[Differentiation of the blood group system of an adult population. I. Testing the homogenity of a medico legal post mortem material].
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ABO Blood-Group System↗
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Statistical design of toxicity assays: role of genetic structure of test animal population.
This paper considers certain statistical aspects of the problem of among-strain differences in cancer susceptibilities and how these differences may affect the design of toxicity assays. First, in order to investigate the magnitude of within-study, between-strain differences in tumor induction, the data of Innes et al. (1969) were examined. It was found that although there was a very high overall association between mouse strains with respect to the induction of hepatomas, several compounds showed evidence of strain-to-strain variability. Next, a number of long-term carcinogenicity studies with DDT were considered, and among-strain differences in cancer susceptibility for this compound were noted. Finally, it was shown that if susceptible subgroups do exist and certain simplifying assumptions are made, then in many cases tumor increases can be detected more readily by using several inbred mouse strains for study rather than a single outbread stock.
Animals↗
Aspects of genetically defined populations in toxicity testing. I. A comparative survey of populations obtained by different breeding systems and "mosaic populations".
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Animals↗
A population screening test for antibody to measles virus.
In areas where sporadic cases of measles continue to occur in spite of vaccination programs, the availability of a simple screening test for determination of seropositivity to measles virus is desirable. A sensitive radioimmunoassay (RIA) screening test (ST) for the detection of IgG antibody to measles virus, based on a solid phase RIA, is described. The assays were performed on polyvinyl microtiter plates for which the RIAST requires only 5 microliters of serum per subject. Antigen consisted of a sonicated extract of measles virus-infected Vero cells. Rabbit antihuman IgG specific for the Fc-segment of human IgG, labeled with 125I, was used to detect human IgG bound to viral antigen. The basic RIA method was characterized by carrying out full titrations of sera of 53 healthy adults, 10 children, and 13 patients with measles-associated illness. These sera were also tested by the hemagglutination inhibition (HI) technique; most of the measles sera were also tested by complement fixation (CF). RIAST results (expressed as binding ratios) obtained for 52 healthy adults are compared with their RIA serum titers. Of the 200 sera of patients of various ages tested by the RIAST, 63 borderline sera were also tested by HI. The RIAST, which does not require serum treatment other than inactivation, proved to be more sensitive as an indicator of seropositivity than HI. Implications of the results and practical applications of the screening test are discussed.
Adolescent↗
Life stress, social support, and problem-solving skills predictive of depressive symptoms, hopelessness, and suicide ideation in an Asian student population: a test of a model.
The present study tested both a stress-problem-solving model and a stress-social support model in the etiology of depressive symptoms, hopelessness, and suicide ideation for a group of Asian international students in the United States. Problem-solving skills and social support were hypothesized as two mediators between life stress and depressive symptoms, hopelessness, and suicide ideation. The results from a series of stepwise regression analyses and a path analysis support the hypotheses, indicating that these models generalized to a sample of Asian international students. The roles of social support and problem-solving skills in depressive symptoms and hopelessness are discussed. The results also suggest that hopelessness may serve as a cognitive factor directly affecting depressive symptoms and indirectly affecting suicide ideation.
Adolescent↗
[Is screening for cervix carcinoma useful and if so, should the general population be tested or only the high-risk groups].
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Female↗
Local variation in susceptibility of Colorado potato beetle (Coleoptera: Chrysomelidae) to insecticide.
The susceptibility status of Colorado potato beetle, Leptinotarsa decemlineata (Say), adults to phosalone was determined by dip and glass jar assay techniques. Bioassay results indicated a narrow variation in Colorado potato beetle insecticide susceptibility among sample sites. LC50 values were generally highest from specimens collected in field that received frequent phosalone applications for seven consecutive growing seasons. In five populations tested, LC50 values ranged from 503.72 to 827.95 ppm in dip test method. In glass jar technique, resistance ratio value of 1.72 for LC50 was obtained. A significant linear relationship between LC50 values of individual populations across test methods was detected. Both bioassay techniques were suitable for monitoring resistance to insecticide in Colorado potato beetle adult populations. Glass jar technique, however, exhibited less variability in LC50 estimates and showed a higher degree of sensitivity than the dip method. Filter paper and leaf disk techniques for larvae were two bioassay methods used to determine phosalone susceptibility in L. decemlineata populations. Both bioassay techniques exhibited a similar level of susceptibility of the larvae to phosalone; however, the fiducial limit values from filter paper method were narrow than the leaf disk assay technique. A significant direct relationship between LC50 values of individual population across test methods was observed. Differences in LC50 ranking among fields between adults and larvae indicated a differential susceptibility to insecticide between life stages. Low LC50 values obtained from Colorado potato beetle in sample sites indicated that phosalone resistance was not severe in these fields. The glass jar and filter paper testing methods are simple and sensitive test techniques for measuring susceptibility of Colorado potato beetle adults and larvae to phosalone, respectively.
Animals↗
Cell surface antigens detected on mature and leukemic granulocytic populations by cytotoxicity testing.
Using a microcytotoxicity assay, the serological reactivity of human granulocytes, namely neutrophils and eosinophils, and chronic myeloid leukemia (CML) cells and cultured CML cell lines (K562, NALM-1) were examined. Mature granulocyte forms and cord granulocytes are readily lysed by specific granulocyte cytotoxins that do not react with random T and B lymphocytes, monocytes, red blood cells, or platelets. Furthermore, certain antisera were preferentially cytotoxic for eosinophil-enriched populations. Granulocytotoxin detected antigens on one of three CML blast cell populations tested and K562, but failed to react with NALM-1. By cytotoxicity, mature granulocytes were poor targets for B2-microglobulin and the appropriate HLA antisera although both sera types are absorbed with granulocytes. Furthermore, granulocytes did not possess B-lymphocytes (Ia-like) or blood group A, B, and Rh (D) antigens. Except for K562, both HLA and heterologous B-lymphocyte antisera were cytotoxic for the CML blast cell populations tested.
ABO Blood-Group System↗
D1S80 VNTR locus genotypes in population of south Poland; meta-analysis pointer to genetic disequilibrium of human populations.
A highly variable number of tandem repeats (VNTRs) in a human locus D1S80 can prove to be useful for forensic science purposes. As with other genetic polymorphisms, a database of a local population allelic frequencies is needed to ensure that no departure from genetic equilibrium exists. DNA from the locus D1S80 was amplified by polymerase chain reaction (PCR) and analyzed by horizontal PAGE followed by silver staining. Samples from 133 unrelated inhabitants of Southern Poland were examined. The amplified fragment length polymorphism (AMP-FLP) analysis of the D1S80 locus demonstrated 21 alleles and heterozygosity of 0.85%. Out of the 231 possible genotypes, 47 were observed. The results were compared to the published D1S80 population studies and a meta-analysis of the genotype frequencies was performed. The G statistics revealed a deviation from genetic equilibrium in the Spanish population. Replicated goodness of fit tests showed highly significant heterogeneity of genotype distribution between tested populations. Therefore, interpretation of the casework on the basis of D1S80 locus typing may be biased by interpopulation differences.
Adult↗
Distribution of GPT types in Norway.
GPT phenotype determinations were performed in 4,148 unrelated Norwegians. The frequencies of the two common alleles were Gpt1 = 0.537 and Gpt2 = 0.461. A total of 13 individuals showed the phenotypic expression of 3 rare GPT alleles, Gpt3, Gpt6, and Gpt7. No heterogeneity in phenotype distribution was found, neither in the two sexes nor regionally in Norway. 97 foreigners involved in paternity cases in Norway showed a phenotype distribution not differing from that of Norwegians. In two small additional samples of Ethiopians and Easter Islanders, Gpt1 frequencies were 0.737 and 0.531, respectively. There were significant differences in phenotype distribution between NOrwegians and all African populations tested, some of the Asiatic population, Lapps and a few other populations.
Alanine Transaminase↗
Lack of direct correlation between CD4 T-lymphocyte counts and induration sizes of the tuberculin skin test in human immunodeficiency virus type 1 seropositive patients.
SETTING: The study was conducted in Bobo-Dioulasso, Burkina Faso, where Mycobacterium tuberculosis infection and human immunodeficiency virus type 1 (HIV-1) infection are prevalent. OBJECTIVE: To identify proportions of representative (test) populations who are reactive to the tuberculin skin test, and to study the relationship between CD4 T-lymphocyte counts and the induration size of the tuberculin skin test in these groups. DESIGN: A group of 435 healthy students was tuberculin skin tested in order to evaluate the intensity of skin testing in a 'normal' population. The study group consisted of 195 subjects with or without tuberculosis, and with or without HIV-1 infection, who received a tuberculin skin test and a CD4 T lymphocyte count on the same day. RESULTS: In total, 90% of the control (nontuberculous, HIV negative) subjects, 32% of the HIV-1 seropositive subjects, 76.5% of the tuberculous patients and 57% of the tuberculous HIV-1 seropositive patients were tuberculin positive. There was no direct correlation between the induration size of reactions to the tuberculin skin test and CD4 T-lymphocyte count in these study groups using linear regression analysis. CONCLUSION: In vivo skin testing using tuberculin yields clinically significant information on the degree of immunodeficiency which is different from that of CD4 T-lymphocyte counts. The tuberculin skin test should therefore be used as an independent marker of the weakened immunological status of HIV-1 seropositive subjects.
AIDS-Related Opportunistic Infections↗
A perspective on standardizing the predictive power of noninvasive cardiovascular tests by likelihood ratio computation: 1. Mathematical principles.
The current practice of reporting positive and negative predictive value (PV), sensitivity (Se), and specificity (Sp) as measures of the power of noninvasive cardiovascular tests has significant limitations. A test result's PV and its comparison with other test results are highly dependent on the pretest disease prevalence at which it is determined; the citation of sensitivity and specificity provides no succinct or explicit quantitation of the rule-in and rule-out power of a test. This article presents a rationale for the use of an alternative standard for expressing predictive power in the form of positive and negative likelihood ratios, (+)LR and (-)LR. The likelihood ratios are composite expressions of test power, which incorporate the Se and Sp and their respective complements [(1 - Se) and (1 - Sp)], thus yielding single unambiguous measures of positive and negative predictive power. The likelihood ratios are calculated as follows: (+)LR = Se/(1 - Sp) and (-)LR = Sp/(1 - Se). On analysis of the predictive value equations, the likelihood ratios equal the quotients of the posttest predictive value odds to the pretest prevalence odds for disease and no disease, respectively, as follows: (+)LR = (+)PVOd/POD and (-)LR = (-)PVOn/PON, where (+)PVOd is positive predictive value odds for disease, POD is prevalence odds for disease, (-)PVOn is negative predictive value odds for no disease, and PON is prevalence odds for no disease. Thus, the likelihood ratios are measures of the odds advantage in posttest probability of disease or no disease relative to pretest probability, independent of disease prevalence in the tested population. The quotients of the (+)LR or the (-)LR among test results studied in a common population are direct expressions of their relative predictive power in that population. The likelihood ratio principle is applicable to the evaluation of the predictive power of multiple tests performed in a common population and to estimating predictive power at multiple test thresholds.
Confidence Intervals↗
Prevalence of reactive serological tests for syphilis in the Jamaican population.
Serological tests for syphilis (STS) were performed on sera from 15,876 members of the general adult population, 3,039 pregnant women and 1,029 children, in order to assess the prevalence and value of reactive STS in Jamaicans; 2.7% of sera from the general adult population, 4.7% from pregnant women and 2.2% from children were reactive in the Venereal Disease Research Laboratory (VDRL) test. Reactive Fluorescent Treponemal Absorption (FTA-ABS) tests occurred in significantly higher frequency in pregnant women (4%) than in the general population (2.2%; p less than 0.001). The prevalence of reactive STS in children did not differ significantly from that of the general adult population. The predictive value of a reactive VDRL test in pregnant women (85%) was higher than that of the general population (79%). These results suggest that adequate screening with the inexpensive VDRL test would enable the early detection and treatment of syphilis, and could prevent increasing incidence of congenital syphilis in Jamaica.
Adult↗
Genetic affinities of Jewish populations.
Genetic relations between various Jewish (J) and non-Jewish (NJ) populations were assessed using two sets of data. The first set contained 12 pairs of matched J and NJ populations from Europe, the Middle East, and North Africa, for which 10 common polymorphic genetic systems (13 loci) were available. The second set included 22 polymorphic genetic systems (26 loci) with various numbers of populations (ranging from 21 to 51) for each system. Therefore, each system was studied separately. Nei's standard genetic distance (D) matrices obtained for these two sets of data were tested against design matrices specifying hypotheses concerning the affiliations of the tested populations. The tests against single designs were carried out by means of Mantel tests. Our results consistently show lower distances among J populations than with their NJ neighbors, most simply explained by the common origin of the former. Yet, there is evidence also of genetic similarity between J and corresponding NJ populations, suggesting reciprocal gene flow between these populations or convergent selection in a common environment. The results of our study also indicate that stochastic factors are likely to have played a role in masking the descent relationships of the J populations.
Gene Frequency↗
Natural infection of dogs by influenza C virus.
To date, only one seroepidemiological survey, carried out in Japan, gave a strong indication that dogs may be naturally infected by the influenza C virus, long considered to be exclusively human. In the present work, 134 serum samples were collected during the winter of 1988/89 from dogs aged 6 months to 16 years in northern France. Samples were tested for the presence of antibodies to influenza C virus by both haemagglutination inhibition (HI) and ELISA. Using antibody absorption by staphylococcal protein A, we demonstrated the specificity of the results. In 62% of cases, the results were identical using the two methods. Significant HI activity was found in 32% of the 134 tested sera and titres ranged from 20 to 320. Of the sera tested, 42% were positive by ELISA and titres ranged from 500 to 8,000. The discordant results are discussed. The population tested was divided into five age groups: less than 4 years, 4 to 6 years, 7 to 9 years, 10 to 11 years and greater than 12 years. The distribution of antibodies in the tested canine population, in contrast to that of humans, did not show a significant degree of association with age.
Aging↗
The cost-effectiveness of testing for hepatitis C in former injecting drug users.
OBJECTIVES: To evaluate the effectiveness and cost-effectiveness of testing for hepatitis C (HCV) among former injecting drug users (IDUs). DATA SOURCES: Electronic databases 1996-October 2004. Trent Regional Database Study. Routine UK mortality data. REVIEW METHODS: A decision analytic model was developed to investigate the impact of case-finding and treatment on progression of HCV disease in a hypothetical cohort of 1000 people. This was compared with a cohort in whom no systematic case-finding is implemented but spontaneous presentation for testing is allowed to occur. A group of epidemiological and clinical experts informed the structure of the model, which has three main components: (1) testing and diagnosis, (2) treatment, and (3) long-term consequences of infection. A fourth component, case-finding strategies, examines the potential impact of case-finding in three settings: prisons, general practice and drug services. RESULTS: Case-finding for HCV is likely to prevent, for 1000 people approached, three cases of decompensated cirrhosis, three deaths due to HCV and one case of hepatocellular cancer (at 30 years). Twenty-five additional people are likely to undergo combination therapy as a result of initial case-finding. One liver transplant is likely to be prevented for 10,000 people included in case-finding. Case-finding is likely to cost, in the general case, around pounds sterling 760,000 more than a policy of not case-finding. The total cost of either strategy is high and driven predominantly by the cost of treatment with combination therapy (the costs of long-term consequences are heavily discounted owing to the duration of the model). Systematically offering testing to 1000 people would cost around pounds sterling 70,000. In terms of life-years gained, case-finding is likely to result in an additional life-year gained for an investment of pounds sterling 20,084. Taking impacts on quality of life into account gives an estimate for the cost-utility of case-finding as pounds sterling 16,514 per QALY. The probabilistic sensitivity analysis shows that, if NHS policy makers view pounds sterling 30,000 per QALY as an acceptable return on investment, there is a 74% probability that case-finding for HCV would be considered cost-effective. At pounds sterling 20,000 per QALY, the probability that case-finding would be considered cost-effective is 64%. In all analyses, the probability of case-finding being considered cost-effective at a level of pounds sterling 30,000 per QALY was high. Case-finding in drug services is likely to be the most expensive, owing to the high prevalence of cases in the tested population. Correspondingly, benefits are highest for this strategy and cost-effectiveness is similar, in average terms, to the general case. Case-finding in general practice by offering testing to the whole population aged 30-54 years is, paradoxically, estimated to be the least expensive option as only a small number of people accept the offer of testing and HCV prevalence in this group is much higher than would be expected from the general population. Two approaches to case-finding in prison were considered, based on the results of studies in Dartmoor and the Isle of Wight prisons. These differed substantially in the prevalence of cases identified in the tested populations. The analysis based on data from Dartmoor prison had the least favourable average cost-effectiveness of the strategies considered (pounds sterling 20,000 per QALY). Subgroup analyses based on duration of infection show that case-finding is likely to be most cost-effective in people whose infection is more long-standing and who are consequently at greater risk of progression. In people who were infected more than 20 years previously, case-finding yields benefits at around pounds sterling 15,000 per QALY. Treatment effectiveness was modelled using estimates from randomised controlled trials and lower rates of viral response may be seen in practice. However, estimates of cost-effectiveness remained below pounds sterling 30,000 for all levels of treatment effectiveness above 58% of those shown in the relevant trials. The value of information analysis, based on assumptions that 10,000 people might be eligible for case-finding and that programmes would run for 15 years, suggests that the maximum value of further research into case-finding is in excess of pounds sterling 19 million. Partial expected value of perfect information (EVPI) analysis shows that the utility estimates used in the model eclipse all other factors in terms of importance to parameter uncertainty. This is not surprising, since the point estimates for differences in utility between states and across the arms of the model are small. CONCLUSIONS: Case-finding for hepatitis C is likely to be considered cost-effective by NHS commissioners. Although there remains considerable uncertainty, it appears unlikely that cost-effectiveness would exceed the levels considered acceptable. Further improvements in the effectiveness of treatments to slow or halt disease progression are likely to improve the cost-effectiveness of case-finding. Case-finding is likely to be most cost-effective if targeted at people whose HCV disease is probably more advanced. Further empirical work is required to specify, in practice, different approaches to case-finding in appropriate settings and to evaluate their effectiveness and cost-effectiveness directly.
Adult↗
Spirometric lung function. Distribution and determinants of test failure in a young adult population.
Spirometric test failure has been defined as failure by a subject to meet the acceptability and/or reproducibility criteria laid down by the American Thoracic Society for measurements derived from forced expiratory maneuvers. The prevalence and determinants of spirometric test failure were examined in 416 men and women aged 20 to 45 yr working in an office environment. In this study population, 11.5% (28 men and 20 women) exhibited test failure for forced expiratory volume in one second (FEV1). The main determinant of test failure in men was bronchial hyperresponsiveness to methacholine challenge (odds ratio 6.7; confidence interval 1.7, 27.1) and in women being a current smoker (odds ratio 4.02; confidence interval 1.13, 14.33). There was also a relationship to eczema in both men and women, but not at a statistically significant level. When FEV1 variability was defined as the difference (in milliliters) between the two best FEV1 values and the results of men and women combined for analysis, significant predictors were a history of eczema, recurrent chest illness in the past 3 yr, and level of bronchial responsiveness to inhaled methacholine. These findings contribute to the gathering evidence that test failure may be of itself an indicator of impaired respiratory health, and its association with bronchial hyperresponsiveness to methacholine in men suggests that in them test failure is related to airway lability, but in women the relationship to smoking suggests an irritative mechanism.
Adolescent↗
Manufacturing of gene-modified cytotoxic T lymphocytes for autologous cellular therapy for lymphoma.
BACKGROUND: The production of therapeutic T-cell populations for adoptive immunotherapy of cancer requires extensive ex vivo cell processing, including the isolation or creation of Ag-specific T cells and their subsequent propagation to clinically relevant numbers. These procedures must be performed according to the principles of current good manufacturing practices (cGMP) for phase I clinical trials to ensure the identity, purity potency and safety of the cellular product. In this report we describe our approach to manufacturing and characterizing bulk populations of gene-modified autologous T cells for use in treating follicular lymphoma. METHODS: PBMC from healthy donors, obtained after informed consent, were stimulated in vitro with Ab to CD3epsilon (OKT3) and recombinant human IL-2 and then electroporated with plasmid DNA containing a human CD19-specific chimeric Ag receptor (CAR) gene and HSV-1 thymidine kinase (TK) gene. Stably transfected cells were selected in cytocidal concentrations of hygromycin B over multiple 14-day stimulation culture cycles and then cryopreserved. Vials of cryopreserved/selected T cells were used to initiate T-cell expansion cultures to produce cell products for clinical infusion. These cultures were characterized for phenotype, function and suitability for use in adoptive immunotherapy studies. RESULTS: Our results demonstrate that bulk populations of gene-modified T cells derived from peripheral blood of healthy donors express CD19+ chimeric Ag receptor at low levels and can specifically lyse CD19+ target cells in vitro. These cells display a differentiated T-effector phenotype, are sensitive to ganciclovir-mediated killing and display a non-transformed phenotype. TCR Vbeta usage indicated that all populations tested were polyclonal. Ex vivo cell expansion from cryopreserved cell banks is sufficient to produce doses of between 5 x 10(9) and 1 x 10(10) cells/run. One of three transductions resulted in a population of cells that was not suitable for infusion but was identified during release testing. No populations displayed any evidence of bacterial, fungal or mycoplasma contamination. DISCUSSION: We have established a manufacturing strategy that is being used to produce T cells for a phase I clinical trial for follicular lymphoma. Genetically modified T cells have been characterized by cell-surface marker phenotype, functional activity against CD19+ targets and requisite safety testing. These pre-clinical data confirm the feasibility of this approach to manufacturing T-cell products.
Antigens, CD↗