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P Clayton

Publications and source records attributed to P Clayton.

At least 37 records · Page 2Linked to original sources
PubMed1998

BAPS prize lecture: New insight into mechanisms of parenteral nutrition-associated cholestasis: role of plant sterols. British Association of Paediatric Surgeons.

BACKGROUND PURPOSE: Infants on long-term parenteral nutrition frequently will have progressive cholestatic liver disease, the cause of which remains largely unknown. The aim of this study is to establish a possible role for plant sterols (phytosterols) in the pathogenesis of parenteral nutrition-associated cholestasis (PNAC). METHODS: Two experimental studies were used: (1) A study on neonatal piglets involved the daily injection of plant sterols; measurement of their concentrations in serum, liver, and bile during a 14-day period; and determination of serum bile acid concentrations, bile acid secretion, and bile flow at the end of the 14-day period. (2) Isolated rat hepatocyte couplets were used to study the effects of sterols on canalicular secretion. RESULTS: The daily injection of phytosterols (in amounts similar to those given to infants who receive parenteral nutrition) led to their progressive accumulation in the piglets' serum, liver, and bile. Serum bile acid levels were significantly higher in the sterol-treated piglets. Maximal bile acid excretion was significantly lower in the sterol group. Phytosterols caused a significant inhibition of secretory function in isolated rat hepatocyte couplets. CONCLUSION: Important contaminants of commercial lipid emulsions (phytosterols) have been identified as a possible cause of PNAC.

Animals↗
PubMed1998

Defective galactosylation of serum transferrin in galactosemia.

The glycosylation of serum transferrin from galactosemic patients with a deficiency of galactose-1-phosphate uridyl transferase (EC 2. 7.7 12) is abnormal but becomes normal after treatment with a galactose-free diet. To understand the structural and biochemical basis of the abnormal glycosylation, transferrin was purified from the serum of untreated and treated galactosemic patients and normal controls and the N-linked glycans analyzed by HPLC. The glycans from normal transferrin consisted predominantly (86%) of the disialylated biantennary complex type. The glycans from untreated galactosemic patients were more heterogeneous and contained four major truncated glycans in addition to a smaller amount (13%) of the disialylated biantennary complex type. The truncated glycans were deficient in galactose and sialic acid and their structures were consistent with a decrease in galactosyltransferase activity in hepatocytes, the probable cells of origin of the transferrin. This is postulated to be due to direct inhibition of the galactosyltransferase activity by the accumulated galactose-1-phosphate or to an effect on the formation of UDP-galactose, the donor substrate in the reaction. After treatment the proportion of the truncated glycans decreased and the proportion of the disialylated biantennary complex type increased, returning almost but never completely to normal, even after prolonged treatment in some cases. There was no clear relationship between the length of treatment and the normalization of glycosylation and the level of galactose-1-phosphate in red blood cells, the usual parameter for monitoring the treatment of galactosemics. It is suggested that the persistence of abnormally glycosylated proteins may contribute to the long-term complications in galactosemia.

Carbohydrate Sequence↗
PubMed1998

Smith-Lemli-Opitz syndrome: a variable clinical and biochemical phenotype.

We have reviewed all known UK cases of Smith-Lemli-Opitz syndrome. Among 49 cases with proven 7-dehydrocholesterol reductase deficiency, half had been terminated or had died in infancy. The minimum incidence is 1 in 60,000. The frequent occurrence of hypospadias may account for 71% of recognised cases being male. Important common features which emerged include short thumbs, severe photosensitivity, aggressive behaviour, and atrioventricular septal defect. The typical facial appearance becomes less obvious with age and 20% of cases did not have 2/3 toe syndactyly. Biochemical measurements of serum 7-dehydrocholesterol did not correlate with clinical severity.

Adult↗
PubMed1998

Androgens and fetal growth.

Boys are heavier than girls at term birth. Children with a 46,XY karyotype and androgen insensitivity syndrome (clinically complete form and/or proven mutations in the androgen receptor gene) were found to have a birth weight comparable to that of girls. These findings support the hypothesis that the difference in birth weight between boys and girls is generated by androgen action.

Androgen-Insensitivity Syndrome↗
PubMed1998

Prenatal diagnosis of the carbohydrate-deficient glycoprotein syndrome type 1A (CDG1A) by a combination of enzymology and genetic linkage analysis after amniocentesis or chorionic villus sampling.

Two pregnancies at risk for the carbohydrate-deficient glycoprotein syndrome Type 1A (CDG1A, phosphomannomutase deficient) were monitored by enzyme and genetic linkage analyses. The index case in both families had a proven deficiency of phosphomannomutase (PMM). An unaffected fetus was predicted in family 1 following amniocentesis. Normal PMM activity was found in cultured amniotic fluid cells and there was no elevation of lysosomal enzymes in the amniotic fluid. Genetic linkage analysis using microsatellite markers closely linked to the CDG1A gene confirmed this prediction. A healthy child was born. In the second family direct assay of chorionic villi showed a profound deficiency of PMM and genetic linkage analysis showed the fetus to have the same haplotype as the proband. The pregnancy was terminated and a deficiency of PMM was confirmed in cultured fibroblasts from the fetus. Reliable prenatal diagnosis of CDG Type 1A (PMM-deficient) can be achieved by a combination of biochemical and molecular genetic tests.

Amniocentesis↗
PubMed1997

Dicarboxyphenylglycines antagonize AMPA- but not kainate-induced depolarizations in neonatal rat motoneurones.

Ionotropic glutamate receptors have been categorized into three main groups according to the selective agonists that activate them, the N-methyl-D-aspartate (NMDA), (S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoic acid (AMPA) and (2S,3S,4S)-3-carboxymethyl-4-isopropenylpyrrolidine-2-carboxylic acid (kainate) receptors. Both AMPA and kainate induce depolarizations in neonatal rat spinal motoneurones. However, selective antagonists capable of discriminating between the effects of these two antagonists are not widely available. As part of a search for such compounds we report the actions of (RS)-3,4-dicarboxyphenylglycine (DCPG) and (RS)-3,5-dicarboxyphenylglycine on agonist-induced motoneuronal depolarizations in the neonatal rat spinal cord preparation. In addition, the actions of (R)- and (S)-3,4-DCPG are also described. (RS)-3,4-DCPG and (RS)-3,5-DCPG antagonized AMPA-induced depolarizations (apparent Kd = 137 microM (n = 3) and 167 microM (n = 5), respectively). However, (RS)-3,5-DCPG (1 mM) potentiated responses due to kainate (n = 5) while (RS)-3,4-DCPG (1 mM) displayed weak antagonism of these responses (apparent Kd > 12 mM, n = 3). (RS)-3,4- and (RS)-3,5-DCPG at 500 microM both displayed antagonism at the NMDA receptor (apparent Kd = 472 microM and 346 microM, respectively) and a postsynaptic subgroup I metabotropic glutamate receptor activated by (1S,3R)-ACPD. The AMPA receptor antagonist activity of (RS)-3,4-DCPG was shown to reside in the (R)-enantiomer (apparent Kd = 77 microM, n = 3). The same isomer was responsible for the NMDA receptor antagonism while showing little or no antagonism of kainate-induced depolarizations (apparent Kd > 3 mM, n = 3), and a weak antagonistic effect at (1S,3R)-ACPD receptors. (S)-3,4-DCPG (500 microM) was unable to antagonize kainate-induced depolarizations, showed weak or no antagonism of NMDA- and AMPA-induced depolarizations, but antagonized (1S,3R)-ACPD-induced depolarizations. Thus (RS)-3,4-, (RS)-3,5- and (R)-3,4-DCPG demonstrate useful discrimination of responses due to AMPA and kainate, strongly suggesting that pharmacologically distinct AMPA and kainate receptors exist in motoneurones in the neonatal rat spinal cord.

Animals↗
PubMed1997

A case of the carbohydrate-deficient glycoprotein syndrome type 1 (CDGS type 1) with normal phosphomannomutase activity.

The carbohydrate-deficient glycoprotein syndrome (CDGS) is a group of disorders characterized biochemically by abnormal glycosylation of serum and cellular glycoproteins. It has been classified into four forms on the basis of the isoelectric focusing pattern of serum transferrin and difference in clinical presentation. A deficiency of phosphomannomutase (PMM) has been reported in most patients with type 1. Seven of our eight CDGS patients, classified clinically as type 1, were shown to have a deficiency of phosphomannomutase in their fibroblast or lymphoblastoid cells (0.04-0.2 nmol/min per mg, compared with a control range of 1.0-2.1 nmol/min per mg). The eighth patient, who had many clinical features of the severe neonatal form of CDGS type 1, but lacked definite signs of CNS and ocular involvement, had a normal phosphomannomutase activity in his fibroblasts. There were approximately equal amounts of disialo- and tetrasialotransferrin and only a trace amount of asialotransferrin in the serum and ascitic fluid of this patient. The disialo- and tetrasialotransferrin isoforms were purified by ion-exchange chromatography and analysed by SDS-PAGE. The disialotransferrin had a lower molecular mass than the tetrasialotransferrin, consistent with the absence of an N-linked glycan. The N-linked glycans released enzymically from both isoforms consisted exclusively of disialylated biantennary chains, suggesting that disialotransferrin results from underglycosylation, as in the PMM-deficient CDGS type 1 patients. It is concluded that the clinical and biochemical phenotype in CDGS type 1 can result from more than one basic defect.

Ascitic Fluid↗
PubMed1997

Anterior segment dysgenesis in mosaic Turner syndrome.

AIMS/BACKGROUND: Females with Turner syndrome commonly exhibit ophthalmological abnormalities, although there is little information in the literature documenting findings specific to Turner syndrome mosaics. Ophthalmic findings are described in four patients with mosaic Turner syndrome. All had anterior chamber abnormalities and all four had karyotypic abnormalities with a 45, X cell line. The possible relation between the karyotypic and the phenotypic findings in these patients is discussed. METHODS: Four girls with mosaic Turner syndrome underwent a full ophthalmological assessment, including examination under anaesthesia where indicated. RESULTS: Three of the four patients presented with congenital glaucoma. Two had the karyotype 45, X/46, X, idic(Y) and one a 45, X/47, XXX karyotype. The remaining child had a Rieger malformation of the iris and the karyotype 45, X/46, X, r(X). CONCLUSIONS: These findings suggest that Turner syndrome mosaicism (where there are two abnormal cell lines) is associated with anterior segment dysgenesis. The findings in these four patients are compared with those seen in other mosaic phenotypes and it is postulated that the presence of two or more genetically different cell lines may have an adverse effect on anterior segment development.

Anterior Chamber↗
PubMed1995

Switching from 'unipolar' to bipolar II. An 11-year prospective study of clinical and temperamental predictors in 559 patients.

BACKGROUND: Given the therapeutic and prognostic importance of the unipolar-bipolar dichotomy, predicting which patients will become bipolar subsequent to index diagnosis of major depressive disorder (MDD) is of paramount clinical significance. We sought to characterize the profile of patients with MDD who would convert to the more subtle bipolar subtype (known as BPII) on the basis of clinical and personality variables obtained during MDD episodes. METHODS: A total of 559 patients, comprehensively evaluated with the Schedule of Affective Disorders and Schizophrenia and "unipolar" MDD at entry, were administered 17 self-report personality measures. Hypomanic and manic episodes were systematically recorded over a prospective observation period of up to 11 years. We compared 48 converters to BPII (8.6%) with 22 converters to bipolar I (BPI) (3.9%) and the remaining larger group of unipolar patients. RESULTS: Except for greater acuteness, severity, and psychotic symptomatology, BPI converters were essentially similar to MDD nonconverters. By contrast, BPII converters were robustly distinguished from those with MDD who remained unipolar on the basis of self-report measures along the newly derived factors of Mood Lability, Energy-Activity, and Daydreaming. This profile was associated with early age at onset of MDD and pleomorphic psychopathology beyond the usual affective realm, high rates of substance abuse, as well as educational, marital, and occupational disruption and minor antisocial acts prior to discrete hypomanic episodes. Overall, BPII switchers had a more protracted and tempestuous course with shorter well intervals. "Habitual self" descriptions of temperamental instability during MDD episodes provided useful clinical information for predicting which depressed patients will switch to BPII, attaining a sensitivity of 91% for all three factors combined (23 items); Mood Lability alone (nine items) was the most specific predictor (86%), though of lower sensitivity (42%). CONCLUSIONS: The BPII subtype is best understood by such lability intruding into, and possibly its accentuation during, depressive episodes, thereby creating an intimate interweaving of trait and state. Clinicians must note that the foregoing temperamental profile appears more fundamental in defining the affective dysregulation of the BPII subtype than hypomanic episodes emphasized in DSM-IV.

Adult↗
PubMed1995

Using intermediate states to improve the ability of the Arden Syntax to implement care plans and reuse knowledge.

The Arden Syntax is one of a few knowledge representation languages currently in use for clinical decision support. While some of these languages are being used in active patient care settings, none have gained widespread acceptance as a clinical tool. Prior attempts to represent temporally complex care plans in the Arden Syntax have revealed difficulties in representing and tracking series of consecutive time-oriented events and recommendations, in sharing and reusing knowledge and in dealing with unobtainable data. In an attempt to improve Arden's ability to deal with these problems and demonstrate the importance of these factors, the clinical event monitor has been adapted to store coded data representing Intermediate States in the Columbia Presbyterian Medical Center (CPMC) central data repository. The Intermediate States define the current state of the patient as laid out in the care plan. Four care plans were constructed. The findings include an improved ability to track complex series of events and recommendations over long periods of time. The knowledge generated by the electronic care plans was able to be reused by the care plan that generated it, by other elements of the knowledge base and by non-decision support applications. Modular development, facilitated by the changes, simplified dealing with data not available to the central data repository by aiding the implementation of those parts of the care plan for which sufficient data is available.

Artificial Intelligence↗
PubMed1995

Applying a controlled medical terminology to a distributed, production clinical information system.

To maximize the value of computerized medical records systems, an organizing structure is needed. That structure can be provided by a controlled medical terminology (CMT). At Columbia-Presbyterian Medical Center, we have been employing a controlled medical terminology, our Medical Entities Dictionary (MED), to mediate the storage and retrieval of patient data and enable decision support applications. This paper describes how the MED is actually used for data management in our distributed clinical information systems environment. Our system tools which access the MED for production purposes facilitate the mapping of terms from many sources to a uniform representation of concepts and also return information about the relationships between concepts. Applications which access a CMT for production purposes should be optimized for performance in high volume settings, fault tolerant, synchronizable, extensible, portable, and maintainable. We briefly describe our system architecture and then demonstrate how we utilize the MED for translation and semantic information as data is moved into and out of our patient database. We discuss our current tools and present a preview of the next generation of applications which will manage access to the MED for our production systems.

Computer Communication Networks↗