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Biomedical subjects

N E Haites

Publications and source records attributed to N E Haites.

At least 37 records · Page 2Linked to original sources
PubMed1999

Asthma, wheezy bronchitis, and atopy across two generations.

Although the prevalence of asthma has risen significantly during the last 30 yr, it is not clear whether this has occurred primarily in persons with a strong genetic predisposition to asthma and atopy or in other sections of the population. We have investigated outcomes in children of nuclear families selected through probands previously characterized by studies in 1964 and 1989 as having histories of persistent childhood onset atopic asthma, transient childhood wheezy bronchitis, and no respiratory symptoms or atopy. Children of wheezy bronchitic probands had a significantly better symptomatic outcome in adolescence, irrespective of the atopic status of the parent proband, than do children of either asthmatic or asymptomatic probands, suggesting that this may be a syndrome that shows familial aggregation and is distinct from asthma. Total serum IgE levels were significantly lower in children of nonatopic asymptomatic probands, including those with wheezing symptoms. In contrast children of nonatopic asymptomatic probands had an unexpectedly high prevalence of wheezing (33%), positive skin prick tests (56%), and positive specific serum IgE to common allergens (48%) that was similar to that found in children of atopic asthmatic probands. Our findings support the concept that wheezy bronchitis is a separate syndrome from atopic asthma. High total serum IgE levels within our population appear to be an important marker of genetic predisposition to atopy. Our data also suggest that much of the increase in asthma prevalence is associated with specific IgE sensitization and is occurring in persons previously considered to be at low risk of developing asthma or atopy.

Adolescent↗
PubMed1999

A protective role for common p21WAF1/Cip1 polymorphisms in human ovarian cancer.

The objective of this study was to compare the frequency of two common p21WAF1/Cip1 gene polymorphisms in ovarian cancer patients with that in age-matched controls, from a population originating from Eastern Scotland. Both polymorphisms were found significantly less frequently in both the constitutive and tumour tissue DNA of ovarian cancer patients (3/65; 4.6%), than in that from geographically and age-matched controls (25/186; 13.4%) (p=0.0495, chi2). Furthermore, we found no p21WAF1/Cip1 gene mutations in any of the tumours, reflected by a relatively low degree of loss of heterozygosity (LOH) at the chromosomal region where the gene maps, providing further evidence that the p21WAF1/Cip1 gene is not mutated in ovarian cancer. The data suggest however, that there may potentially be a protective function for the two p21WAF1/Cip1 gene polymorphisms in the population under study.

Alleles↗
PubMed1999

Novel PCR-based diagnostic tools for Charcot-Marie-Tooth type 1A and hereditary neuropathy with liability to pressure palsies.

The majority of cases of Charcot-Marie-Tooth type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) are the result of DNA duplications and deletions respectively of a 1.5 Mb region on 17p11.2. The region contains the peripheral myelin protein 22 gene (PMP-22) and is flanked by homologous proximal and distal CMT1A-REP elements. The majority of duplications and deletions arise during meiotic recombination following misalignment and unequal crossing-over between the proximal and distal CMT1A-REP elements. The cross-over breakpoints are most frequently located within a 1.7 Kb hotspot of recombination and produce novel duplication or deletion junctional CMT1A-REPs with unique restriction patterns. Here we describe the use of PCR based tests, which amplify a 3.6 Kb region including the 1.7 Kb hotspot from specific CMT1A-REPs, for the rapid diagnosis of CMT1A and HNPP patients. In an analysis of 96 CMT1A and 30 HNPP patients, duplication and deletion events were detected in all samples with cross-over breakpoints known to be within the region amplified by PCR.

Charcot-Marie-Tooth Disease↗
PubMed1998

Comparative genomic hybridization analysis of chromosomal alterations induced by the development of resistance to thymidylate synthase inhibitors.

Acquired resistance to chemotherapy is a major obstacle to the successful treatment of cancer. In the past, technical limitations prevented the detection of genetic alterations associated with such resistance on a genome-wide scale. This study evaluated comparative genomic hybridization (CGH) as a tool to detect candidate regions of the genome associated with chemoresistance. Using a variation of conventional CGH, DNA from cell lines that were resistant to thymidylate synthase inhibitors (raltitrexed and 5-fluorouracil) and their sensitive parent cells were evaluated. In MCF-7 and H630 cells that were resistant to raltitrexed, only a single region of change (18p gain) was apparent. The third cell line, H630R10, which was resistant to 5-fluorouracil, had changes in several genomic regions following the acquisition of resistance, including 18p gain. Gain in the chromosomal region containing the thymidylate synthase gene (18p11.32) was detected by CGH in all three resistant cell lines. However, additional novel regions of interest were identified in the cells that were resistant to 5-fluorouracil. These results suggest that CGH is of potential use in the detection of regions of the genome involved in chemoresistance.

Antimetabolites, Antineoplastic↗
PubMed1998

Current policies for surveillance and management in women at risk of breast and ovarian cancer: a survey among 16 European family cancer clinics. European Familial Breast Cancer Collaborative Group.

The recent isolation of breast cancer predisposing genes (BRCA1 and BRCA2) allows the identification of carriers within affected families. These carriers have a 50-85% risk of developing breast or ovarian cancer and need careful follow-up. The purpose of this study was to evaluate the management and screening protocols implemented in high risk families at various family cancer clinics in Europe. A questionnaire was mailed to the members of the European Familial Breast Cancer Collaborative Group (n = 30) requesting information on the following issues: indication for surveillance of breasts and ovaries, the recommended protocol, coordination of the screening examination, prophylactic surgery, the specific management of breast cancer in a mutation carrier and the use of oestrogen. 16 centres from nine countries responded. Most centres recommend surveillance of the breasts if the lifetime risk exceeds 15-20%. The surveillance protocol that is generally advised comprises monthly self breast examination, examination by a specialist every 6 months and annual mammography, all starting from an age between 25 and 35 years. Surveillance of the ovaries is recommended in BRCA1 and BRCA2-mutation carriers, in members from breast/ovarian cancer families and in some centres in 'breast cancer only' families with an early onset of breast cancer. The recommended protocol includes gynaecological examination, sonography and estimation of CA-125 at yearly intervals starting from the age 30-35 years. Prophylactic mastectomy is considered for proven mutation carriers in some centres. Most centres consider prophylactic oophorectomy in mutation carriers and some centres also consider it for members of breast/ovarian cancer families. This survey provides insight into the guidelines for surveillance and management of familial breast cancer used at various family cancer clinics in Europe; this insight may contribute to the appropriate management of these high risk women. It should be emphasised that most recommendations are based on experts' opinion rather than on any specific studies.

Adult↗
PubMed1998

Rapid diagnosis and identification of cross-over sites in patients with glucocorticoid remediable aldosteronism.

Glucocorticoid remediable aldosteronism (GRA) is an autosomal dominant cause of primary aldosteronism and high blood pressure resulting from a chimeric 11beta-hydroxylase/aldosterone synthase gene. Abnormal expression of aldosterone synthase causes primary aldosteronism, which can be inhibited by glucocorticoids. Diagnosis of GRA has depended on the identification of a restriction enzyme product in genomic DNA of affected individuals. Recently, a two-tube long PCR method was described that allowed diagnosis of GRA in a kindred in Australia. A similar long PCR method confirmed the diagnosis of GRA in members of five northeastern Scotland families previously identified by Southern blotting and detected affected members of five GRA families previously identified in Glasgow. A multiplex PCR protocol is described here that allows the control aldosterone synthase amplification and chimeric gene amplification to be carried out in the same tube. We describe the regions of cross-over in each of 10 kindreds identified in Scotland. To identify cross-over regions in each of the kindreds, the chimeric long PCR product was cloned and sequenced. Five cross-over sites were identified ranging from intron 2 to exon 4, indicating the reliability of the method in identifying chimeric genes resulting from different sites of cross-over.

Base Sequence↗
PubMed1998

Paget's disease of bone: evidence for a susceptibility locus on chromosome 18q and for genetic heterogeneity.

Paget's disease of bone is a common condition characterized by bone pain, deformity, pathological fracture, and an increased incidence of osteosarcoma. Genetic factors play a role in the pathogenesis of Paget's disease but the molecular basis of the disease remains unclear. Previous genetic linkage studies have mapped the rare Paget's disease-like bone dysplasia familial expansile osteolysis (FEO) to chromosome 18q21-22, and recent work has shown evidence of linkage between this locus and Paget's disease in one family. Here we studied the relationship between the 18q21-22 locus and Paget's disease in eight large multiplex families from diverse ethnic backgrounds with inherited Paget's disease. Paget's disease was inherited as an autosomal dominant trait in all families, with high penetrance by the sixth decade. Analysis of seven highly polymorphic markers from chromosome 18q21-22 showed positive summated two-point log10 odds ratio (lodscores) of +2.97 with the marker D18S42 at a recombination fraction (theta) = 0.05, and of +2.95 with the marker D18S60 at theta = 0.00, values which are close to the cut-off of +3.0, which is generally accepted as evidence of linkage. Segregation analysis of the haplotypes and formal statistical analysis using the HOMOG program provided evidence for genetic heterogeneity, however, with evidence for linkage in five families and against linkage in the remaining three families (chi square 8.82; df = 2; p < 0.025). Multipoint linkage analysis in the five linked families showed lodscores of above +3.5 across the whole susceptibility region and a maximum summated lodscore of 3.89 at the marker D18S465. In the three nonlinked families, negative multipoint results were obtained for the whole region, with lodscores below -2.0 in one family, excluding this as a candidate locus for the disease. Our studies demonstrate the importance of hereditary factors in the pathogenesis of Paget's disease and confirm evidence of linkage between Paget's disease and chromosome 18q21-22 in some families. This raises the possibility that Paget's disease and FEO may share a common molecular basis, perhaps due to different mutations in the same gene or family of genes. Data from three families did not support evidence of linkage to 18q21-22 however, indicating that Paget's disease is genetically heterogeneous and suggests the presence of at least one additional locus which remains to be discovered.

Chromosome Aberrations↗
PubMed1997

Upregulation and co-localization of connexin43 and cellular adhesion molecules in inflammatory renal disease.

Connexin43 (Cx43) is a major component of gap junctions. These are widely distributed in the human kidney and are thought to be involved in the inflammatory response and in the regulation of cell growth. Cellular adhesion molecules (CAMs) are also thought to be important in these processes, where they possibly facilitate gap junction formation. The aims of the current study were to define for the first time the expression of Cx43 in inflammatory glomerulonephritis and to compare the localization of this connexin with that of the intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. Human renal biopsies and control sections of normal human kidney were stained using the alkaline phosphatase/anti-alkaline phosphatase immunohistochemical technique, demonstrating that Cx43 was strongly expressed on inflammatory cells, on damaged tubular cells, and on interstitial cells. This pattern of expression was paralleled closely by that of ICAM-1 and, to a lesser extent, by that of VCAM-1. Cx43 is therefore primarily implicated in tubulointerstitial inflammation.

Adult↗
PubMed1997

Outcome of children of parents with atopic asthma and transient childhood wheezy bronchitis.

BACKGROUND: Childhood asthma and wheeze only in the presence of respiratory infection (wheezy bronchitis) appear to have different prognoses and may differ in their aetiology and heritability. In particular, slight reductions in lung function may be associated with episodes of wheezing associated with intercurrent viral infection. METHODS: Outcomes for wheezing symptoms and lung function were studied in 133 offspring of three distinct groups of 69 middle aged probands with childhood histories of (1) atopic asthma (n = 18), (2) wheeze associated with upper respiratory tract infection (wheezy bronchitis, n = 24), and (3) no symptoms (n = 27). Probands were selected from a previously studied cohort in which outcomes of wheezy bronchitis and asthma had been shown to differ. RESULTS: Children of probands with wheezy bronchitis had a lower prevalence of current wheezing symptoms. Forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) in boys of probands with a history of wheezy bronchitis were significantly reduced compared with either of the other two groups (p < 0.0001). In a multivariate analysis, grouping based on parent proband had a significant effect on lung function, independent of factors such as symptoms, atopy or smoking history. CONCLUSIONS: The different symptomatic and lung function outcome in children of probands with wheezy bronchitis and asthma provides further evidence that wheezy bronchitis and asthma differ in their natural history and heritability, and suggests that there may be familial factors specific to each wheezing syndrome.

Aging↗
PubMed1997

The expression of connexin 43 in human kidney and cultured renal cells.

Gap junctions enable intercellular communication and play an important role in a variety of vital cellular functions including differentiation and the control of growth. These junctions are formed by a hexameric of proteins known as connexins. We investigated the distribution of the connexin 43 (Cx43) gap junction protein in renal cells and human kidney using the alkaline phosphatase anti-alkaline phosphatase immunohistochemical technique with a monoclonal antibody directed against the cytoplasmic domain of this antigen. Strong staining was demonstrated on the vascular endothelium, the smooth muscle of larger vessels and on glomerular epithelial cells. In addition, Cx43 was expressed on proximal tubular cells, glomerular endothelial cells and occasional cells infiltrating the interstitium. In areas of tubular atrophy there was increased staining for Cx43. Using reverse transcription-polymerase chain reaction we have also demonstrated that cultured human and rat mesangial cells and human proximal tubular cells express Cx43 messenger RNA. In summary, we have described for the first time the distribution of Cx43 in human kidney and cultured renal cells.

Alkaline Phosphatase↗
PubMed1997

Effect of angiotensin II on plasminogen activator inhibitor-1 production by cultured human mesangial cells.

Angiotensin II is a vasoactive peptide that has been widely implicated in the pathogenesis of glomerular disease. Some of its effects are thought to be independent of changes in blood pressure. Plasmin is a key regulator of fibrinolysis and extracellular matrix turnover. The conversion of plasminogen to plasmin by plasminogen activators (PAs) is controlled by their specific inhibitor, PAI-1. In this study we report the effects of angiotensin II on the production of PA inhibitor-1 (PAI-1) and tissue-type PA (t-PA) by glomerular mesangial cells in culture. Angiotensin II significantly increased the production of PAI-1 in the supernatant of mesangial cells (p < 0.05) in a dose-dependent manner, the maximum stimulation occurring at a concentration of 10(-5) M. The effect was not mediated by transforming growth factor-beta (TGF-beta), which is known to be induced by angiotensin II; TGF-beta itself can increase PAI-1 expression. Angiotensin II did not alter t-PA production or incorporation of matrix fibronectin but did increase cellular proliferation and 3H-thymidine uptake. The increase in PAI-1 by angiotensin II may contribute to the persistence of fibrin deposits and extracellular matrix accumulation, providing another mechanism whereby angiotensin II contributes to glomerular dysfunction.

Angiotensin II↗
PubMed1996

Cranial desmoid tumor associated with homozygous inactivation of the adenomatous polyposis coli gene in a 2-year-old girl with familial adenomatous polyposis.

BACKGROUND: Familial adenomatous polyposis (FAP) is a dominantly inherited disorder characterized by the presence of more than 100 adenomatous polyps in the colon and rectum starting in the second decade of life. FAP is associated with extra colonic manifestations, including desmoid tumors. METHODS: A 2-year-old girl presented with a rapidly enlarging tumor of the forehead and a family history of FAP. The tumor was cultured for cytogenetic studies. A DNA linkage study using flanking and intragenic polymorphisms of the adenomatous polyposis coli (APC) gene was performed to identify the allele loss in the tumor. Germline mutation identification was by single strand conformation polymorphism analysis of exon 15 of the APC gene, with subsequent double stranded sequencing of fragments with conformational changes. A mutation-induced loss of a restriction site was used to confirm allele loss in the tumor. RESULTS: Microscopically, the tumor had desmoid features. Cytogenetic analysis of the tumor demonstrated loss of chromosome region 5(q21q22). A truncating adenomatous polyposis coli (APC) gene mutation was identified in the leukocyte DNA from the child and her affected father. Linked DNA markers suggested that the tumor had lost the maternal, wild-type allele. A mutation-induced restriction endonuclease site alteration demonstrated hemizygosity of the mutant sequence in the tumor DNA. CONCLUSIONS: These findings are compatible with the presence of a "second hit" inactivation of the APC gene and implicate this gene in the pathogenesis of desmoid tumors.

Adenomatous Polyposis Coli↗
PubMed1996

Epidermal growth factor (EGF) increases the in vitro invasion, motility and adhesion interactions of the primary renal carcinoma cell line, A704.

Metastasis is a multistep process that involves alterations in a tumour cell's invasion, motility and adhesive capabilities. This study examined the effect of EGF on the in vitro invasion, motility and adhesion of the primary renal adenocarcinoma cell line, A704. Stimulation of the tumour cells by EGF (40 ng/ml) for a period of 24 h increased the in vitro invasion (P = 0.040) and motility (P = 0.039). Cell adhesion was examined on fibronectin, laminin, collagen IV and a 1:1:1 mix of the three extracellular matrix components. After EGF (40 ng/ml) stimulation, adhesion was significantly decreased on fibronectin (P = 0.022) and collagen type IV (P = 0.026), but increased on the 1:1:1 mix of extracellular matrix components (P = 0.022). The 92 kDa matrix metalloproteinase (MMP-9) present in the cell-conditioned medium was also increased after a 24 h stimulation with EGF (40 ng/ml) when measured. Hence, EGF can modulate the in vitro invasion, motility, adhesiveness and matrix metalloproteinase production in the A704 cell line, and subsequently may have a role in the metastatic potential of some renal carcinomas.

Adenocarcinoma↗