Latest Developments in the Management of Nut Allergies.

PURPOSE OF REVIEW: In this review, we sought to describe the most recent advances in the dietary and medical management of peanut and tree nut allergy, including selective introduction and immunotherapy. RECENT FINDINGS: Dietary updates include changes to labeling laws, improved information sources, and new apps for buying foods in shops and overseas to better protect individuals with nut allergies. There are still issues in the management of nut allergies in schools, such as parents having to resort to packed lunches instead of school meals and patients experiencing bullying. Air travel also poses concern, but additional resources are now available to travelers, and recent evidence suggest limited airborne exposure to nuts. The medical management of anaphylaxis is use of epinephrine; however, this remains underutilized. Needle length and administration devices have been recently debated considering the risk of bone penetration vs subcutaneous administration, and autoinjectors seem to deliver higher peak concentrations than syringes. Selective nut introduction has gained momentum in the last 5 years, demonstrating improved quality of life but with the need for motivated parents for continued consumption and available resources for challenges. Immunotherapy to nuts is also a rapidly developing field, with the balance of efficacy and safety being important considerations in the differing modes of administration. SUMMARY: The management of nut allergies is a rapidly developing field, and dietary and medical management have progressed significantly in the last 5 years. Future research directions include improving safety and efficacy of food immunotherapy and examining patients' goals for therapy and treatment outcomes.

Effects of triiodothyronine replacement on the anemia of chronic renal failure.

Patients and/or experimental animals with chronic renal failure have decreased serum levels of triiodothyronine (T3), a hormone well known for its erythropoietic activity. The following studies were designed in order to determine whether this observed abnormality in T3 metabolism is an important contributory factor to the etiology of the anemia of uremia. Groups of rats were made chronically uremic by a standard 5/6 nephrectomy technique and received slightly above physiological doses of T3 either by intermittent S.C. injections (twice daily) or by continuous infusion from intraperitoneally implanted osmotic minipumps. After 2 weeks of such treatment, and despite a normalization of serum T3 levels, there were no significant changes in the hematocrit, individual red cell mass, or serum erythropoietin levels of the uremic animals given T3 compared to control rats. We conclude that (1) the decreased serum T3 levels observed in uremia are not an important contributory factor to the pathogenesis of the anemia, and (2) treatment with replacement doses of T3 does not result in significant improvement of erythropoiesis.

High-dose methylprednisolone treatment for acute graft-versus-host disease after bone marrow transplantation in adults.

High-dose methylprednisolone (HDMP) was used to treat 18 episodes of severe (grades III and IV) acute graft-versus-host disease (GVHD) that developed after allogeneic bone marrow transplantation in 12 patients with acute leukemia and in 2 with aplastic anemia. Most of the patients showed rapid improvement in GVHD, with complete resolution of the skin and gut manifestations. However, the response of liver disease to the treatment was slow and incomplete. Complications seen were interstitial pneumonia and fungal and viral infections. Seven patients survived for more than two months following the treatment of acute GVHD. Five of these became long-term survivors with a median survival of 22+ months (range 11-38 months); all five long-term survivors developed chronic GVHD and are alive at the time of this report. It appears that HDMP is an effective treatment for severe acute GVHD. However, its true efficacy can only be ascertained in a randomized study comparing high-dose and conventional-dose methylprednisolone.

The effect of estrogens on erythroid stem cells in polycythemic mice.

Plethoric mice treated with pharmacological doses of estradiol have decreased concentration of erythropoietin-responsive cells (ERC) in the marrow. We used the methylcellulose-culture system for growth of erythroid stem cells (CFU-E and BFU-E) to define more accurately these estrogen-induced changes. As an animal model we utilized plethoric mice given repeated injections of estradiol cypionate and found that at 14 days after the onset of treatment there was no significant change in the concentration of femoral CFU-E whereas there was a significant decrease of the BFU-E content. Both CFU-E and BFU-E increased progressively in the spleen over a 42-day period. Addition of estradiol directly to the cell-culture system showed no effect on CFU-E growth but induced a significant depression of BFU-E growth. This depression seemed to require the presence of adherent cells. It is our hypothesis that estrogens suppress only the early stages of erythroid proliferation and/or differentiation by a mechanism involving possibly the stromal (adherent) cells of the marrow microenvironment.

Effect of fish oil concentrates on hemorheological and hemostatic aspects of diabetes mellitus: a preliminary study.

Fish oil concentrates (Max EPA) were given without other diet modification for eight weeks to five insulin-dependent diabetics and five healthy volunteers, in order to determine their effect on possible in vitro indices of thrombosis. Cholesterol, HDL, LDL, fasting blood sugar, hemoglobin A1c, platelet count, and the osmotic fragility of red blood cells were not significantly changed from baseline values after eight weeks of fish oil consumption. Serum triglyceride levels were lowered by the fish oil (diabetics 130 +/- 23 to 89 +/- 26 mg/dl: normals 107 +/- 16 to 57 +/- 5 mg/dl). Nine out of ten subjects required more arachidonic acid to aggregate their platelets, and six out of ten required more collagen. Whole blood viscosity at low shear rates was increased in diabetics before the fish oil ingestion, and was reduced both in normals and in diabetics after eight weeks of treatment. Before fish oil administration, the diabetics had higher levels of von Willebrand Factor (vWF) (208 +/- 31%) than did controls (117 +/- 26%). There was a statistically significant decrease of serum von Willebrand Factor both in diabetics (p less than 0.01) and in normals (p less than 0.05) after six weeks of treatment. Analysis of the multimeric composition of the vWF indicated that the vWF molecule was not altered. Addition of eicosapentaenoic acid (EPA) or crude fish oil to human umbilical cord endothelial cell cultures did not change vWF levels in the supernatant. Whether these changes in platelet aggregation, whole blood viscosity and vWF can actually be translated into an in vivo amelioration of the vascular complications in diabetes remains to be determined in a carefully controlled clinical trial.

Synergism of hemopoietic growth factors on endothelial cell proliferation.

Endothelial cells, which are nonhemopoietic cells, express and/or produce most of the known hemopoietic receptors and cytokines. The biological role of these factors, and their respective receptors, on endothelial cells is still unknown. In this study, the authors assessed the effect of different hemopoietic growth factors, ie, interleukin-3 (IL-3), erythropoietin (EPO), macrophage-colony stimulating factor (M-CSF), granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), singly or in conjunction with others, on proliferation and chemotaxis of human umbilical vein endothelial cells (HUVECs). They found growth stimulatory activity with IL-3, EPO, and GM-CSF and potent synergism between EPO and IL-3, less with IL-3 and GM-CSF, and none with EPO and either GM-CSF or G-CSF. All the singly tested hemopoietic growth factors stimulated the migration of HUVECs, but in conjunction with other factors, they did not show any additive or synergistic effect.

The effect of protein deprivation on erythroid stem cell growth.

The anemia of protein deprivation is due mainly to a decrease in erythropoietin (Ep) production. In this study we investigated the effect of protein deprivation on the number of erythroid stem cells (CFU-E, BFU-E). Mice given a protein-free diet for six days had significantly fewer CFU-E and BFU-E numbers per femur compared to mice given a diet with normal protein content. The decrease in BFU-E cannot be ascribed solely to decreased Ep production and occurs before changes in the femoral multipotential haematopoietic stem cells (CFU-S).

Economic modelling of diagnostic and treatment pathways in National Institute for Health and Care Excellence clinical guidelines: the Modelling Algorithm Pathways in Guidelines (MAPGuide) project.

BACKGROUND: National Institute for Health and Care Excellence (NICE) clinical guidelines (CGs) make recommendations across large, complex care pathways for broad groups of patients. They rely on cost-effectiveness evidence from the literature and from new analyses for selected high-priority topics. An alternative approach would be to build a model of the full care pathway and to use this as a platform to evaluate the cost-effectiveness of multiple topics across the guideline recommendations. OBJECTIVES: In this project we aimed to test the feasibility of building full guideline models for NICE guidelines and to assess if, and how, such models can be used as a basis for cost-effectiveness analysis (CEA). DATA SOURCES: A 'best evidence' approach was used to inform the model parameters. Data were drawn from the guideline documentation, advice from clinical experts and rapid literature reviews on selected topics. Where possible we relied on good-quality, recent UK systematic reviews and meta-analyses. REVIEW METHODS: Two published NICE guidelines were used as case studies: prostate cancer and atrial fibrillation (AF). Discrete event simulation (DES) was used to model the recommended care pathways and to estimate consequent costs and outcomes. For each guideline, researchers not involved in model development collated a shortlist of topics suggested for updating. The modelling teams then attempted to evaluate options related to these topics. Cost-effectiveness results were compared with opinions about the importance of the topics elicited in a survey of stakeholders. RESULTS: The modelling teams developed simulations of the guideline pathways and disease processes. Development took longer and required more analytical time than anticipated. Estimates of cost-effectiveness were produced for six of the nine prostate cancer topics considered, and for five of eight AF topics. The other topics were not evaluated owing to lack of data or time constraints. The modelled results suggested 'economic priorities' for an update that differed from priorities expressed in the stakeholder survey. LIMITATIONS: We did not conduct systematic reviews to inform the model parameters, and so the results might not reflect all current evidence. Data limitations and time constraints restricted the number of analyses that we could conduct. We were also unable to obtain feedback from guideline stakeholders about the usefulness of the models within project time scales. CONCLUSIONS: Discrete event simulation can be used to model full guideline pathways for CEA, although this requires a substantial investment of clinical and analytic time and expertise. For some topics lack of data may limit the potential for modelling. There are also uncertainties over the accessibility and adaptability of full guideline models. However, full guideline modelling offers the potential to strengthen and extend the analytical basis of NICE's CGs. Further work is needed to extend the analysis of our case study models to estimate population-level budget and health impacts. The practical usefulness of our models to guideline developers and users should also be investigated, as should the feasibility and usefulness of whole guideline modelling alongside development of a new CG. FUNDING: This project was funded by the Medical Research Council and the National Institute for Health Research through the Methodology Research Programme [grant number G0901504] and will be published in full in Health Technology Assessment; Vol. 17, No. 58. See the NIHR Journals Library website for further project information.

An improved method for the diagnostic approach of alpha+-thalassaemia.

An improved method for the diagnostic approach of alpha(+)-thalassaemia is described. The method is based on five common parameters: absence of iron deficiency, mild morphological abnormalities of erythrocytes, normal or slightly reduced erythrocytic indices MCV and MCH, normal chromatographic findings, and presence of haemoglobin H inclusions in erythrocytes with methyl-violet stain after, but not before, incubation with oxidant agent. We studied by DNA analysis, 58 subjects fulfilling the above mentioned diagnostic criteria and we found that 50 of them (86.2%) had a alpha-globin gene defect. In the remaining eight subjects (13.8%) no alpha-gene defect could be documented with the techniques used in the DNA analysis, which detect the six well-known alpha(+)-thalassaemic defects in the Greek population. We conclude that the improved method, we described has a high sensitivity and accuracy in the screening of alpha(+)-thalassaemia.

dl-alpha-tocopherol induces apoptosis in erythroleukemia, prostate, and breast cancer cells.

Vitamin E, best known as a potent antioxidant, has been shown to have other functions that are not mediated by this activity. Recent reports have suggested that vitamin E may inhibit smooth muscle cell and also cancer cell growth. We have studied the effect of dl-alpha-tocopherol (vitamin E) on a series of well-established cancer cell lines that included two erythroleukemia cell lines and a hormone-responsive breast and prostate cancer cell line. Cell proliferation was examined in these cell lines, which were maintained at optimal growth conditions. A dose-dependent inhibition of cell growth was found in all cell lines examined, with the MCF-7 breast and CRL-1740 prostate cancer cell lines showing potent suppression of growth at 0.1 mM vitamin E, whereas the erythroleukemia cell lines, HEL and OCIM-1, responded only at > 0.25 mM vitamin E with inhibition of proliferation. Studies of [3H]thymidine incorporation showed that vitamin E supplementation reduced DNA synthesis in all cell lines. Analysis of high-molecular-weight DNA revealed extensive fragmentation, indicating apoptosis of all cell lines supplemented with vitamin E. Our studies thus give evidence of a general inhibition of cell proliferation by dl-alpha-tocopherol, with breast and prostate cancer cells distinctly more sensitive than erythroleukemia cells.

Effect of erythropoietin therapy on the red cell volume of uraemic and non-uraemic rats.

Studies were performed to determine the effect of injecting repeated doses of erythropoietin (Ep) on the red cell volume of chronically uraemic rats and on that of non-uraemic sham operated ones. After 13 doses of Ep (5 u/dose), started either 5 or 21 d after removal of five-sixths of the renal mass, the increase in the red cell volume of uraemic rats was as great as that of non-uraemic ones. The significance of these results is discussed.

Effect of protein deprivation on hematopoietic stem cells and on peripheral blood counts.

Experiments were performed to determined the effect of protein deprivation on CFU-S in the spleen and femoral marrow, on the peripheral blood counts, and on the rate at which these parameters regenerate following radiation. Splenic CFU-S decrease in number after only 3 days on diets containing 5% protein or less. Marrow CFU-S, on the other hand, decrease only after mice are fed a protein-free diet for 4 weeks or more. The hematocrits, platelet counts, and WBC counts fall in the latter group. Marrow CFU-S regenerate more slowly in irradiated mice fed diets containing 5% protein or less. Also, the hemocrits, WBC counts, and platelet counts of irradiated mice fed diets containing 5% protein regenerate more slowly than do those of irradiated mice fed normal diets. The effect of protein deprivation on erythropoietin production, erythropoiesis, granulocyte function, and immunocompetence is well known. The studies reported here indicate, in addition, that protein deprivation also causes the numbers of CFU-S and the platelet counts to decline.

Determination of plasma erythropoietin levels: an early marker of tumor activity.

A young female patient developed erythrocytosis during the third recurrence of a cerebellar hemangioblastoma. Elevated erythropoietin levels were found in the patient's plasma with normalization after resection of the tumor. High erythropoietin titers were also found in the tumor saline extract. A fourth recurrence of the tumor was heralded by a rising plasma erythropoietin level and gradual erythrocytosis despite the absence of change in the clinical picture or the brain scan. In this case, serial plasma erythropoietin determinations served as a useful early marker of the tumor activity.

Effect of carbon tetrachloride on extrarenal erythropoietin production in rats.

Liver regeneration after partial hepatectomy is associated with an increase in extrarenal Ep production; however, this surgical procedure is time-consuming and difficult to standardize. Carbon tetrachloride (CCl4) ingestion in rats is an easy and reproducible way to induce liver damage and regeneration. We therefore studied the effects of CCl4 on extrarenal Ep production in rats. Just as is the case following partial hepatectomy, extrarenal Ep production in response to hypoxia was reduced immediately after ingestion of CCl4. Thereafter it rose to supranormal levels which peaked 3 to 4 days after CCl4 ingestion (at this time Ep titers of nephrectomized, CCl4-fed rats rose to greater than 1.0 U/ml of plasma after exposure to 0.42 atmosphere for 7 hr). Extrarenal Ep production then declined, but was still supranormal 7 days after CCl4. Carbon tetrachloride did not significantly affect extrarenal Ep production in rats nephrectomized 18 hr prior to initiation of hypoxia even if they received injections of renin prior to being made hypoxic, nor did it affect Ep production in response to hypoxia in nonnephrectomized rats under the conditions used in this study.

Recurrence of Hodgkin's disease 29 years later.

This article documents a case of recurrence in Hodgkin's disease, lymphocyte depletion type, 29 years after remission. This is the longest remission reported in the literature.

S-allylmercaptocysteine inhibits cell proliferation and reduces the viability of erythroleukemia, breast, and prostate cancer cell lines.

Organosulfur compounds are the biologically active components of allium vegetables. Many health benefits have been ascribed to them, including inhibition of carcinogenesis. Inasmuch as several of these thioallyl compounds are quite unstable and others are rapidly inactivated in the body, we have investigated one of the stable components present in aged garlic extract, S-allylmercaptocysteine (SAMC), in an effort to determine whether it can inhibit proliferation of cancer cells. Proliferation and viability of two erythroleukemia cell lines, HEL and OCIM-1, two hormone-responsive breast and prostate cancer cell lines, MCF-7 and CRL-1740, respectively, and normal human umbilical vein endothelial cells in response to different concentrations of SAMC were studied for up to two weeks. There were variations in sensitivity to this organosulfur compound in the different cell lines examined, but the two hormone-responsive cancer cell lines of breast and prostate clearly were far more susceptible to the growth-inhibitory influence of the thioallyl compound. The antiproliferative effect of SAMC was limited to actively growing cells. Human umbilical vein endothelial cells that had reached confluence escaped the reduction in viability so noticeable in the cancer cell lines tested. Our studies thus give evidence of a direct effect of SAMC on established cancer cells.