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Results for “Phenotype modifier”

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PubMed1996

Phenotypic and quantitative changes in mast cells after syngeneic unilateral lung transplantation in the rat.

1. Lung transplantation causes a total interruption of the inneration and vascularization within the transplanted organ, followed by repair processes. This is frequently associated with bronchial hyper-responsiveness. A common feature of tissue repair is an increase in the number of mast cells. Three phenotypically distinct mast cell subsets, with respect to their protease content, have been identified in rat lung, and it is probable that mast cells of differing protease phenotype fulfil different functions. 2. We have compared the number, protease phenotype and distribution of mast cells in left lung from transplanted and control Lewis rats 1 month after syngeneic unilateral left lung transplantation, without interference of inflammation, graft rejection or of any treatment. Connective and mucosal-type mast cell phenotypes were characterized using antibodies directed against their specific rat mast cell proteases, RMCPI and RMCPII, respectively. 3. After transplantation, RMCPI and RMCPII tissue concentrations increased by 172% and 239%, respectively, compared with controls (13.1 +/- 1.2 and 5.6 +/- 1.0 micrograms/g). 4. Localization of mast cell phenotypes was studied by immunohistochemistry after double immunostaining. The number of mast cells increased after transplantation: the increase in the number of RMCPI-immunoreactive mast cells (RMCPI+) was significant around bronchioles and arterioles, around large vessels and in the pleura. The number of RMCPII+ mast cells also significantly increased around bronchioles and arterioles, as well as in the smooth muscle layer of large airways. Some mast cells stained for the presence of both RMCPI and RMCPII, supporting the existence of co-expressing phenotype in rat lung. The number of mast cells of the RMCPI+/II+ phenotype significantly increased around bronchioles and arterioles and in the pleura. Moreover, the distribution of the mast cell phenotypes was modified in the different areas after transplantation. 5. This indicates a local differentiation/maturation of mast cells after transplantation.

Animals↗

PubMed2005

Creutzfeldt-Jakob disease (CJD) with a mutation at codon 148 of prion protein gene: relationship with sporadic CJD.

Creutzfeldt-Jakob disease (CJD), the most common human prion disease, includes sporadic (s) and familial (f) forms. Regardless of etiology, both forms are thought to share the pathogenic mechanism whereby the cellular prion protein (PrP(C)) converts into its pathogenic isoform (PrP(Sc)). While PrP(C) conversion is thought to be random in sCJD, conversion in fCJD is facilitated by the congenital presence of mutated PrP. Differences in PrP genotype (PRNP) and in conversion circumstances lead to PrP(Sc) with distinct characteristics that elicit different disease phenotypes. Here, we describe a case of fCJD with a substitution of histidine (H) for arginine (R) at codon 148 (R148H) and heterozygosity of the methionine/valine (M/V) polymorphic codon 129, with the 129M allele coupled with the mutation. The disease phenotype and all major characteristics of PrP(Sc) of fCJD(R148H) were virtually indistinguishable from those of sCJDMV2, which has features different from those of any other sCJD. Therefore, despite the differences in etiology, PRNP, and conversion process, the two forms of PrP(Sc) had similar characteristics. Furthermore, comparison of fCJD(R148H) with a recently reported case carrying R148H and homozygosity at codon 129 suggests that codon 129 coupled with the mutation as well as that located on the normal allele can modify major phenotypic and PrP(Sc) features of fCJD(R148H).

Amino Acid Substitution↗

PubMed2003

Generation of dendritic cells from CD14+ monocytes positively selected by immunomagnetic adsorption for multiple myeloma patients enrolled in a clinical trial of anti-idiotype vaccination.

Circulating monocytes from multiple myeloma patients enrolled in a clinical study of anti-idiotype vaccination were labelled with clinical-grade anti-CD14 microbeads and positively selected with the CliniMACS instrument. Cells were then grown, according to good manufacturing practice guidelines, in fetal-calf-serum-free medium in cell culture bags and differentiated to dendritic cells (DC) with granulocyte-macrophage colony stimulating factor plus interleukin 4 (IL-4), followed by either tumour necrosis factor-alpha (TNF-alpha) or a cocktail of IL-1beta, IL-6, TNF-alpha and prostaglandin-E2. The CD14+ cell yield was increased from 17.6 +/- 6.5% to 93.8 +/- 6.3% (recovery 64.4 +/- 15.4%, viability > 97%). After cell culture, phenotypic analysis showed that 86.7 +/- 6.8% of the cells were DC: 2.27 +/- 0.9 x 108 DC/leukapheresis were obtained, which represented 20.7 +/- 4.6% of the initial number of CD14+ cells. Notably, the cytokine cocktail induced a significantly higher percentage and yield (28.6 +/- 3% of initial CD14+ cells) of DC than TNF-alpha alone, with secretion of larger amounts of IL-12, potent stimulatory activity on allogeneic T cells and efficient presentation of tumour idiotype to autologous T cells. Storage in liquid nitrogen did not modify the phenotype or functional characteristics of preloaded DC. The recovery of thawed, viable DC was 78 +/- 10%. Finally, interferon-alpha-2b was at least as efficient as IL-4 in inducing the differentiation of mature, functional DC from monocytes.

Antibodies, Anti-Idiotypic↗

PubMed1995

Changes in the concentrations of extracellular Mg++ and Ca++ down-regulate E-cadherin and up-regulate alpha 2 beta 1 integrin function, activating keratinocyte migration on type I collagen.

We have demonstrated recently that shifts in the concentrations of extracellular Mg++ and Ca++ occur during cutaneous injury in vivo. These shifts correlate well with the timing of migration of various cell types involved in wound healing, including keratinocytes. In the present study, we examined the potential of such cation shifts to activate the keratinocyte migratory phenotype. In modified Boyden chamber migration assays, alpha 2 beta 1 integrin-mediated migration of human keratinocytes (HaCaT) on type I collagen was supported by Mg++ but not by Ca++ alone. Migration could be increased up to twofold, however, by using both cations in combination, as long as the Mg++ concentration was in the optimal range for migration in Mg++ only (1-3 mM) and Ca++ was present at concentrations of approximately 0.1-1 mM. Further examination of this divalent-cation-induced migratory keratinocyte phenotype demonstrated that, as Mg++ is elevated and Ca++ is reduced, mature E-cadherin and cell-cell contacts are reduced and the alpha 2 beta 1 integrin is redistributed from cell-cell contacts to the periphery. These in vitro observations corroborate what occurs in vivo at the keratinocyte migrating front during wound healing. Together these data suggest that changes in the concentrations of extracellular Mg++ and Ca++ can regulate the competitive interplay between Ca(++)-dependent E-cadherin-mediated and Mg(++)-dependent alpha 2 beta 1-integrin-mediated adhesion, promoting the development of an activated keratinocyte phenotype.

Antigens, CD↗

PubMed2006

Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes.

BACKGROUND: Kallmann's syndrome (KS) is a clinically and genetically heterogeneous disorder consisting of idiopathic hypogonadotropic hypogonadism (IHH) and anosmia. Mutations in KAL1 causing the X-linked form of KS have been identified in 10% of all KS patients and consistently result in a severe reproductive phenotype. KAL1 gene encodes for anosmin-1, a key protein involved in olfactory and GnRH neuronal migration through a putative interaction with FGFR1. Heterozygous mutations in the FGFR1 gene accompanied by a high frequency of cleft palate and other facial dysmorphisms were recently identified in 8% of a large KS cohort, yet the reproductive phenotype of KS patients harboring FGFR1 mutations has not been described. RESULTS: One hundred and fifty probands with KS (130 males and 20 females) were studied to determine the frequency and distribution of FGFR1 mutations and their detailed reproductive phenotypes. Fifteen heterozygous mutations in unrelated probands were identified. Twelve missense mutations (p.R78C, p.V102I, p.D224H, p.G237D, p.R254Q, p.V273M, p.E274G, p.Y339C, p.S346C, p.I538V, p.G703S and p.G703R) were distributed among the first, second and third immunoglobulin-like domains (D1-D3), as well as the tyrosine kinase domain (TKD). The mutations Y339C and S346C are located in exon 8B and code for the isoform FGFR1c. Additionally, two nonsense mutations (p.T585X and p.R622X) were documented in the TKD of the protein. A wide spectrum of reproductive function was observed among KS probands including: (1) a severe phenotype demonstrated by microphallus, cryptorchidism, no pubertal development, undetectable serum gonadotropins and low serum testosterone (T) and inhibin B; (2) partial pubertal development; (3) the fertile eunuch variant of IHH with normal testicular size and active spermatogenesis with a reversal of HH after T therapy. In addition, we found an even wider spectrum of reproductive function within pedigrees carrying an FGFR1 mutation ranging from IHH to delayed puberty to normal reproductive function (anosmia only or asymptomatic carriers). These observations strongly suggest a role for other genes that modify the phenotype of FGFR1 mutations. CONCLUSION: KS patients and family members carrying an FGFR1 mutation present a broad spectrum of pubertal development in contrast to the almost uniform severe clinical phenotype described in KS subjects with a KAL1 mutation. Additionally, this report implicates the isoform FGFR1c in the pathogenesis of KS.

Adolescent↗

PubMed1990

Modulation of the antigenic phenotype of early-passage human melanoma cells derived from multiple autologous metastases by recombinant human leukocyte, fibroblast and immune interferon.

We have investigated the relationship between in vitro cultivation of autologous melanoma metastases derived from different patients and their levels of expression of class-I and -II major histocompatibility complex (MHC) antigens and melanoma-associated antigens (MAAs). Cell cultures were established from 23 individual metastatic melanoma lesions from 10 patients and were tested early after isolation (between 3rd and 10th passages) for both constitutive expression and modulation by recombinant human leukocyte (IFN-alpha), fibroblast (IFN-beta) or immune (IFN-gamma) interferon of MHC antigens and MAA. All of the melanoma cell lines displayed altered antigen expression following IFN treatment. While in vitro cultures derived from different individuals varied in both constitutive and IFN-modified antigenic expression, cultures of autologous metastases derived from the same patient were very similar. In addition, differences in antigenic profile were apparent when early-passage in vitro cultures were compared with the same melanoma lesion, not established in culture, from which they were derived. The unique de novo and IFN-modified antigenic phenotype of cultures derived from different patients indicates that the antigenic phenotype displayed by melanoma cultures grown in vitro is genetically determined. The differences found between in vitro cultures and their corresponding in vivo lesions, as well as the antigenic heterogeneity displayed by multiple autologous melanoma lesions in vivo, suggest that the in vivo antigenic phenotype may be determined, at least in part, at an epigenetic level.

Antigens, Neoplasm↗

PubMed2004

Influence of MECP2 gene mutation and X-chromosome inactivation on the Rett syndrome phenotype.

To date, approximately 200 different mutations in the MECP2 gene have been identified. We analyzed the entire coding sequence of the MECP2 gene and the X-chromosome inactivation pattern in 42 sporadic cases of Rett syndrome. Of the 42 patients, 30 had pathogenic mutations, including 14 different mutations: 9 missense mutations, 4 nonsense mutations, and 1 frameshift mutation. One was a novel mutation (S134P). There was a tendency for patients who had a nonsense mutation in the transcriptional repression domain region to show earlier onset of regression and more severe language retardation than patients with a mutation in the methyl-CpG binding domain region. However, the parameters of clinical severity were variable among patients with the same type of mutation, depending on the pattern of X-chromosome inactivation. This study suggests that the X-chromosome inactivation pattern can modify the phenotype of Rett syndrome, which is primarily determined by the type and site of MECP2 gene mutation.

Age of Onset↗

PubMed1992

Phenotypic and functional modifications of thymocytes during tumor growth.

Thymocytes (T) from mice bearing the syngeneic tumor 3LL inhibit the immune response to SRBC by syngeneic splenocytes derived from control mice and cultured in Mishell and Dutton's antibody forming systems. T from control mice are devoid of this capacity but acquire it after in vitro incubation with tumor cells. It has been shown that metabolites of arachidonic acid (PGE-2, LTB-4 and LTC-4) synthesized in excess by tumor cells act as mediators for the acquisition of the above capacity by thymic cells in vitro. Surface phenotypical analysis by flow-cytometry demonstrated that in the thymus of tumor bearing mice the proportion of both single positive thymocytes (L3T4+/LY2- and L3T4-/LY2+) and of double negative thymocytes (L3T4-/LY2-) increased with a parallel decrease in the proportion of double positive cells (L3T4+/LY2+). In the mean time the total number of thymocytes markedly decreased. An attempt was done to mimic in vitro what happens in vivo. For this purpose T from control mice were incubated with conditioned culture medium in which 3LL cells had grown or with arachidonic acid metabolites. After one or the other of these treatments T from control mice did not modify their phenotypic antigenic pattern but acquired the capacity to negatively interfere with the in vitro immune response of normal spleen cells to SRBC. Since serum from tumor bearing mice contains large amounts of PGE-2, LTB-4 and LTC-4 we tested its effects on normal syngeneic T. Serum from tumor bearing mice, but not serum from normal mice, induces T from control syngeneic animals to acquire both immunosuppressive capacity and differentiation pattern clusters similar to those that characterize T derived from the thymus of tumor bearing mice. We demonstrated that metabolites of arachidonic acid are active as inducers of immunosuppressive capacity in T. On the other hand, a yet unknown factor present in serum of tumor bearing mice plays a role as inducer of differentiation of these cells.

Animals↗

PubMed2004

Potassium carrier TRH1 is required for auxin transport in Arabidopsis roots.

Disruption of the TRH1 potassium transporter impairs root hair development in Arabidopsis, and also affects root gravitropic behaviour. Rescue of these morphological defects by exogenous auxin indicates a link between TRH1 activity and auxin transport. In agreement with this hypothesis, the rate of auxin translocation from shoots to roots and efflux of [3H]IAA in isolated root segments were reduced in the trh1 mutant, but efflux of radiolabelled auxin was accelerated in yeast cells transformed with the TRH1 gene. In roots, Pro(TRH1):GUS expression was localized to the root cap cells which are known to be the sites of gravity perception and are central for the redistribution of auxin fluxes. Consistent with these findings, auxin-dependent DR5:GUS promoter-reporter construct was misexpressed in the trh1 mutant indicating that partial block of auxin transport through the root cap is associated with upstream accumulation of the phytohormone in protoxylem cells. When [K+] in the medium was reduced from 20 to 0.1 mm, wild type roots showed mild agravitropic phenotype and DR5:GUS misexpression in stelar cells. This pattern of response to low external [K+] was also affected by trh1 mutation. We conclude that the TRH1 carrier is an important part of auxin transport system in Arabidopsis roots.

Arabidopsis↗

PubMed2000

Genetically altered transgenic models of Alzheimer's disease.

Abnormal processing and aggregation of synaptic proteins might play an important role in the pathogenesis of neurodegenerative disorders. Among them, amyloid precursor protein (APP) has been clearly associated with Alzheimer's disease (AD) and various transgenic (tg) animal models have been developed where mutant APP is overexpressed under the regulatory control of neuronal promoters. These studies have shown that AD-like pathology (namely plaques and synapse damage) begins to develop at 6-8 months of age in mice expressing human APP under Thy1, platelet-derived growth factor (B-chain) or protease-resistant prion protein promoters, provided that levels of APP are higher than 5-7 fold of endogenous levels. None of these models have shown the presence of tangles; however, tau-immunoreactive neurites in plaques and astroglial/microglial activation are observed after 12 months of age. Neuronal loss and alterations of synaptic function and connectivity are found in the CA1 region in the PDAPP tg mice lacking the Swiss Webster background. Co-expression of other genes associated with AD modify this phenotype, for example, mutant presenilin 1 accelerates the onset of plaque formation, transforming growth factor beta enhances vascular amyloidosis, and apolipoprotein E decreases amyloid deposition. In conclusion, tg mice which are capable of mimicking some aspects of AD (provided that high enough levels of expression are achieved) can potentially be used to test novel drugs for the treatment of neurodegenerative disorders.

Alzheimer Disease↗

PubMed2005

Haptoglobin phenotype, sleep-disordered breathing, and the prevalence of cardiovascular disease: the Sleep Heart Health Study.

BACKGROUND: Diabetes is an independent risk factor for cardiovascular disease, and there is growing evidence that sleep-disordered breathing also may increase the risk of cardiovascular disease. The mechanism responsible for increased susceptibility of people with diabetes to cardiovascular disease is thought to share several features with sleep-disordered breathing, notably increased oxidative stress. We recently demonstrated that a particular haptoglobin phenotype that is associated with differential antioxidant activity is an independent risk factor for cardiovascular disease in individuals with diabetes. We therefore sought to determine whether sleep-disordered breathing and cardiovascular disease are more strongly associated among people with the unfavorable haptoglobin phenotype. METHODS: We tested this hypothesis in 2612 middle-aged and older participants from the Sleep Heart Health Study. Haptoglobin phenotyping was performed by gel electrophoresis. Respiratory disturbance index was assessed by standard methods. Logistic regression analysis was performed to estimate the association between haptoglobin phenotype and cardiovascular disease, adjusting for known cardiovascular risk factors (age, sex, diabetes, smoking, lipid levels, and hypertension). Possible modification by haptoglobin phenotype of the association of sleep-disordered breathing with cardiovascular disease prevalence was explored by examining interaction terms. RESULTS: We found no significant association between haptoglobin phenotype and prevalent cardiovascular disease in this cohort, nor were significant interactions found between haptoglobin phenotype and sleep-disordered breathing on the prevalence of cardiovascular disease. CONCLUSIONS: Sleep-disordered breathing did not appear to interact with haptoglobin phenotype in modifying the association with prevalent cardiovascular disease in the Sleep Heart Health Study. These findings could be due to the absence of association or to survivor bias in these cross-sectional analyses.

Aged↗

PubMed1999

[Turner syndrome in a girl with marker chromosome in karyotype].

OBJECTIVES: There are suggestion, that Turner syndrome (TS) patients with mosaic karyotype for a Y-DNA-containing cell line are at risk of Y-induced gonadoblastoma. The TS patients in whom some or all cells contain a marker chromosome of unknown origin and those in whom there is clitoromegaly or other evident virillisation should be tested by FISH or PCR techniques. DESIGN: The aim of our study to present a TS girl with mosaic karyotype and marker chromosome, which origin from X chromosome was detected by FISH method. MATERIAL AND METHODS: 5-years old girl in whom TS was established. Clinical analysis included the full dysmorphic and clinical phenotype of TS. Chromosome analysis was performed on peripheral blood samples using routine cytogenetic methods and FISH technique. RESULTS: Clinical examination of girl showed many typical signs of TS besides of normal weight and length at birth and not typical for TS patients heart defect. First routine chromosome analysis, at age of 6 month, showed only 45,X cell line, Second study revealed mosaic karyotype with marker chromosome. FISH analysis for interphase nuclei and metaphase chromosomes using X centromere probe explained origin of marker from X chromosome. The karyotype was 45,X[155]/46,X,+mar[8].fish mar(X)(DXZ1+). CONCLUSION: Presence of marker chromosome in karyotype of patient with TS may modify their phenotype and it is a indication for molecular examination by FISH technique.

Adolescent↗

PubMed2002

Contrasting genotypes of the tau gene in two phenotypically distinct patients with P301L mutation of frontotemporal dementia and parkinsonism linked to chromosome 17.

Association between clinical characteristics and types of the tau gene mutation has been observed in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). P301L mutation seldom causes parkinsonism as a leading symptom; instead it usually causes personality changes with aggressiveness and disinhibition. We experienced two patients of FTDP-17 from separate families (designated as patient 1 from family 1 and patient 2 from family 2). They had P301L mutation in common. However, their phenotypes were distinct from each other. Aggressive behaviors and disinhibition were the main symptoms in patient 1, whereas parkinsonism was the most prominent feature in patient 2. Their genotypes of the tau gene were different at three sites, i. e. in exon 6, in intron segment before exon 10, and in exon 13, though they do not bring amino acid change. Patient 1 had more prevalent C/C, C/C, and rare T/C respectively. Patient 2 had less prevalent T/T, A/A, and more prevalent T/T respectively. These findings suggest two things. Firstly, they do not share a common founder for P301L mutation. Secondly, either of the two less prevalent genotypes observed in patient 2 may be the factor to modify the phenotype of P301L mutation into those unusual clinical features with prominent parkinsonism. Accumulation of information as to phenotype-genotype association will settle this hypothesis.

Age of Onset↗

PubMed1997

CD4+ T-cell lymphopenia in Q fever endocarditis.

Valvular endocarditis is the most serious complication of chronic Q fever, an infectious disease due to Coxiella burnetii. Although its pathogenesis is poorly understood, the role of the immune system has been evoked. The aim of this study was to investigate lymphocyte subsets in the peripheral blood of infected patients by analyzing the distribution of T- and B-lymphocyte subsets. Since various infectious diseases have been found to be associated with modified antigen expression, we also measured the antigen density of the main lymphocyte markers by quantitative flow cytometry. The absolute values of CD3+ T cells and CD19+ B cells were lower in infected subjects than in controls. The decrease in the CD4+ T-cell count was more pronounced than that in the CD8+ T-cell count, leading to a significantly lower CD4/CD8 ratio in patients. The decreases in CD4+ T cells and CD19+ B cells were correlated with levels of C. burnetii-specific immunoglobulin G, showing that CD4+ lymphopenia is related to the activity of chronic Q fever. Quantitation of antigen expression on lymphocytes showed that CD3, CD4, CD8, and CD19 were expressed similarly in patients and controls. In contrast, CD2 and CD11a expression levels, which are both related to naive and memory phenotypes, were modified in patients. The study of CD45RO and CD45RA expression by CD4+ T cells provided evidence that lymphopenia preferentially affected unprimed lymphocytes.

Adult↗

PubMed1998

Different clinical forms of hereditary tyrosinemia (type I) in patients with identical genotypes.

Hereditary tyrosinemia type I (HTI, McKusick 276700) is an autosomal recessive disease caused by deficient fumarylacetoacetate hydrolase (FAH, EC 3.7.1.2) activity. HTI is characterized by progressive liver dysfunction with nodular cirrhosis often leading to hepatocellular carcinoma. Two extremes of the clinical phenotype have been described: the "acute" (severe, early onset and death) and "chronic" (delayed onset and slow course) phenotype. Allelic heterogeneity and/or mutation reversion in hepatic cells have been proposed earlier to explain the clinical heterogeneity. Two probands (one "acute," one "chronic") from the French-Canadian isolate where HTI is prevalent were studied. Both were homozygous (germ line) for the severe splice mutation IVS12 + 5g --> a; both showed liver mosaicism for FAH immunoreactivity with evidence for mutation reversion to heterozygosity (IVS12 + 5g --> a/+) in FAH-stained nodules as shown by amplification of DNA extracted from microdissected nodules. Western blot analysis of proteins from a reverted FAH-expressing nodule showed 29 +/- 3% FAH immunoreactive material as compared to an average normal liver. This was consistent with the measured FAA hydrolytic activity (25%) in this large regenerating nodule. These findings show that genotypic heterogeneity is not a sufficient explanation for clinical heterogeneity and implicate epigenetic and other factors modifying the phenotype in HTI.

Acute Disease↗

PubMed2000

Identification of novel imprinted transcripts in the Prader-Willi syndrome and Angelman syndrome deletion region: further evidence for regional imprinting control.

Deletions and other abnormalities of human chromosome 15q11-q13 are associated with two developmental disorders, Prader-Willi syndrome (PWS) and Angelman syndrome (AS). Loss of expression of imprinted, paternally expressed genes has been implicated in PWS. However, the number of imprinted genes that contribute to PWS, and the range over which the imprinting signal acts to silence one copy of the gene in a parent-of-origin-specific manner, are unknown. To identify additional imprinted genes that could contribute to the PWS phenotype and to understand the regional control of imprinting in 15q11-q13, we have constructed an imprinted transcript map of the PWS-AS deletion interval. The imprinting status of 22 expressed sequence tags derived from the radiation-hybrid human transcript maps or physical maps was determined in a reverse transcriptase-PCR assay and correlated with the position of the transcripts on the physical map. Seven new paternally expressed transcripts localize to an approximately 1.5-Mb domain surrounding the SNRPN-associated imprinting center, which already includes four imprinted, paternally expressed genes. All other tested new transcripts in the deletion region were expressed from both alleles. A domain of exclusive paternal expression surrounding the imprinting center suggests strong regional control of the imprinting process. This study provides the means for further investigation of additional genes that cause or modify the phenotypes associated with rearrangements of 15q11-q13.

Alleles↗

PubMed2005

Serum from achalasia patients alters neurochemical coding in the myenteric plexus and nitric oxide mediated motor response in normal human fundus.

BACKGROUND AND AIMS: Achalasia is a disease of unknown aetiology. An immune mechanism has been suggested on the basis of previous morphological observations. The objective of this study was to test whether the serum of achalasia patients could reproduce the phenotype and functional changes that occur with disease progression in an ex vivo human model. METHODS: Specimens of normal human fundus were maintained in culture in the presence of serum from patients with achalasia, gastro-oesophageal reflux disease (GORD), or healthy subjects (controls). Immunohistochemical detection of choline acetyltransferase (ChAT), neurone specific enolase (NSE), vasoactive intestinal polypeptide (VIP), nitric oxide synthase (NOS), and substance P was carried out in whole mounts of gastric fundus myenteric plexus. In addition, the effects of achalasia serum on electrical field stimulation (EFS) induced contractions were measured in circular muscle preparations. RESULTS: Serum from achalasia patients did not affect the number of myenteric neurones. Tissues incubated with serum from achalasia patients showed a decrease in the proportion of NOS (-26% of NSE positive neurones; p=0.016) and VIP (-54%; p=0.09) neurones, and a concomitant increase in ChAT neurones (+16%; p<0.001) compared with controls. In contrast, GORD serum did not modify the phenotype of myenteric neurones. Area under the curve of EFS induced relaxations (abolished by N-nitro-L-arginine methyl ester) was significantly decreased following incubation with serum from achalasia patients compared with controls (-7.6 (2.6) v -14.5 (5.0); p=0.036). CONCLUSIONS: Serum from achalasia patients can induce phenotypic and functional changes which reproduce the characteristics of the disease. Further identification of putative seric factors and mechanisms involved could lead to the development of novel diagnostic and/or therapeutic strategies in achalasia.

Adult↗

PubMed2003

The contribution of human leucocyte antigen complex genes to disease phenotype in ulcerative colitis.

Linkage and association studies implicate the human leucocyte antigen (HLA) region in genetic susceptibility to ulcerative colitis (UC). However, associations with specific variants have been inconsistent, even within defined ethnic groups. A genetic basis for the disease heterogeneity of UC may account for these discrepant findings from studies in unselected populations. Here, we examine the contribution of the HLA region to the clinical phenotype of UC. We studied 321 accurately phenotyped patients recruited from a single UK centre, with a median follow-up time of 15 years. Individuals were genotyped for 340 polymorphisms constructed into 25 gene-specific allelic haplotypes between HLA-A and Tapasin. Data were analysed with respect to age of onset, disease extent and severity. Strongest association with overall susceptibility was identified with HLA-DRB1 alleles replicating previous studies (DRB1*0103, DRB1*1502 and DRB1*0401). We report a novel association with homozygosity of a tumour necrosis factor (TNF) promoter haplotype (TNF-1031T, -863C, -857C, -380G, -308G and -238G) and distal disease extent that does not extend with time (distal vs total 40.9 vs 25.7%; RR = 2.0; 95% CI 1.23-3.24). We confirm the association of DRB1*0103 with total disease and/or disease requiring colectomy and further demonstrate that DRB1*0103 is associated with shorter time to surgery. Genes in the HLA play a role in modifying disease phenotype. Further studies are required to dissect how these genes functionally interact with each other and with environmental factors to determine clinical patterns of disease

Adolescent↗