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Biomedical subjects

P J Berry

Publications and source records attributed to P J Berry.

At least 19 recordsLinked to original sources
PubMed2001

Classification and genetic features of neonatal haemochromatosis: a study of 27 affected pedigrees and molecular analysis of genes implicated in iron metabolism.

Neonatal haemochromatosis (NH) is a severe and newly recognised syndrome of uncertain aetiology, characterised by congenital cirrhosis or fulminant hepatitis and widespread tissue iron deposition. NH occurs in the context of maternal disease including viral infection, as a complication of metabolic disease in the fetus, and sporadically or recurrently, without overt cause, in sibs. Although an underlying genetic basis for NH has been suspected, no test is available for predictive analysis in at risk pregnancies. As a first step towards an understanding of the putative genetic basis for neonatal haemochromatosis, we have conducted a systematic study of the mode of transmission of this disorder in a total of 40 infants born to 27 families. We have moreover carried out a molecular analysis of candidate genes (beta(2)-microglobulin, HFE, and haem oxygenases 1 and 2) implicated in iron metabolism. No pathogenic mutations in these genes were identified that segregate consistently with the disease phenotype in multiplex pedigrees. However, excluding four pedigrees with clear evidence of maternal infection associated with NH, a pedigree showing transmission of maternal antinuclear factor and ribonucleoprotein antibodies to the affected infants, and two families with possible matrilineal inheritance of disease in maternal half sibs, a large subgroup of the affected pedigrees point to the inheritance of an autosomal recessive trait. This included 14 pedigrees with affected and unaffected infants and a single pedigree where all four affected infants were the sole offspring of consanguineous but otherwise healthy parents. We thus report three distinct patterns of disease transmission in neonatal haemochromatosis. In the differentiation of a large subgroup showing transmission of disease in a manner suggesting autosomal recessive inheritance, we also provide the basis for further genome wide studies to define chromosomal determinants of iron storage disease in the newborn.

Adolescent↗
PubMed2000

Abnormal nephron development associated with a frameshift mutation in the transcription factor hepatocyte nuclear factor-1 beta.

BACKGROUND: The transcription factor hepatocyte nuclear factor (HNF)-1 beta functions as a homodimer or as a heterodimer with the structurally related protein HNF-1 alpha. Both are expressed sequentially in rat kidney development, with HNF-1 beta being detected from the earliest inductory phases. HNF-1 beta gene mutations are associated with a unique disorder characterized by maturity-onset diabetes of the young (MODY) and early-onset and progressive nondiabetic renal dysfunction, which may lead to chronic renal failure. METHODS: The HNF-1 beta gene was screened for mutations in six subjects with early-onset diabetes and a history of renal dysfunction in the subjects or their families. RESULTS: A novel frameshift mutation in exon 4 of the HNF-1 beta gene and a deletion of CCTCT at codons 328 to 329 were detected in one subject. She was diagnosed as diabetic at the age of 21 in her second pregnancy. Glucose tolerance rapidly deteriorated over 18 months as a result of beta-cell dysfunction. The HNF-1 beta mutation arose de novo on a paternal chromosome and cosegregated with renal abnormalities in her family. The proband had bilateral small cysts in normal-sized kidneys and a reduced creatinine clearance of 66 mL/min (NR 80-120). Her first pregnancy was terminated at 17 weeks following an ultrasound diagnosis of bilateral, nonfunctioning cystic kidneys. Her first-born child had a small multicystic, dysplastic right kidney and a dysplastic left kidney with a reduced creatinine clearance (40 mL/min per 1.73 m2). Histologic examination of the large (5.8 vs. 1.4 g), polycystic fetal kidneys showed no normal nephrogenesis. CONCLUSIONS: These studies indicate that HNF-1 beta plays a central role in normal kidney development and pancreatic beta-cell function, and suggest that one mechanism by which HNF-1 beta gene mutations may cause renal dysfunction are by their effects on nephron development.

Abortion, Induced↗
PubMed2000

A clinical comparison of SIDS and explained sudden infant deaths: how healthy and how normal? CESDI SUDI Research Group. Confidential Inquiry into Stillbirths and Deaths in Infancy study.

OBJECTIVES: To compare the clinical characteristics associated with sudden infant death syndrome (SIDS) and explained sudden unexpected deaths in infancy (SUDI). DESIGN: Three year population based, case control study with parental interviews for each death and four age matched controls. SETTING: Five regions in England (population, > 17 million; live births, > 470,000). SUBJECTS: SIDS: 325 infants; explained SUDI: 72 infants; controls: 1,588 infants. RESULTS: In the univariate analysis, all the clinical features and health markers at birth, after discharge from hospital, during life, and shortly before death, significant among the infants with SIDS were in the same direction among the infants who died of explained SUDI. In the multivariate analysis, at least one apparent life threatening event had been experienced by more of the infants who died than in controls (SIDS: 12% v 3% controls; odds ratio (OR) = 2.55; 95% confidence interval (CI), 1.02 to 6.41; explained SUDI: 15% v 4% controls; OR = 16.81; 95% CI, 2.52 to 112.30). Using a retrospective illness scoring system based on "Baby Check", both index groups showed significant markers of illness in the last 24 hours (SIDS: 22% v 8% controls; OR = 4.17; 95% CI, 1.88 to 9.24; explained SUDI: 49% v 8% controls; OR = 31.20; 95% CI, 6.93 to 140.5). CONCLUSIONS: The clinical characteristics of SIDS and explained SUDI are similar. Baby Check might help identify seriously ill babies at risk of sudden death, particularly in high risk infants.

Case-Control Studies↗
PubMed2000

Weight gain and sudden infant death syndrome: changes in weight z scores may identify infants at increased risk.

AIMS: To investigate patterns of infant growth that may influence the risk of sudden infant death syndrome (SIDS). DESIGN: Three year population based case control study with parental interviews for each death and four age matched controls. Growth was measured from prospective weight observations using the British 1990 Growth Reference. SETTING: Five regions in England (population greater than 17 million, more than 470 000 live births over three years). SUBJECTS: 247 SIDS cases and 1110 controls. RESULTS: The growth rate from birth to the final weight observation was significantly poorer among the SIDS infants despite controlling for potential confounders (SIDS mean change in weight z score (deltazw) = -0.38 (SD 1.40) v controls = +0.22 (SD 1.10), multivariate: p < 0.0001). Weight gain was poorer among SIDS infants with a normal birth weight (above the 16th centile: odds ratio (OR) = 1.75, 95% confidence interval (CI) 1. 48-2.07, p < 0.0001) than for those with lower birth weight (OR = 1. 09, 95% CI 0.61-1.95, p = 0.76). There was no evidence of increased growth retardation before death. CONCLUSIONS: Poor postnatal weight gain was independently associated with an increased risk of SIDS and could be identified at the routine six week assessment.

Birth Weight↗
PubMed1999

Babies sleeping with parents: case-control study of factors influencing the risk of the sudden infant death syndrome. CESDI SUDI research group.

OBJECTIVE: To investigate the risks of the sudden infant death syndrome and factors that may contribute to unsafe sleeping environments. DESIGN: Three year, population based case-control study. Parental interviews were conducted for each sudden infant death and for four controls matched for age, locality, and time of sleep. SETTING: Five regions in England with a total population of over 17 million people. SUBJECTS: 325 babies who died and 1300 control infants. RESULTS: In the multivariate analysis infants who shared their parents' bed and were then put back in their own cot had no increased risk (odds ratio 0.67; 95% confidence interval 0.22 to 2.00). There was an increased risk for infants who shared the bed for the whole sleep or were taken to and found in the parental bed (9.78; 4.02 to 23.83), infants who slept in a separate room from their parents (10.49; 4.26 to 25.81), and infants who shared a sofa (48.99; 5.04 to 475.60). The risk associated with being found in the parental bed was not significant for older infants (>14 weeks) or for infants of parents who did not smoke and became non-significant after adjustment for recent maternal alcohol consumption (>2 units), use of duvets (>4 togs), parental tiredness (infant slept </=4 hours for longest sleep in previous 24 hours), and overcrowded housing conditions (>2 people per room of the house). CONCLUSIONS: There are certain circumstances when bed sharing should be avoided, particularly for infants under four months old. Parents sleeping on a sofa with infants should always be avoided. There is no evidence that bed sharing is hazardous for infants of parents who do not smoke.

Beds↗
PubMed1999

Pacifier use and sudden infant death syndrome: results from the CESDI/SUDI case control study. CESDI SUDI Research Team.

OBJECTIVES: To investigate the relation between pacifier use and sudden infant death syndrome (SIDS). DESIGN: Three year population based, case control study with parental interviews for each death and four age matched controls. SETTING: Five regions in England (population > 17 million). SUBJECTS: 325 infants who had died from SIDS and 1300 control infants. RESULTS: Significantly fewer SIDS infants (40%) than controls (51%) used a pacifier for the last/reference sleep (univariate odds ratio (OR), 0.62; 95% confidence interval (CI), 0.46 to 0.83) and the difference increased when controlled for other factors (multivariate OR, 0.41; 95% CI, 0. 22 to 0.77). However, the proportion of infants who had ever used a pacifier for day (66% SIDS v 66% controls) or night sleeps (61% SIDS v 61% controls) was identical. The association of a risk for SIDS infants who routinely used a pacifier but did not do so for the last sleep became non-significant when controlled for socioeconomic status (bivariate OR, 1.39 (0.93 to 2.07)). CONCLUSIONS: Further epidemiological evidence and physiological studies are needed before pacifier use can be recommended as a measure to reduce the risk of SIDS.

Breast Feeding↗
PubMed1999

Epidemiology of SIDS and explained sudden infant deaths. CESDI SUDI Research Group.

OBJECTIVES: To establish whether epidemiologic characteristics for sudden infant death syndrome (SIDS) have changed since the decrease in death rate after the "Back to Sleep" campaign in 1991, and to compare these characteristics with sudden and unexpected deaths in infancy (SUDI) from explained causes. DESIGN: Three-year, population-based, case-control study. Parental interviews were conducted soon after the death and for 4 controls matched for age and date of interview. All sudden unexpected deaths were included in the study and the cause of death was established by a multidisciplinary panel of the relevant health care professionals taking into account past medical and social history of the mother and infant, the circumstances of death, and a full pediatric postmortem examination. Contributory factors and the final classification of death were made using the Avon clinicopathologic system. SETTING: Five regions in England, with a total population of >17 million people, took part in the study. The number of live births within these regions during the particular time each region was involved in the study was 473 000. STUDY PARTICIPANTS: Three hundred twenty-five SIDS infants (91.3% of those available), 72 explained SUDI infants (86.7% of those available), and 1588 matched control infants (100% of total for cases included). RESULTS: Many of the epidemiologic features that characterize SIDS infants and families have remained the same, despite the recent decrease in SIDS incidence in the United Kingdom. These include the same characteristic age distribution, few deaths in the first few weeks of life or after 6 months, with a peak between 4 and 16 weeks, a higher incidence in males, lower birth weight, shorter gestation, and more neonatal problems at delivery. As in previous studies there was a strong correlation with young maternal age and higher parity and the risk increased for infants of single mothers and for multiple births. A small but significant proportion of index mothers had also experienced a previous stillbirth or infant death. The majority of the SIDS deaths (83%) occurred during the night sleep and there was no particular day of the week on which a significantly higher proportion of deaths occurred. Major epidemiologic features to change since the decrease in SIDS rate include a reduction in the previous high winter peaks of death and a shift of SIDS families to the more deprived social grouping. Just more than one quarter of the SIDS deaths (27%) occurred in the 3 winter months (December through February) in the 3 years of this study. In half of the SIDS families (49%), the lone parent or both parents were unemployed compared with less than a fifth of control families (18%). This difference was not explained by an excess of single mothers in the index group. Many of the significant factors relating to the SIDS infants and families that distinguish them from the normal population did not distinguish between SIDS and explained SUDI. In the univariate analysis many of the epidemiologic characteristics significant among the SIDS group were also identified and in the same direction among the infants dying as SUDI attributable to known causes. The explained deaths were similarly characterized by the same infant, maternal, and social factors, 48% of these families received no waged income. Using logistic regression to make a direct comparison between the two index groups there were only three significant differences between the two groups of deaths: 1) a different age distribution, the age distribution of the explained deaths peaked in the first 2 months and was more uniform thereafter; 2) more congenital anomalies were noted at birth (odds ratio [OR] = 3.14; 95% confidence intervals [CI]: 1.52-6. (ABSTRACT TRUNCATED)

Age Distribution↗
PubMed1998

Microdissecting the genetic events in nephrogenic rests and Wilms' tumor development.

Nephrogenic rests are precursor lesions associated with about 40% of Wilms' tumors. This study identifies genetic steps occurring in the development of Wilms' tumor. Thirty-four Wilms' tumors with nephrogenic rests and/or areas of anaplasia were microdissected from paraffin sections to determine whether and at what stage loss of heterozygosity (LOH) occurred, using polymerase chain reaction-based polymorphic markers at 11p13, 11p15, and 16q. LOH at these loci have been identified in Wilms' tumors and are associated with identified or putative tumor suppressor genes. Three cystic nephromas/cystic partially differentiated nephroblastomas were also examined. LOH was detected in six cases at 11p13 and in six cases at 11p15, and two of these cases had LOH at both loci. All intralobar rests showing LOH also showed LOH in the tumor. A case with a small perilobar rest showed LOH of 11p13 only in the tumor. Five cases showing LOH at 16q were identified (this was identified only in the tumor, and not in the associated rest), and three of these had recurrence of the tumor. Two cases had a WT1 mutation (one germline and the other somatic), as well as LOH in both the intralobar rest and the tumor. A cystic partially differentiated nephroblastoma showed loss at 11p13 and 11p15, as well as at 16q. This study suggests that LOH at 11p13 and 11p15 and WT1 mutations are early events but that LOH at 16q occurs late in the pathogenesis of Wilms' tumor. Intralobar and perilobar nephrogenic rests are known to have different biological behaviors, and this study suggests that they are genetically different. A multistep model of Wilms' tumor pathogenesis is supported by these findings.

Adolescent↗
PubMed1997

Congenital malignant rhabdoid tumour of the gum margin.

The case of an infant born with a large polypoid tumour arising from the mouth is described. The tumour had the histological, immunohistochemical and ultrastructural phenotype of an extrarenal malignant rhabdoid tumour and followed an aggressive clinical course. This is one of the few reported cases of malignant rhabdoid tumour to present at birth. The oral tumour was associated with a mass in the posterior cranial fossa. This was most likely to be a simultaneous second primary tumour.

Fatal Outcome↗
PubMed1997

Immunohistochemical detection of the Wilms' tumour gene WT1 in desmoplastic small round cell tumour.

The desmoplastic small round cell tumour (DSRCT) is a rare, highly malignant neoplasm usually presenting in the abdomen of adolescent males. A characteristic translocation between the Ewing's sarcoma gene on chromosome 22 and the Wilms' tumour gene WT1 on chromosome 11 has been described, producing a fusion gene with expression of the DNA binding area of WT1. Some Wilms' tumour antibodies recognize epitopes of this part of the WT1 protein. All four cases of DSRCT examined showed strong staining of the tumours with an anti-WT1 antibody, suggesting this may be useful in the diagnosis of these tumours.

Abdominal Neoplasms↗
PubMed1997

Expression of the Wilms' tumour gene WT1 in the developing human and in paediatric renal tumours: an immunohistochemical study.

AIMS: The Wilms' tumour gene (WT1) product is expressed during the development of the urogenital system. This study was undertaken to evaluate four anti-WT1 antibodies and use the most specific one to examine the expression of WT1 in formalin fixed, paraffin wax embedded tissues from human embryos, fetuses, and paediatric renal neoplasms. METHODS: The antibodies were assessed on paraffin sections of fetal kidney and by western blotting. Immunohistochemical techniques were optimised and performed on a range of embryonic, fetal, and infant tissues from 35 days post-conception to three months of age, and on a selection of paediatric renal neoplasms. RESULTS: The antibodies tested were found to vary in their specificity. Anomalous expression in smooth muscle was seen with one batch of a commercial polyclonal antibody. WT1 protein was detected in both the metanephros and the mesonephros, the spleen, the gonads, and in the peritoneal mesothelium in fetuses. WT1 was expressed in nuclei and was strongest in the podocytes of fetal kidney. The podocytes of infant glomeruli were also positive. There was focal positive staining in Wilms' tumours, nephrogenic rests, and in a cystic partially differentiated nephroblastoma. Staining of nuclei was seen in one of two rhabdoid tumours of the kidney. No positive staining was seen in other renal tumours. CONCLUSIONS: WT1 is detected readily in formalin fixed material. There were differences in specificity between batches of the polyclonal antibodies used. The distribution of the WT1 gene product in tissues and tumours reflected previous findings with in situ hybridisation studies of WT1 mRNA.

Antibodies↗