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Biomedical subjects

B J Clark

Publications and source records attributed to B J Clark.

At least 73 records · Page 4Linked to original sources
PubMed1998

Update on lung transplantation in children.

Lung transplantation is an important treatment option in children with acquired and congenital pulmonary disease. Indications for lung transplantation include pulmonary hypertension, bronchopulmonary dysplasia, pulmonary vein stenosis, and cystic fibrosis. The early outcome following lung transplantation has improved considerably. Longterm complications, however, including infections, bronchiolitis obliterans, and complications of immunosuppression remain significant problems. Donor availability, especially for neonates, continues to limit the utilization of lung transplantation.

Child↗
PubMed1998

The effect of dose on the characterization of aerodynamic particle-size distributions of beclomethasone dipropionate metered-dose inhalers.

The aerodynamic particle-size distribution for two doses of a Becloforte metered-dose inhaler (MDI) was measured by use of a twin-stage impinger (TSI), the new multi-stage (five-stage) liquid impinger (MSLI) and the Andersen cascade impactor (ACI) (n = 5 for each apparatus). The mean (s.d.) fine-particle doses measured by the three techniques for the Becloforte MDI were 40.3 (1.2), 45.7 (0.5) and 41.8 (0.4)% w/w, respectively; the median mass aerodynamic diameters (MMAD) measured using the MSLI and the ACI were 3.50 and 3.73 microns, respectively. The MSLI fine particle (< 6.8 microns) doses for 2, 5, 10, 20, 30 and 40 doses from Becloforte MDIs (n = 5 for each dose) were 49.7 (0.7), 52.9 (1.2), 45.3 (0.6), 45.5 (0.71), 45.9 (0.7) and 46.4 (0.7)% w/w, respectively. Values obtained using the ACI (< 5.8 microns) were 40.8 (1.0), 41.0 (0.8), 44.4 (0.5), 43.1 (0.4), 42.8 (0.5) and 40.4 (0.4)% w/w (n = 4). MMAD values measured with the MSLI were 3.39, 3.46, 3.75, 3.91, 4.15 and 4.45 microns, respectively; using the ACI they were 3.46, 3.54, 3.61, 3.66, 3.73 and 3.85 microns. The results indicate that the measured aerodynamic particle-size distributions of beclomethasone dipropionate MDIs are affected by the dose dispensed and by the apparatus used for measurement.

Administration, Inhalation↗
PubMed1997

Targeted disruption of the mouse gene encoding steroidogenic acute regulatory protein provides insights into congenital lipoid adrenal hyperplasia.

An essential component of regulated steroidogenesis is the translocation of cholesterol from the cytoplasm to the inner mitochondrial membrane where the cholesterol side-chain cleavage enzyme carries out the first committed step in steroidogenesis. Recent studies showed that a 30-kDa mitochondrial phosphoprotein, designated steroidogenic acute regulatory protein (StAR), is essential for this translocation. To allow us to explore the roles of StAR in a system amenable to experimental manipulation and to develop an animal model for the human disorder lipoid congenital adrenal hyperplasia (lipoid CAH), we used targeted gene disruption to produce StAR knockout mice. These StAR knockout mice were indistinguishable initially from wild-type littermates, except that males and females had female external genitalia. After birth, they failed to grow normally and died from adrenocortical insufficiency. Hormone assays confirmed severe defects in adrenal steroids-with loss of negative feedback regulation at hypothalamic-pituitary levels-whereas hormones constituting the gonadal axis did not differ significantly from levels in wild-type littermates. Histologically, the adrenal cortex of StAR knockout mice contained florid lipid deposits, with lesser deposits in the steroidogenic compartment of the testis and none in the ovary. The sex-specific differences in gonadal involvement support a two-stage model of the pathogenesis of StAR deficiency, with trophic hormone stimulation inducing progressive accumulation of lipids within the steroidogenic cells and ultimately causing their death. These StAR knockout mice provide a useful model system in which to determine the mechanisms of StAR's essential roles in adrenocortical and gonadal steroidogenesis.

Adrenal Cortex Hormones↗
PubMed1997

Steroidogenic factor 1 acts at all levels of the reproductive axis.

The conversion of cholesterol into steroid hormones occurs through the sequential actions of the cytochrome P450 steroid hydroxylases. Attempts to understand the mechanisms responsible for the temporal and spatial expression patterns of these enzymes led to the identification of a shared regulator, termed steroidogenic factor 1 (SF-1). SF-1 coordinately regulates the steroid hydroxylase genes and thus functions as a global mediator of steroidogenesis. Of greater significance, recent studies using a knockout mouse model have further implicated SF-1 in a variety of processes ranging from development of the steroidogenic organs to the normal function of gonadotropes and the development of the ventromedial hypothalamic nucleus. A fundamental aspect of elucidating the role of SF-1 at all levels of the reproductive axis is to identify its cell-specific target genes. The recent purification and cloning of the steroidogenic acute regulatory (StAR) protein has provided an intriguing new candidate through which SF-1 acts to mediate its effects on reproductive competence. These studies yield novel insights into the processes of steroidogenesis, endocrine development, and reproductive function.

Adrenal Glands↗
PubMed1997

Rapid resolution of drugs and related substances with an eCAP polyamine coated capillary.

The long term stability of a commercial polyamine coated capillary (eCAP) is described. The capillary, which can be used in the CZE and MEKC mode, is based on coating with a polyamine after conditioning with 1 M NaOH and regeneration of this coating after each run. The stability was tested over 6 months on the drug trimethoprim and the R.S.D. values for migration time and peak area were 2.86 and 3.62% respectively (n = 8, each time of determination) (> 600 sample injections over the period). This stability was utilised in the validated method developed for trimethoprim and four of its related impurities. The repeatability of peak area for trimethoprim (without normalisation or external standard) was, within-day R.S.D. = 1.02% (n = 8) and between-days R.S.D. = 2.02% (n = 8 each day). Linearity was good (for 50 micrograms ml-1 target) (y = 249.6x + 17.3 (r = 0.992, n = 6). These results for trimethoprim and for other drug mixtures were comparison with conventional capillaries and the advantage of reducing the polyamine treated eCAP capillary to a minimum length is described, to achieve rapid assay of the 5 component timethoprim mixture in < 2 min.

Acyclovir↗
PubMed1997

The 22q11.2 deletion: screening, diagnostic workup, and outcome of results; report on 181 patients.

A submicroscopic deletion of chromosome 22q11.2 has been identified in the majority of patients with the DiGeorge syndrome, velocardiofacial syndrome, conotruncal anomaly face syndrome, and in some patients with isolated conotruncal cardiac anomalies, Opitz G/BBB syndrome, and Cayler cardiofacial syndrome. We have evaluated 181 patients with this deletion. We describe our cohort of patients, how they presented, and what has been learned by having the same subspecialists evaluate all of the children. The results help define the extremely variable phenotype associated with this submicroscopic deletion and will assist clinicians in formulating a management plan based on these findings.

Abnormalities, Multiple↗
PubMed1997

A novel pattern of oculocerebral malformation.

AIMS/BACKGROUND: To report a novel pattern of oculocerebral malformation related to the group of diseases characterised by cobblestone lissencephaly. METHODS: By means of a case report with specialist descriptions of the novel neuropathological and ophthalmic pathology features. RESULTS: The patient, born to healthy consanguineous parents, presented in the neonatal period with jaundice, convulsions, and macrocephaly. Computed tomography demonstrated hydrocephalus and abnormal cerebral gyration. Ophthalmic examination revealed severe myopia and segments of retinal atrophy. Cytogenetic investigation revealed a balanced reciprocal translocation (46,XX,t(5p11;19q13.1)) that was inherited from the mother and was present in several normal relatives. Mild short stature and profound mental handicap were evident. The child died aged 7 years. At necropsy the brain showed 'cobblestone' (type II) lissencephaly. Cerebellar cortical architecture was abnormal and the brain stem lacked cerebral peduncles, basis pontis, and pyramids. Biopsies of skeletal muscles were normal. The ocular abnormalities included discrete sectors of retina of varying thickness with disordered neuronal lamination and gliosis. The optic nerve was gliotic and contained few nerve fibres. The anterior iris surface was studded with cellular stromal nodules which appear to be melanocytic in nature. CONCLUSION: Retinal dysgenesis occurs in the group of syndromes with 'cobblestone lissencephaly', the best known being Walker-Warburg syndrome. In this case, relatively long survival, lack of muscular dystrophy, and novel ocular pathology distinguish it from the other diagnoses in this group of syndromes. We suggest this child was affected by a distinct and novel oculocerebral syndrome.

Abnormalities, Multiple↗
PubMed1997

Inhibition of transcription affects synthesis of steroidogenic acute regulatory protein and steroidogenesis in MA-10 mouse Leydig tumor cells.

Hormonal induction of steroidogenesis in the adrenal and gonads is dependent on the synthesis and function of the steroidogenic acute regulatory protein (StAR). As a first approach to investigate the role of translation in the control of StAR expression, we examined StAR protein synthesis and steroid production in MA-10 mouse Leydig tumor cells in the presence of the transcriptional inhibitor, actinomycin D. We show that human CG (hCG)-induced StAR synthesis, as determined by radiolabeling MA-10 cells with [35S]methionine and immunoprecipitation of StAR, is blocked by actinomycin D. The rate of hCG-stimulated progesterone production is also decreased, but not completely blocked, suggesting a possible StAR-independent mechanism that may contribute approximately 10-20% of the acute steroidogenic potential of the cells. When MA-10 cells were pretreated with hCG to increase StAR messenger RNA levels and then the proteins radiolabeled in the presence of hCG or hCG plus actinomycin D, no difference was observed in the amount of the 30-kDa StAR protein synthesized. However, a 50% increase in the precursor form of StAR protein was detected with hCG treatment alone. These data suggest that ongoing StAR protein synthesis is not inhibited by actinomycin D, but that continued synthesis requires transcriptional activity. Progesterone production was inhibited by actinomycin D in the hCG-pretreated cells, supporting the proposal that maintaining StAR protein synthesis is required for optimal steroid production in MA-10 mouse Leydig tumor cells.

Animals↗
PubMed1997

Characterization of the promoter region of the mouse gene encoding the steroidogenic acute regulatory protein.

Steroidogenic acute regulatory protein (StAR) delivers cholesterol to the inner mitochondrial membrane, where the cholesterol side-chain cleavage enzyme carries out the first committed step in steroid hormone biosynthesis. StAR expression is restricted to steroidogenic cells and is rapidly induced by treatment with trophic hormones or cAMP. We analyzed the 5'-flanking region of the mouse StAR gene to elucidate the mechanisms that regulate its cell-specific and hormone-induced expression. In transient transfection assays, a luciferase reporter gene driven by the StAR 5'-flanking region was preferentially expressed by steroidogenic Y1 adrenocortical and MA-10 Leydig cells in a cAMP-responsive manner. 5'-Deletion and site-directed mutagenesis studies identified a region between -254 and -113 that is essential for full levels of promoter activity. This region contains a binding site for the orphan nuclear receptor steroidogenic factor-1 (SF-1) that, although not required for hormone induction, is critical for basal promoter activity, thus implicating SF-1 in StAR expression. Analyses of knockout mice deficient in SF-1 further supported an important role for SF-1 in StAR gene expression. These studies provide novel insights into the mechanisms that regulate StAR gene expression and extend our understanding of SF-1's global roles within steroidogenic cells.

Animals↗
PubMed1997

Detection of a 22q11.2 deletion in cardiac patients suggests a risk for velopharyngeal incompetence.

OBJECTIVE: Conotruncal cardiac anomalies frequently occur in patients with DiGeorge or velocardiofacial syndrome. Additionally, these patients may have overt or submucousal cleft palate, as well as velopharyngeal incompetence (VPI). Previous studies have demonstrated that the majority of these patients have a submicroscopic deletion of chromosome 22q11.2. We hypothesized that a subpopulation of newborns and children with congenital heart defects caused by a 22q11.2 deletion are at a high risk for having unrecognized palatal abnormalities. Therefore, we proposed to evaluate a cohort of patients with conotruncal cardiac malformations associated with a 22q11.2 deletion to determine the frequency of palatal abnormalities. METHODS: We identified 14 deletion-positive patients with congenital cardiac defects who had no overt cleft palate. Of the 14 patients evaluated for the 22q11.2 deletion, 8 patients were recruited from a previous study looking for deletions among patients with isolated conotruncal cardiac anomalies. Informed consent was obtained in these cases. The remaining patients had the deletion study on a clinical basis, ie, conotruncal cardiac defect and an absent thymus, immunodeficiency, or minor dysmorphia appreciated by the clinical geneticist. These patients were evaluated by a plastic surgeon and speech pathologist looking for more subtle palatal anomalies such as a submucousal cleft palate, absence of the musculous uvuli, and VPI. Some patients underwent videofluoroscopy or nasendoscopy depending on their degree of symptoms and age. VPI was not ruled out until objective evaluation by a speech pathologist and plastic surgeon was obtained. In addition, the child had to be old enough to provide an adequate speech sample. RESULTS: Of the 14 patients evaluated, 6 patients older than 1 year were found to have VPI. It is noteworthy that 3 of these patients were older than 5 years and had remained unrecognized until this study. The remaining 6 patients had inconclusive studies based on their age (younger than 26 months) and their inability to participate in adequate speech evaluations. Two of these patients, however, had histories of nasal regurgitation suggesting VPI and, in addition, had incomplete closure of the velopharyngeal mechanism during crying and swallowing observed during nasendoscopic examination-consistent with the diagnosis of VPI. Thus, 8 of 14 patients evaluated had evidence of VPI by history and examination. The remaining 6 patients will require further study when they are older before a definitive palatal diagnosis can be made. CONCLUSIONS: A significant number of patients with a 22q11.2 deletion in a cardiac clinic may have unrecognized palatal problems. Recognition of such abnormalities will afford patients the opportunity for intervention as needed, ie, speech therapy and/or surgical intervention. Notably, two of our patients with findings suggesting VPI were infants and will, therefore, be afforded the opportunity for close follow-up and early intervention. Furthermore, three school-aged children had palatal abnormalities that were unrecognized until this study. Thus, we recommend 22q11.2 deletion studies in patients with conotruncal cardiac malformations, followed by extensive palatal and speech evaluations when a deletion is present.

Abnormalities, Multiple↗
PubMed1996

Outcome of children with pulmonary hypertension referred for lung or heart and lung transplantation.

We reviewed our institutional experience with 24 children with pulmonary hypertension, who were referred for lung or heart and lung transplantation. Diagnosis, age, and previously published predictive survival scores calculated at the time of referral were analyzed as predictors of pretransplant death. Among the 24 children, 7 did not meet criteria for listing and 17 were listed for transplantation. Of those listed, eight died waiting, two await transplantation, and seven were transplanted and are alive and well 7-20 months after transplantation. Poor functional status (New York Heart Association class 3 or 4) at the time of referral was significantly associated with death before transplant (P=0.05) in univariate analysis. Analysis of the predictive scores was possible in 21 of 24 patients; lower predictive scores were significantly associated with death before transplantation and shorter duration of survival without transplantation in univariate analysis. Multivariate analysis (Cox regression) confirmed that lower scores were significantly associated with poor survival. We conclude that children with pulmonary hypertension are often referred for transplantation too late in the course of their disease. Early complete hemodynamic evaluation before the onset of severe symptoms, followed by serial evaluations of disease progression and consultation with a transplant center, should result in earlier, more appropriate time of listing and improved survival. A systematic study of pretransplant mortality among all children listed for lung transplantation would provide a basis for clinical decision making and policies affecting organ allocation.

Adolescent↗
PubMed1996

Epstein-Barr virus-associated hepatic smooth muscle neoplasm in a cardiac transplant recipient.

Host immunosuppression is increasingly recognized as a significant risk factor for the development of a primary neoplasm. Chronic immunosuppressive therapy, as used in organ transplantation, may perturb the immunosurveillance ability of the host, making the patient more susceptible to virus-associated malignancies. We have taken care of a care of a child who received an orthotopic heart transplant and who then developed both a generalized lymphoproliferative disorder and a leiomyoma of the liver a year later. Epstein-Barr virus DNA was detected in a lymph node initially and the hepatic tumor cells subsequently. The former responded to a reduction in the immunosuppressive medications and the latter responded to surgical resection. This is the first report of a hepatic smooth cell neoplasm occurring following cardiac transplant and the development of two sequential Epstein-Barr virus-associated disorders in an immunosuppressed patient.

Child↗