Cryptococcal choroiditis in advanced AIDS with clinicopathologic correlation.

PurposeTo describe a case of disseminated cryptococcal meningitis with multifocal choroiditis and provide optical coherence tomography (OCT) findings correlated with described histopathology in a patient with advanced acquired immunodeficiency syndrome (AIDS).ObservationsThe patient was a 54-year-old man with AIDS who presented with dyspnea and headache followed by acute vision loss. OCT demonstrated a lesion with a small area of fluid that was limited by a more prominent and irregular external limiting membrane with underlying nodular choroidal thickening, mild RPE disorganization, and hyperreflectivity of the overlying photoreceptor layer. Patient was found to have disseminated cryptococcal infection and passed away despite aggressive therapy. Autopsy was performed including bilateral enucleation and a Cryptococcus lesion was confirmed on histopathology.Conclusion and importanceThis case highlights the clinical, imaging, and histopathologic findings of cryptococcal choroiditis and provides a review of the updated treatment recommendations for disseminated infection in a patient with advanced AIDS. Although currently fundoscopy has proven most useful in directing the diagnostic algorithm in choroiditis in the setting of advanced immunosuppression, OCT may provide insight into the spread of Cryptococcus within the eye

Retinal Expression of Wnt-Pathway Mediated Genes in Low-Density Lipoprotein Receptor-Related Protein 5 (Lrp5) Knockout Mice

Mutations in low-density lipoprotein receptor-related protein 5 (Lrp5) impair retinal angiogenesis in patients with familial exudative vitreoretinopathy (FEVR), a rare type of blinding vascular eye disease. The defective retinal vasculature phenotype in human FEVR patients is recapitulated in Lrp5 knockout $(Lrp5^{-/-})$ mouse with delayed and incomplete development of retinal vessels. In this study we examined gene expression changes in the developing $Lrp5^{−/−}$ mouse retina to gain insight into the molecular mechanisms that underlie the pathology of FEVR in humans. Gene expression levels were assessed with an Illumina microarray on total RNA from $Lrp5^{−/−}$ and WT retinas isolated on postnatal day (P) 8. Regulated genes were confirmed using RT-qPCR analysis. Consistent with a role in vascular development, we identified expression changes in genes involved in cell-cell adhesion, blood vessel morphogenesis and membrane transport in $Lrp5^{−/−}$ retina compared to WT retina. In particular, tight junction protein claudin5 and amino acid transporter slc38a5 are both highly down-regulated in $Lrp5^{−/−}$ retina. Similarly, several Wnt ligands including Wnt7b show decreased expression levels. Plasmalemma vesicle associated protein (plvap), an endothelial permeability marker, in contrast, is up-regulated consistent with increased permeability in $Lrp5^{−/−}$ retinas. Together these data suggest that Lrp5 regulates multiple groups of genes that influence retinal angiogenesis and may contribute to the pathogenesis of FEVR

Optical Coherence Tomography Angiography of Punctate Inner Choroidopathy

Purpose. To report a case of bilateral choroidal neovascularization (CNV) in punctate inner choroidopathy (PIC) visualized utilizing optical coherence tomography angiography (OCT-A). Methods. Case report. Results. A 29-year-old woman presented with new visual symptoms in both eyes. Fundoscopic exam revealed bilateral multifocal, small, well-defined lesions consistent with PIC. Optical coherence tomography demonstrated subretinal fluid and retinal pigment epithelium detachments (RPEDs) in both eyes. OCT-A revealed bilateral abnormal increased flow within the RPEDs consistent with CNV. Fluorescein angiography confirmed the presence of bilateral CNV. Conclusion. CNV secondary to PIC may be identified using noninvasive optical coherence tomography angiography

Optical Coherence Tomography Angiography of Punctate Inner Choroidopathy

Purpose. To report a case of bilateral choroidal neovascularization (CNV) in punctate inner choroidopathy (PIC) visualized utilizing optical coherence tomography angiography (OCT-A). Methods. Case report. Results. A 29-year-old woman presented with new visual symptoms in both eyes. Fundoscopic exam revealed bilateral multifocal, small, well-defined lesions consistent with PIC. Optical coherence tomography demonstrated subretinal fluid and retinal pigment epithelium detachments (RPEDs) in both eyes. OCT-A revealed bilateral abnormal increased flow within the RPEDs consistent with CNV. Fluorescein angiography confirmed the presence of bilateral CNV. Conclusion. CNV secondary to PIC may be identified using noninvasive optical coherence tomography angiography

Cryptococcal choroiditis in advanced AIDS with clinicopathologic correlation

Purpose: To describe a case of disseminated cryptococcal meningitis with multifocal choroiditis and provide optical coherence tomography (OCT) findings correlated with described histopathology in a patient with advanced acquired immunodeficiency syndrome (AIDS). Observations: The patient was a 54-year-old man with AIDS who presented with dyspnea and headache followed by acute vision loss. OCT demonstrated a lesion with a small area of fluid that was limited by a more prominent and irregular external limiting membrane with underlying nodular choroidal thickening, mild RPE disorganization, and hyperreflectivity of the overlying photoreceptor layer. Patient was found to have disseminated cryptococcal infection and passed away despite aggressive therapy. Autopsy was performed including bilateral enucleation and a Cryptococcus lesion was confirmed on histopathology. Conclusion and importance: This case highlights the clinical, imaging, and histopathologic findings of cryptococcal choroiditis and provides a review of the updated treatment recommendations for disseminated infection in a patient with advanced AIDS. Although currently fundoscopy has proven most useful in directing the diagnostic algorithm in choroiditis in the setting of advanced immunosuppression, OCT may provide insight into the spread of Cryptococcus within the eye. Keywords: Cryptococcus neoformans, Cryptococcal choroiditis, Meningitis, HIV, AIDS, Clinicopathologic correlatio

DNA sequence variants in PPARGC1A, a gene encoding a coactivator of the ω-3 LCPUFA sensing PPAR-RXR transcription complex, are associated with NV AMD and AMD-associated loci in genes of complement and VEGF signaling pathways.

Increased intake of ω-3 long-chain polyunsaturated fatty acids (LCPUFAs) and use of peroxisome proliferator activator receptor (PPAR)-activating drugs are associated with attenuation of pathologic retinal angiogenesis. ω-3 LCPUFAs are endogenous agonists of PPARs. We postulated that DNA sequence variation in PPAR gamma (PPARG) co-activator 1 alpha (PPARGC1A), a gene encoding a co-activator of the LCPUFA-sensing PPARG-retinoid X receptor (RXR) transcription complex, may influence neovascularization (NV) in age-related macular degeneration (AMD).We applied exact testing methods to examine distributions of DNA sequence variants in PPARGC1A for association with NV AMD and interaction of AMD-associated loci in genes of complement, lipid metabolism, and VEGF signaling systems. Our sample contained 1858 people from 3 elderly cohorts of western European ancestry. We concurrently investigated retinal gene expression profiles in 17-day-old neonatal mice on a 2% LCPUFA feeding paradigm to identify LCPUFA-regulated genes both associated with pathologic retinal angiogenesis and known to interact with PPARs or PPARGC1A.A DNA coding variant (rs3736265) and a 3'UTR-resident regulatory variant (rs3774923) in PPARGC1A were independently associated with NV AMD (exact P = 0.003, both SNPs). SNP-SNP interactions existed for NV AMD (P<0.005) with rs3736265 and a AMD-associated variant in complement factor B (CFB, rs512559). PPARGC1A influences activation of the AMD-associated complement component 3 (C3) promoter fragment and CFB influences activation and proteolysis of C3. We observed interaction (P ≤ 0.003) of rs3736265 with a variant in vascular endothelial growth factor A (VEGFA, rs3025033), a key molecule in retinal angiogenesis. Another PPARGC1A coding variant (rs8192678) showed statistical interaction with a SNP in the VEGFA receptor fms-related tyrosine kinase 1 (FLT1, rs10507386; P ≤ 0.003). C3 expression was down-regulated 2-fold in retinas of ω-3 LCPUFA-fed mice - these animals also showed 70% reduction in retinal NV (P ≤ 0.001).Ligands and co-activators of the ω-3 LCPUFA sensing PPAR-RXR axis may influence retinal angiogenesis in NV AMD via the complement and VEGF signaling systems. We have linked the co-activator of a lipid-sensing transcription factor (PPARG co-activator 1 alpha, PPARGC1A) to age-related macular degeneration (AMD) and AMD-associated genes

Description of Cohorts.

<p>Abbreviations: SE, standard error; NV AMD, neovascular AMD.</p

Association results of <i>PPARGC1A</i> SNPs for NV AMD in three cohorts and in meta-analysis using multivariable models.

<p>Abbreviations: 3′UTR, 3′ untranslated region; SNP, single-nucleotide polymorphism. a, SNPs in nearly complete linkage disequilibrium (r² = 0.96) – no other SNPs were in linkage disequilibrium; ADD, additive model (minor allele count –2|1|0); DOM, dominant model (grouping minor allele homozygotes with heterozygotes). SNPs were tested from the panel of the ILLUMINA HumanCNV370v1 chip (SNP batch IDs at <a href="http://www.ncbi.nlm.nih.gov/SNP/snp_viewBatch.cgi?sbid=1047132" target="_blank">http://www.ncbi.nlm.nih.gov/SNP/snp_viewBatch.cgi?sbid=1047132</a>). People in the reference groups (controls) were AMD-free and at least 65-years-of-age at the time of phenotype classification. We computed odds ratios (ORs) and 95% confidence intervals (95% CI) from age-, sex, and smoking-adjusted logistic regression analyses on 506 cases and 512 controls in the Discovery Cohort (University of Michigan), 123 cases and 198 controls in Replication Cohort 1 (University of Pennsylvania), and 205 cases and 314 controls in Replication Cohort 2 (Mayo Clinic, Rochester). Combined estimates (OR_meta) were computed with age-, sex, and smoking-adjusted meta-regression – random effects models were applied in instances indicated by Cochrane’s Q statistic. All <i>P</i> values are 2-sided, with the exception of those for the replication cohorts. Exact (empirical) <i>P</i> values are from <i>max(T)</i> permutation with 10000 iterations on the full sample.</p