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Radiocarbon dating of the earliest occupational phases at the Cooper’s Ferry site in western Idaho indicates that people repeatedly occupied the Columbia River basin, starting between 16,560 and 15,280 calibrated years before the present (cal yr B.P.). Artifacts from these early occupations indicate the use of unfluted stemmed projectile point technologies before the appearance of the Clovis Paleoindian tradition and support early cultural connections with northeastern Asian Upper Paleolithic archaeological traditions. The Cooper’s Ferry site was initially occupied during a time that predates the opening of an ice-free corridor (≤14,800 cal yr B.P.), which supports the hypothesis that initial human migration into the Americas occurred via a Pacific coastal route.

Cardiac troponin-I (cTnI) is a highly sensitive and specific marker of myocardial injury detectable in plasma by immunoassay techniques. Inclusion criteria over a 3-year period required a diagnosis of cardiac disease accompanied by electrocardiographic (ECG) and cardiac ultrasound examinations (n = 23) in adult horses (≥2 years of age). A second group of normal adult ponies (n = 12) was studied as a reference group. Heparinized jugular venous blood samples were collected and centrifuged within 30 min, and the plasma was separated and frozen at −70 °C for subsequent batched cTnI analysis. The lower limit of detection was 0.01 ng/mL, and the upper limit was 100 ng/mL of plasma. Normal equine plasma cTnI concentrations ranged from 0.01 to 0.03 ng/mL (n = 12). Horses with non-arrhythmogenic murmurs (n = 4) included tricuspid (0.05 ng/mL cTnI), mitral (0.07), and aortic insufficiencies (0.01, 0.02). Horses with benign atrial fibrillation (n = 8) had a cTnI range of <0.01–0.09 ng/mL, with four horses having cTnI concentrations falling slightly outside the reference range (0.04, 0.05, 0.06, and 0.09). Horses with ventricular arrhythmias (ventricular premature contractions or ventricular tachycardia) and documentable myocardial toxicities or immunological reactions (n = 5) had cTnI concentrations of 0.05, 0.21, 0.31, 15.18, and >100 ng/mL. Horses with ventricular arrhythmias but no documentation of myocardial toxicity (n = 3) had cTnI concentrations of 0.34, 0.46, and 80.42 ng/mL. When grouped by arrhythmia type and compared using the Mann–Whitney Rank Sum Test, the median ventricular arrhythmia cTnI (0.40 ng/mL) was significantly higher than the median atrial fibrillation cTnI (0.04 ng/mL, p < 0.001). It was concluded that horses with myocardial toxicities and ventricular arrhythmias often had severe elevations in plasma cTnI.

Abstract Cardiac troponin-I (cTnI) is a highly sensitive and specific marker of myocardial injury and can be detected in plasma by immunoassay techniques. The purpose of this study was to establish a reference range for plasma cTnI in a population of healthy dogs using a human immunoassay system and to determine whether plasma cTnI concentrations were high in dogs with acquired or congenital heart disease, specifically cardiomyopathy (CM), degenerative mitral valve disease (MVD), and subvalvular aortic stenosis (SAS). In total, 269 dogs were examined by physical examination, electrocardiography, echocardiography, and plasma cTnI assay. In 176 healthy dogs, median cTnI was 0.03 ng/mL (upper 95th percentile = 0.11 ng/mL). Compared with the healthy population, median plasma cTnI was increased in dogs with CM (0.14 ng/mL; range, 0.03-1.88 ng/mL; P <.001; n = 26), in dogs with MVD (0.11 ng/mL; range, 0.01–9.53 ng/mL; P <.001; n = 37), and in dogs with SAS (0.08 ng/mL; range, 0.01-0.94 ng/mL; P <.001; n = 30). In dogs with CM and MVD, plasma cTnI was correlated with left ventricular and left atrial size. In dogs with SAS, cTnI demonstrated a modest correlation with ventricular wall thickness. In dogs with CM, the median survival time of those with cTnI >0.20 ng/mL was significantly shorter than median survival time of those with cTnI <0.20 ng/mL (112 days versus 357 days; P= .006). Plasma cTnI is high in dogs with cardiac disease, correlates with heart size and survival, and can be used as a blood-based biomarker of cardiac disease.

Cardiac troponin-I (cTnI) is a highly sensitive and specific marker of myocardial injury and can be detected in plasma by immunoassay techniques. The purpose of this study was to establish a reference range for plasma cTnI in a population of healthy dogs using a human immunoassay system and to determine whether plasma cTnI concentrations were high in dogs with acquired or congenital heart disease, specifically cardiomyopathy (CM), degenerative mitral valve disease (MVD), and subvalvular aortic stenosis (SAS). In total, 269 dogs were examined by physical examination, electrocardiography, echocardiography, and plasma cTnI assay. In 176 healthy dogs, median cTnI was 0.03 ng/mL (upper 95th percentile = 0.11 ng/mL). Compared with the healthy population, median plasma cTnI was increased in dogs with CM (0.14 ng/mL; range, 0.03-1.88 ng/mL; P < .001; n = 26), in dogs with MVD (0.11 ng/mL; range, 0.01-9.53 ng/mL; P < .001; n = 37), and in dogs with SAS (0.08 ng/mL; range, 0.01-0.94 ng/mL; P < .001; n = 30). In dogs with CM and MVD, plasma cTnI was correlated with left ventricular and left atrial size. In dogs with SAS, cTnI demonstrated a modest correlation with ventricular wall thickness. In dogs with CM, the median survival time of those with cTnI >0.20 ng/mL was significantly shorter than median survival time of those with cTnI <0.20 ng/mL (112 days versus 357 days; P = .006). Plasma cTnI is high in dogs with cardiac disease, correlates with heart size and survival, and can be used as a blood-based biomarker of cardiac disease.Cardiac troponin-I (cTnI) is a highly sensitive and specific marker of myocardial injury and can be detected in plasma by immunoassay techniques. The purpose of this study was to establish a reference range for plasma cTnI in a population of healthy dogs using a human immunoassay system and to determine whether plasma cTnI concentrations were high in dogs with acquired or congenital heart disease, specifically cardiomyopathy (CM), degenerative mitral valve disease (MVD), and subvalvular aortic stenosis (SAS). In total, 269 dogs were examined by physical examination, electrocardiography, echocardiography, and plasma cTnI assay. In 176 healthy dogs, median cTnI was 0.03 ng/mL (upper 95th percentile = 0.11 ng/mL). Compared with the healthy population, median plasma cTnI was increased in dogs with CM (0.14 ng/mL; range, 0.03-1.88 ng/mL; P < .001; n = 26), in dogs with MVD (0.11 ng/mL; range, 0.01-9.53 ng/mL; P < .001; n = 37), and in dogs with SAS (0.08 ng/mL; range, 0.01-0.94 ng/mL; P < .001; n = 30). In dogs with CM and MVD, plasma cTnI was correlated with left ventricular and left atrial size. In dogs with SAS, cTnI demonstrated a modest correlation with ventricular wall thickness. In dogs with CM, the median survival time of those with cTnI >0.20 ng/mL was significantly shorter than median survival time of those with cTnI <0.20 ng/mL (112 days versus 357 days; P = .006). Plasma cTnI is high in dogs with cardiac disease, correlates with heart size and survival, and can be used as a blood-based biomarker of cardiac disease.

[...]the article explains the key issues that arise during a bankruptcy that are relevant to the franchise industry, including the automatic stay and the contract assumption and rejection process. [...]there is an intersection of state franchise law with bankruptcy law. [...]it is important for a potential debtor to understand its filing options. [...]a franchisor may contest a franchisee's bankruptey, either by proving a discharge exception or seeking dismissal of the bankruptcy case.

It is challenging to differentiate congestive heart failure (CHF) from noncardiac cause of dyspnea.BACKGROUNDIt is challenging to differentiate congestive heart failure (CHF) from noncardiac cause of dyspnea.Circulating concentrations of atrial natriuretic peptide (NT-proANP), B-type natriuretic peptide (BNP), endothelin-I (ET-1), and cardiac troponin-I (cTnI) can be used to help distinguish between cardiac and noncardiac causes of dyspnea in dogs.HYPOTHESISCirculating concentrations of atrial natriuretic peptide (NT-proANP), B-type natriuretic peptide (BNP), endothelin-I (ET-1), and cardiac troponin-I (cTnI) can be used to help distinguish between cardiac and noncardiac causes of dyspnea in dogs.Forty-eight client-owned dogs admitted to a veterinary teaching hospital for respiratory distress.ANIMALSForty-eight client-owned dogs admitted to a veterinary teaching hospital for respiratory distress.Blood samples from patients were prospectively obtained. The etiology of dyspnea was determined by using physical examination, thoracic radiographs, and echocardiography.METHODSBlood samples from patients were prospectively obtained. The etiology of dyspnea was determined by using physical examination, thoracic radiographs, and echocardiography.CHF was diagnosed in 22 dogs, and dyspnea of noncardiac origin (noHD group) was diagnosed in 26 dogs. Analyses revealed significant difference between groups for NT-proANP (geometric mean, 95% confidence [CI]; no HD: 0.26 nmol/mL, 95% CI 0.17-1.09; CHF: 1.38 nmol/mL, 95% CI 1.09-1.74 nmol/mL; P < .0001), BNP (noHD: 12.18 pg/mL, 95% CI 10.91-16.17 pg/mL; CHF: 34.97 pg/mL, 95% CI 23.51-52.02 pg/mL; P < .0001), and ET-1 (noHD: 0.32 fmol/mL, 95% CI 0.23-0.46 fmol/mL; CHF: 1.26 fmol/mL, 95% CI 0.83-1.91 fmol/mL; P < .0001). Plasma cTnI concentrations were not significantly different between groups (noHD: 0.29 ng/mL, 95% CI 0.12-0.72 ng/mL; CHF: 0.42 ng/mL, 95% CI 0.18-0.97, P = .53). Receiver operating curves indicated areas under the curve for NT-proANP, BNP, and ET-1 of 0.946, 0.886, and 0.849, respectively.RESULTSCHF was diagnosed in 22 dogs, and dyspnea of noncardiac origin (noHD group) was diagnosed in 26 dogs. Analyses revealed significant difference between groups for NT-proANP (geometric mean, 95% confidence [CI]; no HD: 0.26 nmol/mL, 95% CI 0.17-1.09; CHF: 1.38 nmol/mL, 95% CI 1.09-1.74 nmol/mL; P < .0001), BNP (noHD: 12.18 pg/mL, 95% CI 10.91-16.17 pg/mL; CHF: 34.97 pg/mL, 95% CI 23.51-52.02 pg/mL; P < .0001), and ET-1 (noHD: 0.32 fmol/mL, 95% CI 0.23-0.46 fmol/mL; CHF: 1.26 fmol/mL, 95% CI 0.83-1.91 fmol/mL; P < .0001). Plasma cTnI concentrations were not significantly different between groups (noHD: 0.29 ng/mL, 95% CI 0.12-0.72 ng/mL; CHF: 0.42 ng/mL, 95% CI 0.18-0.97, P = .53). Receiver operating curves indicated areas under the curve for NT-proANP, BNP, and ET-1 of 0.946, 0.886, and 0.849, respectively.Plasma NT-proANP, BNP, and ET-1, but not cTnI, appear useful for distinguishing between dogs with cardiac and noncardiac causes of dyspnea, with plasma NT-proANP having the highest sensitivity (95.5%) and specificity (84.6%).CONCLUSIONS AND CLINICAL IMPORTANCEPlasma NT-proANP, BNP, and ET-1, but not cTnI, appear useful for distinguishing between dogs with cardiac and noncardiac causes of dyspnea, with plasma NT-proANP having the highest sensitivity (95.5%) and specificity (84.6%).

Abstract The median survival of patients with idiopathic pulmonary fibrosis (IPF) continues to be approximately 3 years from the time of diagnosis, underscoring the lack of effective medical therapies for this disease. In the United States alone, approximately 40,000 patients die of this disease annually. In November 2012, the NHLBI held a workshop aimed at coordinating research efforts and accelerating the development of IPF therapies. Basic, translational, and clinical researchers gathered with representatives from the NHLBI, patient advocacy groups, pharmaceutical companies, and the U.S. Food and Drug Administration to review the current state of IPF research and identify priority areas, opportunities for collaborations, and directions for future research. The workshop was organized into groups that were tasked with assessing and making recommendations to promote progress in one of the following six critical areas of research: (1) biology of alveolar epithelial injury and aberrant repair; (2) role of extracellular matrix; (3) preclinical modeling; (4) role of inflammation and immunity; (5) genetic, epigenetic, and environmental determinants; (6) translation of discoveries into diagnostics and therapeutics. The workshop recommendations provide a basis for directing future research and strategic planning by scientific, professional, and patient communities and the NHLBI.

The airway mucin Muc5b (but not Muc5ac) is required for mucociliary clearance, defence against bacterial infection in the airways and middle ear, and maintenance of immune homeostasis in the lungs; Muc5b deficiency causes accumulation of apoptotic macrophages, impairment of phagocytosis and reduced production of interleukin-23, leading to infection and inflammation. How Muc5b glycoprotein protects airways The mucosal surfaces in the lungs are a first line of defence against airborne pathogens but overproduction of mucus can itself cause respiratory disease. This study identifies a specific glycoprotein component of airway mucus, called Muc5b, as essential for mucociliary clearance in mice. Surprisingly Muc5b also contributes to innate defence against bacterial infection through the regulation of macrophage function both in mice and in humans with allergic asthma. Absence of Muc5b causes materials to accumulate in the airways, culminating in chronic infection by multiple bacterial species. This work could have relevance for the treatment of airway diseases. Respiratory surfaces are exposed to billions of particulates and pathogens daily. A protective mucus barrier traps and eliminates them through mucociliary clearance (MCC) 1 , 2 . However, excessive mucus contributes to transient respiratory infections and to the pathogenesis of numerous respiratory diseases 1 . MUC5AC and MUC5B are evolutionarily conserved genes that encode structurally related mucin glycoproteins, the principal macromolecules in airway mucus 1 , 3 . Genetic variants are linked to diverse lung diseases 4 , 5 , 6 , but specific roles for MUC5AC and MUC5B in MCC, and the lasting effects of their inhibition, are unknown. Here we show that mouse Muc5b (but not Muc5ac) is required for MCC, for controlling infections in the airways and middle ear, and for maintaining immune homeostasis in mouse lungs, whereas Muc5ac is dispensable. Muc5b deficiency caused materials to accumulate in upper and lower airways. This defect led to chronic infection by multiple bacterial species, including Staphylococcus aureus , and to inflammation that failed to resolve normally 7 . Apoptotic macrophages accumulated, phagocytosis was impaired, and interleukin-23 (IL-23) production was reduced in Muc5b −/− mice. By contrast, in mice that transgenically overexpress Muc5b , macrophage functions improved. Existing dogma defines mucous phenotypes in asthma and chronic obstructive pulmonary disease (COPD) as driven by increased MUC5AC, with MUC5B levels either unaffected or increased in expectorated sputum 1 , 8 . However, in many patients, MUC5B production at airway surfaces decreases by as much as 90% 9 , 10 , 11 . By distinguishing a specific role for Muc5b in MCC, and by determining its impact on bacterial infections and inflammation in mice, our results provide a refined framework for designing targeted therapies to control mucin secretion and restore MCC.

Abstract Apoptosis of fibroblasts/myofibroblasts is a critical event in the resolution of tissue repair responses; however, mechanisms for the regulation of (myo)fibroblast apoptosis/survival remain unclear. In this study, we demonstrate counter-regulatory interactions between the plasminogen activation system and transforming growth factor-β1 (TGF-β1) in the control of fibroblast apoptosis. Plasmin treatment induced fibroblast apoptosis in a time- and dose-dependent manner in association with proteolytic degradation of extracellular matrix proteins, as detected by the release of soluble fibronectin peptides. Plasminogen, which was activated to plasmin by fibroblasts, also induced fibronectin proteolysis and fibroblast apoptosis, both of which were blocked by α2-antiplasmin but not by inhibition of matrix metalloproteinase activity. TGF-β1 protected fibroblasts from apoptosis induced by plasminogen but not from apoptosis induced by exogenous plasmin. The protection from plasminogen-induced apoptosis conferred by TGF-β1 is associated with the up-regulation of plasminogen activator-1 (PAI-1) expression and inhibition of plasminogen activation. Moreover, lung fibroblasts from mice genetically deficient in PAI-1 lose the protective effect of TGF-β1 against plasminogen-induced apoptosis. These findings support a novel role for the plasminogen activation system in the regulation of fibroblast apoptosis and a potential role of TGF-β1/PAI-1 in promoting (myo)fibroblast survival in chronic fibrotic disorders.

Reversible axonal swelling and brainstem auditory evoked potential (BAEP) changes were observed in standard chronic (9‐month) toxicology studies in dogs treated with ritlecitinib, an oral Janus kinase 3/tyrosine kinase expressed in hepatocellular carcinoma family kinase inhibitor, at exposures higher than the approved 50‐mg human dose. To evaluate the clinical relevance of the dog toxicity finding, this phase 2a, double‐blind study assessed BAEP changes and intraepidermal nerve fiber (IENF) histology in adults with alopecia areata treated with ritlecitinib. Patients were randomized to receive oral ritlecitinib 50 mg once daily (QD) with a 4‐week loading dose of 200 mg QD or placebo for 9 months (placebo‐controlled phase); they then entered the active‐therapy extension and received ritlecitinib 50 mg QD (with a 4‐week loading dose of 200 mg in patients switching from placebo). Among the 71 patients, no notable mean differences in change from baseline (CFB) in Waves I–V interwave latency (primary outcome) or Wave V amplitude on BAEP at a stimulus intensity of 80 dB nHL were observed in the ritlecitinib or placebo group at Month 9, with no notable differences in interwave latency or Wave V amplitude between groups. The CFB in mean or median IENF density and in percentage of IENFs with axonal swellings was minimal and similar between groups at Month 9. Ritlecitinib treatment was also not associated with an imbalanced incidence of neurological and audiological adverse events. These results provide evidence that the BAEP and axonal swelling finding in dogs are not clinically relevant in humans. Results of this placebo‐controlled study, which assessed the neurological and neuroaudiological effects of ritlecitinib in adults with alopecia areata, provide evidence that the brainstem auditory evoked potential (BAEP) changes and axonal swelling finding in standard chronic toxicology studies in dogs are not clinically relevant in humans.