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Mucosa-associated lymphoid tissue (MALT) type lymphoma has generally been thought not to show increased fluorine 18-fluorodeoxyglucose (FDG) accumulation on positron emission tomography (PET), based on previous research. Only a limited numbers of articles have been published on this topic, however, involving a small number of cases. Although positive FDG PET results might be uncommon in this entity, a case of increased FDG accumulation in a case of MALT type lymphoma of the lung is presented.

In 1983, Schoell et al. [Schoell, M., Faber, E., Coleman, M.L., 1983. Carbon and hydrogen isotopic compositions of the NBS 22 and NBS 21 stable isotope reference materials: an inter-laboratory comparison. Organic Geochemistry 5, 3–6] carried out an inter-laboratory comparison of the International Atomic Energy Agency (IAEA) reference materials NBS 21 (a graphite) and NBS 22 (an oil). At that time they found that NBS 22 in particular to be more depleted in 13C than the values published by the IAEA at that time (i.e., δ13C of −29.81‰ PDB ±0.06 as opposed to δ13C of −29.4‰ PDB). Even so, to this day, the IAEA has subsequently used a value of δ13C of −29.7‰ ± 0.2 VPDB. Following the advent of the new IAEA VPDB scale, defined by NBS 19 (a carbonate), this laboratory at the Commonwealth Scientific and Industrial Research Organisation (CSIRO) Petroleum and Exploration and Mining Divisions in North Ryde, NSW, Australia found that a number of the reference materials depleted in 13C (especially “organic” type reference materials) to be more depleted in 13C on the VPDB scale than expected. In particular, NBS 22 appears to be 0.25‰ more depleted in 13C than generally accepted values compared with a suite of carbonate standards run together. We suggest that the NBS 22 and other “organic” reference materials have probably all been calibrated to NBS 21 or 22 and should now be redefined on the VPDB scale.

A description of the relationship between Sir Hans Sloane and Johann Amman is given, particularly the latter's appointment as Professor of Botany in St Petersburg and their subsequent correspondence. In particular, Amman's description of the flora of Russia as outlined in these letters is examined, that around St Petersburg which he observed personally, that of Bashkiria collected by Heinzelmann, and that of Siberia. The plant specimens sent by Amman which have survived and are now held in the Sloane Herbarium are identified and the circumstances of their acquisition set out. The specimens are divided into two groups. The first is attributed to collections made by Amman himself in the vicinity of St Petersburg, and the second group is attributed to collections made in Siberia and Dauria by D. G. Messerschmidt, and the unique nature of these specimens is set out.

Purpose To discuss the absolute benefits from adjuvant systemic therapy knowledge of long-term outcomes and baseline risks of relapse and disease-specific survival are required. We assessed the 10-year outcomes in a population-based cohort of node-negative (N−) lymphovascular negative (LV−) early breast cancers diagnosed from 1989 to 1991 who did not receive adjuvant systemic therapy. Methods One thousand one hundred eighty-seven cases of pT1–2N0 LV− breast cancers with a median follow-up of 10.4 years were reviewed. Kaplan-Meier survival curves for relapse free survival (RFS), breast cancer–specific survival (BCSS) and overall survival (OS) were compared with log-rank tests with cohorts stratified for tumor size and grade. Results The median age of this series was 62 years. Four hundred thirty tumors were ≤ 1 cm in diameter (cohort 1), 507 were 1.1–2 cm (cohort 2), and 250 were 2.1 to 5 cm in diameter (cohort 3). The 10-year outcomes for cohorts 1, 2, and 3, respectively, were significantly different: RFS, 82%, 75%, and 66%; BCSS, 92%, 90%, and 77%; and OS, 79%, 78%, and 66%. Tumor grade significantly altered outcome within size cohorts, particularly in pT1N0 breast cancers. Conclusion This study provides detailed information on the continued relapse and breast cancer death rate to 10 years of follow-up. Specifically, without adjuvant systemic therapy, patients with LV−, N − breast cancer had a ≥ 25% 10-year risk of relapse and a corresponding 10-year breast cancer death rate of ≥ 10% if they had either a grade 3 tumor ≤ 1 cm, a grade 2 to 3 tumor from 1.1 to 2 cm, or any grade tumor greater than 2 cm.

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 report that antigen-independent effects of IgE antibodies can promote immune sensitization to haptens in the skin. Contact sensitivity was markedly impaired in IgE(-/-) mice but was restored by either transfer of sensitized cells from wild-type mice or administration of hapten-irrelevant IgE before sensitization. Moreover, IgE(-/-) mice exhibited impairment in the reduction of dendritic cell numbers in the epidermis after hapten exposure. Monomeric IgE has been reported to influence mast cell function. We observed diminished contact sensitivity in mice lacking FcepsilonRI or mast cells, and mRNA for several mast cell-associated genes was reduced in IgE(-/-) versus wild-type skin after hapten exposure. We speculate that levels of IgE normally present in mice favor immune sensitization via antigen-independent but FcepsilonRI-dependent effects on mast cells.

Background. There is considerable variability in the reported value of clinical examination in the diagnosis of abdominal aortic aneurysms (AAA). This study aims to assess accuracy of abdominal examination by a doctor, a nurse and the patient in the diagnosis of AAA and whether this accuracy is related to the size of the aneurysm and/or the BMI of the patient. Methods. 164 patients, 138 men and 26 women, median age 71 years, consented to participate in this prospective, single blind, controlled study. Thirty-nine patients attending for carotid duplex were used as controls. Abdominal examination was performed by a doctor and a nurse. Patients then performed self-examination. Results. Examination by a doctor, a nurse and the patient were similar in accuracy in diagnosing/excluding AAA which was directly related to AAA size and patient BMI. The Negative Predicted Value of abdominal examination exceeds 0.9 with AAA diameters ≥4 cm and the Positive Predictive Value exceeds 0.8 with AAA diameters ≥5 cm. Conclusions. Abdominal examination by a doctor, a nurse and the patient is of value in the exclusion and diagnosis of significant AAA. It should be promoted and may represent a useful adjunct to population screening with ultrasound.

We investigated whether CT signs can be used to predict hepatofugal flow in the main portal vein in patients with cirrhosis.We retrospectively identified 36 patients with cirrhosis, 18 with hepatopetal and 18 with hepatofugal flow in the main portal vein, who underwent contemporaneous abdominal sonography and CT. Two independent observers evaluated the following features on the randomized CT studies: diameter of the portal, splenic, and superior mesenteric veins; spleen size; and the presence of ascites, varices, or arterial phase portal venous enhancement. These data were correlated with the flow direction seen on sonography.A small main portal vein was the only sign significantly (p/= 0.05) predictive of hepatofugal flow by univariate and multivariate analyses. Observers 1 and 2 recorded a portal vein diameter of less than 1 cm in eight (44%) and seven (39%) of the 18 patients with hepatofugal flow compared with one (6%) and none of the 18 patients with hepatopetal flow, respectively (p0.02). Receiver operating characteristic analysis using the size of the portal vein to predict flow direction revealed an area under the curve of 0.83 for observer 1 and 0.74 for observer 2.A diameter of less than 1 cm for the main portal vein is highly specific, although not sensitive, for hepatofugal portal venous flow in patients with cirrhosis. This sign may be useful when sonography is limited, or this sign may prompt sonographic assessment in patients not known to have hepatofugal flow.

The insulin/interleukin-4 (IL-4) receptor (I4R) motif mediates the association of insulin receptor substrate (IRS)-2 with the interleukin-4 (IL-4)Rα chain and transduces mitogenic signals in response to IL-4. Its physiological functions were analyzed in mice with a germline point mutation that changed the motif's effector tyrosine residue into phenylalanine (Y500F). The Y500F mutation abrogated IRS-2 phosphorylation and impaired IL-4–induced CD4+ T lymphocyte proliferation but left unperturbed Stat6 activation, up-regulation of IL-4-responsive gene products, and Th cell differentiation under Th2 polarizing conditions. However, in vivo the Y500F mutation was associated with increased allergen-induced IgE production, airway responsiveness, tissue eosinophilia, and mucus production. These results define an important role for the I4R motif in regulating allergic inflammation.

The resource-based view holds that firms can earn supranormal returns if and only if they have superior resources and those resources are protected by some form of isolating mechanism preventing their diffusion throughout industry. One isolating mechanism that has been proposed for intangible assets is their accumulation process. The hypothesis is that intangible assets are inherently inimitable because would-be imitators need to replicate the entire accumulation path to achieve the same resource position. Thus, entrants can never catch up to incumbents. An interesting challenge to this hypothesis is counterfactual evidence that entrants sometimes outperform incumbents. Such counterfactual evidence should not exist if the theory is strictly correct. This paper attempts to reconcile resource accumulation theory with the counterfactual evidence. We do so by building an intermediate good-production function for a firm's intangible asset stocks. We test the contribution of the intangible asset stock to the firm's final good-production function and examine the extent to which that asset stock deters rival mobility in the pharmaceutical industry. We find that the asset accumulation process itself cannot deter rivals, because asset stocks reach steady state rather quickly. Entrants can achieve an incumbent's intangible asset stock merely by matching its investment until steady state. Thus, we conclude that the accumulation process per se is not an isolating mechanism. While this is perhaps the most important contribution, another contribution is an empirical methodology for characterizing the accumulation function.

We have measured the concentration and isotopic composition of lead in blood over a 15-month period for a subject who undertook recreational shooting in outdoor and indoor firing ranges on an irregular basis. We have also measured the isotopic composition in cast lead, Cu-jacketed and Teflon-coated bullets, propellant and primer from which he assembled the cartridges. Blood lead concentration increased from 3.2 to 6.7 microg/dl with use of dominantly cast lead bullets in the outdoor range. In two intervals when no firing was undertaken for 3-4 months, the blood lead concentrations either decreased towards a baseline value in the case where only Cu-jacketed bullets were fired or remained elevated when dominantly cast lead bullets were fired. The propellants contained2 ppm Pb and contribute negligibly to blood lead. The isotopic composition of the primer used for all bullets was consistent with a source from the US. The bullets were of different materials and made in Australia and the US, with lead from sources of different geological age and hence different isotopic signatures. Variations in blood lead concentration and isotopic composition appear most strongly influenced by the bullets. Although more expensive, the use of Cu-jacketed bullets, non-lead primers and well-ventilated indoor firing ranges would lessen the health impacts of recreational shooting.

Differences or disorders of sex development (DSD) are a wide range of relatively rare conditions with diverse pathophysiology that most often present in the newborn or the adolescent. Given their rarity and the need for input from a range of clinical disciplines, the management of the child with a complex form of DSD may be quite complicated, and the situation is worsened by a lack of evidence for many diagnostic and interventional procedures that are undertaken. It is, therefore, not surprising that there will be variation in the management as well as the outcome of patients with this group of conditions. By working as a network of clinical and research centres it is possible that these variations can themselves be better managed and studied. Over the last decade there has been a major shift in the field of rare diseases towards greater collaboration in clinical as well as research activity, and this chapter will summarise these developments.

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease characterized pathologically by eosinophil infiltration. In addition to loss of barrier integrity, a dominant T Helper 2-associated immune response and strong allergic connection, the esophagus tissue undergoes dramatic changes, with frequent presence of mucosal rings, strictures, linear furrows, and trachealization. Although the inflammatory mechanisms behind this disease are being increasingly well understood, the structural features remain unexplained. We examined the expression of key members of the Wnt-signaling pathway in biopsies from patients with EoE. This pathway has been shown to be critically important in regulating cellular homeostasis, growth, and differentiation and to be dysregulated in several disease conditions. Biopsies from adult EoE patients were collected by endoscopy and mRNA extracted. After cDNA synthesis, the relative gene expression from key upstream (secreted frizzled-related protein 1) and downstream (c-myc and Cyclin D1) molecules in the Wnt pathway, as well as several Wnt pathway members (Wnt1, Axin1, low-density lipoprotein receptor-related protein 6, glycogen synthase kinase 3 beta, and β-catenin), were determined. Biopsies from patients with EoE displayed significantly higher expression of secreted frizzed-related protein 1 than controls, as well as reductions in Cyclin D1 and c-myc. In contrast, there were no differences in the Wnt pathway molecules. The levels of expression of Cyclin D1 and c-myc, as well as β-catenin, in EoE patients showed strong correlations with the frequency of esophageal eosinophils. Our findings suggest that although there are no changes in the overall levels of key Wnt pathway genes in adult EoE, there is evidence for dysregulation of upstream and downstream regulators of Wnt signaling. Importantly, the associations with eosinophilia suggest that these may participate in the pathogenesis of this disease and be markers of disease severity.

Chronic restraint stress impairs hippocampal-mediated spatial learning and memory, which improves following a post-stress recovery period. Here, we investigated whether brain-derived neurotrophic factor (BDNF), a protein important for hippocampal function, would alter the recovery from chronic stress-induced spatial memory deficits. Adult male Sprague-Dawley rats were infused into the dorsal hippocampal cornu ammonis (CA)3 region with an adeno-associated viral vector containing the sequence for a short hairpin RNA (shRNA) directed against BDNF or a scrambled sequence (Scr). Rats were then chronically restrained (wire mesh, 6 h/day for 21 days) and assessed for spatial learning and memory using a radial arm water maze (RAWM) either immediately after stressor cessation (Str-Imm) or following a 21-day post-stress recovery period (Str-Rec). All groups learned the RAWM task similarly, but differed on the memory retention trials. Rats in the Str-Imm group, regardless of adeno-associated viral contents, committed more errors in the spatial reference memory domain on the single retention trial during day 3 than did the non-stressed controls. Importantly, the typical improvement in spatial memory following the recovery from chronic stress was blocked with the shRNA against BDNF, as Str-Rec-shRNA performed worse on the RAWM compared with the non-stressed controls or Str-Rec-Scr. The stress effects were specific for the reference memory domain, but knockdown of hippocampal BDNF in unstressed controls briefly disrupted spatial working memory as measured by repeated entry errors on day 2 of training. These results demonstrated that hippocampal BDNF was necessary for the recovery from stress-induced hippocampal-dependent spatial memory deficits in the reference memory domain.

This article examines the use of “authorities” as nonprofit public enterprises in the US. It focuses on their formation, financing and operation, along with the types of activities that are devolved to them. It appreciates that such authorities exist in other developed countries and that the experience of using these bodies may provide valuable lessons for other countries which are involved in re-engineering their administrative systems.

Allergic diseases are an increasing health concern, particularly in the developed world. The standard clinical approach to treatment of allergic disease focuses on allergen avoidance and symptom control but does little to address the underlying Th2 bias of disease. Specific immunotherapy (SIT) consisting of controlled administration of allergen, however, has been demonstrated to successfully induce desensitization and tolerance in an antigen-specific manner for a variety of Th2-mediated diseases. This review focuses on the mechanisms by which current SIT approaches induce tolerance as well as discussing attempts to modify the safety and efficacy of SIT. These refinements focus on three major aspects of SIT: the route of antigen administration, modification of the antigen to remove allergenic epitopes and reduce adverse events and choice of adjuvant used to induce tolerance and/or immune deviation from Th2 to Th1 and regulatory T-cell (Treg) phenotypes. Synthesis of these recent developments in SIT provides considerable promise for more robust therapies with improved safety profiles to improve resolution of allergic disease and its associated costs.

The ongoing pressurized water reactor (PWR) main steam line break (MSLB) benchmark problem, sponsored by the Office for Economic Cooperation and Development (OECD), the United States Nuclear Regulatory Commission (US NRC), and the Pennsylvania State University (PSU) consists of three exercises, whose combined purpose is to verify the capability of system codes to analyze complex transients with coupled core/plant interactions; to test fully the 3D neutronics/thermal-hydraulic coupling; and to evaluate discrepancies between the predictions of coupled codes in best-estimate transient simulations. Exercise two is intended to test core response to imposed system thermal-hydraulic conditions. For this exercise, the participants are provided with transient boundary conditions and two cross-section libraries. Results are submitted for six steady-state cases and two transient scenarios. The boundary conditions, the details for each case, and the output requested are described in the final specifications for the benchmark problem. To fully analyze the data for comparison in the final report, a suite of statistical methods has been developed, to serve as a reference in the absence of experimental data. A corrected arithmetical mean and standard deviation are calculated for all data types: single-value parameters, 1D axial distributions, 2D radial distributions, and time histories. Each participant's deviation from the mean and a corresponding figure-of-merit are reported for the purposes of comparison and discussion. Selected mean values and standard deviations are presented in this paper for several parameters at specific points of interest: for the initial steady-state 2, at hot-full power, radial and axial power distributions are presented, along with effective multiplication factor, power peaking factors, and axial offset. For the snapshot taken at the time of highest return-to-power in transient Scenario 2, parameters presented include axial and radial power distributions, total and fission power levels, power peaking factors, and axial offset. Additionally, some features of the time histories for total power and fission power in Scenario 2 are presented and discussed.

In this paper we study the Bardeen–Cooper–Schrieffer energy gap equation at finite temperatures. When the kernel is positive representing a phonon-dominant phase in a superconductor, the existence and uniqueness of a gap solution is established in a class which contains solutions obtainable from bounded domain approximations. The critical temperatures that characterize superconducting–normal phase transitions realized by bounded domain approximations and full space solutions are also investigated. It is shown under some sufficient conditions that these temperatures are identical. In this case the uniqueness of a full space solution follows directly. We will also present some examples for the nonuniqueness of solutions. The case of a kernel function with varying signs is also considered. It is shown that, at low temperatures, there exist nonzero gap solutions indicating a superconducting phase, while at high temperatures, the only solution is the zero solution, representing the dominance of the normal phas...

Companies worldwide are expanding their use of outsourcing for services and products. This article appraises what is known about the impact of outsourcing on company value, and the emergent picture is not an unblemished one. Company managers frequently complain about the downsides, some companies have retrieved what they had sourced out, failures can be seen here and there, and the long-term potential consequences of outsourcing too much are yet to be seen. Still, the weight of the research evidence indicates that, when well designed and well managed, outsourcing reduces operating cost, enhances competitive strategy, and enlarges shareholder value.

In this work we propose a new method for investigating connection problems for the class of nonlinear second‐order differential equations known as the Painleve equations. Such problems can be characterized by the question as to how the asymptotic behaviours of solutions are related as the independent variable is allowed to pass towards infinity along different directions in the complex plane. Connection problems have been previously tackled by a variety of methods. Frequently these are based on the ideas of isomonodromic deformation and the matching of WKB solutions. However, the implementation of these methods often tends to be heuristic in nature and so the task of rigorising the process is complicated. The method we propose here develops uniform approximations to solutions. This removes the need to match solutions, is rigorous, and can lead to the solution of connection problems with minimal computational effort. Our method relies on finding uniform approximations of differ ential equations of the generic form \( \frac{{\text d}^2\phi}{{\text d}\eta^2} = - \xi^2F(\eta,\xi)\phi \) as the complex‐valued parameter \(\xi \to \infty\). The details of the treatment rely heavily on the locations of the zeros of the function F in this limit. If they are isolated, then a uniform approximation to solutions can be derived in terms of Airy functions of suitable argument. On the other hand, if two of the zeros of F coalesce as \(|\xi| \to \infty\), then an approximation can be derived in terms of parabolic cylinder functions. In this paper we discuss both cases, but illustrate our technique in action by applying the parabolic cylinder case to the “classical” connection problem associated with the second Painleve transcendent. Future papers will show how the technique can be applied with very little change to the other Painleve equations, and to the wider problem of the asymptotic behavio ur of the general solution to any of these equations.

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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. Cancer 1998;83:948-955. © 1998 American Cancer Society.

Purpose: This study was performed to investigate the feasibility of predicting survival in squamous cell carcinoma of the head and neck (SCCHN) with an artificial neural network (ANN), and to compare ANN performance with conventional models. Methods and Materials: Data were analyzed from a Phase III trial in which patients with locally advanced SCCHN received hyperfractionated irradiation with or without concurrent cisplatin and 5-fluorouracil. Of the 116 randomized patients, 95 who had 2-year follow-up and all required data were evaluated. ANN and logistic regression (LR) models were constructed to predict 2-year total survival using round-robin cross-validation. A modified staging model was also examined. Results: The best LR model used tumor size, nodal stage, and race to predict survival. The best ANN used nodal stage, tumor size, stage, and resectability, and hemoglobin. Treatment type did not predict 2-year survival and was not included in either model. Using the respective best feature sets, the area under the receiver operating characteristic curve (Az) for the ANN was 0.78 ± 0.05, showing more accurate overall performance than LR (Az = 0.67 ± 0.05, p = 0.07). At 70% sensitivity, the ANN was 72% specific, while LR was 54% specific (p = 0.08). At 70% specificity, the ANN was 72% sensitive, while LR was 54% sensitive (p = 0.07). When both models used the five predictive variables best for an ANN, Az for LR decreased [Az = 0.61 ± 0.06, p < 0.01 (ANN)]. The models performed equivalently when using the three variables best for LR. The best ANN also compared favorably with staging [Az = 0.60 ± 0.07, p = 0.02 (ANN)]. Conclusions: An ANN modeled 2-year survival in this data set more accurately than LR or staging models and employed predictive variables that could not be used by LR. Further work is planned to confirm these results on larger patient samples, examining longer follow-up to incorporate treatment type into the model.

The relation between population density and the extent of damage incurred by bark stripping behaviour was investigated in a Scots Pine plantation known to have suffered considerable damage. Population density was estimated by three non-interventionist methods that could potentially be applied elsewhere: line surveys, drey counts and cone counts. The different methods of estimating the population size proved to be consistent and produced an unusually high value of four Red Squirrels per hectare. Within the study area, fresh damage was related to local population densities.

Changes in the distribution of Red and Grey Squirrels in Forestry Commission land were examined using a replacement index for the period of 1980–94. Data from each administrative region in Scotland were examined separately. No region was found to have experienced a significant replacement of Red Squirrels by Grey Squirrels. However, significant trends in the area occupied by one or both Squirrel species were observed in the Borders and Strathclyde. Other areas appear to have experienced little or inconsistent changes in the last 15 years.

An urban community in New Zealand was the site of a field experiment designed to assess different approaches to increasing household participation in a cnrbside recycling program. Two different commitment interventions were delivered using a 2 × 2 factorial design, and weekly participation data were collected over 12 weeks. Half of the households were asked to make an explicit verbal commitment to participate in the program, while half were not. Half of the households were also requested to pay for their recycling bins, while half received bins free of charge. All households received the same educational and promotional information, specifically designed to maximize participation, regarding program details. The verbal commitment intervention significantly increased participation relative to the no commitment intervention, while difficulties in the operationalization of the financial commitment intervention made it difficult to assess its validity as a construct. Notably, differences in participation rates between the control group, who received only educational and promotional materials, and the experimental treatment groups were not statistically significant. The discussion focuses oh the increasing importance of well-designed educational materials for encouraging voluntary curb-side recycling.

A spectrum-resolved numerical model for the gain clamped EDFA is developed. Good agreement between the model and experimental results is achieved. The model results reveal the gain, clamped gain spectral distribution and noise figure characteristics of the amplifier. The model is used to optimize the selection of the clamped amplifier laser wavelength and laser output coupling to minimize the noise figure.

Background/aim: Recent studies have demonstrated that tear lipocalin (TL) and phospholipids have a crucial role in maintaining tear film stability. The level of TL in patients with meibomian gland dysfunction (MGD) was examined and these data were correlated with the severity of their clinical disorder. Methods: 12 patients with obstructive MGD, 12 patients with seborrhoeic MGD, and 12 age matched normal control subjects participated in this study. 3 μl of unstimulated tears were collected with a micropipette from the inferior tear meniscus in the right eye of all subjects. Tear samples were fractionated by high performance liquid chromatography, and TL concentrations were assayed with a bicinchoninic acid technique. Results: The mean concentration of TL in patients with obstructive and seborrhoeic MGD was significantly lower than in normal controls. TL concentration correlated positively with tear film break up time and negatively with fluorescein staining scores. Conclusion: These results suggest that TL deficiency may be a predisposing factor for the manifestation of symptoms in MGD.

Histamine is a major product of activated mast cells and basophils. Acute allergic reactions requiring emergency room visits are associated with elevated plasma histamine levels (1). While antihistamines are an established therapy for many allergic diseases, these anti-allergic compounds block only the activity of histamine receptor 1 (H1R) (2) and histamine possesses four known receptors (H1R–H4R). Recent guidelines for the treatment for food allergy concluded that in the hospital-based setting, the adjunctive use of both diphenhydramine (an H1R antihistamine) and ranitidine (an H2R antihistamine) was beneficial (3). In support of this, previous clinical studies had demonstrated the beneficial effects of combined H1R/H2R blocking therapy on outcomes of acute allergic reactions in randomized, double-blinded, placebo-controlled trials (4), suggesting that the H2R may be contributing to acute allergic responses. The rationale for inhibiting H2R in allergy is not clear. This receptor is best associated with acid production, reflux, and ulcers in the stomach, a site in which histamine is not produced by mast cells or basophils but by enterochromaffin-like cells that act via H2R on parietal cells to stimulate acid (5). However, H2R is expressed on many of the same cell types as H1R, including immune cells, endothelium, and smooth muscle cells (6). While studies have established the role of H1R histamine receptors in anaphylaxis using pharmacological inhibitors (7), there is controversy on the importance of H2R. Makabe-Kobayashi et al. (8), in addition to defining the critical importance of histamine in anaphylaxis using histamine-deficient mice, concluded that both H1R and H2R were important. However, this was based on the effects of relatively high, single doses of pyrilamine (H1R blocker) or cimetidine (H2R blocker). In contrast, Finkelman and colleagues recently showed that blocking platelet-activating factor (PAF) plus triprolidine (H1R blocker) was sufficient to prevent allergen-triggered anaphylactic shock (9), supporting previous findings that focused specifically on anaphylaxis-associated hypotension (10). However, such approaches are hindered by differences in effective doses between mice and humans and potential offtarget effects of pharmacological inhibitors. In this study, we took advantage of mice with genetic ablation of either H1R or H2R to provide complete loss of each receptor in an attempt to definitively establish the necessity for each histamine receptor. These mice have been previously reported and shown to have selective loss of the respective histamine receptors (11, 12). To address synergy and/or compensation, we also generated a H1R/H2R knockout (KO) strain that lacked both receptors by breeding mice of either single KO strain. All mice were on a C57BL/6 genetic background and confirmed to be deficient in expression of each specific receptor by RT-PCR on skin. No changes in expression of the other histamine receptors were observed in each case (data not shown). Because histamine has been shown to be elevated in the blood of patients experiencing clinical anaphylaxis (1), we initially utilized a murine model of IgE-dependent anaphylaxis to determine the role of the histamine receptors in such responses. Mice were initially primed with intravenous injection of 50 µg of ovalbumin (OVA)-specific murine IgE [TOe clone (13), generated by the Northwestern University Recombinant Protein Production Core Facility] and anaphylactic-like responses initiated 24 h later by intravenous injection of 40 µg of OVA in 100 µl of PBS. In wild-type (WT) mice, anaphylaxis was observed as a significant decrease in core body temperature (Fig. 1A) and observable symptom scores (Fig. 1B), as previously described (14) whereby 0 was assigned if no symptoms were evident, 1 through to 5 was given if symptoms were observed where 1 represents mild scratching and/or rubbing of the nose, head, or feet, scores of 2 and 3 represent intermediate symptoms, for example, edema around the eyes or mouth, pilar erection, and/or labored breathing, 4 represents significantly reduced motility, tremoring, and/or significant respiratory distress, and 5 represents death. In contrast, both H1R KO and H2R KO mice had clear protection against the decrease in body temperature (P ≤ 0.05 by 2-way anova on data in Fig. 1A), suggesting that both receptors contribute to these responses. H1R/H2R double KO mice demonstrated further protection than seen with either single KO strain (P ≤ 0.001 by 2-way anova on data in Fig. 1A) and were indistinguishable from C57BL/6 histidine decarboxylase KO mice (15), which lack the ability to synthesize histamine. This similarity between mice with no histamine and H1R/H2R KO mice suggests that the other histamine receptors are unlikely to be contributing to the immediate responses of anaphylaxis. Interestingly, some responsiveness persisted in both these strains, which may be due to PAF-mediated anaphylaxis, as previously demonstrated in mice (7). Despite this, there was significant improvement in the observable symptom score rankings in both strains (Fig. 1B). To rule out potential differences in mast cell activation, we also measured levels of the mast cell protease mMCP1 in serum from all groups, and compared with the vehicle group, this was signficantly elevated and similar between WT and the histamine receptor-deficient strains (WT Vehicle 427 ± 119 pg/ml, WT IgE/OVA 3809 ± 857 pg/ml, H1R KO IgE/OVA 8823 ± 3275 pg/ml, H2R KO IgE/OVA 2483 ± 767 pg/ml, H1R/H2R KO IgE/ OVA 8057 ± 2331 pg/ml). No differences in basal mMCP1 levels between any strain were observed either (data not shown). Figure 1 H1R and H2R both contribute to anaphylactic responses. Mice were administered 50 µg ovalbumin (OVA)-specific IgE intravenously and challenged 24 h later with 50 µg OVA in 100 µl PBS intravenously. Vehicle mice received PBS alone. ... To examine the receptor involvement in responses to histamine specifically, we next examined the responses seen upon direct delivery of histamine. As shown in Fig. 2, intravenous injection of 2 mg of histamine in 100 µl of PBS was sufficient to evoke significant decreases (P ≤ 0.001 by 2-way anova) in core body temperature in WT mice but this was reduced to a similar amount in either H1R or H2R KO mice. In contrast, the responses in H1R/H2R double KO mice were statistically indistinguishable from mice receiving PBS alone by 2-way anova. Figure 2 H1R and H2R both contribute to acute systemic responses to histamine. Mice of the specified strains were administered 2 mg histamine in 100 µl PBS intravenously. Rectal body temperatures were determined at 10-min intervals. All measurements were ... Taken together, our data demonstrate that both H1R and H2R contribute to the systemic responses that occur during anaphylaxis and upon increased blood histamine levels. Interestingly, studies on the effects of histamine in isolated vascular vessels have suggested that histamine can elicit an endothelial-dependent vasodilation that is H1R driven and an endothelial-independent vasodilation that is H2R driven, likely via smooth muscle cells (16). Consequently, the contribution of each receptor in anaphylaxis may involve tissue-specific mechanisms. The contribution of H2R in histamine-dependent responses that we have clearly demonstrated helps to mechanistically explain the observed therapeutic benefits from combination H1R/H2R blockade in acute anaphylaxis (4), as well as potentially explain the relative lack of effectiveness of H1R-targeted antihistamine compounds in the treatment for some other allergic diseases, including asthma.

Objective: Sacrectomy creates a large, complex tissue defect that presents a reconstructive challenge for plastic surgeons. Several myocutaneous flaps have been described for reconstruction following sacral tumor extirpation; however, current publications focus on the reconstructive options applicable to adults. We present a method of reconstruction following sacral tumor extirpation in a pediatric patient. Methods: The patient was 22 months old and in need of complex closure following low sacral amputation (S3-S4 osteotomy) and en bloc resection of a yolk sac tumor. Following tumor extirpation, the patient was left with a complex defect including extensive dead space, multiple exposed nerve roots, projection of the rectum into the wound, and inadequate soft tissue for primary closure. Results: Reconstruction with human acellular dermal matrix to address the risk of posterior rectal herniation and bilateral gluteal V to Y advancement flaps for obliteration of the dead space allowed for durable closure of the surgical defect. Conclusions: This represents the first case report documenting sacral resection and reconstruction with bilateral V to Y gluteal advancement flaps in a pediatric patient.

Histamine is a bioactive amine stored in mast cells and basophils and released upon antigen-specific IgE-dependent activation, mediating responses during allergic reactivity, including vasodilation, smooth muscle constriction and inflammatory cell recruitment. These are regulated through four receptors (H1R-H4R) that are differentially expressed on various cell types. Despite this, increasing evidence suggests that histamine can be produced during the priming phase of allergen responses, with H4R on dendritic cells being important for initiating Type 2 immunity. Here, we sought to determine the roles of these receptors in supporting antigen-specific B cell responses. Interestingly, our data demonstrates that both murine and human B cells only expressed H1R and H2R; these also showed differential expression levels on specific B cell subsets and upon activation. Using an Ovalbumin-alum (OVA-alum) model of allergic immunization, mice lacking H2R produced significantly lower levels of OVA-IgE, whereas mice lacking H1R were unaffected. Surprisingly, absence of both H1R and H2R (H1R/H2R DKO) exhibited undetectable levels of OVA-IgE. This was not due to T cell-intrinsic influences since restimulation of splenocytes from immunized H1R/H2R DKO mice showed that Th2 cytokine production was unaltered compared to WT. Instead, in vitro stimulation of B220+ B cells by αCD40 and IL-4 yielded significantly lower IgE production from H1R/H2R DKO mice than WT and defines a key requirement for these receptors in permitting B cells from generating IgE antibodies. Our data establishes a novel requirement for histamine, a molecule typically considered in regulating allergic responses, in supporting the generation of allergic sensitivity.

Mast cells (MC) and basophils (BΦ) are key effector cells in allergy that are developmentally related. Functionally, they both release mediators like histamine and granule proteases. However, studies also suggest that MC and BΦ have non-redundant roles in allergic diseases. Their ability to respond to IL-33—an epithelium-derived cytokine that helps initiate allergic inflammation—is not well understood. To fully characterize the transcriptional responses and heterogeneity of MC and BΦ, we performed large-scale comparative microarrays of bone marrow-derived mast cells (BMMCs) and basophils (BMBs) either at rest, upon IgE activation, or upon IL-33 activation. Hierarchical clustering demonstrated that BMMCs had activation-specific transcriptional signatures. IgE-crosslinking upregulated 1803 unique genes including Ccl7, Fxyd6, and Cd33; while IL-33 stimulation induced 1918 genes including Il1b, Cd72, and Tnfaip2. Focused bioinformatics pathway analysis demonstrated IgE-activation aligned with pathways relating to complement activation and CD137 signaling, while IL-33 initiated responses in the NF-κB and IL-10 signaling pathways. Furthermore, BMBs activated via IgE-crosslinking induced type 2 immune response genes like Il2, Il4, Ccl17 and Il13 which were surprisingly absent in IL-33 stimulated BMBs. Further analysis revealed cell-specific transcriptional signatures with 4360 genes that were significant in BMBs but not in BMMCs after IgE activation, and 1645 after IL-33 stimulation. Here we show that MC and BΦ have cell-specific and activation-specific transcriptional responses, and our data suggest novel gene networks and pathways that may shape how the immune system responds to allergens and innate cytokines.

Atopic dermatitis (AD) often precedes asthma and food allergy, indicating that epicutaneous sensitization to allergens may be important in the induction of allergic responses at other barrier surfaces. Our study demonstrated a central role for IL-33 in this “atopic march.” We showed that mice exposed to antigen in the skin, in the presence of IL-33, developed severe airway inflammation when later challenged in the lung, and developed allergic diarrhea following oral antigen challenge. In addition, IL-33-driven allergic disease occurred in a thymic stromal lymphopoietin (TSLP)-independent manner. In contrast, IL-33 signaling was required for local inflammation following epicutaneous TSLP/OVA sensitization and during challenge in allergic gastrointestinal disease, but was dispensable during challenge in TSLP-mediated airway disease. These data reveal critical, site-specific roles for IL-33 in the “atopic march” that lead from atopic dermatitis to allergic asthma and gastrointestinal allergy.

Background Adjuvant chemotherapy is often required for the treatment of bone cancers after tumor resection, which often results in a large continuity defect. The immunosuppressive side effects could instead be exploited to allow immediate reconstruction with a composite tissue allograft (CTA) that would provide for replacement of tissues. We used a short course of doxorubicin to achieve a novel method of immunosuppression in a rat model undergoing CTA to create an immunological environment for allograft survival. Materials & methods The Institutional Animal Care and Use Committee-approved protocol consisted of 3 experimental groups. Groups 2 and 3 consisted of Brown Norway rats (n = 5) as allograft donors and Lewis rats (n = 5) as transplant recipients. An abdominal wall CTA was harvested off the superficial inferior epigastric vessels. Doxorubicin therapy was administered in group 3 animals. Survival of the CTA was assessed by physical examination and histological analysis. Results Allotransplant without treatment showed complete clinical and histologic rejection by day 7. Allotransplant rats treated with doxorubicin had clinically and histologically normal grafts through day 10. Kaplan-Meier survival analysis showed a statistically significant difference, with increased CTA survival time to end point with doxorubicin treatment, from a mean of 8.8 days in group 2 to 16.4 days in group 3. Conclusions Allotransplant flaps without treatment developed complete clinical and histological rejection. The allotransplant group which received doxorubicin showed a delay of allograft rejection with an 86% increased CTA graft survival time. This demonstrates the feasibility of the immunosuppression side effect caused by chemotherapy to prevent rejection of a CTA.