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Biomedical subjects

J Nicholls

Publications and source records attributed to J Nicholls.

At least 19 recordsLinked to original sources
PubMed1995

The mRNAs for the three chains of human collagen type XI are widely distributed but not necessarily co-expressed: implications for homotrimeric, heterotrimeric and heterotypic collagen molecules.

In cartilage collagen type XI exists as heterotrimeric molecules composed of alpha 1(XI), alpha 2(XI) and alpha 3(XI) subunits. Messenger RNAs for some of the alpha chains of collagen type XI have also been found in non-chondrogenic tissues but the chain composition of the molecule in these sites is not known. Some non-chondrogenic tissues also contain heterotrimers containing collagen alpha 2(V) and alpha 1(XI) chains. We have explored the possibility that collagen type XI could exist in differing trimeric forms in non-chondrogenic tissues and aimed to predict the subunit composition of this collagen in those tissues. The distribution and relative levels of expression of collagen alpha 1(XI), alpha 2(XI) and alpha 3(XI)/alpha 1(II) mRNAs in different human fetal tissues were studied. Expression of mRNAs for all three genes of collagen type XI is not restricted to cartilage but is widespread. However, in some non-chondrogenic tissues, the mRNAs for all three alpha chains of collagen type XI were not co-expressed, but collagen alpha 1(XI) and alpha 2(XI) mRNAs were found either singly or without collagen alpha 3(XI) transcripts. Collagen type XI may therefore exist as homotrimers and/or heterotrimers composed of two collagen alpha(XI) chains in some tissues. The distribution of mRNAs for collagen alpha 2(V) and alpha 1(I) were also studied. Co-expression of collagen type XI, alpha 2(V) and alpha 1(I) mRNAs was found for many tissues. These findings have implications for the possibility of additional chain associations for collagen types XI and V in cross-type heterotrimers within heterotypic fibrils.

Cartilage↗
PubMed1995

Tissue-specific and differential expression of alternatively spliced alpha 1(II) collagen mRNAs in early human embryos.

Expression of the alpha 1(II) procollagen gene is not confined to chondrogenic tissues during vertebrate development. Transcripts of the human gene (COL2A1) are alternatively spliced to give mRNAs which either exclude (type IIB mRNA) or include (type IIA mRNA) an exon encoding a cysteine-rich domain in the amino-propeptide. The distribution of COL2A1 mRNAs in 27- to 44-day human embryos and 8- to 24-week fetuses was studied by in situ hybridization and RNase protection analyses. Type IIA mRNAs were expressed in prechondrogenic cells and were also preferentially expressed in chondrogenic tissues at regions of chondrocyte commitment and cartilage growth. During maturation of chondrocytes, there is a switch to expression of type IIB mRNAs. In non-chondrogenic tissues of early embryos, type IIA mRNA expression was associated with active tissue remodeling, epithelial organization, and sites of tissue interaction. Type IIA mRNAs were also expressed in some non-chondrogenic tissues where expression had previously been undetected, such as the tooth bud, liver, adrenal cortex, apical ectodermal ridge, and indifferent gonad. In older fetuses type IIA mRNAs were the sole or major transcript in most non-chondrogenic tissues except the choroid plexus and tendon. In the meninges there was a unique switch from type IIB to type IIA expression. The expression pattern of COL2A1 transcripts suggests that, in addition to contributing to the structural integrity of the cartilage extracellular matrix, type II procollagen may serve a morphogenetic role in embryonic development. Our findings clearly show that the pattern of expression of type II procollagen mRNAs is largely conserved between man and mouse. However, some differences exist, and these should be taken into consideration when animal models are used to study human diseases associated with COL2A1.

Alternative Splicing↗
PubMed1995

High-dose carboplatin and etoposide for salvage chemotherapy of germ cell tumours.

We evaluated high-dose carboplatin and etoposide with autologous bone marrow stem cell support in the salvage treatment of patients with metastatic germ cell tumours who had failed previous chemotherapy. The treatment programme comprised initial conventional dose chemotherapy. 23 patients received a first cycle of high-dose treatment, and 12 who showed no evidence of progression had a second cycle 2-3 months later. 8 of the 23 patients treated with high-dose chemotherapy are alive in remission 4-29 months from the start of high-dose treatment. 3 of these 8 required further treatment for recurrence. In the initial part of the study, the dose of carboplatin was escalated in successive patients. Grade 3/4 treatment-related toxicity occurred in 4 of 18 patients (1 fatal) who received carboplatin doses to give a AUC (area under the serum concentration/time curve) of 30 mg.min/ml or less and 3 of 5 patients (2 fatal) who received higher doses. We, therefore, recommend 30 mg.min/ml for further evaluation in chemotherapy sensitive patients.

Adolescent↗
PubMed1995

Nine-month changes of maternal expressed emotion in conduct and emotional disorders of childhood: a follow-up study.

In this follow-up study, mothers of 28 children with conduct disorders (CD) and 29 children with emotional disorders (ED) of 6-11 years of age, were interviewed and rated for expressed emotion 9 months after their first clinical assessment. Mothers of children with CD expressed significantly less criticism and higher warmth after 9 months. Initial externalizing scores in the CD group and initial internalizing scores in the ED group at the first assessment predicted symptomatic change, in contrast with EE scales. Initial externalizing scores and low levels of maternal warmth predicted presence of conduct disorder at the last contact with the clinician. The implications of the findings on the development of treatment techniques are discussed.

Affective Symptoms↗
PubMed1995

Expression of immune regulatory molecules in Epstein-Barr virus-associated nasopharyngeal carcinomas with prominent lymphoid stroma. Evidence for a functional interaction between epithelial tumor cells and infiltrating lymphoid cells.

Undifferentiated nasopharyngeal carcinomas (UNPC) are characterized by an association with Epstein-Barr virus and an abundant lymphoid stroma. The role of this lymphoid stroma is uncertain but is mostly thought to represent an immune response against viral or tumor antigens. We have analyzed the expression of immune regulatory receptor/ligand pairs in snap-frozen biopsies of 20 UNPCs. All cases were Epstein-Barr virus positive and the virus-encoded latent membrane protein, LMP1, was expressed in 6 cases. By immunohistochemistry, we have demonstrated the expression of CD70 and CD40 in the tumor cells of 16 and 18 cases, respectively. Infiltrating lymphoid cells expressing CD27, the CD70 receptor, and the CD40 ligand were present in all cases. The Bcl-2 protein was detected in 17 cases. Unexpectedly, tumor cells of 5 cases expressed at least one member of the B7 family (CD80, CD86, and B7-3) and many lymphoid cells expressing the corresponding counter-receptor, CD28, were detected in all cases. Interestingly, 5 of 6 LMP1-positive cases also expressed B7, whereas all 14 LMP1-negative cases were also B7 negative. Our results indicate that T cells and carcinoma cells communicate in the microenvironment of UNPCs and suggest that the presence of a lymphoid stroma may be a requirement for UNPC growth at least in certain stages of tumor development.

Carcinoma↗
PubMed1994

Application of a composite faecal egg count procedure in diagnostic parasitology.

Egg counts from a simple composite faecal counting procedure using equal amounts of sample from ten sheep were compared statistically against the arithmetic means of the same ten samples prepared by a conventional egg counting method. Forty separate data sets were analysed in an untransformed bivariate plot and after natural logarithmic transformation. A sign test analysis indicated a high degree of similarity between the two data sets. A confidence interval for the composite count (n = 10) was calculated to give a result between five eggs more and 15 eggs less than the arithmetic mean count of the ten samples. When multiple faecal samples are to be examined, the composite method has significant advantages in time saving and increased throughput whilst still providing an accurate result. This technique has been used to monitor gastrointestinal helminthosis and for faecal egg count reduction testing to assess anthelmintic efficacy.

Animals↗
PubMed1994

Primary chemotherapy for stage II nonseminomatous germ cell tumors of the testis.

Between 1979 and 1989, 122 patients with clinical stage II testicular nonseminoma were treated with primary platinum-based combination chemotherapy following orchiectomy. Of the patients 58 had Royal Marsden Hospital stage IIA (nodes less than 2 cm. in diameter) and the other 64 had stage IIB (nodes 2 to 5 cm. diameter) disease. With a median followup after chemotherapy of 5.5 years, 118 patients (97%) were disease-free. Two patients died of progressive germ cell tumors, 1 of bleomycin toxicity and 1 of coincidental disease. The 5-year actuarial survival probability was 95% (95% confidence intervals 91 to 99%) and the 5-year failure-free survival probability was 92% (95% confidence intervals 88 to 97%). Tumor substage was not predictive of relapse but did indicate the probability of lymphadenectomy for a post-chemotherapy residual mass since this was performed in 17% of the patients with stage IIA disease and 39% with stage IIB disease (p < 0.05). Resected specimens contained mature teratoma (29), necrosis alone (5) or embryonal carcinoma (1). We conclude that for these clinical stages primary chemotherapy was as effective as primary lymph node dissection and a major operation was avoided in 68% of the cases.

Actuarial Analysis↗
PubMed1994

Peripheral blood involvement in non-Hodgkin's lymphoma detected by clonal gene rearrangement as a biological prognostic marker.

Peripheral blood from 67 patients with non-Hodgkin's lymphoma was examined at initial diagnosis for the presence of circulating lymphoma cells by DNA hybridisation using immunoglobulin and T-cell receptor gene probes. Clonal gene rearrangement was found in 31% (21/67) of patients and correlated with clinical stage, histological grade and bone marrow involvement. Clinical stage and the presence of lymphoma cells in peripheral blood were prognostic factors for progression-free survival in all patients on univariate analysis, but the detection of lymphoma cells was not independent of stage. It was also not a significant predictor for survival. In patients with intermediate- and high-grade lymphoma, the detection of lymphoma cells in peripheral blood was a significant prognostic factor for progression-free survival (PFS) and survival only on univariate analysis. The 3-year PFS was 17% in patients with circulating lymphoma cells compared with 75% if these were absent (P < 0.05). The presence of lymphoma cells in peripheral blood is associated with extensive disease and may be a biological marker of poor disease control. Sensitive techniques of detection should form part of large prospective studies in non-Hodgkin's lymphoma.

Adult↗
PubMed1994

Maternal expressed emotion in conduct and emotional disorders of childhood.

Maternal expressed emotion (EE) scales were rated for children aged 6-11 with conduct disorders, emotional disorders and a group of non-referred children matched for sex and age (N = 30 in each of the three groups). Maternal warmth distinguished significantly between the three groups (CD < ED < Controls), while criticism distinguished the group of conduct disordered children. Maternal criticism was positively associated with child behaviour ratings even within the non-referred group. These observational ratings of warmth and criticism were found to be much more strongly associated with child behaviour than maternal ratings of their family environment.

Adult↗
PubMed1994

Detection of wild type and exon 5-deleted splice variant oestrogen receptor (ER) mRNA in ER-positive and -negative breast cancer cell lines by reverse transcription/polymerase chain reaction.

Using reverse transcription (RT)/PCR we have shown that four breast cancer cell lines expressed oestrogen receptor (ER) mRNA, irrespective of whether they were assessed as ER-positive (MCF-7 and BT-474) or ER-negative (MDA-MB-231 and BT-20) by enzyme immunoassay (EIA). In addition to the wild type (WT) form, they were all found to express the exon 5-deleted variant (V) form of ER mRNA by RT/PCR; this is thought to code for a truncated constitutively active protein. By Northern blot analysis only the ER-positive cell lines (MCF-7 and BT-474) were found to express detectable levels of ER mRNA. Oestradiol-induced growth was found only in the ER-positive (by EIA) cell lines. These results confirm that the differences between ER-positive and ER-negative cell lines are quantitative rather than qualitative. As low levels of ER mRNA could be detected by RT/PCR, this may reflect the greater sensitivity of this approach. The presence of exon 5-deleted V form ER mRNA in addition to the WT form in all four breast cancer cell lines may allow these lines to be used to assess differential regulation of transcription and the impact of this on their oestrogen dependence.

Base Sequence↗
PubMed1994

GnRH neurons and other cell populations migrating from the olfactory neuroepithelium.

Cell migration from the olfactory neuroepithelium to the brain has been widely studied during vertebrate development. Immunocytochemical analysis has revealed that many of the migrating cells contain GnRH (Gonadotropin-Releasing Hormone). The GnRH positive cells migrate from the medial olfactory placode, steam along the nasal septum, cross the basal forebrain and reach the hypothalamic and septal areas from where they control the release of hypophyseal gonadotropic peptides. A peculiar feature of these cells is that they start expressing GnRH during migration. We have analysed the presence of immunoreactivity for peptides typically expressed in olfactory neurones, along the migratory pathway followed by GnRH neurones. We have used polyclonal antibodies raised against carnosine and olfactory marker protein (OMP), and performed double immunolabelling on mouse embryos and on early neonatal Brazilian opossum (Monodelphis domestica) tissues. Beside the GnRH neurones we observed other migrating cells along the pathway traced by olfactory terminal and vomeronasal nerves. Most of these cells co-express carnosine and OMP. The carnosine/OMP migrating cells are detectable in later developmental stages than GnRH neurones. GnRH neurones do not express either OMP or carnosine. By keeping in culture explants of the brain together with the olfactory region from newborn opossums, we have shown that it is possible to obtain the migration of the different populations in vitro. Moreover the GnRH cells are co-distributed, but different from those expressing olfactory markers.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Control of aromatase in breast cancer cells and its importance for tumor growth.

Three approaches have been taken to elucidate further the biological importance of intratumoural aromatase activity. (i) MCF7 and T47D hormone-dependent breast cancer cell lines both showed detectable aromatase activity in vitro. The up-regulation of this by TGF alpha indicates the possible existence of an autocrine growth stimulatory loop involving aromatase. (ii) Both tamoxifen and cytotoxic chemotherapy caused the suppression of aromatase activity in breast carcinomas in vivo. Aromatase activity prior to treatment did not predict for clinical response to tamoxifen. (iii) Transfection of aromatase into MCF7 cells led to their growth being stimulated by low doses of androgens and this was inhibited by the aromatase inhibitor CGS 16949A.

Aromatase↗
PubMed1993

In-situ carcinoma adjacent to recurrent nasopharyngeal carcinoma. Evidence of a new growth?

Eighty biopsies from 74 patients with recurrent nasopharyngeal carcinoma diagnosed in the years 1988 to 1990 inculsive were reviewed. The overlying epithelium was assessed for the presence of in-situ malignant change using a Gomori reticulin stain in addition to the routine haematoxylin and eosin stain. In-situ change was seen in the overlying epithelium or adjacent epithelium in 11 of these biopsies from 10 patients (13.5%). These changes were extensive and where normal epithelium was seen there was an abrupt transition from the normal to abnormal epithelium. As patients treated for NPC sustain such a high risk of developing another new growth, close and careful follow up of these patients will allow a good opportunity for research into the carcinogenesis of this tumor.

Carcinoma in Situ↗
PubMed1993

Assessment of psychosocial experiences in childhood: methodological issues and some illustrative findings.

The development of a new standardised investigator-based interview, PACE (Psychosocial Assessment of Childhood Experiences), for the assessment of acute life events and long-term psychosocial experiences is described. An application of PACE to a sample of 84 children referred to psychiatric clinics and 22 general population controls, is presented. Reliability was assessed using a separate clinic sample of 15 child-parent pairs. The findings showed that PACE has satisfactory reliability and discriminant validity.

Adaptation, Psychological↗
PubMed1993

Characterization and ontogeny of P1-purinoceptors on rat vas deferens.

1. The P1-purinoceptors which mediate the inhibition by adenosine of nerve-mediated contraction of the rat vas deferens have been investigated by use of the agonists N6-cyclopentyladenosine (CPA) and 5'-N-ethylcarboxamidoadenosine (NECA) and the A1-selective antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX). The ontogeny of the responses to adenosine and to the two co-transmitters which induce the contractions in this tissue, adenosine 5'-triphosphate (ATP) and noradrenaline (NA), have also been studied. 2. The order of potency for the adenosine agonists in inhibiting the nerve-mediated contractions was CPA = NECA > adenosine. Micromolar concentrations of DPCPX were required to antagonize the inhibition by adenosine and NECA of nerve-mediated responses, whereas the inhibitory effect of CPA was antagonized by nanomolar concentrations of the antagonist. 3. NECA and adenosine inhibited contractions induced by ATP (10 microM) or by NA (10 microM), NECA being at least ten fold more potent than adenosine, whereas CPA was inactive. Micromolar concentrations of DPCPX were required to antagonize the effect of adenosine on the contractions induced by ATP (10 microM). 4. Nerve-stimulated contractions could be observed in neonatal tissues from day 15 and increased with age, and could be inhibited by adenosine from this time, the potency of adenosine decreasing with age. Responses to ATP also appeared at day 15 and increased with age up to day 25, while responses to NA were present from day 10 (the earliest day tested) and decreased with age. 5. These results show that the rat vas deferens contains both prejunctional Al-receptors and postjunctional A2-receptors, and that adenosine acts on the latter populations to inhibit nerve-mediated contractions.The high potency of adenosine in the neonate and the parallel development of responses to ATP and to nerve-mediated contractions support suggestions that purinergic responses may be particularly important in neonatal tissues.

Adenosine↗