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Showing papers by "John Radcliffe Hospital published in 1999"


Journal ArticleDOI
20 May 1999-Nature
TL;DR: It is indicated that the interaction between HIF-1 and pVHL is iron dependent, and that it is necessary for the oxygen-dependent degradation of HIF α-subunits, which may underlie the angiogenic phenotype of VHL-associated tumours.
Abstract: Hypoxia-inducible factor-1 (HIF-1) has a key role in cellular responses to hypoxia, including the regulation of genes involved in energy metabolism, angiogenesis and apoptosis. The alpha subunits of HIF are rapidly degraded by the proteasome under normal conditions, but are stabilized by hypoxia. Cobaltous ions or iron chelators mimic hypoxia, indicating that the stimuli may interact through effects on a ferroprotein oxygen sensor. Here we demonstrate a critical role for the von Hippel-Lindau (VHL) tumour suppressor gene product pVHL in HIF-1 regulation. In VHL-defective cells, HIF alpha-subunits are constitutively stabilized and HIF-1 is activated. Re-expression of pVHL restored oxygen-dependent instability. pVHL and HIF alpha-subunits co-immunoprecipitate, and pVHL is present in the hypoxic HIF-1 DNA-binding complex. In cells exposed to iron chelation or cobaltous ions, HIF-1 is dissociated from pVHL. These findings indicate that the interaction between HIF-1 and pVHL is iron dependent, and that it is necessary for the oxygen-dependent degradation of HIF alpha-subunits. Thus, constitutive HIF-1 activation may underlie the angiogenic phenotype of VHL-associated tumours. The pVHL/HIF-1 interaction provides a new focus for understanding cellular oxygen sensing.

4,845 citations


Journal ArticleDOI
TL;DR: It is shown that interleukin (IL)-10 is an essential mediator of the regulatory functions of the CD45RBlow population, providing the first clear evidence that IL-10 plays a nonredundant role in the functioning of regulatory T cells that control inflammatory responses towards intestinal antigens.
Abstract: A T helper cell type 1–mediated colitis develops in severe combined immunodeficient mice after transfer of CD45RBhigh CD4+ T cells and can be prevented by cotransfer of the CD45RBlow subset. The immune-suppressive activities of the CD45RBlow T cell population can be reversed in vivo by administration of an anti-transforming growth factor β antibody. Here we show that interleukin (IL)-10 is an essential mediator of the regulatory functions of the CD45RBlow population. This population isolated from IL-10–deficient (IL-10−/−) mice was unable to protect from colitis and when transferred alone to immune-deficient recipients induced colitis. Treatment with an anti–murine IL-10 receptor monoclonal antibody abrogated inhibition of colitis mediated by wild-type (WT) CD45RBlow CD4+ cells, suggesting that IL-10 was necessary for the effector function of the regulatory T cell population. Inhibition of colitis by WT regulatory T cells was not dependent on IL-10 production by progeny of the CD45RBhigh CD4+ cells, as CD45RBlow CD4+ cells from WT mice were able to inhibit colitis induced by IL-10−/− CD45RBhigh CD4+ cells. These findings provide the first clear evidence that IL-10 plays a nonredundant role in the functioning of regulatory T cells that control inflammatory responses towards intestinal antigens.

1,639 citations


Journal ArticleDOI
01 Jul 1999-Nature
TL;DR: It is shown that intact malaria-infected erythrocytes adhere to dendritic cells, inhibit the maturation of dendedritic cells and subsequently reduce their capacity to stimulate T cells, demonstrating both a novel mechanism by which malaria parasites induce immune dysregulation and a functional role beyond endothelial adhesion for the adhesive phenotypes expressed at the surface of infected ery Throcytes.
Abstract: The malaria parasite Plasmodium falciparum is one of the most successful human pathogens. Specific virulence factors remain poorly defined, although the adhesion of infected erythrocytes tothe venular endothelium has been associated with some of thesyndromes of severe disease1. Immune responses cannot prevent the development of symptomatic infections throughout life, and clinical immunity to the disease develops only slowly during childhood. An understanding of the obstacles to the development of protective immunity is crucial for developing rational approaches to prevent the disease. Here we show that intact malaria-infected erythrocytes adhere to dendritic cells, inhibit the maturation of dendritic cells and subsequently reduce their capacity to stimulate T cells. These data demonstrate both a novel mechanism by which malaria parasites induce immune dysregulation and a functional role beyond endothelial adhesion for the adhesive phenotypes expressed at the surface of infected erythrocytes.

625 citations


Journal Article
TL;DR: It is inferred that direct T cell control of viral replicative lesions is maintained in long term carriers of EBV and is an important component of the immune response to this virus.
Abstract: EBV is a gammaherpesvirus that can establish both nonproductive (latent) and productive (lytic) infections within the cells of its host. Although T cell responses to EBV latent proteins have been well characterized, little is known about the importance of responses to lytic proteins in long term virus carriers. Here we have compared the frequencies of CD8+ T cells specific for EBV latent and lytic Ags in healthy virus carriers, using three techniques: limiting dilution analysis, enzyme-linked immunospot assay, and FACS staining with tetrameric MHC-peptide complexes. T cells specific for EBV lytic protein epitopes were readily detectable in all donors and were usually more abundant than those specific for latent epitopes. We infer that direct T cell control of viral replicative lesions is maintained in long term carriers of EBV and is an important component of the immune response to this virus. Estimates of CD8+ T cell frequencies varied considerably according to methodology; values obtained from MHC-peptide tetramer staining were, on the average, 4.4-fold higher than those obtained from enzyme-linked immunospot assays, which were, in turn, on the average, 5.3-fold higher than those obtained from limiting dilution analysis. Tetramer staining showed that as many as 5.5% circulating CD8+ T cells in a virus carrier were specific for a single EBV lytic protein epitope. Such values are much greater than previously imagined and illustrate how antigenic challenge from a persistent herpesvirus can influence the composition of the host's CD8+ T cell pool.

537 citations


Journal ArticleDOI
TL;DR: High frequencies of naive Melan-A–specific CD8+ T cells can be found in a large proportion of HLA-A*0201+ individuals, and as demonstrated for one patient followed over time, dramatic phenotype changes of circulating Melan–A-specific cells can occur in vivo.
Abstract: Using fluorescent HLA-A*0201 tetramers containing the immunodominant Melan-A/MART-1 (Melan-A) tumor-associated antigen (Ag), we previously observed that metastatic lymph nodes of melanoma patients contain high numbers of Ag-experienced Melan-A–specific cytolytic T lymphocytes (CTLs). In this paper, we enumerated and characterized ex vivo Melan-A–specific cells in peripheral blood samples from both melanoma patients and healthy individuals. High frequencies (≥1 in 2,500 CD8+ T cells) of Melan-A–specific cells were found in 10 out of 13 patients, and, surprisingly, in 6 out of 10 healthy individuals. Virtually all Melan-A–specific cells from 6 out of 6 healthy individuals and from 7 out of 10 patients displayed a naive CD45RAhi/RO− phenotype, whereas variable proportions of Ag-experienced CD45RAlo/RO+ Melan-A–specific cells were observed in the remaining 3 patients. In contrast, ex vivo influenza matrix–specific CTLs from all individuals exhibited a CD45RAlo/RO+ memory phenotype as expected. Ag specificity of tetramer-sorted A2/Melan-A+ cells from healthy individuals was confirmed after mitogen-driven expansion. Likewise, functional limiting dilution analysis and interferon γ ELISPOT assays independently confirmed that most of the Melan-A–specific cells were not Ag experienced. Thus, it appears that high frequencies of naive Melan-A–specific CD8+ T cells can be found in a large proportion of HLA-A*0201+ individuals. Furthermore, as demonstrated for one patient followed over time, dramatic phenotype changes of circulating Melan-A–specific cells can occur in vivo.

507 citations


Journal ArticleDOI
TL;DR: Owing to the high prevalence of familial cases, screening for subtle chromosomal rearrangements is warranted in children with unexplained moderate to severe mental retardation.

477 citations


Journal ArticleDOI
TL;DR: It is suggested that aggressive tumours rapidly outgrow their vascular supply in certain areas, leading to areas of prolonged hypoxia within the tumour and, subsequently, to necrosis.
Abstract: Necrosis is a common feature of invasive carcinoma of the breast and is caused by chronic ischaemia leading to infarction Although necrosis was previously assumed to be due to a generally poor blood supply in the tumour, in this study we show that it is present in tumours with focal areas of high vascular density situated away from the actual sites of necrosis This may account, in part, for the previous observation that necrosis is linked to poor prognosis in this disease Highly angiogenic tumours often display blood vessel shunting from one tumour area to another, which further exacerbates ischaemia and the formation of tumour necrosis We have recently demonstrated that high focal microphage infiltration into breast tumours is significantly associated with increased tumour angiogenesis and poor prognosis and that the macrophages accumulate in poorly vascularized, hypoxic areas within breast tumours In order to investigate the interactions of macrophages with chronic ischaemia (as reflected by the presence of necrosis) and angiogenesis in breast tumours, we quantified the levels of these three biological parameters in a series of 109 consecutive invasive breast carcinomas We found that the degree of tumour necrosis was correlated with both microphage infiltration (Mann-Whitney U, P-value = 00009; chi-square, P-value = 001) and angiogenesis (Mann-Whitney U P-value = 00008, chi square P-value = 003) It was also observed that necrosis was a feature of tumours possessing an aggressive phenotype, ie high tumour grade (chi-square, P-value < 0001), larger size (Mann-Whitney U, P-value = 0003) and low oestrogen receptor status (Mann-Whitney U, P-value = 0008; chi-square, P-value < 0008) We suggest, therefore, that aggressive tumours rapidly outgrow their vascular supply in certain areas, leading to areas of prolonged hypoxia within the tumour and, subsequently, to necrosis This, in turn, may attract macrophages into the tumour, which then contribute to the angiogenic process, giving rise to an association between high levels of angiogenesis and extensive necrosis

459 citations


Journal ArticleDOI
TL;DR: Gavin Sacks and colleagues draw attention to substantial and contrasting changes in the maternal innate system and hypothesize that its function and that of monocytes in particular, has a central role in the mothers-fetal relationship.

439 citations


Journal ArticleDOI
TL;DR: Elevated plasma cytokines in severe malaria are associated with systemic pathologic abnormalities, not cerebral involvement, and both the overall magnitude of the cytokine responses and the eventual imbalance between the pro- and antiinflammatory responses are important determinants of mortality.
Abstract: Pro- and antiinflammatory cytokines were measured on admission in 287 consecutive Vietnamese adults with severe falciparum malaria. Plasma interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-alpha concentrations and the IL-6: IL-10 ratio were significantly higher in patients who died than in survivors (P<.001). On multivariate analysis, hyperparasitemia, jaundice, and shock were all associated independently with raised IL-6, IL-10, and interferon-gamma, and acute renal failure specifically with raised TNF-alpha levels. Cerebral malaria patients, particularly those without other vital organ dysfunction, had significantly lower levels of these cytokines (P=.006), reflecting a more localized pathology. Serial IL-6 and IL-10 measurements made on 43 patients who died and matched survivors indicated a relative deficiency in IL-10 production as death approached. Elevated plasma cytokines in severe malaria are associated with systemic pathologic abnormalities, not cerebral involvement. Both the overall magnitude of the cytokine responses and the eventual imbalance between the pro- and antiinflammatory responses are important determinants of mortality.

430 citations


Journal ArticleDOI
TL;DR: Intermittent presumptive treatment with sulphadoxine-pyrimethamine is an effective, practicable strategy to decrease the risk of severe anaemia in primigravid women living in malarious areas.

402 citations


Journal ArticleDOI
TL;DR: It is shown that, after infection with HTLV-I, the class I allele HLA-A*02 halves the odds of HAM/TSP, implying that an efficient antiviral CTL response can reduce virus load and so prevent disease in persistent virus infections.
Abstract: The risk of disease associated with persistent virus infections such as HIV-I, hepatitis B and C, and human T-lymphotropic virus-I (HTLV-I) is strongly determined by the virus load. However, it is not known whether a persistent class I HLA-restricted antiviral cytotoxic T lymphocyte (CTL) response reduces viral load and is therefore beneficial or causes tissue damage and contributes to disease pathogenesis. HTLV-I-associated myelopathy (HAM/TSP) patients have a high virus load compared with asymptomatic HTLV-I carriers. We hypothesized that HLA alleles control HTLV-I provirus load and thus influence susceptibility to HAM/TSP. Here we show that, after infection with HTLV-I, the class I allele HLA-A*02 halves the odds of HAM/TSP (P < 0.0001), preventing 28% of potential cases of HAM/TSP. Furthermore, HLA-A*02+ healthy HTLV-I carriers have a proviral load one-third that (P = 0.014) of HLA-A*02− HTLV-I carriers. An association of HLA-DRB1*0101 with disease susceptibility also was identified, which doubled the odds of HAM/TSP in the absence of the protective effect of HLA-A*02. These data have implications for other persistent virus infections in which virus load is associated with prognosis and imply that an efficient antiviral CTL response can reduce virus load and so prevent disease in persistent virus infections.

Journal ArticleDOI
TL;DR: It is found that FAP patients with germline APC mutations within a small region mainly show allelic loss in their colorectal adenomas, in contrast to other F AP patients, whose 'second hits' tend to occur by truncating mutations in the mutation cluster region.
Abstract: APC is often cited as a prime example of a tumor suppressor gene. Truncating germline and somatic mutations (or, infrequently, allelic loss) occur in tumors in FAP (familial adenomatous polyposis). Most sporadic colorectal cancers also have two APC mutations1. Clues from attenuated polyposis2, 3, 4, missense germline variants with mild disease5, 6 and the somatic mutation cluster region (codons 1,250−1,450)1, 7, 8 indicate, however, that APC mutations might not result in simple loss of protein function. We have found that FAP patients with germline APC mutations within a small region (codons 1,194−1,392 at most) mainly show allelic loss in their colorectal adenomas, in contrast to other FAP patients, whose 'second hits' tend to occur by truncating mutations in the mutation cluster region. Our results indicate that different APC mutations provide cells with different selective advantages, with mutations close to codon 1,300 providing the greatest advantage. Allelic loss is selected strongly in cells with one mutation near codon 1,300. A different germline−somatic APC mutation association exists in FAP desmoids. APC is not, therefore, a classical tumor suppressor. Our findings also indicate a new mechanism for disease severity: if a broader spectrum of mutations is selected in tumors, the somatic mutation rate is effectively higher and more tumors grow.

Journal ArticleDOI
TL;DR: The evidence for macrophage responses to hypoxia, the involvement of co‐stimuli, and their implications for the role of macrophages in various disease processes are reviewed.
Abstract: Macrophages are ubiquitous in the stromal compartment of tissues under normal physiological conditions and the number of these cells increases markedly with the onset and progression of many pathological states. The mechanisms underlying this response are well described in such conditions as wound healing and malignant tumors, where tissue-specific signals enhance the extravasation of blood monocytes and their subsequent differentiation into macrophages. Recent evidence suggests that macrophages may also be stimulated by microenvironmental factors present in diseased tissues to perform distinct, tissue-specific activities. One such factor, hypoxia (low oxygen tension), results from insufficient vascular perfusion of a given tissue. Various studies have shown that experimental hypoxia alters the morphology, expression of cell surface markers, viability, phagocytosis, metabolic activity, and release of cytokines by macrophages. Here we review the evidence for these macrophage responses to hypoxia, the involvement of co-stimuli, and their implications for the role of macrophages in various disease processes. Because the intracellular mechanisms mediating the effects of hypoxia on gene expression in other cell types have been characterized recently, we discuss their possible involvement in the effects of hypoxia on gene expression in macrophages.

Journal ArticleDOI
TL;DR: These recent advances provide for the identification of mutant MEN1 gene carriers who are at a high risk of developing this disorder and thus require regular and biochemical screening to detect the development of endocrine tumours.
Abstract: Combined clinical and laboratory investigations of multiple endocrine neoplasia type 1 (MEN1) have resulted in an increased understanding of this disorder which may be inherited as an autosomal dominant condition. Defining the features of each disease manifestation in MEN1 has improved patient management and treatment, and has also facilitated a screening protocol to be instituted. The application of the techniques of molecular biology has enabled the identification of the gene causing MEN1 and the detection of mutations in patients. The function of the protein encoded by the MEN1 gene has been shown to be in the regulation of JunD-mediated transcription but much still remains to be elucidated. However, these recent advances provide for the identification of mutant MEN1 gene carriers who are at a high risk of developing this disorder and thus require regular and biochemical screening to detect the development of endocrine tumours.

Journal ArticleDOI
TL;DR: P. vivax malaria during pregnancy is associated with maternal anaemia and low birthweight, and antimalarial prophylaxis against P.vivax in pregnancy may be justified.

Journal ArticleDOI
TL;DR: FMRI data suggest that the perceptual improvements effected by synthesizing matched multisensory inputs are realised by reciprocal amplification of the signal intensity in participating unimodal cortices.
Abstract: Integrating information across the senses can enhance our ability to detect and classify stimuli in the environment. For example, auditory speech perception is substantially improved when the speaker's face is visible. In an fMRI study designed to investigate the neural mechanisms underlying these crossmodal behavioural gains, bimodal (audio-visual) speech was contrasted against both unimodal (auditory and visual) components. Significant response enhancements in auditory (BA 41/42) and visual (V5) cortices were detected during bimodal stimulation. This effect was found to be specific to semantically congruent crossmodal inputs. These data suggest that the perceptual improvements effected by synthesizing matched multisensory inputs are realised by reciprocal amplification of the signal intensity in participating unimodal cortices.

Journal ArticleDOI
TL;DR: Children and young people with insulin dependent diabetes still have an increased mortality compared with the general population Diabetic ketoacidosis is the leading cause of death, particularly if it is complicated by cerebral oedema Hypoglycaemia is a rare cause ofdeath even in those dying unexpectedly at home
Abstract: BACKGROUND Mortality rates in children with insulin dependent diabetes (IDDM) in the UK are unknown and the causes of death not well documented. AIM To determine the mortality rate and causes of death in children with IDDM. METHODS The Office of National Statistics (England and Wales) and the General Register Office (Scotland) notified all deaths under 20 years of age from 1990 to 1996 with diabetes on the certificate. Further details were provided by coroners, pathologists, and clinicians. RESULTS 116 deaths were notified and 83 were caused by diabetes. The standardised mortality ratio was 2.3 (95% confidence interval (CI), 1.9 to 2.9), being highest in the age group 1–4 years, at 9.2 (95% CI, 5.4 to 14.7). Of the 83 diabetic deaths, hyperglycaemia/diabetic ketoacidosis (DKA) was implicated in 69 and hypoglycaemia in 7. Cerebral oedema was the most common cause of death in young children (25 of 36 diabetes related deaths in children under 12 years of age). 34 young people (10–19 years; 24 male) were either found dead at home (n = 26) or moribund on arrival at hospital (n = 8). In 24 of these, it appeared that DKA was the cause of death, in four hypoglycaemia was likely. Nine of these were found “dead in bed”. CONCLUSIONS Children with IDDM have a higher mortality than the general population. Cerebral oedema accounts for most hospital deaths in young children. There are a large number of young men dying at home from neglected IDDM. Early diagnosis of IDDM in children and closer supervision of young people might prevent some of these deaths. Key messages Children and young people with insulin dependent diabetes still have an increased mortality compared with the general population Diabetic ketoacidosis is the leading cause of death, particularly if it is complicated by cerebral oedema Hypoglycaemia is a rare cause of death even in those dying unexpectedly at home

Journal ArticleDOI
TL;DR: It is shown that a second gene family, rif, which is associated with var at subtelomeric sites in the genome, encodes clonally variant proteins (rifins) that are expressed on the infected red cell surface, indicating an important role for rifins in malaria host-parasite interaction.
Abstract: Many pathogens evade the host immune response or adapt to their environment by expressing surface proteins that undergo rapid switching. In the case of Plasmodium falciparum, products of a multigene family known as var are expressed on the surface of infected red cells, where they undergo clonal antigenic variation and contribute to malaria pathogenesis by mediating adhesion to a variety of host endothelial receptors and to uninfected red blood cells by forming rosettes. Herein we show that a second gene family, rif, which is associated with var at subtelomeric sites in the genome, encodes clonally variant proteins (rifins) that are expressed on the infected red cell surface. Their high copy number, sequence variability, and red cell surface location indicate an important role for rifins in malaria host–parasite interaction.

Journal ArticleDOI
TL;DR: This study provides the first ex vivo evidence that the highest frequency of circulating HBV-specific CD8 cells coincides with the clinically acute phase of hepatitis B and exhibits an activated phenotype with limited further proliferative capacity that is restored during recovery.

Journal ArticleDOI
01 Dec 1999-Immunity
TL;DR: A unique role is defined in the generation of optimal CD4+ T cell responses in vivo by finding that the formation of extrafollicular plasma cells, germinal centers, and antibody responses was independent of OX40.

Journal ArticleDOI
05 Aug 1999-Nature
TL;DR: The sub-telomeric regions of chromosome 3 show a conserved order of features, including repetitive DNA sequences, members of multigene families involved in pathogenesis and antigenic variation, a number of conserved pseudogenes, and several genes of unknown function.
Abstract: Analysis of Plasmodium falciparum chromosome 3, and comparison with chromosome 2, highlights novel features of chromosome organization and gene structure. The sub-telomeric regions of chromosome 3 show a conserved order of features, including repetitive DNA sequences, members of multigene families involved in pathogenesis and antigenic variation, a number of conserved pseudogenes, and several genes of unknown function. A putative centromere has been identified that has a core region of about 2 kilobases with an extremely high (adenine + thymidine) composition and arrays of tandem repeats. We have predicted 215 protein-coding genes and two transfer RNA genes in the 1,060,106-base-pair chromosome sequence. The predicted protein-coding genes can be divided into three main classes: 52.6% are not spliced, 45.1% have a large exon with short additional 5' or 3' exons, and 2.3% have a multiple exon structure more typical of higher eukaryotes.

Journal Article
TL;DR: It is shown that free HLA-B27 heavy chains can form a disulfide-bonded homodimer, dependent on residue Cys67 in their extracellular alpha 1 domain, which might explain the ability of HLA -B27 to induce spondyloarthropathy in beta 2-microglobulin-deficient mice.
Abstract: HLA-B27 has a striking association with inflammatory arthritis. We show that free HLA-B27 heavy chains can form a disulfide-bonded homodimer, dependent on residue Cys67 in their extracellular alpha 1 domain. Despite the absence of beta 2-microglobulin, HLA-B27 heavy chain homodimers (termed HC-B27) were stabilized by a known peptide epitope. HC-B27 complexes were recognized by the conformation-specific Ab W6/32, but not the ME1 Ab. Surface labeling and immunoprecipitation demonstrated the presence of similar W6/32-reactive free heavy chains at the surface of HLA-B27-transfected T2 cells. HC-B27 homodimer formation might explain the ability of HLA-B27 to induce spondyloarthropathy in beta 2-microglobulin-deficient mice.

Journal ArticleDOI
01 May 1999-Blood
TL;DR: The present cases of ALCL associated with a novel t(1;2)(q25;p23) translocation demonstrate that at least one fusion partner other than NPM can activate the intracytoplasmic domain of the ALK kinase.

Journal ArticleDOI
TL;DR: This review examines colorectal cancer as a classical example of multistep carcinogenesis and examines the mutations that comprise these pathways and the possible functional sequelae of these are explored.

Journal ArticleDOI
01 Mar 1999-Immunity
TL;DR: Evidence that the TCR and/or peptide-MHC have flexible binding surfaces that are stabilized upon binding is reported, which is likely to contribute to cross-reactivity in antigen recognition.

Journal ArticleDOI
TL;DR: An increase in BMI from adolescence to adulthood was associated with higher levels of concern over shape and weight and more intense dietary restraint, especially among females, and may contribute to poor glycemic control and to risk of complications.
Abstract: OBJECTIVE: To examine disordered eating, insulin misuse, weight change, and their relationships with glycemic control and diabetic complications in adolescents with type 1 diabetes followed up over eight years. RESEARCH DESIGN AND METHODS: Of 76 adolescents (43 male, 33 female) with type 1 diabetes aged 11-18 years at the first assessment, 65 were interviewed as young adults (aged 20-28 years). Eating habits were assessed using a standardized Eating Disorder Examination. Height and weight were determined and BMI calculated. Three consecutive urine specimens were collected for measurement of albumin/creatinine ratio and other significant diabetic complications were recorded. Glycemic control was assessed by glycated hemoglobin. RESULTS: Weight and BMI increased from adolescence to young adulthood. Females were overweight as adolescents and both sexes were overweight as young adults. Concern over weight and shape increased significantly for both sexes from adolescence to young adulthood. This increase in concern was reflected in increased levels of dietary restraint. Features of disordered eating were apparent in females at both assessments, but no patients met the criteria for anorexia nervosa or bulimia nervosa at either assessment. A total of 10 (30%) females, but none of the males admitted underusing insulin to control weight. Five (45%) females with microvascular complications had intentionally misused insulin to prevent weight gain. CONCLUSIONS: An increase in BMI from adolescence to adulthood was associated with higher levels of concern over shape and weight and more intense dietary restraint, especially among females. Overt eating disorders were no more prevalent in these patients than in the general population, but milder forms of disordered eating were common and had implications for diabetes management. Insulin omission for weight control was frequent among females and may contribute to poor glycemic control and to risk of complications.

Journal ArticleDOI
TL;DR: The role that interleukin 10 cells play in the regulation of immune responses to enteric antigens is discussed and a deficiency in these cells might be involved in the pathogenesis of inflammatory bowel disease.

Journal ArticleDOI
TL;DR: Direct ex vivo visualization of mHag-specific CTLs during GvHD using tetrameric HLA-class and I-mHag HA-1 and HY peptide complexes is shown.
Abstract: Graft-versus-host disease (GvHD) is a chief complication of allogeneic bone marrow transplantation1. In HLA-identical bone marrow transplantation, GvHD may be induced by disparities in minor histocompatibility antigens (mHags) between the donor and the recipient, with the antigen being present in the recipient and not in the donor2. Cytotoxic T lymphocytes (CTLs) specific for mHags of the recipients can be isolated from the blood of recipients with severe GvHD (ref. 3). A retrospective study demonstrated an association between mismatch for mHags HA-1, -2, -4 and -5 and the occurrence of GvHD in adult recipients of bone marrow from HLA genotypically identical donors4. Tetrameric HLA-peptide complexes have been used to visualize and quantitate antigen-specific CTLs in HIV-infected individuals and during Epstein-Barr virus and lymphocytic choriomeningitis virus infections5,6,7,8. Here we show the direct ex vivo visualization of mHag-specific CTLs during GvHD using tetrameric HLA-class and I-mHag HA-1 and HY peptide complexes. In the peripheral blood of 17 HA-1 or HY mismatched marrow recipients, HA-1- and HY-specific CTLs were detected as early as 14 days after bone marrow transplantation. The tetrameric complexes demonstrated a significant increase in HA-1- and HY-specific CTLs during acute and chronic GvHD, which decreased after successful GvHD treatment. HLA class I–mHag peptide tetramers may serve as clinical tools for the diagnosis and monitoring of GvHD patients.

Journal ArticleDOI
TL;DR: Ian Tomlinson and Walter Bodmer point out that an increased mutation rate does not necessarily cause a tumor to grow and that selection is in fact the mechanism that drives the cellular, somatic evolution that leads to cancer.
Abstract: In considering tumorigenesis, much attention is paid to genome instability and mutation rates. While reflecting on the circumstances that have led to this emphasis on mutation rates, Ian Tomlinson and Walter Bodmer point out that an increased mutation rate does not necessarily cause a tumor to grow and that selection is in fact the mechanism that drives the cellular, somatic evolution that leads to cancer.

Journal ArticleDOI
TL;DR: The relationship between pfmdr1 and resistance to structurally distinct antimalarial agents confirms the presence of a true multidrug-resistant phenotype.
Abstract: On the western border of Thailand, Plasmodium falciparum has become resistant to almost all antimalarial agents. The molecular basis of resistance in these parasite populations has not been well characterized. This study assessed genetic polymorphisms in the pfmdr1 gene in 54 parasites collected from the western border of Thailand to determine the relationship of pfmdr1 copy number and codon mutations with parasite sensitivities to mefloquine, chloroquine, halofantrine, quinine, and artesunate assessed in vitro. A point mutation at codon 86 (resulting in a change of Asn to Tyr) was associated with a significantly lower 50% inhibitory concentration (IC(50)) of mefloquine (median, 9 ng/ml versus 52.4 ng/ml; P = 0.003). Overall 35% of the isolates (19 of 54) had an increase in pfmdr1 copy number, and all 19 carried the wild-type allele at codon 86. Increased pfmdr1 copy number was associated with higher IC(50)s of mefloquine (P = 0.04) and artesunate (P = 0.005), independent of polymorphism at codon 86. The relationship between pfmdr1 and resistance to structurally distinct antimalarial agents confirms the presence of a true multidrug-resistant phenotype.