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K J Bradley

Publications and source records attributed to K J Bradley.

15 recordsLinked to original sources
PubMed2006

Parafibromin is a nuclear protein with a functional monopartite nuclear localization signal.

Parafibromin is a nuclear protein with a tumour suppressor role in the development of non-hereditary and hereditary parathyroid carcinomas, and the hyperparathyroidism-jaw tumour (HPT-JT) syndrome, which is associated with renal and uterine tumours. Nuclear localization signal(s), (NLS(s)), of the 61 kDa parafibromin remain to be defined. Utilization of computer-prediction programmes, identified five NLSs (three bipartite (BP) and two monopartite (MP)). To investigate their functionality, wild-type (WT) and mutant parafibromin constructs tagged with enhanced green fluorescent protein or cMyc were transiently expressed in COS-7 cells, or human embryonic kidney 293 (HEK293) cells, and their subcellular locations determined by confocal fluorescence microscopy. Western blot analyses of nuclear and cytoplasmic fractions from the transfected cells were also performed. WT parafibromin localized to the nucleus and deletions or mutations of the three predicted BP and one of the predicted MP NLSs did not affect this localization. In contrast, deletions or mutations of a MP NLS, at residues 136-139, resulted in loss of nuclear localization. Furthermore, the critical basic residues, KKXR, of this MP NLS were found to be evolutionarily conserved, and over 60% of all parafibromin mutations lead to a loss of this NLS. Thus, an important functional domain of parafibromin, consisting of an evolutionarily conserved MP NLS, has been identified.

Amino Acid Sequence↗
PubMed2006

Parafibromin mutations in hereditary hyperparathyroidism syndromes and parathyroid tumours.

OBJECTIVE: To investigate two patients with the hyperparathyroidism-jaw tumour (HPT-JT) syndrome and three patients with familial isolated hyperparathyroidism (FIHP), together with 31 parathyroid tumours (2 HPT-JT, 2 FIHP and 27 sporadic) for HRPT2 mutations. The HPT-JT syndrome and FIHP are autosomal dominant disorders that may be caused by abnormalities of the HRPT2 gene, located on chromosome 1q31.2. HRPT2 encodes a 531 amino acid protein, parafibromin, which interacts with human homologues of the yeast Paf1 complex. DESIGN: Leukocyte and tumor DNA was used with HRPT2-specific primers for polymerase chain reaction amplification of the 17 exons and their splice junctions, and the DNA sequences of the polymerase chain reaction products determined. RESULTS: Three heterozygous germline HRPT2 mutations, two in HPT-JT and one in FIHP patients, were identified. These consisted of one 1-bp duplication (745dup1bp), 1 nonsense (Arg234Stop) and 1 missense (Asp379Asn) mutation. One parathyroid tumour from an FIHP patient was demonstrated to harbour a germline deletion of 1 bp together with a somatic missense (Leu95Pro) mutation, consistent with a 'two-hit' model for hereditary cancer. The 27 sporadic benign parathyroid tumours did not harbour any HRPT2 somatic mutations. Six HRPT2 polymorphisms with allele frequencies ranging from 2% to 15% were detected. CONCLUSIONS: Our results have identified three novel HRPT2 mutations (two germline and one somatic). The Asp379Asn mutation is likely to disrupt interaction with the human homologue of the yeast Paf1 complex, and the demonstration of combined germline and somatic HRPT2 mutations in a parathyroid tumour provide further evidence for the tumour suppressor role of the HRPT2 gene.

Adult↗
PubMed2005

Uterine tumours are a phenotypic manifestation of the hyperparathyroidism-jaw tumour syndrome.

The hyperparathyroidism-jaw tumour (HPT-JT) syndrome is an autosomal dominant disorder characterized by parathyroid tumours, which are frequently carcinomas, and ossifying jaw fibromas. In addition, some patients may develop renal tumours and cysts. The gene causing HPT-JT, which is referred to as HRPT2 and is located on chromosome 1q31.2, encodes a 531 amino acid protein called PARAFIBROMIN. To date 42 mutations, of which 22 are germline, have been reported and 97% of these are inactivating and consistent with a tumour suppressor role for HRPT2. We have investigated another four HPT-JT families for germline mutations, searched for additional clinical phenotypes, and examined for a genotype-phenotype correlation. Mutations were found in two families. One family had a novel deletional-insertion at codon 669, and the other had a 2 bp insertion at codon 679, which has been reported in four other unrelated patients. These five unrelated patients and their families with the same mutation were not found to develop the same tumours, thereby indicating an absence of a genotype-phenotype correlation. An analysis of 33 HPT-JT kindreds revealed that affected women in 13 HPT-JT families suffered from menorrhagia in their second to fourth decades. This often required hysterectomy, which revealed the presence of uterine tumours. This resulted in a significantly reduced maternal transmission of the disease. Thus, the results of our analysis expand the spectrum of HPT-JT-associated tumours to include uterine tumours, and these may account for the decreased reproductive fitness in females from HPT-JT families.

Adult↗
PubMed2005

Utilisation of a cryptic non-canonical donor splice site of the gene encoding PARAFIBROMIN is associated with familial isolated primary hyperparathyroidism.

More than 99% of all splice sites conform to consensus sequences that usually include the invariant dinucleotides gt and ag at the 5' and 3' ends of the introns, respectively. We report on the utilisation of a non-consensus (non-canonical) donor splice site within exon 1 of the HRPT2 gene in familial isolated primary hyperparathyroidism (FIHP). HRPT2 mutations are more frequently associated with the hyperparathyroidism-jaw tumour syndrome (HPT-JT). Patients with FIHP were identified to have a donor splice site mutation, IVS1+1 g-->a, and the consequences of this for RNA processing were investigated. The mutant mRNA lacked 30 bp and DNA sequence analysis revealed this to result from utilisation of an alternative cryptic non-canonical donor splice site (gaatgt) in exon 1 together with the normally occurring acceptor splice site in intron 1. Translation of this mutant mRNA predicted the in-frame loss of 10 amino acids in the encoded protein, termed PARAFIBROMIN. Thus, these FIHP patients are utilising a ga-ag splice site pair, which until recently was considered to be incompatible with splicing but is now known to occur as a rare (<0.02%) normal splicing variant.

Adult↗
PubMed2003

Non-functioning pituitary adenomas with positive immunoreactivity for ACTH behave more aggressively than ACTH immunonegative tumours but do not recur more frequently.

OBJECTIVES: Anecdotal reports have suggested that silent corticotroph tumours behave in an aggressive fashion; however, clear comparative data with other non-functioning adenomas (NFAs) are lacking. The aims of the study were, first, to review the natural history of those non-functioning pituitary adenomas with positive immunoreactivity for ACTH and secondly, to determine whether this subgroup behave more aggressively than ACTH immunonegative NFAs by means of comparison with existing departmental data. METHODS AND PATIENTS: Twenty-eight patients (16 men, mean age 51.3 years) who underwent transsphenoidal surgery in Oxford between 1975 and 2001 for clinically non-functioning adenomas where the subsequent immunostaining was positive for ACTH were identified from the patient database. All patients with silent corticotroph tumours who presented during this time period have been included in the analysis; three of the patients have subsequently died but none have been lost to follow-up. The mean follow-up period was 7.4 years (range 0.5-26.9 years) and the results were compared with departmental data for NFAs which were immunonegative for ACTH. None of the patients had clinical evidence of Cushing's syndrome. Tumour invasiveness was classified according to the modified Hardy criteria (Grade 1 = microadenoma (< 1 cm), Grade 2 = macroadenoma (> 1 cm) +/- suprasellar extension, Grade 3 = local invasion with bony destruction and tumour in sphenoid/cavernous sinus and Grade 4 = central nervous system (CNS) spread or extracranial spread, i.e. metastatic). Tumour recurrence was defined as an increase in tumour size compared with the first postoperative scan which was used as a baseline. Visual field defects were documented in 79% of the 28 patients at presentation compared to 69% in the non-functioning population as a whole (P = 0.3). The preoperative imaging in the silent corticotroph group (13 CT, 14 MRI and one air encephalogram) revealed 68% Grade 2 and 32% Grade 3 adenomas. RESULTS: The recurrence rate in the ACTH immunopositive tumours was 32% at a mean of 5.8 years (range 1-16 years) which was not significantly different from the 33% recurrence rate previously recorded in the ACTH immunonegative tumours (P = 0.9). Two of the patients with silent corticotroph adenomas have suffered multiple recurrences; one patient has had three operations and two courses of radiotherapy for two episodes of recurrence and one patient has had four operations, two courses of radiotherapy and gamma knife therapy after three recurrences in total. In contrast, no patient with an ACTH immunonegative tumour has required more than one course of treatment for tumour regrowth. CONCLUSIONS: This is the first single-centre comparative study of a series of clinically silent ACTH immunopositive tumours and has demonstrated that although they do not recur more often than ACTH immunonegative tumours, when they do regrow they show a more aggressive course. The practical implication of this is that there is no evidence for different postoperative imaging and radiotherapy protocols for ACTH immunopositive and immunonegative NFAs at initial presentation. However, if regrowth of a silent corticotroph tumour does occur then very careful monitoring is essential, after further treatment.

Adenoma↗
PubMed2001

Prevalence of polycystic kidney disease in Persian cats in the United Kingdom.

The prevalence of polycystic kidney disease was assessed in 132 Persian cats, 46 of them referred for the investigation and treatment of medical or surgical conditions, and 86 apparently healthy cats referred specifically to be screened for the disease. Cats referred for the investigation of renomegaly or renal failure were excluded, and cats under 10 months old were only included if they had been examined postmortem. One hundred and twenty-six of the cats were examined ultrasonographically with a 7.5 MHz sector scanner, and the other six cats were examined postmortem. Forty-nine of the 86 cats referred specifically for screening (57.0 per cent) and 16 of the 46 cats referred for other clinical reasons (34.8 per cent) were affected by the disease, giving an overall prevalence of 49.2 per cent.

Age Distribution↗
PubMed2001

Ultrasonographic appearance of the superficial supramammary lymph nodes in lactating dairy cattle.

The superficial supramammary lymph nodes of 54 lactating dairy cows were examined ultrasonographically with a 7.5 MHz linear transducer; each node was measured in two planes within 24 hours of recording the milk somatic cell count. In most cows, the nodes were well demarcated from the surrounding tissue. The parenchyma of the nodes ranged from hypoechoic to anechoic, with a central bright hyperechoic area, and a thin hyperechoic line surrounded the nodes. The size of the nodes varied, but their internal architecture remained relatively consistent. Their mean length was 7.4 cm (range 3.5 to 15 cm) and their mean depth was 2.5 cm (range 1.2 to 5.7 cm). They were significantly larger in cows with more lactations (P<0.05), but there were no correlations between their size and either the time calved or the milk somatic cell count. The lymph nodes on sides which were positive in a California milk test were significantly larger than those on sides which were negative (P<0.05).

Animals↗
PubMed2000

Dysuria resulting from an encapsulated haematoma in a recently spayed bitch.

A 15-month-old bitch was presented for investigation of a two-month history of dysuria. Clinical signs had developed within one day of routine ovariohysterectomy. A rounded mass was palpable in the caudal abdomen which was shown radiographically to displace and compress the urinary bladder. On ultrasonography, the mass was composed primarily of pockets of hypoechoic fluid divided by hyperechoic septae; blood was obtained on fine-needle aspiration. The mass was surgically removed and the dog regained normal urinary function within a few days. Histopathological examination showed the mass to be an encapsulated haematoma, which is likely to have developed as a result of the ovariohysterectomy.

Animals↗
PubMed1997

Effect of agmatine on spinal nociceptive reflexes: lack of interaction with alpha2-adrenoceptor or mu-opioid receptor mechanisms.

Agmatine has been tested i.v. in alpha-chloralose anaesthetised rats for its effects on spinal nociceptive reflexes evoked by mechanical and electrical stimuli. Agmatine did not affect reflexes until very high doses (200 mg/kg, i.v.) which also caused complex cardiovascular disturbances. In spinally intact rats agmatine reduced reflexes; it was slightly less potent when there was carrageenan-induced hind paw inflammation. The alpha2-adrenoceptor antagonist atipamezole (80 microg/kg) did not significantly affect these reductions. In spinalised animals, agmatine caused a generalised increase in background firing which in animals with a non-inflamed paw was significantly reduced after atipamezole. There was no significant change in evoked responses once corrected for background activity. In all groups of animals agmatine, when administered at various doses and times prior to the mu-opioid receptor agonist fentanyl, had no effect on the ID50 of fentanyl.

Adrenergic alpha-Antagonists↗
PubMed1997

Using qualitative research in the management of health care.

Studying everyday life of health care clients and workers can increase the nurse administrator's understanding of the process and impact of changes occurring in today's health care environment. In this article the authors describe qualitative research and the contributions it can make to health care management. Examples of published qualitative research in four areas (organizational behavior, organizational processes, individual perceptions, and leaders' roles and functions) illustrate these contributions. Ways in which nurse administrators can apply qualitative research methods to their work are addressed, including needs assessment, marketing, and program evaluation.

Delivery of Health Care↗
PubMedDate not supplied

Making sense of a new nursing role: a phenomenological study of an organizational change.

Although health care organizational change is a constant phenomenon, little is understood as to how staff experience this change. Unsuccessful change efforts have suggested the possible important relationship between understanding staff's experience and improved results. The purpose of this phenomenological study was to describe what staff on a medical-surgical unit experience during the initial phase of the implementation of a nursing care coordinator position, a first step in a broad organizational change. A purposeful sample of 11 nursing and non-nursing staff, considered unit experts, were interviewed using broad, open-ended questions designed to solicit their experience. Additionally, observations and document abstraction were used to add depth and clarification to the interviews. Analysis of data was conducted using a combination of Giorgi's and Colaizzi's procedures. Contextual elements framing staff's experiences included introduction of a new role with no organizational history into an increasingly demanding environment that staff perceived as constantly changing. Major themes of "experiencing the effect" and "struggling to make sense" were revealed. These findings suggest that the introduction of a new role can create turmoil and job insecurity in the current health care environment. Recommendations to support staff's efforts to "make sense" are provided.

Hospitals, University↗
PubMedDate not supplied

Nurse practitioner services: content and relative work value.

The resource-based relative value scale is used to quantify work for reimbursement of services in the Medicare Fee Schedule. This pilot study explored use of the resource-based relative value scale for services provided by nurse practitioners. Estimation of relative work values for office visits by nurse practitioners was consistent with the Medicare Fee Schedule. Content analysis revealed that nurse practitioners provide additional services including comprehensive patient evaluation and education and attendance to social factors. Future research is needed to examine systems that identify and reimburse nurse practitioners for their services.

Feasibility Studies↗