Extensive acquired cholesteatoma in children: when the penny drops

OBJECTIVES: To determine the factors associated with the diagnosis of acquired cholesteatoma (AC) in children, we performed a retrospective chart review at a tertiary care center. METHODS: We reviewed children with a diagnosis of AC that extended beyond the mesotympanum in the presence of a nonintact tympanic membrane who underwent surgical treatment over a 14-year period. RESULTS: There were 116 children (78 male, 38 female) between 3 and 18 years of age (mean, 9.5 years). Their average period of management in a specialist otolaryngology clinic before the diagnosis of cholesteatoma was made was 3.2 years, and 68% of the children had previously undergone insertion of tympanostomy tubes. Symptoms and signs included chronic otorrhea (59%), recurrent acute otitis media (58%), and conductive hearing loss (51%). The diagnosis of AC was eventually made after office otoscopy (26%), temporal bone computed tomography (24%), or examination under anesthesia (17%). In 33% of children, the diagnosis was made only after surgical exploration of the middle ear and mastoid. CONCLUSIONS: Our data underscore the importance of maintaining a high index of suspicion for AC in managing children with long-standing otologic symptoms, and considering otomicroscopy, computed tomographic scanning, or tympanomastoid exploration if medical treatment fails.     

Experimental autoimmune anti-glomerular basement membrane glomerulonephritis: a protective role for IFN-gamma

IL-12 and IFN-gamma play key roles in murine lupus and planted antigen models of glomerulonephritis. However, their roles in renal organ-specific autoimmunity are unknown. To establish the roles of endogenous IFN-gamma and IL-12 in experimental autoimmune anti-glomerular basement membrane (GBM) glomerulonephritis (EAG), EAG was induced in normal C57BL/6 mice (WT), IL-12p40-deficient (IL-12p40-/-) mice, and IFN-gamma-deficient (IFN-gamma-/-) mice by immunization with alpha3-alpha5(IV)NC1 heterodimers. At 13 wk, WT mice developed EAG with linear mouse anti-GBM antibody deposition, histologic injury, proteinuria, and mild tubulointerstitial disease. Compared with WT mice, IL-12p40-/- mice had decreased histologic injury and trends to decreased leukocyte infiltrates. In contrast, 40% (4 of 10) of IFN-gamma-/- mice developed significant crescent formation and focal or diffuse interstitial infiltrates (WT, 0 of 8). Compared with WT and/or IL-12p40-/- mice, IFN-gamma-/- mice developed increased injury: histologic injury, total glomerular cell numbers, leukocytes in glomeruli, and renal expression of P-selectin and intercellular adhesion molecule 1. All groups developed similar serum anti-alpha3-alpha5(IV)NC1 antibodies and glomerular Ig deposition, but IFN-gamma-/- mice had decreased anti-alpha3-alpha5(IV)NC1 IgG2a. Therefore, IFN-gamma-/- mice developed increased cellular reactants despite a potentially less damaging antibody response. Dermal delayed-type hypersensitivity was increased in alpha3-alpha5(IV)NC1 immunized IFN-gamma-/- mice and was suppressed by recombinant murine IFN-gamma. CD4+ cells from draining nodes of immunized IFN-gamma-/- mice showed increased proportions of proliferating CD4+ cells but similar numbers of apoptotic cells. These studies demonstrate that in renal organ-specific autoimmunity, IL-12 is pathogenetic but IFN-gamma is protective. They lend weight to the hypothesis that depending on the context/severity of the nephritogenic immune response IFN-gamma has different effects.     

Exposure assessment for a population-based case-control study combining a job-exposure matrix with interview data

OBJECTIVES: A system that combines the ease of use of a job-exposure matrix while taking into account job-specific data is needed. This study aimed to produce a detailed method for combining interview data with expert assessments for a large population-based case-control study of Parkinson's disease. METHOD: An interview-administered core questionnaire with a series of questions that triggers substance-specific questionnaires to gather information on key parameters is administered. Using a job-exposure matrix to generate base estimates, assessors can modify this estimate of exposure intensity using worker-specific data such as the use of control measures, reports of substance-specific acute symptoms, and the quantity of material being processed. Detailed guidance for making adjustments to exposure estimates for these modifiers is presented. RESULTS: The method has been partially validated through the use of a comparison of estimates for a separate cohort with previously validated exposure reconstructions. Agreement was high, with a Spearman's rho of 0.89 (P < 0.01). The results from a quality assurance system employed as part of the methodology show a high degree of repeatability in generated exposure values both over time (Spearman's rho 0.98, P < 0.01) and between different assessors (Spearman's rho 0.88, P < 0.01). CONCLUSIONS: The method provides detailed quantitative exposure indices for occupational epidemiology. It has particular strengths both in terms of ease and speed of use. It is hoped that it will provide a useful structure for future epidemiologic work.     

Providing written information for patients with head and neck cancer

Nurses in one Northern Ireland hospital asked patients, their relatives and members of the multidisciplinary care team for their input in compiling an information booklet for patients undergoing major surgery for head and neck cancer, with the aim of creating an information source which would be attractive to a range of patients with head and neck cancer.     

Near-fatal asthma: a population-based study of risk factors

BACKGROUND: The study of near-fatal asthma (NFA) may provide a means to further our understanding of fatal asthma. Studies of NFA often are derived from a single ICU rather than from a defined population. We therefore aimed to identify factors distinguishing NFA patients (cases) from those persons treated in an emergency department (ED) [ED control subjects] and in the community (community control subjects [CCs]). METHODS: This was a population-based case-control study conducted over 20 months of 45 NFA patients (age range, 5 to 50 years), 197 ED control subjects treated in an ED, and 303 CCs, all of whom were residents of Alberta. RESULTS: The age distribution was similar between NFA patients and control subjects, with the majority being < 22 years of age (NFA patients, 68.9%; ED control subjects, 71.3%; CCs, 60.7%). Those patients with NFA were significantly more likely to have received a diagnosis before 5 years of age (66.6%), compared to ED control subjects (39.6%) and CCs (28.7%). The NFA group was significantly more likely to report moderate-to-severe disease and more frequent symptoms than the other groups. Therapy with bronchodilators was used most frequently by the NFA group compared to the ED control subjects and CCs (p < 0.001), as was therapy with inhaled steroids (p < 0.001) and oral steroids (p < 0.001). NFA patients had higher scores for vulnerability and were most likely to admit to stress as an asthma trigger. All groups had high exposure to cigarette smoke and pets. CONCLUSION: NFA patients have many modifiable risk factors and many similarities to ED control subjects and CCs with asthma. General measures to improve asthma control and awareness of risks are required in all groups.     

Acellularization of human placenta with preservation of the basement membrane: a potential matrix for tissue engineering

Basement membrane directs cell migration, cell adherence, and tissue organization in vivo. These qualities would be advantageous in tissue engineering, during which repopulation of scaffolds by functional cells is a common problem. The purpose of this study was to expose human term placenta to a chemical acellularization protocol using the isolated cotyledon perfusion technique to develop an acellular scaffold rich in extracellular matrix components for tissue engineering applications. The processed blocks of tissue demonstrated no cellular material on histologic examination. Periodic acid-Schiff staining, type IV collagen labeling, and transmission electron microscopy demonstrated preservation of the extracellular matrix and basement membrane. Maintenance of the extracellular matrix architecture was seen on scanning electron microscopy. Placenta-derived acellular matrix is a potential volume scaffold for tissue engineering. It is rich in extracellular matrix, has a complex architecture of vascular channels, and has unique donor opportunities.     

Inherited resistance to arsenate toxicity in two populations of Lumbricus rubellus

No unequivocal evidence exists of genetically inherited resistance to metals/metalloids in field populations of earthworms. We studied cocoon production in adult Lumbricus rubellus Hoffmeister collected from an abandoned arsenic and copper mine (Devon Great Consols, Devon, UK), and abandoned tungsten mine (Carrock Fell, Cumbria, UK) and an uncontaminated cultured population. The earthworms were kept in uncontaminated soil for nine weeks. From a total of 42 L. rubellus from each site, Devon Great Consols adults produced 301 cocoons, of which 42 were viable; Carrock Fell 60 cocoons, of which 11 were viable; and the reference population 101 cocoons, of which 62 were viable. The hatchlings were collected and stored at 4 degrees C at weekly intervals. After 12 weeks, all hatchlings were transferred to clean soil and maintained at 15 degrees C for 20 weeks until they showed evidence of a clitellum. In toxicity trials, F1 generation L. rubellus were exposed to 2,000 mg As/kg as sodium arsenate or 300 mg Cu/kg as copper chloride for 28 d. The F1 generation L. rubellus from Devon Great Consols mine demonstrated resistance to arsenate but not copper. All L. rubellus from Devon Great Consols kept in soil treated with sodium arsenate remained in good condition over the 28-d period but lost condition rapidly and suffered high mortality in soil treated with copper chloride. The control population suffered high mortality in soil treated with sodium arsenate and copper chloride. Previous work has shown that field-collected adults demonstrate resistance to both arsenate and Cu toxicity under these conditions. Thus, while arsenate resistance may be demonstrated in F1 generation L. rubellus from one of the contaminated sites, Cu resistance is not. The F1 adults and F2 cocoons did not have significantly higher levels of As than the control population, with no residual As tissue burden, suggesting that resistance to As in these populations may be inherited.     

Intrinsic renal cell expression of CD40 directs Th1 effectors inducing experimental crescentic glomerulonephritis

Evidence suggests that human and experimental crescentic GN results from Th1-predominant immunity to glomerular antigens. CD40/CD154 signaling plays a key role in initiating Th1 responses and may direct Th1 effector responses. The role of CD40 in the development of GN was assessed in murine experimental anti-glomerular basement membrane GN. In this model, C57BL/6 wild-type (WT) mice sensitized to sheep globulin develop crescentic GN resulting from Th1 effector responses when challenged with sheep globulin planted in glomeruli. CD40-/- mice do not develop immunity in response to sheep globulin and thus fail to develop effector responses or significant GN. CD40 is expressed in nephritic glomeruli, suggesting a potential role for intrarenal CD40-CD154 interactions in injurious effector responses. Immune neutralization of the CD40 ligand (CD154) at the time of challenge significantly reduced accumulation of Th1 effectors and injury. The role of CD40 expression by renal cells was assessed by comparing GN in WT-->CD40-/- chimeras (absent renal but intact bone marrow CD40) and sham chimeric mice (WT-->WT). Both groups developed strong antigen-specific immune responses (antibody and IFN-gamma production). However, WT-->CD40-/- chimeras demonstrated reduced renal monocyte chemotactic protein 1 and IFN-inducible protein 10 mRNA levels and minimal T cell and macrophage influx and were protected from renal injury. Sham chimeric mice developed reduced GFR, with prominent renal expression of monocyte chemotactic protein 1 and IFN-inducible protein 10 mRNA and effector cell accumulation. In conclusion, the expression of CD40 by nonimmune renal cells plays a major role in Th1 effector responses by inducing Th1 chemokine production. Therefore, CD40-CD154 interactions are a potential therapeutic target in GN.