Case Report: Renal Transplantation in Patients with Pre-existing Hypogammaglobulinemia.

Hypogammaglobulinemia (HGG) is well-characterized as a common phenomenon after kidney transplantation. However, no reports of pre-existing HGG from kidney transplantation seem to be available. We have reviewed three patients who developed HGG prior to kidney transplantation, and all three were treated successfully with immunoglobulin replacement therapy before and after kidney transplantation. The kidney grafts were functioning at follow-up 1.5-8 years (mean: 3.6 years) after transplantation, and there were no diagnosed episodes of clinical rejections and no severe infection complications post-transplantation.

Physical activity increases survival after heart valve surgery.

OBJECTIVES: Increased physical activity predicts survival and reduces risk of readmission in patients with coronary heart disease. However, few data show how physical activity is associated with survival and readmission after heart valve surgery. Objective were to assess the association between physical activity levels 6-12 months after heart valve surgery and (1) survival, (2) hospital readmission 18-24 months after surgery and (3) participation in exercise-based cardiac rehabilitation. METHODS: Prospective cohort study with registry data from The CopenHeart survey, The Danish National Patient Register and The Danish Civil Registration System of 742 eligible patients. Physical activity was quantified with the International Physical Activity Questionnaire and analysed using Kaplan-Meier analysis and Cox regression and logistic regression methods. RESULTS: Patients with a moderate to high physical activity level had a reduced risk of mortality (3 deaths in 289 patients, 1%) compared with those with a low physical activity level (13 deaths in 235 patients, 5.5%) with a fully adjusted HR of 0.19 (95% CI 0.05 to 0.70). In contrast, physical activity level was not associated with the risk of hospital readmission. Patients who participated in exercise-based cardiac rehabilitation (n=297) were more likely than the non-participants (n=200) to have a moderate or high physical activity level than a low physical activity level (fully adjusted OR: 1.52, 95% CI 1.03 to 2.24). CONCLUSIONS: Moderate to high levels of physical activity after heart valve surgery are positively associated with higher survival rates and participation in cardiac rehabilitation.

Plasma levels of marine n-3 fatty acids and cardiovascular risk markers in renal transplant recipients.

BACKGROUND/OBJECTIVES: Cardiovascular (CV) disease is the leading cause of death after renal transplantation. Marine n-3 polyunsaturated fatty acids (PUFAs) exert potential cardio-protective metabolic effects and might reduce CV morbidity and mortality in renal transplant recipients (RTRs). SUBJECTS/METHODS: In this cross-sectional study of 1990 Norwegian RTRs, transplanted between 1999 and 2011, associations between plasma phospholipid marine n-3 PUFA levels and various CV risk markers at 10 weeks after transplant were evaluated. RESULTS: Higher plasma marine n-3 PUFA levels were associated with lower resting heart rate (rHR), lower fasting plasma glucose (fPG) levels, lower plasma triglyceride levels and higher plasma high-density lipoprotein (HDL) cholesterol levels. Plasma levels of eicosapentaenoic acid, but not docosahexaenoic acid, showed a positive association with plasma HDL cholesterol levels. Plasma marine n-3 PUFA levels were not associated with plasma low-density lipoprotein cholesterol levels, pulse wave velocity or systolic and diastolic blood pressure. A negative association between plasma marine n-3 PUFA levels and CV mortality was weakened by additional adjustment for plasma triglyceride levels and rHR. The ratio of n-6 to n-3 PUFAs showed similar associations with CV risk markers as absolute plasma marine n-3 PUFA levels. CONCLUSIONS: This is the first study in RTRs showing that marine n-3 PUFAs are negatively associated with rHR and fPG in addition to beneficial effects on plasma HDL cholesterol and triglyceride levels. Especially, effects on autonomic nervous function and triglyceride metabolism might contribute to explain the lower CV mortality risk with higher plasma marine n-3 PUFA levels previously shown in this cohort.

Intravenous Infusion of Nitroglycerine Leads to Increased Permeability on Dynamic Contrast-Enhanced MR Imaging in Pig Brains.

BACKGROUND AND PURPOSE: It has been suggested that off-label use of transdermal nitroglycerine patches to prevent frostbite may lead to severe acute mountain sickness and ataxia. The aim of this study was to investigate the effect of nitroglycerine on brain vascular permeability by using dynamic contrast-enhanced MR imaging in a swine model. MATERIALS AND METHODS: Eight Danish Landrace-Yorkshire-Danish Landrace pigs of approximately 20-25 kg were scanned with a dynamic contrast-enhanced MR perfusion protocol with and without nitroglycerine intravenous infusion. Compartmental analysis was performed on the basis of the Tofts model, and voxel-based quantitative values of the volume transfer constants from the vascular to the extracellular space were determined. RESULTS: The scan with nitroglycerine infusion resulted in significantly higher volume transfer constant values than values derived from the first scan without nitroglycerine infusion. Increased volume transfer constant values were observed in 6 of 8 animals. CONCLUSIONS: Infusion of nitroglycerine increases the vascular permeability of the swine brain on the basis of the transfer constant estimated from dynamic contrast-enhanced MR imaging.

Alpacas fed calcium propionate seem to moderate their energy intake.

Alpacas have evolved digestive and metabolic adaptations that enable them to survive in environments where the available feed varies in nutritional quality. Alpacas are thought to derive glucose from the deamination of amino acids in the liver, rather than via the conversion of propionate like true ruminants. Because fibre growth is dependent on the availability of absorbed amino acids, alpacas using amino acids as a source of energy should leave less amino acids available for fibre growth. If alpacas were to obtain glucose from a source of propionate, such as calcium propionate, the dependence on amino acids would be reduced leaving more available for fibre growth. Calcium propionate was added to the ration fed to 32 alpaca wethers, and fibre production was measured to monitor important fibre attributes in response to calcium propionate. Although the diets supplemented with calcium propionate should have provided more energy than the diets without calcium propionate, the metabolisable energy intake of all animals was similar (p = 0.278). It seems that rather than sparing amino acids, the alpacas regulated their energy intake and refused to consume the additional energy offered as calcium propionate. Consequently, they produced less fibre, and the diameter of their fibre was smaller than those alpacas that were not fed calcium propionate. It seems that alpacas rely on their digestive and metabolic adaptations to efficiently obtain and conserve energy for their survival.

EZH2 in normal and malignant hematopoiesis.

The histone methyltransferase Enhancer of Zeste Homologue 2 (EZH2), a component of the polycomb group complex, is vital for stem cell development, including hematopoiesis. Its primary function, to deposit the histone mark H3K27me3, promotes transcriptional repression. The activity of EZH2 influences cell fate regulation, namely the balance between self-renewal and differentiation. The contribution of aberrant EZH2 expression to tumorigenesis by directing cells toward a cancer stem cell (CSC) state is increasingly recognized. However, its role in hematological malignancies is complex. Point mutations, resulting in gain-of-function, and inactivating mutations, reported in lymphoma and leukemia, respectively, suggest that EZH2 may serve a dual purpose as an oncogene and tumor-suppressor gene. The reduction of CSC self-renewal via EZH2 inhibition offers a potentially attractive therapeutic approach to counter the aberrant activation found in lymphoma and leukemia. The discovery of small molecules that specifically inhibit EZH2 raises the exciting possibility of exploiting the oncogenic addiction of tumor cells toward this protein. However, interference with the tumor-suppressor role of wild-type EZH2 must be avoided. This review examines the role of EZH2 in normal and malignant hematopoiesis and recent developments in harnessing the therapeutic potential of EZH2 inhibition.

Risk and protective factors of adolescent exclusive snus users compared to non-users of tobacco, exclusive smokers and dual users of snus and cigarettes.

The use of snus is increasing in Norway. In this study we examined differences between adolescents who were exclusive snus users, and adolescent non-users, smokers and dual users of snus and cigarettes on a number of psychosocial factors, categorized as risk variables and protective variables associated with involvement in health compromising behavior. We applied separate logistic regression models, where exclusive snus users (n=740) were compared with non-users (n=904), smokers (n=219), and dual users (n=367). Compared to non-users, the group of exclusive snus users was associated with variables traditionally predicting health risk behavior, such as smoking friends (OR=1.74, SD 1.27-2.38) and truancy (OR=2.12, SD 1.65-2.78). Compared to smokers, exclusive snus users were related to variables traditionally associated with protection against involvement in health risk behavior, e.g. higher academic orientation (OR=1.66, SD 1.12-2.45). Associations with protective factors were also observed when exclusive snus users were compared with dual users. While the group of exclusive snus users was associated with a pattern of psychosocial risk compared to non-users, they showed a more conventional pattern when compared to smokers and dual users. The group of exclusive snus users may be described on a continuum varying from psychosocial risk factors to protective factors of risk involvement depending on the group of comparison.

An alternative allergen:adjuvant formulation potentiates the immunogenicity and reduces allergenicity of a novel subcutaneous immunotherapy product for treatment of grass-pollen allergy.

BACKGROUND: Subcutaneous specific immunotherapy (SCIT) has proven sustained clinical efficacy against allergy. The recommended regimen for SCIT is a gradual updosing over a period of weeks. Commonly, in commercial products for SCIT, the specific allergen is formulated with an adjuvant, most often in the form of aluminium hydroxide (AlOH). It has been shown that allergen-specific IgG antibodies are induced as a result of successful SIT. OBJECTIVE: To investigate the possibility of optimizing the formulation of AlOH-based grass-pollen allergy vaccines for SCIT in a way that allows for shorter updosing regimens while maintaining the immunogenicity of the vaccine. METHODS: Mice were immunized with various concentrations of Phleum pratense (Phl p) allergen extract and AlOH or a fixed dilution of the maintenance doses of one conventional and one alternatively formulated vaccine. The kinetics of Phl p-specific IgG antibody responses in serum and spleen T cell responses were determined. Allergenicity, measured as the ability of the formulations to activate human basophils, was also determined. In addition, human T cell responses and the expression of dendritic cell surface markers after vaccine challenge in vitro were analysed. RESULTS: Specific IgG antibody responses were shown to depend on the AlOH concentration, but not on the allergen concentrations. The immunogenicity of the conventional formulation and the alternative formulation was shown to be similar with regard to the in vivo-induced IgG and T cell responses. In contrast, the allergenicity of the alternative formulation was significantly reduced compared with the conventional formulation. CONCLUSION: The optimization of the formulation allows for administration of a lower dose of allergen while maintaining the immunogenicity of the product and at the same time reducing allergenicity. CLINICAL RELEVANCE: This study indicates that the optimization of the allergen and the adjuvant formulation could benefit the safety/efficacy profile and allow for shorter updosing.

The complexity of allergic patients' IgE repertoire correlates with serum concentration of allergen-specific IgE.

BACKGROUND: The governing factor of both effector-cell activation and facilitated antigen presentation is IgE-repertoire complexity (IgE-clonality, -affinity and -concentration). Yet, the compositions of individual IgE repertoires and correlation between IgE-repertoire complexity and establishment of allergic sensitization remain to be determined. OBJECTIVE: In complex formation assays with recombinant IgE, allergen and CD23(+) B cells, we assess the composition of serum IgE repertoires and examine the correlation between IgE-titre and IgE-repertoire complexity. METHODS: The capacity of sera, from house dust mite-sensitized individuals, to mediate IgE-Der p 2-CD23 complex formation on CD23(+) B cells was measured. In parallel experiments, the effect of supplementing each serum with one or more Der p 2-specific monoclonal recombinant IgE antibodies on complex formation was determined. RESULTS: Only sera with the highest concentration of Der p 2-specific IgE resulted in complex formation without supplementary recombinant IgE. Intermediately titred sera supported complex formation to various degrees when supplemented with individual recombinant IgE. The degree of complex formation depended on the affinity and epitope specificity of the recombinant IgE. Complex formation by combining serum and recombinant IgEs could not be obtained with sera of relatively low titres of specific IgE. However, these sera had the capacity to dramatically enhance the low complex formation achieved with pairs of affinity-engineered recombinant IgEs. CONCLUSION AND CLINICAL RELEVANCE: Serum IgE complexity can be indirectly assessed by combining sera with defined monoclonal IgEs in IgE-allergen-CD23 complex assays. The observed differences in epitope-coverage of Der p 2-specific serum-IgE in sera of different specific IgE titres indicate that increased IgE titres correlate with increased complexity of the IgE-repertoire. A detailed knowledge of the composition and complexity of allergen-specific IgE repertoires (and the relation to IgE titre), particularly in the early phase of sensitization, may be used to improve the prediction of the persistence and severity of allergic symptoms, as well as the progression of the Allergic March.

Functional rather than immunoreactive levels of IgG4 correlate closely with clinical response to grass pollen immunotherapy.

BACKGROUND: Induction of allergen-specific IgG(4) antibodies is the most consistent immunological finding in immunotherapy trials. However, quantitative assessments of IgG(4) antibodies have not proven beneficial in evaluating clinical changes during or after immunotherapy. In the current study, we investigated the relationship between clinical outcome and allergen-specific IgG(4) titres or functional antibody responses following immunotherapy. We hypothesized that functional assays of serum IgG-associated inhibitory activity such as inhibition of IgE-allergen interactions (IgE-blocking factor) and inhibition of CD23-dependent IgE-facilitated allergen binding (IgE-FAB) correlate more closely with clinical outcome and may be biomarkers of clinical response. METHODS: In an 8-month dose-response randomized double-blind placebo-controlled study, 221 polysensitized subjects with severe seasonal rhinitis received Alutard SQ, Phleum pratense 100,000 SQ-U, 10,000 SQ-U or placebo injections. Serum specimens were collected before treatment, after up-dosing, during the peak season and at the end of the study. Allergen-specific IgG(4) titres and IgG-associated inhibitory activity were evaluated. RESULTS: A time- and dose-dependent increase in serum inhibitory activity for both the IgE-blocking factor and IgE-FAB was observed, which paralleled increases in grass pollen-specific IgG(4) antibodies. A modest but significant inverse relationship was demonstrated between postimmunotherapy serum inhibitory activity and combined symptom-rescue medication scores (IgE-FAB: r = -0.25, P = 0.0002; IgE-blocking factor: r = -0.28, P < 0.0001), whereas this was not observed for immunoreactive IgG(4) levels (r = -0.11, P = 0.12). CONCLUSIONS: Functional assays of inhibitory IgG(4) and IgE-blocking factor may be more useful surrogates of clinical response than IgG(4). Whether these antibody effects may serve as predictive biomarkers of clinical efficacy in individual patients requires further investigation.

A Canada-Bangladesh partnership for nurse education: case study.

AIM: To describe the lessons learned from a partnership in nurse education between a Bangladesh university and a group of Canadian volunteers. BACKGROUND: In the host country, nursing enjoys low status and pay, which adversely affect professional standards. METHOD: The paper describes implementation details of training a core of nurses to international standards, using limited resources. The first cohort received their Bachelor of Nursing degrees in 2009. OUTCOMES: The Bangladeshi partners benefit from access to up-to-date curriculum materials, current clinical expertise, and interaction with visiting faculty and students. The Canadian nursing instructors enjoy professional development opportunities; visiting Canadian students gain exposure to a practice setting in a low-income country. LESSONS LEARNED: These include the importance of (1) integrating nurse training with a general university able to provide core courses (e.g. English as second language, computer training), (2) countering the low status of nursing and inculcating a caring attitude among students, and (3) instilling critical thinking as opposed to rote learning. Next, the following were identified: mechanisms to support networking in the local health system, sharing of resources (e.g. electronic course material adapted to host country context), and assuring programme quality. IMPLICATIONS FOR PRACTICE: The paper will be of interest to those concerned with nurse education and human resource development in less developed countries.

Shorter dosing intervals of sublingual immunotherapy lead to more efficacious treatment in a mouse model of allergic inflammation.

Current day practice of sublingual immunotherapy (SLIT) includes varying modalities of treatment that differ with regard to formulation, dosing and administration regimens. The aim of this study was to explore the importance of the dosing intervals in SLIT. The immunological effect of increased SLIT dosing frequency was tested in a mouse model of allergic inflammation. Mice sensitized to Phleum pratense (Phl p) were SLIT-treated with the same weekly cumulative dose administered with different administration frequencies. A SLIT sham-treated group was also included. All mice were challenged intra-nasally with Phl p extract following SLIT. Local and systemic cytokine production, eosinophil infiltration into airways and the development of Phl p-specific antibody responses were determined. Higher frequency of sublingual administration of allergen extract has a profound positive impact on the effect of SLIT, measured as induction of IgG and IgA antibodies. The once daily SLIT was the only treatment regimen being able to reduce all systemic Th2 cytokines and systemic IgE antibody responses when compared to sham-treated mice after the intra-nasal challenge period. The group receiving SLIT with the highest frequency of administration had the most pronounced effect of the treatment. In the same group, there was also a higher degree of protection against increase in IgE antibody levels after intra-nasal challenge with the allergen, our data demonstrate that a once daily regimen is more efficacious than regimens where SLIT, with the same weekly cumulative allergen dose, is administered with longer intervals but higher doses.

The T cell response to major grass allergens is regulated and includes IL-10 production in atopic but not in non-atopic subjects.

BACKGROUND: The incidence of allergic diseases is increasing in industrialized countries and the immunological mechanisms leading to tolerance or allergy are poorly understood. Cytokines with suppressive abilities and CD4(+)CD25(+) regulatory T cells have been suggested to play a central role in allergen-specific responses. The aim was to determine whether major grass allergens induce production of suppressive cytokines in allergic and healthy subjects and to examine the inhibitory effect of these cytokines on allergic responses. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from healthy and grass-allergic donors and stimulated with the major grass allergens Phl p 1 or Phl p 5. The effects of endogenous IL-10 and/or TGF-beta on proliferation and cytokine production were determined by use of blocking antibodies. In addition, the number of CD4(+)CD25(+) T cells and their expression of chemokine receptors were investigated by flow cytometry. RESULTS: Phl p 1 and Phl p 5 induced IL-10 production, which down-regulated proliferation and cytokine production, in PBMC cultures from atopic but not from non-atopic donors. Comparable frequencies of CD4(+)CD25(+) T cells were present in PBMCs in the two groups, but fewer cells from atopic donors were CD4(+)CD25(+)CCR4(+) and more cells were CD4(+)CD25(+)CLA(+) compared to healthy donors. CONCLUSION: Allergen-specific responses of grass allergic patients but not in non-atopic subjects are influenced by regulatory cytokines produced in response to the important allergens. Differences in CD4(+)CD25(+) T cell expression of chemokine receptors in allergic compared to non-atopic donors could suggest that the homing of CD4(+)CD25(+) T cells is important for the regulation of allergen-specific responses.

The validity and reliability of automated and manually measured toe blood pressure in ischemic legs of diabetic patients.

OBJECTIVES: Modern guidelines for evaluation of leg ischemia in patients with diabetes and foot ulcer recommend toe blood pressure (TBP) measurements rather than the often unreliable ankle blood pressure (ABP). A drawback with TBP is the complicated measurement procedure, unsuitable the outpatient clinic. The aim of this study was to evaluate the validity of a new automatic TBP device (PresTo, Moor Instruments Ltd) developed for use outside vascular laboratories. DESIGN: Cross-sectional comparative study. METHODS: Twenty-three legs in 16 consecutively included diabetic patients with PAD were examined. TBP was measured three times with 2 min in-between. Three examiners read the obtained graphs (n=69), which were analyzed for variability over time and between examiners. These results were compared with those obtained from an automated TBP device. RESULTS: The mean TBP was 50.9 mm Hg (SD 10.9) when read by examiners compared to 56.4 mm Hg (SD 12.6) when automatically assessed. The 2-min variability was 4.9 mm Hg (SD) for visual readings and 8.1 mm Hg for automatic measurements. The short, long term and examiner dependent variability of visually read TBP ranged from 3.9 to 9.6% of the values. In patients with TBP <45 mm Hg the difference between automatic and visual assessments was small. CONCLUSION: The automatic TBP device is reliable for measuring low pressures and thus for exclusion of critical limb ischemia in patients with diabetes. After algorithm adjustment the device's reliability appears to be acceptable in the entire spectrum of TBP values. TBP appears to have less inter and intraobserver variability than what is reported for ABP.

A double-blind placebo-controlled birch allergy vaccination study II: correlation between inhibition of IgE binding, histamine release and facilitated allergen presentation.

BACKGROUND: The pathogenesis of IgE-mediated allergic disease is closely related to the production of T-helper type 2 (Th2) cytokines, which lead to IgE production pivotal for activation of mast cells and basophils. Proliferating T cells along with eosinophils expanded and attracted by Th2 cytokines are major contributors to the late-phase reaction. The activation of these Th2 cells is strongly enhanced by CD23-mediated IgE facilitated allergen presentation (FAP). OBJECTIVE: The present study aims to investigate the effect of specific immunotherapy (SIT)-induced allergen-specific non-IgE antibodies (blocking antibodies) on IgE binding to allergen, histamine release (HR) and CD23-mediated allergen uptake in antigen-presenting cells. METHODS: Competition between IgE and non-IgE for allergen binding was studied by Advia Centaur antibody measurements, passively sensitized basophils were used to study HR and IgE-facilitated binding of allergen to B cells (FAP) was studied by flow cytometry. FAP measurements were performed both with and without the addition of a reference IgE serum, which was included to obtain optimal complex formation. The serum samples were obtained from birch pollen immunotherapy (n=21) or placebo control patients (n=21) before and after 1 and 2 years of treatment. RESULTS: Statistically significant reduction of all parameters investigated was observed after 1 year of treatment and the effect was maintained during the second year of treatment. There was a clear correlation between the two FAP measurements and between each of them and the level of T cell activation reported upon previously. Moreover, strong correlations were found between changes in FAP, IgE binding and HR. CONCLUSION: The present study clearly demonstrates that SIT induces changes in the composition of serum antibodies that inhibit IgE binding, HR and FAP to a similar extent. This suggests that these measurements, individually or in combination, may be used to monitor the immunological effect of SIT, even though direct correlations to changes in clinical parameters could not be demonstrated.

Sublingual immunotherapy reduces allergic symptoms in a mouse model of rhinitis.

BACKGROUND: Sublingual immunotherapy (SLIT) is a clinically effective treatment in both pollen and house dust mite-induced rhinitis and asthma. However, the mechanisms by which this is accomplished are not clear. OBJECTIVE: The objective of the current study was to establish a mouse model of rhinitis in order to study the effect and mechanisms of SLIT. METHODS: Mice were sensitized by intraperitoneal injections of alum-adsorbed Phleum pratense extract. Sensitized mice were SLIT-treated and subsequently challenged intranasally and analysed for clinical symptoms, antibody levels, eosinophilia and T cell response. RESULTS: Intranasal challenge of sensitized mice led to the development of rhinitis characterized by significantly increased sneezing and influx of eosinophils into the nose. Levels of specific IgE were fivefold increased in nasopharyngeal lavage (NAL) fluid and more than doubled in serum. Furthermore, a T-helper type 2 (Th2) like T cell response was observed in local draining lymph nodes. SLIT treatment of sensitized mice reduced sneezing, eosinophilia and IgE levels in the NAL by more than 50%. Moreover, serum levels of IgE and IgG1 as well as T cell response in the draining lymph nodes were also significantly reduced. Treatment for a shorter time or with a lower dose only led to minor reductions of the clinical and immunological parameters, indicating that the effect of SLIT is time and dose dependent. CONCLUSION: In the present study, we have established a mouse model displaying the hallmarks of allergic rhinitis using a clinically relevant allergen. Using this model, we have demonstrated that SLIT treatment is able to reduce allergic symptoms in a time- and dose-dependent manner.

Migration of formaldehyde and melamine monomers from kitchen- and tableware made of melamine plastic.

Migration of one or both formaldehyde and/or melamine monomers was found in seven of ten tested melamine samples bought on the Danish market. The samples were a bowl, a jug, a mug, a ladle, and different cups and plates. No violation of the European Union-specific migration limits for melamine (30 mg kg-1) and formaldehyde (15 mg kg-1) was found after three successive exposures to the food stimulant 3% acetic acid after 2 h at 70 degrees Celsius. To investigate the effects of long-term use, migration tests were performed with two types of cups from a day nursery. Furthermore, medium-term use was studied by ten successive exposures of a plate to 3% acetic acid for 30 min at 95 degrees Celsius. The results indicate that continuous migration of formaldehyde and melamine takes place during the lifetime of these articles. The molar ratio of released formaldehyde to melamine was seen to decrease from 12 to about 5. This indicates that, first, the migration of residual monomers is most important, but in the long-term, breakdown of the polymer dominates. Two CEN methods were used to determine the concentration of monomers: a spectrophotometric method for formaldehyde and a UV-HPLC method for melamine.