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Psychologic components of the premenstrual syndrome. Evaluating the research and choosing the treatment.

Methodologic problems that impede the evaluation of the psychologic components of the premenstrual syndrome (PMS) include: (1) the lack of a consensus on the definition of PMS (resulting in significant variations between studies with respect to severity, timing and course of the symptoms); (2) the use of retrospective, rather than prospective, methods of data collection (which increases the likelihood of culturally based response bias); (3) sampling errors; (4) failure to assess and/or control for experimental bias introduced as a function of the subject's perception of the purpose of the evaluation; and (5) inadequate attention paid to timing within the cycle of data collection. Treatment of the psychologic components of PMS requires an individualized approach. Given our current knowledge of this syndrome (or syndromes), there is no way to predict with a high level of assurance which patients will benefit most from behavioral, pharmacologic, nutritional or hormonal therapy. The most urgent priorities in future research on PMS treatment are controls for placebo effects and more sophisticated approaches to sample selection.

Female↗

Contact matrices for multipopulation epidemic models: how to build a consistent matrix close to data.

In models of the dynamics of sexually transmitted diseases between and within N interacting populations, it is necessary to specify the matrix of contacts between populations. Mixing matrices have to satisfy a consistency condition that generally will not be satisfied by empirically obtained matrices. The problem of inferring a mixing matrix from data is phrased here as the problem of finding a matrix in a prescribed set that minimizes an opportune distance from the matrix of data. Two different distances that attempt to measure relative errors are suggested. When no constraints are posed on the activity rates of the populations, the author shows that the minimum distance from data is attained at Knox's (1986) matrix. When activity rates are to be preserved, the minimum cannot be found explicitly for N greater than 2. An algorithm proposed by Arcà, Perucci, Spadea, and Rossi (1990) is then investigated, and shown always to converge to a consistent matrix. Through several examples, it is shown that this limiting matrix does not minimize distance from data, but is generally close to the minimum. Finally, the author simulated the collection of data with sampling errors and possible bias and evaluated the performance of this algorithm in approximating the 'true' contact matrix starting from the simulated 'data' matrix.

Algorithms↗

Follow-up study of blindness attributed to cataract in Karnataka State, India.

AIM: Presentation of the results of rapid assessments of bilateral cataract blindness in persons 50 years of age and older in 19 districts of Karnataka State, India. MATERIALS: A total of 21,950 persons 50 years of age and older in 19 out of 20 districts were examined. In each district, 15 clusters were randomly selected and in each cluster the visual acuity and lens status were assessed in 90 persons 50 years of age and older. METHODS: Systematic Random Cluster Sampling was used. Assuming a prevalence of at least 4.3% and a design effect of 1.5, the survey was designed to give an estimated prevalence with a sampling error of 20% or less at 80% confidence. Visual acuity was measured with a tumbling E chart at 6 meters distance with available correction. Lens status was assessed by distant direct ophthalmoscopy with undilated pupil under semi-dark conditions. RESULTS: The average age and sex adjusted prevalence of cataract blindness was 4.93%, with a variation of 1.58% to 7.24% in different districts. The prevalence in females was higher than in males. Cataract Surgical Coverage, an indicator for coverage and service utilization, varied from 42% to 68% in different districts. On average, males had a higher coverage than females. Of all aphakic eyes in the sample, 26.4% could not see 6/60. Barriers to cataract surgery are linked to service providers. CONCLUSIONS: Rapid assessments for cataract blindness in persons aged 50 years and older can be conducted at district level in India with existing resources and at affordable costs. The results suggest an increase in cataract blindness since the previous survey of 1986. The long-term visual outcome needs improvement. Change in barriers to cataract surgery requires a shift in health education strategy and messages. The large variation in prevalence justifies district-level surveys. A change in the sampling frame from 15 clusters of 90 to 28 x 40 or 37 x 30 will increase the precision.

Blindness↗

Papanicolaou smear quality assurance: providing feedback to physicians.

BACKGROUND: The effective management of Papanicolaou (Pap) smears depends on the reliability and accuracy of obtaining and interpreting the specimen. Provider sampling error is one of the important factors contributing to inadequate specimens. Feedback on provider performance may be an effective way to improve the quality of Pap smears. METHODS: A pilot study in a university-based residency program involving resident and faculty physicians was initiated to assess the impact of feedback on performance of Pap smears. After establishing adequacy and inadequacy criteria and recording adequacy rates for 3 months, individual and group feedback was implemented. No formal educational intervention on Pap smear technique was undertaken. RESULTS: The quality of 836 Pap smears performed by 9 faculty and 13 resident physicians showed continued improvement in both sampling and slide preparation to 90% adequacy over a 9-month period. This improvement, though clinically useful, was not statistically significant owing to the relatively small numbers of smears performed by each physician. This form of feedback may be useful in both practice and educational settings. CONCLUSIONS: Feedback without any formal educational intervention led to a clinically useful trend of improvement in the quality of Pap smears, which has been sustained since the study began. This type of simple feedback may be useful in practice settings and particularly valuable in pinpointing areas for improvement for learners in residency programs.

Academic Medical Centers↗

Can transcriptome size be estimated from SAGE catalogs?

MOTIVATION: SAGE (Serial Analysis of Gene Expression) can be used to estimate the number of unique transcripts in a transcriptome. A simple estimator that corrects for sequencing and sampling errors was applied to a SAGE library (137 832 tags) obtained from mouse embryonic stem cells, and also to Monte Carlo simulated libraries generated using assumed distributions of 'true' expression levels consistent with the data. RESULTS: When the corrected data themselves were taken as the underlying model of 'ground truth', the estimator converged to the 'true' value (53 535) only after counting 300 000 simulated tags, more than twice the number in the experiment. The SAGE data could also be well fit by a Monte Carlo model based on a truncated inverse-square distribution of expression levels, with 130 000 'true' transcripts and 10(6) samples needed for convergence. We conclude that the size of a transcriptome is ill-determined from SAGE libraries of even moderately large size. In order to obtain a valid estimate, one must sample a number of tags inversely proportional to the lowest abundance level, which is not known a priori. This constrains the design of SAGE experiments intended to determine biological complexity. AVAILABILITY: The 'homemade' software used for this analysis was not designed for general or 'production' use, but the authors will be happy to share Fortran sourcecode with interested parties. CONTACT: sternm@grc.nia.nih.gov

Algorithms↗

Gallium-67 imaging in patients with dilated cardiomyopathy and biopsy-proven myocarditis.

Current standards for detection of myocarditis in a clinical setting rely on endomyocardial biopsy for accurate diagnosis. With this technique a subset of patients with dilated cardiomyopathy show unsuspected myocarditis histologically. Endomyocardial biopsy, despite its specificity, may lack sensitivity due to sampling error if the inflammation is patchy or focal. Therefore, inflammation-sensitive radioisotopic imaging may be a useful adjunct in the diagnosis of myocarditis. This study was designed to evaluate the applicability of gallium-67 (67Ga) myocardial imaging as an adjunct to endomyocardial biopsy in the diagnosis of myocarditis. Sixty-eight consecutive patients referred for evaluation of dilated cardiomyopathy underwent 71 parallel studies with 67Ga imaging and biopsies that served as the basis of comparison for this study. Histologic myocarditis was identified in 8% of biopsy specimens. Clinical and hemodynamic parameters could not be used to predict the presence of myocarditis. Five of six biopsy samples (87%) with myocarditis showed dense 67Ga uptake, whereas only nine of 65 negative biopsy samples (14%) were paired with equivocally positive 67Ga scans (p less than .001). The single patient with myocarditis and no myocardial 67Ga uptake had dense mediastinal lymph node uptake that may have obscured cardiac uptake. The incidence of myocarditis on biopsy with a positive 67Ga scan was 36% (5/14); however, the incidence of myocarditis with a negative 67Ga scan was only 1.8% (1/57). Follow-up scans for three patients showed close correlation of 67Ga uptake with myocarditis on biopsy. In conclusion 67Ga may be a useful screening test for identifying patients with a high yield of myocarditis on biopsy, and serial scans may eliminate the need for frequent biopsies in patients with proven myocarditis.

Adult↗

Establishment and study of different real-time polymerase chain reaction assays for the quantification of cells with deletions of chromosome 7.

The evaluation of residual disease, which has prognostic value in the treatment of hematological malignancies, is currently assessed by scoring a limited number of cells by karyotyping and molecular cytogenetics. Real-time polymerase chain reaction (PCR) is an easier and more sensitive technique, enables analysis of a larger number of cells, and decreases sampling error. However, real-time PCR has been applied only to target transcripts of fusion genes. Here, we considered two real-time PCR strategies to quantify a number of cells carrying a partial deletion of chromosome 7 mixed with normal disomic cells. The first strategy was based on the amplification of two sequences, one on chromosome 7 and the other on chromosome 14. In the second strategy residual disease was assessed by the ratio between the two alleles of a bi-allelic marker, mapped on chromosome 7, measured with allele-specific assays. Precision and accuracy of the two approaches were tested by reference samples with nominal values of residual disease ranging from 2 to 95%. As expected the second strategy resulted in more precise and accurate monitoring within the range from 5 to 95%. Furthermore, this method may be applied to assess the number of dysplastic or neoplastic clones carrying any unbalanced chromosome changes.

Base Sequence↗

Model selection for covariance structures analysis in nursing research.

Covariance structures analysis is often used in nursing research to appraise statistical models reflecting complex human health processes. The model selection approach in covariance structures analysis is designed to select the "best" model from a specified set of theoretically defensible, competing alternatives, all of which are viewed as approximations. Model selection criteria explicitly incorporate both model misfit in the population and sampling error to evaluate the set of models. The result is that interpretability of model parameters and goodness-of-fit are enhanced simultaneously. Relative merits of the model selection approach are identified in light of technical concerns, parsimony, and use of scientific theory in nursing.

Analysis of Variance↗

Molecular markers in prostate cancer: the role in preoperative staging.

Radical prostatectomy as a primary treatment for clinically localized prostate cancer has increased dramatically over the past decade due to prostate-specific antigen (PSA) screening and the awareness of the increased incidence of localized disease. Despite the stage migration to increase clinically localized disease, there are still vast numbers of men who harbor occult extraprostatic extension and develop recurrence after surgery. The study of molecular markers in the blood or tissue of surgical patients prior to treatment, called " molecular staging, " is the focus of this review. The reverse transcriptase- polymerase chain reaction (RT-PCR) test for PSA gene expression in peripheral blood or bone marrow has received considerable attention since its first report in 1992. The test detects messenger RNA species for prostate-specific/abundant genes such as PSA and prostate-specific membrane antigen. These messenger RNAs were not detected in normal blood or bone marrow, but were detected in some prostate cancer patients presumably due to circulating prostatic epithelial cells. These prostate epithelial cells are thought to be occult metastases cells, and early studies correlated a positive RT-PCR test with surgical pathology adverse features such as positive margins. Despite the many studies over the past few years, there have been inconsistent results, and the most recent studies have not been able to confirm clinical utility. Bone marrow RT-PCR has been more promising; however, it is still a research tool that needs further study. The study of molecular markers in tissue material, ie, prostate biopsy samples prior to radical prostatectomy, is problematic due to the sampling error inherent in a multifocal heterogeneous tumor such as prostate cancer. The tumor suppressor proteins p53 and p27, Bcl-2 oncoprotein, Ki-67 proliferation index protein, E-cadherin, and microvessel density have been assessed in preradical prostatectomy needle biopsy. Results have been conflicting, and none are yet accepted as a clinically useful marker. Current and future work is focusing on analysis of multiple gene expressions or proteins simultaneously via gene chip or proteomics technology. While these expression profiles might be of value in whole prostate surgical specimens where tissues are well characterized, it is unclear how this new technology will be applied to the needle biopsy samples. Although molecular staging of radical prostatectomy patients has been under study for a decade, all assays remain research tools. Still, this area holds great promise for improving the accuracy of staging and providing a more accurate prognosis of individual men with clinically localized prostate cancer.

Biomarkers, Tumor↗

[Quantitative ultrastructural findings of the myocardium in the failing heart. I. Aortic valve insufficiency (author's transl)].

Quantitative ultrastructural changes of the left ventricular (LV) myocardium and contractile function were studied in 9 symptomatic patients with severe aortic insufficiency (AI). The volume fractions of myofibrils, sarcoplasm, and mitochondria in myocardial cells were determined by electron microscopic morphometry in small LV tissue samples. Interstitial fibrosis was measured by light microscopic morphometry. Transmural biopsies of the LV free wall perfused by the left anterior descending coronary artery (LAD) were obtained during aortic valve replacement. Biopsies from the LAD-perfusion area of 10 surgical patients with coronary artery disease but moderate LAD-stenosis and normal regional motion of LAD-area were taken as controls for morphometric data. LV-function was analyzed from preoperative heart catheterization. In initial reproducibility studies of biopsy samples of 17 patients a sampling error for evaluation of myocardium was defined and differences exceeding 6.2% transmural fibrosis and 6.5% myofibrils were considered biologically significant differences. Patients with AI had higher LV end-diastolic volume (180 versus 77 ml/m2, p less than 0.001), and lower LV ejection fraction (51 versus 69%, p less than 0.001) than 10 control individuals. The volume fraction of myofibrils was lower in AI than in controls (44 versus 53%, p less than 0.01), and sarcoplasm was higher (33 versus 21%, p less than 0.01). Mitochondria and interstitial fibrosis did not differ between groups (p greater than 0.05). Thus reduction in the volume fraction of myofibrils was the major ultrastructural finding in LV biopsy samples of patients with heart failure due to aortic insufficiency.

Adult↗

Prevalence of youth substance use: the impact of methodological differences between two national surveys.

This study compared two major Federally sponsored surveys of adolescent substance use and assessed the impact that methodological differences have on the prevalence estimates they generate. The Monitoring the Future Survey, a school-based survey, was compared to the National Household Survey on Drug Abuse, a household survey of the population aged 12 years and older. Response rates were higher in the household survey due to high rates of refusal in the school based survey. The school survey has a larger overall sample size, but sampling errors more similar than one might expect, because of the larger design effects in the school survey. Rates of drug use obtained were larger in the school survey than in the household survey, possibly because of greater under-reporting in the household setting than in the classroom and the different questionnaires used in the two surveys.

Adolescent↗

Use of a combination of brushing technique and the loop-mediated isothermal amplification method as a novel, rapid, and safe system for detection of Helicobacter pylori.

Gastric mucosal biopsy is widely used in the detection of Helicobacter pylori but is associated with a number of problems, including false-negative results due to sampling error and massive bleeding after biopsy. Given the extended period required to culture H. pylori, detection would be further improved by the use of rapid detection methods such as PCR. Here, we developed a rapid, safe, and convenient method for collecting H. pylori which combines endoscopic brushing with the loop-mediated isothermal amplification (LAMP) method. The specificity and sensitivity of LAMP were examined using nine urease-generating non-H. pylori bacterial species, Escherichia coli, Clostridium perfringens, Campylobacter jejuni, Helicobacter hepaticus, and 51 H. pylori strains. Results showed that H. pylori-specific LAMP primers amplified H. pylori DNA only and that the lowest detection limit of the LAMP reaction was 10(2) CFU. Brushing and biopsy samples taken from 200 patients with peptic ulcer at Nagoya University Hospital and a regional health care center were subjected to both LAMP and culturing. No adverse effects such as severe bleeding or penetration occurred during the procedure. By LAMP assay, 123 patients were confirmed as H. pylori positive when brushing technique samples were assayed, whereas only 100 were positive when biopsy samples were assayed. Culture assay detected H. pylori in 117 patients when it was combined with the brushing technique and in 96 when it was combined with biopsy. Combination of the endoscopic brushing technique with LAMP is considered a useful and safe system for identifying H. pylori infection.

Base Sequence↗

MRI assessment of right ventricular dysplasia.

Right ventricular dysplasia is a new entity of unknown origin in the classification of cardiomyopathies. Also known as arrhythmogenic right ventricular cardiomyopathy (ARVC) or arrhythmogenic right ventricular dysplasia, it is a disease of the heart muscle characterised by fibroadipose atrophy mainly involving the right ventricle and responsible for severe ventricular arrhythmias and sudden death also in young people. Magnetic resonance imaging provides evidence of ventricular dilatation at the outflow tract, thinning and thickening of the wall, diastolic bulging areas (especially located at the level of the right ventricle outflow tract) and fatty substitution of the myocardium mainly at the level of the right ventricle. Many radiologists erroneously consider the previously described fatty substitution as the main sign of ARVC, even though an evaluation of fat substitution alone may be a source of error for two reasons: firstly, because isolated areas of fatty replacement are not synonymous with ARVC since small non-transmural focal fatty areas of fat are also present in the normal patients; and secondly, because the MRI detection of fat may be overestimated due to partial-volume artefacts with normal subepicardial fat. Cardiac MRI can also be employed for the diagnosis of idiopathic right ventricular outflow tract tachycardia. Considering the evolutive nature of the disease, the non-invasiveness of MRI allows the follow-up of these patients and may be considered an excellent screening modality for the diagnosis of ARVC in family members. Finally, MRI can be employed in electrophysiological studies to locate the arrhythmogenic focus and reduce sampling errors.

Adipose Tissue↗

An approach to definition of genetic alterations in prostate cancer.

Growth patterns in prostatic cancer can reduce detectability of genetic alterations. Tumors show histologic grade heterogeneity, multifocality, interdigitation of benign and malignant glands, and varying amounts of stroma. These characteristics introduce sampling errors when one uses traditional methods for genetic analysis that depend on disaggregated cells [metaphase or interphase chromosome studies] or on tissue extracts [Southern blotting or polymerase chain reaction (PCR)] to detect molecular events. To circumvent these problems, we used two approaches to study paraffin-embedded tumors, which permit focused analysis of critical tissue components. Serial 4- to 5-microns sections are applied to slides in groups of three. Every second slide is hematoxylin and eosin stained to visualize areas of carcinoma, dysplasia, hyperplasia, and stroma; tumor-rich areas are circled with ink and used as templates to examine or excise the same areas from adjacent nonstained sections. PCR methods for quantitative and qualitative gene assay are effective in evaluating samples when alteration at a particular locus is suspected. Fluorescence in situ hybridization with chromosome-specific paracentromeric probes for detection of copy number of the relevant chromosome is applied to the adjacent section. Normal chromosome controls for both methods were demonstrated. This protocol enables us to correlate genetic alterations precisely with tumor extent and morphology.

Chromosomes, Human↗

The bone marrow in polycythemia vera.

The sequential biopsies and the careful clinical and laboratory studies in this large prospective study of PV patients offer a unique opportunity to properly evaluate the diagnostic and prognostic importance of the biopsy and to study the complications of this condition. The results of the study to date confirm and extend previous studies. Because of the long natural history of PV, the results of studies relating to leukemia, other myeloproliferative diseases, myelofibrosis, and effects of therapy are tentative at this time, even though the study is in its eleventh year. Hypercellularity of the marrow, together with hyperplasia and hypertrophy of megakaryocytes, is an almost constant finding in untreated PV. A very few cases (7 of 281) had relatively normal cellularities and normal megakaryocytic concentrations. Whether these findings were the result of sampling errors could not be determined, since only one site was biopsied. In any event, we found no unique clinical or laboratory features to distinguish these patients. At this time, the course of these patients appears to be the same as that of the other patients. Although increases in reticulin were regularly found during the spent phase of polycythemia, the relationship was not a precise one. For example, a moderate to marked increase in reticulin was found in 12 percent of the patients early in the course of the disease and was not predictive that the spent phase with myeloid metaplasia was imminent. In addition, in a given patient with serial biopsies taken over several years, some variability in reticulin was noted among the biopsies. Whether this represented variation in sampling or fluctuation in reticulin content could not be decided at this time. Using the standard criteria for examination of the marrows, we have found it impossible to predict which patients will develop leukemia, since the pretreatment and posttreatment biopsies almost up to the clinical onset cannot be separated from the remainder of the group.

Acute Disease↗

Prevalence of Behçet's disease in Istanbul, Turkey.

BACKGROUND: The prevalence of Behçet's disease (BD) is much higher in countries along the ancient Silk Route, extending from Japan to Mediterranean countries including Turkey, than in northern Europe and the USA. Three previous epidemiologic surveys have been carried out in different regions of Turkey. PATIENTS AND METHODS: This study investigated the cross-sectional prevalence of BD in individuals aged > 12 years in Istanbul, Turkey, in two stages. The first stage aimed to identify individuals with recurrent oral ulcers (ROUs) by visiting them in their homes, and the second stage aimed to further examine those with ROUs for the presence of other BD-related manifestations under hospital conditions. The sample size was determined to be 24,000 with an expected BD prevalence rate of 1/1000 and a sampling error of 4/10,000, with a 95% confidence interval (CI) of 6-14/10,000. The number of individuals to be screened in each district was determined in proportion to the population of all districts in Istanbul. RESULTS: The standard questionnaire was applied to a total of 23,986 individuals at their homes. A history of ROU was recorded in 2289 individuals (9.5%), and a previous diagnosis of BD was recorded in 47. The diagnosis of ROU was confirmed in 700, and the diagnosis of BD was established in 101 according to the International Study Group criteria. The prevalence rate of BD was estimated as 42/10,000 (95% CI, 34-51/10,000) in Istanbul, Turkey. CONCLUSIONS: This survey conducted in Istanbul, the largest cosmopolitan city in Turkey with immigrants from all over the country, has a larger sample size than other previous studies, and therefore the reported prevalence rate of BD has a more acceptable confidence interval. This study aids in the estimation of the prevalence of BD in Turkey, and supports previous findings that Turkey has the highest prevalence rate of the disease in the world.

Adolescent↗

A non-invasive approach to detecting organ rejection by MRI: monitoring the accumulation of immune cells at the transplanted organ.

Organ transplantation is the generally preferred medical procedure of treatment for patients with end-stage organ failure. The immunological reaction of rejection is a major cause of functional failure in transplant patients. The current "gold standard" for detecting or confirming graft rejection following solid organ transplantation requires biopsy samples in order to detect immune cell (e.g., T-cells, macrophages, etc.) infiltration into the graft and other pathological changes. This procedure is not only invasive, having associated risks, but is also prone to sampling errors that can yield false negative results. To circumvent the need for biopsies, we are developing magnetic resonance imaging (MRI) techniques to monitor the accumulation of immune cells at the transplanted organ as a means to detect graft rejection. By labeling immune cells with an MRI contrast agent, dextran-coated ultrasmall superparamagnetic iron oxide (USPIO) particles, we can monitor the accumulation of these labeled immune cells at the rejecting graft as a non-invasive method to detect graft rejection. Cells can be labeled ex vivo and then infused into the animal, or MRI contrast agents can be introduced directly into the animal in vivo. Our results show excellent correlation among the MRI signal intensity due to the USPIO-labeled macrophages at the rejecting graft, immuno-staining for macrophages, histo-pathology for graft rejection, and the iron staining of tissue samples. In this article, we shall give a summary of our progress from detecting single immune cells in vitro to monitoring the accumulation of immune cells in vivo at the transplanted kidneys, hearts, and lungs in our rat models for organ transplantation by MRI.

Animals↗

Coronary collateral vessels: their significance for left ventricular histologic structure.

Whether coronary collateral vessels protect the left ventricular myocardium is unknown. Light microscopic morphometry was carried out on myocardial tissue samples from 56 surgically treated patients with coronary artery disease. Transmural biopsy of the myocardium perfused by the left anterior descending coronary artery was obtained during open heart surgery. In initial reproducibility studies of biopsy samples of 17 patients a sampling error for evaluation of myocardium was defined and differences in transmural fibrosis exceeding +/- 6.2 percent were considered biologically significant. Stenosis of the left anterior descending artery was determined from preoperative angiography. Group A (control group) comprised patients with less than 75 percent area reduction of the left anterior descending coronary artery (mean +/- standard deviation 65 +/- 10 percent). Patients in group B (more than 95 percent area reduction [mean 99 +/- 2 percent] without collateral supply on arteriography) were compared with patients in group C (identical stenosis [mean 99 +/- 2 percent] but with collateral supply). Fibrosis averaged 17 percent in group A, 68 percent in group B (p less than 0.001 versus group A) and 29 percent in group C (p greater than 0.05 versus group A, p less than 0.001 versus group B). Thus, in severe coronary stenosis myocardium supplied by collateral vessels shows less fibrosis on biopsy sample than does myocardium without collateral supply.

Adult↗