Blocking airway mucous cell metaplasia by inhibiting EGFR antiapoptosis and IL-13 transdifferentiation signals

Epithelial hyperplasia and metaplasia are common features of inflammatory and neoplastic disease, but the basis for the altered epithelial phenotype is often uncertain. Here we show that long-term ciliated cell hyperplasia coincides with mucous (goblet) cell metaplasia after respiratory viral clearance in mouse airways. This chronic switch in epithelial behavior exhibits genetic susceptibility and depends on persistent activation of EGFR signaling to PI3K that prevents apoptosis of ciliated cells and on IL-13 signaling that promotes transdifferentiation of ciliated to goblet cells. Thus, EGFR blockade (using an irreversible EGFR kinase inhibitor designated EKB-569) prevents virus-induced increases in ciliated and goblet cells whereas IL-13 blockade (using s-IL-13Ralpha2-Fc) exacerbates ciliated cell hyperplasia but still inhibits goblet cell metaplasia. The distinct effects of EGFR and IL-13 inhibitors after viral reprogramming suggest that these combined therapeutic strategies may also correct epithelial architecture in the setting of airway inflammatory disorders characterized by a similar pattern of chronic EGFR activation, IL-13 expression, and ciliated-to-goblet cell metaplasia.     

Role of neoadjuvant chemotherapy in congenital intracranial haemangiopericytoma

Infantile haemangiopericytoma of the CNS is a rare entity. We report the first case of a congenital haemangiopericytoma successfully treated by preoperative chemotherapy. The patient presented shortly after birth with the diagnosis of a haemangiopericytoma. As neurosurgery was too risky due to size, location and age of the patient an anthracycline‐based chemotherapeutic regimen was applied and resulted in a significant decrease in tumour size, making a postchemotherapy complete surgical resection possible. Chemotherapy may benefit patients with congenital haemangiopericytoma especially if the tumour cannot initially be treated by complete neurosurgical resection. Pediatr Blood Cancer. 2010;56:161–163. © 2010 Wiley‐Liss, Inc.     

Structure–function relations of primate lower incisors: a study of the deformation of Macaca mulatta dentition using electronic speckle pattern interferometry (ESPI)

Teeth adopt a variety of different morphologies, each of which is presumably optimized for performing specific functions during feeding. It is generally agreed that the enamel cap is a crucial element in controlling the mechanical behavior of mammalian teeth under load. Incisors are particularly interesting in terms of structure–function relations, as their role in feeding is that of the ‘first bite’. However, little is known how incisor cap morphology is related to tooth deformation. In the present paper we examine the mechanical behavior of mandibular central incisors in the cercopithecine primate Macaca mulatta under loads similar to those encountered during ingestion. We map three‐dimensional displacements on the labial surface of the crown as it is compressed, using electronic speckle pattern interferometry (ESPI), an optical metrology method. In addition, micro‐computed tomography is used to obtain data regarding the morphology of the enamel cap, which in the M. mulatta lower incisors exhibits missing or very little enamel on the lingual face. The results showed that although compressed along a longitudinal axis, deformation in the incisors mostly occurred in the lingual direction and orthogonal to the direction of the applied load. Both isolated, embedded teeth and teeth in the mandible showed considerable lingual deformation. Incisor deformation in the mandible was generally greater, reflecting the additional freedom of movement enabled by the supporting structures. We show that the association with adjacent teeth in the arch is significant for the behavior of the tooth under load. Finally, loading two teeth simultaneously in the mandible showed that they work as one functional unit. We suggest that these results demonstrate the importance of enamel cap morphology in directing deformation behavior; an ability stemming from the stiffness of the enamel cap overlying the more pliable dentin.     

Elevated ANA titers in patients with severely abnormal gastrointestinal motility

We studied a group of six patients with clinical, radiological, and/or manometric features of severely abnormal gastrointestinal motility. Symptoms suggestive of esophageal, small bowel, or colonic involvement were present from 1 1/2 to 40 years. All patients had elevated antinuclear antibody (ANA) titers. None had clinical or radiographic features suggestive of progressive systemic sclerosis or other connective tissue diseases. Two patients had pathologic examinations of intestinal specimens, and these did not show changes suggestive of progressive systemic sclerosis. We conclude that patients with severe gastrointestinal motility disorders can have elevated ANA titers without features of progressive systemic sclerosis or other connective tissue diseases.This study was supported by the National Institutes of Health grant AM 25965 and grant RR 59 from the General Research Centers Program, Division of Research Resources, National Institutes of Health.     

Adherence to self‐care behavior and glycemic effects using structured education

Aims/Introduction

The purpose of the present study was to examine glycemic control in suboptimally controlled type 2 diabetes provided by a structured education group using the Diabetes Conversation Map™ (CM™) vs usual care in a university-based hospital primary care clinic.

Materials and Methods

This was a randomized, pragmatic clinical trial. Patients with type 2 diabetes were randomly assigned to structured education or usual care groups. The primary outcome was the difference in the mean change of glycated hemoglobin (HbA1c) from baseline to 12 months. Secondary outcomes included the percentage achieving therapeutic HbA1c goal and self-behavioral changes.

Results

A total of 245 patients were randomly assigned to two groups (CM™ group n = 121; usual care group, n = 116). The absolute reduction of HbA1c was significantly greater in the CM™ group at 3 and 6 months (Δ = −0.59% and Δ = −1.13%, P < 0.01), but the difference was no longer statistically significant at 9 and 12 months (Δ = −0.43% and Δ = −0.49%), based on an intention-to-treat analysis. A per-protocol analysis showed the significant change was maintained at 12 months (Δ = −0.67%). In the intervention group, greater percentages of patients achieved their American Association of Diabetes Educators Self-Care Behaviours™ framework (AADE7) behavioral goals at 3 months, in particular being active, problem-solving, reducing risk and health coping.

Conclusions

In type 2 diabetic patients with suboptimally controlled glucose, there were greater improvements in glucose control and self-care behavioral goals in those who underwent the CM™ education program compared with outcomes achieved in patients receiving usual care.     

Incidental colorectal computed tomography abnormalities: would you send every patient for a colonoscopy?

BACKGROUND: The clinical significance of colorectal wall thickening (CRWT) in patients undergoing abdominal computed tomography (CT) has not yet been definitively established. OBJECTIVES: To compare alleged findings on abdominal CT with those of a follow-up colonoscopy. METHODS: Ninety-four consecutive patients found to have large-bowel abnormalities on abdominal CT were referred for colonoscopy. Of these patients, 48 were referred for a suspected colorectal tumour and 46 for CRWT. Colonoscopy was performed and findings were compared. RESULTS: Of the 48 suspected colorectal tumours, 34 were determined to be neoplastic lesions on colonoscopy. Of these, 26 were malignant and eight were benign. Colonoscopy revealed no abnormality in 30 of 46 patients with CRWT as a solitary finding, and revealed some abnormality in 16 patients (12 had diverticular disease, four had benign neoplastic lesions). CONCLUSIONS: CRWT as an incidental and solitary finding on CT should not be regarded as a pathology prompting a colonoscopy. Approximately two-thirds of the patients had a normal colonoscopy and the remaining patients had benign lesions (12 had diverticular disease and four had benign neoplastic lesions). However, many of these patients seem to warrant colonoscopy regardless of CT findings, particularly patients who have a family history of colorectal cancer, have positive fecal occult blood test results or who are older than 50 years of age.     

Acute and chronic airway responses to viral infection: implications for asthma and chronic obstructive pulmonary disease

Despite the high clinical impact of established and emerging respiratory viruses, some critical aspects of the host response to these pathogens still need to be defined. In that context, we aimed at two major issues: first, what are the innate immune mechanisms that control common respiratory viral infections; and second, whether these mechanisms also cause long-term airway disease. Using a mouse model of viral bronchiolitis, we found that antiviral defense depends at least in part on a network of mucosal epithelial cells and macrophages specially programmed for immune-response gene expression. When this network is compromised, the host is highly susceptible to infection, but network components can be engineered to provide increased resistance to infection. Similar alterations appear in asthma and chronic bronchitis/chronic obstructive pulmonary disease, suggesting that evolving attempts to improve antiviral defense may also lead to inflammatory airway disease. Indeed, in genetically susceptible mice, respiratory paramyxoviruses cause a "hit and run" phenomenon that is manifested by the development of a permanent airway disease phenotype long after the infection has cleared. The phenotype can be segregated into individual traits to achieve more precise definition of just how viruses reprogram host behavior. Identifying specific components of the mucosal immune system that manifest an aberrant antiviral response may thereby allow for adjusting this response to improve acute and chronic outcomes after viral infection.