bluuebunny/crossref_metadata_2025 huggingface dataset:
Apoptosis and leukaemia
Authors: Brady Hugh J. M.
Published: November 2003

Defects in the intrinsic ability of haematopoietic progenitor cells to undergo apoptosis may allow the cell to acquire further mutations, survive inappropriately and eventually become malignant. Additionally, this defect could account for the resistance to cell death, observed in leukaemic cells, following treatment with chemotherapy. This review discusses some of the molecules known to influence apoptosis in leukaemic cells, particularly the novel fusion proteins produced as a result of leukaemia‐associated chromosomal translocations. The ultimate aim of understanding how apoptosis is altered in leukaemia cells is so that the process can be modulated to overcome resistance to chemotherapy and improve clinical outcomes. The relationship of leukaemia‐related fusion proteins such as PML‐RARα, BCR‐ABL, E2A‐HLF, AML1‐ETO and the various MLL fusions to the biochemical pathways involved in apoptosis are discussed as well as the consequences for therapeutic applications.
TCR Vβ repertoire analysis in CD56+ CD16dim/− T‐cell large granular lymphocyte leukaemia: association with CD4 single and CD4/CD8 double positive phenotypes
Authors: Karasawa Masamitsu , Mitsui Takeki , Isoda Atsushi , Tsumita Yuki , Irisawa Hiroyuki , Yokohama Akihiko , Handa Hiroshi , Matsushima Takafumi , Tsukamoto Norifumi , Murakami Hirokazu , Nojima Yoshihisa
Published: November 2003

Summary.  We report 10 patients with T‐cell large granular lymphocyte (LGL) leukaemia: four patients had CD16+ CD56− LGL lymphocytes (typical for LGL leukaemia), and six patients had CD56+ CD16dim/− LGL lymphocytes (atypical). Among the CD56+ CD16dim/− patients, LGL lymphocytes were CD4+ CD8− in one patient, CD4/CD8 double positive (DP) in three, and CD4− CD8+ in two. The CD4+ CD8dim DP cells expressed a CD8αα homodimer. T‐cell receptor (TCR) Vβ complementarity‐determining region 3 (CDR3) size distribution analysis and direct sequencing identified at least 1 in‐frame clonal TCR Vβ transcript in each patient; three patients had two or three different clonal sequences. To determine whether these transcripts were translated into cell surface TCR, we performed flow cytometric analysis using Vβ monoclonal antibodies (mAbs). A single Vβ protein was identified in patients, even those with multiple in‐frame transcripts. Previous and present results suggest that CD56+ CD16dim/− LGL leukaemia is more common than previously thought, and is associated with unusual phenotypes. When assessed using only molecular techniques, the monoclonal status of this disease may be misinterpreted as oligoclonal; thus, flow cytometric analysis using Vβ mAb is quite useful. Because mAbs do not cover the entire Vβ repertoire, assessing clonality using a combination of molecular methods and mAbs is preferable.
Expression of nm23‐H1 is associated with poor prognosis in peripheral T‐cell lymphoma
Authors: Niitsu Nozomi , Nakamine Hirokazu , Okamoto Masataka , Akamatsu Hiroko , Honma Yoshio , Higashihara Masaaki , Okabe‐Kado Junko , Hirano Masami
Published: November 2003

Summary. We have reported previously that the serum nm23‐H1 level is a prognostic factor for non‐Hodgkin's lymphoma. In this study, we examined nm23‐H1 expression in T‐ and natural killer (NK)‐cell lymphoma in order to evaluate whether lymphoma cells produce the protein. The clinical significance of the cytotoxic molecules, T‐cell intracellular antigen‐1 (TIA‐1) and granzyme  B and nm23‐H1 expression were also examined. Expression of nm23‐H1, TIA‐1, or granzyme  B was examined by immunohistochemistry in 137 previously untreated lymphoma patients. The relationship between the results and clinical outcome was examined in 81 patients with angioimmunoblastic T‐cell lymphoma, anaplastic large cell lymphoma, or peripheral T‐cell lymphoma, unspecified. The neoplastic cells of some lymphomas produced nm23‐H1 and the expression rates of nm‐23‐H1, TIA‐1 and granzyme  B were 36·5%, 78·8% and 32·8% respectively. The nm23‐H1‐positive or TIA‐1‐positive groups had significantly shorter overall and disease‐free survivals. Multivariate analysis confirmed nm23‐H1 expression to be an independent prognostic factor. The nm23‐H1 protein can be an important prognostic factor in the lymphomas studied here. New treatments that target nm23 overexpression could be developed as a result of nm23‐HI production by lymphoma cells.
Dissociation of putative graft‐versus‐haematopoiesis and graft‐versus‐myeloma effects in patients with rapidly progressive multiple myeloma*
Authors: Luft Thomas , Moos Marion , Goldschmidt Hartmut , Ho Anthony D. , Görner Martin
Published: November 2003

Summary.  This study evaluates the immunological effects in 21 patients with multiple myeloma (MM) following allogeneic stem cell transplantation with a non‐myeloablative conditioning regimen. Patients were heavily pretreated, most of them having progressed despite one to three courses of high dose chemotherapy followed by autologous stem cell rescue. For patients conditioned with low dose total body irradiation and Fludarabine, development of full (100%) donor chimerism (FDC) within the first 3–4 months strongly depended on the number of T cells transplanted. This putative graft‐versus‐haematopoiesis effect, however, did not coincide with clinical response. Rather, 10 of 17 patients progressed although FDC in peripheral blood was achieved. In contrast, clinical graft‐versus‐host disease (GvHD) of grade III–IV was associated with disease remission. Four of six patients achieved complete remission (CR) and one patient achieved a partial remission (PR) in close temporal relation with their acute GvHD. Two of four patients in CR succumbed to the consequences of this side effect. One patient in PR progressed soon after successful treatment of the GvHD, one of two patients with a long‐lasting CR developed chronic GvHD. Our observations suggest the existence of two distinct immune effects in MM following allogeneic transplantations with reduced conditioning regimen. First, the putative graft‐versus‐haematopoiesis effect that induced FDC was observed in all patients receiving unmanipulated grafts. Secondly, the graft‐versus‐myeloma effect that induced CR did not correlate with FDC but was associated with grade III–IV GvHD in our group of heavily pretreated patients.
Evaluation of the haemostatic potential of factor VIII‐heparin cofactor II hybrid proteins in a mouse model
Authors: Schatz Simone , Turecek Peter L. , Fiedler Christian , Zimmermann Klaus , Gritsch Herbert , Voorberg Jan , Schwarz Hans Peter , Dorner Friedrich , Scheiflinger Friedrich
Published: November 2003

Summary.  We constructed factor VIII‐heparin cofactor II (FVIII‐HCII) hybrid molecules, which are more readily activated by thrombin in vitro than the respective wild‐type molecules. The hybrid proteins were tested in a murine model of haemophilia A to investigate their haemostatic efficacy in vivo. Bleeding characteristics, measured using standard tail‐tip cutting techniques, were total blood loss, bleeding time and survival rate. FVIII‐HCII hybrids were found to be effective in preventing bleeding in FVIII knockout mice. While in vitro experiments showed that the chimaeric molecules had higher haemostatic functions than the wild‐type proteins, the variables analysed in vivo were similar for both proteins.
Disparity for a newly identified minor histocompatibility antigen, HA‐8, correlates with acute graft‐versus‐host disease after haematopoietic stem cell transplantation from an HLA‐identical sibling
Authors: Akatsuka Yoshiki , Warren Edus H. , Gooley Ted A. , Brickner Anthony G. , Lin Ming‐Tseh , Hansen John A. , Martin Paul J. , Madtes David K. , Engelhard Victor H. , Takahashi Toshitada , Riddell Stanley R.
Published: November 2003

Summary.  We recently identified a new minor histocompatibility antigen, termed HA‐8, which is presented by human leucocyte antigen (HLA)‐A*0201 or HLA‐A*0202 and expressed ubiquitously among tissues. A retrospective analysis of 577 Caucasian patients with HLA‐A*0201 or A*0202 who had received a haematopoietic stem cell transplant from a human leucocyte antigen (HLA)‐identical sibling was conducted to determine whether HA‐8 disparity correlated with clinical outcome. HA‐8 disparity was detected in 72 recipients, and grades II–IV graft‐versus‐host disease (GVHD) occurred in 46 (64%), compared with 251 (50%) of the 503 patients without HA‐8 disparity. After adjusting for known risk factors for acute GVHD, this difference was statistically significant (odds ratio, 1·8; 95% confidence interval, 1·0–3·1; P = 0·04). However, the hazards of clinical extensive chronic GVHD, overall mortality and recurrent malignancy were not statistically significantly different between the two groups. These data suggest that the increased risk of acute GVHD associated with recipient HA‐8 disparity was not sufficient to change other clinical outcomes.
New TPO treatment schedules of increased safety and efficacy: pre‐clinical validation of a thrombopoiesis simulation model
Authors: Skomorovski Kirill , Harpak Hila , Ianovski Anton , Vardi Moshe , Visser Trudi P , Hartong Simone CC , van Vliet Huub HDM , Wagemaker Gerard , Agur Zvia
Published: November 2003

Summary.  Thrombopoietin (TPO) immunogenicity hampers its development as a therapeutic agent for attenuating thrombocytopenia and improving platelet harvest in donors. This work was aimed at validating, in mouse and in monkey experiments, a thrombopoiesis computer‐model prediction that platelet counts, similar to those obtained with accepted TPO dose scheduling, can also be achieved by new and safer schedules of significantly reduced doses. To this end we compared, in a two‐arm mouse experiment, platelet increases obtained with a single intraperitoneal dosing of recombinant mouse TPO (17·5 μg/kg), with those obtained by the model‐suggested protocol of a significantly reduced dose (2 μg/kg on 4 consecutive days). The two TPO regimens generated similar platelet profiles, peaking at ca. 2700 × 109/l platelets. In rhesus monkeys, treated by rhesus monkey recombinant TPO (5 μg/kg on 4 consecutive days), the suggested protocol yielded effective platelet stimulation with significantly reduced immunogenicity. The model's ability to predict individual monkey responses to several new TPO administration protocols was further validated, proving sufficient robustness in providing good predictions with limited input data. The simulation tool could be used for testing the effects of different therapeutic agents on thrombopoiesis. Human trials are warranted for testing the suggested improved TPO protocol, possibly in conjunction with chemotherapy.
Early and late G2 arrest of cells undergoing radiation‐induced apoptosis or micronucleation
Authors: Abend M. , Gilbertz K‐P. , Rhein A. , Beuningen D. van
Published: November 2003

Conventional flow cytometric DNA measurements combined with the microscopic detection of cells in the late G2 phase of the cell cycle (characterized by the occurrence of paired kinetochores) enabled us to differentiate and to quantify early and late G2 cells 0–40 h after irradiation using a radioresistant (L929) and a radiosensitive (HL‐60) cell line. This approach provided us with (1) a new kind of G2 arrest characteristic revealing changes in the G2 phase which can not be detected by flow cytometric DNA measurements, (2) cell line dependent differences in the radiation‐induced transition through G2, accompanied by the occurrence of micronucleation and apoptosis, and (3) the characterization of apoptotic cells occurring probably during early G2 and bearing a rapidly reduced number of kinetochores in contrast to mitotic cells, suggesting processes different from those that operate in mitosis.
Direct comparison of bromodeoxyuridine and Ki‐67 labelling indices in human tumours
Authors: Wilson G. D. , Saunders M. I. , Dische S. , Daley F. M. , Robinson B. M. , Martindale C. A. , Joiner B. , Richman P. I.
Published: November 2003

Direct comparison of bromodeoxyuridine (BrdUrd) and Ki‐67 labelling indices was achieved by selecting similar areas from serial sections of human tumours. Fifteen patients were selected who had been administered BrdUrd in vivo and both proliferation markers were assessed by immunohistochemistry. The data show a good correlation between both BrdUrd LI and MIB‐1 LI and Tpot (calculated using the flow cytometry derived duration of S phase) and MIB‐1 LI. The contribution of BrdUrd LI to growth fraction varied as a function of proliferation characteristics. In tumours with a high LI, the number of DNA synthesizing cells represented half the growth fraction, whilst in tumours with lower LI's (<10%) the ratio of DNA precursor labelled cells as a function of growth fraction fell to between 10% and 20%. Tpot showed a linear correlation with MIB‐1/BrdUrd ratio with a slope approaching unity. It was apparent that both intra‐ and interpatient variation in proliferation index was greater for BrdUrd labelling than for MIB‐1 expression.
Optimal control problems arising in cell‐cycle‐specific cancer chemotherapy
Authors: Swierniak A. , Polanski A. , Kimmel M.
Published: November 2003

We explore mathematical properties of models of cancer chemotherapy including cell‐cycle dependence. Using the mathematical methods of control theory, we demonstrate two assertions of interest for the biomedical community: 1 Periodic chemotherapy protocols are close to the optimum for a wide class of models and have additional favourable properties. 2 Two possible approaches, (a) to minimize the final count of malignant cells and the cumulative effect of the drug on normal cells, or (b) to maximize the final count of normal cells and the cumulative effect of the drug on malignant cells, lead to similar principles of optimization.

From the mathematical viewpoint, the paper provides a catalogue of simplest mathematical models of cell‐cycle dependent chemotherapy. They can be classified based on the number of compartments and types of drug action modelled. In all these models the optimal controls are complicated by the singular and periodic trajectories and multiple solutions. However, efficient numerical methods have been developed. In simpler cases, it is also possible to provide an exhaustive classification of solutions.

We also discuss developments in estimation of cell cycle parameters and cell‐cycle dependent drug action.
Children, death and ageism
Authors: Thompson Neil
Published: November 2003

The position of children in the social order can be seen as an ambiguous one. On the one hand, they are highly valued, at a rhetorical level at least, as the basis of the future generation. On the other hand, however, they can be seen to be marginalized and disenfranchised, protected from more aspects of social life than is strictly necessary. This paper explores some of the important issues relating to children’s disenfranchised social position, with specific reference to issues relating to death, dying and bereavement.
User‐centred responses to child sexual abuse: the way forward?
Authors: Gray Sharon , Higgs Marietta , Pringle Keith
Published: November 2003

Two parallel surveys were carried out based in the north‐east of England and Cumbria: one ascertaining statutory social work services provided for child and adult survivors of sexual abuse, the other drawing upon the perceptions of adult survivors of child sexual abuse about existing and desirable forms of provision for adults and children. The surveys indicate the need for greater genuine partnership between service users and statutory agencies in the field of child sexual abuse, similar to that which is being pioneered in the field of adult care and disability. A community‐orientated response to sexual abuse, centred on service‐users, is required if one of the largest social problems facing us today is to be effectively challenged.
Parallel processes in researching and assessing potential carers
Authors: Clifford Derek , Cropper Andrea
Published: November 2003

This paper proposes a model for assessing potential parents, based on our research and practice in which we examined current methods of assessment in the light of anti‐oppressive principles and methods. We participated in and observed the work of two differing fostering and adoption agencies, and have drawn from our experiences and analysis to produce a pattern for assessment which critically draws on best practices. The paper also draws on previously published papers which discuss theories of research and assessment (Clifford 1992–93; Clifford 1994; Clifford 1995; Clifford & Cropper 1994), and draws a parallel between the processes of research and those of assessment. Our view is that research methods provide a foundation for assessment methods in various ways, mutually illuminating oppressive and anti‐oppressive processes.
Critical understandings of child development: the development of a module for a post‐qualifying certificate course in child protection studies
Authors: Daniel Brigid , Wassell Sally , Ennis Jim , Gilligan Robbie , Ennis Elaine
Published: November 2003

This paper explores the dilemmas involved in selecting appropriate theoretical and research material to help social workers in practice. Concentrating on the needs of those working in child care and protection, the paper uses the example of the area of child development knowledge to illustrate a process of presenting theory for practice. Specifically, the focus is on the redevelopment of a child development module for a post‐qualifying certificate course in child care and protection that aims to encourage students to make critical use of current research and theory. The paper explains the reasoning behind the choice of attachment theory as the underpinning theoretical framework. It also addresses possible pitfalls in an uncritical use of such theory. The paper finally sets out how the module addresses the need social workers have for a framework to guide intervention in individual cases. The dimensions described are those of individual vulnerability or resilience and factors in the environment that are adverse or protective.
Protecting children in new times: child protection and the risk society
Authors: Ferguson Harry
Published: November 2003

This paper examines the nature of late‐modern child protection by placing it in the context of the paradigm of `risk society'. It traces out a structural transformation in the relationship between expertise and lay people that has occurred since the 1970s which resulted in the emergence of child abuse inquiries and new public disclosures of professional ‘failures’'. The dynamic and empowering features of social developments are identified in how institutions, professionals and lay people re‐appropriate power, knowledge and reskill themselves. Traditionally repressed problems like child sexual abuse have gained recognition in a context where abused women and children – like all late‐modern citizens – are reflexively engaged in constructing their own biographies and using expertise in the planning of their life projects. A radically new professional risk consciousness in child protection is traced to late‐modern existential crises associated with death and sexuality and the emergence of manufactured risk, which is known and experienced by social workers as risk in the context of radically uncertain futures for children. Drawing on the work of sociologists of ‘reflexive modernity’, the paper aims to advance our understandings of social work and child protection beyond the one‐dimensional focus of post‐modernist critics on power, control and bureaucracy to recognize the new opportunities, as well as the dangers, involved in child protection in risk society.
Tolerance to a rice hydrolysate formula in children allergic to cow's milk and soy
Authors: Fiocchi A. , Travaini M. , D'Auria E. , Banderali G. , Bernardo L. , Riva E.
Published: November 2003

Background
Even hydrolysed cow's milk formulae may retain residual allergens and there are few nutritional options for children with cow's milk allergy (CMA) who also react to soy.

Objective  To assess clinical tolerance to a rice‐based hydrolysate in children with such a clinical presentation.

Patients and methods
Eighteen children (six girls and 12 boys; median age 5 years; range 1–9 years) with CMA, who developed clinical reactions to a soy‐based formula after 2–18 months' treatment, were recruited between January 1998 and June 1999. Clinical evaluation was by skin prick test (SPT) with cow's milk, casein, lactalbumin, soy and rice allergen extracts, fresh cow's milk, soy and hydrolysated rice formula (HRF). Serology was investigated by CAP system technology and immunoblotting. Assessment of the rice formula was carried out by double‐blind, placebo‐controlled food challenge with rice hydrolysate.

Results
Thirteen children had positive SPT to casein, 10 to lactalbumin, eight to rice and two to rice hydrolysate. Positive serology was found in all patients' sera tested with cow's milk, with soy in 13 sera and with rice in seven. Double‐blinded, placebo‐controlled challenge with an HRF was negative in all cases.

Conclusions
Children allergic to cow's milk and soy tolerate an HRF clinically. This suggests that rice hydrolysate may be used as a protein source for children with multiple food‐induced reactions.
Oral administration of an edible‐mushroom‐derived protein inhibits the development of food‐allergic reactions in mice
Authors: Hsieh K.‐Y. , Hsu C.‐I. , Lin J.‐Y. , Tsai C.‐C. , Lin R.‐H.
Published: November 2003

Background
Food allergy is a common disease without effective treatment. Since strict elimination of food allergens may be difficult, strategies for effective intervention are urgently needed.

Objective  The aim was to investigate the prophylactic use of orally administrated FIP‐fve, an immunomodulatory protein isolated from the edible mushroom Flammulina velutipes, in a murine model of food allergy.

Methods
BALB/c mice were immunized twice intraperitoneally with ovalbumin (OVA), at an interval of 2 weeks. Before and during each period of immunization, FIP‐fve (200 μg per mouse) or phosphate‐buffered saline was given orally every other day with a total of five doses. Then OVA‐specific antibodies and cytokine profiles were determined. Subsequently, the mice were orally challenged with OVA. Symptoms of anaphylaxis, levels of plasma histamine, and histology of intestines were examined.

Results
Mice receiving oral FIP‐fve treatment during sensitization to OVA had an impaired OVA‐specific IgE response with a Th1‐predominant cytokine profile. These mice were protected from systemic anaphylaxis‐like symptoms induced by subsequent oral challenge with OVA.

Conclusion
Oral administration of FIP‐fve has a Th1‐skewing effect on the development of the allergen‐specific immune response, and may serve the purpose of immunoprophylaxis for food allergy and other allergic diseases.
In vitro expansion of human basophils by interleukin‐3 from granulocyte colony‐stimulating factor‐mobilized peripheral blood stem cells
Authors: Takao K. , Tanimoto Y. , Fujii M. , Hamada N. , Yoshida I. , Ikeda K. , Imajo K. , Takahashi K. , Harada M. , Tanimoto M.
Published: November 2003

Background
A number of studies support the belief that human basophils play an important role in allergic inflammation. The exact mechanism of basophil activation at the site of allergic inflammation, however, has not been well understood, mainly due to their low number in blood and difficulty in obtaining a sufficient number of highly purified basophils for investigation.

Objective
The purpose of this study is to expand human basophils in vitro with high yield and purity by culturing peripheral blood stem cells (PBSCs).

Methods
We collected PBSC‐rich mononuclear cells containing CD34+ cells (0.15–4.9%) by leukapheresis from patients with malignant lymphoma and lung cancer during haematopoietic recovery after chemotherapy plus granulocyte colony‐stimulating factor‐induced mobilization. PBSC‐rich mononuclear cells were cultured in the presence of IL‐3.

Results
When PBSC‐rich mononuclear cells containing more than 1% of CD34+ cells were cultured, 20.0–83.3% of the cells, mostly with a yield of >10%, were metachromatic cells after 3 weeks of culture. These cells resembled mature peripheral blood basophils morphologically when examined by light and electron microscopy. Flow cytometric analysis showed that they expressed both FcɛRI and FcγRII. FcɛRI cross‐linking resulted in intracellular calcium mobilization, histamine release and synthesis of cysteinyl leukotrienes. The intracellular histamine content and the release of these chemical mediators triggered by anti‐IgE antibodies were comparable to those of peripheral blood basophils.

Conclusion
These findings suggest that PBSC‐derived basophils expanded in vitro are morphologically and functionally mature and will be a useful tool for the analysis of basophil functions.
Levels of soluble CD30 in cord blood and peripheral blood during childhood are not correlated with the development of atopic disease or a family history of atopy
Authors: Holmlund U. , Bengtsson Å. , Nilsson C. , Kusoffsky E. , Lilja G. , Scheynius A. , Sverremark‐Ekström E.
Published: November 2003

Background
The CD30 molecule has been linked to Th2 responses. Furthermore, elevated levels of the soluble form of CD30 (sCD30) in blood as well as of the expression of CD30 on the plasma membrane of T cells are associated with atopic disease.

Objective
To assess the potential usefulness of sCD30 levels as a prognostic indicator of and/or diagnostic marker for the development of atopic disease in children.

Methods
sCD30 levels in cord blood and peripheral blood from 36 2‐year‐old (10 atopic and 26 non‐atopic) and 74 7‐year‐old (35 atopic and 39 non‐atopic) children were determined employing an ELISA procedure. Atopy was diagnosed on the basis of clinical evaluation in combination with a positive skin prick test.

Results
No significant correlation between sCD30 levels in cord blood and the development of atopic disease at 2 or 7 years of age was observed. At 7 years of age, the circulating sCD30 levels in children with atopic disease (median 41 U/mL, range 6–503 U/mL) did not differ from the corresponding values for non‐atopic subjects (median 41 U/mL, range 8–402 U/mL). The same was true for children at 2 years of age. Furthermore, the sCD30 levels of children who had developed atopic eczema/dermatitis syndrome by the age of 7 years (median 49 U/mL, range 14–503 U/mL) were not significantly elevated in comparison with those of the non‐atopic children. Finally, neither sCD30 levels in cord blood nor peripheral blood at 2 or 7 years of age could be linked to a family history of atopy.

Conclusion
These findings indicate that the sCD30 concentration in cord blood is not a reliable prognostic indicator of, nor a useful diagnostic marker for, atopic disease in children up to 7 years of age. If such correlations do exist, they might be masked by age‐dependent variations in the circulating levels of sCD30, which may reflect individual differences in the maturation of children's immunological responses.
Evaluation of protein allergenic potential in mice: dose–response analyses
Authors: Dearman R. J. , Stone S. , Caddick H. T. , Basketter D.A. , Kimber I.
Published: November 2003

Background
With the increasing interest in novel foods derived from transgenic crop plants, there is a growing need for the development of approaches for the characterization of the allergenic potential of proteins. Whereas immunogenicity is a common property of foreign proteins, including food proteins, relatively few are significant dietary allergens with the inherent capacity to provoke IgE antibody production and immediate‐type hypersensitivity responses.

Objective
In order to evaluate an approach for the measurement of the allergenic potential of proteins, detailed dose–response analyses of humoral immune responses induced following systemic exposure of BALB/c strain mice to proteins known to differ in terms of sensitizing activity have been conducted.

Results
Mice were exposed to a range of concentrations of ovalbumin, a major allergenic constituent of hen's egg, a purified peanut allergen, Arachis hypogea agglutinin, or to the milk allergen bovine serum albumin, and to materials considered to lack significant allergenicity: a crude potato protein extract and a purified potato protein, potato agglutinin. The specific IgE antibody was measured by homologous passive cutaneous anaphylaxis assay, and the specific IgG antibody was measured by enzyme‐linked immunosorbent assay. Each of the five proteins was immunogenic in mice, inducing IgG antibody responses at all doses tested, although there was some variation with respect to the vigour of IgG responses. Marked differences in the capacity of these proteins to induce IgE responses were observed, however, with relatively high‐titre IgE antibody provoked by all three allergens over the dose ranges examined, whereas the potato proteins stimulated low‐titre IgE antibody at the highest dose (10%) only. Importantly, differences in IgE antibody production have been observed against a background of equivalent immunogenicity (IgG antibody responses).

Conclusion
The data presented here suggest that the measurement of antibody (IgE) responses in BALB/c mice appears to identify allergens accurately and to distinguish them from those materials that apparently lack allergenicity.
Early‐life exposure to antibacterials and the subsequent development of hayfever in childhood in the UK: case–control studies using the General Practice Research Database and the Doctors' Independent Network
Authors: Bremner S. A. , Carey I. M. , DeWilde S. , Richards N. , Maier W. C. , Hilton S. R. , Strachan D. P. , Cook D. G.
Published: November 2003

Background
Theoretically, antibacterial agents in early life might influence allergic sensitization in two ways: (i) as an indicator of infectious illness, they might be expected to protect against allergy; (ii) alternatively they might increase the risk through effects on the commensal bowel flora. Epidemiological evidence linking the prescription of antibacterial agents in early life to the subsequent development of hayfever is conflicting.

Objective
To establish definitively whether an association exists between early‐life antibacterial exposure and childhood hayfever diagnosis.

Methods
Nested case–control studies were based on birth cohorts of children identified within two large UK general practice databases of electronic patient records. One hundred and sixteen thousand and four hundred and ninety‐three children from 605 general practices were identified as being continuously registered from birth to at least age 5 years. Seven thousand and ninety‐eight cases were diagnosed with hayfever after the age of 2 years. One control per case was matched for practice, birth month, sex and still being registered on case diagnosis date. Odds ratios were derived from conditional logistic regressions within each database followed by pooling using a fixed‐effect model.

Results
The pooled odds ratio for hayfever was 1.11, 95% CI (1.03–1.20) if exposed to antibacterials in the first year of life, 1.35 (1.25–1.46) in year 2 and 1.47 (1.37–1.59) in year 3. Adjusting for consultation frequency reduced these odds ratios to 0.92, 1.05 and 1.10, respectively. There was no evidence that broader spectrum antibacterials, exposure in any specific month of year 1 or in the grass pollen season influenced the risk of hayfever.

Conclusion
These data exclude any important effect of antibacterial exposure in infancy on subsequent hayfever risk. Associations reported in earlier studies have likely been exaggerated through publication bias and by lack of control for the tendency of some families to consult frequently for a range of conditions.
Presentation of allergen in different food preparations affects the nature of the allergic reaction – a case series
Authors: Grimshaw K. E. C. , King R. M. , Nordlee J. A. , Hefle S. L. , Warner J. O. , Hourihane J. O.'B.
Published: November 2003

Background
Characterization of fatal and non‐fatal reactions to food indicates that the majority of reactions are due to the ingestion of prepared foods rather than the non‐processed allergen. In an ongoing study that used a double‐blind placebo‐controlled food challenge to investigate peanut allergy and clinical symptoms, the observed reaction severity in four of the first six subjects was greater than anticipated. We hypothesized that this was due to differences in the composition of the challenge vehicle.

Objective
The aim was to investigate whether the severity of observed challenge reactions would be repeated on re‐challenge with a lower fat challenge vehicle.

Methods
Peanut‐allergic subjects were re‐challenged with a lower fat recipe after reacting more severely than was anticipated to an initial peanut challenge. Similar challenge vehicle recipes were used, the only difference being the lower fat content (22.9% compared with 31.5%). The peanut content of the two recipes was analysed using RAST inhibition studies and ELISA tests.

Results
Three of four subjects reacted to much smaller doses of peanut protein on re‐challenge (mean dose equivalence – 23 times less peanut) with the lower fat recipe. RAST inhibition showed that neither recipe altered epitope recognition. The higher fat recipe required twice as much peanut to cause 50% inhibition. ELISA detected far lower levels of peanut in the higher fat recipe (220 000 parts per million (p.p.m.)) than in the lower fat recipe (990 000 p.p.m.).

Conclusion
The fat content of a challenge vehicle has a profound effect on the reaction experienced after allergen ingestion. This is another factor to be considered in assessing the risk of certain foods to food‐allergic consumers and adds another dimension to clinical, research and regulatory practice.
Age at bacille Calmette–Guérin vaccination and risk of allergy and asthma
Authors: Bager P. , Rostgaard K. , Nielsen N.M. , Melbye M. , Westergaard T.
Published: November 2003

Background
It has been proposed that early age at bacille Calmette–Guérin (BCG) vaccination protects against the development of allergy.

Objective
To study whether early age at BCG vaccination was associated with a decreased risk of atopy, allergic rhinitis, and asthma compared to BCG vaccination at later ages in childhood.

Methods
The occurrence of atopy, allergic rhinitis, and asthma was studied in nearly 2000 women participating in the Danish National Birth Cohort study. Detailed information on age at BCG vaccination (age 0–15 years) was available from school health records. Atopic status was assessed serologically by a specific response to 11 common inhalant allergens using serum samples obtained from the women during the period 1997–2001. Information on allergic rhinitis and asthma was available from telephone interviews.

Results
Approximately 85% of the women had been BCG‐vaccinated. Age at BCG vaccination was not associated with risk of atopy, allergic rhinitis, or asthma. The odds ratio of atopy, allergic rhinitis, and asthma associated with being vaccinated during the first year of life was 1.05 (95% CI 0.71–1.56), 1.42 (95% CI 0.85–2.36), and 1.71 (95% CI 0.91–3.20), respectively, compared with being vaccinated at the age of 7 years. Adjustment for birth cohort, sibship size, age of the woman's mother at birth, and social class in childhood did not affect the results.

Conclusion
Our findings suggest that age at BCG vaccination in childhood does not influence the development of allergy or asthma.
Intranasal exposure to a damp building mould, Stachybotrys chartarum, induces lung inflammation in mice by satratoxin‐independent mechanisms
Authors: Leino M. , Mäkelä M. , Reijula K. , Haahtela T. , Mussalo‐Rauhamaa H. , Tuomi T. , Hintikka E.‐L. , Alenius H.
Published: November 2003

Background
Stachybotrys chartarum is a damp building mould and a potent toxin producer that has been related to serious cases of respiratory health problems. However, the direct link between exposure and health symptoms has not been established.

Objective
To examine the mechanism by which exposure to spores of satratoxin producing and non‐producing S. chartarum strains induce inflammatory responses in murine lungs.

Methods
BALB/c mice were intranasally exposed for 3 weeks to spores of a satratoxin‐producing and a non‐producing S. chartarum strain. Inflammatory cell infiltration was characterized from bronchoalveolar lavage (BAL) fluid. Cytokine and chemokine mRNA expression in lung tissue was measured with real‐time PCR. Bronchial responsiveness to methacholine (MCh) was determined by whole‐body plethysmography and serum antibody levels by ELISA.

Results
A dose‐dependent increase in monocytes, neutrophils and lymphocytes was observed in BAL fluid after intranasal (i.n.) instillation of S. chartarum spores. There was no difference in the BAL between exposure to the satratoxin‐producing and the non‐producing strains. Infiltration of inflammatory cells was associated with an induction of pro‐inflammatory cytokine (IL‐1β, IL‐6 and TNF‐α) and chemokine (CCL3/MIP‐1α, CCL4/MIP‐1β and CCL2/MCP‐1) mRNA levels in the lungs. Interestingly, CXCL5/LIX was the only chemokine that showed significantly higher mRNA levels after exposure to the satratoxin‐producing strain compared with the non‐producing strain. MCh‐induced bronchial responsiveness was not altered significantly after mould instillation. Moreover, no significant increase in total or specific IgE, IgG2a and IgG1 antibody levels were found after S. chartarum exposure.

Conclusion
These results indicate that lung inflammation induced by i.n. instillations of S. chartarum spores is regulated by the induction of pro‐inflammatory cytokines and leucocyte‐attracting chemokines. The data also imply that S. chartarum‐derived components, other than satratoxins, are mediating the development of this inflammatory response.
Molecular diagnosis of von Hippel‐Lindau disease in a kindred with a predominance of familial phaeochromocytoma
Authors: Garcia Arnald , Matias‐Guiu Xavier , Cabezas Rosa , Chico Ana , Prat Jaime , Baiget Montserrat , De Leiva Alberto
Published: November 2003

OBJECTIVE To study the presence of germline mutations in the von Hippel‐Lindau gene (vhl ) in a kindred with a predominance of familial phaeochromocytoma in order to confirm the diagnosis of von Hippel‐Lindau disease (VHLD) as well as to identify asymptomatic members.

DESIGN DNA extracted from peripheral blood was amplified by the polymerase chain reaction using oligonucleotide primers corresponding to exon 3 of the vhl gene. Specific mutations in codon 238 were screened by restriction endonuclease digestion of PCR products with Msp I. The results were confirmed by DNA sequence analysis.

PATIENTS Two generations of a family consisting of 15 individuals were studied.

RESULTS A germline missense point mutation at codon 238 of the vhl gene (CGG → TGG; Arg → Trp) was detected in all patients with phaeochromocytoma and in only one of the asymptomatic family members.

CONCLUSION Mutational analysis of the vhl gene in patients with familial phaeochromocytoma may permit specific diagnosis of von Hippel‐Lindau disease, and is a good method for the identification of asymptomatic individuals at risk of von Hippel‐Lindau disease.
Ovarian hyperthecosis, diabetes and hirsuties in post‐menopausal women
Authors: Barth J. H. , Jenkins M. , Belchetz P. E.
Published: November 2003

OBJECTIVE We describe four patients with ovarian hyperthecosis and the effects of gonadotrophin releasing hormone on clinical and metabolic variables.

DESIGN Open out‐patient study.

PATIENTS Four women presented with post‐menopausal hirsuties. They had significant hair growth across the chest, upper back and shoulders. Three had histologically proven ovarian hyperthecosis and a fourth had large ovaries visualized on ultrasound. All four women had pronounced risk factors for vascular disease; hypertension, hyperlipidaemia and glucose intolerance, and three had already developed symptomatic vascular disease.

RESULTS Gonadotrophin releasing hormone agonist therapy resulted in significant reduction in plasma androgens and cosmetic reduction in hair growth but had no effect on hyperlipidaemia.

CONCLUSION The post‐menopausal women described in this report were clinically considered to have hyperandrogenism due to the pathological pattern of marked body hair over the upper trunk. Treatment with GnRH was very effective at reducing the severity of the hirsuties.

The post‐menopausal women with hyperthecosis in this report had a high prevalence of cardiovascular disease. Since hyperandrogenism and insulin are considered risk factors for cardiovascular disease in premenopausal women with polycystic ovaries, we discuss the possible relationship between insulin and the post‐menopausal ovary.
Influence of endogenous cholinergic tone and growth hormone‐releasing peptide‐6 on exercise induced growth hormone release
Authors: Nooitgedagt Aldert , Koppeschaar Hans P. F. , De Vries Wouter R. , Sidorowicz Anna , Klok Lammert J. , Dieguez Carlos , Mallo Federico
Published: November 2003

OBJECTIVE The neuroendocrine mechanisms of exercise‐induced GH release remain incompletely understood. In this study we have investigated the influence of endogenous cholinergic tone and growth hormone‐releasing peptide‐6 (GHRP‐6) on exercise induced GH release.

DESIGN Analysis of responses of serum GH to administration of pyridostigmine (PD, 120 mg, orally) or GHRP‐6 (100 μg, i.v.), to exercise alone, and to the combinations of PD plus exercise or GHRP‐6 plus exercise. An indirect estimation of the secretory pattern of GH was calculated by the deconvolution technique. Exercise was performed on a bicycle ergometer with a 20‐minute workload near the individual lactate threshold of 4 mmol/l. The five tests were performed in random order after an overnight fast, and at least 3 days apart.

SUBJECTS Eleven healthy, non‐obese male subjects (age 23.9 ± 0.3 years, body mass index 23 ± 0.7 kg/m2, VO2 max: 52.4 ± 2.0 ml/min/kg body weight; mean ± SEM) participated in this study.

MEASUREMENTS Serial blood samples from an indwelling catheter were taken before, during and after exercise for analysis of GH (IRMA), lactate (YSI 2300) and haematocrit (micromethod).

RESULTS Irrespective of the tests, peak values of GH were found between the 18th and 26th minute. The secretory pattern showed differences between the tests. Exercise alone induced relatively short lasting peaks of medium amplitude, whereas PD induced long lasting peaks with low amplitudes. PD plus exercise showed additive effects on the amplitude of GH peaks. GHRP‐6 induced long lasting peaks with high amplitude, and GHRP‐6 plus exercise also had additive effects on the amplitude.

CONCLUSIONS The increase in frequency and amplitude of GH peaks, which occurred during the GHRP‐6 plus exercise, indicates that exercise‐induced GH release is not mediated through an increment in the release of an endogenous GHRP‐6‐like ligand, favouring the possibility that exercise‐induced GH release is mediated through an increase in endogenous GHRH release.
Intractable hypercalcaemia due to parathyroid hormone‐related peptide secretion by a carcinoid tumour
Authors: Mantzoros Christos S. , Suva Larry J. , Moses Alan C. , Spark Richard
Published: November 2003

Hypercalcaemia, a common complication of malignancy, may result from either the lytic effect of multiple osseous metastases or the effect of tumour‐derived humoral factors. Excessive secretion of parathyroid hormone‐related peptide (PTHrP), a major cause of humoral hypercalcaemia of malignancy, has been incriminated as the cause of hypercalcaemia in patients with lung, breast, renal, head and neck and, occasionally, haematological malignancies. Carcinoid tumours, while frequently the source of ectopic hormone secretion, are infrequently associated with hypercalcaemia. We report the case of a 59‐year‐old woman with fulminant hypercalcaemia due to excessive PTHrP secretion from a hepatic carcinoid and we present the change in her serum PTHrP concentrations during infusion of a somatostatin analogue.
Insulin‐like growth factor‐binding protein‐2 in patients with prostate carcinoma and benign prostatic hyperplasia
Authors: Ho P. Jean , Baxter Robert C.
Published: November 2003

OBJECTIVE Insulin‐like growth factor‐binding protein (IGFBP)‐2 is a major prostatic IGFBP and may be involved in regulating prostate growth. Patients with prostate carcinoma (PC) have elevated serum IGFBP‐2 levels which correlate with the specific PC marker, prostate‐specific antigen (PSA). The aims of this study were to investigate whether elevated serum IGFBP‐2 is unique to PC or also occurs in benign prostatic hyperplasia (BPH), to examine the relations among age, PSA and IGFBP‐2 levels, and to examine longitudinal changes in serum IGFBP‐2 with PSA in prostate carcinoma.

DESIGN AND PATIENTS Sixteen patients (61–83 years) with inoperable PC attending the oncology unit at a tertiary referral hospital were studied. Some serum samples were obtained retrospectively while the majority were collected prospectively over 13 months of treatment. The patients with PC were compared to 8 patients (66–73 years) with histologically proven BPH and 7 male control subjects (61–82 years) with no known prostate abnormality.

MEASUREMENTS A new IGFBP‐2 RIA was developed. Serum PSA (by EIA), and IGFBP‐2, IGFBP‐3, IGF‐I and IGF‐II (by RIA) were measured in all subjects, and serially in patients with PC.

RESULTS Serum IGFBP‐2 was significantly higher in PC with high PSA (560 ± 66 μg/l, n = 12) than PC with normal PSA (292 ± 65 μg/l, n = 4, P = 0.02), BPH (364 ± 61 μg/l, P = 0.03) and controls (367 ± 44 μg/l, P = 0.04). Mean IGFBP‐2 in BPH was not different from controls. IGFBP‐2 and PSA were signi‐ ficantly correlated with age (r = 0.543 and r = 0.433 respectively) and with each other even when the age effect was removed. Serum IGFBP‐2 and PSA levels changed concordantly in all 7 PC patients who had serial sampling. Serum IGF‐II but not IGF‐I or IGFBP‐3 was higher in PC and BPH than in controls (PC 332 ± 23 μg/l), BPH 359 ± 26μg/l vs controls 241 ± 37 μg/l;  P = 0.03 and 0.02 respectively).

CONCLUSIONS Serum IGFBP‐2 levels are uniquely elevated in active prostate carcinoma but not in benign prostatic hypertrophy. In PC, serum IGFBP‐2 levels closely parallel those of PSA and probably reflect tumour burden. The relation between PSA and IGFBP‐2 is partially independent of their individual relations with age. Although serum IGFBP‐2 is less sensitive than PSA in PC, it may have adjunctive value in the management of prostate carcinoma.