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PubMed1997

Comparative genomic hybridization in hypotriploid/hyperdiploid tumors.

Hypotriploidy/hyperdiploidy ("intermediate ploidy") often occurs in testicular germ cell tumors of adolescents and adults. Disomic and trisomic chromosomes represent significant parts of the tumor genome and a few chromosomes fall outside the two- to three-copy number range. We performed comparative genomic hybridization (CGH) with DNA isolated from a cell line from a case of testicular germ cell tumor of adolescents and adults and found most of the ratio values to be dislocated from the baseline 1.0 and placed adjacent of the diagnostic thresholds of 0.8 and 1.2. We attributed that to the fact that, in current software packages for analysis of CGH, the fluorescence ratio baseline is assumed to correspond to the copy number of most loci of the genome. We then evaluated, instead of the commonly used fluorescent ratio value from the whole metaphase, the use of the fluorescence ratios of single chromosomes. The results permitted a clear distinction between the chromosomes with two and three copies and, in particular, of the regions deleted or amplified outside the two- to three-copy range. We concluded that the evaluation of unbalances of DNA copy number in intermediate ploidy cases is best carried out using multiple normalization.

Adolescent↗
PubMed2000

Risk of false positive results in comparative genomic hybridization.

Comparative genomic hybridization, a widely used method for screening for genomic imbalances, suffers from a lack of standardized evaluation. In order to compare a recently proposed data-driven procedure with the commonly used fixed cutoff values, we tested 257 events by both procedures as well as by fluorescence in situ hybridization using selected probes. With the data-driven procedure, a much higher fraction (42/218 vs. 8/218) of false positive results was obtained, whereas a higher sensitivity with respect to the detection of imbalances (30/39 vs. 19/39) was reached. Based on the significantly higher positive likelihood ratios and the positive predictive value, we strongly recommend the use of fixed diagnostic thresholds, because the alternative procedure generates an unacceptably high portion of incorrectly scored chromosomal imbalances. Genes Chromosomes Cancer 28:353-357, 2000.

Chromosome Aberrations↗
PubMed2006

HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin.

OBJECTIVE: Familial autosomal dominant frontotemporal dementia with ubiquitin-positive, tau-negative inclusions in the brain linked to 17q21-22 recently has been reported to carry null mutations in the progranulin gene (PGRN). Hereditary dysphasic disinhibition dementia (HDDD) is a frontotemporal dementia with prominent changes in behavior and language deficits. A previous study found significant linkage to chromosome 17 in a HDDD family (HDDD2), but no mutation in the MAPT gene. Longitudinal follow-up has enabled us to identify new cases and to further characterize the dementia in this family. The goals of this study were to develop research criteria to classify the different clinical expressions of dementia observed in this large kindred, to identify the causal mutation in affected individuals and correlate this with phenotypic characteristics in this pedigree, and to assess the neuropathological characteristics using immunohistochemical techniques. METHODS: In this study we describe a detailed clinical, pathological and mutation analysis of the HDDD2 kindred. RESULTS: Neuropathologically, HDDD2 represents a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U). We developed research classification criteria and identified three distinct diagnostic thresholds, which helped localize the disease locus. The chromosomal region with the strongest evidence of linkage lies within the minimum critical region for FTLD-U. Sequencing of each exon of the PGRN gene led to the identification of a novel missense mutation, Ala-9 Asp, within the signal peptide. INTERPRETATION: HDDD2 is an FTLD-U caused by a missense mutation in the PGRN gene that cosegregates with the disease and with the disease haplotype in at-risk individuals. This mutation is the first reported pathogenic missense mutation in the signal peptide of the PGRN gene causing FTLD-U. In light of the previous reports of null mutations and its position in the gene, two possible pathological mechanisms are proposed: (1) the protein may accumulate within the endoplasmic reticulum due to inefficient secretion; and (2) mutant RNA may have a lower expression because of degradation via nonsense-mediated decay.

Adult↗
PubMed1993

Probability of rejection predicted from ultrasonographic measurement of renal transplant swelling.

Serial ultrasonographic measurements of renal transplant cross-sectional area were used to quantify allograft swelling as a diagnostic test of acute rejection. Eighty consecutive episodes of acute allograft dysfunction (rise in creatinine level > or = 10 per cent or > or = 30 mumol l-1) were investigated. Needle core biopsy was performed in all cases to diagnose acute rejection. Rejecting transplants demonstrated a median (interquartile range) swelling of 16.2 (12.1-25.5) per cent compared with 2.2 (-2.0 to 8.4) per cent for non-rejecting organs (P < 0.001). A > or = 10 per cent increase as the diagnostic threshold for rejection yielded a sensitivity of 80 per cent, specificity of 77 per cent, positive predictive value of 85 per cent, negative predictive value of 71 per cent and overall accuracy of 79 per cent. Using a logistic regression model, predictive probabilities of rejection for individual changes in cross-sectional area were calculated. A 20 per cent increase was associated with a predicted probability of rejection of 87 per cent (95 per cent confidence interval 75-94 per cent). There was a significant correlation between the functional severity of rejection and the degree of transplant swelling (rs = 0.63, P < 0.001). Ultrasonographic measurement of renal transplant cross-sectional area is a simple non-invasive test for the diagnosis of acute rejection.

Graft Rejection↗
PubMed2002

Eating and body image disturbances in adolescent psychiatric inpatients: gender and ethnicity patterns.

OBJECTIVE: To examine gender and ethnicity patterns in eating and body image disturbances in adolescents hospitalized in a psychiatric facility. METHOD: Participants comprised 715 inpatients who completed the Millon Adolescent Clinical Inventory. Gender (317 males, 398 females), ethnicity (553 Caucasians, 77 Latinõ Americans, 85 African Americans), and Gender x Ethnicity interactions in the features of eating disorders and body image disturbance were explored in the study group. RESULTS: Eating-related disturbances at diagnostic threshold were infrequent but participants' reported rates of specific features and symptoms were not. Overall, a significantly higher proportion of females than males reported features of eating and body image disturbances. The three ethnic groups differed significantly in their reports of body image disturbances but not in their endorsement of features of eating disorders. Post-hoc comparisons revealed that a significantly higher proportion of Caucasian participants reported body image concerns than did African American and Latinõ American participants who did not differ significantly from one another. Significant Gender x Ethnicity interactions were observed, with Caucasian females endorsing higher rates of features of eating disorders and body image disturbances than African American and Latinõ American females. DISCUSSION: In adolescent psychiatric inpatients, although Caucasian females report the highest rates of the features of eating and body image disturbances, such concerns are not uncommon in males and in minorities.

Adolescent↗
PubMed1993

Des-gamma-carboxy (abnormal) prothrombin and hepatocellular carcinoma: a critical review.

Des-gamma-carboxyprothrombin (DCP) appears to be a useful tumor marker for the evaluation of patients with HCC. DCP is produced by the malignant hepatocyte and appears to result from an acquired posttranslational defect in the vitamin K-dependent carboxylase system. DCP production is independent of vitamin K deficiency, although pharmacological doses of vitamin K can transiently suppress DCP production in some tumors. DCP levels greater than 0.1 AU/ml (100 ng/ml) on ELISA are highly suggestive of HCC or tumor recurrence. Normalization of DCP levels correlates well with successful tumor resection and appears to be an excellent marker of tumor activity. Plasma DCP does not correlate with AFP levels. However, when used together, DCP and AFP assays increase the sensitivity to HCC in more than 85% of patients. The specificity of the DCP assay appears to be superior to that of AFP; fewer than 5% of patients with nonmalignant liver disorders have DCP levels in excess of 100 ng/ml. In patients with medium to large HCC, DCP levels do correlate with tumor size. In tumors of less than 3 cm, DCP levels are increased in only 20% of patients. However, the diagnostic threshold for the DCP assay may be improved by newer assays that can detect partially carboxylated DCP species not measured by the monoclonal antibody-based ELISA.

Biomarkers↗
PubMed2002

Interphase FISH assays for the detection of translocations with breakpoints in immunoglobulin light chain loci.

Many B-cell malignancies bear chromosomal translocations juxtaposing immunoglobulin (IG) genes with oncogenes, resulting in deregulated expression of the latter. Translocations affecting the IG heavy chain (IGH) locus in chromosomal region 14q32 are most prevalent. However, variant translocations involving the IG kappa (IGK) locus in 2p12 or the IG lambda (IGL) locus in 22q11 occur recurrently in B-cell neoplasias. No routine methods for the detection of all breakpoints involving IG light chain loci independently of the translocation partner have been described. For this reason, we have designed 2 novel interphase fluorescence in situ hybridization (FISH) assays using differentially labeled probes flanking the IGK and IGL locus, respectively. Based on extensive control studies, the diagnostic thresholds for the detection of breakpoints were set at 0.3% for IGK and 1.4% for IGL. Fifteen cases of B-cell malignancies with cytogenetically detectable chromosomal abnormalities in 2p11-14 were investigated with the FISH assay for IGK. Breakpoints affecting the IGK locus were detected in 7 cases including all 4 variant Burkitt's translocations t(2;8)(p12;q24) and a variant BCL2-associated translocation t(2;18)(p12;q21). Other translocation partners were chromosome bands 7q21 and 16q24. Ten cases with abnormalities in 22q11-12 were investigated with the FISH assay for IGL. Breakpoints in the IGL locus were diagnosed in 7 cases including both variant Burkitt's translocations t(8;22)(q24;q11) and a t(3;22)(q27;q11) involving the BCL6 locus. Other translocation partners were 2p13-14, 4q13 and 16p12. Our results show that these FISH assays provide flexible, simple and reliable tools in the diagnosis and characterization of genetic changes in B-cell malignancies.

Adolescent↗
PubMed1996

Sex differences in ADHD: conference summary.

Clinical samples of attention deficit hyperactivity disorder (ADHD) have been dominated by males. Consequently, female manifestations and sex differences have been relatively neglected in the extensive ADHD research. Because ADHD is so common (3% to 5% of school children) and chronic (lifelong in many cases), even a small proportion of females multiplied by such a large base means hundreds of thousands of girls and women with ADHD, a significant public health problem. An NIMH conference concluded that research is needed not only on sex differences related to ADHD, but also on manifestations of ADHD in females as such. Areas of focus should include differences in life course (sex-differential age effects); effects of hormones; effects of ADHD parenting (in utero and postnatal) on the next generation; response to and implications for design of psychosocial treatment; effects of differential comorbidity; normative "background" sex differences that influence the manifestation of ADHD; differences in development of verbal fluency and social behavior; possible interactions of sex and ethnicity; a prospective study of both sex offspring of ADHD adults; and such methodological issues as appropriate instruments and diagnostic thresholds, power to prevent false negatives, valid impairment measures, validity and reliability of child self-reports, and more inclusive samples (all three subtypes: inattentive, hyperactive-impulsive, and combined).

Attention Deficit Disorder with Hyperactivity↗
PubMed1989

Alcohol dependence in ICD-9 and DSM-III-R: a comparative polydiagnostic study.

Diagnoses of alcohol dependence, using the classification systems ICD-9 and DSM-III-R, were compared in a sample of 215 psychiatric outpatients. A lower diagnostic threshold was obtained for DSM-III-R. This category tended to be more inclusive for relatively mild forms of inadequate alcohol use. Of those patients with ICD-9 alcohol dependence, 79% also met criteria for the corresponding DSM-III-R category, whereas 61% of subjects diagnosed as dependent according to DSM-III-R received the equivalent diagnosis in ICD-9. These results were obtained assuming equal base rates (sample frequencies) for dependence and abuse. Diagnoses were further compared with independently derived scores of the Munich Alcoholism Test (MALT), and the validity of DSM-III-R was found to be superior. Checklist-guided interviews had a positive impact upon accuracy and validity of diagnoses.

Adolescent↗
PubMed1999

[Stability and variability of catatonic symptoms in the longitudinal course of illness. Videotape documentation in catatonic schizophrenia].

The symptomatology of a female patient with catatonic schizophrenia is presented with respect to its longitudinal course. The stability and variability of catatonic symptoms are investigated using videotape technique. It is demonstrated that catatonic symptoms are stable in the longitudinal course but due to unsteady arousal the severity of the catatonic symptoms varies markedly. There are fluctuating symptom patterns that dominate the clinical picture: a hyperkinetic form with prevailing restlessness or excitement, with abnormal involuntary movements, stereotypies, and parakinetic movements, and a hypokinetic form with various inhibition phenomena, mutism and stupor. The clinical impression of the catatonic syndrome changes according to the dominating symptom patterns at different times, whereas the less severe symptoms recede into the background and thus, may be overlooked. Considering this finding the problem of a 'diagnostic threshold' is discussed. The authors intend to emphasize videotape documentation of catatonic motor disturbances as most useful. This technique may contribute to differentiating illness related from neuroleptic induced movement disorders.

Adult↗
PubMed2004

Rationale, design and recruitment characteristics of a large, simple international trial of diabetes prevention: the DREAM trial.

AIMS/HYPOTHESIS: Diabetes is a rapidly rising independent risk factor for atherosclerosis and serious illness. This risk can be reduced by lifestyle changes and/or various drugs. Novel therapies to prevent diabetes, as well as new risk factors for diabetes, atherosclerosis and obesity require testing and identification. METHODS: People with impaired fasting glucose or impaired glucose tolerance were randomised to ramipril (15 mg/day) or placebo and rosiglitazone (8 mg/day) or placebo with a 2x2 factorial design. They are assessed semi-annually for the primary outcome (diabetes or death). Diabetes is diagnosed if two consecutive plasma glucose levels exceed diagnostic thresholds (i.e. fasting >/=7.0 mmol/l or 2-h >/=11.1 mmol/l) within a 3-month period. Assuming an annual primary outcome incidence of 5%, there is more than 90% power to detect a 22% reduction. Approximately 20% of participants are having annual carotid ultrasounds to assess the effects on atherosclerosis. Patients screened but not randomised are being followed prospectively to identify determinants of obesity, diabetes and related disorders. RESULTS: A total of 24,872 individuals in 21 countries were screened over 2 years and are eligible for follow-up. Of these, 5269 were randomised: 1835 (35%) had isolated impaired glucose tolerance, 739 (14%) had isolated impaired fasting glucose, and 2692 (51%) had both disorders. Annual carotid ultrasounds are currently being performed in 1406 randomised individuals. CONCLUSIONS/INTERPRETATION: The DREAM trial and related studies will determine if ramipril or rosiglitazone reduces the number of cases of diabetes and atherosclerosis, and will identify novel risk factors for diabetes.

Adult↗
PubMed2006

Bone fragility in men--where are we?

INTRODUCTION: This is a summary of several aspects of the epidemiology, pathogenesis and treatment arising directly and indirectly from the proceedings of the Third International Osteoporosis in Men meeting held in Genoa in May 2005. Advances in the study of bone fragility in men have taken place, but many challenges remain. OBSERVATIONS: Although the epidemiology of hip fractures is well documented, the epidemiology of other non-vertebral fractures is less well defined even though these fractures contribute substantially to the global burden of fractures in men. The epidemiology of vertebral fragility fractures is derived mostly from cross sectional data. The comparable prevalence of vertebral fractures in men and women is likely to be misleading because of traumatic vertebral fractures that arise in young men. Prospective studies are needed to define the proportion of these fractures that are traumatic. After the age of 50 years, the incidence of vertebral fractures in men is about one third to one half of that in women. As in women, most vertebral and non-vertebral fragility fractures occur in persons without osteoporosis. Identifying these individuals is an unmet challenge. The absolute risk for fractures appears no different by sex in men and women of the same age and bone mineral density (BMD) so that the diagnostic threshold for osteoporosis in women can be used in men. Fracture risk varies around the world and is unlikely to be explained solely by variations in BMD, though there are few data comparing men and women of different races. Both the notion that men lose less bone than women from the endosteal envelope and that they gain more on the periosteal envelope during advancing age needs reassessment as recent evidence challenges these observations. Sex differences in the net gain and loss from these surfaces are likely to be site specific, and research is needed to specify this heterogeneity and the reasons for it. The independent and co-dependent effects of sex hormones and the growth hormone/insulin like growth factor 1 axis on periosteal and endosteal modeling and remodeling during growth as well as ageing are poorly defined. The anti-fracture efficacy and safety of androgens and other agents remain incompletely investigated in men. CONCLUSION: A great deal of research is needed to advance our understanding of bone fragility in men.

Aged↗
PubMed2001

Reproducibility of DXA: potential impact on serial measurements and misclassification of osteoporosis.

The reproducibility of bone mineral density (BMD) measurements by dual-energy X-ray absorptiometry (DXA), based on 12 successive monthly determinations, was assessed in a group of 24 subjects (23 postmenopausal women, 1 man) using six trained operators. The variability (S2A) was calculated from both duplicate operator measurements and the standard error of estimate from nonparametric regression of the individual subject series. Robust estimates of SA from the 90th percentile of the sampling distribution of variances were calculated for the spine (25 mg/cm2), femur neck (20 mg/cm2) and total femur (15.5 mg/cm2) using the bootstrap technique. The critical difference for a significant decrease (p = 0.05) at the spine, femoral neck and total femur was estimated at 57, 46 and 36 mg/cm2 respectively. Estimation of S2A allowed calculation of the probability that the true BMD, for an observed BMD near the osteoporosis diagnostic threshold (T-score < -2.5), is not misclassified. Analysis of covariance established a significant operator-subject interaction at all sites, but only the total femur was associated with a significant difference between operators. The percentage of body fat was a significant covariate for the spine and total femur regions. ANOVA showed that the greater proportion of variance was instrument-related. The limitations of DXA as an analytical method are discussed.

Absorptiometry, Photon↗
PubMed2002

Mandibular radiomorphometric indices in the diagnosis of reduced skeletal bone mineral density.

Diagnosis of osteoporosis allows the delivery of preventive and therapeutic intervention and is usually achieved using bone densitometric techniques. One referral criterion for densitometry is osteopenia on radiographs. The aim of this study was to measure the validity of mandibular cortical indices measured on panoramic radiographs in the diagnosis of reduced skeletal bone density. Seventy-four women underwent bone densitometry of the femoral neck, lumbar spine and the forearm. Fifty-five patients (74%) were classified as having a reduced bone density (T-score < or = -1). Twenty-seven patients had a T-score of < -2.5 observed at one or more of the three measurement sites. A panoramic radiograph was taken of each patient and two observers made measurements of cortical thickness at the mental foramen (mental index, MI), antegonion (antegonial index, AI) and gonion (gonial index, GI) regions. Logistic regression and receiver operating characteristic (ROC) curve analyses were used to measure the validity of cortical indices in the diagnosis of reduced bone mineral density. Only MI contributed significantly to a diagnosis of low skeletal bone mineral density (T-score < or = -1). The 95% limits of agreement between observers in measurement of MI were 1.32 to +1.32 mm. When data for both observers were combined, the area under the ROC curve was 0.733 (SE = 0.072; 95% confidence interval = 0.618 to 0.83), indicating moderate accuracy. A diagnostic threshold for MI of 3 mm (or less) is suggested as the most appropriate threshold for referral for bone densitometry. However, the study provided only limited support for the use of panoramic radiomorphometric indices in diagnosing low skeletal bone mineral density. They might, questionably, be used as part of a method of osteoporosis risk assessment.

Absorptiometry, Photon↗
PubMed2004

The effect of sex on avian plasma cholinesterase enzyme activity: a potential source of variation in an avian biomarker endpoint.

Accurate identification of contaminant exposure to nontarget organisms involves understanding sources of variation associated with contaminant specific biomarkers. Cholinesterase (ChE) enzyme activity is the biochemical endpoint most often used to assess organism exposure to organophosphorus (OP) pesticides. A potential source of variation for this biomarker is sex, however, a generalized pattern of sex as a source of variation for avian ChE levels remains equivocal. In this study, sex-dependent variation in plasma ChE activity was examined in breeding northern cardinals (Cardinalis cardinalis) from reference populations free of OP pesticide exposure. Male (n = 32) total ChE activity (1.745 +/- 0.541) was greater than female (n = 26) total ChE activity (1.480 +/- 0.576) (p = 0.015). Likewise, benchmarks based on reference means and used for exposure identification (e.g., 20% reduction and the diagnostic threshold) were higher in males than females. With females having a 15.2% lower ChE activity than males, a substantial source of error exists for exposure assessment since some researchers consider a 20% inhibition as evidence of exposure. A second objective was to survey published literature to examine the extent that studies have accounted or controlled for the potential effect of sex on ChE activity. More studies (56.3%) pooled data for male and female ChE activity than studies that statistically tested for an effect (20.3%) or tested hypotheses using a single sex (23.4%) (p < 0.0001; n = 64). Based on these findings, it is suggested that the effect of sex be considered in future studies using the ChE biomarker for identification of passerine exposure to OP pesticides, particularly if examining plasma sources of ChE in actively breeding passerines.

Animals↗
PubMed2004

Detection of ileocecal Crohn's disease using ultrasound as the primary imaging modality.

At our hospital ultrasound (US) is used as an initial screening procedure in all patients with abdominal symptoms. The purpose of this study was to assess the effect of this policy on the detection of ileocecal Crohn's disease. We retrospectively studied all patients with a new diagnosis of ileocecal Crohn's disease from our institute over the period 1990-2001. The final diagnosis was based on clinical follow-up and pathological, surgical, US, and other radiological findings. We noted who referred the patient to the radiology department, what the initial clinical presumption was, and what the first imaging study was. US diagnoses were determined from the initial US report and US findings were registered from the images. There were a total of 47 patients (20 men, 27 women) with a mean age of 30 years and a median age of 27 years (range 14-75 years). In all patients the initial imaging study was an abdominal US. Using US, a confident diagnosis of ileocecal Crohn's disease was made in 35 of the 47 patients, Crohn's disease was suggested among the differential diagnosis in 10, and an incorrect diagnosis was made in 2 patients. In 28 of 47 patients, the referring physician did not consider Crohn's disease when requesting the initial US examination. In eight patients with appendicitis-like symptoms, the US findings strongly influenced the decision to refrain from operation at that point in time. US, when used as a low-threshold diagnostic procedure, is a reliable and noninvasive means for making an early diagnosis of ileocecal Crohn's disease in patients who present with atypical symptoms. It may prevent both unnecessary therapeutic delay as well as unnecessary surgery.

Adolescent↗
PubMed2002

Hereditary haemochromatosis: only 1% of adult HFEC282Y homozygotes in South Wales have a clinical diagnosis of iron overload.

In northern Europe, about 90% of patients with hereditary haemochromatosis (HH) are homozygous for a single mutation (C282Y) of the HFEgene and approximately 1 in 150 people in the general population carries this genotype. However, the clinical significance of HFE mutations remains uncertain, as is the proportion of people homozygous for C282Y who will develop clinical symptoms leading to a diagnosis of HH. A systematic review of patients with HH over a 2-year period within a defined UK region has revealed that only 1.2% of adult C282Y homozygotes have been diagnosed with iron overload and received treatment. In those in whom body iron load could be estimated, only 51% has more than 4 g iron (the diagnostic threshold for iron overload).

Adult↗
PubMed2006

Reflections on accuracy.

The difference between test accuracy and predictive accuracy is presented and defined. The failure to distinguish between these two types of measures is shown to have led to a misguided debate over the interpretation of prevalence estimates. The distinction between test accuracy defined as sensitivity and specificity, and predictive accuracy defined as positive and negative predictive value is shown to reflect the choice of the denominator used to calculate true positive, false positive, false negative, and true negative rates. It is further shown that any instrument will tend to overestimate prevalence in low base rate populations and underestimate it in those populations where prevalence is high. The implications of these observations are then discussed in terms of the need to define diagnostic thresholds that have clinical and policy relevance.

Behavior, Addictive↗