometrists as front-line informers and educators of ocular health play a significant role in increasing public awareness of the risks of AMD. Cessation of smoking, the use of eye protection in high light conditions, dietary changes, and regular use of dietary supplements should all be considered to reduce the lifetime risk of AMD.

Overview of risk factors for age-related macular degeneration (AMD)

Age related macular degeneration (AMD) is the leading cause of blindness in individuals older than 65 years of age. It is a multifactorial disorder and identification of risk factors enables individuals to make life style choices that may reduce the risk of disease. This review discusses the role of genetics, sunlight, diet, cardiovascular factors, smoking, and alcohol as possible risk factors for AMD. Genetics plays a more significant role in AMD than previously thought, especially in younger patients, histocompatibility locus antigen (HLA) and complement system genes being the most significant. Whether the risk of AMD is increased by exposure to sunlight, cardiovascular risk factors, and diet is more controversial. Smoking is the risk factor most consistently associated with AMD. Current smokers are exposed to a two to three times higher risk of AMD than non-smokers and the risk increases with intensity of smoking. Moderate alcohol consumption is unlikely to increase the risk of AMD. Optometrists as front-line informers and educators of ocular health play a significant role in increasing public awareness of the risks of AMD. Cessation of smoking, the use of eye protection in high light conditions, dietary changes, and regular use of dietary supplements should all be considered to reduce the lifetime risk of AMD.

A Case-Only Genome-wide Association Study of Gender- and Age-specific Risk Markers for Childhood Leukemia

Males and age group 1 to 5 years show a much higher risk for childhood acute lymphoblastic leukemia (ALL). We performed a case-only genome-wide association study (GWAS), using the Illumina Infinium HumanCoreExome Chip, to unmask gender- and age-specific risk variants in 240 non-Hispanic white children with ALL recruited at Texas Children’s Cancer Center, Houston, Texas. Besides statistically most significant results, we also considered results that yielded the highest effect sizes. Existing experimental data and bioinformatic predictions were used to complement results, and to examine the biological significance of statistical results. Our study identified novel risk variants for childhood ALL. The SNP, rs4813720 (RASSF2), showed the statistically most significant gender-specific associations (P < 2 x 10-6). Likewise, rs10505918 (SOX5) yielded the lowest P value (P < 1 x 10-5) for age-specific associations, and also showed the statistically most significant association with age-at-onset (P < 1 x 10-4). Two SNPs, rs12722042 and 12722039, from the HLA-DQA1 region yielded the highest effect sizes (odds ratio (OR) = 15.7; P = 0.002) for gender-specific results, and the SNP, rs17109582 (OR = 12.5; P = 0.006), showed the highest effect size for age-specific results. Sex chromosome variants did not appear to be involved in gender-specific associations. The HLA-DQA1 SNPs belong to DQA1*01:07and confirmed previously reported male-specific association with DQA1*01:07. Twenty one of the SNPs identified as risk markers for gender- or age-specific associations were located in the transcription factor binding sites and 56 SNPs were non-synonymous variants, likely to alter protein function. Although bioinformatic analysis did not implicate a particular mechanism for gender- and age-specific associations, RASSF2 has an estrogen receptor-alpha binding site in its promoter. The unknown mechanisms may be due to lack of interest in gender- and age-specificity in associations. These results provide a foundation for further studies to examine the gender- and age-differential in childhood ALL risk. Following replication and mechanistic studies, risk factors for one gender or age group may have a potential to be used as biomarkers for targeted intervention for prevention and maybe also for treatment.

Moléculas coestimulatórias na leishmaniose visceral

Visceral leishmaniasis (VL) is endemic in many countries, including Brazil. The protozoan Leishmania infantum, is the etiological agent of VL, and is transmitted by the bite of female sandflies during the blood meal. The majority of subjects when exposed to the parasite do not develop the disease, because of development of Th1 cellular responses. Those who have develop signs of VL such as fever, weight loss, hepatosplenomegaly, have impairment of the cellular immune response, specific to the Leishmania antigens. We evaluated whether the specififc anergy during symptomatic VL, may be associated with changes in T cells costimulatory molecules or their ligands in CD14+ monocytes. There is an increase in CTLA-4 porcentage on CD4+ T lymphocytes (p=0.001) and ICOS on CD4+ and CD8+ T cells (p=0.002 to CD4+ and p=0.003 to CD8+), after stimulation by soluble Leishmania antigen (SLA) during active visceral leishmaniasis, and that there is a higher percentage of these molecules ex vivo, when comparing symptomatic to recovered individuals (p=0.04 to CTLA-4 in CD4+, and p=0.001 to ICOS in CD4+ and p=0.026 to CD8+). Moreover, we found a high gene expression of CTLA-4, OX-40 and ICOS during active VL. CD40, CD80, CD86, HLA-DR and ICOSL molecules do not suffer changes during disease. There is IFN-γ production by the peripheral blood cells, after SLA stimulation, by peripheral blood cells in symptomatic subjects; however, there is a decrease of the ratio IFN-γ/IL-10, which is reversed after clinical recovery. The impairment of some costimulatory molecules pathways during symptomatic VL could inhibit the ability of phagocytes to kill Leishmania and could facilitate their survival and the proliferation inside macrophages.

Estudio en aves silvestres de canto ("Passeriformes") de las moléculas MHC y reclasificación molecular de la familia "Carduelini"

The Major Histocompatibility Complex (MHC) comprises the most polymorphic loci in animals. MHC plays an important role during the first steps of the immune response in vertebrates. In humans, MHC molecules (also named human leukocyte antigens, HLA) were initially regarded as class I or class II molecules. Each of them, presents to different T cells subsets. MHC class I molecules, are heterodimers in which the heavy chain (alpha) has three extracellular domains, two of which (alpha 1 and alpha 2) are polymorphic and conform the antigen recognition sites (ARS). The ARS is thought to be subjected to balancing selection for variability, which is the cause of the very high polymorphism of the MHC molecules. Different pathogenic epitopes would be the evolutionary force causing balancing selection. MHC class I genes have been completely sequenced (α1 and α2 protein domains) and thoroughly studied in Gallus gallus (chicken) as well as in mammals. In fact, the MHC locus was first defined in chicken, specifically in the highly consanguineous variety „Leghorn‟. It has been found that, in the case of chickens the MHC genetic region is considerably smaller than it is in mammals (remarkably shorter introns were found in chickens), and is organized quite differently. The noteworthy presence of short introns in chickens; supported the hypothesis that chicken‟s MHC represented a „minimal essential MHC‟. Until now, it has been assumed that chicken (order Galliformes) MHC was similar to all species included in the whole class Aves...

A deimmunised form of the ribotoxin, α-sarcin, lacking CD4+ T cell epitopes and its use as an immunotoxin warhead

Fungal ribotoxins that block protein synthesis can be useful warheads in the context of a targeted immunotoxin. α-Sarcin is a small (17 kDa) fungal ribonuclease produced by Aspergillus giganteus that functions by catalytically cleaving a single phosphodiester bond in the sarcin–ricin loop of the large ribosomal subunit, thus making the ribosome unrecognisable to elongation factors and leading to inhibition of protein synthesis. Peptide mapping using an ex vivo human T cell assay determined that α-sarcin contained two T cell epitopes; one in the N-terminal 20 amino acids and the other in the C-terminal 20 amino acids. Various mutations were tested individually within each epitope and then in combination to isolate deimmunised α-sarcin variants that had the desired properties of silencing T cell epitopes and retention of the ability to inhibit protein synthesis (equivalent to wild-type, WT α-sarcin). A deimmunised variant (D9T/Q142T) demonstrated a complete lack of T cell activation in in vitro whole protein human T cell assays using peripheral blood mononuclear cells from donors with diverse HLA allotypes. Generation of an immunotoxin by fusion of the D9T/Q142T variant to a single-chain Fv targeting Her2 demonstrated potent cell killing equivalent to a fusion protein comprising the WT α-sarcin. These results represent the first fungal ribotoxin to be deimmunised with the potential to construct a new generation of deimmunised immunotoxin therapeutics.

Études du ciblage intracellulaire des molécules non classiques du complexe majeur d'histocompatibilité de classe II

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Ubiquitination et ciblage des molécules du complexe majeur d'histocompatibilité de classe-II aux exosomes

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Outcomes after Unrelated Umbilical Cord Blood Transplantation for Children with Osteopetrosis.

Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for most children with osteopetrosis (OP). Timing of HSCT is critical; therefore, umbilical cord blood transplantation (UCBT) is an attractive option. We analyzed outcomes after UCBT in 51 OP children. Median age at UCBT was 6 months. Seventy-seven percent of the cord blood grafts had 0 or 1 HLA disparity with the recipient. Conditioning regimen was myeloablative (mostly busulfan-based in 84% and treosulfan-based in 10%). Antithymocyte globulin was given to 90% of patients. Median number of total nucleated and CD34(+) cells infused was 14 × 10(7)/kg and 3.4 × 10(5)/kg, respectively. Median follow-up for survivors was 74 months. Cumulative incidence (CI) of neutrophil recovery was 67% with a median time to recovery of 23 days; 33% of patients had graft failure, 81% of engrafted patients had full donor engraftment, and 19% had mixed donor chimerism. Day 100 CI of acute graft-versus-host disease (grades II to IV) was 31% and 6-year CI of chronic graft-versus-host disease was 21%. Mechanical ventilation was required in 28%, and veno-occlusive disease was diagnosed in 16% of cases. Six-year overall survival rate was 46%. Comparative studies with other alternative donors should be performed to evaluate whether UCBT remains a valid alternative for children with OP without an HLA-matched donor.

Études du ciblage intracellulaire des molécules non classiques du complexe majeur d'histocompatibilité de classe II

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Ubiquitination et ciblage des molécules du complexe majeur d'histocompatibilité de classe-II aux exosomes

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Immunologically silent cancer clone transmission from mother to offspring

Rare cases of possible materno-fetal transmission of cancer have been recorded over the past 100 years but evidence for a shared cancer clone has been very limited. We provide genetic evidence for mother to offspring transmission, in utero, of a leukemic cell clone. Maternal and infant cancer clones shared the same unique BCR-ABL1 genomic fusion sequence, indicating a shared, single-cell origin. Microsatellite markers in the infant cancer were all of maternal origin. Additionally, the infant, maternally- derived cancer cells had a major deletion on one copy of chromosome 6p that included deletion of HLA alleles that were not inherited by the infant (i.e., foreign to the infant), suggesting a possible mechanism for immune evasion.

Proprioception in ankle sprain from exercises and bandages

Ankle sprains are the most common injuries in sports, usually causing damage to the lateral ligaments. Recurrence has as usual result permanent instability, and thus loss of proprioception. This fact, together with residual symptoms, is what is known as chronic ankle instability, CAI, or FAI, if it is functional. This problem tries to be solved by improving musculoskeletal stability and proprioception by the application of bandages and performing exercises. The aim of this study has been to review articles (meta-analisis, systematic reviews and revisions) published in 2009-2015 in PubMed, Medline, ENFISPO and BUCea, using keywords such as “sprain instability”, “sprain proprioception”, “chronic ankle instability”. Evidence affirms that there does exist decreased proprioception in patients who suffer from CAI. Rehabilitation exercise regimen is indicated as a treatment because it generates a subjective improvement reported by the patient, and the application of bandages works like a sprain prevention method limiting the range of motion, reducing joint instability and increasing confidence during exercise. As podiatrists we should recommend proprioception exercises to all athletes in a preventive way, and those with CAI or FAI, as a rehabilitation programme, together with the application of bandages. However, further studies should be generated focusing on ways of improving proprioception, and on the exercise patterns that provide the maximum benefit.

Étude du profil des populations cellulaires du sang en vue d’une application au diagnostic du lupus érythémateux disséminé

Le lupus érythémateux disséminé (LED) est une maladie auto-immune systémique dont le diagnostic est très complexe. Le clinicien doit baser son diagnostic sur une liste de 11 critères reliés à des observations cliniques et à des mesures sérologiques. Afin de faciliter ce diagnostic, plusieurs groupes recherchent de nouveaux marqueurs biologiques quantifiables. C’est dans ce but que la cytométrie en flux a été utilisée afin de comparer les cellules du sang des patients et celles de sujets sains. La caractérisation exhaustive des sous-populations cellulaires montre que l’expression de HLA-DR est amplifiée chez les patients même si la maladie est inactive. De plus, l’analyse du contenu sérique en cytokines inflammatoires a montré que la quantité de GM-CSF était plus importante chez les patients LED. Nos travaux suggèrent que HLA-DR et GM-CSF pourraient être considérés comme des candidats intéressants dans les études sur le diagnostic du LED.

Characterization of cancer/testis antigen MAGE-A11 for immunotherapy of prostate cancer

Les antigènes testiculaires du cancer sont des cibles idéales pour l’immunothérapie du cancer car ce sont des protéines immunogéniques dont l’expression est restreinte aux cellules germinales et au cancer. Le but de cette étude est d’évaluer le potentiel de MAGE-A11, un antigène testiculaire du cancer, comme cible pour développer un vaccin contre le cancer de la prostate. Pour ce faire, l’anticorps monoclonal 5C4 qui a la capacité de reconnaître la présence de MAGE-A11 dans les tissus fixés et inclus en paraffine a été produit. De plus, l’expression de MAGE-A11 a été analysée sur plusieurs lignées de cellules cancéreuses. Il a été démontré que MAGE-A11 est exprimé dans plusieurs types de cancers notamment dans le cancer du côlon et du cerveau. Finalement, nous avons identifié trois épitopes du CMH classe II HLA-DR1 dans la protéine MAGE-A11 confirmant ainsi l’immunogénicité de cet antigène et son potentiel comme cible pour l’immunothérapie du cancer.