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Biomedical subjects

P Riley

Publications and source records attributed to P Riley.

At least 19 recordsLinked to original sources
PubMed2005

The metabolic profile of azimilide in man: in vivo and in vitro evaluations.

The metabolic fate of azimilide in man is unusual as it undergoes a cleavage in vivo resulting in the formation of two classes of structurally distinct metabolites. During a metabolite profiling study conducted in human volunteers to assess the contribution of all pathways to the clearance of (14)C-azimilide, greater than 82% of radioactivity was recovered in urine (49%-58%) and feces (33%). Urine, feces, and plasma were profiled for metabolites. A cleaved metabolite, 4-chloro-2-phenyl furoic acid was present at high concentration in plasma (metabolite/parent AUC ratio approx. 4), while other plasma metabolites, azimilide N-oxide (metabolite/parent AUC ratio 0.001), and a cleaved hydantoin metabolite (metabolite/parent AUC ratio = 0.3) were present at lower concentrations than azimilide. In urine, the cleaved metabolites were the major metabolites, (> 35% of the dose) along with phenols (as conjugates, 7%-8%), azimilide N-oxide (4%-10%), a butanoic acid metabolite (2%-3%), and desmethyl azimilide (2%). A limited investigation of fecal metabolites indicated that azimilide (3%-5%), desmethyl azimilide (1%-3%), and the butanoic acid metabolite (< 1%) were present. Contributing pathways for metabolism of azimilide, identified through in vitro and in-vivo studies, were CYPs 1A1 (est. 28%), 3A4/5 (est. 20%), 2D6 (< 1%), FMO (est. 14%), and cleavage (35%). Enzyme(s) involved in the cleavage of azimilide were not identified.

Adult↗
PubMed2004

Neonatal diabetes, with hypoplastic pancreas, intestinal atresia and gall bladder hypoplasia: search for the aetiology of a new autosomal recessive syndrome.

AIMS/HYPOTHESIS: Neonatal diabetes is a rare disease with several identified molecular aetiologies. Despite associations with other malformations, neonatal diabetes with intestinal and biliary anomalies has not been described. The current study aims to describe a new syndrome, and to examine a possible link with one of three genes known to cause neonatal diabetes. METHODS: Five clinical cases are described. Immunohistochemical staining for pancreatic islet hormones was performed on three of the infants. DNA from one infant was analysed for abnormalities of the PLAGL-1 (ZAC), glucokinase and PDX-1 (IPF-1) genes. RESULTS: Five infants (two sibling pairs from two families, and an isolated case) presented with neonatal diabetes, hypoplastic or annular pancreas, jejunal atresia, duodenal atresia and gall bladder aplasia or hypoaplasia. One sibling pair was born to consanguineous parents. One patient with a milder form is surviving free of insulin. Four children died in the first year of life despite aggressive medical management. Pancreatic immunohistochemistry revealed few scattered chromogranin-A-positive cell clusters but complete absence of insulin, glucagon and somatostatin. Exocrine histology was variable. In one case from the consanguineous family, molecular analysis showed no duplication or uniparental isodisomy of PLAGL-1 at 6q24, no contiguous gene deletion involving the glucokinase gene, and no mutation in the coding sequences or splice sites of PDX-1. CONCLUSIONS/INTERPRETATION: This combination of multiple congenital abnormalities has not been previously described and probably represents a new autosomal recessive syndrome involving a genetic abnormality that interferes with normal islet development and whose aetiology is as yet unknown.

Abnormalities, Multiple↗
PubMed2004

A phase I/II study of gemcitabine and fractionated cisplatin in an outpatient setting using a 21-day schedule in patients with advanced and metastatic bladder cancer.

A randomised phase III trial of MVAC (methotrexate, vincristine, doxorubicin, cisplatin) vs gemcitabine and cisplatin (GC) (G 1000 mg m(-2) days 1, 8, and 15 plus C 70 mg m(-2) day 2, q 4 wks) indicated GC had similar efficacy and lower toxicity (JCO 2000). Significant haematologic toxicities in the GC arm occurred on day 15, necessitating dose adjustments in 37% of cycles. We conducted a phase I/II dose escalation trial using GC on a 21-day cycle, with G and C split between days 1 and 8. The objective of the study to define maximum-tolerated dose and dose-limiting toxicity (DLT), objective response rate, and overall survival. In all, 32 patients with locally advanced, relapsed, or metastatic disease received: dose level 1, G/C 1000/35; level 2, 1100/35; level 3, 1200/35; level 4, 1200/45 mg m(-2) (G and C given on days 1 and 8 every 3 wks). A total of 19 patients had glomerular filtration rate <60 ml min(-1) and 19 patients had metastatic disease. Dose-limiting toxicity was haematologic (grade 4 thrombocytopenia) at dose level 2. Of 151 cycles, at day 15, platelets were <100 in 61 cycles; neutrophils <0.5, platelets <50 in 26 cycles. Only seven cycles were deferred due to haematological toxicity; four for renal toxicity (chemotherapy instituted posthydration). Overall response rate was 65.5% on an intention-to-treat analysis (75% [21/28] for assessable patients), with four complete responses (12.5%) and 17 partial responses (53%). After the median follow-up of 17.2 months (range 13.1-32.4 months), 12 patients remain alive. The overall median survival was 16 months (range 10.1-26.6 months). G plus C every 3 weeks is active and well tolerated in an outpatient setting, even in patients receiving prior platinum-based regimens and with poor renal reserve.

Adult↗
PubMed2004

Intravenous cyclophosphamide pulse therapy in juvenile dermatomyositis. A review of efficacy and safety.

OBJECTIVES: To assess the efficacy and safety of intravenous cyclophosphamide (CYP) used in severe and refractory juvenile dermatomyositis (JDM). METHODS: Retrospective case note review of the outcome of 12 patients. RESULTS: Assessment at 6 months of therapy in 10 of the 12 patients showed a significant improvement in muscle function as assessed by the Childhood Myositis Assessment Scale (CMAS) (P = 0.012), muscle strength (P = 0.008), global extramuscular disease score (P = 0.008), skin disease severity (P = 0.015) and lactate dehydrogenase (P = 0.028). There were reductions in creatine kinase, alanine aminotransferase, prednisolone dose and ESR, but these did not reach statistical significance. Clinical improvement was maintained after CYP until the most recent follow-up (between 6 months and 7 yr) and no severe side-effects were seen. Reversible complications included lymphopenia, herpes zoster infections and alopecia. The median cumulative dose was 4.6 g/m(2) (range 3-9 g/m(2)). The available evidence suggests that, at the doses required, risks of malignancy, infertility and gonadal failure are low. Two patients with severe treatment-resistant disease died after one dose of CYP, both of whom were ventilated prior to commencement of CYP and were thought to have died as a result of their severe disease process, and too early for clinical benefit to be obtained from the drug. CONCLUSIONS: In this cohort of children with severe and refractory JDM, CYP appeared to have provided major clinical benefit with no evidence of serious toxicity in the short term.

Antirheumatic Agents↗
PubMed2001

An auroral flare at Jupiter.

Jupiter's aurora is the most powerful in the Solar System. It is powered largely by energy extracted from planetary rotation, although there seems also to be a contribution from the solar wind. This contrasts with Earth's aurora, which is generated through the interaction of the solar wind with the magnetosphere. The major features of Jupiter's aurora (based on far-ultraviolet, near-infrared and visible-wavelength observations) include a main oval that generally corotates with the planet and a region of patchy, diffuse emission inside the oval on Jupiter's dusk side. Here we report the discovery of a rapidly evolving, very bright and localized emission poleward of the northern main oval, in a region connected magnetically to Jupiter's outer magnetosphere. The intensity of the emission increased by a factor of 30 within 70 s, and then decreased on a similar timescale, all captured during a single four-minute exposure. This type of flaring emission has not previously been reported for Jupiter (similar, but smaller, transient events have been observed at Earth), and it may be related directly to changes in the solar wind.

Journal Article↗
PubMed2001

Imaging the post-operative thoracic aorta: normal anatomy and pitfalls.

Following surgical repair or replacement of the thoracic aorta, interpretation of CT and MRI scans of the thorax can be confusing. It is important to be aware of the variety of appearances that can be encountered. There is usually a surgical explanation and close collaboration with surgical colleagues is required. An appreciation of the normal post-operative appearances allows recognition of the abnormal. Potential pitfalls in interpretation are discussed.

Aorta↗
PubMed2000

Severe bronchopulmonary dysplasia increases risk for later neurological and motor sequelae in preterm survivors.

Preterm children who develop severe chronic lung disease may be developmentally compromised by exposure to hypoxic episodes. This study aims to determine if children with severe bronchopulmonary dysplasia (BPD) who required home oxygen therapy were at greater risk for neurological and motor deficits at school age than preterm peers without BPD. This study evaluated 27 subjects with BPD and 27 preterm control infants matched for gestational age, birthweight, sex, and year of birth at a mean age of 9.9 years (2.0 SD) using standardized neuromotor outcome measures. Pair-matched comparisons and regression analyses were used to determine if subjects with BPD were at increased risk for neuromotor sequelae. Neurological abnormalities, including subtle neurological signs, cerebral palsy, microcephaly, and behavioral difficulties were highly prevalent in the BPD group (71% compared with 19% in control group, P<0.005). Over half the BPD cohort had difficulties in gross and/or fine motor skills. There were significant differences in postural stability between groups. Duration of hospitalization and home oxygen treatment, and decreased lung function at school age, markers of severity of illness, correlated with motor outcomes. The findings underline the importance of preventing the cardiorespiratory complications associated with chronic lung disease to minimize disability in preterm children. For children with severe BPD, better recognition and subsequent remediation of neuromotor impairments that manifest at school age may help maximize their functional potential.

Bronchopulmonary Dysplasia↗
PubMed2000

Total plasma clearance of 51Cr-EDTA: variation with age and sex in normal adults.

Although inulin clearance measured during constant infusion is still considered the reference method, single-injection of 51Cr-EDTA with subsequent plasma sampling has become the most popular technique for the routine assessment of glomerular filtration rate. Despite the fact that the technique has been in use for 30 years, there are only a few reports of normal values calculated directly from 51Cr-EDTA data and normal ranges have generally been produced by conversions of inulin data. The aim of this study was to measure the variation in total plasma clearance, calculated directly from 51Cr-EDTA measurements, in normal males and females, of Saudi Arabian origin, over a wide range. Altogether, 201 potential kidney donors aged 16-60 years were studied. No statistically significant association of total plasma clearance with age or sex could be demonstrated; however, predictive equations suggesting a small decline in total plasma clearance with age were developed. The figures presented suggest that the reduction in total plasma clearance of 51Cr-EDTA with age is relatively shallow up to the age of at least 60 years and that normal ranges produced by conversion of inulin data may overestimate the decline with age.

Adolescent↗
PubMed2000

The HAND1 basic helix-loop-helix transcription factor regulates trophoblast differentiation via multiple mechanisms.

The basic helix-loop-helix (bHLH) transcription factor genes Hand1 and Mash2 are essential for placental development in mice. Hand1 promotes differentiation of trophoblast giant cells, whereas Mash2 is required for the maintenance of giant cell precursors, and its overexpression prevents giant cell differentiation. We found that Hand1 expression and Mash2 expression overlap in the ectoplacental cone and spongiotrophoblast, layers of the placenta that contain the giant cell precursors, indicating that the antagonistic activities of Hand1 and Mash2 must be coordinated. MASH2 and HAND1 both heterodimerize with E factors, bHLH proteins that are the DNA-binding partners for most class B bHLH factors and which are also expressed in the ectoplacental cone and spongiotrophoblast. In vitro, HAND1 could antagonize MASH2 function by competing for E-factor binding. However, the Hand1 mutant phenotype cannot be solely explained by ectopic activity of MASH2, as the Hand1 mutant phenotype was not altered by further mutation of Mash2. Interestingly, expression of E-factor genes (ITF2 and ALF1) was down-regulated in the trophoblast lineage prior to giant cell differentiation. Therefore, suppression of MASH2 function, required to allow giant cell differentiation, may occur in vivo by loss of its E-factor partner due to loss of its expression and/or competition from HAND1. In giant cells, where E-factor expression was not detected, HAND1 presumably associates with a different bHLH partner. This may account for the distinct functions of HAND1 in giant cells and their precursors. We conclude that development of the trophoblast lineage is regulated by the interacting functions of HAND1, MASH2, and their cofactors.

Animals↗
PubMed2000

Resistance patterns of urinary tract infections diagnosed in a genitourinary medicine clinic.

We aimed to assess the prevalence of antibiotic resistance amongst urinary tract isolates within our clinic. Local protocol has been to prescribe a 3-day course of trimethoprim for uncomplicated urinary tract infections (UTIs). Notes of all culture-proven UTIs (October 1998 to September 1999) were examined. Eighty-six urinary isolates were identified in 84 patients. Seventy-three of the isolates were coliforms with 46 being Escherichia coli. Of the 86 urinary isolates 28 (32.6%) were resistant to trimethoprim, 37 (43.5%) to amoxycillin, 5 (5.8%) to cephradine and 3 (3.5%) to nitrofurantoin. Seventy-four (86%) of the UTIs were known to have been treated; 41 at initial presentation and 33 once sensitivities were available. Of the 41 patients who received treatment initially, 11 needed to return to the clinic for a further course of antibiotics. To try and reduce the number of inappropriate treatments and unnecessary visits a number of options regarding clinic protocol were explored.

Adolescent↗