Serum and cutaneous transcriptional expression levels of IL31 are minimal in cutaneous T cell lymphoma variants.

AIM: Recent studies suggested a role for IL31 in the pathogenesis of pruritus and disease severity in patients with cutaneous T cell lymphomas (CTCL). However, discrepant results were reported for IL31 serum levels, transcriptional expression levels or immunohistochemistry studies and its relation to pruritus intensity and/or disease severity in CTCL. Most studies did not distinguish between different CTCL variants. We investigated IL31 serum levels in different subtypes of CTCL, including Mycosis Fungoides (MF) (typically not pruritic), Folliculotropic Mycosis Fungoides (FMF) and Sézary syndrome (SS) (both often pruritic). METHODS: From 54 CTCL patients (17 SS, 21 FMF and 16 classic MF) serum samples were analyzed with a high sensitivity V-PLEX immunoassay for IL31. The study group included 35/54 (65%) patients with complaints of pruritus. Thirty-five patients had advanced stage disease (≥stage IIB). A visual analog scale score (VAS score) for pruritus was available in 29 CTCL patients (7 SS, 9 FMF and 13 classic MF) and in other cases complaints of pruritus were retrieved from medical records. qPCR analyses for IL31 expression were performed in lesional skin biopsies from 8 CTCL patients. Serum samples from 4 healthy individuals without pruritus and from 5 atopic dermatitis (AD) patients with severe pruritus were included as controls. RESULTS: In 11/54 (20%) of CTCL patients low serum levels of IL31 were detected (mean 0.48 pg/mL, range 0.20-1.39 pg/mL) including 6/17 (35%) SS patients (mean 0.57 pg/mL) and 5/21 (24%) FMF patients (mean 0.33 pg/mL). All 11 patients with detectable levels of IL31 reported complaints of moderate to severe pruritus and 9/11 patients presented with advanced stage disease (≥IIB). qPCR analyses resulted in lowly expressed IL31 expression levels in 4 of 8 patients; these patients all suffered from pruritus and advanced stage disease. CONCLUSIONS: Translational and transcriptional expression levels of IL31 were very low or undetectable in CTCL patients. Detectable low IL31 serum levels were exclusively observed in SS and FMF patients and not in patients with classic MF. However, these marginal IL31 levels in a small proportion of CTCL patients do not support an essential role for IL31 in CTCL patients.

Recommendations for treatment in folliculotropic mycosis fungoides: report of the Dutch Cutaneous Lymphoma Group.

BACKGROUND: Folliculotropic mycosis fungoides (FMF) is an aggressive variant of mycosis fungoides (MF) and generally less responsive to standard skin-directed therapies (SDTs). Recent studies distinguished indolent (early-stage FMF) and more aggressive (advanced-stage FMF) subgroups. The optimal treatment for both subgroups remains to be defined. OBJECTIVES: To evaluate initial treatment results in patients with early- and advanced-stage FMF. METHODS: A study was undertaken of 203 patients (84 early-stage, 102 advanced-stage, 17 extracutaneous FMF) included in the Dutch Cutaneous Lymphoma Registry between 1985 and 2014. Type and results of initial treatment were retrieved from the Dutch Registry. Main outcomes were complete remission (CR); sustained complete remission; partial remission (PR), > 50% improvement; and overall response (OR; CR + PR). RESULTS: Patients with early-stage FMF were treated with nonaggressive SDTs in 67 of 84 cases resulting, respectively, in CR and OR of 28% and 83% for monotherapy topical steroids, 0% and 83% for ultraviolet B (UVB), and 30% and 88% for psoralen plus ultraviolet A (PUVA). In patients with advanced-stage FMF these SDTs were less effective (combined CR and OR 10% and 52%, respectively). In patients with advanced-stage FMF local radiotherapy (CR 63%; OR 100%), total skin electron beam irradiation (CR 59%; OR 100%) and PUVA combined with local radiotherapy (CR 5%, OR 75%) were most effective. CONCLUSIONS: The results of the present study demonstrate that not all patients with FMF should be treated aggressively. Patients with early-stage FMF may benefit very well from standard SDTs also used in early-stage classic MF and have an excellent prognosis.

Rho kinase signalling mediates radiation-induced inflammation and intestinal barrier dysfunction.

BACKGROUND: Radiotherapy is important in the management of pelvic malignancies, but radiation-induced intestinal damage is a dose-limiting factor. Microvascular injury and epithelial barrier dysfunction are considered to be rate-limiting aspects in radiation-induced enteropathy. This study investigated the role of Rho kinase signalling in radiation-induced inflammation and intestinal barrier dysfunction. METHODS: The specific Rho kinase inhibitor Y-27632 (1 and 10 mg/kg) was given to C57BL/6J mice before challenge with 20 Gy radiation. Leucocyte- and platelet-endothelium interactions in the colonic microcirculation were assessed by intravital microscopy. Levels of myeloperoxidase (MPO) and CXC chemokines (macrophage inflammatory protein 2 and cytokine-induced neutrophil chemoattractant), and intestinal leakage were quantified after 16 h. RESULTS: Radiation increased leucocyte and platelet recruitment, MPO activity, CXC chemokine production and intestinal leakage. Y-27632 significantly reduced radiation-induced leucocyte rolling and abolished adhesion; it also decreased platelet rolling and adhesion by 55 and 74 per cent respectively (P < 0·050). Inhibition of Rho kinase signalling significantly decreased radiation-provoked formation of CXC chemokines, MPO activity by 52 per cent, and intestinal leakage by 67 per cent (P < 0·050). CONCLUSION: Rho kinase activity constitutes an important signalling mechanism in radiation-induced inflammation and intestinal barrier dysfunction.

p38 Mitogen-activated protein kinase signalling regulates vascular inflammation and epithelial barrier dysfunction in an experimental model of radiation-induced colitis.

BACKGROUND: : Microvascular injury and epithelial barrier dysfunction are rate-limiting aspects in radiation enteropathy. This study examined the role of p38 mitogen-activated protein kinase (p38 MAPK) signalling in radiation-induced colitis in an experimental model. METHODS: : The p38 MAPK inhibitor SB239063 was administered to mice immediately before exposure to 20 Gy radiation. Leucocyte- and platelet-endothelium interactions in the colonic microcirculation were assessed by intravital microscopy. Levels of myeloperoxidase (MPO) and CXC chemokines (macrophage inflammatory protein (MIP) 2 and cytokine-induced neutrophil chemoattractant (KC)), and albumin leakage were quantified 16 h after irradiation. RESULTS: : Irradiation induced an increase in leucocyte and platelet recruitment, MPO activity, CXC chemokine levels and intestinal leakage. Inhibition of p38 MAPK by SB239063 decreased radiation-induced leucocyte and platelet recruitment (leucocyte rolling and adhesion by 70 and 90 per cent, both P < 0.001; that of platelets by 70 and 74 per cent, both P < 0.001). It also reduced radiation-provoked increases in colonic MPO activity by 88 per cent (P < 0.001), formation of MIP-2 and KC by 72 and 74 per cent respectively (P = 0.003 and P < 0.001), and intestinal leakage by 81 per cent (P < 0.001). CONCLUSION: : p38 MAPK is an important signalling pathway in radiation-induced colitis.

P-selectin glycoprotein ligand-1 regulates chemokine-dependent leukocyte recruitment in colonic ischemia-reperfusion.

OBJECTIVE AND DESIGN: Leukocyte recruitment is a key feature in ischemia-reperfusion (I/R) -provoked tissue injury. This study evaluated the role of P-selectin-glycoprotein ligand-1 (PSGL-1) in CXC chemokine- and ischemia-reperfusion- induced leukocyte rolling and adhesion in the colon. MATERIALS: Balb/c mice were used in an inverted intravital fluorescence microscopy study of the microvascular bed in the colon. TREATMENT: Mice were challenged with macrophage inflammatory protein-2 (MIP-2) intraperitonally and leukocyte-endothelium interactions were analysed 3 h later. In separate experiments, mice were exposed to I/R by clamping of the superior mesenteric artery for 30 min and leukocyte rolling and adhesion were analysed after 120 min of reperfusion. RESULTS: MIP-2 dose-dependently increased leukocyte rolling and adhesion in the colon. Pretreatment with an anti-PSGL-1 antibody reduced MIP-2-provoked leukocyte rolling and adhesion by more than 89%. I/R increased expression of MIP-2 as well as leukocyte rolling and adhesion. Immunoneutralization of PSGL-1 decreased reperfusion-induced leukocyte rolling by 85% and adhesion by 93% in colonic venules. CONCLUSIONS: Our data demonstrates that PSGL-1 is a dominant adhesion molecule supporting MIP-2- and I/R-provoked leukocyte rolling. Inhibition of PSGL-1 abolished leukocyte rolling and abrogated I/R-induced leukocyte adhesion in colonic venules. These findings suggest that targeting PSGL-1 may be an effective strategy to prevent I/R-induced inflammation in the colon.

[A woman with shock as first sign of Zollinger-Ellison syndrome]. / Een vrouw met shock als eerste uiting van een zollinger-ellisonsyndroom.

A 49-year-old woman presented at the emergency ward in shock with upper gastrointestinal bleeding. Extensive ulceration confirmed by gastroduodenoscopy was suggestive of Zollinger-Ellison syndrome. Further evaluation by fasting gastrin assessment, CT, endosonography with cytological biopsy and somatostatin-receptor scintigraphy confirmed the diagnosis ofgastrinoma. Three enlarged lymph nodes near the pancreatic head were surgically removed; each was found to contain neuroendocrine tumour cells. The patient recovered rapidly after surgery and the gastrin level normalised. Zollinger-Ellison syndrome is uncommon but should be considered as a possible cause of upper gastrointestinal bleeding. Shock is very rarely the first sign ofZollinger-Ellison syndrome. In this case, the use of a proton-pump inhibitor may have masked the disease for years.

Pediatric urinary tract infection.

UTIs are common in children. They may present with a range of severity from cystitis to febrile UTI or pyelonephritis. The presentation may be vague and have nonspecific symptoms. Therefore, a UTI should be considered in all children with a fever in whom other sources have been excluded. Treatment depends on the age, location of infection, and degree of illness in the child. Sick children and infants less than 3 months should be treated as inpatients, and healthy children and older infants may be treated as outpatients. Urinalysis provides presumptive evidence of infection, whereas urine culture is definitive. Close follow-up and outpatient evaluations are needed to prevent long-term consequences of infection.

Patients' understanding of the roles of interns, residents, and attending physicians in the emergency department.

OBJECTIVE: To assess patients' knowledge of the responsibilities and roles of physician training in the ED. METHODS: This was a prospective survey of a convenience sample of 345 adult patients and family members in an academic county ED. Thirty questions addressed the different roles, responsibilities, and hierarchies of physician levels of training. Four opinion-based questions assessed patients' willingness to have physicians-in-training care for them. RESULTS: 96.5% of the surveys were returned. Of the participants responding, 68% were Hispanic, 23% were non-Hispanic white, and 55% were women. Forty percent of the participants indicated that they had education greater than a high school diploma. Most participants answered fewer than 50% of the questions correctly, indicating that they did not understand the levels of physician training. Participants with higher education were more likely to know the correct answer. Seventy-nine percent of the participants believed that it is very important to know the level of training of their physicians. However, only 34% of the participants actually thought they knew the training level of their physicians when they were being treated. Twenty-nine percent of the participants did not want learning to take place on themselves by physicians-in-training. CONCLUSION: Participants believe that it is important to know their physicians' level of training, but they do not understand the roles and responsibilities of physicians-intraining in the medical training system in which they receive care. In particular, patients who have less than a high school education seem to know least about this system.

Follow-up compliance in febrile children: a comparison of two systems.

OBJECTIVES: Follow-up compliance is critical in febrile children because they may harbor unrecognized life-threatening illnesses. This study compares follow-up rates between 2 systems: Wilford Hall Medical Center (WHMC), with preset appointments after ED release, and free medical care; and Fairfax Hospital (FFX), where parents must arrange follow-up appointments after ED release, and are responsible for payment for their follow-up visits. The study also investigated factors associated with follow-up compliance. METHODS: This was a prospective, observational study of febrile children seen in 2 EDs with different systems for patient follow-up. From ED records and parental phone calls, diagnosis, follow-up compliance, and demographics were collected. Data were analyzed using logistic regression and chi2. RESULTS: 423 children met entrance criteria, and 330 parents were successfully contacted after the child's ED release (146 from WHMC; 184 from FFX). The WHMC children were more likely to comply with follow-up than were the children in the FFX system (92% vs 67% follow-up, odds ratio 2.5, 95% CI 1.1-5.3). Other factors associated with noncompliance with recommended follow-up were: Hispanic ethnicity, non-English-speaking parents, and follow-up suggested for >24 hours after ED release. For FFX, self-pay, lack of a follow-up physician, parents' dissatisfaction with the ED medical care, and diagnosis of otitis media were also significant factors found associated with noncompliance. CONCLUSION: Febrile children evaluated in a medical system with prearranged follow-up appointments and free medical care are more likely to comply with recommended follow-up than are those evaluated in a system where payment and appointments are the responsibility of the parents. Efforts should be made to improve follow-up compliance by modeling the WHMC system.

Molecular cloning and tissue distribution of cDNA encoding a novel chemoattractant-like receptor.

With the application of a homology screening strategy, including PCR amplification and southern blot hybridization, a novel cDNA was cloned from rat liver and anterior pituitary libraries. It was found to encode a 371-amino acid protein which has the characteristics of a heptahelix receptor and shows structural identity to members of the chemoattractant receptor family. A primary receptor message of 3.5 kb size was identified by northern blot hybridization. This RNA species showed high expression in heart and lung, while expression was lower in small intestines, colon, kidney, liver, uterus, and in brain. Another larger RNA species of 6.3 kb appeared in heart and lung. In situ hybridization histochemistry performed on tissue from liver and kidney revealed a mainly vascular distribution of the receptor message.

Ophthalmologic procedures.

Step-by-step instructions for the most common and difficult ophthalmologic procedures that are performed in an emergency department. Foreign body removal, including rust rings, is explained with an emphasis on limiting further injury to the corneal epithelium and stroma. Patching, irrigation, contact lens removal and corneal culture techniques are explained. Three methods of assessing intraocular pressure are described.