Melioidosis presenting as septic arthritis in Bengali men in east London.
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Arthritis, Infectious↗
Biomedical subjects
E Sheridan
Publications and source records attributed to E Sheridan.
Screening SMAD1, SMAD2, SMAD3, and SMAD5 for germline mutations in juvenile polyposis syndrome.
BACKGROUND AND AIMS: Juvenile polyps occur in several Mendelian disorders, whether in association with gastrointestinal cancer alone (juvenile polyposis syndrome, JPS) or as part of known syndromes (Cowden, Gorlin, and Bannayan-Zonana) in association with developmental abnormalities, dysmorphic features, or extraintestinal tumours. Recently, some JPS families were shown to harbour germline mutations in the SMAD4 (DPC4) gene, providing further evidence for the importance of the TGFbeta signalling pathway in colorectal cancer. There remains, however, considerable, unexplained genetic heterogeneity in JPS. Other members of the SMAD family are excellent candidates for JPS, especially SMAD2 (which, like SMAD4, is mutated somatically in colorectal cancers), SMAD3 (which causes colorectal cancer when "knocked out" in mice), SMAD5, and SMAD1. METHODS: SMAD1, SMAD2, SMAD3, and SMAD5 were screened for germline mutations in 30 patients with JPS and without SMAD4 mutations. RESULTS: No mutations were found in any of these genes. A G-A C89Y polymorphism with possible effects on protein function was found in SMAD3, but the frequencies of the G and A alleles did not differ between patients with JPS and controls. CONCLUSIONS: It remains to be determined whether or not this polymorphism is involved in a minor predisposition to colorectal or other carcinomas. SMAD4 may be the only member of the SMAD family which causes JPS when mutant in the germline. The other genes underlying JPS remain to be identified.
Adenomatous Polyposis Coli↗
Identifying and screening patients at high risk of colorectal cancer in general practice.
OBJECTIVES: To determine the feasibility and acceptability of selecting patients at risk of colorectal cancer by taking family histories by means of a postal questionnaire. To determine if this information could be translated into simple risk categories to guide subsequent management. SETTING: Patients aged between 30 and 69 years inclusive, registered with a mixed suburban and rural training general practice in south west England. METHOD: A postal questionnaire survey seeking demographic information and family history of colorectal cancer was sent to all eligible patients. Personal risk of colorectal cancer was stratified according to predetermined criteria. Risk assessment was modified if necessary after the general practitioner conferred with a geneticist. Patients were subsequently offered colonoscopy (high risk) or faecal occult blood testing (intermediate risk). RESULTS: Response to the questionnaire was 84.7%. 250 patients had a family history of colorectal cancer, of whom 52 were assigned to the high risk group, 104 to the intermediate group, and 94 to the low risk group. The geneticist reassigned five intermediate risk patients to the high risk group. Of 27 patients who had a colonoscopy, two were found to have an adenocarcinoma and a further two adenomatous polyps. In the group given faecal occult blood testing, two patients presented with colorectal cancer before being screened. CONCLUSIONS: A postal questionnaire is feasible and acceptable for the collection of information about a family history of colorectal cancer from patients in general practice. The personal risk of developing the disease according to standard criteria can be estimated and then managed by a simple protocol.
Adult↗
Mutations in DPC4 (SMAD4) cause juvenile polyposis syndrome, but only account for a minority of cases.
Juvenile polyps are present in a number of Mendelian disorders, sometimes in association only with gastrointestinal cancer [juvenile polyposis syndrome (JPS)] and sometimes as part of known syndromes (Cowden, Gorlin and Banayan-Zonana) in association with developmental abnormalities, dysmorphic features or extra-intestinal tumours. Recently, a gene for JPS was mapped to 18q21.1 and the candidate gene DPC4 (SMAD4) was shown to carry frameshift mutations in some JPS families. We have analysed eight JPS families for linkage to DPC4. Overall, there was no evidence for linkage to DPC4; linkage could be excluded in two of the eight pedigrees and was unlikely in two others. We then tested these eight families and a further 13 familial and sporadic JPS cases for germline mutations in DPC4. Just one germline DPC4 mutation was found (in a familial JPS patient from a pedigree unsuitable for linkage analysis). Like all three previously reported germline mutations, this variant occurred towards the C-terminus of the DPC4 protein. However, our patient's mutation is a missense change (R361C); somatic missense mutations in DPC4 have been reported previously in tumours. We therefore confirm DPC4 as a cause of JPS, but show that there is considerable remaining, uncharacterized genetic heterogeneity in this disease.
DNA-Binding Proteins↗
Cytokine dermatosis: reactivation of eczema during interleukin-2 infusion.
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Adult↗
Counselling implications of chromosomal abnormalities other than trisomy 21 detected through a maternal serum screening programme.
OBJECTIVE: To identify counselling requirements, we reviewed the frequency and type of non-trisomy 21 chromosome abnormalities found at amniocentesis after maternal serum screening for Down's syndrome. DESIGN: The study involved a review of the cytogenetic results of amniocenteses performed because of a raised maternal serum screening risk. SETTING: The maternal serum screening and amniocenteses were performed at hospitals in the Yorkshire region. SAMPLE: 1715 amniocenteses were performed as a result of a raised maternal serum screening risk for the period 1990 to 1993. METHODS: The cytogenetic results were classified into the main categories of numerical and structural chromosomal abnormalities. MAIN OUTCOME MEASURES: The nature and frequency of abnormal cytogenetic results were identified in which parental samples were required in order to determine if the abnormal finding was de novo or familial and/or for which specialist genetic counselling was required. RESULTS: Sixty-nine pregnancies of 1715 amniocenteses were identified with a chromosomal abnormality (4.0%): 35 (2.0%) with trisomy 21 and 34 (2.0%) with another chromosomal abnormality. For 20 of these 34 abnormalities, parental karyotypes were required and in 29 of the 34 specialist genetic counselling was required. CONCLUSIONS: Women undergoing maternal serum screening and, in particular, those proceeding to amniocentesis, should be informed that there is an equal chance that a chromosomal abnormality other than trisomy 21 will be found at amniocentesis, the nature of which usually requires parental samples and specialist counselling.
Amniocentesis↗
Small cell carcinoma of the cervix.
Small cell carcinoma of the cervix represents an uncommon variant of cervical cancer with a particularly poor prognosis. Traditionally, the diagnosis was established from routine histopathological sections, but there has been a trend to refer to this tumour as neuroendocrine carcinoma, with a requirement to demonstrate cytoplasmic granules. Five patients are described, who share the clinical features of young age of onset, early metastasis in the presence of apparently low stage disease, early failure of appropriate local treatment, and extreme chemosensitivity (features that are quite distinct from those seen in squamous cell cancer of the cervix). Light microscopy suggested a diagnosis of small cell cancer in all five tumours, but not all showed evidence of neuroendocrine differentiation. It is proposed that the present criteria for the diagnosis of cervical small cell carcinoma are too strict. The diagnosis should rely on the light microscopy of haemotoxylin and eosin sections and the distinctive clinical behaviour. The absence of neuroendocrine differentiation should not exclude the diagnosis, it does not appear to influence the clinical behaviour. The appropriate management of small cell carcinoma of the cervix is systemic, with chemotherapy as the first line of treatment. Surgery and radiotherapy may improve control of local disease but are unlikely significantly to influence the overall prognosis.
Adult↗
P53 mutation in a series of epithelial ovarian cancers from the U.K., and its prognostic significance.
In an initial study of 20 fresh ovarian tumour samples, we compared the immunohistochemical positivity of staining of the p53 protein with the presence of missense mutations of the p53 gene. This revealed a prevalence of 50% with a perfect correlation between mutation and immunohistochemical staining. Detection of the p53 protein by immunohistochemistry was, therefore, used as a reliable indicator for the presence of P53 mutation, and was applied to a study of an archival series of 93 ovarian tumours. Positive immunostaining of the p53 protein was observed in 47% of this series. Cox regression was used to assess whether various clinical variables and P53 mutation were related to survival. As a result, it was found that positive staining of the p53 protein was independent of age, tumour differentiation, tumour type, though possibly not stage. There was some evidence that p53 positivity was associated with reduced survival after adjusting for other variables, but the result was not statistically significant.
Biomarkers, Tumor↗
Analysis of the p53 gene, its expression and protein stabilization in non-Hodgkin's lymphomas.
We have investigated the p53 gene, expression of its mRNA, and stabilization of its protein in a series of non-Hodgkin's lymphomas (NHLs). Immunohistochemistry revealed positive staining of the p53 protein in node biopsies from 6/36 NHL patients, all of whom had high-grade disease. The remaining NHL samples, together with 3 reactive nodes, showed either negative staining or the staining of only occasional cells. In one case that exhibited intense nuclear staining in 90% of the cells, a mutation in the p53 gene was also observed. There was no evidence of rearrangements of the p53 gene in any of the NHL samples. Although p53 mRNA could not be detected in nonmalignant tissue, it was apparently overexpressed in 16/38 NHL, but this did not correlate with positive staining of the p53 protein. These data suggest that p53 dysfunction might play an important role in the evolution of some cases of NHL, and that mechanisms other than mutation of the p53 gene may be involved in stabilizing the p53 protein in these neoplasms.
Gene Expression↗
High incidence of mutations of the p53 gene detected in ovarian tumours by the use of chemical mismatch cleavage.
We have investigated a series of ovarian tumours for evidence of mutations in the p53 tumour suppressor gene. In this study we have made use of the chemical mismatch cleavage technique which, from analyses of other genes, has been shown to consistently identify all point mutations present within a region of DNA. This approach revealed mutations of p53 in 11/20 tumours studied, mainly in exons 5 or 7. After sequencing the relevant regions of the gene it was shown that ten of these mutations would have resulted in an amino acid substitution in the protein and only one represented a polymorphism. The observed incidence of p53 missense mutations in our series (50%) was the highest recorded in ovarian tumours and demonstrated the potential of the mismatch cleavage technique as a reliable method for the detection of p53 mutations in human tumours.
Base Sequence↗
Treatment of malignant melanoma and renal cell carcinoma with recombinant human interleukin-2: analysis of cytokine levels in sera and culture supernatants.
In this study we evaluated the clinical response of 12 patients with malignant melanoma and renal cell carcinoma (RCC) following administration of recombinant human interleukin-2 (rhIL-2) by continuous infusion. Serum samples taken before, during and following sequential courses of IL-2 were assayed for the presence of tumour necrosis factor alpha (TNF-alpha) IL-1 alpha, IL-6 and interferon gamma (IFN-gamma) and the presence or changes in these cytokines were examined with respect to clinical response data: our results did not show any direct correlation between the parameters measured and clinical outcome. In addition, peripheral blood mononuclear cells (PBMC) derived from 3 RCC patients were cultured in a serum-free environment and the resulting supernatants assayed for the production of these cytokines and compared to the corresponding serum levels. During one or more courses of treatment only 1 patient, who had metastatic bone disease, demonstrated detectable serum TNF-alpha; serum IL-6 levels were elevated in a proportion of all patients studied and a sustained IL-6 response occurred in a patient who had complete disease remission; IL-1 alpha was detected in the serum of 3 RCC patients; IFN-gamma could not be detected in any serum sample tested. Cytokine levels in sera and supernatants derived from 3 RCC patients were compared but no correlation was found: TNF-alpha and IL-6 were shown to be present at much higher concentrations in supernatants when compared to sera whereas the levels of IL-1 alpha were almost undetectable. This lack of correlation is probably due to the presence of "interfering" proteins in sera which either depress or enhance the ability to detect cytokines in sera using enzyme immunoassays.
Carcinoma, Renal Cell↗
Malignant melanoma and renal cell carcinoma: immunological and haematological effects of recombinant human interleukin-2.
The immunological and haematological effects of continuous infusion of recombinant human interleukin-2 (rhIL-2) in 6 patients with metastatic melanoma and 6 with disseminated renal cell carcinoma are reported. In patients with malignant melanoma dacarbazine was given before IL-2; in renal cell carcinoma IL-2 alone was given. In malignant melanoma, 1 complete (CR) and 1 partial response (PR) were seen; 2 patients had stable disease (SD) and 2 progressive disease (PD). In renal cell carcinoma 4 patients had SD and 2 PD. Toxicity of IL-2 therapy was minimal. All patients showed increased cytotoxicity, that was not major histocompatibility complex restricted, towards target cells sensitive and insensitive to natural killer cells. These activities varied between individual patients and were less marked in cases of renal cell carcinoma. Cellular proliferative responses increased in all patients, being consistently higher following the first course of therapy, as did HLA-DR, CD16 and CD25 activation marker expression. Hypersegmentation of neutrophils and eosinophilia were commonly observed, and in renal cell carcinoma these changes were accompanied by abnormal lymphocyte morphology.
Aged↗
Asthmatic patients with panic disorders: report of three cases with management and outcome.
Panic disorders, a subgroup of the primary anxiety disorders, have an estimated worldwide prevalence of 2.5% to 5%. Although the causes of these disorders have not been completely elucidated, it seems that environmental and genetic factors in addition to central nervous system biochemical abnormalities play important roles. Mild to moderate anxiety levels may prove advantageous in the management of asthmatics but when their anxiety level becomes maladaptive, as in the case of panic attacks, their medical care is placed in jeopardy. Herein are three case reports of asthmatics who also exhibited panic disorders and their clinical outcome. It is concluded that a team approach, involving the primary physician and psychologist or psychiatrist, is beneficial in the long-term management of these patients.
Adult↗
Endoscopic localization of the squamocolumnar junction before cervical cone biopsy in 284 patients.
A preoperative examination of the endocervical canal was performed in 284 patients scheduled for excisional cone biopsy because of abnormal cervical cytology and unsatisfactory colposcopy. The information obtained regarding the depth of the new squamocolumnar junction (SCJ) was used to tailor the length of the cone specimen in an attempt to remove the entire transformation zone (TZ), and was associated with a low rate of incomplete disease excision. An analysis of the data generated by this study indicates that the position of the new SCJ is influenced by age, menopausal status, and the use of estrogen-containing medication.
Adult↗
Thyroid function in choriocarcinoma: demonstration of a thyroid stimulating activity in serum using FRTL-5 and human thyroid cells.
Hyperthyroidism is a well recognized complication of gestational trophoblastic tumours (GTT) and may be due to high circulating concentrations of human chorionic gonadotrophin (hCG) or its variants. We have studied 24 clinically euthyroid women with GTT. Eight were biochemically hyperthyroid with low or undetectable serum thyrotrophin (TSH) and had a mean serum hCG of 361.2 x 10(3) IU/l compared to 76.2 x 10(3) IU/l in the other patients (P less than 0.01). Purified hCG stimulated iodide uptake into FRTL-5 cells with 25 x 10(3) IU/l being equivalent in potency to 1 mU/l of thyrotrophin (TSH). Sixteen out of the 24 sera (67%) stimulated iodide uptake when applied to the cells at a 1:10 dilution. Sera from all eight hyperthyroid patients contained thyroid stimulating activity. The mean hCG concentration in the 16 stimulatory sera was 238.2 x 10(3) IU/l compared to 37.1 x 10(3) IU/l in the other eight sera (P less than 0.01). Six men with hCG-secreting testicular tumours were biochemically euthyroid although three of their sera stimulated iodide uptake into FRTL-5 cells. In human thyroid cells the mean cAMP production over 4 h with sera from five healthy controls was 54.2 +/- 1.81 pmol/mg cell protein compared to 67.0 +/- 3.8 pmol/mg protein with sera from five choriocarcinoma patients (P less than 0.02). Serum from patients with gestational trophoblastic tumours contains a thyroid stimulating activity which may be hCG and whose presence correlates with hyperthyroidism.
Adolescent↗
Nucleolar organiser regions in adenocarcinoma in situ and invasive adenocarcinoma of the cervix.
Silver binding nucleolar regions (AgNORs) were evaluated in normal endocervix, adenocarcinoma, and its potential precursor, adenocarcinoma in situ (AIS), in an attempt to increase an understanding of the natural history of cervical adenocarcinoma and to identify a marker for abnormal endocervical (atypical glandular) cells which could aid diagnosis and follow up of endocervical lesions. For every 50 cells the mean AgNOR counts were as follows: normal endocervical cells (n = 15) 79.8 (95% Cl 68-91); AIS (n = 20) 200.7 (95% Cl 182-219); and invasive adenocarcinoma (n = 30) 299 (271-328). There was no overlap between the groups of normal endocervical cells and invasive adenocarcinoma, but there was significant overlap between cases of invasive adenocarcinoma and carcinoma in situ. In six out of 17 cases with AIS, NOR count in adjacent morphologically normal glandular cells ("internal" controls) was increased when compared with the "external" (normal endocervical) control group. This suggests the presence of wider field changes not previously identified using routine histological methods. The findings suggest that AIS is a potential premalignant precursor of invasive adenocarcinoma, but that assessment of NORs is of no practical use in discriminating between the histological types of cervical carcinoma.
Adenocarcinoma↗
Reabsorption of dicarboxylic acids from the proximal convolution of rat kidney.
The transport of dicarboxylic acid in the late proximal convolution was investigated by measuring the 3.5 s efflux of 2-oxoglutarate from the tubular lumen of rats starved for 3 days. The 3.5 s efflux of 2-oxoglutarate comprises two components, one due to movement across the brush border, obeying Michaelis Menten kinetics with an apparent Km of 0.13 mmol/l and a Jmax of 0.41 pmol cm-1 s-1 and the other due to diffusional movement presumably via the paracellular pathway with a permeability of 23.0 microns2 s-1. Omission of sodium from the perfusion fluid reduced the transcellular efflux of 2-oxoglutarate by 76%, indicating a sodium-dependent transport system. Addition of 5 mmol/l lithium to the liminal and capillary perfusate reduced it by 56% indicating a specific inhibitory effect of lithium on dicarboxylic acid transport. Addition of 5 mmol/l H2DIDS to the luminal perfusate reduced 3.5 s transcellular 2-oxoglutarate efflux by 35%. The molecular specificity of the system was assessed by studying the inhibitory effects of a series of dicarboxylates, both aliphatic and aromatic, on the 3.5 s efflux of 2-oxoglutarate. Inhibitory constants (apparent Ki) were calculated for comparative purposes assuming competitive inhibition. From this, the system was found to have optimal affinity for dicarboxylates in the trans-configuration with a four or five carbon chain (i.e. succinate and glutarate). Substitution on the 2-carbon atom with CH3-, OH-, SH-, and O = resulted in little reduction in inhibitory potency as compared to succinate itself. However, 2-substitution with NH3+ (not with N-acetyl) as well as 2,3-disubstitution with CH3-, OH- or SH-, strongly reduced or abolished the inhibitory potency. Only with the exception of pyruvate all monocarboxylates tested, did not inhibit 2-oxoglutarate transport, but all tricarboxylates tested, i.e. citrate, isocitrate and tricarballate had an inhibitory effect. Citrate inhibition was higher at acidic than alkaline pH. A number of aromatic compounds was also tested. In most cases the inhibitory potency of the aromatic compounds was considerably weaker than that of the effective 4-5 carbon chain aliphatic compounds. Only benzene-1,4-dicarboxylate, benzene-2-nitro-1,4-dicarboxylate, and benzene-1,2-diacetate had a high inhibitory potency. In the case of the aromatic dicarboxylates the most important feature relating molecular structure to transport was the distance between the two carboxyl-groups in the molecule.(ABSTRACT TRUNCATED AT 400 WORDS)
Absorption↗
The detection of microsatellite instability in blind endometrial samples--a potential novel screening tool for endometrial cancer in women from hereditary nonpolyposis colorectal cancer families?
Microsatellite instability (MSI) is the phenotypic molecular characteristic of the majority of tumors associated with the hereditary nonpolyposis colorectal cancer syndrome (HNPCC). Women in this group have an increased risk of endometrial cancer (EC). This study aimed to determine whether MSI could be demonstrated in blind endometrial samples from women with EC, HNPCC kindreds undergoing screening for EC, and women with normal endometrium. Twenty-four women with EC, 20 women from HNPCC kindreds, and 20 women undergoing gynecological surgery for benign indications underwent blind sampling. MSI analysis was performed by conventional polymerase chain reaction using fluorescent-labeled primers and automated analysis. Twelve microsatellites were studied with MSI defined as evident when novel alleles were seen in endometrial biopsy samples compared to genomic DNA. Of the 24 EC samples obtained, sufficient DNA for analysis was extracted in 17 cases. Three cases had evidence of MSI in at least 7/12 loci. None of the endometrium from the two other study groups revealed evidence of MSI. This is the first demonstration of MSI in blind endometrial biopsies. The ability to demonstrate MSI in heterogeneous endometrial samples suggests potential for the development of a novel EC screening tool for women in HNPCC kindreds.
Adult↗