Anomalies in neurovascular coupling during early diabetes: A review.

Diabetic retinopathy is the most feared complication for those with diabetes. Although visible vascular pathology traditionally defines the management of this condition, it is now recognised that a range of cellular changes occur in the retina from an early stage of diabetes. One of the most significant functional changes that occurs in those with diabetes is a loss of vasoregulation in response to changes in neural activity. There are several retinal cell types that are critical for mediating so-called neurovascular coupling, including Müller cells, microglia and pericytes. Although there is a great deal of evidence that suggests that Müller cells are integral to regulating the vasculature, they only modulate part of the vascular tree, highlighting the complexity of vasoregulation within the retina. Recent studies suggest that retinal immune cells, microglia, play an important role in mediating vasoconstriction. Importantly, retinal microglia contact both the vasculature and neural synapses and induce vasoconstriction in response to neurally expressed chemokines such as fractalkine. This microglial-dependent regulation occurs via the vasomediator angiotensinogen. Diabetes alters the way microglia regulate the retinal vasculature, by increasing angiotensinogen expression, causing capillary vasoconstriction and contributing to a loss of vascular reactivity to physiological signals. This article summarises recent studies showing changes in vascular regulation during diabetes, the potential mechanisms by which this occurs and the significance of these early changes to the progression of diabetic retinopathy.

Fractalkine-induced microglial vasoregulation occurs within the retina and is altered early in diabetic retinopathy.

Local blood flow control within the central nervous system (CNS) is critical to proper function and is dependent on coordination between neurons, glia, and blood vessels. Macroglia, such as astrocytes and Müller cells, contribute to this neurovascular unit within the brain and retina, respectively. This study explored the role of microglia, the innate immune cell of the CNS, in retinal vasoregulation, and highlights changes during early diabetes. Structurally, microglia were found to contact retinal capillaries and neuronal synapses. In the brain and retinal explants, the addition of fractalkine, the sole ligand for monocyte receptor Cx3cr1, resulted in capillary constriction at regions of microglial contact. This vascular regulation was dependent on microglial Cx3cr1 involvement, since genetic and pharmacological inhibition of Cx3cr1 abolished fractalkine-induced constriction. Analysis of the microglial transcriptome identified several vasoactive genes, including angiotensinogen, a constituent of the renin-angiotensin system (RAS). Subsequent functional analysis showed that RAS blockade via candesartan abolished microglial-induced capillary constriction. Microglial regulation was explored in a rat streptozotocin (STZ) model of diabetic retinopathy. Retinal blood flow was reduced after 4 wk due to reduced capillary diameter and this was coincident with increased microglial association. Functional assessment showed loss of microglial-capillary response in STZ-treated animals and transcriptome analysis showed evidence of RAS pathway dysregulation in microglia. While candesartan treatment reversed capillary constriction in STZ-treated animals, blood flow remained decreased likely due to dilation of larger vessels. This work shows microglia actively participate in the neurovascular unit, with aberrant microglial-vascular function possibly contributing to the early vascular compromise during diabetic retinopathy.

The Contribution of Microglia to the Development and Maturation of the Visual System.

Microglia, the resident immune cells of the central nervous system (CNS), were once considered quiescent cells that sat in readiness for reacting to disease and injury. Over the last decade, however, it has become clear that microglia play essential roles in maintaining the normal nervous system. The retina is an easily accessible part of the central nervous system and therefore much has been learned about the function of microglia from studies in the retina and visual system. Anatomically, microglia have processes that contact all synapses within the retina, as well as blood vessels in the major vascular plexuses. Microglia contribute to development of the visual system by contributing to neurogenesis, maturation of cone photoreceptors, as well as refining synaptic contacts. They can respond to neural signals and in turn release a range of cytokines and neurotrophic factors that have downstream consequences on neural function. Moreover, in light of their extensive contact with blood vessels, they are also essential for regulation of vascular development and integrity. This review article summarizes what we have learned about the role of microglia in maintaining the normal visual system and how this has helped in understanding their role in the central nervous system more broadly.

A 17-Gene Panel Genomic Prostate Score Has Similar Predictive Accuracy for Adverse Pathology at Radical Prostatectomy in African American and European American Men.

OBJECTIVE: To validate the 17-gene Oncotype DX Genomic Prostate Score (GPS) as a predictor of adverse pathology (AP) in African American (AA) men and to assess the distribution of GPS in AA and European American (EA) men with localized prostate cancer. METHODS: The study populations were derived from 2 multi-institutional observational studies. Between February 2009 and September 2014, AA and EA men who elected immediate radical prostatectomy after a ≥10-core transrectal ultrasound biopsy were included in the study. Logistic regressions, area under the receiver operating characteristics curves (AUC), calibration curves, and predictive values were used to compare the accuracy of GPS. AP was defined as primary Gleason grade 4, presence of any Gleason pattern 5, and/or non-organ-confined disease (≥pT3aN0M0) at radical prostatectomy. RESULTS: Overall, 96 AA and 76 EA men were selected and 46 (26.7%) had AP. GPS result was a significant predictor of AP (odds ratio per 20 GPS units [OR/20 units] in AA: 4.58; 95% confidence interval (CI) 1.8-11.5, P = .001; and EA: 4.88; 95% CI 1.8-13.5, P = .002). On multivariate analysis, there was no significant interaction between GPS and race (P >.10). GPS remained significant in models adjusted for either National Comprehensive Cancer Network (NCCN) risk group or Cancer of the Prostate Risk Assessment (CAPRA) score. In race-stratified models, area under the receiver operating characteristics curves for GPS/20 units was 0.69 for AAs vs 0.74 for EAs (P = .79). The GPS distributions were not statistically different by race (all P >.05). CONCLUSION: In this clinical validation study, the Oncotype DX GPS is an independent predictor of AP at prostatectomy in AA and EA men with similar predictive accuracy and distributions.

Potential mechanisms of retinal ganglion cell type-specific vulnerability in glaucoma.

Glaucoma is a neurodegenerative disease characterised by progressive damage to the retinal ganglion cells (RGCs), the output neurons of the retina. RGCs are a heterogenous class of retinal neurons which can be classified into multiple types based on morphological, functional and genetic characteristics. This review examines the body of evidence supporting type-specific vulnerability of RGCs in glaucoma and explores potential mechanisms by which this might come about. Studies of donor tissue from glaucoma patients have generally noted greater vulnerability of larger RGC types. Models of glaucoma induced in primates, cats and mice also show selective effects on RGC types - particularly OFF RGCs. Several mechanisms may contribute to type-specific vulnerability, including differences in the expression of calcium-permeable receptors (for example pannexin-1, P2X7, AMPA and transient receptor potential vanilloid receptors), the relative proximity of RGCs and their dendrites to blood supply in the inner plexiform layer, as well as differing metabolic requirements of RGC types. Such differences may make certain RGCs more sensitive to intraocular pressure elevation and its associated biomechanical and vascular stress. A greater understanding of selective RGC vulnerability and its underlying causes will likely reveal a rich area of investigation for potential treatment targets.

The renin-angiotensin system and the retinal neurovascular unit: A role in vascular regulation and disease.

The retina is known to have a local renin-angiotensin system (RAS) and dysfunction in the RAS is often associated with diseases of the retinal vasculature that cause irreversible vision loss. Regulation of the retinal vasculature to meet the metabolic needs of the tissues occurs through a mechanism called neurovascular coupling, which is critical for maintaining homeostatic function and support for neurons. Neurovascular coupling is the process by which support cells, including glia, regulate blood vessel calibre and blood flow in response to neural activity. In retinal vascular diseases, this coupling mechanism is often disrupted. However, the role that angiotensin II (Ang II), the main effector peptide of the RAS, has in regulating both the retinal vasculature and neurovascular coupling is not fully understood. As components of the RAS are located on the principal neurons, glia and blood vessels of the retina, it is possible that Ang II has a role in regulating communication and function between these three cell types, and therefore the capacity to regulate neurovascular coupling. This review focuses on components of the RAS located on the retinal neurovascular unit, and the potential of this system to contribute to blood flow modulation in the healthy and compromised retina.

Engaging African American Men as Citizen Scientists to Validate a Prostate Cancer Biomarker: Work-in-Progress.

BACKGROUND: African American men (AAM) are under-represented in prostate cancer (PCa) research despite known disparities. Screening with prostate-specific antigen (PSA) has low specificity for high-grade PCa leading to PCa over diagnosis. The Prostate Health Index (PHI) has higher specificity for lethal PCa but needs validation in AAM. Engaging AAM as citizen scientists (CSs) may improve participation of AAM in PCa research.Results and Lessons Learned: Eight CSs completed all training modules and 139 AAM were recruited. Challenges included equity in research leadership among multiple principal investigators (PIs) and coordinating CSs trainings. CONCLUSIONS: Engaging AAM CSs can support engaging/recruiting AAM in PCa biomarker validation research. Equity among multiple stakeholders can be challenging, but proves beneficial in engaging AAM in research. OBJECTIVES: Assess feasibility of mobilizing CSs to recruit AAM as controls for PHI PCa validation biomarker study. METHODS: We highlight social networks/assets of stakeholders, CSs curriculum development/implementation, and recruitment of healthy controls for PHI validation.

Self-reported Black race predicts significant prostate cancer independent of clinical setting and clinical and socioeconomic risk factors.

INTRODUCTION AND OBJECTIVE: Studies have linked Black race to prostate cancer (CaP) risk but most fail to account for established risk factors such as 5-ARI use, prostate volume, socioeconomic status, and hospital setting. We assess whether Black race remains associated with CaP and Gleason ≥3 + 4 CaP, after adjusting for clinical setting and socioeconomic and clinical factors at prostate biopsy, with a focus on men aged 40-54 years, who may be excluded from current screening guidelines. METHODS: We recruited 564 men age 40-79 undergoing initial prostate biopsy for abnormal PSA or digital rectal examination (DRE) from three publicly funded and two private hospitals from 2009-2014. Univariate and multivariate analyses examined the associations between hospital type, race, West African Ancestry (WAA), clinical, and sociodemographic risk factors with CaP diagnosis and Gleason ≥3 + 4 CaP. Given changes in CaP screening recommendations, we also assess the multivariate analyses for men aged 40-54. RESULTS: Black and White men had similar age, BMI, and prostate volume. Black men had higher PSA (8.10 ng/mL vs. 5.63 ng/mL) and PSA density (0.22 ng/mL/cm3 vs. 0.15 ng/mL/cm3, all p < 0.001). Blacks had higher frequency of CaP (63.1% vs. 41.5%, p<0.001) and Gleason ≥3+4 CaP relative to Whites in both public (27.7% vs 11.6%, p<0.001) and private (48.4% vs 21.6%, p = 0.002) settings. In models adjusted for age, first degree family history, prostate volume, 5-ARI use, hospital type, income, marital and educational status, Black race was independently associated with overall CaP diagnosis (OR = 2.13, p = 0.002). There was a significant multiplicative interaction with Black race and abnormal DRE for Gleason ≥3 + 4 CaP (OR = 2.93, p = 0.01). WAA was not predictive of overall or significant CaP among Black men. Black race (OR = 5.66, p = 0.02) and family history (OR = 4.98, p = 0.01) were independently positively associated with overall CaP diagnosis for men aged 40 to 54. CONCLUSIONS: Black race is independently associated with CaP and Gleason ≥3+4 CaP after accounting for clinical and socioeconomic risk factors including clinical setting and WAA, and has a higher odds ratio of CaP diagnosis in younger men. Further investigation into optimizing screening in Black men aged 40 to 54 is warranted.

Loss of Function of P2X7 Receptor Scavenger Activity in Aging Mice: A Novel Model for Investigating the Early Pathogenesis of Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a leading cause of irreversible, severe vision loss in Western countries. Recently, we identified a novel pathway involving P2X7 receptor scavenger function expressed on ocular immune cells as a risk factor for advanced AMD. In this study, we investigate the effect of loss of P2X7 receptor function on retinal structure and function during aging. P2X7-null and wild-type C57bl6J mice were investigated at 4, 12, and 18 months of age for macrophage phagocytosis activity, ocular histological changes, and retinal function. Phagocytosis activity of blood-borne macrophages decreased with age at 18 months in the wild-type mouse. Lack of P2X7 receptor function reduced phagocytosis at all ages compared to wild-type mice. At 12 months of age, P2X7-null mice had thickening of Bruchs membrane and retinal pigment epithelium dysfunction. By 18 months of age, P2X7-null mice displayed phenotypic characteristics consistent with early AMD, including Bruchs membrane thickening, retinal pigment epithelium cell loss, retinal functional deficits, and signs of subretinal inflammation. Our present study shows that loss of function of the P2X7 receptor in mice induces retinal changes representing characteristics of early AMD, providing a valuable model for investigating the role of scavenger receptor function and the immune system in the development of this age-related disease.

Race and BMI modify associations of calcium and vitamin D intake with prostate cancer.

BACKGROUND: African Americans have disproportionately higher burden of prostate cancer compared to European Americans. However, the cause of prostate cancer disparities is still unclear. Several roles have been proposed for calcium and vitamin D in prostate cancer pathogenesis and progression, but epidemiologic studies have been conducted mainly in European descent populations. Here we investigated the association of calcium and vitamin D intake with prostate cancer in multiethnic samples. METHODS: A total of 1,657 prostate cancer patients who underwent screening and healthy controls (888 African Americans, 620 European Americans, 111 Hispanic Americans, and 38 others) from Chicago, IL and Washington, D.C. were included in this study. Calcium and vitamin D intake were evaluated using food frequency questionnaire. We performed unconditional logistic regression analyses adjusting for relevant variables. RESULTS: In the pooled data set, high calcium intake was significantly associated with higher odds for aggressive prostate cancer (ORQuartile 1 vs. Quartile 4 = 1.98, 95% C.I.: 1.01-3.91), while high vitamin D intake was associated with lower odds of aggressive prostate cancer (ORQuartile 1 vs. Quartile 4 = 0.38, 95% C.I.: 0.18-0.79). In African Americans, the association between high calcium intake and aggressive prostate cancer was statistically significant (ORQuartile 1 vs. Quartile 4 = 4.28, 95% C.I.: 1.70-10.80). We also observed a strong inverse association between total vitamin D intake and prostate cancer in African Americans (ORQuartile 1 vs. Quartile 4 = 0.06, 95% C.I.: 0.02-0.54). In European Americas, we did not observe any significant associations between either calcium or vitamin D intake and prostate cancer. In analyses stratifying participants based on Body Mass Index (BMI), we observed a strong positive association between calcium and aggressive prostate cancer and a strong inverse association between vitamin D intake and aggressive prostate cancer among men with low BMI (<27.8 kg/m2), but not among men with high BMI (≥27.8 kg/m2). Interactions of race and BMI with vitamin D intake were significant (P Interaction < 0.05). CONCLUSION: Calcium intake was positively associated with aggressive prostate cancer, while vitamin D intake exhibited an inverse relationship. However, these associations varied by race/ethnicity and BMI. The findings from this study may help develop better prostate cancer prevention and management strategies.

Barriers and Facilitators toward HIV Testing and Health Perceptions among African-American Men Who Have Sex with Women at a South Side Chicago Community Health Center: A Pilot Study.

In the United States, African-Americans' (AAs) HIV infection rates are higher than any other racial group, and AA men who have sex with women (MSW) are a significant proportion of new cases. There is little research into AA MSW HIV/AIDS knowledge, barriers, and facilitators of HIV testing in Chicago. We enrolled a convenience sample of AA MSW from a community health clinic who completed self-administered surveys assessing HIV knowledge and testing-related barriers and facilitators. The survey was a combination of questions from several validated instruments, and additional questions were written based on key informant interviews with social scientists to tailor the questionnaire for AA men living on the South Side of Chicago. We recruited 20 AA MSW (mean age 47.4 years). Sixty-five percent had incomes <$10,000/year, 30% were insured, and 50% had post-secondary education. Despite low socioeconomic status, their HIV literacy was relatively high. The identified major barriers to testing were low perceived HIV risk, concerns over privacy, and external stigma at testing sites. Future efforts should focus on educating AA MSW on actual risk for HIV and address issues of privacy and stigma at testing sites.

Common vitamin D pathway gene variants reveal contrasting effects on serum vitamin D levels in African Americans and European Americans.

Vitamin D deficiency is more common among African Americans (AAs) than among European Americans (EAs), and epidemiologic evidence links vitamin D status to many health outcomes. Two genome-wide association studies (GWAS) in European populations identified vitamin D pathway gene single-nucleotide polymorphisms (SNPs) associated with serum vitamin D [25(OH)D] levels, but a few of these SNPs have been replicated in AAs. Here, we investigated the associations of 39 SNPs in vitamin D pathway genes, including 19 GWAS-identified SNPs, with serum 25(OH)D concentrations in 652 AAs and 405 EAs. Linear and logistic regression analyses were performed adjusting for relevant environmental and biological factors. The pattern of SNP associations was distinct between AAs and EAs. In AAs, six GWAS-identified SNPs in GC, CYP2R1, and DHCR7/NADSYN1 were replicated, while nine GWAS SNPs in GC and CYP2R1 were replicated in EAs. A CYP2R1 SNP, rs12794714, exhibited the strongest signal of association in AAs. In EAs, however, a different CYP2R1 SNP, rs1993116, was the most strongly associated. Our models, which take into account genetic and environmental variables, accounted for 20 and 28 % of the variance in serum vitamin D levels in AAs and EAs, respectively.