Trained innate immunity in response to nuclear antigens in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease directed against nuclear antigens, including those derived from apoptotic microparticles (MPs) and neutrophil extracellular traps (NETs). Here we investigated whether nuclear autoantigens can induce trained immunity in SLE patients. Trained immunity is a de facto innate immune memory elicited by an initial stimulus that induces a more vigorous long-term inflammatory response to subsequent stimuli.

Outcomes from a national screening program for Ukrainian refugees at risk of drug resistant tuberculosis in Wales.

High rates of drug-resistant tuberculosis in Ukraine suggest screening is necessary to mitigate public health hazards for host populations. A pathway was implemented in Wales and data prospectively collected Between 8 April and 21 December 2022. Of 5425 Ukrainian arrivals, notifications were received by TB teams on 2395 (44%) of whom 1955 (82%) were screened.

FDG PET-CT imaging of therapeutic response in granulomatous lymphocytic interstitial lung disease (GLILD) in common variable immunodeficiency (CVID).

Common variable immunodeficiency (CVID) is the most common severe adult primary immunodeficiency and is characterized by a failure to produce antibodies leading to recurrent predominantly sinopulmonary infections. Improvements in the prevention and treatment of infection with immunoglobulin replacement and antibiotics have resulted in malignancy, autoimmune, inflammatory and lymphoproliferative disorders emerging as major clinical challenges in the management of patients who have CVID. In a proportion of CVID patients, inflammation manifests as granulomas that frequently involve the lungs, lymph nodes, spleen and liver and may affect almost any organ.

A case of Finegoldia magna (formerly Peptostreptococcus magnus) infection mimicking disseminated malignancy.

A 44-year-old alcoholic (and therefore immunocompromised) hospital cleaner presented with general malaise, weight loss, and erythematous skin nodules. Computed tomography scanning revealed a neck mass invading the thyroid gland, pulmonary infiltrates, liver lesions, and deposits on the anterior abdominal wall, consistent with disseminated malignancy. However, tissue diagnosis showed a necro-inflammatory process with no evidence of malignancy.

The dynamics of autism spectrum disorders: how neurotoxic compounds and neurotransmitters interact.

In recent years concern has risen about the increasing prevalence of Autism Spectrum Disorders (ASD). Accumulating evidence shows that exposure to neurotoxic compounds is related to ASD. Neurotransmitters might play a key role, as research has indicated a connection between neurotoxic compounds, neurotransmitters and ASD.

Over-expression of Grhl2 causes spina bifida in the Axial defects mutant mouse.

Cranial neural tube defects (NTDs) occur in mice carrying mutant alleles of many different genes, whereas isolated spinal NTDs (spina bifida) occur in fewer models, despite being common human birth defects. Spina bifida occurs at high frequency in the Axial defects (Axd) mouse mutant but the causative gene is not known. In the current study, the Axd mutation was mapped by linkage analysis.

Neutrophil functions and autoimmune arthritis in the absence of p190RhoGAP: generation and analysis of a novel null mutation in mice.

Beta(2) integrins of neutrophils play a critical role in innate immune defense, but they also participate in tissue destruction during autoimmune inflammation. p190RhoGAP (ArhGAP35), a regulator of Rho family small GTPases, is required for integrin signal transduction in fibroblasts. Prior studies have also suggested a role for p190RhoGAP in beta(2) integrin signaling in neutrophils.

Contribution of upper airway geometry to convective mixing.

We investigated the axial dispersive effect of the upper airway structure (comprising mouth cavity, oropharynx, and trachea) on a traversing aerosol bolus. This was done by means of aerosol bolus experiments on a hollow cast of a realistic upper airway model (UAM) and three-dimensional computational fluid dynamics (CFD) simulations in the same UAM geometry. The experiments showed that 50-ml boluses injected into the UAM dispersed to boluses with a half-width ranging from 80 to 90 ml at the UAM exit, across both flow rates (250, 500 ml/s) and both flow directions (inspiration, expiration).

Tracheal stenosis: a flow dynamics study.

Patients referred for treatment of tracheal stenosis typically are asymptomatic until critical narrowing of the airway occurs, which then requires immediate intervention. To understand how tracheal stenosis affects local pressure drops and explore how a dramatic increase in pressure drop could possibly be detected at an early stage, a computational fluid dynamics (CFD) study was undertaken. We assessed flow patterns and pressure drops over tracheal stenoses artificially inserted into a realistic three-dimensional upper airway model derived from multislice computed tomography images obtained in healthy men.

Distinct but overlapping functions for the closely related p190 RhoGAPs in neural development.

The p190 RhoGAPs, p190A and p190B, are highly related GTPase-activating proteins for the Rho GTPases. Rho GTPases and p190A reportedly control various aspects of brain development, and we hypothesized that p190B would be likewise involved in neuronal development. We find that like p190A, p190B is prominently expressed in the developing and adult brain.

Influence of glottic aperture on the tracheal flow.

The extra-thoracic mouth-throat area has a major influence on the aerosol delivery to the proximal or peripheral intra-thoracic airways. To characterize the particle deposition in this area, it is important to investigate first the flow structures in this crucial--in relation to the aerosol deposition--region. The glottis, which is delimited by the vocal cords and therefore has the narrowest passage, generates a laryngeal jet and a reverse flow downstream the glottis.

Morphogenetic movements during cranial neural tube closure in the chick embryo and the effect of homocysteine.

In order to unravel morphogenetic mechanisms involved in neural tube closure, critical cell movements that are fundamental to remodelling of the cranial neural tube in the chick embryo were studied in vitro by quantitative time-lapse video microscopy. Two main directions of movements were observed. The earliest was directed medially; these cells invaginated into a median groove and were the main contributors to the initial neural tube closure.

Inhibition of transmethylation disturbs neurulation in chick embryos.

Periconceptional folic acid supplementation can reduce the occurrence of neural tube defects. A low folate status will result in reduced remethylation of homocysteine (Hcy) to methionine and, subsequently, in a rise of Hcy levels. Indeed, elevated Hcy concentrations have been reported in mothers of children with neural tube defects.

Toward positional cloning of the curly tail gene.

Background: The curly tail (ct) mutant mouse is one of the best-studied mouse models of spina bifida. The ct mutation has been localized to distal chromosome 4 in two independent studies and was recently postulated to be in the Grhl-3 gene.

Methods: A recombinant BALB/c-ct strain was generated and used to precisely map the ct gene.

Modulation of CREB activity by the Rho GTPase regulates cell and organism size during mouse embryonic development.

Rho GTPases regulate several aspects of tissue morphogenesis during animal development. We found that mice lacking the Rho-inhibitory protein, p190-B RhoGAP, are 30% reduced in size and exhibit developmental defects strikingly similar to those seen in mice lacking the CREB transcription factor. In p190-B RhoGAP-deficient mice, CREB phosphorylation is substantially reduced in embryonic tissues.

p190 RhoGAP is the principal Src substrate in brain and regulates axon outgrowth, guidance and fasciculation.

The Src tyrosine kinases have been implicated in several aspects of neural development and nervous system function; however, their relevant substrates in brain and their mechanism of action in neurons remain to be established clearly. Here we identify the potent Rho regulatory protein, p190 RhoGAP (GTPase-activating protein), as the principal Src substrate detected in the developing and mature nervous system. We also find that mice lacking functional p190 RhoGAP exhibit defects in axon guidance and fasciculation.

The adhesion signaling molecule p190 RhoGAP is required for morphogenetic processes in neural development.

Rho GTPases direct actin rearrangements in response to a variety of extracellular signals. P190 RhoGAP (GTPase activating protein) is a potent Rho regulator that mediates integrin-dependent adhesion signaling in cultured cells. We have determined that p190 RhoGAP is specifically expressed at high levels throughout the developing nervous system.

Evidence for distinct mechanisms of transition state stabilization of GTPases by fluoride.

GTPase-activating proteins (GAPs) function by stabilizing the GTPase transition state. This has been most clearly demonstrated by the formation of a high-affinity complex between various GAPs and GDP-bound GTPases in the presence of aluminum tetrafluoride, which can mimic the gamma-phosphate of GTP. Herein, we report that p190 RhoGAP forms a high-affinity complex with Rho GTPases in the presence of fluoride ions, suggesting that p190 also functions to stabilize the GTPase transition state.

Mediastinoscopy in patients with presumptive stage I sarcoidosis: a risk/benefit, cost/benefit analysis.

Study Objective: To determine whether persons with asymptomatic bilateral hilar lymphadenopathy (ABHL) and normal results of a physical examination should be observed with a presumptive diagnosis of stage 1 sarcoidosis (S1S) (ABHLps), its most frequent cause, or undergo mediastinoscopy to avoid overlooking an alternative diagnosis (AD) requiring treatment.

Design: We surveyed the English-language medical literature to estimate the proportion of persons with tuberculosis (TB), Hodgkin's disease (HD), and non-Hodgkin's lymphoma (NHL) who present with ABHL and calculated the number of mediastinoscopies required to identify each AD by computing the following ratio: incidence S1S/incidence of each AD presenting as ABHL (I(S1S)/I[ABHL-AD]). Risks of mediastinoscopy and benefits of earlier ascertainment of AD were derived from the published literature.

Rat oxytocin receptor in brain, pituitary, mammary gland, and uterus: partial sequence and immunocytochemical localization.

Partial complementary DNAs of an oxytocin (OT) receptor were cloned from rat brain and uterus. The complementary DNAs encoded for the same amino acid sequence, which showed a high degree of homology with the human and porcine uterine OT receptors, except for a region in the third intracellular loop. Antibodies were raised against nonoverlapping sequences of the third intracellular loop of this rat OT receptor.

Immunocytochemical detection of prostaglandin E2 in microvasculature and in neurons of rat brain after administration of bacterial endotoxin.

The aim of the present study was to identify the site of prostaglandin E2 (PGE2) production in the brain in response to a pyrogenic dose of endotoxin. The presence of PGE2 was detected using immunocytochemistry on Bouin's fixed vibratome sections of control and endotoxin-treated rats. Peripheral administration of endotoxin caused a time-related stimulation of PGE2 immunoreactivity (irPGE2) in the choroid plexus and in the microvasculature of the brain.

Appearance of interleukin-1 in macrophages and in ramified microglia in the brain of endotoxin-treated rats: a pathway for the induction of non-specific symptoms of sickness?

The presence and cellular localization of interleukin-1 beta immunoreactivity (irIL-1) in and around the brain was investigated using immunocytochemistry on Bouin's fixed vibratome brain sections of control and endotoxin-treated rats. Peripheral administration of endotoxin resulted in the appearance of irIL-1 in cells in the meninges, choroid plexus, brain blood vessels and in non-neuronal cells in the brain parenchyma. Using monoclonal and polyclonal antibodies to macrophage and astrocyte antigens, the endotoxin-induced irIL-1 positive cells could be identified as macrophages in the meninges and choroid plexus (ED2), perivascular cells (ED2) and ramified microglial cells (GSA-I-B4 isolectin).