Obesity, diabetes and their metabolic correlates in middle-aged adults with Down syndrome.

BACKGROUND: Obesity in adults without Down syndrome is associated with an adverse metabolic profile including high prevalence of pre-diabetes and diabetes, high levels of insulin, non-high-density lipoprotein (HDL) cholesterol, leptin and high-sensitivity C-reactive protein (hsCRP) and low levels of HDL and adiponectin. We examined whether obesity in middle-aged adults with Down syndrome is also related to an adverse metabolic profile. METHODS: This cross-sectional study included 143 adults with Down syndrome, with a mean age of 55.7 ± 5.7 years and 52.5% women. Body mass index (BMI) was classified as underweight (BMI < 18.5 kg/m2 ), normal (BMI 18.5-24.9 kg/m2 ), overweight (BMI 25-29.9 kg/m2 ) and obese (BMI ≥ 30 kg/m2 ). Diabetes was ascertained by history or by haemoglobin A1c (HbA1c) as normal glucose tolerance (HbA1c < 5.7%), pre-diabetes (HbA1c 5.7-6.4%) and diabetes (HbA1c ≥ 6.5%). We measured non-fasting lipids, hsCRP, insulin, adiponectin and leptin. RESULTS: The majority of the sample had an overweight (46.9%) or obesity (27.3%) status. However, there was a relatively low prevalence of pre-diabetes (9.8%) and diabetes (6.9%). Overweight and obesity status were not associated with lower HDL and adiponectin and higher insulin, non-HDL cholesterol and hsCRP as expected in adults without Down syndrome. However, overweight and obesity were strongly associated with higher leptin (P < 0.001). CONCLUSIONS: The only metabolic correlate of obesity in middle-aged adults with Down syndrome was high leptin levels. Our findings are limited by non-fasting laboratory tests but suggest that middle-aged adults with Down syndrome do not have the adverse metabolic profile related to obesity found in adults without Down syndrome.

Motivation and treatment credibility predict alliance in cognitive behavioral treatment for youth with anxiety disorders in community clinics.

OBJECTIVE: We examined whether motivation and treatment credibility predicted alliance in a 10-session cognitive behavioral treatment delivered in community clinics for youth anxiety disorders. METHOD: Ninety-one clinic-referred youths (meanage  = 11.4 years, standard deviation = 2.1, range 8-15 years, 49.5% boys) with anxiety disorders-rated treatment motivation at pretreatment and perceived treatment credibility after session 1. Youths and therapists (YT) rated alliance after session 3 (early) and session 7 (late). Hierarchical linear models were applied to examine whether motivation and treatment credibility predicted YT early alliance, YT alliance change, and YT alliance agreement. RESULTS: Motivation predicted high early YT alliance, but not YT alliance change or alliance agreement. Youth-rated treatment credibility predicted high early youth alliance and high YT positive alliance change, but not early therapist alliance or alliance agreement. CONCLUSION: Conclusion Efforts to enhance youth motivation and treatment credibility early in treatment could facilitate the formation of a strong YT alliance.

Rapid assessment of cognitive function in down syndrome across intellectual level and dementia status.

BACKGROUND: Adults with Down syndrome (DS) are at risk of developing dementia and cognitive assessment is a fundamental part of the diagnostic process. Previously, we developed a Rapid Assessment for Developmental Disabilities (RADD), a brief, broadly focused direct test of cognition. In the current report, we assess whether the RADD is sensitive to dementia in DS and the degree to which it compares with other cognitive measures of dementia in this population. METHODS: In a sample of 114 individuals with DS, with dementia diagnosed in 62%, the RADD was compared with the Dementia Questionnaire for Mentally Retarded Persons (DMR), the Bristol Activities of Daily Living Scale, Severe Impairment Battery (SIB), and the Brief Praxis Test (BPT). RESULTS: The RADD showed predicted effects across intellectual disability (ID) levels and dementia status (p < 0.001). Six-month test-retest reliability for the subset of individuals without dementia was high (r(41) = 0.95, p < 0.001). Criterion-referenced validity was demonstrated by correlations between RADD scores and ID levels based upon prior intelligence testing and clinical diagnoses (rs (114) = 0.67, p = 0.001) and with other measures of cognitive skills, such as the BPT, SIB, and DMR-Sum of Cognitive scores (range 0.84 through 0.92). Using receiver operating characteristic curves for groups varying in pre-morbid severity of ID, the RADD exhibited high sensitivity (0.87) and specificity (0.81) in discriminating among individuals with and without dementia, although sensitivity was somewhat lower (0.73) for the subsample of dementia cases diagnosed no more than 2 years prior to their RADD assessment. CONCLUSION: Taken together, findings indicated that the RADD, a relatively brief, easy-to-administer test for cognitive function assessment across ID levels and dementia status, would be a useful component of cognitive assessments for adults with DS, including assessments explicitly focused on dementia.

An improved method for detecting telomere size differences in T-lymphocyte interphases from older people with Down syndrome with and without mild cognitive impairment.

Telomere size (quantified by fluorescence intensity and physical lengths) in short-term T-lymphocyte cultures from adults with Down syndrome (DS) with and without mild cognitive impairment (MCI-DS) or dementia was compared. For these studies, dementia status was determined based on longitudinal assessments employing a battery of cognitive and functional assessments developed to distinguish adult-onset impairment from preexisting developmental disability. In the course of our studies using a MetaSystems Image Analyzer in combination with ISIS software and a Zeiss Axioskop 2, we found that Fluorescein isothiocyanate (FITC) telomere fluorescence referenced to chromosome 2-identified FITC probe fluorescence as a nontelomere standard (telomere/cen2 ratio) showed great promise as a biomarker of early decline associated with Alzheimer's disease (AD) in this high-risk population. We have now obtained a cen (2) CY3 probe that can clearly be distinguished from the blue-green FITC interphase telomere probe, providing a clear distinction between telomere and centromere fluorescence in both interphase and metaphase. We used FITC/CY3 light intensity ratios to compare telomere length in interphases in adults with DS with and without MCI-DS or dementia. Five age-matched female and five age-matched male pairs (n = 10) all showed clear evidence of telomere shortening associated with clinical progression of AD (P < 0.002 - P < 0.000001), with distributions of mean values for cases and controls showing no overlap. We also examined the time needed for microscopy using interphase versus metaphase fluorescence preparations. With interphase preparations, examination time was reduced by an order of magnitude compared with metaphase preparations, indicating that the methods employed herein have considerable practical promise for translation into broad diagnostic practice.

Anatomy of the cutaneous surface of the male genitalia, with elaboration upon the inner preputial coronal-shaft junction.

INTRODUCTION: Descriptions of the penile prepuce in anatomical and clinical texts either omit details or contain a small, yet potentially serious, error with regard to the manner of its attachment to the penis. OBJECTIVE: This study sought to cast light on a ubiquitous but poorly understood and under-appreciated structure, while correcting a long-standing mistake in the medical literature. STUDY DESIGN: The foreskins of five male stillborn babies were dissected and carefully examined. Tissue from the apposing surfaces of the various regions of the inner and outer prepuce surfaces and the transition zone itself were collected, embedded in paraffin, sectioned, stained, examined and photographed under microscopy. RESULTS: Contradicting the prevailing descriptions in the literature that the inner prepuce is a single, uniform sheath, this study's observations and histological findings demonstrated that it actually splits into separate laminae that connect distally to the shaft at the base of the corona and proximally with the shaft fascia, respectively (Figure). DISCUSSION: The penile prepuce is a discrete and deceptively complex part of the male anatomy, yet key details of its interposing surfaces are inaccurately described or entirely omitted in the literature. Understanding the normal anatomy of the prepuce is critically relevant, particularly for urologists and others involved in the performance of circumcision. For example, avoiding potentially catastrophic avulsion of the inner preputial remnant beyond the coronal sulcus during circumcision and accurate assessment of tissue positioning prior to penile reconstruction in cases of hypospadias. CONCLUSION: The findings of this study correct a misunderstanding in the anatomy of the prepuce.

Mg(2+) modulates voltage-dependent activation in ether-à-go-go potassium channels by binding between transmembrane segments S2 and S3.

Extracellular Mg(2+) directly modulates voltage-dependent activation in ether-à-go-go (eag) potassium channels, slowing the kinetics of ionic and gating currents (Tang, C.-Y., F. Bezanilla, and D.M. Papazian. 2000. J. Gen. Physiol. 115:319-337). To exert its effect, Mg(2+) presumably binds to a site in or near the eag voltage sensor. We have tested the hypothesis that acidic residues unique to eag family members, located in transmembrane segments S2 and S3, contribute to the Mg(2+)-binding site. Two eag-specific acidic residues and three acidic residues found in the S2 and S3 segments of all voltage-dependent K(+) channels were individually mutated in Drosophila eag, mutant channels were expressed in Xenopus oocytes, and the effect of Mg(2+) on ionic current kinetics was measured using a two electrode voltage clamp. Neutralization of eag-specific residues D278 in S2 and D327 in S3 eliminated Mg(2+)-sensitivity and mimicked the slowing of activation kinetics caused by Mg(2+) binding to the wild-type channel. These results suggest that Mg(2+) modulates activation kinetics in wild-type eag by screening the negatively charged side chains of D278 and D327. Therefore, these residues are likely to coordinate the bound ion. In contrast, neutralization of the widely conserved residues D284 in S2 and D319 in S3 preserved the fast kinetics seen in wild-type eag in the absence of Mg(2+), indicating that D284 and D319 do not mediate the slowing of activation caused by Mg(2+) binding. Mutations at D284 affected the eag gating pathway, shifting the voltage dependence of Mg(2+)-sensitive, rate limiting transitions in the hyperpolarized direction. Another widely conserved residue, D274 in S2, is not required for Mg(2+) sensitivity but is in the vicinity of the binding site. We conclude that Mg(2+) binds in a water-filled pocket between S2 and S3 and thereby modulates voltage-dependent gating. The identification of this site constrains the packing of transmembrane segments in the voltage sensor of K(+) channels, and suggests a molecular mechanism by which extracellular cations modulate eag activation kinetics.

Dementia of the Alzheimer's type and accelerated aging in Down syndrome.

This case study, of a woman with Down syndrome and dementia of the Alzheimer's type (DAT), follows the course of her decline over an 11-year period until death at age 57. Detailed neuropathological findings are also presented. This case illustrates features of premature aging that are typically associated with Down syndrome, and the progressive changes in memory and cognition that are usually associated with DAT. Although the subject's cardiovascular condition and thyroid disorder were treated, they may have contributed to the decline of her memory. This case shows the difficulty in diagnosing dementia in an individual with mental retardation who suffered comorbid episodes of depression and psychosis.

Diagnostic criteria for the neuropathological assessment of Alzheimer's disease: current status and major issues.

A Consensus Conference focusing on Alzheimer's disease (AD) took place in November 1996 to recommend uniform evaluation procedures and diagnostic criteria, co-sponsored by the National Institute on Aging and the Reagan Institute of the Alzheimer's Association. In conjunction with this conference, we reviewed diagnostic practices in current use, together with various neuropathological criteria proposed since 1985. Difficulties were identified in developing "gold standard" criteria for diagnosis and case classification of AD based upon the current state of knowledge. Working criteria for use within research contexts were proposed that acknowledged the realities of scientific limitations by inclusion of a broad and heterogeneous category of "uncertain" cases. (Eventually, methods will be developed for identifying these cases as preclinical AD, dementia due to multiple causes or non-AD, but this is not now possible.) Within applied contexts, the use of CERAD guidelines was supported. Finally, recommendations generated at the Consensus Conference were discussed, emphasizing the rapid pace of recent scientific advancement and the need for ongoing empirical reevaluation and modification of the Group's proposal.

Vascular, glial and neuronal effects of vascular endothelial growth factor in mesencephalic explant cultures.

Vascular endothelial growth factor is a highly conserved, heparin-binding protein which mediates a number of critical developmental processes in both vertebrates and invertebrates, including angiogenesis, vasculogenesis and hematopoiesis. We employed an organotypic rat explant model (produced from embryonic day 17 fetuses) to assess the effects of vascular endothelial growth factor on brain microvasculature in general and the ventral midbrain specifically. Immunohistochemistry using antisera to rat endothelial cell antigen and laminin demonstrated a robust, dose-dependent effect of vascular endothelial growth factor, resulting in increased vessel neogenesis, branching and lumen size by three days in vitro. This effect was blocked by addition of an anti-vascular endothelial growth factor antibody. At higher doses of vascular endothelial growth factor, the effect was attenuated, though a statistically significant increase in both astrocyte, and neuronal density was observed using antisera to glial and neuronal markers. Tyrosine hydroxylase-immunoreactive (i.e. dopaminergic) neurons, particularly, exhibited increased survival in response to vascular endothelial growth factor application. Vascular endothelial growth factor had a mitogenic effect on endothelial cells and astrocytes, but not dopaminergic neurons, as demonstrated by the addition of [3H]thymidine to the cultures 2 h after the cultures were established. Similarly, results of a radioreceptor assay indicated that specific vascular endothelial growth factor binding sites were present on blood vessels and astrocytes, and were up-regulated by exposure to vascular endothelial growth factor. We conclude that, in explants of the ventral mesencephalon, exogenously applied vascular endothelial growth factor is mitogenic for endothelial cells and astrocytes, and promotes growth/survival of neurons in general and dopaminergic neurons in particular.

Genetic and other factors that contribute to variability in cytogenetic expression in fragile X males.

Variability in cytogenetic expression of fragile X has been observed by many investigators. One recent study of families of fragile X brothers concluded that frequency of expression was almost completely controlled by genetic factors. We investigated the extent of genetic control over frequency of expression by evaluating fragile X families from 3 different sources using hierarchal analysis of variance model to calculate the intraclass correlation and the index of heritability, h2. Proportion of variance attributable to families was computed from 2 estimation procedures: 1) a least squares method and 2) a maximum likelihood technique. Results were comparable with one another and indicated that, although genetic factors were significant, differences between laboratories contributed a larger proportion of the total estimated variance. These results partly confirmed previous findings but indicated that the degree of genetic control over the proportion of affected cells was lower than recently suggested.

Fragile X expression in short-term whole blood cultures is affected by cell density.

The effect of cell density on expression of the fragile site at (X)(q27.3) in short-term whole-blood cultures from patients with fragile X [fra(X)] or Martin-Bell syndrome was studied. A significant increase in fra(X) frequency was observed in 7 of 8 samples when cell density was decreased. Higher fra(X) frequency was not always noted at below-routine density, but in some cases fra(X) expression was depressed at above-routine density. We conclude that decay of the FUdR effect explains the fact that fra(X) expression is affected by culture density. It is significant that a relationship exists between the two; it suggests that in order to maximize fra(X) expression in cases with low-percentage fra(X) with standard methods, cell density may have to be adjusted. It is possible that in individuals who are normally nonexpressing, such as some obligate female carriers and nonpenetrant males, fra(X) expression may be sensitive to cell density effects.

Fragile X chromosome frequency is consistent temporally and within replicate cultures.

Fragile X frequencies differ widely between different fra(X)-positive individuals. The basis for this variation is unknown, but may reflect genetic differences or unknown environmental factors. To determine more fully the individual and familial variation in fra(X) frequencies, we studied 15 individuals. The present study showed that fra(X) frequency, with few exceptions, was consistent for the same individual both over time and within replicate cultures. This confirms previous observations by others on the consistency of fra(X) expression by others, and indicates the extent of expected variability within replicate cultures. Consideration of this variability should enable improved fra(X) identification.

Mouse chromosome fragility.

When cultures of fibroblast-like cells from inbred mouse strains RBC/Dn and AEJ/GnRk were exposed to 5-fluorodeoxyuridine (FUdR), non-random strain-specific distributions of chromosome gaps, breaks and exchanges were observed. Throughout the genomes there appeared to be specific sites at which lesions occurred preferentially. Two strain-specific fragile sites were identified in strain RBC/Dn at G-band 15A2, and at G-band 19B in strain AEJ/GnRk. Constitutive fragile sites at G-bands 12A2 and 18A2 were identified in both strains. A strain-specific marker at G-band 9B was found in strain AEJ/GnRk. The fragile sites reported here provide an animal model for the study of chromosome fragility as well as polymorphic markers for linkage studies.

Continuous infusion cyclosporine and nifedipine to day +100 with short methotrexate and steroids as GVHD prophylaxis in unrelated donor transplants.

Unrelated donor marrow transplantation is associated with an increased incidence of graft-versus-host disease (GVHD) compared with sibling donor transplants. Forty-one patients undergoing unrelated donor transplants were treated with a GVHD prophylaxis regimen that consisted of continuous infusion cyclosporine from day -1 to 100 days post transplant along with nifedipine, glucocorticoids and short-course methotrexate. The regimen was well-tolerated in this cohort with mostly high risk disease. Fifty-one percent of patients developed acute GVHD, which was grade III-IV in 22% of patients. Six of 22 patients at risk for chronic GVHD developed extensive chronic GVHD, five of whom were adults. In patients <18 years of age, there was a >40% chance of 2 year disease-free survival. Use of continuous infusion cyclosporine with nifedipine as an immunosuppressant and protectant against cyclosporine-induced toxicities in unrelated donor transplants is well-tolerated, and results in acute GVHD incidence favorable to that reported with bolus cyclosporine.

Metabolic profile of fetal dopamine neurons transplanted to the adult rat striatum.

In the present study, we have examined the expression and distribution of the metabolic marker neuron-specific enolase (NSE) in solid-tissue transplants of fetal substantia nigra (SN) to the striatum of intact and 6-hydroxydopamine lesioned mature rats. Immunocytochemistry was applied to label NSE and tyrosine hydroxylase (TH) respectively. Cellular content of NSE is indicative of metabolic activity as well as synaptogenesis/maturation. Three months after implantation, the fetal grafts exhibited intensely TH-immunoreactive neurons, typically organized in elongated clusters, especially along the graft-host border and along blood vessels penetrating into the graft interior. Moderate to high metabolic activity as indicated by NSE immunoreactivity was observed in neuronal perikarya, principally in non-TH immunoreactive areas. In contrast to these immunohistochemical findings, in situ hybridization for TH mRNA, carried out exclusively on grafts into the intact striatum, demonstrated DA cell bodies both at the graft-host interface and, significantly, throughout the graft interior. The number of transcripts per cell, moreover, did not differ significantly in these two locations. We propose that conditions at the graft-host border promote tissue-specific regulation of nigral DA neurons, and that this regulation occurs post-transcriptionally. Thus, DA neurons relatively distant from the host parenchyma are underregulated, resulting in a higher level of metabolic activity and an increased turnover of TH in the grafted neurons.

Separation of dorsal and ventral dopaminergic neurons from embryonic rat mesencephalon by buoyant density fractionation: disassembling pattern in the ventral midbrain.

The dopaminergic neurons of the ventral mesencephalon, though physically mixed with non-dopamine neurons, are organized into dorsal and ventral 'tiers' with regard to their ontogeny, efferent projections and their relative position in the various mesencephalic sub-nuclei. We have employed buoyant density fractionation to separate the dopaminergic neurons of the two compartments and compare their subsequent phenotype development with respect to their expression of the gene encoding tyrosine hydroxylase, the rate-limiting enzyme in the catecholamine biosynthetic pathway. Using immunocytochemistry, separately and combined with in situ hybridization, we demonstrate here that sedimentation of cell suspensions from E19 rat ventral mesencephalon on 5-step Percoll gradients produces cell fractions enriched in ventral and dorsal tier DA neurons, respectively.

Age differences in the reliability of parent and child reports of child anxious symptomatology using a structured interview.

Test-retest reliability of child and parent reports of anxious symptomatology, using a structured interview (The Anxiety Disorders Interview Schedule for Children; ADIS-C and ADIS-P), was examined with 50 outpatients and their parents. The test-retest was 10 to 14 days. Reliability was examined for three parameters: (1) an exact match on primary anxiety diagnoses; (2) symptom scale scores; and (3) clinician's agreement on severity ratings. Overall, satisfactory reliability across the three parameters was found. The results were viewed to be promising in light of previous research that parents and children tend to be unreliable in making such reports. Age differences in reliability were also examined between children 6 to 11 and 12 to 17 years old. Discrepancies between parent and child reports and age differences between samples (i.e., 6-11, 12-17) are discussed.

Test-retest reliability of anxiety symptoms and diagnoses with the Anxiety Disorders Interview Schedule for DSM-IV: child and parent versions.

OBJECTIVE: To examine the test-retest reliability of the DSM-IV anxiety symptoms and disorders in children with the Anxiety Disorders Interview Schedule for DSM-IV: Child and Parent Versions (ADIS for DSM-IV:C/P). METHOD: Sixty-two children (aged 7-16 years) and their parents underwent two administrations of the ADIS for DSM-IV:C/P with a test-retest interval of 7 to 14 days. RESULTS AND CONCLUSIONS: Results revealed that the ADIS for DSM-IV:C/P is a reliable instrument for deriving DSM-IV anxiety disorder symptoms and diagnoses in children. The ADIS for DSM-IV:C/P was found to have excellent reliability in symptom scale scores for separation anxiety disorder, social phobia, specific phobia, and generalized anxiety disorder and good to excellent reliability for deriving combined diagnoses of these disorders, as well as using child-only and parent-only interview information. Reliability coefficients were generally similar and, in most instances, superior to those found in previous ADIS-C/P reliability studies. Limitations and directions for future research are discussed.

Neuron-specific enolase reflects metabolic activity in mesencephalic neurons of the rat.

Numerous studies on the local rate of energy metabolism of various brain regions during development and following experimental manipulation have been conducted using 2-deoxyglucose uptake and cytochrome oxidase (CO) histochemistry, both considered to be reliable indicators of long-term and short-term alterations in neuronal activity, respectively. Another method which has been related to neuronal activity is neuron-specific enolase (NSE) immunohistochemistry. An isoenzyme of enolase, a key element in the glycolytic pathway, NSE is present in neurons and neural-related cells e.g. neuroendocrine cells, pituicytes, and many tumor cells, but not in glia. The distribution on adjacent tissue sections of immunoreactive NSE and histochemically determined CO were mapped in the rat mesencephalon and adrenal medulla. Both methods showed highly restricted localization of staining which coincided with few exceptions in the most reactive areas, namely the superior colliculus, medial and lateral geniculate nuclei, red nucleus, lateral mammillary nucleus, interpeduncular nucleus and substantia nigra pars lateralis and pars reticulata. Immunoreactivity of varying intensity for NSE was also observed in perikarya and in processes of numerous scattered neurons throughout the mesencephalon, including the substantia nigra pars compacta, and reticular formation. The general correspondence in staining patterns between CO and NSE in the midbrain, supports the utility of NSE as a useful index of metabolic activity in neurons.

The ontogeny of specific prolactin binding sites in the rat choroid plexus.

The development of prolactin receptors in the choroid plexus of the rat was examined using the in vivo autoradiographic approach employing the principle of competitive binding. Experimental animals were injected with [125I]prolactin alone (total binding) while control animals received [125I]prolactin and a 500-fold excess of unlabelled prolactin (non-specific binding). Newborns as well as animals 10, 14 and 18 days postnatal were studied. Three minutes following hormone injection animals received an intracardiac perfusion with fixative and tissues were prepared for quantitative light microscopic autoradiography. The choroid plexus first demonstrated specific binding of prolactin, i.e. a statistically significant difference in the autoradiographic reactions between experimental and control animals, at 14 days postnatal. The lactogen specificity of these binding sites was further defined by the ability of [125I]prolactin to be displaced by unlabelled human growth hormone, which is lactogenic in rats, and not by unlabelled insulin, which is structurally dissimilar to prolactin. Morphometric analyses were performed on electron micrographs of choroid plexus from 10- and 14-day postnatal rats. The volume densities of constituents known to be enriched in polypeptide hormone receptors were measured and compared. Small cytoplasmic vesicles and tubules were statistically significantly more abundant in 10-day-old rats than in 14-day-old animals. It is conjectured that these vesicles and tubules contain an intracellular pool of prolactin receptors whose decrease at 14 days parallels the expression of specific binding sites at the cell surface.