Biomedical subjects
Publications and source records attributed to J Gibbins.
We report a 47-year-old man with myelofibrosis who presented with bilateral nephromegaly secondary to extramedullary haematopoiesis. We discuss diagnosis and treatment of this rare case and review the literature.
OBJECTIVE: to explore, describe and understand the expectations during pregnancy and subsequent experiences of childbirth in primiparae. DESIGN: a qualitative study using a phenomenological approach. Data were collected using unstructured, tape-recorded interviews in late pregnancy and at two weeks post birth. SETTING: the north of England. PARTICIPANTS: eight pregnant women, expecting their first baby. FINDINGS: the women all wanted to take an active part in their labour and the feeling of being 'in control' was the main finding and the 'essence' of this study. This was achieved through support from partners, the positive attitudes of the midwives caring for them during pregnancy and labour, information giving during pregnancy and labour and being able to make and be included in decision making during labour. IMPLICATIONS FOR PRACTICE: if women are to be empowered by making choices for childbirth and feeling 'in control', then it is important for midwives to explore and discover the wishes and feelings of women in their care so that realistic expectations can be promoted and then hopefully fulfilled.
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Palatal clefting is often associated with premature fusion of cranial sutures in human craniosynostosis syndromes, many of which are characterised by mutations affecting the fibroblast growth factor receptor (FGFR) gene family. In palatal fusion, epithelio-mesenchymal transition (EMT) contributes to the dispersion of the midline epithelial seam. EMT has also been observed in neoplastic epithelial cells in relation to the acquisition of malignant characteristics where morphological changes are accompanied by rapid switching in the expression of fgfr2 from the epithelial type (kgfr) to the mesenchymal type (bek). The twist gene codes for a basic helix-loop-helix transcription factor putatively involved in regulation of transcription of fgfr2. Mutations in the TWIST gene have been described as being responsible for the Saethre-Chotzen syndrome, an autosomal dominant craniosynostosis associated with cleft palate as well as other disturbances of the facial skeleton. In this study we have analysed the distribution of twist transcripts during rat palatogenesis in vivo from 14.5 to 17.5 days post coitum by in situ hybridisation with digoxygenin-labelled ssDNA probes. twist transcripts were found to be concentrated in mesenchymal cells beneath the epithelium at the tip of the palatal shelves immediately prior to, and during fusion as well as in a localised epithelial area at the tip of the shelves prior to fusion, thereby implicating twist gene expression in the process of palatogenesis. This pattern of expression illuminates the disturbances of maxillary growth that occur in human craniosynostotic syndromes.
An optimal method for the processing of archival cervical Papanicolaou (pap)-stained smears for the amplification of human papillomavirus (HPV) DNA by polymerase chain reaction (PCR) was developed. This methodology was then applied to a series of 44 pap smears designated as HPV positive or negative (on the basis of both major and minor cytological criteria) or cervical intraepithelial neoplasia (CIN)-cancer. For the detection of HPV DNA, each sample was tested with the consensus GP5/6 primers, and when negative, with CPI-IIG primers. The HPV DNA was detected in 100% (8 of 8) of CIN-cancer smears using the GP5/6 primers. In smears with cytological evidence of HPV without CIN. the use of both sets of primers yielded positive results in 100% (19 of 19) of the samples. Direct sequence analysis of PCR products showed that 16 of the 27 HPV-positive samples contained more recently described HPV types. When tested with both primer combinations, all 17 cytologically negative smears were positive for beta-globin but negative for HPV DNA. The findings show the value of using archival pap smears for further investigations to address issues such as latency, but they indicate that cytological criteria and DNA technology will be critical factors in the reliability of the results.
Since megakaryocytes are the cellular precursors of platelets we have investigated whether they share responses to platelet agonists, in particular collagen. Although previous studies have reported responses to thrombin in non-human megakaryocytes, through studies of single cell calcium responses and protein tyrosine-phosphorylation we demonstrate for the first time that both isolated human megakaryocytes and CD41/61-positive megakaryocytes derived in culture from CD34+ cells share responses to the platelet agonists collagen, collagen-related peptide and thrombin. The responses to either collagen or CRP were seen only in the most mature megakaryocytes and not in megakaryocyte-like cell lines, suggesting that the response to collagen is a characteristic developed late during megakaryocyte differentiation. These primary cells offer the opportunity to use many molecular and cellular techniques to study and manipulate signalling events in response to platelet receptor agonists, which cannot be performed in the small, anucleate platelet itself.
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Stimulation of platelets by the extracellular matrix protein collagen leads to activation of a tyrosine kinase-dependent mechanism resulting in secretion and aggregation. Tyrosine phosphorylation of the tyrosine kinase Syk and phospholipase Cgamma2 are early events in collagen-induced activation. We recently proposed that collagen-signaling in platelets involves a receptor or a receptor-associated protein containing an immunoreceptor tyrosine-based activation motif (ITAM) enabling interaction with Syk. In this report we show that collagen stimulation of platelets causes rapid tyrosine phosphorylation of the ITAM containing Fc receptor gamma-chain and that this is precipitated by the tandem Src homology 2 (SH2) domains of Syk expressed as a fusion protein. In addition we demonstrate an association between the Fc receptor gamma-chain with endogenous Syk in collagen-stimulated platelets. The Fc receptor gamma-chain undergoes tyrosine phosphorylation in platelets stimulated by a collagen-related peptide which does not bind the integrin alpha2beta1 and by the lectin wheat germ agglutinin. In contrast, cross-linking of the platelet low affinity receptor for immune complexes, FcgammaRIIA, or stimulation by thrombin does not induce phosphorylation of the Fc receptor gamma-chain. The present results provide a molecular basis for collagen activation of platelets which is independent of the integrin alpha2beta1 and involves phosphorylation of the Fc receptor gamma-chain, its association with Syk and subsequent phosphorylation of phospholipase Cgamma2. Collagen is the first example of a nonimmune receptor stimulus to signal through a pathway closely related to signaling by immune receptors.
Glutathione-S-transferase (GST)-Grb2 fusion proteins have been used to identify the potential role of Grb2-binding proteins in platelet activation by the platelet low-affinity IgG receptor, Fc gamma RIIA. Two tyrosine phosphoproteins of 38 and 63 kD bind to the SH2 domain of Grb2 following Fc gamma RIIA stimulation of platelets. Both are located in the particulate fraction following platelet activation and are also able to bind to a GST-construct containing the SH2 and SH3 domains of phospholipase C gamma 1. p38 also forms a complex with the tyrosine kinase csk in stimulated cells and is a substrate for the kinase. The SH3 domains of Grb2 form a stable complex with SOS1 and two proteins of 75 kD and 120 kD, which undergo tyrosine phosphorylation in Fc gamma RIIA stimulated cells. The 75-kD protein is recognized by antibodies to SLP-76, which has recently been isolated from T cells and sequenced. Tyrosine phosphorylation of p38 and p63 is also observed in platelets stimulated by the tyrosine kinase-linked receptor agonist collagen and by the G protein-coupled receptor agonist thrombin, although phosphorylation of SLP-76 is only observed in collagen-stimulated platelets. p38 and p63 may provide a docking site for Grb2, thereby linking Grb2 SH3-binding proteins SOS1, SLP-76, and p120 to downstream signalling events.
In view of the reported inflammatory effects of corticotrophin-releasing factor (CRF) and the associated regulatory elements in the gene of its binding protein (BP), we postulate that both BP as well as novel BP-ligands other than CRF may be involved in inflammatory disease. We have investigated BP in the blood of patients with arthritis and septicaemia and have attempted to identify CRF and other BP-ligands in synovial fluid. The BP was found to be significantly elevated in the blood of patients with rheumatoid arthritis and septicaemia. There was less BP-ligand and CRF in synovial fluid from patients with rheumatoid arthritis that from those with osteo- or psoriatic arthritis. There was at least 10-fold more BP-ligand than CRF in the fluid of all three groups of patients. A small amount of immunoreactive human (h)CRF, eluting in the expected position of CRF-41, was detected after high-pressure liquid chromatography of arthritic synovial fluid; however, the bulk of material with BP-ligand binding activity eluted earlier, suggesting that synovial fluid contained novel peptides that interacted with the BP. These results would suggest that the BP and its ligands could play an endocrine immunomodulatory role in inflammatory disease.
In this study, hospital admissions for lower respiratory tract illness before two years of age have been documented for all children born in Western Australia in 1986. Admissions data were linked to birth and death records for individual children. Of the total cohort, 5% of non-Aboriginal and 17% of Aboriginal children were hospitalised only once for lower respiratory tract illness; 1% of non-Aboriginal and 11% of Aboriginal children had repeated admissions. Perinatal conditions comprised the greatest proportion of the admissions for non-Aboriginal children, and pneumonia for Aboriginal children. Non-Aboriginal children had decreasing admission rates from the neonatal period onwards, whereas those for Aboriginal children increased. For all children, those of low or high birthweight, male sex and those with young or unmarried mothers or residing in country regions were more likely to be admitted. This research has highlighted potential risk factors for serious respiratory illness in early childhood and has shown the feasibility of using linked data for the total population to formulate and test hypotheses relating to respiratory morbidity.
This paper describes a linked total population database established in Western Australia for monitoring and evaluating maternal and child health and for conducting epidemiological studies. Good vital statistics data including all Western Australian hospitalisations and excellent birth defects and cerebral palsy registers have ensured that complete data are available. Examples of studies which have been conducted using the database are given.
A linked data file of birth records and hospital admissions was used to investigate inpatient hospital morbidity before 2 years of age for all non-Aboriginal and Aboriginal children born in Western Australia in 1986. Of the non-Aboriginal children, 31.8% were admitted to hospital at least once before the age of 2 years, with an overall admission rate of 526/1000 live births; the corresponding figures for Aboriginal children were 68.7% and 2797. The mean number of days in hospital for each non-Aboriginal child admitted was 7.4, and 26.5 for Aboriginal children. Of the total cohort, 21% of non-Aboriginal and 20% of Aboriginal children were admitted only once, and 4% of non-Aboriginal and 36% of Aboriginal children were admitted at least three times; 23% of non-Aboriginal and 24% of Aboriginal children were admitted for only one major disease category, and 1% of non-Aboriginal and 16% of Aboriginal children were in at least four categories. The highest admission rates and highest percentages of the cohort admitted were for gastrointestinal and respiratory diseases and social admissions. These results illustrate the importance for both descriptive and analytical research of relating admissions to hospital for the total population to the individual child, and of using clinically relevant disease classifications.
The nucleotide sequence of the Azotobacter vinelandii ntrA gene has been determined. It encodes a 56916 Dalton acidic polypeptide (AvNtrA) with substantial homology to NtrA from Klebsiella pneumoniae (KpNtrA) and Rhizobium meliloti (RmNtrA). NtrA has been shown to act as a novel RNA polymerase sigma factor but the predicted sequence of AvNtrA substantiates our previous analysis of KpNtrA in showing no substantial homology to other known sigma factors. Alignment of the predicted amino acid sequences of AvNtrA, KpNtrA and RmNtrA identified three regions; two showing greater than 50% homology and an intervening sequence of less than 10% homology. The predicted protein contains a short sequence near the centre with homology to a conserved region in other sigma factors. The C-terminal region contains a region of homology to the beta' subunit of RNA polymerase (RpoC) and two highly conserved regions one of which is significantly homologous to known DNA-binding motifs. In A. vinelandii, ntrA is followed by another open reading frame (ORF) which is highly homologous to a comparable ORF downstream of ntrA in K. pneumoniae and R. meliloti.
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