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D Kelly

Publications and source records attributed to D Kelly.

At least 37 records · Page 2Linked to original sources
PubMed2001

A clinico-pathological study of Cushing's syndrome at the University Hospital of the West Indies and a review of the literature.

Cushing's syndrome is an uncommon but important disease. Twenty-one confirmed cases of spontaneous Cushing's syndrome were documented at the University Hospital of the West Indies over a 21-year period. They were predominantly young females (F:M ratio of 17:4; mean age 25 years and 3 months). The commonest presenting symptoms were amenorrhoea (41%) and obesity (19%). Common clinical features were cushingnoid features (95%), hypertension (76%) and hirsutism (82%). Twenty-nine per cent had frank hyperglycaemia. Cushing's syndrome was due to Cushing's disease in 10 cases, adrenal adenoma in 3 and adrenal carcinoma in 2 cases. In 4 cases with presumed adrenal hyperplasia, the histology was either unavailable or was not consistent with the diagnosis. Two cases appear now to have had the ectopic ACTH Syndrome. Adrenalectomy was the commonest treatment offered. There were no intra-operative or post-operative deaths but recurrence was common after subtotal adrenalectomy in Cushing's disease. Twenty-seven per cent of the patients developed Nelson's syndrome, which was fatal in 50%. Long-term hormone replacement therapy was unnecessary after surgery for adrenal adenomas. Treatment of Cushing's syndrome was well tolerated by the patients.

ACTH Syndrome, Ectopic↗
PubMed2000

Isolation, characterization, and differential expression of the murine Sox-2 promoter.

Sox proteins are expressed at many stages of development and in numerous tissues. The transcription factor Sox-2 is first expressed throughout the inner cell mass and subsequently becomes localized to the primitive ectoderm, developing central nervous system, and the lens. Sox-2 is also highly expressed in F9 embryonal carcinoma cells, but becomes undetectable following differentiation of these cells. In this study, we have isolated, sequenced, and performed the first characterization of the Sox-2 promoter of any species. Approximately 2kb of the Sox-2 5'-flanking region has been sequenced and the primary transcription start site mapped by primer extension analysis. Additionally, two positive regulatory regions within the promoter region have been identified. We also show that expression of Sox-2 promoter/reporter gene constructs is reduced in differentiated EC cells as compared to their undifferentiated counterparts. Furthermore, we have identified a consensus inverted CCAAT box motif present in the Sox-2 promoter. Mutagenesis of this site significantly reduces the expression of Sox-2 promoter/reporter constructs. We also demonstrate that this CCAAT box motif can bind the trimeric transcription factor NF-Y.

Animals↗
PubMed2000

Early nutrition and the development of immune function in the neonate.

The present review will concentrate on the development of the gut-associated lymphoid tissue and the role of early nutrition in promoting immune function. The intestine is the largest immune organ in the body, and as such is the location for the majority of lymphocytes and other immune effector cells. The intestine is exposed to vast quantities of dietary and microbial antigens, and is the most common portal of entry for pathogens, some of which are potentially lethal. The development of normal immune function of the intestine is therefore vital for survival, and is dependent on appropriate antigen exposure and processing, and also an intact intestinal barrier. In early life innate mechanisms of defence are probably more important than active or adaptive mechanisms in responding to an infectious challenge, since the healthy neonate is immunologically naïve (has not seen antigen) and has not acquired immunological memory. During this period maternal colostrum and milk can significantly augment resistance to enteric infections. The mechanisms of enhancing disease resistance are thought to be passive, involving a direct supply of anti-microbial factors, and active, by promoting the development of specific immune function. A tolerance response to dietary and non-invasive antigens is generally induced in the gut. However, it must also be able to mount an adequate immune response to ensure clearance of foreign antigens. It is now recognized that regulation of tolerance and active immune responses is critical to health, and failure to regulate these responses can lead to recurrent infections, inflammatory diseases and allergies. The education of the immune system in early life is thought to be critical in minimizing the occurrence of these immune-based disorders. During this phase of development maternal milk provides signals to the immune system that generate appropriate response and memory. One factor that has been proposed to contribute to the increase in the incidence of immune-based disorders, e.g. atopic diseases in Western countries, is thought to be the increased prevalence of formula-feeding.

Animals↗
PubMed2000

Endothelial changes precede mucosal ulceration induced by indomethacin: an experimental study in the rat.

BACKGROUND: Indomethacin has been shown to damage the villous microvasculature concomitant with alterations in villous blood flow in the rat. AIM: To test the hypothesis that alterations in blood flow result from ultrastructural damage to microvasculature endothelium. METHODS: In anaesthetized rats, jejunal villi were exteriorized in a chamber and blood flow in surface capillaries visualized by fluorescence microscopy. Villi were exposed both luminally and systemically to indomethacin (100 microg/mL) for 10 min or until blood slowing or stasis had occurred in superficial capillaries (n=3 per group). Control animals received both a luminal and intravenous vehicle for 45 min (n=3). The small intestines were vascular perfusion-fixed with 1.5% glutaraldehyde and studied by transmission electron microscopy. RESULTS: All controls appeared to be ultrastructurally normal. A 10 min exposure to indomethacin had no effect upon the epithelium but resulted in mild endothelial vacuolization and the development of small finger-like projections into the lumen of villus surface microvasculature. At the point of blood slowing, villus tip epithelium was again normal but the endothelial vacuolization and finger-like projections became more obvious. The endothelial projections and vacuolization became severe at the point of blood stasis; this also coincided with epithelial degeneration. CONCLUSION: This study shows that villus surface microvasculature is the earliest site of morphological damage after indomethacin exposure.

Animals↗
PubMed2000

Intervention studies to reduce the prevalence and incidence of pressure sores: a literature review.

Much has been written about the prevention of pressure sores. However, electronic and manual searches located only 10 studies within the literature in the UK that described interventions able to reduce either their incidence or prevalence. All the studies located contained serious methodological flaws. Apparent success in reducing the number or severity of pressure sores could have resulted because staff involved in data collection were aware that the study was being undertaken and thus took more interest in pressure area care. From the review findings it is apparent that there is a dearth of research evidence upon which to base practice in the sphere of pressure sore prevention and further research is urgently required.

Humans↗
PubMed2000

Experience with quinupristin/dalfopristin in treating infections with vancomycin-resistant Enterococcus faecium in children.

BACKGROUND: The emergence and spread of vancomycin-resistant Enterococcus faecium (VREF) has presented serious therapeutic difficulties because of the lack of reliably active antibiotics. Quinupristin/dalfopristin is a new injectable streptogramin antibiotic that is active against most strains of VREF. Experience with this agent in adults with VREF infections is well-documented; however, there are few reports of its use in children. We report on eight children with VREF infections who received quinupristin/dalfopristin under a compassionate use protocol. METHODS: Quinupristin/dalfopristin was administered according to the manufacturer's recommendations. Clinical and laboratory data were recorded for each patient. RESULTS: The infections treated comprised six cases of bacteremia and two of peritonitis. All patients had serious underlying conditions. Seven patients recovered fully. One patient died, having experienced a relapse of his infection after quinupristin/dalfopristin was discontinued. None of the patients experienced side effects or other adverse events. CONCLUSION: Quinupristin/dalfopristin was well-tolerated and generally effective in children with infections caused by VREF. There is increasing evidence that it may be more effective than other currently available antibiotics in some such patients.

Adolescent↗
PubMed2000

A dose ranging study of the pharmacokinetics, safety, and preliminary efficacy of lamivudine in children and adolescents with chronic hepatitis B.

Fifty-three patients with chronic hepatitis B and active viral replication were studied for 4 weeks while on treatment and for 12 weeks after treatment with the oral nucleoside analogue lamivudine. Children aged 2 to 12 years were randomized to receive twice-daily doses of 0.35, 1.5, or 4 mg of lamivudine solution per kg of body weight or once-daily doses of 3 mg of lamivudine solution per kg. Adolescents aged 13 to 17 years received lamivudine at 100 mg (as tablets). Blood samples for pharmacokinetic assay were taken on days 1 and 28. Lamivudine was rapidly absorbed following oral administration, with the maximum concentration in serum being reached 0.5 to 1 h postdosing. Apparent oral clearance (CL/F) was higher in younger children and decreased with age, with CL/F values for adolescents reaching those seen for adults by the age of 12. All doses produced a dramatic fall in serum hepatitis B virus (HBV) DNA levels, with a median reduction of >/=99.5% after 4 weeks of treatment and with the levels returning to the baseline levels posttreatment. The correlation of dose, area under the concentration-time curve (AUC), and changes in HBV DNA levels, as measured by the Chiron Quantiplex assay, showed maximal antiviral effects (99.9% inhibition and a reduction of the amount of HBV DNA of approximately 3 log(10)) at 3 mg/kg/day, with no discernible increase in effect seen whether the drug was given at 4 mg/kg twice daily or whether it was given once daily or twice daily. The limit of detection of the assay (2.5 pg/ml) was reached for some but not all patients across the dose ranges, with the smallest number (n = 2) of those having values negative by the Chiron Quantiplex assay being in the lowest-dose group. The 13- to 17-year-olds showed a similar overall response in terms of the HBV DNA level reduction compared to that for patients younger than age 13. Analysis of the same samples by PCR, which has a lower limit of sensitivity than the Chiron Quantiplex assay, also showed average drops in HBV DNA levels of about 3 log(10) at 4 weeks for patients for which the AUC was >/=4,000 ng. h/ml, confirming the conclusions given above. Lamivudine treatment was well tolerated at all doses, with no significant adverse events or laboratory data changes. On the basis of pharmacokinetic and pharmacodynamic data, a 3-mg/kg/day dose in children (ages 2 to 12 years) with chronic hepatitis B provides levels of exposure and trough concentrations similar to those seen in adults following the receipt of doses of 100 mg. The 100-mg dose is being evaluated in a large phase III study with HBV-infected pediatric patients.

Adolescent↗
PubMed2000

Active surveillance of hepatitis C infection in the UK and Ireland.

AIM: To investigate the prevalence, distribution, and clinical details of paediatric hepatitis C virus (HCV) infection in the UK and Ireland. METHODS: Active monthly surveillance questionnaire study coordinated through the British Paediatric Surveillance Unit, to all consultant paediatricians in 1997 and 1998. RESULTS: A total of 182 HCV infected children were reported from 54 centres and by paediatricians from eight different specialties. In 40 children HCV was acquired through mother to child transmission (MTC children); 142 were infected by contaminated blood products (n = 134), organ transplantation (n = 2), needles (n = 4), or unknown risk factor (n = 2). Intravenous drug use was the risk factor for 35 mothers of MTC children. Twelve children were coinfected with HIV and four with HBV. Recent serum aspartate aminotransferase or alanine aminotransferase values were at least twofold greater than the upper limit of normal in 24 of 152 children; this occurred in five of 11 HIV coinfected children. Liver histology, available in 53 children, showed normal (7%), mild (74%), moderate (17%), or severe (2%) hepatitis. Twenty eight children had received therapy with interferon alfa. CONCLUSION: Most current paediatric HCV infection in UK and Ireland has been acquired from contaminated blood products, and most children are asymptomatic. There is a need for multicentre trials to inform clinical practice and development of good practice guidelines in this area. Long term follow up of this cohort of HCV infected children is planned to help determine the natural history over the long term of HCV acquired during infancy and childhood.

Child↗
PubMed2000

Death, dying and emotional labour: problematic dimensions of the bone marrow transplant nursing role?

Bone marrow transplantation (BMT) is an established intervention for a range of conditions including those of a serious, life-threatening nature such as leukaemias. The experience of those who fail to respond to such aggressive treatment, however, or those who die as a result of treatment-induced complications, is currently under-researched. In this paper the authors suggest that despite the relatively high mortality associated with BMT, cultural, biological and professional factors have contributed to a lack of attention on issues of death and dying and emotional labour within BMT care settings. Current technological, biomedical and quality of life discourses which characterize much of the BMT literature are problematic and, we suggest, may serve to disadvantage those who will not survive such procedures. In addition, the provision of effective palliative care in BMT settings remains open to review through further research and development. As a first step, the authors argue that the role of nursing needs to be reconceptualized within BMT to allow key humane concerns such as suffering and the emotional labour of care to be explored and better understood.

Attitude of Health Personnel↗
PubMed2000

An open trial of plant-source derived phosphatydilserine for treatment of age-related cognitive decline.

We assessed whether the efficacy of plant-source derived phosphatydilserine (one of the phospholipids which play an important functional role in membrane-related processes in the brain) for treatment of age related cognitive decline is consistent with previous (placebo controlled) positive findings with bovine derivative of PS (BC-PS). Eighteen healthy elderly volunteers meeting Age Associated Memory Impairment inclusion and exclusion criteria were treated for 12 weeks with plant-source derived phosphatydilserine (PS) (100 mg x 3/day p.o.) and evaluated at base line, after 6 weeks of treatment and at the end of the trial. Fifteen concluded the study. All but two outcome measures elicited a significant drug over time effect. Post-hoc paired t-tests showed that the significant effect was attributable to an improvement from base line to week 6 and that effect was maintained at week 12. These results are encouraging. However, they await double-blind controlled verification in a large sample before suggesting that this may be a viable approach to the treatment of age-related cognitive decline, without exposing the patients to possible hazards involved in the treatment with bovine derivative of PS (BC-PS).

Aged↗
PubMed1999

Transcriptional regulation of the transforming growth factor-beta2 promoter by cAMP-responsive element-binding protein (CREB) and activating transcription factor-1 (ATF-1) is modulated by protein kinases and the coactivators p300 and CREB-binding protein.

Transcription of the transforming growth factor-beta2 (TGF-beta2) gene is dependent on a cAMP-response element/activating transcription factor (CRE/ATF) site that is bound by CREB and ATF-1 as well as an E-box motif that is bound by upstream stimulatory factors 1 and 2 (USF1 and USF2). To identify additional factors involved in the expression of the TGF-beta2 gene, we employed F9 embryonal carcinoma (EC) cells, which express TGF-beta2 only after the cells differentiate. We show that overexpression of the transcription factors, CREB, ATF-1, USF1, and USF2 dramatically increases TGF-beta2 promoter activity in F9-differentiated cells. We further show that the coactivators p300 and CBP up-regulate the TGF-beta2 promoter when CREB and ATF-1 are expressed in conjunction with protein kinases that phosphorylate CREB on serine 133 and ATF-1 on serine 63. Importantly, we identify the presence of serine 133-phosphorylated CREB in the nucleus of F9-differentiated cells but not in the nucleus of F9 EC cells. This phosphorylated form is present in whole cell extracts of both the parental and differentiated cells, suggesting that nuclear accumulation of serine 133-phosphorylated CREB is regulated during differentiation of F9 EC cells and is likely to play an important role in the activation of the TGF-beta2 gene.

Activating Transcription Factor 1↗
PubMed1999

Escherichia coli K88 receptor expression in intestine of disease-susceptible weaned pigs.

A challenge trial was carried out in which Escherichia coli O157 K88ac was administered to a litter of weaned pigs and the development of the disease monitored over a five-day experimental period. The eight animals in the trial were assigned to two groups depending on whether they exhibited disease symptoms. Six pigs developed diarrhoea and two appeared unaffected; these were designated as the test (or K88-susceptible) group and the control (or K88-resistant) group, respectively. The animals were euthanised and the intestine was removed and sections processed for brush border membrane vesicle preparation. Microscopic and biochemical assays were undertaken on tissue samples from each animal and a strong correlation was observed between the expression of a glycoprotein receptor complex associated with the brush border membrane and the development of disease symptoms. Further investigation revealed the presence of an analogous glycoprotein complex in the K88-resistant group which did not bind the K88-fimbriae antigen. These results suggest that genetic differences in the glycosyl moieties of the receptor complex provide the basis for disease susceptibility to K88-positive E. coli.

Animals↗
PubMed1999

Screening of newborn infants for cholestatic hepatobiliary disease with tandem mass spectrometry.

OBJECTIVE: To assess the feasibility of screening for cholestatic hepatobiliary disease and extrahepatic biliary atresia by using tandem mass spectrometry to measure conjugated bile acids in dried blood spots obtained from newborn infants at 7-10 days of age for the Guthrie test. SETTING: Three tertiary referral clinics and regional neonatal screening laboratories. DESIGN: Unused blood spots from the Guthrie test were retrieved for infants presenting with cholestatic hepatobiliary disease and from the two cards stored on either side of each card from an index child. Concentrations of conjugated bile acids measured by tandem mass spectrometry in the two groups were compared. MAIN OUTCOME MEASURES: Concentrations of glycodihydroxycholanoates, glycotrihydroxycholanoates, taurodihydroxycholanoates, and taurotrihydroxycholanoates. Receiver operator curves were plotted to determine which parameter (or combination of parameters) would best predict the cases of cholestatic hepatobiliary disease and extrahepatic biliary atresia. The sensitivity and specificity at a selection of cut off values for each bile acid species and for total bile acid concentrations for the detection of the two conditions were calculated. RESULTS: 218 children with cholestatic hepatobiliary disease were eligible for inclusion in the study. Two children without a final diagnosis and five who presented at <14 days of age were excluded. Usable blood spots were obtained from 177 index children and 708 comparison children. Mean concentrations of all four bile acid species were significantly raised in children with cholestatic hepatobiliary disease and extrahepatic biliary atresia compared with the unaffected children (P<0.0001). Of 177 children with cholestatic hepatobiliary disease, 104 (59%) had a total bile acid concentration >33 micromol/l (97.5th centile value for comparison group). Of the 61 with extrahepatic biliary atresia, 47 (77%) had total bile acid concentrations >33 micromol/l. Taurotrihydroxycholanoate and total bile acid concentrations were the best predictors of both conditions. For all cholestatic hepatobiliary disease, a cut off level of total bile acid concentration of 30 micromol/l gave a sensitivity of 62% and a specificity of 96%, while the corresponding values for extrahepatic biliary atresia were 79% and 96%. CONCLUSION: Most children who present with extrahepatic biliary atresia and other forms of cholestatic hepatobiliary disease have significantly raised concentrations of conjugated bile acids as measured by tandem mass spectrometry at the time when samples are taken for the Guthrie test. Unfortunately the separation between the concentrations in these infants and those in the general population is not sufficient to make mass screening for cholestatic hepatobiliary disease a feasible option with this method alone.

Age Factors↗
PubMed1999

Prognostic significance of myocardial enzyme release after coronary interventions.

Mild to moderate periprocedural elevation in CK with concurrent CK MB elevation result in increased subsequent myocardial infarction and mortality. However the potential risks that percutaneous revascularization interventions pose must be evaluated in light the risks of alternative procedures and the risks of continued medical management. Prospective clinical trials examining the relationship of periprocedural enzyme elevations to long term prognosis will need to address this issue.

Angioplasty, Balloon, Coronary↗
PubMed1999

Orthotopic liver transplantation for unresectable hepatoblastoma: a single center's experience.

BACKGROUND/PURPOSE: Complete surgical resection after chemotherapy is the definitive treatment for hepatoblastoma. However, orthotopic liver transplantation (OLT) is now accepted as a treatment modality for patients with unresectable tumours. The aim of this study was to review a single center's experience of OLT for unresectable hepatoblastoma. METHODS: A retrospective review of 8 patients with unresectable hepatoblastoma who were referred for liver transplantation was conducted. RESULTS: The patients assessed had an age range of 5 to 105 months at presentation; median, 24 months, (5 boys; 3 girls). Two patients have familial adenomatous polyposis, and one has right hemihypertrophy. All 8 patients had received standard chemotherapy according to SIOP (International Society of Pediatric Oncology) protocols. Extrahepatic metastases were found in 3 patients at diagnosis, but none had detectable metastases at the time of OLT. Four patients continued chemotherapy while awaiting OLT. Three patients received whole grafts, and 5 received reduced grafts. The median follow-up period was 22 months (range, 2 to 78 months). Five patients are alive and well, although 1 patient had a second OLT for biliary cirrhosis secondary to biliary stricture at 6 years. Three patients died: one 26 days post OLT of sepsis and two of disease recurrence at 22 months and 70 months posttransplant. The actuarial survival rate is 88% and 65% at 1 and 5 years, respectively, whereas the overall survival rate is 62.5%. CONCLUSION: OLT for unresectable hepatoblastoma without extra hepatic metastases is highly successful with a low recurrence rate.

Antineoplastic Combined Chemotherapy Protocols↗