Psychogenic Dystonia

Psychogenic movement disorders pose a complex problem in modern neurology, which requires an interdisciplinary approach to solve a number of questions related to classification, diagnosis, treatment, and rehabilitation. The most frequent forms of psychogenic movement disorders include tremor, dystonia, myoclonus, and gait abnormality. A clinical case of a 46-year-old male patient with a psychogenic movement disorder presenting as fixed hand dystonia not accompanied by pain is reported. The terminology issues related to the most accurate determination of this type of hyperkinesis, as well as clinical tests (standard motor-skill tasks, ballpoint pen writing) that allow one to identify the psychogenic nature of hyperkinesis, are discussed using the example provided. The clinical phenomenology of psychogenic dystonia is thoroughly analyzed, and the differential diagnostic criteria of psychogenic and primary (idiopathic) dystonia are presented.     

Laboratory diagnosis of the status of the hemostasis system

Activators of fibrinogen, prothrombin and protein C isolated from venoms of Agkistrodon halys halys and Echis multisquamatus may be used as a tool both for thrombosis investigations in the model systems and for diagnostic in the clinical practice. The complex of diagnostic tests developed on the base of these activators allows to characterize the haemostatic system at different pathologies and as well as to determine the unbalance between separate components of haemostasis. The tests are approved on plasma of patients with heart diseases, ulcers, nephrites, hestoses etc. The tests are sensitive, informative, easy to use and do not require an additional equipment. They have no analogues in Ukraine.     

The use of the potentials of the molecular hybridization of nucleic acids as a method for the laboratory diagnosis of influenza in research on vaccinal infection

The data obtained as the result of the complex examination of volunteers immunized with live influenza vaccine, type A (H3N2), showed that the determination of the RNA-containing structures by the method of the molecular hybridization of nucleic acids (MHNA) was highly sensitive and reliable. This method proved to be more sensitive than common laboratory diagnostic tests (the isolation of the virus in chick embryos, the analysis of seroconversion, the antibody fluorescence test) and was not inferior to the complex of clinical tests based on the analysis of microsymptoms. The reliability of the positive (according to the data obtained by MHNA) results was very high: not less than 85% of them were confirmed by other tests.     

Clinical Utility of Microarrays: Current Status, Existing Challenges and Future Outlook

Microarray-based clinical tests have become powerful tools in the diagnosis and treatment of diseases. In contrast to traditional DNA-based tests that largely focus on single genes associated with rare conditions, microarray-based tests are ideal for the study of diseases with underlying complex genetic causes. Several microarray based tests have been translated into clinical practice such as MammaPrint and AmpliChip CYP450. Additional cancer-related microarray-based tests are either in the process of FDA review or under active development, including Tissue of Tumor Origin and AmpliChip p53. All diagnostic microarray testing is ordered by physicians and tested by a Clinical Laboratories Improvement Amendment-certified (CLIA) reference laboratory. Recently, companies offering consumer based microarray testing have emerged. Individuals can order tests online and service providers deliver the results directly to the clients via a password-protected secure website. Navigenics, 23andMe and deCODE Genetics represent pioneering companies in this field. Although the progress of these microarray-based tests is extremely encouraging with the potential to revolutionize the recognition and treatment of common diseases, these tests are still in their infancy and face technical, clinical and marketing challenges. In this article, we review microarray-based tests which are currently approved or under review by the FDA, as well as the consumer-based testing. We also provide a summary of the challenges and strategic solutions in the development and clinical use of the microarray-based tests. Finally, we present a brief outlook for the future of microarray-based clinical applications.     

Effect of feedback on test ordering behaviour of general practitioners.

OBJECTIVE--To assess the effect of feedback on the test ordering behaviour of general practitioners. DESIGN--Comparison of requests at two diagnostic centres, and internal comparison between tests which were discussed in feedback and tests which were not. SETTING--A diagnostic centre in Maastricht giving feedback and another elsewhere in the Netherlands (laboratory A) not giving feedback. SUBJECTS--All 85 general practitioners in the region of Maastricht, and all general practitioners in the region of laboratory A. MAIN OUTCOME MEASURES--Numbers of tests requested by general practitioners. RESULTS--Requests at the Maastricht diagnostic centre decreased soon after the onset of feedback whereas there was a persistent increase in requests at laboratory A. Tests that were discussed showed the strongest decrease (maximum 40%), though tests that were not discussed decreased as well (maximum 27%). CONCLUSIONS--Feedback on diagnostic requests may exert a strong influence on request behaviour. Four years after the onset of feedback the effects were still noticeable.     

Genetics,Molecular Biology,and Phenotypes of X-Linked Epilepsy

Epilepsy is a common and diverse set of chronic neurological disorders characterized by spontaneous, unprovoked, and recurrent epileptic seizures. Environmental factors and acquired disposition are proposed to play a role to the pathogenesis of epilepsy. Genetic factors are important contributors as well. Comparing to the phenotype of epilepsy caused by mutation of single gene on an autosome, the phenotype of X-linked epilepsy is more complex. X-linked epilepsy usually manifests as part of a syndrome or epileptic encephalopathy, and the variability of clinical manifestations of X-linked epilepsy may be attributed to several factors including the type of genetic mutation, methylation, X chromosome random inactivation, and mosaic distribution. As a result, it is difficult to establish the genotype–phenotype correlation, diagnostic tests, and genetic counseling. In this review, we provide an overview of the X-linked epilepsy including responsible loci and genes, the molecular biology, the associated complex phenotypes, and the interference factors. This information may provide us a better understanding of the pathogenesis of X-linked epilepsy and may contribute to clinical diagnosis and therapy of epilepsy.     

Characterisation of protein microheterogeneity and protein complexes using on-chip immunoaffinity purification-mass spectrometry.

Post-translational modification of proteins may influence their interactions with other plasma proteins, as well as having an effect on many aspects of the metabolism of the protein, such as receptor binding, tissue uptake, degradation and excretion. Many post-translational modifications occur in a physiological context, while others are specific for certain diseases, which is why they are of diagnostic importance in clinical proteomics. Analytical approaches to the study of post-translational modifications and protein complexes through the combined use of on-chip immunological affinity purification on a surface-enhanced laser desorption/ionisation platform and subsequent mass spectrometry are illustrated in the author's own work relating to plasma transthyretin (TTR) and retinol-binding protein (RBP). In those studies, both the aspects of post-translational modifications of TTR and the formation of a protein complex between TTR and RBP have been discussed. Such aspects are of diagnostic interest in clinical proteomics, especially with regard to the modification of TTR in relation to the occurrence of amyloidotic diseases.     

Predictive markers in early research and companion diagnostic developments in oncology

Predictive biomarkers are discovered and used in oncology research to formulate hypotheses aimed at the identification of patients benefiting from specific therapeutic intervention(s). They pave the way to the development of companion diagnostic tests which are tools readily implemented in the clinic and serve to qualify a patient for treatment with a particular targeted drug or the continued use of a particular drug, thus maximizing the benefit to risk ratio of the medical intervention to the patient. Predictive biomarkers are defined by biological characteristics of the patient's or tumor status that can be measured objectively and correlated with clinical outcome: these can be molecular, cellular or biochemical features. Predictive markers need extensive analytical validation - specific for the tool utilized for their assessment - as well as rigorous clinical qualification in the context of the drug treatment for which they define clinical utility. The process of companion diagnostic development is a highly interdisciplinary and complex one, driven by key crucial milestones and accompanying the same and typical process of a whole drug discovery and development continuum, from marker discovery and validation, assay development, clinical qualification until test approval and commercialization.     

PCR-based diagnostics for anaerobic infections

Conventional methods to identify anaerobic bacteria have often relied on unique clinical findings, isolation of organisms, and laboratory identification by morphology and biochemical tests (phenotypic tests). Although these methods are still fundamental, there is an increasing move toward molecular diagnostics of anaerobes. In this review, some of the molecular approaches to anaerobic diagnostics based on the polymerase chain reaction (PCR) are discussed. This includes several technological advances in PCR-based methods for the detection, identification, and quantitation of anaerobes including real-time PCR which has been successfully used to provide rapid, quantitative data on anaerobic species on clinical samples. Since its introduction in the mid-1980s, PCR has provided many molecular diagnostic tools, some of which are discussed within this review. With the advances in micro-array technology and real-time PCR methods, the future is bright for the development of accurate, quantitative diagnostic tools that can provide information not only on individual anaerobic species but also on whole communities.     

The role of test accuracy in predicting acceptance of genetic susceptibility testing for Alzheimer's disease

A survey questionnaire regarding perceptions of risk and genetic susceptibility to Alzheimer's disease (AD) was completed by 518 offspring of AD cases from families with multiple affected, ascertained as part of a genetic linkage study of late onset AD. The questionnaire focused on respondents' perceptions of their own risk for AD as well as on the properties of real and hypothetical susceptibility tests, including error rates for false-positive and false-negative test results. Our findings showed that about 20% of the sample would refuse a susceptibility test with zero error rates, about 40% would accept tests with very high error rates in both directions, and the remainder would exercise some discrimination. Acceptance of high test error rates was significantly associated with male gender, low education, and high perceived lifetime risk of AD. In a previous paper related to this work, we showed that physicians caring for these families exercised much more discrimination in judging the acceptability of genetic tests they would offer to these same respondents. The findings show that there is a pressing need to educate the public, particularly those with relatives affected by a complex disease, to expect standards of accuracy for genetic tests comparable to those that prevail in other diagnostic and prognostic testing efforts in the broad field of clinical medicine.     

The use of rapid dengue diagnostic tests in a routine clinical setting in a dengue-endemic area of Colombia

There is insufficient evidence of the usefulness of dengue diagnostic tests under routine conditions. We sought to analyse how physicians are using dengue diagnostics to inform research and development. Subjects attending 14 health institutions in an endemic area of Colombia with either a clinical diagnosis of dengue or for whom a dengue test was ordered were included in the study. Patterns of test-use are described herein. Factors associated with the ordering of dengue diagnostic tests were identified using contingency tables, nonparametric tests and logistic regression. A total of 778 subjects were diagnosed with dengue by the treating physician, of whom 386 (49.5%) were tested for dengue. Another 491 dengue tests were ordered in subjects whose primary diagnosis was not dengue. Severe dengue classification [odds ratio (OR) 2.2; 95% confidence interval (CI) 1.1-4.5], emergency consultation (OR 1.9; 95% CI 1.4-2.5) and month of the year (OR 3.1; 95% CI 1.7-5.5) were independently associated with ordering of dengue tests. Dengue tests were used both to rule in and rule out diagnosis. The latter use is not justified by the sensitivity of current rapid dengue diagnostic tests. Ordering of dengue tests appear to depend on a combination of factors, including physician and institutional preferences, as well as other patient and epidemiological factors.     

Estimation of the Timing of Perinatal Transmission of HIV

Knowledge of the timing of perinatal transmission of HIV would be valuable for the determination and evaluation of preventive treatments and would shed light on the mechanism of transmission. Estimation of the distribution of the time of perinatal transmission is difficult, however, because tests of infection status can only be undertaken after birth. DNA and RNA polymerase chain reaction (PCR) assays and HIV culture have been the most commonly used diagnostic tests for perinatal HIV infection. Such tests have high sensitivity and specificity, except when they are given shortly after infection. In this paper we use the time-dependent sensitivity of these diagnostic tests to make nonparametric and semiparametric inferences about the distribution of the time of perinatal HIV transmission as well as the cumulative probability of perinatal transmission. The methods are illustrated with data from a clinical trial conducted by the AIDS Clinical Trials group.     

The aetiologies of the unilateral oculomotor nerve palsy: a review of the literature

Abstract

Oculomotor nerve palsy (ONP) is an important and common clinical diagnosis. Its main features are diplopia and ptosis. Its aetiologies are various and complex. A number of different conditions have been reported to cause ONP, such as diabetes mellitus, aneurysm, tumours, painful ophthalmoplegia, pituitary lesions, cavernous sinus lesions, central nervous system infections, and subarachnoid haemorrhage. A patients needs to undergo several tests in order to establish the correct underlying pathology. In this review, we have summarized the aetiologies of the unilateral ONP, and discussed their relative clinical features, pathogenesis, diagnostic criteria, treatment options, and prognosis. We searched PubMed for papers related to ONP and its aetiologies, and selected the publications, which seemed appropriate.     

Mycoplasma and herpesvirus PCR detection in tortoises with rhinitis-stomatitis complex in Spain

Chelonid herpesvirus (ChHV) and mycoplasmal infections cause similar clinical signs in terrestrial tortoises and may be the most important causative agents of rhinitis-stomatitis complex, a common disease in captive tortoises worldwide. Currently, diagnosis of ChHV and Mycoplasma spp. infections is most often based on serologic testing. However, serologic results only detect past exposure, and the specificity of these tests can be reduced due to antigenic cross-reactions with other pathogens. Molecular-based techniques could help to define the causative agent and to better manage infected tortoises. Using polymerase chain reaction, we analyzed 63 tortoises (59 spur-thighed tortoise, Testudo graeca; three Greek tortoise, Testudo ibera; and one Russian tortoise, Agryonemys horsfieldii) with clinical signs of rhinitis-stomatitis complex to identify the causative agent. Molecular evidence of ChHV type I (24%), type II (3%), and Mycoplasma agassizii (6%) infections, as well as coinfection of Mycoplasma-ChHV and both types of ChHV, were detected. Both ChHV and M. agassizii are considered pathogenic in captive tortoises and both are a threat to wild populations. However, neither agent was detected from most of the symptomatic tortoises we evaluated, indicating that other agents could be involved in the rhinitis-stomatitis complex.     

Development of a time‐resolved fluorescence immunoassay for herpes simplex virus type 1 and type 2 IgG antibodies

Enzyme‐linked immunosorbent assays (ELISA) specific for anti‐HSV glycoprotein G (gG) are most commonly used in the clinical diagnosis of HSV infection. But most of them are qualitative and with narrow detection ranges. A novel time‐resolved fluoroimmunoassay (TRFIA) methodology was developed for the quantitative determination of HSV IgG in human serum. The assay was based on an indirect immunoassay format, and performed in 96‐well microtiter plates. HSV‐1 and HSV‐2 were used as the coating antigens. Eu³⁺‐labeled goat anti‐(human IgG) polyclonal antibodies were used as tracers. The fluorescence intensity of each well was measured and serum HSV IgG levels quantified against a calibration curve. The detection range of the novel TRFIA was between 5 and 500 AU/mL. Assay sensitivity was 0.568 AU/mL. The intra‐ and inter‐assay coefficients of variation were 0.59–3.63% and 3.65–6.81%, respectively. Analytical recovery, dilution tests and serum panel tests were performed using TRFIA and the results proved satisfactory. There were no statistically significant differences in sensitivity and specificity between the TRFIA and commercial ELISAs. An effective, sensitive and accurate quantitative HSV type 1 and type 2 IgG TRFIA was successfully developed and provided diagnostic value in clinical use. Copyright © 2014 John Wiley & Sons, Ltd.     

Interpretation of diagnostic data: 5. How to do it with simple maths.

The use of simple maths with the likelihood ratio strategy fits in nicely with our clinical views. By making the most out of the entire range of diagnostic test results (i.e., several levels, each with its own likelihood ratio, rather than a single cut-off point and a single ratio) and by permitting us to keep track of the likelihood that a patient has the target disorder at each point along the diagnostic sequence, this strategy allows us to place patients at an extremely high or an extremely low likelihood of disease. Thus, the numbers of patients with ultimately false-positive results (who suffer the slings of labelling and the arrows of needless therapy) and of those with ultimately false-negative results (who therefore miss their chance for diagnosis and, possibly, efficacious therapy) will be dramatically reduced. The following guidelines will be useful in interpreting signs, symptoms and laboratory tests with the likelihood ratio strategy: Seek out, and demand from the clinical or laboratory experts who ought to know, the likelihood ratios for key symptoms and signs, and several levels (rather than just the positive and negative results) of diagnostic test results. Identify, when feasible, the logical sequence of diagnostic tests. Estimate the pretest probability of disease for the patient, and, using either the nomogram or the conversion formulas, apply the likelihood ratio that corresponds to the first diagnostic test result. While remembering that the resulting post-test probability or odds from the first test becomes the pretest probability or odds for the next diagnostic test, repeat the process for all the pertinent symptoms, signs and laboratory studies that pertain to the target disorder. However, these combinations may not be independent, and convergent diagnostic tests, if treated as independent, will combine to overestimate the final post-test probability of disease. You are now far more sophisticated in interpreting diagnostic tests than most of your teachers. In the last part of our series we will show you some rather complex strategies that combine diagnosis and therapy, quantify our as yet nonquantified ideas about use, and require the use of at least a hand calculator.     

Nonparametric estimation of ROC curves in the absence of a gold standard

In the evaluation of diagnostic accuracy of tests, a gold standard on the disease status is required. However, in many complex diseases, it is impossible or unethical to obtain such a gold standard. If an imperfect standard is used, the estimated accuracy of the tests would be biased. This type of bias is called imperfect gold standard bias. In this article we develop a nonparametric maximum likelihood method for estimating ROC curves and their areas of ordinal-scale tests in the absence of a gold standard. Our simulation study shows that the proposed estimators for the ROC curve areas have good finite-sample properties in terms of bias and mean squared error. Further simulation studies show that our nonparametric approach is comparable to the binormal parametric method, and is easier to implement. Finally, we illustrate the application of the proposed method in a real clinical study on assessing the accuracy of seven specific pathologists in detecting carcinoma in situ of the uterine cervix.     

Estimating the prevalence of infections in vector populations using pools of samples

Several statistical methods have been proposed for estimating the infection prevalence based on pooled samples, but these methods generally presume the application of perfect diagnostic tests, which in practice do not exist. To optimize prevalence estimation based on pooled samples, currently available and new statistical models were described and compared. Three groups were tested: (a) Frequentist models, (b) Monte Carlo Markov‐Chain (MCMC) Bayesian models, and (c) Exact Bayesian Computation (EBC) models. Simulated data allowed the comparison of the models, including testing the performance under complex situations such as imperfect tests with a sensitivity varying according to the pool weight. In addition, all models were applied to data derived from the literature, to demonstrate the influence of the model on real‐prevalence estimates. All models were implemented in the freely available R and OpenBUGS software and are presented in Appendix S1. Bayesian models can flexibly take into account the imperfect sensitivity and specificity of the diagnostic test (as well as the influence of pool‐related or external variables) and are therefore the method of choice for calculating population prevalence based on pooled samples. However, when using such complex models, very precise information on test characteristics is needed, which may in general not be available.     

Clinical examination,xeromammography, and fine-needle aspiration cytology in diagnosis of breast tumours.

The diagnostic accuracy of clinical examination, xeromammography, and fine-needle aspiration cytology was compared with definitive histological findings in 255 breast lumps excised during one year. When suitable aspirates were obtained for cytological examination the diagnostic accuracy of aspiration cytology was higher than clinical examination or xeromammography. A diagnostic accuracy of 99% was achieved when all three screening tests were in agreement. As well as confirming a clinical diagnosis of malignancy, cytology is useful in identifying malignancy when clinical findings suggest that the tumour is benign. The availability of accurate cytology has affected patient management in many ways. Xeromammography did not enhance the diagnostic accuracy of clinical examination and aspiration cytology in patients presenting with a breast lump and, as a procedure with potential hazard, the benefit of routine xeromammography is questionable when an efficient cytological service is available.