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PubMed2004

Neither baseline tests of molecular hypercoagulability nor D-dimer levels predict deep venous thrombosis in critically ill medical-surgical patients.

OBJECTIVE: Predicting patients who are harboring asymptomatic deep venous thrombosis (DVT), or who are at particular risk of developing DVT, is a desirable clinical goal since prevention or early treatment of DVT might reduce the risk of fatal pulmonary embolism. Thus validation of simple laboratory tests that reliably predict venous thromboembolism (VTE) would be clinically very important. Tests that might be useful for these applications include markers of hypercoagulability (predicting patients at risk of DVT) and D-dimer (predicting which patients may have acute DVT). METHODS: In a prospective cohort study we measured a panel of hypercoagulability markers at the time of ICU admission, and six commercial D-dimer assays were performed serially during the ICU stay in medical-surgical ICU patients who were screened for DVT with biweekly lower limb compression ultrasonography. Ultrasonography was also performed at the time of any clinically suspected DVT events. We matched cases with DVT with controls without DVT for length of stay in the ICU to generate receiver operating characteristics (ROC) curves. RESULTS: One hundred ninety-seven patients were enrolled. Blood was collected on a total of 763 occasions (median number of occasions per patient: 3, range 1-21). None of the assays predicted DVT, as indicated by the areas under the ROC curves, that did not differ significantly from 50%. CONCLUSION: In critically ill patients, neither tests of hypercoagulability nor D-dimer levels predict patients at risk of DVT and thus they should not be used to guide diagnostic testing for DVT.

Aged↗

PubMed2005

Test of molecular dynamics force fields in gramicidin A.

The force fields commonly used in molecular dynamics simulations of proteins are optimized under bulk conditions. Whether the same force fields can be used in simulations of membrane proteins is not well established, although they are increasingly being used for such purposes. Here we consider ion permeation in the gramicidin A channel as a test of the AMBER force field in a membrane environment. The potentials of mean force for potassium ions are calculated along the channel axis and compared with the one deduced from the experimental conductance data. The calculated result indicates a rather large central barrier similar to those obtained from other force fields, which are incompatible with the conductance data. We suggest that lack of polarizability is the most likely cause of this problem, and, therefore, urge development of polarizable force fields for simulations of membrane proteins.

Algorithms↗

PubMed1991

[Complex biochemical and molecular approach to prenatal diagnosis of mucoviscidosis].

Prenatal diagnosis of 62 cases of cystic fibrosis was performed in high-risk families at 18-21 gestational weeks using biochemical and molecular tests. The diagnosis was ruled out in 42 and confirmed in 20 cases. The incidence of false-positive results was 8.3% (5 of 62) and that of false-negative results 3.7% (2 of 62). Reliability of prenatal diagnosis in concomitant use of biochemical and molecular tests was over 95%. Advantages of prenatal diagnosis of cystic fibrosis using DNA probes and requirements for its wider adoption in the first trimester are discussed.

Acid Phosphatase↗

PubMed1992

Quality assurance and proficiency testing in molecular oncology.

The College of American Pathologists has recently initiated a Resource Committee on Molecular Pathology to (1) develop appropriate practice guidelines for molecular pathology; and (2) ensure the monitoring of emerging and future changes in the discipline of cellular pathology, including evolving applications of new technical modalities and practice. A laboratory accreditation checklist has been written and will become available to clinical laboratories. A proficiency survey of samples which will test for T-cell and B-cell gene rearrangement and oncogene detection and amplification is planned for 1992.

Genetic Techniques↗

PubMed2004

Familial hypertrophic cardiomyopathy: clinical features, molecular genetics and molecular genetic testing.

Hypertrophic cardiomyopathy is a Mendelian disease characterized by cardiac hypertrophy. It has a prevalence of 1:500 individuals and is the most common cause of sudden death in the young. Other complications include heart failure and the need for heart transplantation. Hypertrophic cardiomyopathy is due to sarcomeric gene mutations, however, phenocopies with myocardial hypertrophy can be due to triplet-repeat syndromes (Friedreich ataxia and myotonic dystrophy), mitochondrial and metabolic diseases. In a peculiar form associated with Wolf-Parkinson-White syndrome, the disease is caused by mutations in the gamma2 regulatory subunit of the AMP-activated protein kinase gene, leading to a glycogen storage cardiomyopathy. In spite of the growing knowledge about the molecular basis of hypertrophic cardiomyopathy, very little is still known about the genotype-phenotype correlations and their clinical implications. In this review, the clinical and molecular genetics of hypertrophic cardiomyopathy are described.

Animals↗

PubMed1998

Genetic analysis of extended life span in Drosophila melanogaster. II. Replication of the backcross test and molecular characterization of the N14 locus.

We are interested in localizing chromosomal regions that extend life span in Drosophila. Using stocks artificially selected for long life by Luckinbill and his colleagues, we have identified marker loci that are highly divergent in allelic frequencies between replicated long-lived lines and controls (Curtsinger et al., 1998). Several of the most divergent loci have been found to be associated with effects on life span in segregating backcross populations. Here we report an independent replication of the backcross test for the N14 marker locus, previously reported to extend male life spans by 12 days. The life span effect successfully replicates in males. N14 accounts for 30% of the total selection response in males. Life span extension occurs by a decrease in age-specific mortality rates at all ages, and is not attributable to modification of the slope of the age-specific mortality curve. The effect in females is small or nonexistent. Sequencing of the N14 locus shows that it is non-coding and not obviously regulatory, suggesting that the phenotypic effect arises from linkage disequilibrium with another locus or loci that directly affect life span. N14 DNA hybridizes to 63F/64A on the left arm of chromosome 3. The location is consistent with previous whole-chromosome substitution studies, and suggests new candidate genes for life span extension in Drosophila, including ras2.

Aging↗

PubMedDate not supplied

Molecular diagnosis of FMF: lessons from a study of 446 unrelated individuals.

BACKGROUND: Traditionally, the diagnosis of familial Mediterranean fever (FMF) has been based on clinical manifestations and the physician's experience. Following the cloning of the gene associated with this disease (MEFV), genetic analysis of its mutations has become available, providing a new tool for the establishment or confirmation of the diagnosis of FMF. OBJECTIVES: We analyzed the results of molecular testing for MEFV mutations in 600 individuals. We wished to determine how many of them bore mutations and what percentage had clinically active FMF. We also compared the rate of genetic confirmation of the FMF diagnosis in referrals with suspected FMF seen by general practitioners with that of persons sent for genetic analysis by FMF experts. METHODS: Of 600 individuals tested for FMF mutations, we analyzed separately 446 unrelated persons for the combination of their mutations, epidemiological data, and clinical manifestations. The five most common mutations in the present cohort were analyzed using the amplification refractory mutation system (ARMS). RESULTS: Of the 446 subjects analyzed, 249 (55%) bore mutations: 147 of these were homozygotes or compound heterozygotes, all of whom had FMF according to clinical criteria. Of the remaining 102 heterozygotes, 72 had FMF according to clinical criteria. Two patients with none of the five mutations also had FMF: North African Jews bore mainly mutations M694V and E148Q. The M6941 mutation was found exclusively in Palestinian Arabs. The rate of confirmation of FMF diagnosis by mutation analysis in subjects sent by FMF experts was significantly higher than that of persons referred by general practitioners. Analysis of the molecular testing of the multicase families (154 individuals) revealed that 141 of them bore MEFV mutations and that 4 persons homozygous for E148Q were asymptomatic. CONCLUSIONS: Molecular analysis of FMF mutations confirmed the diagnosis in about 60% of the referrals with suspected FMF. Some (33%) of the patients were heterozygotes, and there were also FMF patients with none of the 5 mutations analyzed. A second opinion by an FMF expert may decrease the need for mutation analysis in subjects suspected of having FMF.

Africa, Northern↗

PubMed2002

When is molecular genetic testing for colorectal cancer indicated?

The genetic mutations causing many of the syndromes which confer a high inherited risk of colorectal cancer have now been identified. These include familial adenomatous polyposis, hereditary non-polyposis colorectal cancer, Peutz-Jeghers syndrome, Cowden's syndrome and juvenile polyposis. In all these diseases, the precise mutation is nearly always unique to a particular family; there are few mutation hot spots. This means that mutation detection is technically demanding. Nonetheless, genetic testing can now be used clinically to confirm the diagnosis in affected individuals, and to predict whether an "at risk" family member has inherited the disease and should therefore have endoscopic screening. Because current technology does not detect all mutations, a negative result in a definitely affected individual is diagnostically unhelpful and does not allow predictive testing of other family members. When a mutation can be detected, it is diagnostically very useful, and allows better management of all family members.

Adenomatous Polyposis Coli↗

PubMed2002

A viral sampling design for testing the molecular clock and for estimating evolutionary rates and divergence times.

MOTIVATION: The high pace of viral sequence change means that variation in the times at which sequences are sampled can have a profound effect both on the ability to detect trends over time in evolutionary rates and on the power to reject the Molecular Clock Hypothesis (MCH). Trends in viral evolutionary rates are of particular interest because their detection may allow connections to be established between a patient's treatment or condition and the process of evolution. Variation in sequence isolation times also impacts the uncertainty associated with estimates of divergence times and evolutionary rates. Variation in isolation times can be intentionally adjusted to increase the power of hypothesis tests and to reduce the uncertainty of evolutionary parameter estimates, but this fact has received little previous attention. RESULTS: We provide approximations for the power to reject the MCH when the alternative is that rates change in a linear fashion over time and when the alternative is that rates differ randomly among branches. In addition, we approximate the standard deviation of estimated evolutionary rates and divergence times. We illustrate how these approximations can be exploited to determine which viral sample to sequence when samples representing different dates are available.

Computational Biology↗

PubMed1999

Friedreich's ataxia: clinical aspects and pathogenesis.

Friedreich's ataxia is the most frequent inherited ataxia in Caucasians. It is caused by deficiency of frataxin, a highly conserved nuclear-encoded protein localized in mitochondria. The DNA abnormality found in 98% of Friedreich's ataxia chromosomes is the unstable hyperexpansion of a GAA triplet repeat in the first intron of the frataxin gene. Most patients are homozygous for this repeat expansion. The expanded GAA repeat causes frataxin deficiency because it interferes with the transcription of the gene by adopting a non-B (probably triple helical) structure. Longer repeats cause a more profound frataxin deficiency and are associated with earlier onset and increased severity of the disease. Molecular testing has shown that the phenotypic spectrum of Friedreich's ataxia is wider than previously thought. Up to 10% of patients with recessive or sporadic degenerative ataxia who do not fulfill the Friedreich's ataxia diagnostic criteria are homozygous for expanded alleles at the Friedreich's ataxia locus. Late age of onset, retained tendon reflexes, and lack of pyramidal signs are among the atypical features observed in some patients with a positive molecular test. Yeast cells deficient in the frataxin homologue accumulate iron in mitochondria and show increased sensitivity to oxidative stress. This suggests that Friedreich's ataxia is caused by mitochondrial dysfunction and free radical toxicity, with consequent mitochondrial damage, axonal degeneration, and cell death.

Adaptor Proteins, Signal Transducing↗

PubMed2002

[Renal tumors in adults: rare tumors and new tumor entities].

International agreement was reached on the histologic classification of renal epithelial neoplasms during the last years. This classification defines malignant neoplasms as clear-cell (conventional) renal carcinoma, papillary renal carcinoma, chromophobe renal carcinoma, collecting duct carcinoma and renal cell carcinoma, unclassified. Benign neoplasms are papillary adenoma, renal oncocytoma and metanephric nephroadenoma/adenofibroma. Over the past few years, new or rare distinctive kidney tumors have been described. The aim of this review is to present examples of recently recognized clinicopathologic tumor entites and to discuss the value of immunohistochemical and molecular tests for the differential diagnosis. The following tumors will be described: mixed epithelial/stromal renal tumors, primary renal synovial sarcomas, primary renal primitive neuroectodermal tumors, low grade myxoid renal epithelial neoplasms with distal nephron differentiation and epitheloid angiomyolipoma. Detection of SYT-SSX gene fusion transcripts resulting from the t(X;18) and the EWS-FLI-1 gene fusion are described as molecular tests for the diagnosis of renal synovial sarcomas and renal primitive neuroectodermal tumors. Immunohistochemical expression of hormone receptor is helpful to diagnose mixed epithelial/stromal renal tumors. It is important to distinguish these tumor entities from adult Wilms' tumors and sarcomatoid renal cell carcinomas because of a different biological behaviour and different therapeutical approaches.

Adult↗

PubMed2006

Serologic and molecular genetic management of a pregnancy complicated by anti-Rh18.

Antibodies, such as anti-Rh18 (Hr/Hr(S)), that react with the common products of RHCE can cause HDN as well as severe hemolytic transfusion reactions. Individuals with anti-Rh18 antibodies can have different RHCE genetic backgrounds; therefore, sera and RBCs from these individuals may cross-react. In these situations, genotyping may be the best method to determine compatibility. We report a 26-year-old pregnant Puerto Rican woman who presented at 31 weeks' gestation with anti-E and anti-Rh18 in her serum. No potential donors were identified among family members or within the American Rare Donor Program; therefore, a unit of the patient's RBCs was collected one week before her planned caesarian section. To improve our ability to supply blood for this patient in the future, molecular testing was performed. The patient was found to be homozygous for an RH haplotype in which a variant RHD*DAR, is linked to a variant RHCE*ceAR. The DAR-ceAR haplotype has been described in Dutch-African populations, but this is the first report of an individual self-identified of Hispanic ethnicity. This case report demonstrates the clinical importance of molecular testing of patients with rare Rh phenotypes.

ABO Blood-Group System↗

PubMed2006

The potential impact of enhanced diagnostic techniques for tuberculosis driven by HIV: a mathematical model.

OBJECTIVE: To explore the potential impact of enhanced tuberculosis (TB) diagnostic techniques as a TB control strategy in an adult population with high HIV prevalence. DESIGN: A compartmental difference-equation model of TB/HIV was developed using parameter estimates from the literature. METHODS: The impact of five TB control interventions (rapid molecular testing, mycobacterial culture, community-wide and HIV-targeted active case finding, and highly active antiretroviral therapy) on TB incidence, prevalence, and mortality was modeled in a steady-state population with an HIV prevalence of 17% and annual TB incidence of 409 per 100 000. Sensitivity analyses assessed the influence of each model parameter on the interventions' mortality impact. RESULTS: Enhanced diagnostic techniques (rapid molecular testing or culture) are each projected to reduce TB prevalence and mortality by 20% or more, an impact similar to that of active case-finding in 33% of the general community and greater than the effect achievable by case-finding or antiretroviral treatment efforts in HIV-positive patients alone. The projected impact of enhanced diagnostics on TB incidence (< 10% reduction) is smaller. The impact of TB diagnostics is sensitive to the quality of existing diagnostic standards and the level of access to diagnostic services, but is robust across a wide range of population parameters including HIV and TB incidence. CONCLUSIONS: Enhanced TB diagnostic techniques may have substantial impact on TB morbidity and mortality in HIV-endemic regions. As TB rates continue to increase in these areas, enhanced diagnostic techniques merit further consideration as TB control strategies.

AIDS-Related Opportunistic Infections↗

PubMed2006

A review of current and future molecular diagnostic tests for use in the microbiology laboratory.

Nucleic acid-based diagnostics gradually are replacing or complementing culture-based, biochemical, and immunological assays in routine microbiology laboratories. Similar to conventional tests, the first-generation deoxyribonucleic acid assays determined only a single analyte. Recent improvements in detection technologies have paved the way for the development of multiparameter assays using macroarrays or micro-arrays, while the introduction of closed-tube real-time polymerase chain reaction systems has resulted in the development of rapid microbial diagnostics with a reduced contamination risk. The use of these new molecular technologies is not restricted to detection and identification of microbial pathogens but also can be used for genotyping, allowing one to determine antibiotic resistance or to perform microbial fingerprinting.

Bacteria↗

PubMed1995

Molecular diagnostic tests for ascertainment of genotype at the rod cone dysplasia 1 (rcd1) locus in Irish setters.

Rod-cone dysplasia type 1 (rcd1) is one of several canine photoreceptor degenerations, collectively termed progressive retinal atrophy (PRA), that afflict different breeds of dogs. The rcd1 phenotype is an early onset autosomal recessive disease caused by a nonsense amber mutation, at codon 807, in the canine gene for the beta-subunit of rod cyclic GMP phosphodiesterase (canine PDEB). The mutation involves a G to A transition at nucleotide position 2420, which presumably would cause premature termination of the canine PDEB protein by 49 amino acid residues. In both a small pedigree study of Irish setters from the United Kingdom and in larger canine pedigree studies in the United States, this gene defect has been found to be the only mutation causing rcd1. Here we report development of a diagnostic test which unequivocally distinguishes the three genotypes at the rcd1 locus: rcd1/rcd1 (homozygous mutant, affected); rcd1/+ (heterozygous, carrier); and +/+ (homozygous normal, wildtype).

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed1999

Achondroplasia-hypochondroplasia complex in a newborn infant.

We describe the case of an 8-month-old girl with achondroplasia-hypochondroplasia complex. The diagnosis was suggested antenatally when obstetrical ultrasonography at 27 weeks of gestation showed short limbs, small chest, and macrocephaly. The father has achondroplasia due to the common G1138A (G380R) mutation in the fibroblast growth factor receptor 3 (FGFR3) gene, while the mother has hypochondroplasia due to the C1620G (N450K) mutation in the FGFR3 gene. Neither had had genetic counseling or molecular testing prior to the pregnancy. Antenatal ultrasound study at 29 weeks of gestation showed a large head, very short limbs, and a small chest; the findings were more severe than in achondroplasia or hypochondroplasia alone. The patient was born by cesarean section at 37 weeks of gestation and had rhizomelic shortness of limbs with excess skin creases, large head, and small chest, diagnostic of achondroplasia. Radiographs showed shortness of the long bones and flaring of the metaphyses. She had mild hypoplasia of lungs. Molecular testing showed both the G1138A and the C1620G mutations in FGFR3, confirming the diagnosis of achondroplasia-hypochondroplasia complex. At 8 months, she has disproportionate shortness of the long bones and a large head with frontal bossing and a depressed nasal bridge. Her chest remains small, and she is on home oxygen at times of respiratory stress. She has a large gibbus. She is delayed in her motor development and has significant head lag. To our knowledge, there is only one previously published report of achondroplasia-hypochondroplasia complex.

Abnormalities, Multiple↗

PubMed2026

Deep learning techniques in predicting BRAF mutation status in cutaneous melanoma from histopathologic images.

AIMS: To develop and validate a deep learning framework for discriminating BRAF mutation status in cutaneous melanoma from routine H&E whole-slide images (WSIs) as a proof-of-concept complementary approach alongside molecular testing. METHODS: We built a two-stage pipeline comprising U-Net-based tumour segmentation followed by an Inception v3 classifier. In total, 272 institutional melanoma cases with confirmed BRAF status were used for model development (training and internal validation). Generalisability was assessed in an external test set of 76 cutaneous melanoma cases from the Cancer Genome Atlas (TCGA). Dermatopathologist-defined tumour-rich regions of interest were used to train and evaluate segmentation. WSIs were processed at 20×magnification using 512×512 tiles; slide-level mutation probabilities were obtained by averaging the predicted probabilities across all tumour-enriched tiles. RESULTS: Inception v3 achieved area under the receiver operating characteristic curve values of 0.973 (training), 0.954 (validation) and 0.915 (TCGA testing) and outperformed a ResNet50 baseline, showing stable external generalisation. Performance remained robust in advanced pathological T-category primary tumours (pT3-T4). Tumour probability heatmaps supported spatial interpretability by localising regions contributing most strongly to predicted mutation status. CONCLUSIONS: Deep learning applied to routine H&E WSIs can infer BRAF mutation status in cutaneous melanoma with consistent performance across institutional and external cohorts. Given the observed external sensitivity and negative predictive value, the model is not suitable for rule-out use or for deferring/omitting molecular testing. Any workflow integration is future work and would require prospective validation and calibration of probability outputs in real-world clinical series.

Artificial Intelligence↗

PubMed2000

Molecular genetic testing for familial hypercholesterolemia: spectrum of LDL receptor gene mutations in The Netherlands.

Mutations in the LDL receptor are responsible for familial hypercholesterolemia (FH). At present, more than 600 mutations of the LDL receptor gene are known to underlie FH. However, the array of mutations varies considerably in different populations. Therefore, the delineation of essentially all LDL receptor gene mutations in a population represents a prerequisite for the implementation of nation-wide genetic testing for FH. In this study, the frequency and geographical distribution of 13 known mutations were evaluated in a cohort of 1223 FH patients. We identified 358 mutation carriers, representing 29% of the FH cohort. Four mutations (N543H-2393de19, 1359--1G-->A, 313 + 1 G-->A and W23X) occurred with a relatively high frequency, accounting for 22.4% of the entire study cohort. Two of these common FH mutations (N543H-2393de19 and 1359 - 1G-->A) showed a preferential geographic distribution. Second, to further expand the array of LDL receptor gene mutations, we conducted mutation analysis by denaturing gradient gel electrophoresis (DGGE) in 141 children with definite FH. A mutation was identified in 111 patients, involving 16 new single base substitutions and four small deletions and insertions, which brings the number of different FH-causing mutations in our country up to 61. Our data indicate that an estimate of the prevalence of specific mutations, as well as the compilation of a database of all FH-causing mutations in a given country, can facilitate selection of the most appropriate molecular diagnostic approach.

Child↗