Relaxation training for NIDDM. Predicting who may benefit.

OBJECTIVE: To examine the benefits of relaxation training for patients with NIDDM and to investigate individual differences that could predict a positive response to relaxation training. RESEARCH DESIGN AND METHODS: Thirty-eight subjects with NIDDM were treated with intensive conventional diabetes therapy after an initial metabolic evaluation and psychological and pharmacological testing. Half were assigned to also receive biofeedback-assisted relaxation training. Treatment effects on GHb levels and glucose tolerance were evaluated after 8 wk. RESULTS: Subjects demonstrated significant improvements in GHb level, but not in glucose tolerance, after 8 wk of intensive conventional treatment. These improvements persisted throughout the follow-up period. However, the group provided with relaxation training did not experience greater improvements on either measure than the group given conventional diabetes treatment only. Within the group that received relaxation training, correlations occurred between the improvements in glucose tolerance after treatment and individual differences in trait anxiety and in the effect of alprazolam on glucose tolerance. Differences in the effects of EPI on glucose tolerance and personality measures of neuroticism and perceived locus of control also appeared to be related to improvements in glucose tolerance after training. CONCLUSIONS: Relaxation training did not confer added benefit over and above that provided by conventional diabetes treatment for patients with NIDDM. Additional research is needed to determine whether the administration of relaxation training to selected patients, especially those who are most responsive to stress, would provide benefits for glucose control that are not achieved by conventional treatment.

Personality correlates of glycemic control in type 2 diabetes.

OBJECTIVE: To determine whether traits of normal personality are associated with variations in glycemic control in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A longitudinal cohort study was conducted using data from 105 type 2 diabetic patients in a clinical trial of a stress management intervention. Before treatment assignment, patients completed the NEO Personality Inventory, Revised, which is a questionnaire inventory measuring 5 major domains of normal personality and 30 important traits that define these domains. Glycemic control was assessed by measures of HbA1c and average blood glucose levels based on 7 days of self-monitoring at baseline and at 6 and 12 months. Relationships between personality traits and measures of glycemic control were examined by correlation and linear regression models that were adjusted for age, sex, race, duration of diabetes, medication status, and experimental treatment. RESULTS: Lower average blood glucose values at baseline were associated with higher scores for the personality domain of neuroticism and several specific traits including anxiety, angry hostility depression, self-consciousness, and vulnerability but were associated with lower scores for the trait of altruism. Results were similar for HbA1c but were not as strong. Follow-up results were similar but were less consistent. CONCLUSIONS: Personality traits may offer new insights into variations in glycemic control in patients with type 2 diabetes undergoing standard management. The relative tendency to experience fewer negative emotions and to focus on the needs of others instead of oneself could prove to be a risk factor for poor glycemic control.

Metabolic and behavioral effects of a high-sucrose diet during weight loss.

In response to evidence linking obesity and high amounts of dietary fat, the food industry has developed numerous reduced-fat and nonfat food items. These items frequently derive a relatively large percentage of their energy from sugars and the effect of these sugars on weight regulation is not well known. We studied the comparative effects of high- and low-sucrose, low-fat, hypoenergetic diets on a variety of metabolic and behavioral indexes in a 6-wk weight-loss program. Both diets contained approximately 4606 kJ energy/d with 11% of energy as fat, 19% as protein, and 71% as carbohydrate. The high-sucrose diet contained 43% of the total daily energy intake as sucrose; the low-sucrose diet contained 4% of the total daily energy intake as sucrose. Twenty women aged 40.6 +/- 8.2 y (mean +/- SD) with a body mass index (in kg/m2) of 35.93 +/- 4.8 consumed the high-sucrose diet; 22 women aged 40.3 +/- 7.3 y with a body mass index of 34.93 +/- 4.4 consumed the low-sucrose diet. Mixed-design analysis of variance showed a main effect of time (P < 0.01), with both diet groups showing decreases in weight, blood pressure, resting energy expenditure, percentage body fat, free triiodothyronine (FT3), urinary norepinephrine, and plasma lipids. Small but significant interactions were found between group and time in total cholesterol (P = 0.009) and low-density lipoprotein (LDL) (P = 0.01). Both groups showed decreases in depression, hunger, and negative mood, and increases in vigilance and positive mood with time (P < 0.01). Results showed that a high sucrose content in a hypoenergetic, low-fat diet did not adversely affect weight loss, metabolism, plasma lipids, or emotional affect.

Systematic search for uniparental disomy in early fetal losses: the results and a review of the literature.

About 20% of all human conceptuses are estimated to be trisomic and trisomy of all chromosomes remains a common cause of early fetal loss. Uniparental disomy (UPD) has been reported for most human chromosomes and may be an underrecognized contributor to embryonic lethality. To investigate the contribution of UPD to spontaneous abortions, we devised a genome-based screening strategy to identify holochromosomic UPD in 18 fetal losses. No cases of UPD were identified using this approach. Based on our data, UPD does not appear to be a significant contributor to early embryonic lethality. The results of the study are presented along with a review of the cases of UPD reported in the literature by chromosome, parental origin, mode of ascertainment, and phenotypic consequences due to imprinting.

Prenatal diagnosis and clinical findings in a case of hexasomy 12p.

We report the first case of hexasomy 12p mosaicism due to 2 copies of an apparent i(12p) [46,XX/48,XX, +i(12p), +i(12p)]. In every cell that contained the i(12p), 2 copies of the marker were found. The hexasomy was found in amniocytes (16%) and skin fibroblasts (95%) but not in peripheral blood lymphocytes. The chromosomal origin of the marker was confirmed with the use of in situ hybridization of alpha-satellite specific for the centromere of chromosome 12. The present case was diagnosed following chromosome analysis for anomalies on ultrasound. The hexasomy 12p patient showed striking phenotypic similarities with severely affected tetrasomy 12p cases and died shortly after birth. We propose that the more severe presentation of this case is due to the 4 extra copies of 12p.

Further characterization of 19 cases of rea(21q21q) and delineation as isochromosomes or Robertsonian translocations in Down syndrome.

We have used 9 conventional RFLPs and 6 dinucleotide repeat polymorphisms on chromosome 21q to demonstrate that 17 of 19 cases of rea(21q21q) were consistent with isochromosomes i(21q) with the remaining 2 being true Robertsonian translocations. Eight of the 17 isochromosomes were of maternal origin and 9 cases were paternally derived. The 2 Robertsonian translocations were both maternally derived. Of the 17 isochromosomes, 7 were dicentric [idic(21q)] and 10 were monocentric [i(21q)]. Both rob(21q21q) were monocentric. Our findings agree with those made in 17 previously published cases of rea(21q21q). The parental origins of the i(21q) were equally divided between maternal (n = 17) and paternal (n = 15) origins. All 4 true rob(21q21q) reported to date are of maternal origin. Collectively, it appears that most homologous rearrangements of chromosome 21 are isochromosomes and only a small proportion are consistent with true Robertsonian translocations.

Molecular analysis of mosaicism for two different de novo acrocentric rearrangements demonstrates diversity in Robertsonian translocation formation.

Robertsonian translocations (ROBs) involving chromosome 21 occur in about 5% of individuals with Down syndrome. ROBs are the most common chromosomal rearrangements in humans and are formed through whole arm exchanges of any two acrocentric chromosomes. The de novo formation of ROBs occurs at exceptionally high rates. The present case concerns a child with mosaic Down syndrome who has two cell lines that contain two different de novo ROBs: 45,XX,rob(14;21)(q10;q10) and 46,XX,rea(21;21)(q10;q10),+21. To elucidate the mechanisms by which the rearrangements formed, somatic cell hybrids were constructed to allow the parental origins of the chromosomes involved in the ROBs to be distinguished. The analysis of the hybrids showed that the rob(14q21q) must have formed postzygotically because it contained a maternal chromosome 14 and a paternal chromosome 21. Furthermore, hybrid analysis of the rea(21q21q) demonstrated two copies of the same chromosome from the mother and thus, by definition, was an isochromosome [i(21q)]. All free-lying chromosomes 21 isolated in hybrids were of maternal origin. These chromosomes may have originated from either of the patient's cell lines. We present four hypotheses for the formation of the two cell lines of this child. This case is part of an ongoing project to determine the mechanism(s) of de novo ROB formation and the results differ from the other de novo rob(14q21q) studied in our laboratory (n = 7) in that all previously studied translocations were maternally derived, leading to the conclusion that most de novo rob(14q21q) occur in oogenesis. The current case illustrates that other mechanisms may contribute to ROB formation.

Short-limb dwarfism and hypertrophic cardiomyopathy in a patient with paternal isodisomy 14: 45,XY,idic(14)(p11).

Uniparental disomy (UPD) has been shown to result in specific disorders either due to imprinting and/or homozygosity of mutant alleles. Here we present the findings in a child with paternal UPD14. Ultrasound evaluation was performed at 30 weeks of gestation because of abnormally large uterine size. Pertinent ultrasound findings included polyhydramnios, short limbs, abnormal position of hands, small thorax, and nonvisualization of the fetal stomach. Post-natally the infant was found to have a low birth weight, short birth length, contractures, short limbs, and a small thorax with upslanting ribs. Assisted ventilation and gastrostomy were required. At age 6 months, the infant required hospitalization for hypertrophic cardiomyopathy which responded to Atenolol. Initial cytogenetic studies demonstrated an apparently balanced de novo Robertsonian translocation involving chromosomes 14 and a karyotype designation of 45,XY,t(14q14q). No indication of mosaicism for trisomy 14 was observed in metaphase spreads prepared from peripheral blood lymphocytes or skin-derived fibroblasts. C-band and fluorescence in situ hybridization results demonstrated that the chromosome was dicentric. DNA analyses showed paternal uniparental isodisomy for chromosome 14. Based on the cytogenetic and DNA results a final karyotype designation of 45,XY,idic(14)(p11) was assigned to this infant with paternal isodisomy of chromosome 14.

Comprehensive 4-year follow-up on a case of maternal heterodisomy for chromosome 16.

Uniparental disomy for chromosome 16 has been previously identified in fetal deaths and newborn infants with limited follow-up. Thus there is a lack of information about the long-term effects of maternal uniparental disomy 16 on growth and development. We present a case of maternal heterodisomy for chromosome 16 and a comprehensive 4-year physical and cognitive evaluation. Cytogenetic analysis of chorionic villus obtained at 10 weeks gestation for advanced maternal age showed trisomy 16. At 15 weeks, amniocentesis demonstrated low level mosaicism 47,XY,+16[1]/46,XY[25]. Decreased fetal growth was noted in the last 2 months of pregnancy and the infant was small for gestational age at birth. Molecular studies revealed only maternal alleles for chromosome 16 in a peripheral blood sample from the child, consistent with maternal uniparental heterodisomy 16. Although short stature remains a concern, there appears to be no major cognitive effects of maternal disomy 16. Clinical evaluation and follow-up on additional cases should further clarify the role of placental mosaicism and maternal disomy 16 in intrauterine growth retardation and its effects on long-term growth in childhood.

Investigation of two cases of paternal disomy 13 suggests timing of isochromosome formation and mechanisms leading to uniparental disomy.

Uniparental disomy (UPD) is the abnormal inheritance of two copies of a chromosome from the same parent. Possible mechanisms for UPD include trisomy rescue, monosomy rescue, gametic complementation, and somatic recombination. Most of these mechanisms can involve rearranged chromosomes, particularly isochromosomes and Robertsonian translocations. Both maternal and paternal UPD have been reported for most of the acrocentric chromosomes. However, only UPD for chromosomes 14 and 15 show an apparent imprinting effect. Herein, we present two cases of paternal UPD 13 involving isochromosomes. Both cases were referred for UPD studies due to the formation of a de novo rea(13q13q). Case 2 was complicated by the segregation of a familial rob(13q14q) of maternal origin. Both propositi were phenotypically normal at the time of examination. Polymorphic marker analysis in Case 1 showed the distribution of alleles of markers along chromosome 13 to be complete isodisomy, consistent with an isochromosome. This rearrangement could have occurred either meiotically, without recombination, or mitotically. A likely mechanism for UPD in this case is monosomy rescue, through postzygotic formation of the isochromosome. In Case 2 the distribution of proximal alleles indicated an isochromosome, but recombination was evident. Thus, this isochromosome must have formed prior to or during meiosis I. A likely mechanism for UPD in this case is gametic complementation, since the mother carries a rob(13q14q) and is at risk of producing aneuploid gametes. However, trisomy rescue of a trisomy 13 conceptus cannot be completely excluded. Given that both cases were phenotypically normal, these data further support that paternal UPD 13 does not have an adverse phenotypic outcome and, thus, does not show an apparent imprinting effect.

Personality predictors of mood related to dieting.

The clinical utility of a model of normal emotional functioning (vs. psychopathology) and the moderating effects of neuroticism (N) and extraversion (E) on mood were examined during a 6-week weight-loss trial. Participants were 40 obese women who completed measures of negative affect (NA) and positive affect (PA) weekly during the diet and measures of anxiety and depression (Beck Depression Inventory [BDI]) at pre-, mid-, and postdiet. Results indicated that (a) average NA and PA were each uniquely related to postdiet BDI scores, (b) N was significantly related to NA during the diet and postdiet BDI scores, and (c) N and E interacted to predict PA during the diet. The results suggest that assessment of personality and normal mood variation may be useful additions to weight-loss intervention and research.

Food allergy challenges: guidelines and implications.

Double-blind placebo-controlled food challenges were used to determine the presence or absence of food hypersensitivity in 120 children with atopic dermatitis. Foods to be challenged were selected on the basis of history, allergy skin tests, nutritional significance, and patient desires. Dehydrated foods were hidden in capsules or juice and administered twice a day. Antigens were obtained commercially or prepared through a process of freeze-drying and subsequent pulverization. Cutaneous, gastrointestinal, nasal, and/or respiratory symptoms occurred following 133 challenges. Although patients exhibited multiple positive skin tests to foods, 86% experienced a positive response on blinded challenge to only one or two foods. Double-blind placebo-controlled food challenges accurately diagnose food hypersensitivity and minimize the number of foods eliminated from allergy avoidance diets. A new method of elimination diet management and education is based on the identification of "key words" on food labels. Instructional diet sheets were developed to teach this concept, which was found to promote greater confidence, compliance, and creativity in diet planning.

The relation of stress and family environment to atopic dermatitis symptoms in children.

The relation of stress and family environment to symptom severity in children with atopic dermatitis (AD) was examined. Forty-four children with severe AD and their families completed questionnaires measuring life events, chronic everyday problems and family environment. Measures of symptom severity were collected during medical evaluation and included an estimate of body surface affected by AD, course of AD symptoms over time, medication usage, and scratching intensity during the day and night. Regression analyses indicated that the measures of stress and family environment were important predictors of symptom severity even after controlling for demographic and medical status variables such as age and serum IgE level. These results have important implications for health care professionals working with children who have AD. Future research directions in the area of stress and AD are discussed.

Effects of high cholesterol and n-3 polyunsaturated fish oil diets on tissue and serum lipid composition in male rats.

The correlation between dietary cholesterol, high plasma lipids and cardiovascular disease is well recognized in many species. The purpose of the present study was to examine the effects of high cholesterol and moderately high fat intake of n-3 polyunsaturated fish oil diets on serum lipids in male rats. Male rats were fed either 21% menhaden oil (Control) or 21% menhaden oil with high (2%) cholesterol (MOC) for eight weeks. Whole blood was collected, and analyzed spectrophotometrically for serum cholesterol, triglycerides and lipoproteins. The selected tissues were carefully removed, weighed and analyzed for lipid profiles. The aortas were removed and lipogenesis determined. The results showed that except for spleen the total percent lipid content of heart, lung, liver, adrenal, kidney and brain was not affected in the MOC group. The percent fat content of spleen but not the weight was elevated by 4 fold compared to control. The hematocrit values in the MOC group were unaltered. Serum cholesterol was elevated by 62%, whereas the serum triglycerides and HDL cholesterol were unaltered in MOC group when compared to the MO control. High cholesterol feeding did not affect aortic lipogenesis in the MOC group compared to the control. These results suggest that cholesterol feeding along with n-3 polyunsaturated fish oil diet did not attenuate the anti-atherosclerotic effects of fish oil with the exception of serum cholesterol.

Food hypersensitivity and atopic dermatitis: evaluation of 113 patients.

One hundred thirteen patients with severe atopic dermatitis were evaluated for food hypersensitivity with double-blind placebo-controlled oral food challenges. Sixty-three (56%) children experienced 101 positive food challenges; skin symptoms developed in 85 (84%) challenges, gastrointestinal symptoms in 53 (52%), and respiratory symptoms in 32 (32%). Egg, peanut, and milk accounted for 72% of the hypersensitivity reactions induced. History and laboratory data were of marginal value in predicting which patients were likely to have food allergy. When patients were given appropriate restrictive diets based on oral food challenge results, approximately 40% of the 40 patients re-evaluated lost their hypersensitivity after 1 or 2 years, and most showed significant improvement in their clinical course compared with patients in whom no food allergy was documented. These studies demonstrate that food hypersensitivity plays a pathogenic role in some children with atopic dermatitis and that appropriate diagnosis and exclusionary diets can lead to significant improvement in their skin symptoms.

Very low maternal serum chorionic gonadotropin levels in association with fetal triploidy.

OBJECTIVE: The objective of this study was to identify the parental origin of the extra haploid set of chromosomes in triploid pregnancies and to correlate the parental origin to very low levels of human chorionic gonadotropin and unconjugated estriol levels (multiple of the median < or = 0.20) and normal alpha-fetoprotein levels. STUDY DESIGN: Three triploid pregnancies were ascertained retrospectively, and three pregnancies were identified prospectively. Maternal sera samples were analyzed for levels of alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol. Deoxyribonucleic acid analysis was performed on parental bloods and fetal fibroblasts in two prospectively identified pregnancies to establish the parental origin of the extra set of chromosomes. RESULTS: Levels of alpha-fetoprotein were normal in all pregnancies. Levels of human chorionic gonadotropin were very low in five of six of pregnancies, and unconjugated estriol levels were low in three of six pregnancies. Deoxyribonucleic acid analysis indicated maternal origin of the extra haploid set of chromosomes in two triploids. CONCLUSION: When the extra haploid set of chromosomes are maternally derived, some triploid pregnancies exhibit very low levels of maternal serum human chorionic gonadotropin and unconjugated estriol with normal levels of alpha-fetoprotein.

Identification of uniparental disomy following prenatal detection of Robertsonian translocations and isochromosomes.

Rearrangements of the acrocentric chromosomes (Robertsonian translocations and isochromosomes) are associated with an increased risk of aneuploidy. Given this, and the large number of reported cases of uniparental disomy (UPD) associated with an acrocentric rearrangement, carriers are presumed to be at risk for UPD. However, an accurate risk estimate for UPD associated with these rearrangements is lacking. A total of 174 prenatally identified acrocentric rearrangements, including both Robertsonian translocations and isochromosomes, were studied prospectively to identify UPD for the chromosomes involved in the rearrangements. The overall goal of the study was to provide an estimate of the risk of UPD associated with nonhomologous Robertsonian translocations and homologous acrocentric rearrangements. Of the 168 nonhomologous Robertsonian translocations studied, one showed UPD for chromosome 13, providing a risk estimate of 0.6%. Four of the six homologous acrocentric rearrangements showed UPD, providing a risk estimate of 66%. These cases have also allowed delineation of the mechanisms involved in producing UPD unique to Robertsonian translocations. Given the relatively high risk for UPD in prenatally identified Robertsonian translocations and isochromosomes, UPD testing should be considered, especially for cases involving the acrocentric chromosomes 14 and 15, in which UPD is associated with adverse clinical outcomes.

A clinical and molecular study of mosaicism for trisomy 17.

Trisomy 17 has never been reported in a live birth. We present a case of mosaic trisomy 17 in a male presenting with mental retardation, seizures, attention deficit hyperactivity and autistic disorders, hearing loss, growth retardation, microcephaly, and minor anomalies. Although peripheral blood lymphocyte chromosomes were normal, trisomy 17 was present in the skin fibroblasts. The percentage of abnormal cells appears to have increased from 18% in an initial skin biopsy at age 3 years 8 months to 80% at age 8 years 8 months. Molecular analysis using 13 highly polymorphic markers spanning the length of chromosome 17 demonstrated the extra chromosome 17 in the skin to be of paternal origin. Three alleles were never seen in the trisomic cell line, suggesting that the extra chromosome arose through a mitotic duplication error after conception. Uniparental disomy was excluded in the euploid blood sample. Although Smith-Magenis syndrome involves a deletion of proximal 17p, some of the clinical features of this mosaic trisomy 17 patient, such as decreased REM sleep and increased tolerance to pain, are suggestive of phenotypic features observed in Smith-Magenis syndrome. We speculate that there are dosage-sensitive genes located in 17p11.2 that produce these phenotypes for either deficiencies or over-expression of their gene products.

Deletions of the elastin gene at 7q11.23 occur in approximately 90% of patients with Williams syndrome.

To investigate the frequency of deletions of the elastin gene in patients with Williams syndrome (WS), we screened 44 patients by both FISH and PCR amplification of a dinucleotide repeat polymorphism. FISH was performed using cosmids containing either the 5' or the 3' end of the elastin gene. PCR analysis was performed on the patients and their parents with a (CA)n repeat polymorphism found in intron 17 of the elastin locus. Of the 44 patients screened, 91% were shown to be deleted by FISH. Using the DNA polymorphism, both maternally (39%) and paternally (61%) derived deletions were found. Four patients were not deleted for elastin but have clinical features of WS. Since deletions of elastin cannot account for several features found in WS, these patients will be valuable in further delineation of the critical region responsible for the WS phenotype. Although PCR can be useful for determining the parental origin of the deletion, our results demonstrate that FISH analysis of the elastin locus provides a more rapid and informative test to confirm a clinical diagnosis of WS. The presence of two copies of the elastin locus in a patient does not, however, rule out WS as a diagnosis.