An inverse oblique effect in human vision

AbstractIn the classic oblique effect contrast detection thresholds, orientation discrimination thresholds, and other psychophysical measures are found to be smallest for vertical or horizontal stimuli and significantly higher for stimuli near the ±45° obliques. Here we report a novel inverse oblique effect in which thresholds for detecting translational structure in random dot patterns [Glass, L. (1969). Moiré effect from random dots. Nature, 223, 578–580] are lowest for obliquely oriented structure and higher for either horizontal or vertical structure. Area summation experiments provide evidence that this results from larger pooling areas for oblique orientations in these patterns. The results can be explained quantitatively by a model for complex cells in which the final filtering stage in a filter–rectify–filter sequence is of significantly larger area for oblique orientations

Chronic Thromboembolic Pulmonary Hypertension

The pulmonary hypertension (PH) and right heart dysfunction that results from chronic thromboembolic involvement of the pulmonary vascular bed is potentially curable with surgical endarterectomy. Over the past several decades, growing clinical experience has brought about increased recognition of this treatable form of PH. Moreover, advances in cardiothoracic surgical techniques have given an increasing number of patients with chronic thromboembolic PH (CTEPH) a surgical remedy with decreasing perioperative morbidity and mortality risks. The availability of pulmonary hypertensive—specific medical therapy for CTEPH patients with surgically inaccessible disease also has been a positive therapeutic advance over the past several years. However, despite this progress, chronic thromboembolic disease as a sequela of acute pulmonary emboli continues to be underappreciated. Furthermore, even if CTEPH has been appropriately diagnosed, misinterpretation of diagnostic information may lead to the inappropriate exclusion of patients from surgical consideration. This may result in the prescription of pulmonary hypertensive medical therapy in CTEPH patients with potentially surgically correctable disease. This difficulty arises from a lack of objective criteria as to what constitutes surgical chronic thromboembolic disease, which primarily is a result of the variability in surgical experience in specialty centers in the United States. Consequently, clinicians must be wary about using pulmonary hypertensive medications in CTEPH patients. Before prescription, it is important to exclude patients from surgical consideration by consulting a specialized center with expertise in this discipline

Rapid Genotyping of Common MeCP2 Mutations with an Electronic DNA Microchip Using Serial Differential Hybridization

Rett syndrome is a neurodevelopmental disorder that affects females almost exclusively, and in which eight common point mutations on the X-linked MeCP2 gene are knows to cause over 70% of mutation-positive cases. We explored the use of a novel platform to detect the eight common mutations in Rett syndrome patients to expedite and simplify the process of identification of known genotypes. The Nanogen workstation consists of a two-color assay based on electric hybridization and thermal discrimination, all performed on an electronically active NanoChip. This genotyping platform was tested on 362 samples of a pre-determined genotype, which had been previously identified by a combination of DHPLC (denaturing high performance liquid chromatography) and direct sequencing. This genotyping technique proved to be rapid, facile, and displayed a specificity of 100% with 3% ambiguity. In addition, we present consecutive testing of seven mutations on a single pad of the NanoChip. This was accomplished by tagging down two amplimers together and serially hybridizing for seven different loci, allowing us to genotype samples for seven of the eight common Rett mutations on a single pad. This novel method displayed the same level of specificity and accuracy as the single amplimer reactions, and proved to be faster and more economical

Inhibition of mTOR attenuates store-operated Ca2+ entry in cells from endarterectomized tissues of patients with chronic thromboembolic pulmonary hypertension

Pulmonary vascular remodeling occurs in patients with chronic thromboembolic pulmonary hypertension (CTEPH). One factor contributing to this vascular wall thickening is the proliferation of pulmonary artery smooth muscle cells (PASMC). Store-operated Ca2+ entry (SOCE) and cytosolic free Ca2+ concentration ([Ca2+]cyt) in PASMC are known to be important in cell proliferation and vascular remodeling in pulmonary hypertension. Rapamycin is widely known for its antiproliferative effects in injured coronary arteries. Although several reports have suggested favorable effects of rapamycin in animal models of pulmonary hypertension, no reports have been published to date in human tissues. Here we report that rapamycin has an inhibitory effect on SOCE and an antiproliferative effect on PASMC derived from endarterectomized tissues of CTEPH patients. Cells were isolated from endarterectomized tissues obtained from patients undergoing pulmonary thromboendarterectomy (PTE). Immunohistochemical analysis indicated high deposition of platelet-derived growth factor (PDGF) in tissue sections from PTE tissues and increased PDGF receptor expression. PDGF transiently phosphorylated Akt, mammalian target of rapamycin (mTOR), and p70S6 kinase in CTEPH cells from CTEPH patients. Acute treatment (30 min) with rapamycin (10 nM) slightly increased cyclopiazonic acid (10 μM)-induced Ca2+ mobilization and significantly reduced SOCE. Chronic treatment (24 h) with rapamycin reduced Ca2+ mobilization and markedly inhibited SOCE. The inhibitory effects of rapamycin on SOCE were less prominent in control cells. Rapamycin also significantly reduced PDGF-stimulated cell proliferation. In conclusion, the data from this study indicate the importance of the mTOR pathway in the development of pulmonary vascular remodeling in CTEPH and suggest a potential therapeutic benefit of rapamycin (or inhibition of mTOR) in these patients

Identification of putative endothelial progenitor cells (CD34+CD133+Flk-1+) in endarterectomized tissue of patients with chronic thromboembolic pulmonary hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by a fibrotic thrombus persisting and obliterating the lumen of pulmonary arteries; its pathogenesis remains poorly defined. This study investigates a potential contribution for progenitor cell types in the development of vascular obliteration and remodeling in CTEPH patients. Endarterectomized tissue from patients undergoing pulmonary thromboendarterectomy was collected and examined for the structure and cellular composition. Our data show an organized fibrin network structure in unresolved thromboemboli and intimal remodeling in vascular wall tissues, characterized by smooth muscle α-actin (SM-αA)-positive cell proliferation in proximal regions (adjacent to thromboemboli) and neoangiogenesis/recanalization in distal regions (downstream from thromboemboli). Cells that are positively stained with CD34 and fetal liver kinase-1 (Flk-1) (CD34+Flk-1+) were identified in both the proximal and distal vascular tissues; a subpopulation of CD34+Flk-1+CD133+ cells were further identified by immunostaining. Triple-positive cells are indicative of a population of putative endothelial progenitor cells or potential colony-forming units of endothelial cells. In addition, inflammatory cells (CD45+) and collagen-secreting cells (procollagen-1+) were detected in the proximal vascular wall. Some of the CD34+ cells in CTEPH cells isolated from proximal regions were also positive for SM-αA. Our data indicate that putative progenitor cell types are present in the neointima of occluded vessels of CTEPH patients. It is possible that the microenvironment provided by thromboemboli may promote these putative progenitor cells to differentiate and enhance intimal remodeling

Excess neuropeptides in lung signal through endothelial cells to impair gas exchange.

Although increased neuropeptides are often detected in lungs that exhibit respiratory distress, whether they contribute to the condition is unknown. Here, we show in a mouse model of neuroendocrine cell hyperplasia of infancy, a pediatric disease with increased pulmonary neuroendocrine cells (PNECs), excess PNEC-derived neuropeptides are responsible for pulmonary manifestations including hypoxemia. In mouse postnatal lung, prolonged signaling from elevated neuropeptides such as calcitonin gene-related peptide (CGRP) activate receptors enriched on endothelial cells, leading to reduced cellular junction gene expression, increased endothelium permeability, excess lung fluid, and hypoxemia. Excess fluid and hypoxemia were effectively attenuated by either prevention of PNEC formation, inactivation of CGRP gene, endothelium-specific inactivation of CGRP receptor gene, or treatment with CGRP receptor antagonist. Neuropeptides were increased in human lung diseases with excess fluid such as acute respiratory distress syndrome. Our findings suggest that restricting neuropeptide function may limit fluid and improve gas exchange in these conditions