Neurotransmitter modulation of extracellular H+ fluxes from isolated retinal horizontal cells of the skate

Self-referencing H+-selective microelectrodes were used to measure extracellular H+ fluxes from horizontal cells isolated from the skate retina. A standing H+ flux was detected from quiescent cells, indicating a higher concentration of free hydrogen ions near the extracellular surface of the cell as compared to the surrounding solution. The standing H+ flux was reduced by removal of extracellular sodium or application of 5-(N-ethyl-N-isopropyl) amiloride (EIPA), suggesting activity of a Na+–H+ exchanger. Glutamate decreased H+ flux, lowering the concentration of free hydrogen ions around the cell. AMPA/kainate receptor agonists mimicked the response, and the AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) eliminated the effects of glutamate and kainate. Metabotropic glutamate agonists were without effect. Glutamate-induced alterations in H+ flux required extracellular calcium, and were abolished when cells were bathed in an alkaline Ringer solution. Increasing intracellular calcium by photolysis of the caged calcium compound NP-EGTA also altered extracellular H+ flux. Immunocytochemical localization of the plasmalemma Ca2+–H+-ATPase (PMCA pump) revealed intense labelling within the outer plexiform layer and on isolated horizontal cells. Our results suggest that glutamate modulation of H+ flux arises from calcium entry into cells with subsequent activation of the plasmalemma Ca2+–H+-ATPase. These neurotransmitter-induced changes in extracellular pH have the potential to play a modulatory role in synaptic processing in the outer retina. However, our findings argue against the hypothesis that hydrogen ions released by horizontal cells normally act as the inhibitory feedback neurotransmitter onto photoreceptor synaptic terminals to create the surround portion of the centre-surround receptive fields of retinal neuron

A whole-genome sequence and transcriptome perspective on HER2-positive breast cancers

HER2-positive breast cancer has long proven to be a clinically distinct class of breast cancers for which several targeted therapies are now available. However, resistance to the treatment associated with specific gene expressions or mutations has been observed, revealing the underlying diversity of these cancers. Therefore, understanding the full extent of the HER2-positive disease heterogeneity still remains challenging. Here we carry out an in-depth genomic characterization of 64 HER2-positive breast tumour genomes that exhibit four subgroups, based on the expression data, with distinctive genomic features in terms of somatic mutations, copy-number changes or structural variations. The results suggest that, despite being clinically defined by a specific gene amplification, HER2-positive tumours melt into the whole luminal-basal breast cancer spectrum rather than standing apart. The results also lead to a refined ERBB2 amplicon of 106 kb and show that several cases of amplifications are compatible with a breakage-fusion-bridge mechanism

Machine learning uncovers the most robust self-report predictors of relationship quality across 43 longitudinal couples studies

Given the powerful implications of relationship quality for health and well-being, a central mission of relationship science is explaining why some romantic relationships thrive more than others. This large-scale project used machine learning (i.e., Random Forests) to 1) quantify the extent to which relationship quality is predictable and 2) identify which constructs reliably predict relationship quality. Across 43 dyadic longitudinal datasets from 29 laboratories, the top relationship-specific predictors of relationship quality were perceived-partner commitment, appreciation, sexual satisfaction, perceived-partner satisfaction, and conflict. The top individual-difference predictors were life satisfaction, negative affect, depression, attachment avoidance, and attachment anxiety. Overall, relationship-specific variables predicted up to 45% of variance at baseline, and up to 18% of variance at the end of each study. Individual differences also performed well (21% and 12%, respectively). Actor-reported variables (i.e., own relationship-specific and individual-difference variables) predicted two to four times more variance than partner-reported variables (i.e., the partner’s ratings on those variables). Importantly, individual differences and partner reports had no predictive effects beyond actor-reported relationship-specific variables alone. These findings imply that the sum of all individual differences and partner experiences exert their influence on relationship quality via a person’s own relationship-specific experiences, and effects due to moderation by individual differences and moderation by partner-reports may be quite small. Finally, relationship-quality change (i.e., increases or decreases in relationship quality over the course of a study) was largely unpredictable from any combination of self-report variables. This collective effort should guide future models of relationships

Sarcoidosis: Sex-Dependent Variations in Presentation and Management

Sarcoidosis is an inflammatory disease with a wide range of clinical presentations. The manifestations and prognosis in sarcoidosis are dependent upon not only organ involvement but also age and sex. The purpose of this review is to describe the systemic and ocular manifestations of sarcoidosis with a specific focus on sex-dependent difference in presentation and management. Sarcoidosis is more common in women, particularly in patients who present after age of 50 years. Women with sarcoidosis are more likely to develop cystoid macular edema and the mortality rate is higher than that of men

Etiologies of Chronic Anterior Uveitis at a Tertiary Referral Center over 35 years.

Etiologies of Chronic Anterior Uveitis at a Tertiary Referral Center over 35 years

Sarcoidosis in the National Veteran Population

PURPOSE: To describe the distribution of ocular sarcoidosis in the veteran population and to determine the association between ocular disease and all-cause mortality. DESIGN: Retrospective review. METHODS: The Veterans Health Administration National Patient Care Database information on medical diagnoses, date of diagnosis, age, race, gender, and Veterans Administration medical center station number for site-specific calculations for fiscal years 2010 through 2012 was collected. Mortality data were obtained from the Beneficiary Identification Records Locator Subsystem. The patient cohort was identified with a primary diagnosis of sarcoidosis using International Classification of Disease, ninth edition, code of 135 in outpatient treatment files for the study period. The sarcoidosis patients were divided into those with uveitis or orbital inflammation (defined as ocular inflammation for this study) and those without uveitis or orbital inflammation. Survival analysis was performed using the Cox proportional hazard method. MAIN OUTCOME MEASURE: Association between ocular inflammation and 1-year mortality. RESULTS: Of 15 130 subjects with sarcoidosis, 3364 (22.2%) were evaluated in an eye clinic within a Veterans Administration Medical Center. Most patients were diagnosed with anterior uveitis (n = 1013; 80.7% of ocular inflammation), and the least common diagnosis was orbital granuloma (n = 28; 2.2% of ocular inflammation). Male gender was protective to the development of uveitis (estimate, 0.76; 95% confidence interval, 0.65–0.88; P = 0.0005). The overall 1-year all-cause mortality for all patients with a diagnosis of sarcoidosis was 2.0%. Ocular inflammation was associated with a decrease in 1-year all-cause mortality (simple model: hazard ratio, 0.36; P = 0.0015; complex model: hazard ratio, 0.35; P = 0.013). CONCLUSIONS: Veterans with ocular inflammation had significantly lower 1-year all-cause mortality than those without documented ocular inflammation. The reason for this finding remains to be established