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Biomedical subjects

Mark D Kilby

Publications and source records attributed to Mark D Kilby.

24 records · Page 2Linked to original sources
PubMed2003

Differential regulation of vitamin D receptor and its ligand in human monocyte-derived dendritic cells.

The functions of dendritic cells (DCs) are tightly regulated such that protective immune responses are elicited and unwanted immune responses are prevented. 1 alpha 25-dihydroxyvitamin D(3) (1 alpha 25(OH)(2)D(3)) has been identified as a major factor that inhibits the differentiation and maturation of DCs, an effect dependent upon its binding to the nuclear vitamin D receptor (VDR). Physiological control of 1 alpha 25(OH)(2)D(3) levels is critically dependent upon 25-hydroxyvitamin D(3)-1 alpha-hydroxylase (1 alpha OHase), a mitochondrial cytochrome P450 enzyme that catalyzes the conversion of inactive precursor 25-hydroxyvitamin D(3) (25(OH)D(3)) to the active metabolite 1 alpha 25(OH)(2)D(3). Using a human monocyte-derived DC (moDC) model, we have examined the relationship between DC VDR expression and the impact of exposure to its ligand, 1 alpha 25(OH)(2)D(3). We show for the first time that moDCs are able to synthesize 1 alpha 25(OH)(2)D(3) in vitro as a consequence of increased 1 alpha OHase expression. Following terminal differentiation induced by a diverse set of maturation stimuli, there is marked transcriptional up-regulation of 1 alpha OHase leading to increased 1 alpha OHase enzyme activity. Consistent with this finding is the observation that the development and function of moDCs is inhibited at physiological concentrations of the inactive metabolite 25(OH)D(3). In contrast to 1 alpha OHase, VDR expression is down-regulated as monocytes differentiate into immature DCs. Addition of 1 alpha 25(OH)(2)D(3) to moDC cultures at different time points indicates that its inhibitory effects are greater in monocyte precursors than in immature DCs. In conclusion, differential regulation of endogenous 1 alpha 25(OH)(2)D(3) ligand and its nuclear receptor appear to be important regulators of DC biology and represent potential targets for the manipulation of DC function.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed2003

Prenatal bladder drainage in the management of fetal lower urinary tract obstruction: a systematic review and meta-analysis.

OBJECTIVE: To estimate the effect of prenatal bladder drainage on perinatal survival in fetuses with lower urinary tract obstruction. DATA SOURCES: Relevant articles were identified by searching the databases MEDLINE (1966-2002), EMBASE (1988-2002), and the Cochrane library (2000;4). METHODS OF STUDY SELECTION: Studies were selected if the effect of prenatal bladder drainage (vesicocentesis, vesicoamniotic shunt, or open fetal bladder surgery) on perinatal survival was reported in fetuses with ultrasonic evidence of lower urinary tract obstruction. Study selection, quality assessment, and data abstraction were performed independently and in duplicate. TABULATION, INTEGRATION, AND RESULTS: Sixteen observational studies that included nine case series (147 fetuses) and seven controlled series (195 fetuses) were identified. Study characteristics and quality were recorded for each study. Data on the effect of bladder drainage on perinatal survival were abstracted. Where controlled data were available, 2 x 2 tables were generated to compare the effects of bladder drainage versus no bladder drainage on perinatal survival. Pooled odds ratios (ORs) were used as summary measures of effect, and the results were stratified according to predicted fetal prognoses (based on ultrasound features and fetal urinary electrolytes). Among controlled studies, bladder drainage appeared to improve perinatal survival relative to no drainage (OR 2.5; 95% confidence interval [CI] 1.1, 5.9; P =.03). However, this observation was largely because among the subgroup of fetuses with a poor prognosis there was a marked improvement (OR 8.1; 95% CI 1.2, 52.9; P =.03). Improved perinatal outcome was also suggested in those fetuses considered to have a good prognosis (OR 2.8; 95% CI 0.7, 10.8; P =.13). CONCLUSION: There is a lack of high quality evidence to reliably inform clinical practice regarding prenatal bladder drainage in fetuses with ultrasonic evidence of lower urinary tract obstruction. The limited available evidence suggests that prenatal bladder drainage may improve perinatal survival in these fetuses, particularly those with poor predicted prognoses. Further research in the form of a multicenter randomized controlled trial is required to assess the short- and long-term effects of this intervention.

Drainage↗
PubMed2003

Urinary microalbumin/creatinine ratios: reference range in uncomplicated pregnancy.

During uncomplicated pregnancy, the development of proteinuria is accepted as a poor prognostic sign and is associated with increasing maternal and perinatal mortality and morbidity. Physiological proteinuria increases with increasing gestation and one of its largest constituents is albumin. The reference range for the (micro)albumin/creatinine ratio (ACR) has not been described for normal pregnancy. This prospective cross-sectional study describes the gestation-specific 95% reference ranges for urinary microalbumin concentration, creatinine concentration and ACR in uncomplicated pregnancy. There is a significant increase ( P =0.016) in the ACR in the third trimester. The mean difference is 0.091 mg of albumin/mmol of creatinine (95% confidence interval, 0.014-0.168). Our results describe the first well-defined gestation-specific 95% reference range for a point-of-care measurement of the ACR. These data are essential if such testing is to be employed in antenatal care.

Adolescent↗
PubMed2002

Early expression of thyroid hormone deiodinases and receptors in human fetal cerebral cortex.

Thyroid hormones are known to be important for optimal development of the human central nervous system. Classically, maternal thyroid hormones have not been thought to have a major role in defining central nervous system development. However, recent epidemiological evidence has indicated that subtle deficiencies in circulating maternal thyroid hormones in the first trimester of pregnancy are associated with adverse neurodevelopment. We have used real time PCR to quantitate the expression of mRNAs encoding the thyroid receptor isoforms (TR alpha1, alpha2, beta1 and beta2) and thyronine deiodinase subtypes (5'-DI, 5'-DII and 5-DIII) in human fetal cerebral cortex from the first and second trimesters of pregnancy. Deiodinase subtype activities have also been determined in these tissues and compared to 'normal' adult human cerebral cortex. Iodothyronine deiodinase mRNAs were expressed in human fetal cerebral cortex from 7 to 8 weeks of gestation. The expression of 5'-DI mRNA was variable in fetal life but increased relative to adult cortex (P<0.05), whereas the activity of this enzyme was below the level of assay detection. 5'-DII mRNA and activity in fetal cerebral cortex was detectable from as early as 7-8 weeks but not significantly different from that in adult life except at 15-16 weeks when mRNA expression increased (P<0.05). Fetal cortex 5-DIII mRNA expression was present from the early first trimester but less abundant than in adult tissue (P<0.01) and 5-DIII activity appeared greater in fetal cortex (P<0.01) as compared to adults. Only TR alpha1 mRNA was more abundantly expressed in fetal cortex than adult tissues (P<0.01). In contrast, the TR isoforms (alpha2 and beta1) were expressed significantly less than in adult tissues (P<0.05). Only 26% of fetal cerebral cortex samples expressed TR beta 1. There is evidence that the developing fetal brain, as early as the first trimester, expresses TRs and exhibits the mechanisms of pre-receptor control of thyroid hormone supply.

Adult↗
PubMed2002

The ontogeny of 25-hydroxyvitamin D(3) 1alpha-hydroxylase expression in human placenta and decidua.

In addition to its classical calciotropic effects, the active form of vitamin D, 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) is a potent anti-proliferative/immunomodulatory secosteroid. The enzyme that catalyzes the synthesis of 1,25(OH)(2)D(3), 1alpha-hydroxylase (1alpha-OHase), is expressed in many human tissues, highlighting its possible role as an autocrine/paracrine activator of vitamin D. Immunohistochemical and RNA analyses were used to characterize the ontogeny of 1alpha-OHase expression in human placenta and decidua. Protein for 1alpha-OHase was detectable in trophoblast and decidua; the latter being stronger in decidualized stromal cells than macrophages, with no staining of lymphocytes. Quantitative reverse transcriptase-polymerase chain reaction was used to assess changes in mRNA expression for 1alpha-OHase at different gestations: first (mean, 9.1 +/- 1.5 weeks); second (mean, 14 +/- 1.8 weeks), and third trimester (mean, 39.3 +/- 2.5 weeks). 1alpha-OHase expression in decidua was approximately 1000-fold higher in first (95% confidence limits, 611 to 1376) and second (95% confidence limits, 633 to 1623) trimester biopsies when compared with the third trimester (95% confidence limits, 0.36 to 2.81) (both P < 0.001). In placenta, 1alpha-OHase expression was 80-fold higher in the first (range, 42 to 137) and second (range, 30 to 199) trimester when compared with third trimester biopsies (0.6 to 1.6) (both P < 0.001). Similar results were obtained by semiquantitative IHC. Parallel analysis of the receptor for 1,25(OH)(2)D(3) (vitamin D receptor) indicated that, as with 1alpha-OHase, highest levels of expression occurred in first trimester decidua. However, changes in vitamin D receptor mRNA expression across gestation were less pronounced than 1alpha-OHase. These spatiotemporal data emphasize the potential importance of 1alpha-OHase during early fetoplacental life and, in particular, suggest an autocrine/paracrine immunomodulatory function for the enzyme.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗