bluuebunny/crossref_metadata_2025 huggingface dataset:
Contrasting human cytokine responses to promastigote whole-cell extract and the Leishmania analogue receptor for activated C kinase antigen of L. amazonensis in natural infection versus immunization
Authors: Azeredo-Coutinho R B G , Matos D C S , Armôa G G R , Maia R M , Schubach A , Mayrink W , Mendonça S C F
Published: October 2008

It is known that the same antigen can induce different immune responses, depending upon the way that it is presented to the immune system. The objective of this study was to compare cytokine responses of peripheral blood mononuclear cells (PBMC) from cutaneous leishmaniasis patients and subjects immunized with a first-generation candidate vaccine composed of killed Leishmania amazonensis promastigotes to a whole-cell promastigote antigen extract (La) and to the recombinant protein LACK (Leishmania analogue receptor for activated C kinase), both from L. amazonensis. Thirty-two patients, 35 vaccinees and 13 healthy subjects without exposure to Leishmania, were studied. Cytokine production was assessed by enzyme-linked immunosorbent assay and enzyme-linked immunospot assay. The interferon (IFN)-γ levels stimulated by La were significantly higher and the levels of interleukin (IL)-10 significantly lower than those stimulated by LACK in the patient group, while LACK induced a significantly higher IFN-γ production and a significantly lower IL-10 production compared with those induced by La in the vaccinated group. LACK also induced a significantly higher frequency of IFN-γ-producing cells than did La in the vaccinated group. The contrast in the cytokine responses stimulated by LACK and La in PBMC cultures from vaccinated subjects versus patients indicates that the human immune response to crude and defined Leishmania antigens as a consequence of immunization differs from that induced by natural infection.
Differential effects of ifosfamide on dendritic cell-mediated stimulation of T cell interleukin-2 production, natural killer cell cytotoxicity and interferon-γ production
Authors: Kuppner M C , Bleifuß E , Noessner E , Mocikat R , von Hesler C , Mayerhofer C , Issels R D
Published: October 2008

Ifosfamide is a DNA-alkylating agent used frequently in chemotherapy of human malignancies. Ifosfamide and its major decomposition products deplete intracellular glutathione (GSH). Glutathione is the major intracellular thiol reductant that protects cells against oxidative injury. Ifosfamide depletion of intracellular GSH in human dendritic cells (DC), T cells and natural killer (NK) cells impairs their functional activity which can be restored by reconstituting GSH. Here we assessed the effect of ifosfamide on DC-mediated stimulation of NK cell proliferation via T cells and on direct DC stimulation of NK cell cytotoxicity and interferon (IFN)-γ production. Indirect DC stimulation of NK cell proliferation via T cells and T cell-derived interleukin (IL)-2 were reduced by ifosfamide treatment of DC and reconstitution of GSH in DC restored both responses. When DC and NK cells were treated with ifosfamide, DC could overcome the negative effect of ifosfamide on NK cytotoxic function whereas NK cell IFN-γ production was less efficiently restored. The ability of IL-2 activated NK cells to kill autologous immature DC or to induce DC maturation was reduced moderately by treatment of both cell types with ifosfamide. Overall, our results suggest that DC may stimulate anti-tumour effector cells in patients even if they had received treatment with chemotherapeutic agents such as ifosfamide.
Allergenicity, immunogenicity and dose-relationship of three intact allergen vaccines and four allergoid vaccines for subcutaneous grass pollen immunotherapy
Authors: Henmar H , Lund G , Lund L , Petersen A , Würtzen P A
Published: October 2008

Different vaccines containing intact allergens or chemically modified allergoids as active ingredients are commercially available for specific immunotherapy. Allergoids are claimed to have decreased allergenicity without loss of immunogenicity and this is stated to allow administration of high allergoid doses. We compared the allergenicity and immunogenicity of four commercially available chemically modified grass pollen allergoid products with three commercially available intact grass pollen allergen vaccines. The allergenicity was investigated with immunoglobulin (Ig)E-inhibition and basophil activation assays. Human T cell proliferation and specific IgG-titres following mouse immunizations were used to address immunogenicity. Furthermore, intact allergen vaccines with different contents of active ingredients were selected to study the influence of the allergen dose. In general, a lower allergenicity for allergen vaccines was clearly linked to a reduced immunogenicity. Compared with the vaccine with the highest amount of intact allergen, the allergoids caused reduced basophil activation as well as diminished immunogenicity demonstrated by reduced T cell activation and/or reduced induction of murine grass-specific IgG antibodies. Interestingly, intact allergen vaccines with lower content of active ingredient exhibited similarly reduced allergenicity, while immunogenicity was still higher or equal to that of allergoids. The low allergenicity observed for some allergoids was inherently linked to a significantly lower immunogenic response questioning the rationale behind the chemical modification into allergoids. In addition, the linkage between allergenicity, immunogenicity and dose found for intact allergen vaccines and the immunogen as well as allergenic immune responses observed for allergoids suggest that the modified allergen vaccines do not contain high doses of immunologically active ingredients.
Abnormal liver function in common variable immunodeficiency disorders due to nodular regenerative hyperplasia
Authors: Ward C , Lucas M , Piris J , Collier J , Chapel H
Published: October 2008

Patients with common variable immunodeficiency disorders are monitored for liver function test abnormalities. A proportion of patients develop deranged liver function and some also develop hepatomegaly. We investigated the prevalence of abnormalities and types of liver disease, aiming to identify those at risk and determine outcomes. The local primary immunodeficiency database was searched for patients with a common variable immunodeficiency disorder and abnormal liver function and/or a liver biopsy. Patterns of liver dysfunction were determined and biopsies reviewed. A total of 47 of 108 patients had deranged liver function, most commonly raised alkaline phosphatase levels. Twenty-three patients had liver biopsies. Nodular regenerative hyperplasia was found in 13 of 16 with unexplained pathology. These patients were more likely to have other disease-related complications of common variable immunodeficiency disorders, in particular non-coeliac (gluten insensitive) lymphocytic enteropathy. However, five had no symptoms of liver disease and only one died of liver complications. Nodular regenerative hyperplasia is a common complication of common variable immunodeficiency disorders but was rarely complicated by portal hypertension.
Allergy and the gastrointestinal system
Authors: Vighi G , Marcucci F , Sensi L , Di Cara G , Frati F
Published: October 2008

The gastrointestinal system plays a central role in immune system homeostasis. It is the main route of contact with the external environment and is overloaded every day with external stimuli, sometimes dangerous as pathogens (bacteria, protozoa, fungi, viruses) or toxic substances, in other cases very useful as food or commensal flora. The crucial position of the gastrointestinal system is testified by the huge amount of immune cells that reside within it. Indeed, gut-associated lymphoid tissue (GALT) is the prominent part of mucosal-associated lymphoid tissue (MALT) and represents almost 70% of the entire immune system; moreover, about 80% of plasma cells [mainly immunoglobulin A (IgA)-bearing cells] reside in GALT. GALT interacts strictly with gastrointestinal functions in a dynamic manner; for instance, by increasing intestinal permeability in replay to particular stimulations, or orientating the immune response towards luminal content, allowing either tolerance or elimination/degradation of luminal antigens, or sometimes provoking damage to the intestinal mucosa, such as in coeliac disease or food allergy. The immune mechanisms implicated in these actions are very complex and belong to both innate and adaptive immunity; innate immunity supplies an immediate non-specific response that is indispensable before specific adaptive immunity, which needs 7–10 days to be efficacious, takes place. The results of their interactions depend upon different contexts in which contact with external agents occurs and may change according to different genetic settings of the hosts.
Allergy and the cardiovascular system
Authors: Triggiani M , Patella V , Staiano R I , Granata F , Marone G
Published: October 2008

The most dangerous and life-threatening manifestation of allergic diseases is anaphylaxis, a condition in which the cardiovascular system is responsible for the majority of clinical symptoms and for potentially fatal outcome. The heart is both a source and a target of chemical mediators released during allergic reactions. Mast cells are abundant in the human heart, where they are located predominantly around the adventitia of large coronary arteries and in close contact with the small intramural vessels. Cardiac mast cells can be activated by a variety of stimuli including allergens, complement factors, general anesthetics and muscle relaxants. Mediators released from immunologically activated human heart mast cells strongly influence ventricular function, cardiac rhythm and coronary artery tone. Histamine, cysteinyl leukotrienes and platelet-activating factor (PAF) exert negative inotropic effects and induce myocardial depression that contribute significantly to the pathogenesis of anaphylactic shock. Moreover, cardiac mast cells release chymase and renin that activates the angiotensin system locally, which further induces arteriolar vasoconstriction. The number and density of cardiac mast cells is increased in patients with ischaemic heart disease and dilated cardiomyopathies. This observation may help explain why these conditions are major risk factors for fatal anaphylaxis. A better understanding of the mechanisms involved in cardiac mast cell activation may lead to an improvement in prevention and treatment of systemic anaphylaxis.
Allergy and the eye
Authors: Leonardi A , Motterle L , Bortolotti M
Published: October 2008

The eye represents an ideal and frequent site for the allergic reactions. The term ‘allergic conjunctivitis’ refers to a collection of disorders that affect the lid, conjunctiva and/or cornea. Even though the diagnosis is essentially clinical, local tests such as cytology, conjunctival provocation and tear mediator analysis can be performed. The immunoglobulin E (IgE)-mediated mechanism does not explain completely the severity and the clinical course of chronic allergic ocular diseases such as vernal (VKC) and atopic keratoconjunctivitis (AKC), which are probably also related to T cell-mediated responses, massive eosinophil attraction and activation and non-specific hypersensitivity. An altered balance between T helper type 1 (Th1) and Th2 cells and between Th1- and Th2-types of cytokines is thought to be responsible of the development of ocular allergic disorders. New findings suggest that a wide range of cytokines, chemokines, proteases and growth factors are involved by complex interwoven interactions rather than distinct and parallel pathways. In addition, several non-specific enzymatic systems may be activated during acute and chronic allergic inflammation, thus contributing to the complex pathogenesis of the disease. Current drug treatment for ocular allergy targets the key mechanisms involved in the development of clinical disease: mast cells with mast cell stabilizers, histamine with histamine receptor antagonists and inflammation with corticosteroids, severe inflammation with immunomodulators. None of these agents lacks side effects and none abolishes signs and symptoms completely. New therapeutic strategies are still needed to respond to the complex pathogenesis of severe forms of ocular allergy such as VKC and AKC.
Allergy and the skin
Authors: Incorvaia C , Frati F , Verna N , D'Alò S , Motolese A , Pucci S
Published: October 2008

Allergic skin disorders include urticaria, angioedema, contact dermatitis and atopic dermatitis, but the model fitting most closely the systemic concept of allergy is atopic dermatitis (AD), the pathogenesis of which is linked to a complex interaction between skin barrier dysfunction and environmental factors such as allergens and microbes. In particular, an important advance was the demonstration that the mutation of the skin barrier protein filaggrin is related strictly to allergen sensitization and to the development of asthma in subjects with AD. The altered skin barrier function, caused by several factors, results in the passage of allergens through the skin and to systemic responses. A pivotal role in such a response is exerted by Langerhans cells which, via their immunoglobulin E (IgE) receptor, capture the allergens and present them to T cells. When T helper type 2 (Th2) cells are activated, the production of a proinflammatory cytokines and chemokines pattern sustains the persistence of inflammation. Known AD-related cytokines are interleukin (IL)-5, IL-13 and tumour necrosis factor (TNF)-α, with emerging importance for IL-17, which seems to drive airway inflammation following cutaneous exposure to antigens, and IL-31, which is expressed primarily in skin-homing Th2 cells. Skin-homing is another crucial event in AD, mediated by the cutaneous lymphocyte-associated antigens (CLA) receptor, which characterizes T cell subpopulations with different roles in AD and asthma.
Human alpha 1-antitrypsin therapy induces fatal anaphylaxis in non-obese diabetic mice
Authors: Lu Y , Parker M , Pileggi A , Zhang B , Choi Y-K , Molano R D , Wasserfall C , Ricordi C , Inverardi L , Brantly M , Schatz D , Atkinson M , Song S
Published: October 2008

Previous studies have shown that human alpha-1 antitrypsin (hAAT) gene delivery prevents type 1 diabetes (T1D) in non-obese diabetic (NOD) mice. Furthermore, hAAT protein administration prolongs acceptance of islet allografts. Therefore, we evaluated the use of purified hAAT protein therapy to prevent T1D in NOD mice. Female NOD, non-obese resistant (NOR), Balb/c and C57BL/6 mice were injected intraperitoneally with vehicle alone or vehicle containing hAAT, human albumin or mouse albumin (or mg/injection/mouse; 2×/week). Preparations of clinical-grade hAAT included API®, Aralast®, Prolastin® and Zemaira®. Surprisingly, hAAT administration was associated with a high rate of fatal anaphylaxis. In studies seeking T1D prevention at 4 weeks of age, 100% mice died after six injections of hAAT. When administrated at 8–10 weeks of age, most (80–100%) NOD mice died following the fourth injection of hAAT, while 0% of Balb/c and C57BL/6 mice and 10% of NOR mice died. Interestingly, repeated injections of human albumin, but not mouse albumin, also induced sudden death in NOD mice. Antibodies to hAAT were induced 2–3 weeks after hAAT administration and death was prevented by treatment with anti-platelet-activating factor along with anti-histamine. In studies of disease reversal in NOD mice, using the four pharmaceutical grade formulations of hAAT, anaphylactic deaths were observed with all hAAT preparations. The propensity for fatal anaphylaxis following antigenic administration appears to be NOD- but not hAAT-specific. The susceptibility of NOD mice to hypersensitivity provides a significant limitation for testing of hAAT. Development of strategies to avoid this unwanted response is required to use this promising therapeutic agent for T1D.
Transgenic tomato expressing interleukin-12 has a therapeutic effect in a murine model of progressive pulmonary tuberculosis
Authors: Elías-López A L , Marquina B , Gutiérrez-Ortega A , Aguilar D , Gomez-Lim M , Hernández-Pando R
Published: October 2008

Host control of mycobacterial infection, in both human and mouse models, has been shown to be associated with the production of interferon (IFN)-γ by CD4+ T cells. Interleukin (IL)-12 is known to be a crucial cytokine in the differentiation of IFN-γ-producing T helper 1 (Th1) cells. To determine whether continuous administration of IL-12 expressed in transgenic tomato (TT–IL-12) has therapeutic efficacy in a murine model of pulmonary tuberculosis, BALB/c mice were infected with either Mycobacterium tuberculosis H37Rv strain or a multi-drug-resistant clinical isolate (MDR) and treated with a daily oral dose of TT-IL12 crude fruit extracts. For the early H37Rv infection, TT–IL-12 administration was started 1 day before infection and continued for 60 days. In the H37Rv or MDR late infection, treatment was started 60 days after infection and continued for another 60 days. In both phases of infection, TT–IL-12 administration resulted in a reduction of bacterial loads and tissue damage compared with wild-type tomato (non-TT). The Th1 response was increased and the Th2 response was reduced. In the late infection, a long-term treatment with TT–IL-12 was necessary. We demonstrate that TT–IL-12 increases resistance to infection and reduces lung tissue damage during early and late drug-sensitive and drug-resistant mycobacterial infection.
Decreased 4-1BB expression on CD4+CD25high regulatory T cells in peripheral blood of patients with multiple sclerosis
Authors: Liu G-Z , Gomes A C , Fang L-B , Gao X-G , Hjelmstrom P
Published: October 2008

As a tumour necrosis factor receptor superfamily member, 4-1BB (CD137) is preferentially expressed in CD4+CD25+ regulatory T cells (Tregs) and has been suggested to play an important role in regulating the generation or function of Tregs. Recent studies of human Tregs have shown that blood CD4+CD25high T cells were much closer to Tregs in terms of their functionality. Furthermore, CD4+CD25high Tregs have been found to have a decreased effector function in patients with multiple sclerosis (MS). In this study, we examined the expression of 4-1BB and soluble 4-1BB (s4-1BB) protein levels in the peripheral blood of MS patients. Compared with healthy controls, MS patients had decreased 4-1BB expression in their CD4+C25high Tregs and increased plasma s4-1BB protein levels. Moreover, the plasma s4-1BB levels of MS patients were shown to be inversely correlated with the 4-1BB surface expression of CD4+CD25high Tregs. The down-regulated 4-1BB expression on CD4+CD25high Tregs of MS patients may be involved in the impaired immunoactivity of these Tregs. The elevated s4-1BB levels may, at least in part, function as a self-regulatory attempt to inhibit antigen-driven proliferation of Tregs or their immunosuppressive activity.
Human TSLP directly enhances expansion of CD8+ T cells
Authors: Akamatsu T , Watanabe N , Kido M , Saga K , Tanaka J , Kuzushima K , Nishio A , Chiba T
Published: October 2008

Human thymic stromal lymphopoietin (TSLP) promotes CD4+ T-cell proliferation both directly and indirectly through dendritic cell (DC) activation. Although human TSLP-activated DCs induce CD8+ T-cell proliferation, it is not clear whether TSLP acts directly on CD8+ T cells. In this study, we show that human CD8+ T cells activated by T-cell receptor stimulation expressed TSLP receptor (TSLPR), and that TSLP directly enhanced proliferation of activated CD8+ T cells. Although non-stimulated human CD8+ T cells from peripheral blood did not express TSLPR, CD8+ T cells activated by anti-CD3 plus anti-CD28 did express TSLPR. After T-cell receptor stimulation, TSLP directly enhanced the expansion of activated CD8+ T cells. Interestingly, using monocyte-derived DCs pulsed with a cytomegalovirus (CMV)-specific pp65 peptide, we found that although interleukin-2 allowed expansion of both CMV-specific and non-specific CD8+ T cells, TSLP induced expansion of only CMV-specific CD8+ T cells. These results suggest that human TSLP directly enhances expansion of CD8+ T cells and that the direct and indirect action of TSLP on expansion of target antigen-specific CD8+ T cells may be beneficial to adoptive cell transfer immunotherapy.
Antibodies to amino acid 200–239 (p200) of Ro52 as serological markers for the risk of developing congenital heart block
Authors: Strandberg L , Winqvist O , Sonesson S-E , Mohseni S , Salomonsson S , Bremme K , Buyon J P , Julkunen H , Wahren-Herlenius M
Published: October 2008

Maternal autoantibodies to the p200-epitope of Ro52 have been suggested to correlate with development of congenital heart block. The aim of the present study was to evaluate the clinical relevance and predictive value of p200-antibodies in high-risk pregnancies. Sera from 515 Finnish, Swedish and American women were included in the study. Sera originated from 202 mothers with an infant affected by second- or third-degree atrioventricular block (AVB), 177 mothers with rheumatic disease having infants with normal heart rate and female blood donors (n = 136). A novel serological assay for Ro52 p200-antibodies with intra- and inter-assay variability of 3% and 3·8% respectively was developed. Mothers of children affected by AVB II-III had significantly higher p200-antibody levels than mothers with rheumatic disease having children with normal heart rate (P < 0·001). In the Swedish cohort, a distinction between foetuses with normal conduction, AVB I, AVB II and III was possible. A significant difference in anti-p200 levels between AVB I and AVB II-III groups compared with foetuses with normal conduction (P < 0·05 and P < 0·01) was observed. Using p200-antibodies as a second step analysis in Ro52-positive pregnancies increased the positive predictive value for foetal cardiac involvement (AVB I, II or III) from 0·39 (0·27–0·51) to 0·53 (0·37–0·68). In conclusion, Ro52 p200-antibodies may occur in women with unaffected children, but levels are significantly higher in mothers of children with congenital heart block and are suggested as a relevant marker in evaluating the risk for foetal AV block.
Lessons learnt from many years of experience using anti-D in humans for prevention of RhD immunization and haemolytic disease of the fetus and newborn
Authors: Kumpel B M
Published: October 2008

For 40 years prophylactic anti-D has been given to D-negative women after parturition to prevent haemolytic disease of the fetus and newborn. Monoclonal or recombinant anti-D may provide alternatives to the current plasma-derived polyclonal IgG anti-D, although none of them have yet proved as effective in phase 1 clinical trials. The variation in efficacy of the antibodies may have been influenced by heterogeneity in glycosylation of anti-D produced from different cell lines. Some aspects of the conduct of the human studies, most notably the use of low doses of anti-D and target D positive red cells in vivo, may aid the design of the clinical development of other immunomodulatory drugs in order to minimize adverse effects.
Potential therapy of Fc-antigen combination-encoding DNA vaccination in mouse allergic airway inflammation
Authors: Wang Y , Qian G , Wang G , Cheng X , Bai C , Wang X
Published: October 2008

Vaccination with allergen-encoding DNA has been proposed as having potential for allergen-specific immunotherapy. In this study, we examine the therapeutic effect of allergen-encoding DNA vaccination directly to dendritic cells (DCs) on allergen-induced allergic airway inflammation in a mouse model and explore potential mechanism. Ovalbumin (OVA)-sensitized and challenged mice were immunized with DNA vaccine and received bronchoalveolar lavage (BAL) 1 day after the last challenge, to measure BAL levels of interleukin (IL)-4, IL-5, interferon (IFN)-gamma and differential cell count. Pulmonary DCs and Spleen DCs were purified and sorted according to the expression of CD11c+CD80+ and CD11c+CD86+ co-stimulatory molecules. Our data demonstrated that DNA vaccine therapy with OVA-Fc-pcDNA3·1 significantly prevented OVA-increased levels of IL-4, IL-5 and the percentage of eosinophils and OVA-decreased level of IFN-gamma. OVA-Fc-pcDNA3·1-treated mice had less severity of airway inflammation, and lower expression of CD11c+CD80+ and CD11c+CD86+ on pulmonary DCs, as compared with animals with OVA-pcDNA3·1, pcDNA3·1 and OVA respectively. DNA vaccine encoding both Fc and OVA was shown to be more effective than DNA vaccine encoding OVA alone. Our data indicate that Fc-antigen combination-encoding DNA vaccination has better preventive effects on antigen-induced airway inflammation by regulating DCs, and may be a new alternative therapy for asthma.
Expression of inflammatory mediators in the otitis media induced by Helicobacter pylori antigen in mice
Authors: Kariya S , Okano M , Fukushima K , Nomiya S , Kataoka Y , Nomiya R , Akagi H , Nishizaki K
Published: October 2008

Helicobacter pylori is a Gram-negative bacterium that is recognized as one of the key factors in gastric diseases such as gastritis, peptic ulcer and gastric cancer. Recent studies have shown relationships between H. pylori and extra-digestive diseases, and the presence of H. pylori in the middle ear and upper respiratory tract has been reported. However, the role of H. pylori in middle ear disease remains unclear. The present study demonstrated that H. pylori whole-cell protein directly induces macrophage migration inhibitory factor, macrophage inflammatory protein 2, interleukin 1β and tumor necrosis factor α in middle ear epithelium in mice, and severe proliferation of inflammatory cells was observed in middle ear cavity inoculated with H. pylori whole-cell protein. In addition, trans-tympanic injection of macrophage migration inhibitory factor up-regulated expression of macrophage inflammatory protein 2 in the middle ear. These findings indicate that H. pylori infection causes immunological inflammation in middle ear epithelium, and H. pylori may play a significant role in otitis media.
Generation of functionally mature dendritic cells from elutriated monocytes using polyinosinic : polycytidylic acid and soluble CD40 ligand for clinical application
Authors: Kim S , Kim H O , Kim H J , Lee K , Kim H-S
Published: October 2008

Despite the increasing use of dendritic cell (DC) vaccination in clinical trials, optimal conditions for the generation of functionally mature DCs remain to be established. The current standard DC maturation protocol for clinical trials has been used as an inflammatory cytokine cocktail [tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and prostaglandin E2], but this cocktail induced insufficient maturation of DCs derived from elutriated monocytes when cultured in X-VIVO 15. The aim of this study was to define effective combinations of stimulators for generating functionally mature DCs from elutriated monocytes under current good manufacturing practice conditions. We compared the functional capacity of DCs in response to all possible pairwise combinations of four different classes of stimuli: TNF-α, peptidoglycan, polyinosinic : polycytidylic acid [poly(I:C)] and soluble CD40 ligand (CD40L). Maturation status of DCs stimulated with combination of four stimuli was similar to that of the cytokine cocktail as assessed by the cell surface phenotype. However, only the combination of poly(I:C) + CD40L induced complete functional activation of the whole DC population, assessing IL-12p70 production, allostimulatory activity, migratory response to CCL19 and T helper 1-polarizing capacity. Thus, the protocol based on the combination of poly(I:C) and CD40L is more effective for the induction of clinical-grade DCs from elutriated monocytes than the standard cytokine cocktail.
Substandard medicines in resource‐poor settings: a problem that can no longer be ignored
Authors: Caudron J.‐M. , Ford N. , Henkens M. , Macé C. , Kiddle‐Monroe R. , Pinel J.
Published: October 2008

The circulation of substandard medicines in the developing world is a serious clinical and public health concern. Problems include under or over concentration of ingredients, contamination, poor quality ingredients, poor stability and inadequate packaging. There are multiple causes. Drugs manufactured for export are not regulated to the same standard as those for domestic use, while regulatory agencies in the less‐developed world are poorly equipped to assess and address the problem. A number of recent initiatives have been established to address the problem, most notably the WHO pre‐qualification programme. However, much more action is required. Donors should encourage their partners to include more explicit quality requirements in their tender mechanisms, while purchasers should insist that producers and distributors supply drugs that comply with international quality standards. Governments in rich countries should not tolerate the export of substandard pharmaceutical products to poor countries, while developing country governments should improve their ability to detect substandard medicines.
Malaria in pregnancy in an area of stable and intense transmission: is it asymptomatic?
Authors: Tagbor Harry , Bruce Jane , Browne Edmund , Greenwood Brian , Chandramohan Daniel
Published: October 2008

Objective  To report a study of the signs and symptoms of malarial infection during pregnancy in an area of stable and intense transmission.

Methods  As part of a clinical trial, to assess the efficacy and safety of four antimalarial drug regimens in pregnant women, we collected clinical and laboratory data from 900 parasitaemic pregnant women and 223 non‐parasitaemic pregnant women who attended an antenatal clinic at a district hospital in Ghana. Frequencies of signs and symptoms were calculated and their association with the level of parasitaemia was assessed using multivariate logistic regression.

Results  History of fever (7.8%vs. 44.4%; P < 0.0001), headache (12.5%vs. 43.9%; P < 0.0001), vomiting (0 vs. 11.5%; P = 0.01), malaise (1.6%vs. 31.6%; P < 0.0001) dizziness (0%vs. 23%; P < 0.0001) and fatigue (0%vs. 22.5%; P < 0.0001) was substantially higher in parasitaemic primigravidae than in aparasitaemic primigravid women. Similar differences in the distribution of the symptoms and signs were observed between parasitaemic and aparasitaemic multigravid women. The proportion of women with elevated concentrations of aspartate aminotransferase, alanine aminotransferase and total bilirubin and its fractions was also higher in parasitaemic than in non‐parasitaemic women.

Conclusion  In areas of stable malarial transmission, malaria in pregnancy is often symptomatic. Although the symptoms are mostly non‐specific, careful recording of history may be useful to identify women who need a confirmatory test and an effective antimalarial treatment.
Hypothermia of newborns is associated with excess mortality in the first 2 months of life in Guinea‐Bissau, West Africa
Authors: Sodemann Morten , Nielsen Jens , Veirum Jens , Jakobsen Marianne S. , Biai Sidu , Aaby Peter
Published: October 2008

Objective To examine the long‐term effects of neonatal hypothermia (HT) on survival.

Methods Using the longitudinal community and hospital surveillance system of the Bandim Health Project, we followed children born between 1997 and 2002 at the only maternity ward in the city. All children’s axillary temperature was measured within 12 h of birth. They were followed from birth to 6 months of life through regular home visits.

Results We identified 2926 live births in the study area and 177 deaths before 6 months of age. Based on mortality risk, we defined a temperature below 34.5 °C as the cut‐off point for HT. Two hundred and thirty‐eight (8%) children had HT. Controlled for birth weight, HT was associated with a nearly fivefold increase in mortality during the first 7 days of life [mortality ratio (MR) = 4.81 (2.90–8.00)] and with increased mortality from 8 to 56 days of life [MR = 2.55 (1.29–5.04)].

Conclusion HT is associated with excess mortality beyond the perinatal period up to at least 2 months of age, especially among low‐birth‐weight children. Hence, failure to comply with the WHO guidelines for care of newborns in low‐income countries may have long‐term consequences for child survival which have not previously been assessed. The WHO definition of HT should be based on mortality data.
Early atopic disease and early childhood immunization – is there a link?
Authors: Grüber C. , Warner J. , Hill D. , Bauchau V. ,   the EPAAC Study Group
Published: October 2008

Background:  There are frequent concerns about early immunizations among the parents of children at heightened risk for atopy. The study assessed the effect of vaccine immunization before the first birthday on eczema severity and allergic sensitization in the second year of life.

Methods:  A total of 2184 infants, aged 1–2 years, with established atopic dermatitis and a family history of allergy, from 97 study centres in 10 European countries, South Africa and Australia were included. Exposure to vaccines (diphtheria, tetanus, pertussis, polio, Haemophilus influenzae Type B, hepatitis B, mumps, measles, rubella, varicella, BCG, meningococci and pneumococci) and immunization dates were recorded from immunization cards. Immunoglobulin E (IgE) was determined by RAST and eczema severity was assessed by scoring atopic dermatitis (SCORAD).

Results:  Immunization against any target was not associated with an increased risk of allergic sensitization to food or inhalant allergens. Varicella immunization (only 0.7% immunized) was inversely associated with total IgE > 30 kU/l (OR 0.27; 95% CI 0.08–0.87) and eczema severity (OR 0.34; 95% CI 0.12–0.93). Pertussis immunization (only 1.7% nonimmunized) was inversely associated with eczema severity (OR 0.30; 95% CI 0.10–0.89). Cumulative received vaccine doses were inversely associated with eczema severity (P = 0.0107). The immunization coverage of infants before and after the onset of atopic dermatitis was similar.

Conclusion:  In children at heightened risk for atopy, common childhood immunization in the first year is not associated with an increased risk of more severe eczema or allergic sensitization. Parents of atopic children should be encouraged to fully immunize their children.
Clinical usefulness of microarray‐based IgE detection in children with suspected food allergy
Authors: Ott H. , Baron J. M. , Heise R. , Ocklenburg C. , Stanzel S. , Merk H.‐F. , Niggemann B. , Beyer K.
Published: October 2008

Background:  Component‐resolved diagnostics using microarray technology has recently been introduced into clinical allergology, but its applicability in children with food allergy has hardly been investigated so far. The aim of this study was to evaluate the utility of microarray‐based IgE detection in the diagnostic workup of food allergy and to compare this new diagnostic tool with established methods of allergen‐specific IgE detection.

Methods:  We investigated 130 infants and children with suspected allergy to cow’s milk (CM) or hen’s egg (HE). Serum IgE measurements, skin prick tests, allergen microarray assays and controlled oral food challenges with HE and CM were performed.

Results:  We analyzed 145 oral challenges that served as reference parameters for assay performance assessment. On this basis, the panel of microarrayed allergen components was shown to represent a comprehensive repertoire of clinically relevant CM and HE proteins. Additionally, the implemented CM and HE components respectively sufficed for equivalent test performance as compared to the corresponding fluorescence enzyme immunoassay extract and skin testing. However, component‐resolved diagnostics for HE and CM allergy did not make oral food challenges superfluous. Clinical IgE decision points predicting positive oral food challenges could be calculated for both in vitro test methods.

Conclusions:  Allergen microarrays provide a new tool to diagnose symptomatic CM and HE allergy. They show performance characteristics comparable to the current diagnostic tests and may be indicated in small children in whom only small blood volumes are obtainable. However, they are not capable of replacing double‐blind, placebo‐controlled food challenges in most cases.
IgE antibodies to ω‐5 gliadin associate with immediate symptoms on oral wheat challenge in Japanese children
Authors: Ito K. , Futamura M. , Borres M. P. , Takaoka Y. , Dahlstrom J. , Sakamoto T. , Tanaka A. , Kohno K. , Matsuo H. , Morita E.
Published: October 2008

Background:  Gliadins have been implicated in immunoglobulin E (IgE)‐mediated allergy to ingested wheat and ω‐5‐gliadin is known to represent a major allergen in wheat‐dependent exercise‐induced anaphylaxis. Less known is whether ω‐5‐gliadin is a clinically relevant allergen in children with immediate allergy to ingested wheat. This study investigates whether specific IgE antibodies to ω‐5‐gliadin (sIgE‐ω‐5‐gliadin‐ab) could be used as a marker for oral wheat challenge outcome in wheat‐sensitized children. A secondary objective was to study whether the level of sIgE‐ω‐5‐gliadin was related to symptom severity in children with a positive challenge test.

Methods:  Serum samples from 88 children sensitized to wheat, of whom 35 underwent wheat challenge, were collected consecutively. sIgE‐ω‐5‐gliadin‐ab was related to a physician’s diagnosis of wheat allergy and challenge symptoms.

Results:  The mean concentration of sIgE‐ω‐5‐gliadin‐ab was 7.25 kUA/l in patients with wheat allergy and 1.08 kUA/l in patients with no wheat allergy (P < 0.01). sIgE‐ω‐5‐gliadin‐ab was only detected in 12 of the non‐wheat allergic children and 11 of them had a specific IgE to wheat below 1.30 kUA/l. Children reacting with severe symptoms upon challenge (n = 8) had increased levels of sIgE‐ω‐5‐gliadin‐ab compared to children with moderate, mild or no symptoms (P < 0.001).

Conclusions:  The presence of sIgE‐ω‐5‐gliadin‐ab is related to the reaction level to wheat challenge outcome in wheat‐sensitized children. The sIgE‐ω‐5‐gliadin‐ab was found to be associated with a strong convincing history of wheat allergy also in those cases when oral food challenge was avoided. The sIgE‐ω‐5‐gliadin‐ab level may serve as a marker for clinical reactivity in wheat‐sensitized individuals.
Distinct regulation of IgE, IgG4 and IgA by T regulatory cells and toll‐like receptors
Authors: Meiler F. , Klunker S. , Zimmermann M. , Akdis C. A. , Akdis M.
Published: October 2008

Background:  Allergic diseases are characterized by the activation of the immune system and formation of immunoglobulin (Ig)E antibodies against normally innocuous environmental antigens, whereas IgG4 and IgA represent noninflammatory and blocking antibody isotypes. The T helper 2 (Th2) cells induce and T regulatory (Treg) cells suppress several features of allergic inflammation. Our aim was to investigate the role of allergen‐specific T regulatory type 1 (Tr1) cells and CD4+CD25+ Treg cells and toll‐like receptors (TLRs) on IgE, IgG4 and IgA production.

Methods:  Germline or productive Ig‐transcripts are determined by real‐time reverse transcriptase‐polymerase chain reaction, secreted Igs are measured by enzyme‐linked immunosorbent assay and the frequency of Ig‐producing plasma cells is investigated by enzyme‐linked immunosorbent spot. Circulating CD4+CD25+ Treg cells and allergen‐specific Tr1 cells are used.

Results:  Both allergen‐specific, interleukin‐10‐secreting Tr1 cells and CD4+CD25+ Treg cells from healthy individuals induced IgG4 and suppressed IgE production in peripheral blood mononuclear cells and purified B‐cell cultures. In contrast, induction of IgA production is independent of T‐cell help and the role of Tr1 or Treg cells is very limited, whereas it was highly induced by direct B‐cell activation via TLR7 and 9.

Conclusions:  These data suggest that T regulatory cells may contribute to the suppression of allergic diseases by suppression of IgE and induction of IgG4, whereas IgA production is enhanced by B‐cell activation via TLR7 and TLR9.
Does the relationship between IgE and the CD14 gene depend on ethnicity?
Authors: Zhang G. , Goldblatt J. , LeSouëf P. N.
Published: October 2008

This review considers the data from studies analysing associations between the CD14C−159T single nucleotide polymorphism (SNP) and asthmatic phenotypes and discusses the variability of the conclusions. By searching PubMed and EMBASE for articles on CD14C−159T ‐related population or family‐based association studies, 47 were identified up till September 2007. Collectively, the studies reviewed herein consistently showed population differences in frequencies of the alleles of the SNP, with African descent having the highest C allele frequencies, followed by Caucasians and Asians. The T allele of the SNP was associated with increased sCD14 in some studies but not in others. Inconsistently, the C allele, or even occasionally the T allele, was associated with atopic phenotypes in a population subgroup. There are several explanations for these inconsistencies, including lack of power, linkage disequilibrium, gene–gene interactions, population admixture and gene–environment interactions. If the SNP was associated with functional changes to the coded protein and thus modulating susceptibility to allergic disease, its effect may be modest and dependent on other co‐existent, ethnicity‐specific, genetic or environmental risk factors.
Complementary roles for lipid and protein allergens in triggering innate and adaptive immune systems
Authors: Russano A. M. , Agea E. , Casciari C. , De Benedictis F. M. , Spinozzi F.
Published: October 2008

Background:  Recent advances in allergy research mostly focussed on two major headings: improving protein allergen purification, which is aimed towards a better characterization of IgE‐ and T‐cell reactive epitopes, and the potential new role for unconventional innate and regulatory T cells in controlling airway inflammation. These advancements could appear to be in conflict each other, as innate T cells have a poorly‐defined antigen specificity that is often directed toward nonprotein substances, such as lipids.

Method:  To reconcile these contrasting findings, the model of cypress pollinosis as paradigmatic for studying allergic diseases in adults is suggested.

Results:  The biochemical characterization of major native protein allergens from undenatured pollen grain demonstrated that the most relevant substance with IgE‐binding activity is a glycohydrolase enzyme, which easily denaturizes in stored grains. Moreover, lipids from the pollen membrane are implicated in early pollen grain capture and recognition by CD1+ dendritic cells (DC) and CD1‐restricted T lymphocytes. These T cells display Th0/Th2 functional activity and are also able to produce regulatory cytokines, such as IL‐10 and TGF‐β. CD1+ immature DCs expand in the respiratory mucosa of allergic subjects and are able to process both proteins and lipids.

Conclusion:  A final scenario may suggest that expansion and functional activation of CD1+ DCs is a key step for mounting a Th0/Th2‐deviated immune response, and that such innate response does not confer long‐lasting protective immunity.
Gender difference, sex hormones, and immediate type hypersensitivity reactions
Authors: Chen W. , Mempel M. , Schober W. , Behrendt H. , Ring J.
Published: October 2008

Gender differences in the development and prevalence of human diseases have long been recognized. Immense interest grows in the understanding of the role of sex hormones in the homeostasis of immunity. Asthma predominates in boys before puberty and this gender preference reverses after puberty and in adulthood, when adult women tend to have a more severe disease, often recalcitrant to treatment. Atopic eczema in preschool children shows insignificant gender difference or male preponderance in different studies, with more adult females suffering from atopic eczema. The limited data on the prevalence of immediate hypersensitivity to hymenoptera venom show controversial results. Discrepancy exists regarding the gender difference in food allergy, with females reporting significantly more allergic reactions in questionnaire studies. In general, adverse reactions to nonionic iodinated radiocontrast media are more commonly observed in females. The course of allergic diseases varies unpredictably during pregnancy, whereas hormone replacement therapy in postmenopausal women usually has a favorable influence on the course of asthma. Experiments in rodents confirm an effect of estrogens on mast cell activation and allergic sensitization, while progesterone is shown to suppress histamine release but potentiate IgE induction. Dehydroepiandrosterone may antagonize the production of Th2 cytokines but the effect of testosterone and the other androgens remains less defined. Actual data from human studies are lacking.
Comparative assessment of the water balance and hydrology of selected Ethiopian and Kenyan Rift Lakes
Authors: Ayenew Tenalem , Becht Robert
Published: October 2008

The study area is part of the East African Rift system, characterized by a cluster of lakes occupying an extremely faulted rift floor with geothermal manifestations. Some of the lakes illustrated contrasting water levels and size evolution over the last few decennia, believed to have been caused by various natural and anthropogenic factors. The relative importance of these factors, however, is unknown. This study attempts to present the hydrology of the lakes in a broader context, by giving more emphasis to lake water level fluctuations and to the water balance. These factors have far‐reaching implications in regard to future management of the lake basin water. It also provides information on the relation of the groundwater with the lakes, and with the local and regional groundwater flow system from the adjacent highlands to the floor of the Rift. The methods utilized in this study include conventional hydrogeological field surveys, and hydrometeorological and data analyses, coupled with digital image processing and spatial analysis under a Geographic Information System environment. Ancillary supporting information has been obtained from environmental isotopes and hydrochemical data. The study results indicate the terminal Ethiopian lakes changed in size and water level significantly over the last half century. In contrast, the Kenyan lakes only exhibited slight changes. The lakes in both countries exhibit a striking similarity in their subsurface hydraulic connection, and are strongly governed by complex rift geological structures. Groundwater plays a vital role in the water balance of the study lakes. The study results indicate that future sustainable use of the study lakes demands that serious attention be given to the role of the groundwater component of the lake water balances.