Lessons from angiotensin-converting enzyme-deficient mice

Journal ArticleSince the first description of renin by Tigerstedt and Bergman [1] in 1898, many papers have described the biochemistry and physiological roles of the reninangiotensin system [2]. A critical component of this system is angiotensin-converting enzyme (ACE), a peptidase which cleaves the inactive peptide angiotensin (Ang) I to generate the potent vasoconstrictor Ang II. This enzyme also cleaves other peptides, including bradykinin. Its activity increases blood pressure, and ACE inhibitors have become a mainstay in the treatment of hypertension and congestive heart failure. It has recently become possible to create mice which lack ACE. These mice have low systolic blood pressure, striking renal defects and reduced male fertility, phenotypes which emphasize the familiar roles of ACE and provide insight into unexpected functions of this enzyme

Metabolomic analysis of bronchoalveolar lavage fluid from cystic fibrosis patients

Metabolite profiles of bronchoalveolar lavage fluid (BALF) from pediatric patients with cystic fibrosis (CF) were correlated to the degree of airway inflammation using nuclear magnetic resonance spectroscopy-based metabolomics. BALF was collected from 11 children with CF during clinically indicated bronchoscopy. The spectra from BALF with high levels of neutrophilic airway inflammation displayed signals from numerous metabolites, whereas the spectra from subjects with low levels of inflammation were very sparse. The metabolites identified in samples taken from subjects with high inflammation include known markers of inflammation such as amino acids and lactate, as well as many novel signals. Statistical analysis highlighted the most important metabolites that distinguished the high- from the low-inflammation groups. This first demonstration of metabolomics of human BALF shows that clear distinctions in the metabolic profiles can be observed between subjects experiencing high versus low inflammation and is a first step toward the goal of discovering novel biomarkers of airway inflammation

Exhaled breath condensate purines correlate with lung function in infants and preschoolers

Although airway inflammation begins early in life in children with chronic respiratory diseases, current methods to assess this inflammation are invasive and entail significant risk. Measurement of exhaled breath condensate (EBC) purines and other biomarkers offer a less invasive method to assess airway inflammation; however, the feasibility and utility of EBC biomarkers in young children has not been established

Elevated Airway Purines in COPD

Adenosine and related purines have established roles in inflammation, and elevated airway concentrations are predicted in patients with COPD. However, accurate airway surface purine measurements can be confounded by stimulation of purine release during collection of typical respiratory samples

Atopic Asthmatics but not atopics without asthma have enhanced inflammatory response to ozone

Asthma is a known risk factor for acute ozone-associated respiratory disease. Ozone (O3) causes an immediate decrease in lung function and increased airway inflammation. The role of atopy and asthma in modulation of O3-induced inflammation has not been determined

Whole Slide Imaging Versus Microscopy for Primary Diagnosis in Surgical Pathology: A Multicenter Blinded Randomized Noninferiority Study of 1992 Cases (Pivotal Study)

Most prior studies of primary diagnosis in surgical pathology using whole slide imaging (WSI) versus microscopy have focused on specific organ systems or included relatively few cases. The objective of this study was to demonstrate that WSI is noninferior to microscopy for primary diagnosis in surgical pathology. A blinded randomized noninferiority study was conducted across the entire range of surgical pathology cases (biopsies and resections, including hematoxylin and eosin, immunohistochemistry, and special stains) from 4 institutions using the original sign-out diagnosis (baseline diagnosis) as the reference standard. Cases were scanned, converted to WSI and randomized. Sixteen pathologists interpreted cases by microscopy or WSI, followed by a wash-out period of ≥4 weeks, after which cases were read by the same observers using the other modality. Major discordances were identified by an adjudication panel, and the differences between major discordance rates for both microscopy (against the reference standard) and WSI (against the reference standard) were calculated. A total of 1992 cases were included, resulting in 15,925 reads. The major discordance rate with the reference standard diagnosis was 4.9% for WSI and 4.6% for microscopy. The difference between major discordance rates for microscopy and WSI was 0.4% (95% confidence interval, -0.30% to 1.01%). The difference in major discordance rates for WSI and microscopy was highest in endocrine pathology (1.8%), neoplastic kidney pathology (1.5%), urinary bladder pathology (1.3%), and gynecologic pathology (1.2%). Detailed analysis of these cases revealed no instances where interpretation by WSI was consistently inaccurate compared with microscopy for multiple observers. We conclude that WSI is noninferior to microscopy for primary diagnosis in surgical pathology, including biopsies and resections stained with hematoxylin and eosin, immunohistochemistry and special stains. This conclusion is valid across a wide variety of organ systems and specimen types

Aortic valve calcification volumes and chronic brain infarctions in patients undergoing transcatheter aortic valve implantation

Chronic silent brain infarctions, detected as new white matter hyperintensities on magnetic resonance imaging (MRI) following transcatheter aortic valve implantation (TAVI), are associated with long-term cognitive deterioration. This is the first study to investigate to which extent the calcification volume of the native aortic valve (AV) measured with cardiac computed tomography angiography (CTA) predicts the increase in chronic white matter hyperintensity volume after TAVI. A total of 36 patients (79 ± 5 years, median EuroSCORE II 1.9%, Q1–Q3 1.5–3.4%) with severe AV stenosis underwent fluid attenuation inversion recovery (FLAIR) MRI < 24 h prior to TAVI and at 3 months follow-up for assessment of cerebral white matter hyperintensity volume (mL). Calcification volumes (mm3) of the AV, aortic arch, landing zone and left ventricle were measured on the CTA pre-TAVI. The largest calcification volumes were found in the AV (median 692 mm3) and aortic arch (median 633 mm3), with a large variation between patients (Q1–Q3 482–1297 mm3 and 213–1727 mm3, respectively). The white matter hyperintensity volume increased in 72% of the patients. In these patients the median volume increase was of 1.1 mL (Q1–Q3 0.3–4.6 mL), corresponding with a 27% increase from baseline (Q1–Q3 7–104%). The calcification volume in the AV predicted the increase of white matter hyperintensity volume (Δ%), with a 35% increase of white matter hyperintensity volume, per 100 mm3 of AV calcification volume (SE 8.5, p < 0.001). The calcification volumes in the aortic arch, landing zone and left ventricle were not associated with the increase in white matter hyperintensity volume. In 72% of the patients new chronic white matter hyperintensities developed 3 months after TAVI, with a median increase of 27%. A higher calcification volume in the AV was associated with a larger increase in the white matter hyperintensity volume. These findings show the potential for automated AV calcium screening as an imaging biomarker to predict chronic silent brain infarctions

Communications Biophysics

Contains reports on nine research projects split into four sections.National Institutes of Health (Grant 5 P01 NS13126)National Institutes of Health (Grant 5 K04 NS00113)National Institutes of Health (Training Grant 5 T32 NS07047)National Institutes of Health (Grant 5 ROl NS11153-03)National Institutes of Health (Fellowship 1 T32 NS07099-01)National Science Foundation (Grant BNS77-16861)National Institutes of Health (Grant 5 ROl NS10916)National Institutes of Health (Grant 5 ROl NS12846)National Science Foundation (Grant BNS77-21751)National Institutes of Health (Grant 1 RO1 NS14092)Health Sciences FundNational Institutes of Health (Grant 2 R01 NS11680)National Institutes of Health (Grant 2 RO1 NS11080)National Institutes of Health (Training Grant 5 T32 GM07301

Genetic architecture of subcortical brain structures in 38,851 individuals

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness