Depressed mood is a factor in glycemic control in type 1 diabetes.

OBJECTIVE: The diabetes literature contains conflicting evidence on the relationship between depression and glycemic control. This may be due, in part, to the fact that past studies failed to distinguish between patients with type 1 and type 2 diabetes. Because these are actually completely different diseases that are often treated differently and consequently make different demands on patients, the relationship between glycemic control and depressed mood in type 1 and type 2 diabetes was examined separately. METHODS: The relationship between Beck Depression Inventory (BDI) scores and HbA1c, as an index of long-term glycemic control, was measured in samples of 30 patients with type 1 and 34 patients with type 2 diabetes. RESULTS: Groups of patients with type 1 and type 2 diabetes did not differ in mean BDI score or HbA1c level. Correlation analysis revealed a significant positive relationship between BDI scores and HbA1c in the type 1 group (r = .44, p < .02) but not in the type 2 group (r = -0.06, p > .05). This relationship was evident throughout the entire range of BDI scores and was not restricted to scores indicative of clinical depression. Patients with type 1 diabetes who had higher HbA1c and BDI scores reported a lower frequency of home blood glucose monitoring. CONCLUSIONS: Variations in depressive mood, below the level of clinical depression, are associated with meaningful differences in glycemic control in type 1 but not type 2 diabetes. Preliminary data analysis suggests that this effect may be mediated, at least in part, by decreased self-care behaviors in patients with more depressed mood.

Haploinsufficiency of ALX4 as a potential cause of parietal foramina in the 11p11.2 contiguous gene-deletion syndrome.

Heterozygous mutations in MSX2 are responsible for an autosomal dominant form of parietal foramina (PFM). PFM are oval defects of the parietal bones that are also a characteristic feature of a contiguous gene-deletion syndrome caused by a proximal deletion in the short arm of chromosome 11 (Potocki-Shaffer syndrome). We have identified a human bacterial artificial chromosome (BAC) clone mapping to chromosome 11, containing a region homologous to the human homeobox gene MSX2. Further sequence analysis demonstrated that the human orthologue (ALX4) of the mouse Aristaless-like 4 gene (Alx4) is contained within this 11p clone. We used FISH to test for the presence-or for the heterozygous deletion-of this clone in two patients with the 11p11.2-deletion syndrome and showed that this clone is deleted in these patients. ALX4 and Alx4 were shown to be expressed in bone and to be absent from all other tissues tested. The involvement of Alx4 in murine skull development, its bone-specific expression pattern, the fact that Alx4 is a dosage-sensitive gene in mice, and the localization of a human genomic clone containing ALX4 to 11p11.2, with hemizygosity in patients with deletion of 11p11.2 who have biparietal foramina, support the contention that ALX4 is a candidate gene for the PFM in the 11p11.2-deletion syndrome.

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.

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.

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.

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.

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.

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.

Chromosome 1p36 deletions: the clinical phenotype and molecular characterization of a common newly delineated syndrome.

Deletions of the distal short arm of chromosome 1 (1p36) represent a common, newly delineated deletion syndrome, characterized by moderate to severe psychomotor retardation, seizures, growth delay, and dysmorphic features. Previous cytogenetic underascertainment of this chromosomal deletion has made it difficult to characterize the clinical and molecular aspects of the syndrome. Recent advances in cytogenetic technology, particularly FISH, have greatly improved the ability to identify 1p36 deletions and have allowed a clearer definition of the clinical phenotype and molecular characteristics of this syndrome. We have identified 14 patients with chromosome 1p36 deletions and have assessed the frequency of each phenotypic feature and clinical manifestation in the 13 patients with pure 1p36 deletions. The physical extent and parental origin of each deletion were determined by use of FISH probes on cytogenetic preparations and by analysis of polymorphic DNA markers in the patients and their available parents. Clinical examinations revealed that the most common features and medical problems in patients with this deletion syndrome include large anterior fontanelle (100%), motor delay/hypotonia (92%), moderate to severe mental retardation (92%), growth delay (85%), pointed chin (80%), eye/vision problems (75%), seizures (72%), flat nasal bridge (65%), clinodactyly and/or short fifth finger(s) (64%), low-set ear(s) (59%), ear asymmetry (57%), hearing deficits (56%), abusive behavior (56%), thickened ear helices (53%), and deep-set eyes (50%). FISH and DNA polymorphism analysis showed that there is no uniform region of deletion but, rather, a spectrum of different deletion sizes with a common minimal region of deletion overlap.

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.

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.

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.

Analysis of nine pregnancies with confined placental mosaicism for trisomy 2.

Karyotypically normal fetuses with completely trisomic or mosaic placentae may be at increased risk for intrauterine growth restriction (IUGR). Molecular and cytogenetic analyses on nine pregnancies with confined placental mosaicism (CPM) for trisomy 2 were performed at two collaborating centres. Seven cases were identified through prenatal testing of chorionic villi (CVS). Two of these seven cases demonstrated complete trisomy 2 while the remaining five cases showed various levels of trisomy 2 (33 per cent-75 per cent cells). Two cases identified after IUGR was observed in newborn infants demonstrated 65 per cent and 100 per cent trisomy 2 in cultured villi from term placentae. In all nine cases, blood chromosome analysis (n = 4), chromosome analysis of amniotic fluid cultures (n = 4), and cultured amnion (n = 5) were normal, failing to demonstrate any trisomic cells in tissues of fetal origin. Molecular studies on the fetal or newborn tissues using dinucleotide repeat polymorphisms on chromosome 2 revealed normal biparental inheritance of chromosome 2 in all nine cases. The parental origin studies of the extra chromosome 2 in the placenta showed that three cases were maternal in origin, at least two of which were consistent with a maternal meiotic non-disjunction giving rise to the trisomy 2, while in one case a paternal origin of the extra chromosome 2 was established.

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.

Identification of a case of maternal uniparental disomy of chromosome 10 associated with confined placental mosaicism.

We report a case of maternal uniparental disomy of chromosome 10 discovered after chorionic villus sampling (CVS). Direct preparations revealed mosaic trisomy 10, while cultured CVS cells, as well as amniotic fluid cells, showed only a normal 46,XY complement. DNA analysis using microsatellite markers showed both chromosomes 10 to have been inherited from the mother. The pregnancy was complicated by polyhydramnios. A phenotypically normal male infant of appropriate size was delivered by Caesarean section at 41 weeks' gestation. Since only the direct preparations showed trisomy 10, this case illustrates the importance of CVS direct preparations in the detection of pregnancies at risk of uniparental disomy (UPD). Although the increased frequency of confined placental mosaicism (CPM) diagnosed when direct preparations are performed has been viewed negatively, identification of both CPM and UPD may have biological and clinical significance for a pregnancy. Even though only a single case of maternal disomy 10 is reported here, the apparently normal phenotype provides evidence that there are no major imprinted loci on chromosome 10 that affect in utero growth and development. However, other potential effects such as mental retardation will require long-term follow-up of this as well as additional cases.

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.

Single cell analysis demonstrating somatic mosaicism involving 11p in a patient with paternal isodisomy and Beckwith-Wiedemann syndrome.

Partial isodisomy of 11p has been observed in some patients with Beckwith-Wiedemann syndrome. In this study, we demonstrate somatic mosaicism directly through PCR and single cell analysis on blood lymphocytes from a patient with Beckwith-Wiedemann syndrome. Whole genome amplification was performed on single cells and the resultant product was subjected to locus specific microsatellite marker analysis using PCR. Two populations of cells were detected, a population of cells with normal biparental inheritance for chromosome 11 and a population of cells with partial paternal isodisomy of 11p between markers D11S922 (11p15.5) and D11S904 (11p14-p13). These results are consistent with somatic recombination resulting in mosaicism for paternal isodisomy. The use of single cell PCR is ideal for studying the distribution of mosaicism within and between tissues and has been used in this study to identify a cell line with uniparental disomy in a patient with Beckwith-Wiedemann syndrome.

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.