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PubMed2003

A new approach to antenatal screening for Fragile X syndrome.

OBJECTIVES: To describe a new approach to antenatal screening for Fragile X syndrome and to evaluate its effectiveness. METHODS: We propose that Fragile X syndrome should be considered as a different disorder in males and in females. We also propose that only male Fragile X syndrome should be screened for, so the initial screening test would be the determination of fetal sex. This can now be performed from eight-weeks gestation using a polymerase chain reaction (PCR) analysis on maternal serum. If this test reveals a male fetus, then the same blood sample can be used to determine the CGG repeat length in the DNA of the mother, again using the PCR technique and a Southern blot analysis where necessary. Mothers with positive results (>58 repeats) would be offered antenatal diagnosis (chorionic villus sampling or amniocentesis) to determine the CGG repeat length in cells from the fetus. The screening performance of this strategy was determined using the performance of the component tests. RESULTS: The proposed strategy for screening for male Fragile X syndrome would have a 99% detection rate and a 0.1% false-positive rate. CONCLUSION: After antenatal screening for Down syndrome, the proposed screening strategy would be the most effective method of preventing the birth of males with severe mental retardation. It would have a higher detection rate and a lower false-positive rate than any other antenatal screening programme currently being undertaken, and there would be virtually no prenatal diagnosis of female Fragile X syndrome, which, because such a high proportion are phenotypically normal, has been a barrier to the introduction of screening.

Adult↗

PubMed1987

Neonatal hydronephrosis in the era of sonography.

During a 6-year period (1979-1985), 142 neonates with significant hydronephrosis were seen. Seventy-eight percent of the cases were discovered on fetal screening during obstetric sonography. Maternal/fetal intervention was virtually never indicated and most babies were asymptomatic. The most common conditions found were obstruction of the ureteropelvic junction (41%), obstruction of the distal ureter (usually primary megaureter) (23%), upper-pole hydronephrosis associated with duplex anomalies (13%), and posterior urethral valves (10%). Seventeen neonates with multicystic dysplastic kidney were seen (three per year or one for every eight with hydronephrosis). In comparison, during the 30-year period, 1947-1977, 146 neonates with significant hydronephrosis were seen. Most cases were discovered because the patients had signs and/or symptoms--either an abdominal mass (an enlarged kidney or bladder) or urosepsis. The three most common conditions were obstruction of the ureteropelvic junction (22%), posterior urethral valves (19%), and ectopic ureterocele (14%). During this period, 53 neonates with multicystic dysplastic kidney were discovered (two per year or one for every three with hydronephrosis). The dramatic increase in the number of neonates found to have hydronephrosis is primarily due to the widespread use of obstetric sonography and concomitant fetal screening. The pattern of causes before 1979 represented the incidence of symptomatic lesions. The current pattern more accurately reflects the true incidence of congenital anomalies of the urinary tract.

Humans↗

PubMed2004

A novel and conserved pocket of human kappa-Fab fragments: design, synthesis, and verification of directed affinity ligands.

Antibodies of type IgG may be divided into two classes, called lambda or kappa, depending on the type of light chain. We have identified a conserved pocket between the two domains CH1 and CL of human IgG kappa-Fab, which is not present in the lambda type. This pocket was used as a target docking site with the purpose of exploring the possibilities of designing affinity ligands that could function as such even after immobilization to gel. The idea of the design arose mainly from the results of the saturated transfer difference (STD-NMR) screening of 46 compounds identified by means of virtual docking of 60 K diverse compounds from the Available Chemicals Directory (ACD). Surface plasmon resonance (SPR) was used as an alternative method to monitor binding in solution. A total of 24 compounds belonging to a directed library were designed, synthesized, and screened in solution. They consist essentially of an amino acid condensed to a N,N'-methylated phenyl urea. STD-NMR results suggest that a small hydrophobic side chain in the condensed amino acid promotes binding, whereas a hydroxyl-group-containing side chain implies absence of STD-NMR signals. Three compounds of the directed library were immobilized and evaluated as chromatographic probes. In one case, using D-Pro as the condensed amino acid, columns packed with ligand-coupled Sepharose (Amersham Biosciences) retained two different monoclonal samples of kappa-Fab fragments with different variable regions, whereas a sample of monoclonal lambda-Fab fragments was not retained under similar chromatographic conditions.

Antibodies, Monoclonal↗

PubMed2007

Hereditary hemochromatosis screening: effect of mutation penetrance and prevalence on cost-effectiveness of testing algorithms.

Screening for hereditary hemochromatosis, although largely discussed, is not yet implemented in clinical practice. We evaluated the cost-effectiveness of 165 hemochromatosis population-screening algorithms involving two or three of several screening tests by developing a computer program that simulates all possible screening scenarios. Input data comprised government estimates of health services data and costs and a virtual population with user-defined demographic characteristics (including variable HFE mutation frequencies and penetrance values). We show that when C282Y homozygote prevalence is set at 3:1000, population screening appears cost-effective when penetrance of the biochemical phenotype is >0.70. When only hepatocellular carcinoma and cirrhosis are considered as the cost-driving complications, population-based screening is not significantly more cost-efficient than no screening, but life expectancy of individuals identified with hereditary hemochromatosis and treated is still improved by 7 years. Among the 165 screening algorithms tested in 91 different virtual populations of one million individuals, biochemical tests usually perform better as the initial test than genetic testing. Indeed, the genetic testing is most cost-effective as the final confirmatory test. Finally, for most combinations of prevalence and penetrance of HFE, one screening algorithm--unbound iron-binding capacity + transferrin saturation--appeared robust enough to be always within the top 5 most cost-effective strategies.

Algorithms↗

PubMedDate not supplied

A systematic review and lessons learned from early lung cancer detection trials using low-dose computed tomography of the chest.

BACKGROUND: Computed tomography (CT) screening of the chest has shown promise for early detection of lung cancer, but evidence for a reduction in lung cancer mortality by CT screening is not available. METHODS: We reviewed 208 articles to synthesize available evidence for efficacy of CT screening in detecting potentially curative stages of lung cancer and for evidence in reducing lung cancer mortality. Other outcomes of interest included detection rate of cancer and of suspicious lesions, histology and stage of cancer at detection, screening-related morbidity, and the identification of populations uniquely suited for CT screening. We identified eight papers that reported the outcomes for CT of the chest in lung cancer screening. RESULTS: Since none of the studies utilized a control group, quantitative pooling was not done. In two studies, both CT and chest radiography (CXR) were used as screening tools in the same cohorts. A total of 19,107 subjects were screened using CT. The detected prevalence rate for lung cancer ranged from 0.40% to 13.6% and was a function of the subjects' age and smoking history. CT screening resulted in a 3-fold higher detection rate and a 5-fold increase in the rate of resectable cancers compared to CXR. Data on lung cancer and overall mortality and screening-related morbidity and mortality were incomplete. CT screening resulted in selective detection of adenocarcinomas with an approximately 2- to 3-fold oversampling of this histologic subtype. The positive predictive value of CT screening was highest for subjects in the 8th decade of life, and it was virtually nil for those in their 5th decade. CONCLUSIONS: Evidence regarding lung cancer screening by CT shows that this technology detects earlier-stage and smaller lung cancers with greater frequency than other screening methods. To date, no trials have demonstrated that CT screening leads to a reduction in lung cancer mortality. Until mortality trials are completed, low-dose CT screening should be considered an investigative tool rather than the standard of care.

Humans↗

PubMed2006

4SCan/vADME: intelligent library screening as a shortcut from hits to lead compounds.

Managing to solve the first step in drug discovery - the hit finding - can be a quite elaborate task, but it is only the initial step to the final goal; hit-to-lead optimisation still lies ahead and consumes even more time and resources. The solution is rather simple, that is, to take only the most promising compounds into account; but who is going to decide which ones are the most promising among a list of tens of millions of compounds in a virtual combinatorial library? 4SCan/vADME helps by bridging the gap between virtual (combinatorial) libraries designed by chemists and the in silico methods, docking and alignment, for screening databases. After choosing a random starting set, the implemented learning and prediction algorithm iteratively considers only combinations of fragments that have shown to result in more suitable interactions by the chosen method. ADME properties of the final list are then calculated via several in silico methods, resulting in a combined evaluation of the individual compound's target-specific, as well as ADME, properties. Based on the latter list of evaluated compounds, medicinal chemists can then decide which compounds might be the best ones to synthesise first and to serve as possible lead candidates. Following a brief introduction to virtual high-throughput screening techniques, the 4SCan/vADME method is outlined and discussed in this paper, using an example coming out of the 4SC pipeline.

Aryl Hydrocarbon Hydroxylases↗

PubMed2001

Intraoperative accuracy evaluation of virtual fluoroscopy--a method for application in computer-assisted distal locking.

Virtual fluoroscopy integrates intraoperative C-arm fluoroscopy as an imaging modality for surgical navigation. In the operating room, the conditions for application of virtual fluoroscopy may be impaired. In such situations, the surgeon is interested in an intraoperative check to decide whether the accuracy available is sufficient to perform the scheduled procedure. The test principle is to include an artificial landmark within the fluoroscopic images acquired for virtual fluoroscopy. As this landmark is fixed outside the patient, it can be touched with the referenced tool prior to performing the procedure. A mismatch between the actual tool position at the landmark and the virtual tool position as visualized on the computer screen allows estimation of the system's accuracy. The principle described was designed for detection of inaccuracies resulting from input of nonoptimal data to the navigation system. The method was successfully applied during computer-assisted distal locking of intramedullary implants, and the test principle might be adapted for other applications of virtual fluoroscopy.

Fluoroscopy↗

PubMed1997

Computed tomographic colography and virtual colonoscopy.

CT colography (CTC) is a powerful new approach to imaging the colorectum and a promising screening tool for the detection of colorectal neoplasia. From data generated by a helical CT scan, CTC uses virtual reality technology to produce highly discriminant two- and three-dimensional images that permit a thorough and minimally invasive evaluation of the entire colorectum. A dynamic CTC display technique from the endoluminal perspective, called cf2virtual colonoscopy,cf1 simulates colonoscopy by "flying" through the three-dimensional colon image. CTC offers potential advantages in diagnostic performance, safety, and patient acceptance over current screening approaches. Although early data suggest excellent colorectal polyp detection rates, this nascent technology will require rigorous clinical investigation and further refinements to assess adequately its place in the endoscopist's armamentarium.

Barium Sulfate↗

PubMed2006

Screening for postpartum depression in military women with the Postpartum Depression Screening Scale.

Each year, approximately 16,000 women on active duty in the U.S. military experience the birth of a child. A descriptive, longitudinal, prospective design was used to gather data with the Postpartum Depression Screening Scale. Depression was measured after delivery but before hospital discharge (time 1), 2 weeks after delivery (time 2), and 6 to 8 weeks after delivery (time 3). Mothers were found to be experiencing the greatest severity of symptoms in the category of sleeping and eating disturbances. Almost one-half of the mothers in this study scored either significant postpartum depressive symptoms or positive screening for postpartum depression after delivery. This number remained virtually unchanged at time 2. By time 3, 40% of women still reported depressive symptoms. At 2 weeks and 6 weeks after delivery, 13% and 11% of mothers, respectively, had positive screening for postpartum depression, consistent with the national average of 10 to 15%. Future research is needed to examine issues surrounding postpartum depression of military women.

Adolescent↗

PubMed1984

Transfection and cloning of genes for membrane antigens using the FACS.

In order to facilitate cloning of genes for cell surface molecules, we cotransfected LTK- mouse fibroblasts with thymidine kinase (TK) genes and total human or mouse DNA. TK+ cells, selected by growth in HAT medium, were stained with fluorochrome conjugated monoclonal antibodies or other fluorescent ligands which bind to one or another membrane differentiation antigen or receptor. We isolated fluorescent transfectants expressing these molecules using a fluorescence activated cell sorter (FACS). For some antigens, spontaneous gene amplification occurred. By repeated cycles of FACS sorting and regrowth we obtained high expressing clones. We then isolated cDNA and genomic clones using selected cDNA probes to screen phage with cDNA inserts. DNA from virtually any tissue source transfected equally well for the various molecules except for DNA from a trophoblast derived choriocarcinoma cell line which did not transfect for Leu-2.

Animals↗

PubMed2002

Nonsense-mediated RNA decay in the TSC1 gene suggests a useful tool pre- and post-positional cloning.

Many mRNAs carrying mutations that are predicted to encode a truncated protein are subject to a mechanism known as nonsense-mediated mRNA decay (NMD), which results in reduced levels of mutant transcript. Tuberous sclerosis (TSC), an autosomal dominant neurocutaneous disorder with mutations in either of two genes, TSC1 or TSC2, requires comprehensive screening of both genes for molecular diagnosis. Virtually all TSC1 mutations are predicted to truncate the protein product. Coding and newly identified 3' untranslated region polymorphisms in TSC1 were used to develop a transcript imbalance assay to investigate TSC1 transcript levels in patients. This approach allowed the correct identification of six out of seven TSC1 patients tested blind from a panel of TSC1 and TSC2 patients, with no false positives. The extent of NMD in TSC1 was found to correlate with each individual mutation regardless of intra-familial variation in clinical features and with no strong evidence for positional bias. NMD in TSC1 was more pronounced in cultured cells than in RNA prepared directly from peripheral lymphocytes (in which novel splicing of exon 5 was observed). The advent of a dense SNP map of transcribed regions of the genome may allow a similar transcript imbalance assay in the assessment of candidate genes for diseases whose causes are still unknown.

3' Untranslated Regions↗

PubMed2005

VolSurf analysis of pharmacokinetic properties for several antifungal sesquiterpene lactones isolated from Greek Centaurea sp.

Sesquiterpene lactones are terpenoid compounds characteristic of the Asteraceae (Compositae) possessing a variety of biological activities, such as cytotoxic, antitumor, antibacterial, and antifungal. The prediction of the pharmacokinetic profile of several antifungal sesquiterpene lactones, isolated from Greek taxa of Centaurea sp., was undertaken in this study using the VolSurf procedure. The molecules were projected on the following pre-calculated ADME models: Caco-2 cell permeability, plasma protein affinity, blood-brain barrier permeation and thermodynamic solubility. The in silico projection revealed a non optimal pharmacokinetic profile for the studied compounds. ADME in silico screening of a semi-synthetic derivatives virtual library has been performed in order to optimize the pharmacokinetic properties. A number of derivatives were proposed as it was predicted to have higher Caco-2 cell permeability, while the pharmacokinetic behaviour regarding BBB penetration, protein binding and solubility was mainly preserved.

Antifungal Agents↗

PubMed1995

Catalytic subunits of the porcine and rat 5'-AMP-activated protein kinase are members of the SNF1 protein kinase family.

The 5'-AMP-activated protein kinase (AMPK) regulates the fatty acid and sterol synthesizing pathways via phosphorylation of acetyl-CoA carboxylase and HMG-CoA reductase, respectively. Highly purified kinase from porcine liver contains three apparent subunits of molecular mass 63 kDa, 40 kDa and 38 kDa. Peptide sequencing of the 63 kDa protein (AMPK63cat) revealed that this polypeptide is the catalytic subunit of the kinase. Porcine peptide sequences were used to clone by RT-PCR partial length cDNAs for the catalytic domains of the porcine AMPK63cat, and its rat homolog, which were virtually identical in deduced amino acid sequence. Screening of a rat liver cDNA library with these partial length cDNAs and with degenerate oligonucleotides yielded several unique clones, some of which had a 142 bp deletion in the catalytic domain of the kinase. A consensus full-length sequence with a 1.7 kb open reading frame has been constructed from overlapping library and PCR-derived clones. A large mRNA for rat AMPK63cat (8.5 kb) is expressed in nearly all rat tissues, with highest levels detectable in heart and skeletal muscle. Using PCR, the presence of two mRNA species with or without the 142 bp deletion in the catalytic domain was noted in all rat tissues examined. Comparison of the deduced protein sequence of AMPK63cat reveals highly conserved homologies in both the catalytic and non-catalytic domains to several members of the SNF1 kinase family, including kinases from Arabidopsis, barley, rye, and S. cerevesiae, as well as to other mammalian kinases and to a C. elegans kinase. The high evolutionary conservation of both kinase structure and function (metabolite sensing) coupled with their pattern of tissue/organism expression suggest that the mammalian members of this kinase family likely play wider roles than the regulation of cellular lipid metabolism.

AMP-Activated Protein Kinases↗

PubMed2006

Synthesis of bicyclic molecular scaffolds (BTAa): an investigation towards new selective MMP-12 inhibitors.

Starting from 3-aza-6,8-dioxa-bicyclo[3.2.1]octane scaffold (BTAa) a virtual library of molecules was generated and screened in silico against the crystal structure of the Human Macrophage Metalloelastase (MMP-12). The molecules obtaining high score were synthesized and the affinity for the catalytic domain of MMP-12 was experimentally proved by NMR experiments. A BTAa scaffold 20 having a N-hydroxyurea group in position 3 and a p-phenylbenzylcarboxy amide in position 7 showed a fair inhibition potency (IC50 = 149 microM) for MMP-12 and some selectivity towards five different MMPs. These results, taken together with the X-ray structure of the adduct between MMP-12, the inhibitor 20 and the acetohydroxamic acid (AHA), suggest that bicyclic scaffold derivatives may be exploited for the design of new selective matrix metalloproteinase inhibitors (MMPIs).

Bridged Bicyclo Compounds, Heterocyclic↗

PubMed2005

State-of-the-art computed tomographic and magnetic resonance imaging of the gastrointestinal system.

Among the major innovations in radiology of the gastrointestinal (GI) system are the replacement of classic invasive diagnostic methods with noninvasive ones and the improvement in lesion characterization and staging of pancreatobiliary malignancies. Developments in imaging technology have led to many improvements in the field of diagnostic GI radiology. With its fast and thin-section scanning abilities, multidetector-row CT (MDCT) strengthens the place of CT as the most efficient tool to diagnose, characterize, and preoperatively stage pancreatic neoplasms. MR cholangiopancreatography has widely replaced endoscopic retrograde cholangiopancreatography in the diagnosis and staging of pancreatobiliary malignancies. MR imaging, using phased-array or endorectal coils, demonstrates local tumor invasion accurately in rectal cancers and thus allows an improved surgical planning. Virtual colonoscopy with MDCTs is an efficient screening method for colon cancer, and MDCT enterography is becoming the standard imaging technique for many small bowel disorders. The continuing developments in CT and MR technology will most probably further improve the accuracy of these and other imaging applications in the near future.

Gastrointestinal Diseases↗

PubMed2002

Hepatitis C in childhood.

The approach of a pediatric hepatologist in managing children with hepatitis C virus (HCV) differs from adult practice, because the pediatric hepatologist is dealing with the beginning of a chronic illness in which long-term outcomes will not occur for 20 or 40 years, and it is not possible to predict in the early stages of the infection which patients have a more sinister prognosis. The prevalence of chronic HCV in children is low, but varies between different countries in the Asia-Pacific region. In most countries, screening of blood products for HCV has virtually eliminated the risk of post-transfusion HCV, so that in Australia children aged less than 11 years will not have acquired HCV from blood transfusion or extracorporeal membrane oxygenation. The risk of perinatal transmission of this virus is only about 6%, but this remains virtually the only source of HCV transmission for children in most countries. While available data are limited, mild histological changes are present in the majority of children with hepatitis C, and cirrhosis is rare. Unfortunately, long-term natural history studies of the course of HCV infection in children have not been reported. Individual decisions on antiviral treatment are more difficult in childhood, not because the treatment is any less effective or because of the severity of side-effects (which tend to be less severe than for adults), but because the long-term outcome of infection is unclear. At present, treatment should be confined to those with significant hepatic fibrosis and continued moderate to severe necroinflammatory change. Measures to prevent HCV infection in childhood center on whether, as recently suggested, elective cesarean section may reduce the risk of transmission. Despite the presence of HCV-RNA in some breast milk samples, there is no evidence that breast-feeding confers any risk of HCV infection.

Antiviral Agents↗

PubMed2001

Sexually transmitted diseases in travelers.

Prevention of sexually transmitted diseases (STDs) is a low priority among travel clinic services, despite increasing evidence that travelers have an increased risk of acquiring such infections. A proportion of 5%-50% of short-term travelers engage in casual sex while abroad, and this rate is even higher among long-term travelers. Few publications are available on STD preventive interventions among travelers. Education and counseling are recognized as key components of risk reduction. New efforts should be put forth with regard to identifying effective tools to promote safer sexual behaviors and to reduce the spread of infection by promoting condom use. Travelers at increased risk should be identified for targeted interventions; research to validate proposed markers of increased risk is prospectively needed. Hepatitis B infection is the only STD that is preventable by vaccination. The feasibility and cost-effectiveness of STD screening in travelers after exposure is a virtually unexplored field, though it may represent an important component of STD control strategies in developed countries.

Biomarkers↗

PubMed2002

Colonoscopy curriculum development and performance-based assessment criteria on a computer-based endoscopy simulator.

OBJECTIVE: Computer-based colonoscopy simulators (CBCS) have been developed and are being introduced into the training environment. The ability of these simulators to replicate the dimensions of patient-based diagnostic colonoscopy is good. However, the benefit of simulators to either learners or their patients has not yet been established. We describe a process by which a CBCS curriculum and CBCS-based performance criteria were established for first-year gastroenterology fellows at the Mayo Clinic in Rochester, Minnesota. DESCRIPTION: We used a commercially available CBCS (AccuTouch Endoscopy Simulator, Immersion Medical, Gaithersburg, MD), which consists of a specialized colonoscope that is inserted into a computer-based module with a screen showing the colonic lumen of a virtual patient. A tutorial and six cases of varying complexity are available on the CBCS. Performance variables that are measured by the simulator include the time to complete the procedure, the distance that the scope was advanced, the degree to which the mucosa was adequately visualized, the possible complications such as colonic perforation, and the level of pain experienced by the simulated patient. To begin, we established ideal performance standards by measuring the above variables for ten "expert" faculty colonscopists who completed two cases on the CBCS. Next, we measured CBCS performance standards for five partially trained colonoscopists. Finally, two non-physician gastrointestinal assistants, without prior endoscopic training, were asked to practice on the simulator to determine the time and procedure frequency required to improve their CBCS proficiency. By calculating average performance standards within each of these three groups, we were able to estimate the number of CBCS cases and minimal performance standards for new trainees. Based on the learning curves for novice colonoscopists as well as the performances of partially trained and expert colonoscopists, we speculated that if CBCS training were to be beneficial, the benefit would most likely occur at the early stages of training. The curriculum we developed consists of viewing a one-hour, multimedia tutorial, which describes the procedure and various colonoscopy techniques. This is followed by nine hours of hands-on CBCS experience, during which time the trainee will complete approximately 25 CBCS colonoscopies. Before advancing to live-patient colonoscopies, the trainee must meet certain performance standards on specific CBCS cases. These standards include the ability to view the entire colon in less than 15 minutes with minimal pain and no complications. DISCUSSION: If effective, this new colonoscopy training curriculum should result in improved competency at patient-based colonoscopy, particularly in the early stages of training. To address this question, first-year gastroenterology fellows at Mayo Clinic have been randomized into two groups: (1) a group that experiences a tutorial with hands-on CBCS curriculum and (2) a group that experiences a tutorial only. Their performances at patient-based colonoscopy as well as surveys of patient satisfaction will be measured and analyzed to determine what, if any, benefit is provided by CBCS.

Clinical Competence↗