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- Selective Exposure of the Fetal Lung and Skin/Amnion (but Not Gastro-Intestinal Tract) to LPS Elicits Acute Systemic Inflammation in Fetal Sheep. [Journal Article]
- PLoS One 2013; 8(5):e63355.
Inflammation of the uterine environment (commonly as a result of microbial colonisation of the fetal membranes, amniotic fluid and fetus) is strongly associated with preterm labour and birth. Both preterm birth and fetal inflammation are independently associated with elevated risks of subsequent short- and long-term respiratory, gastro-intestinal and neurological complications. Despite numerous clinical and experimental studies to investigate localised and systemic fetal inflammation following exposure to microbial agonists, there is minimal data to describe which fetal organ(s) drive systemic fetal inflammation. We used lipopolysaccharide (LPS) from E.coli in an instrumented ovine model of fetal inflammation and conducted a series of experiments to assess the systemic pro-inflammatory capacity of the three major fetal surfaces exposed to inflammatory mediators in pregnancy (the lung, gastro-intestinal tract and skin/amnion). Exposure of the fetal lung and fetal skin/amnion (but not gastro-intestinal tract) caused a significant acute systemic inflammatory response characterised by altered leucocytosis, neutrophilia, elevated plasma MCP-1 levels and inflammation of the fetal liver and spleen. These novel findings reveal differential fetal organ responses to pro-inflammatory stimulation and shed light on the pathogenesis of fetal systemic inflammation after exposure to chorioamnionitis.
- Peritoneal EMH in a Dog with Immune-Mediated Hemolytic Anemia. [JOURNAL ARTICLE]
- J Am Anim Hosp Assoc 2013 May 20.
Extramedullary hematopoiesis (EMH) is the process by which normal blood cells are produced outside the bone marrow. In humans, EMH effusions are rare and are characterized by the presence of megakaryocytes, immature erythrocytes, immature leukocytes, or combinations of those cells. To the authors' knowledge, this is the first report to describe a case of peritoneal EMH effusion in a dog. A 5 yr old castrated male shorthaired dachshund presented with a 2 day history of pigmenturia and inappetence. A complete blood count revealed regenerative anemia with marked agglutination, spherocytosis, and an acute inflammatory leukogram characterized by a neutrophilia, regenerative left shift, and monocytosis. Ultrasound-guided aspiration of peritoneal effusion yielded a sample of high nucleated cellularity predominantly composed of mature and immature neutrophils and erythroid precursor cells. The patient was diagnosed with primary immune-mediated hemolytic anemia with concurrent EMH peritoneal effusion. The following case description and discussion explore the clinical findings associated with the unusual effusion and outline the possible pathogenesis by which the EMH effusion may have arisen in the dog.
- Cdc42 promotes host defenses against fatal infection. [JOURNAL ARTICLE]
- Infect Immun 2013 May 20.
The small Rho GTPase, Cdc42, regulates key signaling pathways required for multiple cell functions including maintenance of shape, polarity, proliferation, invasion, migration, differentiation and morphogenesis. As the role of Cdc42-dependent signaling in fibroblasts in vivo is unknown, we attempted to specifically delete it in these cells by crossing the Cdc42(fl/fl) mouse with a FSP-1 cre mouse, which is thought to mediate recombination exclusively in fibroblasts. Surprisingly, the FSP-1cre;Cdc42(fl/fl) mice died at 3 weeks of age due to overwhelming suppurative upper airway infections that were associated with neutrophilia and lymphopenia. Even though major aberrations in lymphoid tissue development were present in the mice, the principal cause of death was severe migration and killing abnormalities of the neutrophil population resulting in an inability to control infection. We also showed that in addition to fibroblasts, the FSP-1 cre deleted Cdc42 very efficiently in all leukocytes. Thus, by using this non-specific cre mouse we inadvertently demonstrated the importance of Cdc42 in host protection from lethal infections and suggest a critical role for this small GTPase in innate immunity.
- Hypercholesterolemia and reduced HDL-C promote hematopoietic stem cell proliferation and monocytosis: Studies in mice and FH children. [JOURNAL ARTICLE]
- Atherosclerosis 2013 Apr 19.
Previous studies have shown that mice with defects in cellular cholesterol efflux show hematopoietic stem cell (HSPC) and myeloid proliferation, contributing to atherogenesis. We hypothesized that the combination of hypercholesterolemia and defective cholesterol efflux would promote HSPC expansion and leukocytosis more prominently than either alone. We crossed Ldlr(-/-) with Apoa1(-/-) mice and found that compared to Ldlr(-/-) mice, Ldlr(-/-)/Apoa1(+/-) mice, with similar LDL-cholesterol levels but reduced HDL-cholesterol (HDL-C) levels, had expansion of HSPCs, monocytosis and neutrophilia. Ex vivo studies showed that HSPCs expressed high levels of Ldlr, Scarb1 (Srb1), and Lrp1 and were able to take up both native and oxidized LDL. Native LDL directly stimulated HSPC proliferation, while co-incubation with reconstituted HDL attenuated this effect. We also assessed the impact of HDL-C levels on monocytes in children with familial hypercholesterolemia (FH) (n = 49) and found that subjects with the lowest level of HDL-C, had increased monocyte counts compared to the mid and higher HDL-C levels. Overall, HDL-C was inversely correlated with the monocyte count. These data suggest that in mice, a balance of cholesterol uptake and efflux mechanisms may be one factor in driving HSPC proliferation and monocytosis. Higher monocyte counts in children with FH and low HDL-cholesterol suggest a similar pattern in humans.
- Intussusception in a 7-week-old baby. [Journal Article]
- BMJ Case Rep 2013.
A 7-week-old baby presented to a district general hospital with a history of pallor, lethargy, vomiting and high pitched cry. She had vomited three times at home. It was reported that the last vomitus had a greenish tinge to it. In hospital, she had a non-bilious vomit. There was no history of fever, constipation or diarrhoea. Her birth history and medical history were unremarkable. She was noted to be pale, lethargic and quiet on examination. Her vital signs were unremarkable. She had a soft scaphoid abdomen on examination. No masses were palpable. Investigations for sepsis were done and antibiotics started. Results of all the investigations were normal apart from mildly raised blood glucose and neutrophilia. Later on she passed a small amount of blood per rectum. Examination revealed a palpable mass in the epigastrium. An abdominal x-ray was suggestive of intestinal obstruction. Intussusception was confirmed on ultrasound. The intussusception was successfully reduced following surgery.
- Neutrophilic dermatosis after azathioprine exposure. [Journal Article]
- JAMA Dermatol 2013 May 1; 149(5):592-7.
IMPORTANCE Azathioprine hypersensitivity syndrome can present clinically and histopathologically like Sweet syndrome. Shared clinical features include fever, constitutional symptoms, prompt response to systemic corticosteroid therapy, neutrophilia, and abrupt onset of erythematous cutaneous lesions. Histologically, both azathioprine hypersensitivity syndrome and Sweet syndrome are rich in neutrophils. OBSERVATIONS An 81-year-old woman with Crohn disease presented with fever and an acute eruption of plaques on her extremities within 2 weeks of starting treatment with azathioprine. Laboratory evaluation was notable for leukocytosis and neutrophilia. Skin biopsy of an erythematous plaque on the thigh demonstrated a suppurative folliculitis. Azathioprine treatment was discontinued resulting in resolution of the clinical lesions within 5 days. Our case was compared with 18 cases with similar clinical features.
CONCLUSIONSAND RELEVANCE We report a case of azathioprine hypersensitivity syndrome and review the literature on azathioprine-induced eruptions with features of Sweet syndrome. Our patient's distribution of lesions on the extremities and the finding of suppurative folliculitis on histopathology were not classical for Sweet syndrome. Azathioprine hypersensitivity syndrome seems to be a neutrophil-driven dermatosis; therefore, many overlapping features with Sweet syndrome are not surprising. Due to the potential for anaphylaxis with azathioprine rechallenge, a better term for a Sweetlike presentation in the setting of azathioprine administration is azathioprine hypersensitivity syndrome.
- Detection of Theileria equi in spleen and blood of asymptomatic piroplasm carrier horses. [Journal Article]
- Acta Parasitol 2013 Jun; 58(2):218-22.
This study aimed to determine whether asymptomatic horses naturally infected with Theileria equi retain infected erythrocytes in the spleen and whether the presence of the hemoparasite in this organ is associated with parasitemia. We collected samples from 25 adult horses without clinical signs of any disease. From each animal, we collected whole blood samples from the jugular vein and a splenic puncture blood sample. All samples were submited to blood cell counts and detection of Theileria or Babesia. DNA extraction and PCR were performed in all samples for identification of piroplasm infection (T. equi and B. caballi). From the 25 horses evaluated for piroplasm detection by PCR, seven horses (28%) were positive in jugular vein blood but negative in splenic blood samples, five horses (20%) were positive in splenic blood samples but negative in jugular vein blood samples, and 13 horses (52%) were positive in both jugular vein and splenic blood samples. The hematological evaluation revealed anemia in 13 of 25 (52%) infected horses, lymphopenia in five (20%), neutrophilia in two (8%), neutropenia in one (4%), and thrombocytopenia in one (4%) infected horse. The present study demonstrated that several (20%) of the asymptomatic piroplasm carrier horses did not show parasitemia, but show infected erythrocytes in the spleen.
- Bronchial collapse during bronchoalveolar lavage in horses is an indicator of lung inflammation. [JOURNAL ARTICLE]
- Equine Vet J 2013 May 6.
REASONS FOR PERFORMING STUDY: The bronchoalveolar lavage (BAL) procedure can return variable volumes of fluid, possibly depending on the presence of bronchial collapse during fluid aspiration and on the severity of lung inflammation.
OBJECTIVE:We tested the hypothesis that horses with bronchial collapse during BAL are at higher risk of having severe lung inflammation.
MATERIAL AND METHODS:Bronchial collapse was graded using a new simple scoring method (0, 1 or 2) during standardised BAL procedure in the field on 131 horses with Normal, Mild/Moderate, or Severe inflammation BAL.
RESULTS:Of the 131 horses, 37 (28%), 55 (42%) and 39 (30%) horses had Bronchial Collapse Scores of 0, 1 and 2, respectively. There was a difference in collapse scores between all the BAL inflammation categories (p<0.001). Severe collapse had a positive predictive value of 0.95 for both Mild/Moderate and Severe BAL Inflammation with prevalence of 63% and 20% respectively. The BAL fluid return volume in the horses with severe collapse scores was lower than volumes in the partial (score 1/2) and no collapse (score 0/2) groups (p<0.001). BAL fluid volume was negatively correlated with BAL neutrophil percentage (p<0.001).
CONCLUSION:Airway collapse during BAL is associated with airway inflammation and neutrophilia. POTENTIAL RELEVANCE: During a standardised BAL procedure, clinicians can expect lung inflammation in horses that have bronchial collapse and bronchial collapse in horses with lung inflammation. Lung inflammation may be a contributing factor in the mechanism of bronchial collapse during BAL in horses.
- Interlaboratory Evaluation of Rodent Pulmonary Responses to Engineered Nanomaterials: The NIEHS Nano Go Consortium. [JOURNAL ARTICLE]
- Environ Health Perspect 2013 May 6.
BACKGROUND:Engineered nanomaterials (ENMs) have potential benefits, but also present safety concerns for human health. Inter-laboratory studies in rodents using standardized protocols are needed for ENM toxicity assessment.
METHODS:Four labs evaluated lung responses in C57BL/6 mice to ENMs delivered by oropharyngeal aspiration (OPA). Three labs evaluated Sprague-Dawley (SD) or Fisher (F)344 rats following intratracheal instillation (IT). ENMs tested were three forms of titanium dioxide (TiO2); anatase/rutile spheres (TiO2-P25), anatase spheres (TiO2-A), anatase nanobelts (TiO2-NB), and three forms of multiwalled carbon nanotubes (MWCNT); original (O), purified (P), and carboxylic acid "functionalized" (F). Bronchoalveolar lavage fluid was collected after 1 day for differential cell counts, lactate dehydrogenase (LDH), and protein. Lungs were fixed for histopathology. Responses were also examined at 7 days (TiO2) and 21 days (MWCNTs).
RESULTS:TiO2-A, TiO2-P25, and TiO2-NB caused significant neutrophilia in mice at 1 day in 3 out of 4 labs, respectively. TiO2-NB caused neutrophilia in rats at 1 day in 2 out of 3 labs, while TiO2-P25 or TiO2-A had no significant effect in any of the labs. Inflammation induced by TiO2 in mice and rats resolved by day 7. All MWCNT types caused neutrophilia at 1 day in 3 out of 4 mouse labs and all rat labs. Three out of 4 labs observed similar histopathology to O-MWCNT or TiO2-NB in mice.
CONCLUSIONS:ENMs produced similar patterns of neutrophilia and pathology in rats and mice. Although inter-laboratory variability was found in the degree of neutrophilia caused by the three types of TiO2 nanoparticles, similar findings of relative potency for the three types of MWCNTs were found across all laboratories, thus providing greater confidence in these inter-laboratory comparisons.
- CD8(+) T cells characterize early smoking-related airway pathology in patients with asthma. [JOURNAL ARTICLE]
- Respir Med 2013 Apr 30.