Search

Objective To determine the effects of eosinophilic inflammation on olfactory sensory neuron cell death. Study Design Mice were sensitized to intranasal Aspergillus fumigatus extract and subsequently challenged acutely or chronically with the same allergen. The olfactory neuroepithelium was assessed for immunohistochemical evidence of apoptosis and inflammation. Results Sensitized mice challenged with allergen demonstrated elevated eosinophil infiltration of the respiratory and olfactory mucosae, with olfactory sensory neuron apoptosis. Remarkably, massive neuronal apoptosis without eosinophil infiltration occurred in nonsensitized mice after a single dose of extract. Conclusion Intranasal sensitization with A fumigatus results in a model with multifactorial effects. Protocols using A fumigatus to induce allergic rhinitis may need modification to allow confident interpretation. Significance Fungal allergens may contribute to anosmia through the induction of olfactory sensory neuron apoptosis, with and without prior sensitization.

Filamin B (FLNB) is a cytoplasmic protein that regulates the cytoskeletal network by cross-linking actin, linking cell membrane to the cytoskeleton and regulating intracellular signaling pathways responsible for skeletal development (Stossel, T.P., Condeelis, J., Cooley, L., Hartwig, J.H., Noegel, A., Schleicher, M. and Shapiro, S.S. (2001) Filamins as integrators of cell mechanics and signalling. Nat. Rev. Mol. Cell Biol., 2, 138-145). Mutations in FLNB cause human skeletal disorders [boomerang dysplasia, spondylocarpotarsal (SCT), Larsen, and atelosteogenesis I/III syndromes], which are characterized by disrupted vertebral segmentation, joint formation and endochondral ossification [Krakow, D., Robertson, S.P., King, L.M., Morgan, T., Sebald, E.T., Bertolotto, C., Wachsmann-Hogiu, S., Acuna, D., Shapiro, S.S., Takafuta, T. et al. (2004) Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis. Nat. Genet., 36, 405-410; Bicknell, L.S., Morgan, T., Bonafe, L., Wessels, M.W., Bialer, M.G., Willems, P.J., Cohn, D.H., Krakow, D. and Robertson, S.P. (2005) Mutations in FLNB cause boomerang dysplasia. J. Med. Genet., 42, e43]. Here we show that Flnb deficient mice have shortened distal limbs with small body size, and develop fusion of the ribs and vertebrae, abnormal spinal curvatures, and dysmorphic facial/calvarial bones, similar to the human phenotype. Characterization of the mutant mice demonstrated increased apoptosis along the bone periphery of the distal appendages, consistent with reduced bone width. No changes in the initial proliferative rate of chondrocytes were observed, but the progressive differentiation of chondrocyte precursors was impaired, consistent with reduced bone length. The extracellular matrix appeared disrupted and phosphorylated beta1-integrin (a collagen receptor and Flnb binding partner) expression was diminished in the mutant growth plate. Like integrin-deficient chondrocytes, adhesion to the ECM was decreased in Flnb(-/-) chondrocytes, and inhibition of beta1-integrin in these cells led to further impairments in cell spreading. These data suggest that disruption of the ECM-beta1-integrin-Flnb pathway contributes to defects in vertebral and distal limb development, similar to those seen in the human autosomal recessive SCT due to Flnb mutations.

How can companies break into attractive markets, where incumbents erect many barriers to entry? To answer this question, the authors studied organizations that successfully entered the most profitable industries in the United States between 1990 and 2000. When they dissected the strategies that worked best, one common theme stood out: indirect assault. Smart newcomers don't duplicate existing business models, compete for crowded distribution channels, or go after mainstream customers right away. Instead, they attack the enemy at its weakest points; then gain competitive advantage; and later, if doing so meets their objectives, go after its strongholds. Recent battles in the soft drink industry--where brands, bottling and distribution capabilities, and shelf space are incumbents' main advantages--are a case in point. When Virgin Drinks entered the U.S. cola market in 1998, it advertised heavily and immediately tried to get into the retail outlets that stock the leading brands. Virgin has never garnered more than a 1% share of the market. Red Bull, by contrast, came on the scene in 1997 with a niche product: a carbonated energy drink. The company started by selling the drink at bars and nightclubs. After gaining a loyal following through these outlets, Red Bull elbowed its way into the corner store. In 2005 it enjoyed a 65% share of the $650 million energy drink market. Successful entrants use three basic approaches in their indirect attacks. They leverage their existing assets and resources, reconfigure their value chains, and create niches. These approaches may appear to be simple, but their magic lies in their combination. By mixing and matching them, Bryce and Dyer say, enterprises can defy half a century of economic logic and make money entering highly profitable industries. The authors use Skype, Costco, Skechers, and many other companies to illustrate their argument.

S A T U R D A Y 132 The Relationship of Eosinophilic Esophagitis and Food Allergy: Evaluating the Spectrum of Eosinophilic Esophagitis Barry J. Pelz, MD, Joshua B. Wechsler, MD, Rebecca KrierBurris, MS, Barry Wershil, MD, Amir F. Kagalwalla, MD, Paul Bryce, PhD; Division of Allergy & Immunology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, Division of Gastroenterology, Hepatology, and Nutrition, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, Division of Allergy & Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, Division of AllergyImmunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL. RATIONALE: Studies support roles for both IgE and non-IgE-mediated food reactions in eosinophilic esophagitis (EoE), yet the interplay between EoE and food allergy (FA) remains elusive. We sought to determine the prevalence of EoE and food allergy (EoEwFA) compared to EoE without food allergy (EoEsFA) and to investigate the epidemiologic, pathologic, and histologic differences between these subpopulations. METHODS: A retrospective chart review of pediatric patients with EoE seen at the Ann&Robert H. Lurie Children’s Hospital of Chicago between 2004 and 2014 was performed to identify key characteristics of EoEwFA versus EoEsFA. In addition to routine pathology, immunohistochemistry staining for mast cells on biopsy specimens from both subpopulations was performed. Chi square tests, t-tests, and Mann-Whitney-Wilcoxon tests were used to investigate differences within these subpopulations. RESULTS: From 94 EoE patients, 16 (17%) also had food allergy. EoEwFA patients were more likely to have coexistent allergic rhinitis, eczema, or GERD (p50.02, 0.03, and 0.04, respectively) than EoEsFA. Additionally, they exhibited a higher total IgE at diagnosis, higher specific IgE and positive skin prick tests to several foods, including egg, soy, peanut, and tree nuts compared to children with EoEsFA. Pathologically, while there was no difference in tissue eosinophils between groups, biopsies showed increases in peak mast cells/HPF and percent of activated MC/HPF in patients with EoEwFA. CONCLUSIONS: Our findings demonstrate differences in both diagnostic features and esophageal pathobiology in EoE patients with or without food allergy. Such differences might help explain the spectrum of characteristics observed in EoE.

Contact sensitivity responses require both effective immune sensitization following cutaneous exposure to chemical haptens and antigen-specific elicitation of inflammation upon subsequent hapten challenge. We have observed that that antigen-independent effects of immunoglobulin E (IgE) antibodies promote immune sensitization to haptens in the skin. Contact sensitivity is markedly impaired in IgE-/- mice but can be restored by either transfer of sensitized cells from wild-type mice or administration of hapten-irrelevant IgE before sensitization. Moreover, IgE-/- mice exhibit impairment in the emigration of dendritic cells from the epidermis after hapten exposure. Monomeric IgE has been reported to influence mast cell function. We observe diminished contact sensitivity in mice lacking FcepsilonRI or mast cells, and mRNA for several mast cell-associated genes is reduced in IgE-/- vs. wild-type skin after hapten exposure. We propose that levels of IgE normally present in mice favour immune sensitization via antigen-independent effects on mast cells.

Objective Sclerotherapy (IS) or ambulatory phlebectomy (AP) are required as subsequent interventions in majority of cases following endovenous laser therapy (EVLT). We assessed whether AP performed concomitantly with EVLT (EVLTAP), is effective, acceptable, and reduces subsequent requirement for interventions. Method 67 patients (70 limbs) with great saphenous varicosities underwent EVLTAP. Pain was assessed on days 1, 4 and 7 using a visual analogue scale (VAS) of 0 to 10. Clinical and ultrasound assessments were done at 1, 6 and 12 weeks (no ultrasound at 6 weeks). Residual varicosities underwent further AP or IS. Patients' satisfaction with the cosmetic outcome and overall treatment was assessed at 12 weeks using a VAS rating. Results 49 patients (70%) completed follow-up. Median pain scores were 1.6 (IQR 0.2–4.8), 0.3 (0–1.4) and 0.2 (0–1.1) on days 1, 4 and 7 respectively. Ultrasound demonstrated 69 (99%) and 47 (96%) occluded long saphenous veins at 1 and 12 weeks respectively. Subsequent IS or AP was performed on 3 (4%) or 1 (1%) limbs respectively. Cosmetic satisfaction was 9.6 (IQR 8.9–10) and overall satisfaction 9.8 (IQR 9.3–10). Conclusion EVLTAP produces excellent results, is feasible and acceptable, and obviates need for subsequent procedures in the short-term.

Objective To report on the changing profile of children attending for Dental General Anaesthetic extractions (DGA) at the same centre in 1998 and again in 2004 compared to 1991. Design Prospective clinical. Setting Glasgow Dental Hospital DGA service during August 1999 and August/September 2004. Subjects and method Children presenting for DGA extractions. Data recorded: age, gender, number of teeth extracted and level of behaviour using the Frankl scale. Results In 1999: 190 children (97 boys) mean age five years. In 2004: 106 children (55 boys) mean age five years. There was a significant increase in the mean number of teeth extracted (p < 0.001), 4.2 (1-16) and 7.8 (1-17) in 1999 and 2004 respectively, compared to 3.7 in 1991. Twenty-six per cent of children had between six and 16 teeth extracted in 1999 compared to 74% in 2004. Significantly fewer children demonstrated 'definitely positive' behaviour compared to 1991. Children were in the poorest socioeconomic groups, reflecting the geographic area. Conclusion Over half of the children were aged five years and under. Fewer highly co-operative children were treated. More teeth were extracted per child, suggesting that there should be greater opportunities to carry out restorations, not just extractions under general anaesthesia.

Immunoglobulin E (IgE) is an important mediator in immediate hypersensitivity, as it facilitates mast cell degranulation and the release of immunomodulatory mediators, such as histamine, prostaglandins, and cytokines. Antigen-specific IgE is a hallmark of allergic diseases. Upon interaction with polyvalent antigen, IgE molecules crosslink and transmit signals that drive this process. Recently, an alternative function of IgE has come to light. Rather than merely priming the mast cell, in the absence of antigen, IgE influences mast cells, including their survival, receptor expression, and mediator release. The mechanisms by which IgE induces these effects and the biological consequences are being discovered and are showing that IgE has an important and active role in facilitating immune responses.

The tumor necrosis factor (TNF) family member APRIL binds to the receptors BCMA on B cells and TACI on B and T cells. To investigate the role of APRIL in immunity, we generated APRIL-deficient mice. APRIL-/-mice have normal T and B lymphocyte development, normal T and B cell proliferationin vitro, but increased numbers of CD44hiCD62LloCD4+effector/memory T cells and increased IgG responses to T-dependent antigens. Serum IgA levels were significantly decreased, and serum IgA antibody responses to mucosal immunization with TD antigens and to type 1 T-independent antigens were impaired in APRIL-/-mice. APRIL by itself induced IgA as well as IgG1 isotype switching in CD40-deficient IgM+IgD+sorted B cells. These results suggest that APRIL down-regulates T cell-dependent antibody responses and promotes IgA class switching.

Trichinella spiralis infection elicits a vigorous IgE response and pronounced intestinal and splenic mastocytosis in mice. Since IgE both activates mast cells (MC) and promotes their survival in culture, we examined its role in MC responses and parasite elimination in T. spiralis-infected mice. During primary infection, wild-type but not IgE-deficient (IgE−/−) BALB/c mice mounted a strong IgE response peaking 14 days into infection. The splenic mastocytosis observed in BALB/c mice following infection with T. spiralis was significantly diminished in IgE−/− mice while eosinophil responses were not diminished in either the blood or jejunum. Similar levels of peripheral blood eosinophilia and jejunal mastocytosis occurred in wild-type and IgE-deficient animals. Despite the normal MC response in the small intestine, serum levels of mouse MC protease-1 also were lower in parasite-infected IgE−/− animals and these animals were slower to eliminate the adult worms from the small intestine. The number of T. spiralis larvae present in the skeletal muscle of IgE−/− mice 28 days after primary infection was about twice that in BALB/c controls, and the fraction of larvae that was necrotic was reduced in the IgE-deficient animals. An intense deposition of IgE in and around the muscle larvae was observed in wild-type but not in IgE null mice. We conclude that IgE promotes parasite expulsion from the gut following T. spiralis infection and participates in the response to larval stages of the parasite. Furthermore, our observations support a role for IgE in the regulation of MC homeostasis in vivo.

We have generated mice in which the gene encoding the transcription factor STAT3 can be inactivated in multiple cell types by triggering the endogenous production of type I interferon. Gene inactivation is particularly effective in the liver and the adipose tissue, as well as in macrophages and gut epithelial cells. Upon induction of the mutation, mice develop a wasting syndrome culminating in an aggressive and fatal form of enterocolitis, limited to the large intestine, within 2–3 weeks after the treatment. The disease is characterised by massive infiltration of the gut mucosa by macrophages, granulocytes and CD4+ cells, increased expression of endothelial adhesion molecules and high production of the cytokines interleukin (IL)-6, IL-12, interferon-γ and IL-10. IL-12 p40 plays a pivotal role in disease development as in vivo treatment with neutralising antibodies completely prevents its onset. Interestingly, oral treatment with wide spectrum antibiotics does not have any effect on either the onset or the development of colitis. Taken together, these data show that STAT3 plays a crucial role in the maintenance of intestinal homeostasis and possibly in mediating specialised cell functions in the intestinal epithelium.

Background Atopic dermatitis (AD) is characterized by skin infiltration with eosinophils and lymphocytes and expression of Th 2 cytokines in acute skin lesions. The skin of patients with AD is frequently colonized with enterotoxin-secreting strains of Staphylococcus aureus . Staphylococcal enterotoxins have been implicated in the exacerbations of the inflammatory skin lesions in patients with AD. Objective We sought to determine whether epicutaneous (EC) sensitization of mice with staphylococcal enterotoxin B (SEB) results in allergic skin inflammation. Methods BALB/c mice were EC-sensitized with SEB. Their skin was examined for allergic inflammation and cytokine expression, and their splenocytes were examined for cytokine secretion in response to SEB. Results EC sensitization with SEB elicited a local, cutaneous, inflammatory response characterized by dermal infiltration with eosinophils and mononuclear cells and increased mRNA expression of the Th 2 cytokine IL-4 but not of the Th 1 cytokine IFN-γ. EC-sensitized mice mounted a systemic Th 2 response to SEB evidenced by elevated total and SEB-specific IgG1 and IgE. Although EC sensitization with SEB resulted in selective depletion of SEB-specific T-cell receptor Vβ8+ cells from the spleen and sensitized skin, splenocytes from SEB-sensitized mice secreted relatively more IL-4 and less IFN-γ than did saline-sensitized controls, consistent with Th 2 skewing of the systemic immune response to the superantigen. Conclusion These results suggest that EC exposure to superantigens skews the immune response toward Th 2 cells, leading to allergic skin inflammation and increased IgE synthesis that are characteristic of AD.

We found that mechanical injury to mouse skin, which can be caused by tape stripping, results in rapid induction of IL-10 mRNA. IL-10-/- mice were used to examine the role of IL-10 in a mouse model of allergic dermatitis induced by epicutaneous (EC) sensitization with OVA on tape-stripped skin. Skin infiltration by eosinophils and expression of eotaxin, IL-4, and IL-5 mRNA in OVA-sensitized skin sites were severely diminished in IL-10-/- mice. Following in vitro stimulation with OVA, splenocytes from EC-sensitized IL-10-/- mice secreted significantly less IL-4, but significantly more IFN-gamma, than splenocytes from WT controls. A similar skewing in cytokine secretion profile was observed in the splenocytes of IL-10-/- mice immunized intraperitoneally with OVA. IL-10-/- APCs skewed the in vitro response of OVA T cell receptor (TCR) transgenic T cells towards Th1. Examination of the Th response of WT and IL-10-/- mice immunized with OVA-pulsed WT or IL-10-/- DCs revealed that both DCs and T cells participate in IL-10 skewing of the Th2 response in vivo. These results suggest that IL-10 plays an important role in the Th2 response to antigen and in the development of skin eosinophilia in a murine model of allergic dermatitis.

Background: Histamine elicits many features of immediate hypersensitivity reactions. Recent evidence indicates that H1 receptors modulate immune responses to antigens. Desloratadine (DL), a new, long-acting, H1 receptor antagonist, has both a potent antihistaminic function and anti-inflammatory properties. Objective: We sought to evaluate the effect of DL on allergic-airway responses in mice after inhalation of the naturally occurring aeroallergen Aspergillus fumigatus ( Af ) and to examine the effects of DL on specific immune responses to a defined protein antigen with the use of an ovalbumin (OVA) model of asthma. Methods: Mice were subjected either to repeated, intranasal application of Af extract or to intraperitoneal immunization with OVA, followed by inhalation challenge. DL or a control fluid was given daily throughout the sensitization process. Immunoglobulin E (IgE) levels, bronchoalveolar lavage-fluid cytokines and cytology, lung histology, and physiologic responses to methacholine were assessed in the allergen-treated mice. Anti-OVA IgE responses and OVA-driven T-cell cytokine production were examined. Results: Treatment with DL did not impair IgE production but did inhibit bronchial inflammation and bronchial hyperresponsiveness in both Af- and OVA-treated mice. This inhibition required that DL be administered concurrently with allergen sensitization, indicating that the attenuation of bronchial hyperresponsiveness and inflammation was not caused by anticholinergic receptor effects. OVA-responsive T cells from DL-treated mice exhibited depressed production of IL-4, IL-5, and IL-13 and normal amounts of interferon-γ. The amounts of IL-5 and IL-13 were also diminished in the bronchoalveolar lavage fluid. Conclusion: DL, given at the time of exposure to the allergen, inhibits T H 2 responses, the induction of allergic pulmonary inflammation, and bronchial hyperresponsiveness. These results suggest that DL or similar agents given during times of antigen exposure might alter disease progression in patients with respiratory allergy. (J Allergy Clin Immunol 2003; 112:149-58.)

Many patients with metastatic transitional-cell carcinoma (TCC) are not appropriate candidates for standard cisplatin-based combination, because of inadequate renal function, poor performance status (PS), and other comorbid medical conditions. We have evaluated the efficacy and toxicity of a combination of carboplatin and vinblastine (CV) as a palliative regimen in these patients. The medical records of patients with metastatic TCC, who had been treated with CV at the British Columbia Cancer Agency from 1995 until 1999, were retrospectively reviewed. Treatment consisted of carboplatin (area under the curve = 5) on day 1, and vinblastine (4 mg/m(2)) on days 1 and 8, repeated every 4 weeks. A total of 42 patients were included in this study, of whom 39 had measurable disease. Median age was 73 years. Fifty-two percent of patients had a PS (Eastern Cooperative Oncology Group) of 2 or 3. Node-only disease was present in 26% of patients, bone metastasis in 26%, and liver metastasis in 24%. A total of 119 cycles were administered. Grade IV granulocytopenia occurred in 26% of patients, grade III anemia in 12%, and there were 3 episodes of febrile neutropenia occurring in two patients. The major nonhematologic toxicity was grade III fatigue in 17% of patients. There were no grade IV nonhematologic toxicity or treatment-related deaths. The overall response rate was 33% (13 of 39). Five patients (13%) achieved a complete response and 8 patients (20%) a partial response. The median duration of response was 32 weeks and median overall survival for all patients was 26 weeks. The combination of carboplatin and vinblastine given in this schedule is a feasible, well-tolerated, and active alternative for patients with metastatic TCC unfit for standard chemotherapy.

The CC chemokine receptor 3 (CCR3) is expressed by eosinophils, mast cells, and Th2 cells. We used CCR3(-/-) mice to assess the role of CCR3 in a murine model of allergic skin inflammation induced by repeated epicutaneous sensitization with ovalbumin (OVA), and characterized by eosinophil skin infiltration, local expression of Th2 cytokines, and airway hyperresponsiveness (AHR) to inhaled antigen. Eosinophils and the eosinophil product major basic protein were absent from the skin of sham and OVA-sensitized CCR3(-/-) mice. Mast cell numbers and expression of IL-4 mRNA were normal in skin of CCR3(-/-) mice, suggesting that CCR3 is not important for infiltration of the skin by mast cells and Th2 cells. CCR3(-/-) mice produced normal levels of OVA-specific IgE, and their splenocytes secreted normal amounts of IL-4 and IL-5 following in vitro stimulation with OVA, indicating effective generation of systemic Th2 helper responses. Recruitment of eosinophils to lung parenchyma and bronchoalveolar lavage (BAL) fluid was severely impaired in CCR3(-/-) mice, which failed to develop AHR to methacholine following antigen inhalation. These results suggest that CCR3 plays an essential role in eosinophil recruitment to the skin and the lung and in the development of AHR.

The Pebble Bed Modular Reactor (PBMR), a promising Generation IV nuclear reactor design, raises many novel technological issues for which new experience and techniques must be developed. This brief study explores a few of these issues, utilizes a computational fluid dynamics code to model some simple phenomena, and points out deficiencies in current knowledge that should be addressed by future research and experimentation. A highly simplified representation of the PBMR core is analyzed with FLUENT, a commercial computational fluid dynamics code. The applied models examine laminar and turbulent flow in the vicinity of a single spherical fuel pebble near the center of the core, accounting for the effects of the immediately adjacent fuel pebbles. Several important fluid flow and heat transfer parameters are examined, including heat transfer coefficient, Nusselt number, and pressure drop, as well as the temperature, pressure, and velocity profiles near the fuel pebble. The results of these 'unit cell' calculations are also compared to empirical correlations available in the literature. As FLUENT is especially sensitive to geometry during the generation of a computational mesh, the sensitivity of code results to pebble spacing is also examined. The results of this study show that while a PBMR presents amore » novel and complex geometry, a code such as FLUENT is suitable for calculation of both local and global flow characteristics, and can be a valuable tool for the thermal-hydraulic study of this new reactor design. FLUENT results for pressure drop deviate from the Darcy correlation by several orders of magnitude in all cases. When determining the heat transfer coefficient, FLUENT is again much lower than Robinson's correlation. Results for Nusselt number show better agreement, with FLUENT predicting results that are 10 or 20 times as large as those from the Robinson and Lancashire correlations. These differences may arise because the empirical correlations concern mainly integral parameters, while the FLUENT model focuses on local flow behaviors. Local phenomena are significant in the case of local heat transfer characteristics, fine temperature distribution calculations to identify hot spots, and fission product transport phenomena. All of these are important to a safety analysis of the PBMR reactor during normal operation, as well as during transient circumstances, and should be the focus of future research efforts. (authors)« less

The United States Internal Revenue Service (IRS) and some states require nonprofit hospitals to demonstrate that they provide a substantial community benefit in order to get or maintain their tax-exempt status. This places every nonprofit hospital at risk. This article is about certain common factors that impact the management of all nonprofit hospitals and their ability to comply with such laws.

Many factors probably regulate the process of natural cell death during development. It is present in both the early undifferentiated retina and later following differentiation. Melanin production plays a role in regulating retinal development and when it is absent, cell proliferation and death are enhanced. Here we examine the effects of hyperoxia on this process, as oxygen has been shown to reduce cell death among differentiated photoreceptors late in development. However, in this study we examine its effects much earlier in pigmented and albino pigmentation phenotypes, when most cells are still actively dividing and are not committed to a specific fate. Newborn mice were exposed to high oxygen levels for 24 h and then returned to normal air for varying periods and their retinae examined. Hyperoxia had a dramatic effect on the number of dying cells, reducing them by almost 60% in pigmented animals and by over 80% in albinos. Following the return to normal air there was a gradual increase in their number over 360 min back to normal levels in pigmented mice; however, in albinos there was a complete rebound in levels of cell death within 40 min, reflecting the increased metabolic stress present in albino retinae due to their abnormal levels of proliferation. These results highlight the important role played by oxygen during early natural cell death in the retina and reveal the different developmental conditions present in the retinae of the two pigmentation phenotypes examined.

Objective: Chest radiographs (CXRs) are routinely obtained at many institutions in all pediatric patients following thoracostomy tube removal to search for pneumothorax (PTX). To aid in evaluating the necessity of this practice, this study investigates whether clinical signs and symptoms may be a sensitive predictor of PTX in such patients. Materials and methods: Reports from CXRs obtained following chest tube removal in all pediatric patients (374 patients) who underwent cardiac surgery with chest tube placement over 1 year were reviewed. For cases with reported PTX, the PTX was quantified and chart review was performed to assess whether signs and symptoms of PTX preceded the CXR result. Results: Fifty-one of 374 children (13.6%) had a radiographically defined PTX within 6 h after thoracostomy tube removal. The PTX was large (>40%) in 2 children, moderate (20–40%) in 5 children, and small (

Summary Background: Pegylated liposome technology represents a favourable drug-carrier system, since stealth liposomal drugs have a reduced clearance with prolonged circulation half-life and selective drug accumulation in tissues with increased vascular permeability, such as tumor tissues. Caelyx is a pegylated liposome containing doxorubicin, which has been developed to target drug delivery to cancer cells, thus reducing toxicities. Biodistribution studies have shown a selective tumor uptake in patients with advanced head and neck cancer (HNC), thus justifying the present phase I study. Patients and methods: Patients with recurrent or metastatic HNC were treated with Caelyx administered at the starting dose of 30 mg/m 2 every three weeks and escalated by 5 mg/m 2 per step. Dose escalation was stopped if more than a third of patients of a given cohort had dose-limiting toxicity (DLT), which was defined as grade 4 neutropenia or thrombocytopenia, grade 3 febrile neutropenia, grade 3 thrombocytopenia with bleeding, grade 3 non-hematologic toxicity (except for nausea and alopecia), or > 2 week delay in chemotherapy recycling. The above dose level was defined as maximum tolerated dose (MTD) and the dose level immediately below was recommended for phase II evaluation. Response was evaluated after three courses of chemotherapy. Results: Twenty-four patients were treated at five dose levels. At 50 mg/m 2 , three out of six patients had grade 3 stomatitis; therefore, this level was defined as MTD and 45 mg/m 2 was the selected dose for phase II. Stomatitis occurred in 11 patients across all dose levels, considering all delivered cycles. Neutropenia occurred in 10 of 24 patients, but reached grade 4 in only 2 patients at fourth dose level. Skin toxicity, mainly appearing in the form of palmar-plantar erythrodysestesia, was the most frequent toxicity, occurring in 14 patients. Other side effects were mild. One complete response (4%) and seven partial responses (29%) were observed, for an overall response rate of 33% (95% confidence interval (95% CI): 16%-55%). Conclusions: Caelyx is a safe and promising new treatment in HNC, that deserves further evaluation both alone and integrated within chemo-radiotherapy strategies.

Purpose: To examine the effect of the time interval (interval) between breast-conserving surgery (BCS) and the start of radiation therapy (RT) on the subsequent risk of ipsilateral breast cancer recurrence (IBR). Methods and Materials: We reviewed interval and a number of prognostic and treatment factors among 1,962 women treated with BCS and RT for invasive breast cancer diagnosed between January 1, 1989 and December 31, 1993 in British Columbia, Canada. Subjects were female, less than 90 years old at diagnosis, not treated with chemotherapy, not stage T4 or M1, and had survived more than 30 days from diagnosis. The cumulative incidence of IBR was estimated in four interval groups: 0–5, 6–8, 9–12, and 13+ weeks. Only 23 women had an interval of greater than 20 weeks between BCS and start of RT. To assess whether an imbalance of prognostic and treatment factors could be obscuring real differences between the interval groups, Cox proportional hazards regression analyses were conducted. Results: Median follow-up was 71 months. The crude incidence of IBR for the entire sample was 3.9%. The cumulative incidence of IBR in the 6–8, 9–12, and 13+ week groups was not statistically significantly different from the cumulative incidence of IBR in the 0–5 week group. Multivariate analyses demonstrated that patients not using tamoxifen ( p = 0.027) and those with grade 3 histology ( p = 0.003) were more likely to recur in the breast. Interval between BCS and RT was not a statistically significant predictor of breast recurrence when entered into a model incorporating tamoxifen use and tumor grade (0–5 vs. 6–8 weeks, p = 0.872; 0–5 vs. 9–12 weeks, p = 0.665; 0–5 vs. 13+ weeks, p = 0.573). Conclusions: We found no univariate or multivariate difference in ipsilateral breast cancer recurrence between intervals of 0 to 20 weeks from breast conserving surgery to start of radiation therapy, in a population-based, low risk group of women not receiving adjuvant chemotherapy, after controlling for other factors important in predicting ipsilateral breast cancer recurrence.

The role of the cAMP pathway as an immunomodulatory system has been an area of intensive research. Pharmacological elevation of the cAMP pathway inhibits T lymphocyte proliferation and production of Th1-type cytokines. The effects of cAMP are thought to be mediated via activation of the intracellular receptor, protein kinase A (PKA). We investigated the inhibitory effects of cAMP elevation on human lymphocyte proliferation and function by utilising a range of selective inhibitors of PKA. Elevation of cAMP activity by dbcAMP, Sp-cAMPS and forskolin induced significant decreases of Con A stimulated PBMC proliferation. Co-incubation with the selective PKA inhibitors HA1004, KT5720 and Rp-cAMPS showed these antiproliferative effects to persist, despite measurable PKA activity being inhibited to that of untreated cells or less. IL-2 production was also inhibited by dbcAMP in the presence of HA1004 and Rp-cAMPS. It has been demonstrated that the inhibitory effects of pharmacological elevations in cAMP on human T cell proliferation and IL-2 production do not require PKA activity. These observations indicate that control of lymphocyte proliferation and functional status by cAMP proceeds through PKA-independent events. Identification of the underlying mechanisms behind these effects would increase our understanding of the cAMP cascade and may provide a potentially novel target for immunomodulation.

The increasing use of systemic therapy for women with lymph node negative breast carcinoma and earlier stage of disease at mammographic detection raises questions regarding the need for routine axillary lymph node dissection. Predictive modeling for lymph node involvement may be one way to reduce the need for axillary lymph node dissection and its morbidity.A multivariate analysis of 12 factors predictive of axillary lymph node involvement was conducted in a population-based cohort of 4312 women with invasive breast carcinoma diagnosed between January 1, 1993 and December 31, 1996.Clinical palpability, lymphatic or vascular invasion, lesion size, margin status, histology, and patient age were independent predictors of axillary lymph node involvement. The model correctly identified lymph node status in 76.6% of cases. Model accuracy and fit were equally high when applied to randomly selected halves of the study subjects. Approximately 32.0% of the patients in the study sample (1363/4312) were identified as having an extremely high (91%; n = 1102) or low (10%; n = 261) risk of lymph node involvement. In a second analysis, a clinically useable, three-variable model identified a very low risk group of patients (n = 147) with a 4.8% risk of lymph node metastasis and a high risk group of patients (n = 1008) with a 74.2% risk of lymph node metastasis. Greater than 90% of subjects in the high risk group received adjuvant systemic therapy even if they were lymph node negative pathologically.A clinically useable, three-variable model employing tumor and lymph node palpability, size, and lymphatic or vascular invasion can identify women with invasive breast carcinoma in whom axillary lymph node dissection is very unlikely to alter recommendations regarding adjuvant systemic therapy.

Nigel B. Jamieson , Nigel I.J. Chan , Alan K. Foulis , Euan J. Dickson , Colin J. McKay , C. Ross Carter . West of Scotland Pancreatic Unit, College of Medical, Veterinary and Life of Sciences, University of Glasgow, UK University Department of Surgery, Academic Unit of Surgery, College of Medical, Veterinary and Life of Sciences, University of Glasgow, UK Department of Pathology, Glasgow Royal Infirmary, Alexandra Parade, Glasgow, G31 2ER, UK

In the past, healthcare providers have created value by delivering care on demand to their patients. In the future, however, providers will create value by mastering four core competencies: effective management of health and wellness, effective care delivery, effective population enrollment, and effective management of financial risk.

Nursing staff development departments across the country have responded to the anticipated changes in health care in a variety of ways. This need to reexamine the traditional role of the clinical instructor has resulted in the development of creative strategies designed to meet the unit-based education needs of nurses. In this article, the authors describe a comprehensive approach that not only meets the learning needs of staff members from several specialty units but also fosters their professional development.