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Biomedical subjects

C Azen

Publications and source records attributed to C Azen.

At least 19 recordsLinked to original sources
PubMed1999

Relationship among genotype, biochemical phenotype, and cognitive performance in females with phenylalanine hydroxylase deficiency: report from the Maternal Phenylketonuria Collaborative Study.

OBJECTIVE: To examine the relationship of phenylalanine hydroxylase (PAH) genotypes to biochemical phenotype and cognitive development in maternal phenylketonuria (PKU). METHODOLOGY: PAH gene mutations were examined in 222 hyperphenylalaninemic females enrolled in the Maternal PKU Collaborative Study (MPKUCS). A total of 84 different mutations were detected, and complete genotype was obtained in 199 individuals. Based on previous knowledge about mutation-phenotype associations, 78 of the mutations could be assigned to one of four classes of severity (severe PKU, moderate PKU, mild PKU, and mild hyperphenylalaninemia [MHP]). Then, 189 MPKUCS subjects were grouped according to the various combinations of mutation classifications. The sample sizes were large enough for statistical testing in four groups with at least one mutation that completely abolishes enzyme activity. These patients are considered functionally hemizygous. RESULTS: The biochemical phenotype predicted from the genotype in functionally hemizygous patients was related significantly to the assigned phenylalanine level. Cognitive performance (IQ) was also significantly related to genotype. The IQ of PAH-deficient mothers with a severe PKU mutation in combination with a MHP mutation or a mild PKU mutation was 99 and 96, respectively, whereas the IQ of PKU mothers with two severe PKU mutations or with one severe and one moderate PKU mutation was 83 and 84, respectively. Of the patients with PKU, 92% had been treated during childhood. Those who were untreated or treated late had lower than average IQ scores for their group of mutation combinations. Females with moderate or mild PKU who were treated early and treated for >6 years showed IQ scores 10 points above average for their group. CONCLUSIONS: The reproductive outcome in maternal phenylketonuria is dependent on prenatal metabolic control and postnatal environmental circumstances. Both factors depend on the intellectual resources of the mother with PKU. The significant relationship among genotype, biochemical phenotype, and cognitive performance observed in the present study is of importance for the development of an optimal strategy for future treatment of females with PKU who plan pregnancy.

Female↗
PubMed1998

Neonatal neurological assessment of offspring in maternal phenylketonuria.

This study assesses the impact of prenatal and postnatal factors in maternal phenylketonuria (PKU). The Dubowitz Neurological Assessment of the Preterm and Full-term Newborn Infant was administered within the first 8 days of life to 56 offspring of women with PKU and 45 controls. Follow-up testing of the maternal PKU offspring at age 1 year consisted of the Bayley Scales of Infant Development and the Receptive-Expressive Emergent Language Scale (REEL). In addition, the Home Observation for Measurement of the Environment (HOME Scale) was given. Birth weight was lower (z = 2.0, p = 0.045), birth length was lower (z = 2.1, p = 0.03) and birth head circumference was smaller (z = 3.5, p = 0.0005) in the maternal PKU offspring than in the control infants. Examiners rated 29% of the maternal PKU offspring and 9% of the control infants abnormal (Fisher's exact test, p = 0.01). At 1 year of age, 19% of the maternal PKU offspring attained a Bayley Developmental Quotient (DQ) and a score on the Bayley Motor Scale below 85; 19% had receptive language delay; and 26% had expressive language delay. The gestational age at which the mother attained metabolic control was an important factor associated with birth measurements, the Dubowitz Rating and subsequent developmental scores. The Dubowitz Neurological Assessment score did not predict developmental outcome (chi-square = 1.3, p = 0.53), while the HOME score correlated with the DQ (r = 0.36, p = 0.02). In logistic regression analyses, the home environment was a greater determinant of risk for a low DQ than whether or not the mother attained metabolic control prior to pregnancy (OR = 0.85, p = 0.02). These results suggest that treatment strategies addressing both prenatal and postnatal factors will most effectively reduce risks in maternal PKU.

Developmental Disabilities↗
PubMed1998

Dietary intake of cobalamin in elderly people who have abnormal serum cobalamin, methylmalonic acid and homocysteine levels.

OBJECTIVE: To determine if poor dietary intake can explain the cobalamin-related abnormalities often seen in the elderly. DESIGN: Prospective laboratory survey with a follow-up dietary assessment. SETTING: Social centers for the elderly and an outpatient clinic. SUBJECTS: Ninety-five free-living subjects >60y old with abnormal or suspicious findings in cobalamin-related tests and 78 subjects >60y old with normal results. INTERVENTIONS: Serum cobalamin, methylmalonic acid and homocysteine determinations to assess cobalamin status and a one year food-frequency questionnaire to assess cobalamin intake. RESULTS: Only three of the 173 subjects (1.7%), one of whom had normal cobalamin status, ingested <2 microg cobalamin/d, the Recommended Daily Allowance. Sixty-nine subjects (39.9%) ingested <6 microg/d, but they did not have more abnormal serum cobalamin or metabolite values than those ingesting >6 microg. Ordering all subjects by quintiles according to cobalamin intake revealed no significant trends or differences in any of the serum values either. Moreover, arranging subjects by results of tests of cobalamin status showed that the subjects with abnormal cobalamin status did not differ in cobalamin intake from those with normal cobalamin status, although they did differ in use of supplements. Finally, cobalamin intake, with or without supplements, did not correlate with serum cobalamin or metabolite levels. The absence of any association between cobalamin status and intake contrasts sharply with the significant correlation between folate intake and folate status (P = 0.0001). CONCLUSIONS: The high frequency of mildly abnormal cobalamin status in the elderly cannot be attributed to poor intake of cobalamin. Nondietary explanations, such as malabsorption and other phenomena, must always be sought to explain mild cobalamin deficiency in the elderly.

Aged↗
PubMed1997

Maternal Phenylketonuria Collaborative Study (MPKUCS) offspring: facial anomalies, malformations, and early neurological sequelae.

Maternal phenylketonuria (PKU) in untreated women has resulted in offspring with microcephaly, mental retardation, congenital heart disease (CHD), and intrauterine growth retardation. The Maternal Phenylketonuria Collaborative Study (MPKUCS) was designed to determine the effect of dietary control of blood phenylalanine (Phe) during pregnancy in preventing damage to the fetus associated with untreated Maternal PKU. A cohort of offspring from MPKUS pregnancies was ascertained and examined to evaluate malformations, including CHD, craniofacial abnormalities, microcephaly, intrauterine and postnatal growth retardation, other major and minor defects, and early abnormal neurological signs. For analysis, the women were grouped according to their mean Phe levels in mumol/liter, < or = 360, 361-600, 601-900, or > 900, during critical gestational weeks of 0-8 (N = 203) and 8-12 (N = 190), and average for Phe exposure throughout pregnancy (N = 183). Frequencies of congenital abnormalities increased with increasing maternal Phe levels. Significant relationships included average Phe 0-8 weeks and CHD (P = 0.001); average Phe 8-12 weeks and brain, fetal, and postnatal growth retardation (P < 0.0005 for all), wide nasal bridge (P < 0.0005), and anteverted nares (P = 0.001); and average Phe exposure during the entire pregnancy and neurological signs (P < 0.0005). Although 14% of infants had CHD, none of the CHD occurred at 120-360 mumol/liter and only one (3%) at 361-600 mumol/liter. At levels of 120-360 mumol/liter, there were three infants (6%) with microcephaly, two (4%) with postnatal growth, and none with intrauterine growth retardation, in contrast to 85%, 51%, and 26%, respectively, with Phe above 900 mumol/liter. These data support the concept that women with PKU should begin a low-phenylalanine diet to achieve Phe levels of < 360 mumol/liter prior to conception and should maintain this throughout pregnancy.

Cohort Studies↗
PubMed1997

The relationship of genotype to phenotype in phenylalanine hydroxylase deficiency.

Seventy-two adults with phenylketonuria were evaluated to investigate the genotypic relationship to phenotype. Patient data were collected by chart review and medical follow-up as well as current psychological evaluation. Nineteen diagnosed neonatally had remained on a phenylalanine-restricted diet all their lives, whereas 34 who were also diagnosed on newborn screening had discontinued dietary restriction during childhood. Nineteen others who were born prior to newborn screening were diagnosed later than the newborn period on clinical grounds but have remained on dietary restriction. Comparison between intellectual ability, academic achievement, and mental illness was made with degree of diet control as defined by range of blood phenylalanine levels over time. Diet discontinuation in childhood did not significantly lower IQ per se but appeared to diminish academic achievement. The lowest IQ scores were associated with poor dietary restriction of phenylalanine in the diet during childhood. While there appears to be a strong genotypic relationship to phenotypic metabolic parameters in phenylketonuria, there does not seem to be a similar relationship to intellectual ability in adults. Mutation R408W was not strongly related to the occurrence of mental illness in this sample. We conclude that dietary restriction of phenylalanine neonatally and good control contributed to normal intellectual development. Continuation of dietary treatment into adulthood appeared to improve academic achievement in patients with severe phenylalanine hydroxylase mutations.

Adult↗
PubMed1996

Summary of findings from the United States Collaborative Study of children treated for phenylketonuria.

The Collaborative Study of children treated for phenylketonuria (PKUCS) was conducted to investigate prospectively the effects of dietary restriction of phenylalanine on the growth and development of these children. Patients with classic phenylketonuria were identified by newborn screening and began treatment shortly thereafter. All were given the restricted diet until age 6 years, when half were randomly assigned to continue and half to discontinue dietary therapy. By age 10 years, 35% had deviated from randomization. The effects of diagnostic, treatment, and psychosocial factors on cognitive test scores were evaluated through 12 years of age. After controlling for parent IQ, significant correlations were noted between various measures of control of blood phenylalanine and their scores on intelligence, reading, spelling and behavior tests, but not for arithmetic or language scores. Bender Gestalt test scores were related to phenylalanine level at the time of testing, but not to early treatment history. These findings strongly support the importance of early initiation of dietary treatment and continuation of therapy throughout childhood.

Child↗
PubMed1996

The International Collaborative Study on maternal phenylketonuria: organization, study design and description of the sample.

The International Maternal Phenylketonuria (PKU) Collaborative Study commenced in 1984 to evaluate the efficacy of the low-phenylalanine diet in reducing the morbidity associated with maternal PKU syndrome. Four hundred and sixty eight (468) pregnancies resulted in 331 live births, 3 stillbirths, 61 spontaneous abortions, 2 ectopic pregnancies and 71 elective terminations. Since its inception, the study has steadily progressed toward its goal of diet initiation preconception or early in pregnancy. By 1994, 51% of the sample began the diet preconceptionally, with an additional 41% doing so by 8 weeks gestation. The number of adolescent pregnancies has decreased from 31% to 9%, college attendance has increased from 5% to 16%, number of women in the lowest socioeconomic classes has decreased from 95% to 59% and average IQ has increased from 78 to 88. The organization of the network of 130 referral centers and clinics within the U.S.A., Canada and Germany and the objectives of the scientific research investigation have served to provide a derived benefit of outreach, education, reproductive counseling and early diet intervention in a large cohort of PKU women.

Adolescent↗
PubMed1996

Nutrition and reproductive outcome in maternal phenylketonuria.

Maternal weight gain and intake of selected nutrients were correlated with plasma phenylalanine (Phe) concentrations and reproductive outcomes (in 150 and 142 subjects respectively) in the Maternal PKU Collaborative Study. Daily protein intake was negatively correlated with plasma Phe concentration. Birth length, weight and head circumference of offspring were negatively influenced by the length of time required for the maternal plasma Phe to decline below 600 mumol/l (10 mg/dl) and positively influenced by weight gain of mother as a percentage of recommended weight gain. Birth weight and length were positively correlated with maternal protein and energy intakes. During the first trimester, intakes of fat, calcium, phosphorus, vitamin A and folate were significantly greater in women who had a good reproductive outcome than by women who had a poor outcome. In addition to plasma Phe control in maternal phenylketonuria (PKU), maternal weight gain and dietary intake of protein, energy and fat were correlated with outcome. Therefore, nutrient intake and maternal weight gain should be considered along with plasma Phe concentration when managing the therapy of a pregnant woman with PKU.

Diet, Protein-Restricted↗
PubMed1996

The North American Maternal Phenylketonuria Collaborative Study, developmental assessment of the offspring: preliminary report.

Preliminary results of 2-year Bayley and 4-year McCarthy test scores are presented. To date numbers are too small to statistically correlate:- offspring from pregnancies in which diet was started prior to conception, offspring from pregnancies with phenylalanine (Phe) levels of 120-360 mumol/l versus 360-600 mumol/l, influence of home environment, influence of maternal nutrition, language development, behaviour/hyperactivity, Revised Wechsler Intelligence Score, school performance and learning disabilities. Two-year Bayley scores (mental and motor) revealed a median developmental quotient of 113 in 58 offspring from control pregnancies, 104 in 19 offspring from untreated "non-phenylketonuria (PKU) mild hyperphenylalaninaemia" (natural Phe levels < 600 mumol/l) pregnancies, 104 in 32 offspring from pregnancies whose Phe levels decreased on treatment to < 600 mumol/l by 10 weeks gestation and remained in that range for the remainder of the pregnancy, 98 in offspring from 32 pregnancies where permanent control was not achieved until 10-20 weeks and 72 in offspring from 51 pregnancies where control was not attained until after 20 weeks gestation. IQ scores determined by the McCarthy test at age 4-5 years revealed a mean of 112 in 43 offspring of control mothers, 99 in 12 offspring of "non PKU mild hyperphenylalaninaemia" women, 93 in 14 offspring whose mother's Phe levels were continuously under 600 mumol/l by 10 weeks gestation, 88 in 24 offspring from pregnancies in metabolic control by 10-20 weeks and 73 in 28 offspring of pregnancies not in metabolic control until after 20 weeks gestation. These preliminary results suggest that early and adequate dietary treatment during pregnancy in maternal PKU may provide some protection to the fetus for later intellectual development but much more data is required before definitive statements about cognition can be made.

Child Development↗
PubMed1996

Care of the adult with phenylketonuria.

Forty-three adults with classical phenylketonuria were identified by neonatal screening and treated with a phenylalanine (Phe) restricted diet. Nineteen have remained on dietary treatment with varying levels of blood Phe control and 24 have discontinued the diet at an average age of 7.8 years. Follow up at an average age of 22 years revealed that the cohort remaining on dietary treatment have achieved substantially better social and academic achievement than the 24 who discontinued dietary treatment. Another group of 19 adults who were not diagnosed until an average age of 2.5 years have also been evaluated after an average of 22 years on a Phe restricted diet. This report is based upon Wechsler Adult Intelligence Revised Test scores, attendance at college, employment and marital status.

Adolescent↗
PubMed1996

Hormone replacement therapy and cobalamin status in elderly women.

Serum cobalamin concentrations are frequently low in the elderly but the cause is often not apparent. Because oral contraceptives have been associated with low cobalamin concentrations in young women, we compared hormone use with cobalamin status in elderly women to determine whether it could account for their unexplained low cobalamin concentrations. Thirty-eight of the 111 women had abnormal cobalamin status (defined by low cobalamin, elevated methylmalonic acid, and/or elevated homocysteine concentrations) and 73 had normal status. There was no difference in hormone use between the two groups: 7 (18.4%) of the 38 cobalamin-deficient subjects used estrogens compared with 20 (27.4%) of the 73 control subjects. No differences in hormone use were apparent either when analysis was confined to abnormal serum cobalamin concentrations alone. Similarly, the 27 women taking hormones and the 84 women not taking hormones did not have significantly different serum cobalamin or serum total homocysteine concentrations. Indeed, hormone users had slightly, though not significantly, higher cobalamin concentrations and lower homocysteine concentrations than nonusers; furthermore, hormone users also had significantly lower serum methylmalonic acid concentrations. Thus, neither cobalamin concentrations nor cobalamin metabolic status were significantly worse in elderly women taking estrogen than in those not taking it (and, if anything, may have been slightly better). Hormone use does not appear to be a significant contributor to the low cobalamin concentrations or the mild metabolic evidence of cobalamin deficiency so often seen in the elderly.

Aged↗
PubMed1995

Tumor marker trends in asymptomatic women at risk for ovarian cancer: relevance for ovarian cancer screening.

The purpose of our study was to examine single and serial determinations of five biomarkers in asymptomatic women at risk for epithelial ovarian cancer to define median values and trends in a cancer-free cohort. Women were enrolled in the Gilda Radner Ovarian Cancer Detection program at Cedars-Sinai Medical Center, Los Angeles, California from July 1, 1991, to July 1, 1993. Biomarkers studied include CA-125, LASA, DM-70K, UGP, and HER-2. Biomarker values that were analyzed included those obtained on the first patient visit and in a subset of values evaluated at 6-month follow-ups. A total of 590 women were included in the study; 425 were premenopausal and 165 were postmenopausal. No one in this study group has developed ovarian cancer within a 12-month follow-up period. Postmenopausal women had significantly lower values for CA-125 (12 vs 19 U/ml, P = 0.0001) and higher values of LASA (16.6 vs 15.4 mg/dl, P = 0.0001), DM/70K (11 vs 0 U/ml, P < 0.001), UGP (3.3 vs 0.3 U/ml, P < 0.001), and HER-2 (12 vs 11 U/ml, P = 0.009) than premenopausal women. Less than 5% of the women had elevated tumor marker values on both screens except for CA-125, where 15% of women studied had two consecutive visits with elevated values (> 35 U/ml). Two women demonstrated an exponential rise in CA-125 between visits. Premenopausal women differ in median biomarker values compared to postmenopausal women. Elevations in single tumor markers, combinations of markers, and exponential increases of markers have all produced false-positive results for ovarian cancer within the 12-month follow-up period. Exponential increases produced the smallest false positive rate (n = 2), but further study and follow-up are needed to determine the efficacy of these tests in ovarian cancer screening.

Adult↗
PubMed1995

Lupus in the 1980s: III. Influence of clinical variables, biopsy, and treatment on the outcome in 150 patients with lupus nephritis seen at a single center.

Of 500 patients with systemic lupus erythematosus observed at our center, 150 fulfilled criteria for lupus nephritis. Of these 150 patients, 91% were female, and 67% were white. The mean age of onset was 26.2 years, and the mean follow-up duration was 11.7 years. Biopsies (n = 142) performed on 107 patients showed the following World Health Organization (WHO) class distribution: class I, n = 1; class II, n = 13; class III, n = 19; class IV, n = 69; class V, n = 17; class VI, n = 8; and class not determinable, n = 15. Ninety-five patients were nephrotic. Therapeutic intervention courses given to all patients (n = 356) included parenteral (IV) cyclophosphamide (n = 58), high-dose oral steroids (n = 126), pulse steroids (n = 49), apheresis (n = 39), azathioprine (n = 43), oral cyclophosphamide (n = 5), nitrogen mustard (n = 27), and chlorambucil (n = 6). In addition to examining the course of disease for various subsets, various predictors for fatality and end-stage renal disease (ESRD) were analyzed. Descriptive data for the short-term response to five therapies are provided for the complete patient sample, proliferative disease, and nephrotic syndrome. Twenty patients died, primarily from cardiovascular complications and sepsis, with 97% and 92% 5- and 10-year survival rates, respectively. Twenty-nine were dialyzed, and 11 were transplanted. Risk of ESRD by WHO class at 5 years was as follows: class III, 0%; IV, 9%; V, 16% (P = .04 for class V v other patterns).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Abnormal somatosensory evoked potentials in patients with classic galactosemia: correlation with neurologic outcome.

In classic galactosemia, long-term neurologic sequelae can include low cognitive functioning and a curious neurologic syndrome with tremors, dysmetria, and ataxia. An abnormal white-matter signal on cerebral magnetic resonance imaging (MRI) is present in almost all patients; some have mild cerebral or cerebellar atrophy and focal white-matter lesions. The present study was undertaken to assess the integrity of myelinated pathways by recording somatosensory evoked potentials. Results were correlated with age at diagnosis, severity of illness, age at evoked potentials, neurologic examination, MRI studies and cognitive outcome as measured by the Woodcock-Johnson Revised Standard Cognitive Battery. Evoked potentials were abnormal in 17 (28%) of 60 patients who had median nerve, and 26 (77%) of 34 patients who had posterior tibial nerve studies. Abnormalities of the central rather than the peripheral nervous system were most common. Evoked potentials correlated with severity of presenting symptoms (P = .011), age at evoked potential testing (P = .029), and presence of focal white-matter lesions on MRI (P = .049). Results of neurophysiologic testing showed no correlation with the Woodcock-Johnson Battery. Patients with classic galactosemia may have abnormal conduction along myelinated pathways that is associated with other central deficits. Myelin, which contains galactose, may be adversely affected in this inborn error of metabolism.

Adolescent↗
PubMed1994

The international collaborative study of maternal phenylketonuria: status report 1994.

Neonatal screening for phenylketonuria (PKU) has created a problem as females with PKU are reaching child-bearing age. Surveys have revealed that maternal phenylalanine blood concentrations greater than 1200 mumol/l are associated with fetal microcephaly, congenital heart defects and intrauterine growth retardation. It is estimated that as many as 3000 hyperphenylalaninemic females may be at risk of producing these fetal abnormalities. To examine this problem, the international maternal PKU collaborative study was developed to evaluate the efficacy of a phenylalanine-restricted diet in reducing fetal morbidity. Preliminary findings have indicated that phenylalanine restriction should begin before conception for females with PKU planning a pregnancy. Dietary control should maintain maternal blood phenylalanine levels between 120 and 360 mumol/l and should provide adequate energy, protein, vitamin and mineral intake. Pregnant hyperphenylalaninemic females who achieved metabolic control after conception or by the 10th week of pregnancy had a better offspring outcome than anticipated. The results of 402 pregnancies are reviewed.

Adult↗
PubMed1994

A reanalysis of the Cu-7 intrauterine contraceptive device clinical trial and the incidence of pelvic inflammatory disease: a paradigm for assessing intrauterine contraceptive device safety.

OBJECTIVE: We calculated and compared the incidence of pelvic inflammatory disease in a 10% random sample of the Cu-7 intrauterine contraceptive device (G.D. Searle & Co., Skokie, Ill.) clinical trial with the rates reported to the Food and Drug Administration and those in subsequent trials published in the world literature. STUDY DESIGN: A 10% random sample of the Cu-7 clinical trial was examined because calculations had demonstrated this random sample to be sufficient in size (n = 1614) to detect a difference in rates of pelvic inflammatory disease from those reported to the Food and Drug Administration. An audit of a subset of the patient files, compared with the original files in Skokie, Illinois, confirmed that the files available for analysis were complete. Standard definitions were used to identify cases of pelvic inflammatory disease and to calculate rates of pelvic inflammatory disease. The world literature on Cu-7 clinical trials was reviewed. RESULTS: The calculated crude and Pearl index rates of pelvic inflammatory disease were consistent with those rates previously reported to the Food and Drug Administration and published in the medical literature. Life-table pelvic inflammatory disease rates were not different between nulliparous and parous women and pelvic inflammatory disease did not differ from basal annual rates in fecund women. CONCLUSION: On the basis of the analysis of this 10% sample, the pelvic inflammatory disease patient rates reported to the Food and Drug Administration for the entire Cu-7 clinical trial are accurate and are similar to those published in the world literature.

Adult↗