bluuebunny/crossref_metadata_2025_split huggingface dataset:
Burden of disease attributable to selected environmental factors and injury among children and adolescents in Europe
Authors: Reading Richard 
Published: December 2004

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Valent F,
Little D,
Bertollini R,
Nemer LE,
Barbone F &
Tamburlini G
. (
2004
)

,
363
,
2032
–
2039
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Background  Environmental exposures contribute to the global burden of disease. We have estimated the burden of disease attributable to outdoor and indoor air pollution, inadequate water and sanitation, lead exposure, and injury among European children and adolescents.Methods  Published studies and reports from international agencies were reviewed for calculation of risk‐factor exposure in Europe. Disability‐adjusted life years (DALYs) or deaths attributable to each factor, or both, were estimated by application of the potential impact fraction to the estimates of mortality and burden of disease from the WHO global database of burden of disease.Findings  Among children aged 0–4 years, between 1.8% and 6.4% of deaths from all causes were attributable to outdoor air pollution; acute lower‐respiratory‐tract infections attributable to indoor air pollution accounted for 4.6% of all deaths and 3.1% of DALYs; and mild mental retardation resulting from lead exposure accounted for 4.4% of DALYs. In the age‐group 0–14 years, diarrhoea attributable to inadequate water and sanitation accounted for 5.3% of deaths and 3.5% of DALYs. In the age‐group 0–19 years, injuries were the cause of 22.6% of all deaths and 19.0% of DALYs. The burden of disease was much higher in European subregions B and C than subregion A. There was substantial uncertainty around some of the estimates, especially for outdoor air pollution.Interpretation  Large proportions of deaths and DALYs in European children are attributable to outdoor and indoor air pollution, inadequate water and sanitation, lead exposure, and injuries. Interventions aimed at reducing children's exposure to environmental factors and injuries could result in substantial gains. The pronounced differences by subregion and age indicate the need for targeted action.
Expression of CC and CXC chemokines and chemokine receptors in human leprosy skin lesions
Authors: KIRKALDY A A , MUSONDA A C , KHANOLKHAR-YOUNG S , SUNEETHA S , LOCKWOOD D N J 
Published: December 2004

SUMMARYWe have investigated the expression of chemokines and their receptors in leprosy skin lesions using immunohistochemistry. Skin biopsies from 25 leprosy patients across the leprosy spectrum, 11 patients undergoing type I reversal reactions and four normal donors were immunostained by ABC peroxidase method using antibodies against CC and CXC chemokines and their receptors. Using an in situ hybridization technique we have also studied the expression of monocyte chemoattractant protein 1 (MCP-1), RANTES and interleukin (IL)-8 chemokines mRNA in leprosy skin lesions. Chemokines and receptor expression was detected in all leprosy skin biopsies. Expression of CC chemokines MCP-1 (P &lt; 0·01) and RANTES (P &lt; 0·01) were elevated significantly in borderline tuberculoid leprosy in reversal reaction compared to non-reactional borderline tuberculoid leprosy, but there was no difference in the expression of IL-8 chemokine. Surprisingly, there was no significant difference in the expression of CC (CCR2 and CCR5) and CXC (CXCR2) chemokine receptors across the leprosy spectrum. Similarly, there was no significant difference in the expression of mRNA for MCP-1, regulated upon activation normal T cell expressed and secreted (RANTES) and IL-8 chemokines. Here, the presence of a neutrophil chemoattractant IL-8 in leprosy lesions, which do not contain neutrophils, suggests strongly a role of IL-8 as a monocyte and lymphocyte recruiter in leprosy lesions. These results suggest that the chemokines and their receptors, which are known to chemoattract T lymphocytes and macrophages, are involved in assembling the cellular infiltrate found in lesions across the leprosy spectrum.
CD4 responses to conserved HIV-1 T helper epitopes show both negative and positive associations with virus load in chronically infected subjects
Authors: BOAZ M J , WATERS A , MURAD S , EASTERBROOK P J , D'SOUSA E , VAN WHEELEY C , VYAKARNAM A 
Published: December 2004

SUMMARYCharacterization of immune responses to immunodominant CD4 epitopes in HIV-1 that are associated with control of HIV infection could be used to strengthen the efficacy of polyepitope HIV vaccines. We measured both the proliferative and the CD4 interferon (IFN)-γ and interleukin (IL)-2 cytokine responses specific for 11 previously identified HIV-1 T helper epitopes in 10 HIV-infected non-progressors (LTNPs) (infected for a median of 15 years with a stable CD4 count of &gt;500 cells × 106/l), and seven slow progressors (SPs) (infected for a median of 15 years with a CD4 count that had declined to &lt;500 cells × 106/l). Both groups were antiretroviral treatment-naive at the time of evaluation. The median virus load of SP group was higher than that of the LTNP group (P = 0·0002). The CD4 response to a peptide pool representing all potential CD4 Gag epitopes and to Gag p24 protein was also studied. Compared to SPs, LTNPs had higher numbers of Gag-specific IFN-γ+IL-2+ CD4s (P = 0·0059). The Gag-specific cytokine and proliferative responses correlated inversely with virus load (P = 0·03 and 0·0002, respectively), highlighting the potential importance of this response in immunity to HIV. A direct correlation was noted between proliferation and the Gag-specific IL-2 (P = 0·0053) rather than IFN-γ response (P = 0·1336), demonstrating that the proliferation assay reflected the IL-2 rather than the IFN-γ secreting capacity of CD4 cells. Several subjects with diverse class II DRB1 alleles responded, confirming the 11 selected peptides to be both antigenic and conserved. CD4 cytokine responses to one Gag and two conserved Pol peptides correlated negatively with virus load. The cytokine response to two additional Pol peptides correlated positively with virus load. The data indicate that there is not an absolute correlation between the CD4 immune response to conserved and broadly antigenic helper T cell epitopes in HIV non-progression.
The role of antigen in the selection of the human V3-23 immunoglobulin heavy chain variable region gene
Authors: MACKWORTH-YOUNG C G , HARMER I J , MAGEED R A 
Published: December 2004

SUMMARYThe immune system mounts antibody responses using few of the available immunoglobulin variable region (IgV) genes with some, such as the V3-23 heavy chain gene, regularly over-represented in responses to many antigens. The reasons for the over-representation of some V genes have not been established; the process could be either stochastic or selective. We demonstrated previously that the V3-23 gene, which is over-represented in the primary B lymphocyte repertoire in humans, encodes antibodies with differing antigen-binding reactivities in transgenic mice that express the human V3-23 gene. The aim of the current study was to assess if V3-23 gene over-representation is stochastic or could be influenced by antigen exposure. Transgenic mice were immunized with human IgG-Fc (hIgG-Fc), bovine collagen type II (bCII) or tetanus toxoid (TT), and hybridomas secreting human µ chain-containing  antibodies  generated.  These  were  tested  for  binding  to  the  immunogens  and  a  panel  of self- and exogenous antigens. In hybridomas derived from hIgG-Fc-immunized mice, 53% secreted antibodies specific for hIgG-Fc. A similar proportion (54%) of hybridomas from bCII-immunized mice secreted antibody that bound to collagen. By contrast, only 21% of hybridomas from mice immunized with TT bound to tetanus toxoid. Intriguingly, chimaeric antibodies generated from mice immunized with bCII or TT were mainly polyreactive, similar to antibodies generated from naive transgenic mice. However, hybridomas generated from mice immunized with hIgG-Fc were mainly specific, reacting exclusively with hIgG-Fc. These results suggest that selection and eventual expansion of B lymphocytes expressing the V3-23 gene are likely to be determined by exposure to self- and/or environmental antigens.
Serum nitric oxide (NO) levels in systemic sclerosis patients: correlation between NO levels and clinical features
Authors: TAKAGI K , KAWAGUCHI Y , HARA M , SUGIURA T , HARIGAI M , KAMATANI N 
Published: December 2004

SUMMARYVascular damage in systemic sclerosis (SSc) may be a factor in the abnormal regulation of several vasoactive agents. It has been well confirmed that plasma endothelin-1, as a vasoconstrictive factor, is elevated in patients with SSc. However, it is still controversial whether the levels of serum nitric oxide (NO), a strong vasodilator, are increased or decreased in SSc patients compared to healthy donors. In this study, we measured the levels of serum NO metabolites in SSc patients and determined the contribution of the excessive production of NO synthase (NOS)-2 by skin fibroblasts to NO synthesis. Serum NO levels of 45 patients with SSc were significantly higher than those of 20 healthy volunteers. In addition, some clinical features of SSc (the extent of skin fibrosis, short disease duration, and the complication of active fibrosing alveolitis) were all correlated positively with the levels of NO metabolites in SSc patients. To evaluate the levels of NOS-2 produced by skin fibroblasts, skin fibroblast cultures were established from SSc patients and healthy volunteers. Reverse transcription-polymerase chain reaction indicated that NOS-2 mRNA was spontaneously expressed in cultured fibroblasts derived from SSc patients, but not in those derived from healthy normal controls. Immunohistochemical staining also showed that NOS-2 proteins were detected in SSc fibroblasts but not in normal fibroblasts. The production of NO by cultured fibroblasts was visualized directly by a reagent (DAF-2 DA) used for the fluorescent detection of NO. Cultured SSc fibroblasts were capable of NO synthesis in culture media containing l-arginine, whereas normal fibroblasts (with no expression of NOS-2) did not synthesize detectable NO. These observations indicate that NO production is increased markedly in early-stage diffuse cutaneous SSc patients with active fibrosing alveolitis, and that constitutive NOS-2 expression in SSc fibroblasts may contribute to increased NO production.
Osteopenia, excess adiposity and hyperleptinaemia during 2 years of treatment for childhood acute lymphoblastic leukaemia without cranial irradiation
Authors: Davies J. H. , Evans B. A. J. , Jones E. , Evans W. D. , Jenney M. E. M. , Gregory J. W. 
Published: December 2004

Summaryobjective  Osteopenia and excess adiposity occur following treatment of childhood acute lymphoblastic leukaemia (ALL) and the use of cranial irradiation is thought to be a significant contributory factor. Hyperleptinaemia has also been demonstrated following cessation of treatment for childhood ALL. Therefore a prospective study was undertaken to evaluate serial changes in percentage bone mineral content (BMC), adiposity and serum leptin concentrations during 2 years of treatment of children with ALL with chemotherapy but without cranial irradiation.design and patient  Only patients treated using the MRC ALL 97/ALL 97 (modified 99) protocols for childhood ALL were eligible for entry into the study. A total of 14 patients (seven male, with a median age of 7·5 years (range 3·4–16·7 years) were recruited. Serial dual energy X‐ray absorptiometry (DEXA) scanning was undertaken at diagnosis and during two years of treatment. Serum leptin concentrations were determined at the same time as the scans.results  Reductions in %BMC were observed at the hip and lumbar spine by 12 months (P < 0·01) and remained low after 24 months of treatment. Subanalysis of %BMC measurements at the hip demonstrated a greater reduction in %BMC at the trochanteric region compared to the femoral neck. The percentage corrected fat mass increased from 6 months whereas the body mass index (BMI) standard deviation score (SDS) was increased after 24 months of treatment (P < 0·05). Serum leptin concentrations increased following 24 months of therapy (P < 0·05).conclusions  Children treated for ALL with contemporary regimens have a predisposition to osteopenia, excess adiposity and hyperleptinaemia during treatment without cranial irradiation administration. We speculate that in addition to glucocorticoid administration, leptin resistance may account in part for these observations.
The relationship of ghrelin to biochemical and anthropometric markers of adult growth hormone deficiency
Authors: Malik Iqbal A. , English Patrick J. , Ghatei Mohammed A. , Bloom Stephen R. , MacFarlane Ian A. , Wilding John P. H. 
Published: December 2004

Summaryintroduction  Ghrelin is the natural ligand of the growth hormone secretagogue receptor (GHS‐R) and potently stimulates GH release in humans. Ghrelin is found in the hypothalamus, but most circulating ghrelin is derived from the stomach. Ghrelin stimulates food intake but circulating levels are low in obesity. We hypothesized that GH deficiency (GHD) might be associated with increased circulating ghrelin concentrations as a result of low GH levels. We therefore measured circulating ghrelin concentrations, leptin and body composition in subjects with GHD and healthy controls.methods  Subjects with GHD (n = 18) were compared to healthy control subjects (n = 18), matched for body mass index (BMI). They underwent assessment of body composition [waist circumference, BMI and percentage body fat (using bioimpedance)]. Plasma ghrelin, leptin, insulin, GH and IGF‐1 were measured in the fasting state. Plasma ghrelin was measured using a specific radioimmunassay, and the other hormones using commercially available assays.results  The groups were well‐matched for BMI (GHD vs. control; 32·9 ± 10·8 vs. 31·3 ± 11·7, P = ns) and waist circumference (GHD vs. control; 102·9 ± 20·0 vs. 99·8 ± 25·2, P = ns), but percentage body fat (GHD vs. control; 37·0 ± 9·1 vs. 29·4 ± 13·0, P = 0·06) tended to be higher in the GHD group. As expected, IGF‐1 was lower in GHD (GHD vs. control; 12·5 ± 6·8 vs. 19·2 ± 5·8 nmol/l, P = 0·003). Ghrelin [GHD vs. controls; geometric mean (95% CI); 828·8 (95% CI 639·9–1074·2) vs. 487·9 (95% CI 297·2–800·2) pmol/l] and leptin [GHD vs. controls; 13·2 (95% CI 6·6–26·5) vs. 7·9 (95% CI 3·7–16·9) ng/ml] were similar in the two groups. Plasma ghrelin correlated inversely with waist circumference and waist hip ratio in GHD subjects (r = −0·6, P = 0·02) but not with IGF‐1 or GH concentrations. There was no significant correlation in the control subjects.conclusion  Circulating ghrelin concentrations are influenced by body fat distribution, but not by levels of either GH or IGF‐1. However, given that obesity is associated with reduced ghrelin concentrations and that GHD is commonly associated with increased body fat, it is possible that these two opposing influences on circulating ghrelin levels result in normal concentrations in subjects with GHD.
A reappraisal of the Rb1 gene abnormalities in the diagnosis of parathyroid cancer
Authors: Cetani Filomena , Pardi Elena , Viacava Paolo , Pollina Giada Di , Fanelli Giovanni , Picone Antonella , Borsari Simona , Gazzerro Elisabetta , Miccoli Paolo , Berti Piero , Pinchera Aldo , Marcocci Claudio 
Published: December 2004

Summaryobjectives  Some histological features may suggest the malignant nature of a parathyroid tumour. However, the diagnosis of parathyroid cancer can only be definitively established in the presence of local invasion or metastases.design  We further investigated the role of the retinoblastoma gene (Rb1) and the breast cancer susceptibility gene (BRCA2) in the differential diagnosis between benign and malignant parathyroid tumours by evaluating loss of heterozygosity (LOH) at these loci and Rb protein (pRb) immunohistochemistry.patients and measurements  Fifty‐three parathyroid adenomas from patients with sporadic primary hyperparathyroidism (PHPT) and 10 parathyroid cancer specimens were studied. Microsatellite polymorphisms at the Rb1 and BRCA2 loci were polymerase chain reaction (PCR) amplified from each patient's paired tumour and leucocyte DNA samples, using oligonucleotide primers flanking the repeat sequence. Immunohistochemical staining of pRb was carried out using a monoclonal antibody.results  All but one of the 53 tumour–leucocyte pairs was informative for at least one of the three polymorphic markers of the Rb1 gene. Fifteen adenomas (28·8%) showed LOH. Regarding the BRCA2 gene, 46 tumour–leucocyte pairs were informative and LOH was present in eight (17·4%). All six carcinomas had LOH for at least one marker at the Rb1 locus. LOH for the BRCA2 microsatellite was found in three of the five informative primary tumour samples. Immunohistochemical analysis revealed that all adenomas were positive and the number of pRb‐positive cells varied significantly among different samples. The mean percentage of stained cells was 15·7%. Eleven of the 30 (36·7%) adenomas showed sparse positive staining, 13 (43·3%) intermediate staining and six (20%) extensive staining. All parathyroid cancers were entirely negative for pRb immunostaining.conclusions  Inactivation of the Rb1 gene is a common event in parathyroid tumorigenesis. Retention of heterozygosity seems to exclude parathyroid malignancy, which is suggested by the combined finding of LOH and lack of protein expression.
Effect of flutamide and metformin administered alone or in combination in dieting obese women with polycystic ovary syndrome
Authors: Gambineri Alessandra , Pelusi Carla , Genghini Silvia , Morselli‐Labate Antonio Maria , Cacciari Mauro , Pagotto Uberto , Pasquali Renato 
Published: December 2004

Summarybackground  Hyperandrogenism, hyperinsulinaemia and obesity play a key and coordinating roles in the pathogenesis of polycystic ovary syndrome (PCOS), contributing in different ways to the clinical expression of the syndrome. Weight loss is beneficial, but the additional administration of insulin‐lowering drugs, such as metformin, and antiandrogens may produce further benefits, due to their different spectrum of action. The effects of long‐term metformin and flutamide, an antiandrogen drug, added alone or in combination with a low‐calorie diet, on body weight and fat distribution, androgens, metabolic parameters and clinical status in obese women with PCOS were investigated.methods  Forty obese women with PCOS were enrolled in the study. After a 1‐month diet, according to single‐blind design, the patients were allocated to treatment with placebo, metformin (850 mg/orally, twice daily), flutamide (250 mg/orally, twice daily) or metformin (850 mg/orally, twice daily) + flutamide (250 mg/orally, twice daily) for the following 6 months, while continuing hypocaloric dieting. At baseline and at the end of the study, sex hormone, SHBG, lipid, insulin and insulin sensitivity determinations were evaluated. At the same time, clinical parameters such as anthropometry, total (TAT), visceral (VAT) and subcutaneous (SAT) adipose tissue, hirsutism and menses were also measured.results  We found that, in obese PCOS women, following a hypocaloric diet the addition of metformin, flutamide or the combined metformin + flutamide treatment had some specific additional favourable effects with respect to the low‐calorie diet alone. In particular, flutamide treatment seemed to add a significant effect in decreasing visceral fat, androstenedione, DHEA‐S, total and low density lipoprotein (LDL) cholesterol and in improving hirsutism. Conversely, metformin had significant benefits on the menstrual status. The two drugs showed an additive effect in reducing testosterone concentrations and a synergistic effect in increasing high density lipoprotein (HDL) cholesterol and SHBG levels. Improvement of insulin sensitivity and hyperinsulinaemia appeared to depend on hypocaloric diet, without any further significant effect of the pharmacological treatments, either alone or in combination.conclusions  We conclude that, in obese PCOS women, following a hypocaloric diet the addition of metformin, flutamide or the combined metformin + flutamide treatment appears to have a more favourable outcome on body fat distribution, androgens, lipids, hirsutism and menses. However, our data emphasize the dominant role of hypocaloric dieting in improving insulin resistance and hyperinsulinaemia. Therefore, this study provides a rationale for specifically targeting different therapeutical options for PCOS according to the required outcomes.
Insulin resistance and endothelial dysfunction in the brothers of Indian subcontinent Asian women with polycystic ovaries
Authors: Kaushal R. , Parchure N. , Bano G. , Kaski J‐C. , Nussey S. S. 
Published: December 2004

Summarybackground  Ultrasonographic appearances of polycystic ovaries (PCO) are found in 50% of South London Indian subcontinent Asians, a population at high risk of coronary disease and type 2 diabetes (DM). PCO is a familial condition but the genetics remain to be clarified. At present, the only characteristic documented in male family members is premature male pattern balding before the age of 30 years. Our aim was to quantify insulin resistance and endothelial cell function in the brothers of Indian subcontinent Asian women with PCO and/or a family history of type 2 DM.methods  Indian subcontinent Asian women (n = 40, age 16–40 years) with a brother available for study were recruited from the local population. They were stratified into four groups according to the ultrasound appearances of PCO and/or a family history of type 2 DM. Control subjects had no PCO and no family history of DM. Insulin sensitivity (KITT) was measured using a short insulin tolerance test and endothelial function using brachial artery ultrasound to measure flow‐mediated dilatation (FMD).findings  Groups were well matched for age, body mass index (BMI) and waist–hip circumference ratios. Asian women with PCO demonstrated insulin resistance independent of BMI or family history of diabetes. Women with PCO and a family history of DM have reduced FMD, though PCO alone was not a marker. The brothers of women with PCO also have insulin resistance, comparable to that associated with a family history of type 2 DM. This was associated with elevations of blood pressure, abnormalities in serum lipid concentrations and impaired endothelial cell function. Endothelial cell function was particularly impaired in those subjects with both a sister with PCO and a family history of DM.interpretation  In an ethnic minority population at higher risk of coronary heart disease, brothers of women with PCO have evidence of insulin resistance and endothelial cell dysfunction in early adult life. Further study is required to establish whether these findings are associated with an increased incidence of cardiovascular events in this population.