A key requirement for CD300f in innate immune responses of eosinophils in colitis.

Eosinophils are traditionally studied in the context of type 2 immune responses. However, recent studies highlight key innate immune functions for eosinophils especially in colonic inflammation. Surprisingly, molecular pathways regulating innate immune activities of eosinophil are largely unknown. We have recently shown that the CD300f is highly expressed by colonic eosinophils. Nonetheless, the role of CD300f in governing innate immune eosinophil activities is ill-defined. RNA sequencing of 162 pediatric Crohn's disease patients revealed upregulation of multiple Cd300 family members, which correlated with the presence of severe ulcerations and inflammation. Increased expression of CD300 family receptors was also observed in active ulcerative colitis (UC) and in mice following induction of experimental colitis. Specifically, the expression of CD300f was dynamically regulated in monocytes and eosinophils. Dextran sodium sulfate (DSS)-treated Cd300f-/- mice exhibit attenuated disease activity and histopathology in comparison with DSS-treated wild type (WT). Decreased disease activity in Cd300f-/- mice was accompanied with reduced inflammatory cell infiltration and nearly abolished production of pro-inflammatory cytokines. Monocyte depletion and chimeric bone marrow transfer experiments revealed a cell-specific requirement for CD300f in innate immune activation of eosinophils. Collectively, we uncover a new pathway regulating innate immune activities of eosinophils, a finding with significant implications in eosinophil-associated gastrointestinal diseases.

Interleukin-33 requires CMRF35-like molecule-1 expression for induction of myeloid cell activation.

BACKGROUND: IL-33 is a potent activator of various cells involved in allergic inflammation, including eosinophils and mast cells. Despite its critical role in Th2 disease settings, endogenous molecular mechanisms that may regulate IL-33-induced responses remain to be defined. We have recently shown that eosinophils express CMRF35-like molecule (CLM)-1. Yet, the role of CLM-1 in regulating eosinophil functions is still elusive. METHODS: CLM-1 and CLM-8 expression and cellular localization were assessed in murine bone marrow-derived and/or peritoneal cells at baseline and following IL-33 stimulation (flow cytometry, western blot). IL-33-induced mediator release and signaling were assessed in wild-type (wt) and Clm1(-/-) cells and mice. RESULTS: BM-derived eosinophils express high levels of glycosylated CLM-1. IL-33 induced a rapid, specific, concentration- and time-dependent upregulation of CLM-1 in eosinophils (in vitro and in vivo). Clm1(-/-) eosinophils secreted less IL-33-induced mediators than wt eosinophils. CLM-1 co-localized to ST2 following IL-33 stimulation and was required for IL-33-induced NFκB and p38 phosphorylation. Th2 cytokine (e.g., IL-5, IL-13) and chemokine (e.g., eotaxins, CCL2) secretion was markedly attenuated in IL-33-treated Clm1(-/-) mice. Subsequently, IL-33-challenged mice displayed reduced infiltration of mast cells, macrophages, neutrophils, and B cells. Despite the markedly impaired IL-33-induced eotaxin expression in Clm1(-/-) mice, eosinophil accumulation was similar in wt and Clm1(-/-) mice, due to hyperchemotactic responses of Clm1(-/-) eosinophils. CONCLUSIONS: CLM-1 is a novel regulator of IL-33-induced eosinophil activation. These data contribute to the understanding of endogenous molecular mechanisms regulating IL-33-induced responses and may ultimately lead to receptor-based tools for future therapeutic intervention in IL-33-associated diseases.

Rasmussen's chronic encephalitis in adults.

OBJECTIVE: Rasmussen's chronic encephalitis, a cause of intractable epilepsy in childhood, is described in three adults. SETTING: Inpatient epilepsy unit. PATIENTS: Of 11 patients with pathological confirmation of Rasmussen's encephalitis, three were adults with intractable seizures, progressive sensorimotor deficits, and cognitive decline beginning at the ages of 36, 24, and 16 years. RESULTS: Clinical, electroencephalographic, and magnetic resonance imaging findings indicated patchy, multifocal involvement of primarily one hemisphere, but the adults had more evidence of disease in the opposite hemisphere than occurs in children. The sensorimotor deficit that the adults developed was greater and the cognitive decline was less than in children. Seizure control following multilobe resection was proportionate to the amount of tissue removed. Cytomegalovirus genome was found in the resected cortical tissue of all three patients. CONCLUSIONS: Rasmussen's encephalitis is a cause of intractable epilepsy with progressive neurological deficit in adults as well as children. Cytomegalovirus may be involved in the pathogenesis of the disease.

Effects of fentanyl, sufentanil, and alfentanil on brain retractor pressure.

Sufentanil and alfentanil have been reported to increase cerebral blood flow and intracranial pressure. Agents producing these effects may adversely affect the relationship between brain retractors and underlying cerebral tissues during craniotomy, potentially predisposing the patient to brain retractor injury. The effects of fentanyl, sufentanil, alfentanil, and a placebo (saline) on brain retractor pressure were therefore evaluated prospectively in 24 adults undergoing elective craniotomy. None of these narcotics significantly affected brain retractor pressure. Each significantly and similarly decreased arterial pressure and cerebral perfusion pressure. If these narcotics are administered in doses that avoid adverse hemodynamic changes that could compromise cerebral tissues indirectly, each of the narcotics studied appears safe for intraoperative administration once the cranium is open.

Adrenal hemangioblastoma in Von Hippel-Lindau disease as a cause of secondary erythrocytosis.

Von Hippel-Lindau disease (VHLD) is an inherited disorder with protean manifestations including tumors that may cause secondary erythrocytosis: cerebellar hemangioblastoma, renal cell carcinoma, and pheochromocytoma. The case of a woman with VHLD whose secondary erythrocytosis resolved after removal of an adrenal hemangioblastoma is reported. This is the first reported case of adrenal hemangioblastoma in VHLD. Furthermore, it appears that adrenal hemangioblastoma is a cause of secondary erythrocytosis.

Effects of steroids and nonsteroid anti-inflammatory agents on vascular permeability in a rat glioma model.

Cerebral edema produced by brain tumors is clinically and experimentally reduced by steroid therapy. Nonsteroid anti-inflammatory drugs (NSAID's) which have been used to treat non-neural inflammation and swelling have not been evaluated for their ability to affect edema produced by brain tumors. The authors have used the rat C6 glioma spheroid implantation model to compare the effects of two steroids (dexamethasone and methylprednisolone) and two NSAID's (ibuprofen and indomethacin) on protein extravasation caused by intracranial gliomas. Evans blue dye was used as a marker for serum albumin extravasation. The concentration of Evans blue dye was measured in the tumor and peritumoral and contralateral brain tissue 1 hour after intravenous injection. Extravasation of Evans blue dye within the tumor was decreased in all treatment groups when compared to placebo-injected control animals. The differences between the control specimens and those treated with dexamethasone, methylprednisolone, and indomethacin were highly significant (p less than 0.005). The Evans blue staining was also decreased in the peritumoral and contralateral brain. These results indicate that NSAID's compare favorably with steroids in diminishing tumor-induced protein extravasation. It is suggested that NSAID's may prove to be beneficial in clinical instances used either in conjunction with steroid therapy or alone when steroids are contraindicated.