Anandamide is an Early Blood Biomarker of Hermansky-Pudlak Syndrome Pulmonary Fibrosis.

Hermansky-Pudlak syndrome (HPS) is a group of rare genetic disorders, with several subtypes leading to fatal adult-onset pulmonary fibrosis (PF) and no effective treatment. Circulating biomarkers detecting early PF have not been identified. We investigated whether endocannabinoids could serve as blood biomarkers of PF in HPS. We measured endocannabinoids in the serum of HPS, IPF, and healthy human subjects and in a mouse model of HPSPF. Pulmonary function tests (PFT) were correlated with endocannabinoid measurements. In a pale ear mouse model of bleomycin-induced HPSPF, serum endocannabinoid levels were measured with and without treatment with zevaquenabant (MRI-1867), a peripheral CB1R and iNOS antagonist. In three separate cohorts, circulating anandamide levels were increased in HPS-1 patients with or without PF, compared to healthy volunteers. This increase was not observed in IPF patients or in HPS-3 patients, who do not have PF. Circulating anandamide (AEA) levels were negatively correlated with PFT. Furthermore, a longitudinal study over the course of 5-14 years with HPS-1 patients indicated that circulating AEA levels begin to increase with the fibrotic lung process even at the subclinical stages of HPSPF. In pale ear mice with bleomycin-induced HpsPF, serum AEA levels were significantly increased in the earliest stages of PF and remained elevated at a later fibrotic stage. Zevaquenabant treatment reduced the increased AEA levels and attenuated progression in bleomycin-induced HpsPF. Circulating AEA may be a prognostic blood biomarker for PF in HPS-1 patients. Further studies are indicated to evaluate endocannabinoids as potential surrogate biomarkers in progressive fibrotic lung diseases.

Automated Digital Quantification of Pulmonary Fibrosis in Human Histopathology Specimens.

Pulmonary fibrosis is characterized by abnormal interstitial extracellular matrix and cellular accumulations. Methods quantifying fibrosis severity in lung histopathology samples are semi-quantitative, subjective, and analyze only portions of sections. We sought to determine whether automated computerized imaging analysis shown to continuously measure fibrosis in mice could also be applied in human samples. A pilot study was conducted to analyze a small number of specimens from patients with Hermansky-Pudlak syndrome pulmonary fibrosis (HPSPF) or idiopathic pulmonary fibrosis (IPF). Digital images of entire lung histological serial sections stained with picrosirius red and alcian blue or anti-CD68 antibody were analyzed using dedicated software to automatically quantify fibrosis, collagen, and macrophage content. Automated fibrosis quantification based on parenchymal tissue density and fibrosis score measurements was compared to pulmonary function values or Ashcroft score. Automated fibrosis quantification of HPSPF lung explants was significantly higher than that of IPF lung explants or biopsies and was also significantly higher in IPF lung explants than in IPF biopsies. A high correlation coefficient was found between some automated quantification measurements and lung function values for the three sample groups. Automated quantification of collagen content in lung sections used for digital image analyses was similar in the three groups. CD68 immunolabeled cell measurements were significantly higher in HPSPF explants than in IPF biopsies. In conclusion, computerized image analysis provides access to accurate, reader-independent pulmonary fibrosis quantification in human histopathology samples. Fibrosis, collagen content, and immunostained cells can be automatically and individually quantified from serial sections. Robust automated digital image analysis of human lung samples enhances the available tools to quantify and study fibrotic lung disease.

CB1 R and iNOS are distinct players promoting pulmonary fibrosis in Hermansky-Pudlak syndrome.

Hermansky-Pudlak syndrome (HPS) is a rare genetic disorder which, in its most common and severe form, HPS-1, leads to fatal adult-onset pulmonary fibrosis (PF) with no effective treatment. We evaluated the role of the endocannabinoid/CB1 R system and inducible nitric oxide synthase (iNOS) for dual-target therapeutic strategy using human bronchoalveolar lavage fluid (BALF), lung samples from patients with HPS and controls, HPS-PF patient-derived lung fibroblasts, and bleomycin-induced PF in pale ear mice (HPS1ep/ep ). We found overexpression of CB1 R and iNOS in fibrotic lungs of HPSPF patients and bleomycin-infused pale ear mice. The endocannabinoid anandamide was elevated in BALF and negatively correlated with pulmonary function parameters in HPSPF patients and pale ear mice with bleomycin-induced PF. Simultaneous targeting of CB1 R and iNOS by MRI-1867 yielded greater antifibrotic efficacy than inhibiting either target alone by attenuating critical pathologic pathways. Moreover, MRI-1867 treatment abrogated bleomycin-induced increases in lung levels of the profibrotic interleukin-11 via iNOS inhibition and reversed mitochondrial dysfunction via CB1 R inhibition. Dual inhibition of CB1 R and iNOS is an effective antifibrotic strategy for HPSPF.

Internet-of-Things Devices in Support of the Development of Echoic Skills among Children with Autism Spectrum Disorder.

A significant therapeutic challenge for people with disabilities is the development of verbal and echoic skills. Digital voice assistants (DVAs), such as Amazon's Alexa, provide networked intelligence to billions of Internet-of-Things devices and have the potential to offer opportunities to people, such as those diagnosed with autism spectrum disorder (ASD), to advance these necessary skills. Voice interfaces can enable children with ASD to practice such skills at home; however, it remains unclear whether DVAs can be as proficient as therapists in recognizing utterances by a developing speaker. We developed an Alexa-based skill called ASPECT to measure how well the DVA identified verbalization by autistic children. The participants, nine children diagnosed with ASD, each participated in 30 sessions focused on increasing vocalizations and echoic responses. Children interacted with ASPECT prompted by instructions from an Echo device. ASPECT was trained to recognize utterances and evaluate them as a therapist would-simultaneously, a therapist scored the child's responses. The study identified no significant difference between how ASPECT and the therapists scored participants; this conclusion held even when subsetting participants by a pre-treatment echoic skill assessment score. This indicates considerable potential for providing a continuum of therapeutic opportunities and reinforcement outside of clinical settings.

Genetic variants associated with Hermansky-Pudlak syndrome.

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by defective biogenesis of lysosome-related organelles. Clinical manifestations include a bleeding diathesis due to a platelet delta storage pool deficiency, oculocutaneous albinism, inflammatory bowel disease, neutropenia, and pulmonary fibrosis. Ten genes associated with HPS are identified to date, and each gene encodes a protein subunit of either Biogenesis of Lysosome-related Organelles Complex (BLOC)-1, BLOC-2, BLOC-3, or the Adaptor Protein-3 complex. Several genetic variants and phenotypic heterogeneities are reported in individuals with HPS, who generally exhibit easy bruisability and increased bleeding. Desmopressin, pro-coagulants, or platelet transfusion may be used as prophylaxis or treatment for excessive bleeding in patients with HPS. However, response to desmopressin can be variable. Platelets are effective in preventing or treating bleeding in individuals with HPS, but platelets should be transfused judiciously to limit alloimmunization in patients with HPS who are at risk of developing pulmonary fibrosis and may be potential candidates for lung transplantation. The discovery of new genes associated with HPS in people with excessive bleeding and hypopigmentation of unknown etiology may be facilitated by the use of next-generation sequencing or panel-based genetic testing.

Aortic distensibility in alkaptonuria.

INTRODUCTION: Alkaptonuria (AKU) is a rare inherited disorder of tyrosine metabolism resulting in an accumulation of homogentisic acid oxidation products in the joints and cardiovascular system. Aortic distensibility may be a non-invasive indicator of cardiovascular complications. Descending thoracic aortic distensibility in alkaptonuria has not been studied. METHODS: Patients diagnosed with alkaptonuria underwent Magnetic Resonance Imaging (MRI) and gated non-contrast and contrast-enhanced cardiovascular computed tomography. Using MRI cine images, aortic distensibility of the descending thoracic aorta was determined. RESULTS: Seventy-six patients with alkaptonuria were imaged. When compared to literature normal values, aortic distensibility in AKU was impaired (5.2 vs 6.2 × 10-3, p < .001). Aortic distensibility was inversely related to age (r = -0.6, p = .0001). Hypertensive patients with alkaptonuria had impaired distensibility compared to normotensive patients with alkaptonuria (4.6 vs 5.6 × 10-3, p = .03), and hyperlipidemic patients with alkaptonuria had impaired distensibility compared to non-hyperlipidemic patients with alkaptonuria (4.1 vs 6.0 × 10-3, p = .001). Male hypertensive patients with alkaptonuria had greater distensibility than their female counterparts (5.3 vs 2.9 × 10-3, p = .02). Similarly, male hyperlipidemic patients with alkaptonuria had greater distensibility than their female counterparts (4.8 vs 2.5 × 10-3, p < .01). Of patients with alkaptonuria, those with a coronary artery calcium (CAC) score greater than 100 had more impaired distensibility than those with a CAC score less than 100 (3.5 vs 5.1 × 10-3, p = .01) and those with aortic calcium score greater than 100 had impaired distensibility compared to those with an aortic calcium score less than 100 (3.2 vs 4.9 × 10-3, p = .02). Univariate analysis revealed age, aortic calcification, and hyperlipidemia to be significant factors of distensibility, and multiple regression analysis showed age as the only significant risk factor of distensibility. CONCLUSIONS: Patients with alkaptonuria have impaired aortic distensibility, which is likely an early marker for reduced cardiovascular health. Variables such as age, hypertension, hyperlipidemia, and aortic and coronary calcification were associated with impaired distensibility.

Neurological manifestations of Erdheim-Chester Disease.

OBJECTIVE: To characterize the spectrum of neurologic involvement in Erdheim-Chester Disease (ECD), a treatable inflammatory neoplasm of histiocytes. METHODS: Sixty-two patients with ECD were prospectively enrolled in a natural history study that facilitated collection of clinical, imaging, laboratory, neurophysiologic, and pathologic data. RESULTS: Ninety-four percent of the patients had neurologic abnormalities on examination or imaging, and 22% had neurologic symptoms as the initial presentation of ECD. The most common neurologic findings were cognitive impairment, peripheral neuropathy, pyramidal tract signs, cranial nerve involvement, and cerebellar ataxia. Imaging revealed atrophy and demyelination along with focal lesions that were located throughout the nervous system, dura, and extra-axial structures. The BRAF V600E variant correlated with cerebral atrophy. Brain pathology revealed lipid-laden, phagocytic macrophages (histiocytes) accompanied by demyelination and axonal degeneration. INTERPRETATION: In patients with ECD, neurologic morbidity is common and contributes significantly to disability. Since neurologic symptoms can be the presenting feature of ECD and, given the mean delay in ECD diagnosis is 4.2 years, it is critical that neurologists consider of ECD and other histiocytosis in patients with inflammatory, infectious, or neoplastic-appearing white matter. Furthermore, given the broad spectrum of neurologic involvement, neurologists have an important role in a team of specialists treating ECD patients.

Hermansky-Pudlak syndrome: Mutation update.

Hermansky-Pudlak syndrome (HPS) is a group of 10 autosomal recessive multisystem disorders, each defined by the deficiency of a specific gene. HPS-associated genes encode components of four ubiquitously expressed protein complexes: Adaptor protein-3 (AP-3) and biogenesis of lysosome-related organelles complex-1 (BLOC-1) through -3. All individuals with HPS exhibit albinism and a bleeding diathesis; additional features occur depending on the defective protein complex. Pulmonary fibrosis is associated with AP-3 and BLOC-3 deficiency, immunodeficiency with AP-3 defects, and gastrointestinal symptoms are more prevalent and severe in BLOC-3 deficiency. Therefore, identification of the HPS subtype is valuable for prognosis, clinical management, and treatment options. The prevalence of HPS is estimated at 1-9 per 1,000,000. Here we summarize 264 reported and novel variants in 10 HPS genes and estimate that ~333 Puerto Rican HPS subjects and ~385 with other ethnicities are reported to date. We provide pathogenicity predictions for missense and splice site variants and list variants with high minor allele frequencies. Current cellular and clinical aspects of HPS are also summarized. This review can serve as a manifest for molecular diagnostics and genetic counseling aspects of HPS.

Evaluation of the Commercial, Off-the-Shelf (COTS) King-Devick Eye Tracking System.

Concussion biomarkers are important guides for diagnosis and return-to-duty decisions. Recent literature describes the King-Devick (KD) test as a sensitive sports-related concussion screener. This test involves timing an individual reading aloud 120 digits printed on three test cards. The test is commonly considered to evaluate the effects of concussion and other factors on reading-related eye movements (EMs). However, the extent to which the KD test reflects EMs remains a matter of conjecture since the test reports only reading speed and number of errors. An off-the-shelf, computerized KD with eye tracking system recently became commercially available. Two early model KD with eye tracking systems were purchased in 2015 and evaluated before deploying them for research. The evaluation consisted of two studies; one with 20 volunteers assessing the comparability of the two systems and the other with 5 volunteers to quantify the systems' stability and repeatability over 5 successive days. The results showed that several of the systems' reported EM response parameters lacked face validity; consequently, the systems could not be used for scientific research. This conclusion emphasizes the importance of systematic test and evaluation of new equipment before it is used for research.

Hermansky-Pudlak syndrome and oculocutaneous albinism in Chinese children with pigmentation defects and easy bruising.

BACKGROUND: Determining the etiology of oculocutaneous albinism is important for proper clinical management and to determine prognosis. The purpose of this study was to genotype and phenotype eight adopted Chinese children who presented with oculocutaneous albinism and easy bruisability. RESULTS: The patients were evaluated at a single center; their ages ranged from 3 to 8 years. Whole exome or direct sequencing showed that two of the children had Hermansky-Pudlak syndrome (HPS) type-1 (HPS-1), one had HPS-3, one had HPS-4, and four had non-syndromic oculocutaneous albinism associated with TYR variants (OCA1). Two frameshift variants in HPS1 (c.9delC and c.1477delA), one nonsense in HPS4 (c.416G > A), and one missense variant in TYR (c.1235C > T) were unreported. The child with HPS-4 is the first case with this subtype reported in the Chinese population. Hypopigmentation in patients with HPS was mild compared to that in OCA1 cases, who had severe pigment defects. Bruises, which may be more visible in patients with hypopigmentation, were found in all cases with either HPS or OCA1. Whole mount transmission electron microscopy demonstrated absent platelet dense granules in the HPS cases; up to 1.9 mean dense granules per platelet were found in those with OCA1. Platelet aggregation studies in OCA1 cases were inconclusive. CONCLUSIONS: Clinical manifestations of oculocutaneous albinism and easy bruisability may be observed in children with HPS or OCA1. Establishing definitive diagnoses in children presenting with these phenotypic features is facilitated by genetic testing. Non-syndromic oculocutaneous albinism and various HPS subtypes, including HPS-4, are found in children of Chinese ancestry.

Severe bleeding with subclinical oculocutaneous albinism in a patient with a novel HPS6 missense variant.

Hermanský-Pudlák syndrome (HPS), a rare autosomal recessive disorder, manifests with oculocutaneous albinism and a bleeding diathesis. However, severity of disease can be variable and is typically related to the genetic subtype of HPS; HPS type 6 (HPS-6) is an uncommon subtype generally associated with mild disease. A Caucasian adult female presented with a history of severe bleeding; ophthalmologic examination indicated occult oculocutaneous albinism. The patient was diagnosed with a platelet storage pool disorder, and platelet whole mount electron microscopy demonstrated absent delta granules. Genome-wide SNP analysis showed regions of homozygosity that included the HPS1 and HPS6 genes. Full length HPS1 transcript was amplified by PCR of genomic DNA. Targeted next-generation sequencing identified a novel homozygous missense variant in HPS6 (c.383 T > C; p.V128A); this was associated with significantly reduced HPS6 mRNA and protein expression in the patient's fibroblasts compared to control cells. These findings highlight the variable severity of disease manifestations in patients with HPS, and illustrate that HPS can be diagnosed in patients with excessive bleeding and occult oculocutaneous albinism. Genetic analysis and platelet electron microscopy are useful diagnostic tests in evaluating patients with suspected HPS. Clinical Trial registration: Registrar: ClinicalTrials.gov Website: www.clinicaltrials.gov Registration Numbers: NCT00001456 and NCT00084305.

Clinical and Histopathologic Features of Interstitial Lung Disease in Erdheim⁻Chester Disease.

Limited information is available regarding interstitial lung disease (ILD) in Erdheim⁻Chester disease (ECD), a rare multisystemic non-Langerhans cell histiocytosis. Sixty-two biopsy-confirmed ECD patients were divided into those with no ILD (19.5%), minimal ILD (32%), mild ILD (29%), and moderate/severe ILD (19.5%), based on computed tomography (CT) findings. Dyspnea affected at least half of the patients with mild or moderate/severe ILD. Diffusion capacity was significantly reduced in ECD patients with minimal ILD. Disease severity was inversely correlated with pulmonary function measurements; no correlation with BRAF V600E mutation status was seen. Reticulations and ground-glass opacities were the predominant findings on CT images. Automated CT scores were significantly higher in patients with moderate/severe ILD, compared to those in other groups. Immunostaining of lung biopsies was consistent with ECD. Histopathology findings included subpleural and septal fibrosis, with areas of interspersed normal lung, diffuse interstitial fibrosis, histiocytes with foamy cytoplasm embedded in fibrosis, lymphoid aggregates, and focal type II alveolar cell hyperplasia. In conclusion, ILD of varying severity may affect a high proportion of ECD patients. Histopathology features of ILD in ECD can mimic interstitial fibrosis patterns observed in idiopathic ILD.

Prolonged treatment with open-label pirfenidone in Hermansky-Pudlak syndrome pulmonary fibrosis.

PURPOSE: Limited information is available regarding chronic treatment with pirfenidone, an anti-fibrotic drug. Effects of long-term open-label pirfenidone were evaluated in a small cohort with Hermansky-Pudlak syndrome (HPS), a rare autosomal recessive disorder with highly penetrant pulmonary fibrosis. RESULTS: Three patients with HPS pulmonary fibrosis treated with open-label pirfenidone and twenty-one historical controls randomized to placebo were studied at a single center. Mean duration of treatment with pirfenidone for 3 patients with HPS pulmonary fibrosis was 13.1 years. Annual changes in FVC and DLCO with pirfenidone treatment were 0.46 and - 0.93% predicted, respectively. In comparison, historical controls randomized to receive placebo experienced mean annual changes in FVC and DLCO of -4.4 and - 2.3% predicted, respectively. High-resolution computed tomography (HRCT) scans revealed improved ground glass opacities with development of minimal interstitial reticulations in 1 patient after 12.8 years of treatment with pirfenidone. Slowly progressive increase in bilateral interstitial fibrosis developed in a different patient, who received pirfenidone for 18.1 years and died at 73 years of age due to HPS pulmonary fibrosis. Another patient treated with pirfenidone for 8.4 years had attenuated ground glass opacification on HRCT scan and improved oxygenation; this patient died due to chronic complications from colitis, and not pulmonary fibrosis. Adverse effects were generally limited to mild gastrointestinal discomfort and transient elevations of alanine aminotransferase in one patient. CONCLUSIONS: Chronic treatment with pirfenidone may provide clinical benefit with few adverse effects for some patients with HPS pulmonary fibrosis. These results suggest that compassionate use of pirfenidone could be considered on a case-by-case basis for patients with HPS pulmonary fibrosis.

Clinical management and outcomes of patients with Hermansky-Pudlak syndrome pulmonary fibrosis evaluated for lung transplantation.

Pulmonary fibrosis is a progressive, fatal manifestation of Hermansky-Pudlak syndrome (HPS). Some patients with advanced HPS pulmonary fibrosis undergo lung transplantation despite their disease-associated bleeding tendency; others die while awaiting donor organs. The objective of this study is to determine the clinical management and outcomes of a cohort with advanced HPS pulmonary fibrosis who were evaluated for lung transplantation. Six patients with HPS-1 pulmonary fibrosis were evaluated at the National Institutes of Health Clinical Center and one of two regional lung transplant centers. Their median age was 41.5 years pre-transplant. Three of six patients died without receiving a lung transplant. One of these was referred with end-stage pulmonary fibrosis and died before a donor organ became available, and donor organs were not identified for two other patients sensitized from prior blood product transfusions. Three of six patients received bilateral lung transplants; they did not have a history of excessive bleeding. One patient received peri-operative desmopressin, one was transfused with intra-operative platelets, and one received extracorporeal membrane oxygenation and intra-operative prothrombin complex concentrate, platelet transfusion, and desmopressin. One transplant recipient experienced acute rejection that responded to pulsed steroids. No evidence of chronic lung allograft dysfunction or recurrence of HPS pulmonary fibrosis was detected up to 6 years post-transplant in these three lung transplant recipients. In conclusion, lung transplantation and extracorporeal membrane oxygenation are viable options for patients with HPS pulmonary fibrosis. Alloimmunization in HPS patients is an important and potentially preventable barrier to lung transplantation; interventions to limit alloimmunization should be implemented in HPS patients at risk of pulmonary fibrosis to optimize their candidacy for future lung transplants.

The Immunome in Two Inherited Forms of Pulmonary Fibrosis.

The immunome (immune cell phenotype, gene expression, and serum cytokines profiling) in pulmonary fibrosis is incompletely defined. Studies focusing on inherited forms of pulmonary fibrosis provide insights into mechanisms of fibrotic lung disease in general. To define the cellular and molecular immunologic phenotype in peripheral blood, high-dimensional flow cytometry and large-scale gene expression of peripheral blood mononuclear cells and serum proteomic multiplex analyses were performed and compared in a cohort with familial pulmonary fibrosis (FPF), an autosomal dominant disorder with incomplete penetrance; Hermansky-Pudlak syndrome pulmonary fibrosis (HPSPF), a rare autosomal recessive disorder; and their unaffected relatives. Our results showed high peripheral blood concentrations of activated central memory helper cells in patients with FPF. Proportions of CD38+ memory CD27- B-cells, IgA+ memory CD27+ B-cells, IgM+ and IgD+ B-cells, and CD39+ T helper cells were increased whereas those of CD39- T helper cells were reduced in patients affected with either familial or HPSPF. Gene expression and serum proteomic analyses revealed enrichment of upregulated genes associated with mitosis and cell cycle control in circulating mononuclear cells as well as altered levels of several analytes, including leptin, cytokines, and growth factors. In conclusion, dysregulation of the extra-pulmonary immunome is a phenotypic feature of FPF or HPSPF. Further studies investigating the blood immunome are indicated to determine the role of immune system dysregulation in the pathogenesis of pulmonary fibrosis. Clinical Trial Registration: www.ClinicalTrials.gov, identifiers NCT00968084, NCT01200823, NCT00001456, and NCT00084305.

Developmental trends in infant temporal processing speed.

Processing speed, which can be measured behaviorally in various sensory domains, has been shown to be a strong marker of central nervous system health and functioning in adults. Visual temporal processing speed (measured via critical flicker fusion [CFF] thresholds) represents the maximum speed at which the visual system can detect changes. Previous studies of infant CFF development have been limited and inconsistent. The present study sought to characterize the development of CFF thresholds in the first year of life using a larger sample than previous studies and a repeated measures design (in Experiment 2) to control for individual differences. Experiment 1 (n=44 infants and n=24 adults) used a cross-sectional design aimed at examining age-related changes that exist in CFF thresholds across infants during the first year of life. Adult data were collected to give context to infant CFF thresholds obtained under our specific stimulus conditions. Experiment 2 (N=28) used a repeated-measures design to characterize the developmental trajectory of infant CFF thresholds between three and six months of age, based on the results of Experiment 1. Our results reveal a general increase in CFF from three to four and one-half months of age, with a high degree of variability within each age group. Infant CFF thresholds at 4.5months of age were not significantly different from the adult average, though a regression analysis of the data from Experiment 2 predicted that infants would reach the adult average closer to 6months of age. Developmental and clinical implications of these data are discussed.

Macular Carotenoid Supplementation Improves Visual Performance, Sleep Quality, and Adverse Physical Symptoms in Those with High Screen Time Exposure.

The dramatic rise in the use of smartphones, tablets, and laptop computers over the past decade has raised concerns about potentially deleterious health effects of increased "screen time" (ST) and associated short-wavelength (blue) light exposure. We determined baseline associations and effects of 6 months' supplementation with the macular carotenoids (MC) lutein, zeaxanthin, and mesozeaxanthin on the blue-absorbing macular pigment (MP) and measures of sleep quality, visual performance, and physical indicators of excessive ST. Forty-eight healthy young adults with at least 6 h of daily near-field ST exposure participated in this placebo-controlled trial. Visual performance measures included contrast sensitivity, critical flicker fusion, disability glare, and photostress recovery. Physical indicators of excessive screen time and sleep quality were assessed via questionnaire. MP optical density (MPOD) was assessed via heterochromatic flicker photometry. At baseline, MPOD was correlated significantly with all visual performance measures (p < 0.05 for all). MC supplementation (24 mg daily) yielded significant improvement in MPOD, overall sleep quality, headache frequency, eye strain, eye fatigue, and all visual performance measures, versus placebo (p < 0.05 for all). Increased MPOD significantly improves visual performance and, in turn, improves several undesirable physical outcomes associated with excessive ST. The improvement in sleep quality was not directly related to increases in MPOD, and may be due to systemic reduction in oxidative stress and inflammation.

The clinical spectrum of Erdheim-Chester disease: an observational cohort study.

Erdheim-Chester Disease (ECD) is a rare, potentially fatal, multi-organ myeloid neoplasm occurring mainly in adults. The diagnosis is established by clinical, radiologic, and histologic findings; ECD tumors contain foamy macrophages that are CD68+, CD163+, CD1a-, and frequently S100-. The purpose of this report is to describe the clinical and molecular variability of ECD. Sixty consecutive ECD patients (45 males, 15 females) were prospectively evaluated at the NIH Clinical Center between 2011 and 2015. Comprehensive imaging and laboratory studies were performed, and tissues were examined for BRAF V600E and MAPK pathway mutations. Mean age at first manifestations of ECD was 46 years; a diagnosis was established, on average, 4.2 years after initial presentation. Bone was the most common tissue affected, with osteosclerosis in 95% of patients. Other manifestations observed in one-third to two-thirds of patients include cardiac mass and periaortic involvement, diabetes insipidus, retro-orbital infiltration, retroperitoneal, lung, CNS, skin and xanthelasma, usually in combination. Methods of detection included imaging studies of various modalities. Mutation in BRAF V600E was detected in 51% of 57 biopsies. One patient had an ARAF D228V mutation, and one had an activating ALK fusion. Treatments included interferon alpha, imatinib, anakinra, cladribine, vemurafenib and dabrafenib with trametinib; eleven patients received no therapy. The diagnosis of ECD is elusive because of the rarity and varied presentations of the disorder. Identification of BRAF and other MAPK pathway mutations in biopsies improves ECD diagnosis, allows for development of targeted treatments, and demonstrates that ECD is a neoplastic disorder.

Contrast Sensitivity and Lateral Inhibition Are Enhanced With Macular Carotenoid Supplementation.

Purpose: Once deposited in the retina, the so-called macular carotenoids lutein (L), zeaxanthin (Z), and mesozeaxanthin (MZ) have been shown to enhance visual performance. The purpose of our study was to investigate whether increasing macular pigment optical density (MPOD) could enhance lateral inhibitory processes, and thereby improve contrast sensitivity (CS). Methods: A total of 59 young (18-25 years), healthy individuals participated in this 1-year, double-masked, placebo-controlled study. MPOD was assessed via heterochromatic flicker photometry. Lateral inhibition sensitivity (LIS) was determined with a computer-based, user-adjustable Hermann grid. CS (at 8 cycles/degree) was determined with a two-alternative, forced-choice procedure. Subjects received either the placebo (n = 10), 12 mg total macular carotenoids (n = 24), or 24 mg total macular carotenoids (n = 25). Results: MPOD, LIS, and CS increased significantly in treatment groups between baseline and 6 months, and between 6 and 12 months (P < 0.05 for all) versus placebo. The relationships between changes in MPOD and both LIS and CS were significant at 6 and 12 months (P < 0.05 for both). Changes in CS and LIS over the 12-month study period were found to be significantly related (r = 0.41; P = 0.0014). Conclusions: Increases in MPOD led to enhanced lateral inhibitory processes, which correspond to improved CS. Because optical filtering has the same net effect on dark versus light bars, it cannot explain these improvements. Improvement in CS with increases in MPOD therefore appears to involve enhancement of the fundamental physiological systems that give rise to edge detection.