Longitudinal Assessment of Remnant Foveal Cone Structure in a Case Series of Early Macular Telangiectasia Type 2

PURPOSE: To determine the extent of remnant cone structure within early foveal ellipsoid zone (EZ) lesions in macular telangiectasia type 2 longitudinally using both confocal and split detector adaptive optics scanning light ophthalmoscopy (AOSLO). METHODS: Spectral domain optical coherence tomography (SDOCT), confocal and split detector AOSLO were acquired from seven patients (10 eyes) with small (early) EZ lesions on SDOCT secondary to macular telangiectasia type 2 at baseline, 6 months, and 12 months. The presence of cone structure on AOSLO in areas of EZ loss as well as cones at 1° eccentricity, and their change over time were quantified. RESULTS: By split detector AOSLO, remnant cone structure was identified within and on the borders of all foveal EZ lesions. Within the extent of these lesions, cone spacing ranged from 4.97 to 9.95 µm at baseline, 5.30 to 6.10 µm at 6 months, and 4.99 to 7.12 µm at 12 months. Four eyes with significantly smaller EZ lesions showed evidence of recovery of EZ reflectivity on SDOCT B-scans. Remnant cone structure was identified in some areas where EZ reflectivity recovered at the following time point. Eyes that showed recovery of EZ reflectivity had a continuous external limiting membrane. CONCLUSIONS: Remnant cone structure can persist within small SDOCT-defined EZ lesions, which can wax and wane in appearance over time. AOSLO can help to inform the interpretation of SDOCT imaging. TRANSLATIONAL RELEVANCE: The absence of EZ in early macular telangiectasia type 2 and other retinal conditions needs careful interpretation because it does not always indicate an absence of underlying cone structure. The integrity of the external limiting membrane may better predict the presence of remnant cone structure and recovery of EZ reflectivity

A novel malaria vaccine candidate antigen expressed in Tetrahymena thermophila

Development of effective malaria vaccines is hampered by the problem of producing correctly folded Plasmodium proteins for use as vaccine components. We have investigated the use of a novel ciliate expression system, Tetrahymena thermophila, as a P. falciparum vaccine antigen platform. A synthetic vaccine antigen composed of N-terminal and C-terminal regions of merozoite surface protein-1 (MSP-1) was expressed in Tetrahymena thermophila. The recombinant antigen was secreted into the culture medium and purified by monoclonal antibody (mAb) affinity chromatography. The vaccine was immunogenic in MF1 mice, eliciting high antibody titers against both N- and C-terminal components. Sera from immunized animals reacted strongly with P. falciparum parasites from three antigenically different strains by immunofluorescence assays, confirming that the antibodies produced are able to recognize parasite antigens in their native form. Epitope mapping of serum reactivity with a peptide library derived from all three MSP-1 Block 2 serotypes confirmed that the MSP-1 Block 2 hybrid component of the vaccine had effectively targeted all three serotypes of this polymorphic region of MSP-1. This study has successfully demonstrated the use of Tetrahymena thermophila as a recombinant protein expression platform for the production of malaria vaccine antigens

Antibodies elicited in adults by a primary Plasmodium falciparum blood-stage infection recognize different epitopes compared with immune individuals

<p>Abstract</p> <p>Background</p> <p>Asexual stage antibody responses following initial <it>Plasmodium falciparum </it>infections in previously healthy adults may inform vaccine development, yet these have not been as intensively studied as they have in populations from malaria-endemic areas.</p> <p>Methods</p> <p>Serum samples were collected over a six-month period from twenty travellers having returned with falciparum malaria. Fourteen of these were malaria-naïve and six had a past history of one to two episodes of malaria. Antibodies to seven asexual stage <it>P. falciparum </it>antigens were measured by ELISA. Invasion inhibitory antibody responses to the 19kDa fragment of merozoite surface protein 1 (MSP1₁₉) were determined.</p> <p>Results</p> <p>Short-lived antibody responses were found in the majority of the subjects. While MSP1₁₉antibodies were most common, MSP1 block 2 antibodies were significantly less frequent and recognized conserved domains. Antibodies to MSP2 cross-reacted to the dimorphic allelic families and anti-MSP2 isotypes were not IgG3 skewed as shown previously. MSP1₁₉invasion inhibiting antibodies were present in 9/20 patients. A past history of malaria did not influence the frequency of these short-lived, functional antibodies (p = 0.2, 2-tailed Fisher's exact test).</p> <p>Conclusion</p> <p>Adults infected with <it>P. falciparum </it>for the first time, develop relatively short-lived immune responses that, in the case of MSP1₁₉, are functional. Antibodies to the polymorphic antigens studied were particularly directed to allelic family specific, non-repetitive and conserved determinants and were not IgG subclass skewed. These responses are substantially different to those found in malaria immune individuals.</p

Effect of treating Schistosoma haematobium infection on Plasmodium falciparum-specific antibody responses

<p>Abstract</p> <p>Background</p> <p>The overlapping geographical and socio-economic distribution of malaria and helminth infection has led to several studies investigating the immunological and pathological interactions of these parasites. This study focuses on the effect of treating schistosome infections on natural human immune responses directed against plasmodia merozoite surface proteins MSP-1 (DPKMWR, MSP1₁₉), and MSP-2 (CH150 and Dd2) which are potential vaccine candidates as well as crude malaria (schizont) and schistosome (whole worm homogenate) proteins.</p> <p>Methods</p> <p>IgG1 and IgG3 antibody responses directed against <it>Schistosoma haematobium </it>crude adult worm antigen (WWH) and <it>Plasmodium falciparum </it>antigens (merozoite surface proteins 1/2 and schizont extract), were measured by enzyme linked immunosorbent assay (ELISA) in 117 Zimbabweans (6–18 years old) exposed to <it>S. haematobium </it>and <it>P. falciparum </it>infection. These responses were measured before and after anti-helminth treatment with praziquantel to determine the effects of treatment on anti-plasmodial/schistosome responses.</p> <p>Results</p> <p>There were no significant associations between antibody responses (IgG1/IgG3) directed against <it>P. falciparum </it>and schistosomes before treatment. Six weeks after schistosome treatment there were significant changes in levels of IgG1 directed against schistosome crude antigens, plasmodia crude antigens, MSP-1₁₉, MSP-2 (Dd2), and in IgG3 directed against MSP-1₁₉. However, only changes in anti-schistosome IgG1 were attributable to the anti-helminth treatment.</p> <p>Conclusion</p> <p>There was no association between anti-<it>P. falciparum </it>and <it>S. haematobium antibody </it>responses in this population and <it>a</it>nti-helminth treatment affected only anti-schistosome responses and not responses against plasmodia crude antigens or MSP-1 and -2 vaccine candidates.</p

Brain-Derived Neurotrophic Factor Gene Val66Met Polymorphism Modulates Reversible Cerebral Vasoconstriction Syndromes

BACKGROUND: Reversible cerebral vasoconstriction syndrome (RCVS) could be complicated by cerebral ischemic events. Hypothetical mechanisms of RCVS involve endothelial dysfunction and sympathetic overactivity, both of which were reported to be related to brain-derived neurotrophic factor (BDNF). The study investigated the association between functional BDNF Val66Met polymorphism and RCVS. METHODS: Patients with RCVS and controls were prospectively recruited and genotyped for the BDNF Val66Met polymorphism. Magnetic resonance angiography (MRA) and transcranial color-coded Doppler sonography were employed to evaluate cerebral vasoconstriction. Genotyping results, clinical parameters, vasoconstriction scores, mean flow velocities of the middle cerebral artery (V(MCA)), and Lindegaard indices were analyzed. Split-sample approach was employed to internally validate the data. PRINCIPAL FINDINGS: Ninety Taiwanese patients with RCVS and 180 age- and gender-matched normal controls of the same ethnicity completed the study. The genotype frequencies did not differ between patients and controls. Compared to patients with Met/Met homozygosity, patients with Val allele had higher mean vasoconstriction scores of all arterial segments (1.60±0.72 vs. 0.87±0.39, p<0.001), V(MCA) values (116.7±36.2 vs. 82.7±17.9 cm/s, p<0.001), and LI (2.41±0.91 vs. 1.89±0.41, p = 0.001). None of the Met/Met homozygotes, but 38.9% of the Val carriers, had V(MCA) values of >120 cm/s (p<0.001). Split-sample validation by randomization, age, entry time or residence of patients demonstrated concordant findings. CONCLUSIONS: Our findings link BDNF Val66Met polymorphism with the severity of RCVS for the first time and implicate possible pathogenic mechanisms for vasoconstriction in RCVS

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Brain correlates of pro-social personality traits: a voxel-based morphometry study

Of the five personality dimensions described by the Big Five Personality Model (Costa and McCrae 1992), Extraversion and Agreeableness are the traits most commonly associated with a pro-social orientation. In this study we tested whether a pro-social orientation, as expressed in terms of Extraversion and Agreeableness, is associated with a specific grey matter phenotype. Fifty-two healthy participants underwent magnetic resonance imaging (MRI) and completed the NEO-Five Factor Inventory (NEO-FFI), a self-report measure of the Big Five personality traits. Voxel-based morphometry (VBM) was used to investigate the correlation between brain structure and the personality traits of Agreeableness and Extraversion. We found that Extraversion was negatively correlated with grey matter density in the middle frontal and orbitofrontal gyri while Agreeableness was negatively correlated with grey matter density in the inferior parietal, middle occipital and posterior cingulate gyri. No positive correlations were found. These results suggest that pro-social personality traits seem to be associated with decreases in grey matter density in more frontal regions for Extraversion, and more posterior regions for Agreeableness.This research was funded by the Portuguese Foundation for Science and Technology (FCT): PIC/IC/83290/2007, which is supported by FEDER (POFC - COMPETE), and postdoctoral grant number: SFRH/BPD/75014/2010

The Breadth, but Not the Magnitude, of Circulating Memory B Cell Responses to P. falciparum Increases with Age/Exposure in an Area of Low Transmission

BACKGROUND: Malaria caused by Plasmodium falciparum remains a major cause of death in sub-Saharan Africa. Immunity against symptoms of malaria requires repeated exposure, suggesting either that the parasite is poorly immunogenic or that the development of effective immune responses to malaria may be impaired. METHODS: We carried out two age-stratified cross-sectional surveys of anti-malarial humoral immune responses in a Gambian village where P. falciparum malaria transmission is low and sporadic. Circulating antibodies and memory B cells (MBC) to four malarial antigens were measured using ELISA and cultured B cell ELISpot. FINDINGS AND CONCLUSIONS: The proportion of individuals with malaria-specific MBC and antibodies, and the average number of antigens recognised by each individual, increased with age but the magnitude of these responses did not. Malaria-specific antibody levels did not correlate with either the prevalence or median number of MBC, indicating that these two assays are measuring different aspects of the humoral immune response. Among those with immunological evidence of malaria exposure (defined as a positive response to at least one malarial antigen either by ELISA or ELISPOT), the median number of malaria-specific MBC was similar to median numbers of diphtheria-specific MBC, suggesting that the circulating memory cell pool for malaria antigens is of similar size to that for other antigens

Longitudinal Replication Studies of GWAS Risk SNPs Influencing Body Mass Index over the Course of Childhood and Adulthood

Genome-wide association studies (GWAS) have identified multiple common variants associated with body mass index (BMI). In this study, we tested 23 genotyped GWAS-significant SNPs (p-value<5*10-8) for longitudinal associations with BMI during childhood (3–17 years) and adulthood (18–45 years) for 658 subjects. We also proposed a heuristic forward search for the best joint effect model to explain the longitudinal BMI variation. After using false discovery rate (FDR) to adjust for multiple tests, childhood and adulthood BMI were found to be significantly associated with six SNPs each (q-value<0.05), with one SNP associated with both BMI measurements: KCTD15 rs29941 (q-value<7.6*10-4). These 12 SNPs are located at or near genes either expressed in the brain (BDNF, KCTD15, TMEM18, MTCH2, and FTO) or implicated in cell apoptosis and proliferation (FAIM2, MAP2K5, and TFAP2B). The longitudinal effects of FAIM2 rs7138803 on childhood BMI and MAP2K5 rs2241423 on adulthood BMI decreased as age increased (q-value<0.05). The FTO candidate SNPs, rs6499640 at the 5 ′-end and rs1121980 and rs8050136 downstream, were associated with childhood and adulthood BMI, respectively, and the risk effects of rs6499640 and rs1121980 increased as birth weight decreased. The best joint effect model for childhood and adulthood BMI contained 14 and 15 SNPs each, with 11 in common, and the percentage of explained variance increased from 0.17% and 9.0*10−6% to 2.22% and 2.71%, respectively. In summary, this study evidenced the presence of long-term major effects of genes on obesity development, implicated in pathways related to neural development and cell metabolism, and different sets of genes associated with childhood and adulthood BMI, respectively. The gene effects can vary with age and be modified by prenatal development. The best joint effect model indicated that multiple variants with effects that are weak or absent alone can nevertheless jointly exert a large longitudinal effect on BMI

Dietary cadmium and risk of invasive postmenopausal breast cancer in the VITAL cohort.

This study does not support the hypothesis that dietary cadmium intake is a risk factor for breast cancer. However, non-differential measurement error in the estimate of cadmium intake is likely the most important factor that could have obscured an association