Population genetics of phenylketonuria

Phenylketonuria (PKU) is an autosomal recessive disorder caused by a large number of mutations at the phenylalanine hydroxylase (PAH) locus, most of which are strongly associated with specific RFLP or VNTR haplotypes. One of the major questions remaining in PKU research is why this apparently maladaptive disorder has been maintained at a frequency of approximately 1 in 10000 among Caucasians. A growing number of studies have provided evidence that both the relatively high frequency of PKU and the strong mutation/haplotype associations might reflect the existence of multiple founding populations for PKU. Examples of putative founding populations for PKU in both Europe and Asia will be presented. Some PAH mutations are associated with multiple haplotypes, suggesting recurrence. Evidence for and against recurrence as the mechanism responsible for the association of the R408W mutation with RFLP haplotypes 1 and 2 will be discussed.     

Molecular analysis of PKU in Ireland

Classical phenylketonuria (PKU: McKusick No. 261600) is caused by mutations occurring at the phenylalanine hydroxylase (PAH) locus on chromosome 12 and has a prevalence in Ireland of 1 in 4500. We examined 304 independent alleles from 350 patients for the presence of six mutations and have characterized VNTR alleles within the minisatellite region 3' to the PAH gene in patients carrying the most prevalent mutation. R408W was the most common mutation found, with a relative frequency of 42%. All other mutations had relative frequencies of <10%. VNTR analysis showed that the R408W mutation is associated with the VNTR-8 allele in the Irish population, indicating that R408W is associated with RFLP haplotype 1. This differs from that reported from eastern Europe where R408W is associated with RFLP haplotype 2/VNTR-3; an observation which has led several groups to propose a Balto-Slavic origin for this mutation. These results support the hypothesis of a second, independent founding event for the R408W mutation on an RFLP haplotype 1 VNTR-8 chromsome background in the Irish/Celtic population.     

Prevalence of behaviour disorders in low birthweight infants

OBJECTIVE--To determine the prevalence of behaviour disorders in low birthweight infants. DESIGN--Children of birth weight < or = 2000 g born to mothers resident in Merseyside in 1980-1 assessed using the Rutter parent and teacher behaviour questionnaires and the Conner modification of the Rutter teacher questionnaire. Children attending normal schools were assessed with controls matched for age, sex, and class in school. Children attending special schools were assessed unmatched. SUBJECTS--233 matched case-control pairs attending normal primary schools and 46 unmatched children attending special schools. SETTING--Primary and special schools. MAIN OUTCOME MEASURES--Emotional, conduct, and undifferentiated behaviour disorders and hyperactivity. RESULTS--On the parental questionnaire screen, 36% of the cases and 22% of the controls had a behaviour disorder and on the teacher questionnaire the proportions were 27% and 12% respectively. Hyperactivity was significantly more common among male cases than their controls (21% v 5.0%) but differed little among female cases and controls (9% v 7%). CONCLUSIONS--Improving neonatal survival of low birthweight infants is accompanied by a higher prevalence of behaviour disorders. The long term implications for psychiatric morbidity and other adult disease must be monitored.     

The quantitative analysis of zearalenone and its derivatives in plasma of patients with breast and cervical cancer.

Zearalenone (6-[10-hydroxy-6-oxo-trans-1-undecenyl]-beta-resorcylic acid-p-lactone), a mycotoxin produced in corn, is able to adopt a conformation which sufficiently resembles 17beta-oestradiol to allow it to bind to the oestrogen receptor in target cells of the body and exert (agonist) oestrogenic action. We adopted an analytical approach to isolate and quantify the mycotoxin and its derivatives using high-performance liquid chromatography and gas chromatography-mass spectrometry. In this study, the quantity of zearalenone and its congeners (alpha-zearalenol and beta-zearalenol) present in the plasma of patients with breast (n = 28) and cervical carcinoma (n=54) were compared with levels in patients presenting with other diagnoses (n = 26) and healthy volunteers (n = 24). There were no significant differences between the groups in the levels of zearalenone and its congeners, using analysis of covariance (0.2 < p < 0.6). These results suggest that the presence of this mycotoxin in blood does not indicate causal relationship between exposure to this exogenous myco-oestrogen and the subsequent biological effect in our study population but may be used as an indicator of exposure. The presence of zearalenone in the study groups is, however, of growing concern, due to the possible effects of cumulative long-term exposure of oestrogenic target organs to this compound.     

Rotator cuff tear: clinical experience with sonographic detection

Between June 1986 and April 1988, 86 sonographic examinations of the shoulder were performed on patients suspected of having rotator cuff tears. Major sonographic diagnostic criteria included (a) a well-defined discontinuity usually visible as a hypoechoic focus within the cuff, (b) nonvisualization of the cuff and (c) an echogenic focus within the cuff. Seventy-five patients underwent both sonography and arthrography. Compared with arthrography alone, ultrasound examinations enabled detection of 92% of rotator cuff tears (24 of 26 tears), with a specificity of 84% and a negative predictive value of 95%. Correlation was obtained in 30 of these patients who underwent surgery for rotator cuff tear or other soft-tissue abnormality. In this group, the sensitivity of sonography for detection of a tear was 93%, with a specificity of 73%, while for arthrography sensitivity was 87% and specificity was 100%. These data indicate that sonography is a useful, noninvasive screening procedure for patients suspected of having rotator cuff injury.     

Quality assessment and assurance in diagnostic imaging. Theoretical and practical considerations and a quality audit of the excretory urogram

Concepts necessary to an understanding of the basics of quality assurance audits are presented. Included are specific examples that bridged theory and practice by applying the protocol to a real-life diagnostic imaging situation. This method meets the present requirements of the Joint Commission of the Accrediation of Hospitals.     

Release by phenobarbital of the repression of UDP-glucuronyltransferase activity in ovo

UDP-Glucuronyltransferase activity in chick-embryo liver and kidney, known to be induced by hatching or by culture, appears to be repressed in ovo. Injection of phenobarbital into the egg overcomes this repression. Chick-embryo liver and kidney cells can thus exhibit high transferase levels whilst still in ovo. Response to phenobarbital by liver tissue occurs in situ or when grafted on to the chorioallantoic membrane, and can be elicited by 96 hr of age. The ability of phenobarbital to over-ride the natural regulation of liver UDP-glucuronyltransferase development in ovo is contrasted with its inability in utero. Overall glucuronidation, as well as the transferase, is elicited by phenobarbital in ovo; differences between regulation of glucuronidating and hydroxylating enzymes are noted.