IgG4-related disease (IgG4-RD) can cause fibroinflammatory lesions in nearly any organ. Correlation among clinical, serological, radiological and pathological data is required for diagnosis. This ...work was undertaken to develop and validate an international set of classification criteria for IgG4-RD. An international multispecialty group of 86 physicians was assembled by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). Investigators used consensus exercises; existing literature; derivation and validation cohorts of 1879 subjects (1086 cases, 793 mimickers); and multicriterion decision analysis to identify, weight and test potential classification criteria. Two independent validation cohorts were included. A three-step classification process was developed. First, it must be demonstrated that a potential IgG4-RD case has involvement of at least one of 11 possible organs in a manner consistent with IgG4-RD. Second, exclusion criteria consisting of a total of 32 clinical, serological, radiological and pathological items must be applied; the presence of any of these criteria eliminates the patient from IgG4-RD classification. Third, eight weighted inclusion criteria domains, addressing clinical findings, serological results, radiological assessments and pathological interpretations, are applied. In the first validation cohort, a threshold of 20 points had a specificity of 99.2% (95% CI 97.2% to 99.8%) and a sensitivity of 85.5% (95% CI 81.9% to 88.5%). In the second, the specificity was 97.8% (95% CI 93.7% to 99.2%) and the sensitivity was 82.0% (95% CI 77.0% to 86.1%). The criteria were shown to have robust test characteristics over a wide range of thresholds. ACR/EULAR classification criteria for IgG4-RD have been developed and validated in a large cohort of patients. These criteria demonstrate excellent test performance and should contribute substantially to future clinical, epidemiological and basic science investigations.
Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection that results in thousands of deaths each year, mostly in African children. The in vivo mechanisms underlying this ...fatal condition are not entirely understood. Using the animal model of experimental cerebral malaria (ECM), we sought mechanistic insights into the pathogenesis of CM. Fatal disease was associated with alterations in tight junction proteins, vascular breakdown in the meninges / parenchyma, edema, and ultimately neuronal cell death in the brainstem, which is consistent with cerebral herniation as a cause of death. At the peak of ECM, we revealed using intravital two-photon microscopy that myelomonocytic cells and parasite-specific CD8+ T cells associated primarily with the luminal surface of CNS blood vessels. Myelomonocytic cells participated in the removal of parasitized red blood cells (pRBCs) from cerebral blood vessels, but were not required for the disease. Interestingly, the majority of disease-inducing parasite-specific CD8+ T cells interacted with the lumen of brain vascular endothelial cells (ECs), where they were observed surveying, dividing, and arresting in a cognate peptide-MHC I dependent manner. These activities were critically dependent on IFN-γ, which was responsible for activating cerebrovascular ECs to upregulate adhesion and antigen-presenting molecules. Importantly, parasite-specific CD8+ T cell interactions with cerebral vessels were impaired in chimeric mice rendered unable to present EC antigens on MHC I, and these mice were in turn resistant to fatal brainstem pathology. Moreover, anti-adhesion molecule (LFA-1 / VLA-4) therapy prevented fatal disease by rapidly displacing luminal CD8+ T cells from cerebrovascular ECs without affecting extravascular T cells. These in vivo data demonstrate that parasite-specific CD8+ T cell-induced fatal vascular breakdown and subsequent neuronal death during ECM is associated with luminal, antigen-dependent interactions with cerebrovasculature.
Threespine stickleback fish offer a powerful system to dissect the genetic basis of morphological evolution in nature. Marine sticklebacks have repeatedly invaded and adapted to numerous freshwater ...environments throughout the Northern hemisphere. In response to new diets in freshwater habitats, changes in craniofacial morphology, including heritable increases in tooth number, have evolved in derived freshwater populations. Using a combination of quantitative genetics and genome resequencing, here we fine-mapped a quantitative trait locus (QTL) regulating evolved tooth gain to a cluster of ten QTL-associated single nucleotide variants, all within intron four of Bone Morphogenetic Protein 6 (Bmp6). Transgenic reporter assays revealed this intronic region contains a tooth enhancer. We induced mutations in Bmp6, revealing required roles for survival, growth, and tooth patterning. Transcriptional profiling of Bmp6 mutant dental tissues identified significant downregulation of a set of genes whose orthologs were previously shown to be expressed in quiescent mouse hair stem cells. Collectively these data support a model where mutations within a Bmp6 intronic tooth enhancer contribute to evolved tooth gain, and suggest that ancient shared genetic circuitry regulates the regeneration of diverse vertebrate epithelial appendages including mammalian hair and fish teeth.
The clinical effectiveness of neurally adjusted ventilatory assist (NAVA) has yet to be demonstrated, and preliminary studies are required. The study aim was to assess the feasibility of a randomized ...controlled trial (RCT) of NAVA versus pressure support ventilation (PSV) in critically ill adults at risk of prolonged mechanical ventilation (MV).
An open-label, parallel, feasibility RCT (n = 78) in four ICUs of one university-affiliated hospital. The primary outcome was mode adherence (percentage of time adherent to assigned mode), and protocol compliance (binary-≥ 65% mode adherence). Secondary exploratory outcomes included ventilator-free days (VFDs), sedation, and mortality.
In the 72 participants who commenced weaning, median (95% CI) mode adherence was 83.1% (64.0-97.1%) and 100% (100-100%), and protocol compliance was 66.7% (50.3-80.0%) and 100% (89.0-100.0%) in the NAVA and PSV groups respectively. Secondary outcomes indicated more VFDs to D28 (median difference 3.0 days, 95% CI 0.0-11.0; p = 0.04) and fewer in-hospital deaths (relative risk 0.5, 95% CI 0.2-0.9; p = 0.032) for NAVA. Although overall sedation was similar, Richmond Agitation and Sedation Scale (RASS) scores were closer to zero in NAVA compared to PSV (p = 0.020). No significant differences were observed in duration of MV, ICU or hospital stay, or ICU, D28, and D90 mortality.
This feasibility trial demonstrated good adherence to assigned ventilation mode and the ability to meet a priori protocol compliance criteria. Exploratory outcomes suggest some clinical benefit for NAVA compared to PSV. Clinical effectiveness trials of NAVA are potentially feasible and warranted.
ClinicalTrials.gov, NCT01826890. Registered 9 April 2013.
In nature, multiple adaptive phenotypes often coevolve and can be controlled by tightly linked genetic loci known as supergenes. Dissecting the genetic basis of these linked phenotypes is a major ...challenge in evolutionary genetics. Multiple freshwater populations of threespine stickleback fish (
) have convergently evolved two constructive craniofacial traits, longer branchial bones and increased pharyngeal tooth number, likely as adaptations to dietary differences between marine and freshwater environments. Prior QTL mapping showed that both traits are partially controlled by overlapping genomic regions on chromosome 21 and that a regulatory change in
likely underlies the tooth number QTL. Here, we mapped the branchial bone length QTL to a 155 kb, eight-gene interval tightly linked to, but excluding the coding regions of
and containing the candidate gene
Further recombinant mapping revealed this bone length QTL is separable into at least two loci. During embryonic and larval development,
was expressed in the branchial bone primordia, where allele specific expression assays revealed the freshwater allele of
was expressed at lower levels relative to the marine allele in hybrid fish. Induced loss-of-function mutations in
revealed an essential role in stickleback craniofacial development and show that bone length is sensitive to
dosage in heterozygotes. Combined, these results suggest that closely linked but genetically separable changes in
and
contribute to a supergene underlying evolved skeletal gain in multiple freshwater stickleback populations.
We report the discovery of KELT-10b, the first transiting exoplanet discovered using the KELT-South telescope. KELT-10b is a highly inflated sub-Jupiter mass planet transiting a relatively bright V = ...10.7 star (TYC 8378-64-1), with T
eff = 5948 ± 74 K, log g =
$4.319_{-0.030}^{+0.020}$
and Fe/H =
$0.09_{-0.10}^{+0.11}$
, an inferred mass M
* =
$1.112_{-0.061}^{+0.055}$
M⊙ and radius R
* =
$1.209_{-0.035}^{+0.047}$
R⊙. The planet has a radius R
p =
$1.399_{-0.049}^{+0.069}$
R
J and mass M
p =
$0.679_{-0.038}^{+0.039}$
M
J. The planet has an eccentricity consistent with zero and a semimajor axis a =
$0.052\,50_{-0.000\,97}^{+0.000\,86}$
au. The best-fitting linear ephemeris is T
0 = 2457 066.720 45 ± 0.000 27 BJDTDB and P = 4.166 2739 ± 0.000 0063 d. This planet joins a group of highly inflated transiting exoplanets with a larger radius and smaller mass than that of Jupiter. The planet, which boasts deep transits of 1.4 per cent, has a relatively high equilibrium temperature of T
eq =
$1377_{-23}^{+28}$
K, assuming zero albedo and perfect heat redistribution. KELT-10b receives an estimated insolation of
$0.817_{-0.054}^{+0.068}$
× 109 erg s−1 cm−2, which places it far above the insolation threshold above which hot Jupiters exhibit increasing amounts of radius inflation. Evolutionary analysis of the host star suggests that KELT-10b may not survive beyond the current subgiant phase, depending on the rate of in-spiral of the planet over the next few Gyr. The planet transits a relatively bright star and exhibits the third largest transit depth of all transiting exoplanets with V < 11 in the Southern hemisphere, making it a promising candidate for future atmospheric characterization studies.
The ligands of the Bone Morphogenetic Protein (BMP) family of developmental signaling molecules are often under the control of complex cis-regulatory modules and play diverse roles in vertebrate ...development and evolution. Here, we investigated the cis-regulatory control of stickleback Bmp6. We identified a 190bp enhancer ~2.5 kilobases 5′ of the Bmp6 gene that recapitulates expression in developing teeth and fins, with a core 72bp sequence that is sufficient for both domains. By testing orthologous enhancers with varying degrees of sequence conservation from outgroup teleosts in transgenic reporter gene assays in sticklebacks and zebrafish, we found that the function of this regulatory element appears to have been conserved for over 250 million years of teleost evolution. We show that a predicted binding site for the TGFβ effector Smad3 in this enhancer is required for enhancer function and that pharmacological inhibition of TGFβ signaling abolishes enhancer activity and severely reduces endogenous Bmp6 expression. Finally, we used TALENs to disrupt the enhancer in vivo and find that Bmp6 expression is dramatically reduced in teeth and fins, suggesting this enhancer is necessary for expression of the Bmp6 locus. This work identifies a relatively short regulatory sequence that is required for expression in multiple tissues and, combined with previous work, suggests that shared regulatory networks control limb and tooth development.
•A 190bp enhancer of Bmp6 drives expression in developing fins and teeth.•Enhancer function has been conserved for >250 million years of teleost evolution.•This enhancer requires a predicted Smad3 binding site.•This enhancer is turned off by pharmacological disruption of TGF-B signaling.•This enhancer is required for expression of Bmp6 in fins and teeth.
Objective
To determine whether cortisol is present in equine tears at rest and during simulated stress and compare tear cortisol to serum free and total cortisol.
Materials and methods
Fourteen ...healthy adult horses were included. Paired tear total cortisol and serum total and free cortisol concentrations were measured with ELISA, chemiluminescent immunoassay, and ultrafiltration methodology, respectively, in 10 horses at rest once daily for five consecutive days. In an additional four horses, paired tear and serum samples were collected for cortisol measurement before and after adrenocorticotropic hormone (ACTH) stimulation (cosyntropin, 1 μg/kg IV).
Results
Cortisol was detectable in equine tears at rest. Following ACTH stimulation, tear cortisol increased significantly from baseline at 60–120 min (P ≤ 0.001). Serum total and free cortisol also increased significantly at 30–180 min after ACTH stimulation (P ≤ 0.001). Both serum and tear cortisol returned to baseline concentrations by 360 min. Changes in tear cortisol were similarly associated with changes in serum total and free cortisol, although high tear cortisol concentrations suggest a portion of tear cortisol may be protein‐bound.
Discussion
Cortisol is present in equine tears and increases in concert with serum cortisol following ACTH stimulation. Further study is needed to determine whether endogenous cortisol in tears contributes to ocular pathology.
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